Infectious Diseases & Immunology Questions 11-20

Infectious Diseases & Immunology Question 11

An obstetrician asks the neonatology fellow to evaluate an asymptomatic term infant’s risk for
early-onset sepsis. The infant’s mother is Group B Streptococcus positive, received adequate
intrapartum antibiotic prophylaxis, and did not have a fever. She did not have any other infectious risk
factors during labor. The neonatology fellow determines that this infant does not require additional
screening.
Which of the following statements about neonatal sepsis is FALSE?
A.Group B Streptococcus and Escherichia coli are the two most common pathogens associated
with early-onset sepsis
B.Group B Streptococcus is a more frequent cause of early-onset sepsis in preterm infants
because of unknown maternal Group B Streptococcus status
C.Group B Streptococcus type III serotype is typically associated with late-onset sepsis
D.The risk of early-onset sepsis is 10-fold higher in very low birthweight infants compared to
term infants
E.All of the above statements are true
Infectious Diseases & Immunology Question 12
A 2-month old male infant delivered at 28 weeks’ gestation is now 36 weeks’ postmenstrual age.
He was born in Cambodia with initial laboratory evidence of a maternally acquired human
immunodeficiency virus infection. He has an appointment with his pediatrician to receive his first set
of vaccinations.
Which of the following vaccines should NOT be administered to the infant in this vignette?
A. Diphtheria
B. Hepatitis B
C. Pneumococcal
D. All of the above vaccinations should be administered
E. None should be administered given the infant’s premature delivery and postmenstrual age of
only 36 weeks
Infectious Diseases & Immunology Question 13
A 10-month old infant born at 39 weeks’ gestation has had recurrent infections over the past
several months. The pediatrician identifies a specific immunodeficiency in this infant.
Which of the following immunoglobulins (Ig) crosses the placenta and may have offered initial
passive immunity during the neonatal period?
A. IgA
B. IgD
C. IgE
D. IgG
E. IgM
Infectious Diseases & Immunology Question 14
A 2-month old infant is admitted to a pediatric hospital for treatment of pneumonia. At one month
of age he had required intravenous antibiotics for an omphalitis. The pediatric resident is concerned
because the infant’s umbilical cord is still present. She asks the neonatologist for advice.
Of the following, the MOST likely etiology of the infant’s delayed cord separation is:
A. Chédiak-Higashi syndrome
B. Chronic granulomatous disease
 C. Hyperimmunoglobulin E syndrome
D. Kostmann syndrome
E. Leukocyte adhesion deficiency
Infectious Diseases & Immunology Question 15
Please indicate the type of precautions that are indicated for the care of hospitalized infants with
the following known or suspected infections (Check all that apply.)
Infection Standard Contact Droplet Airborne
Cytomegalovirus
Rubella
Herpes simplex virus
Toxoplasmosis
Human immunodeficiency virus
Tuberculosis
Varicella
Respiratory syncytial virus
Parvovirus B19
Listeria
Infectious Diseases & Immunology Question 16
Please match the clinical scenario with the appropriate management. Check all that apply.
Management #1. #2. Mother with + #3. Mother with + #4.
Mother RPR, + FTA-ABS, and RPR, + FTA-ABS, and Mother
with + received PCN > 4 wk received PCN < 4 wk with -
RPR, - before birth with ≥ 4x before birth without ≥ RPR, +
FTA- drop in titers 4x drop in titers FTA-
ABS ABS
No treatment in mother
No treatment in infant
Check non-treponemal
titers in mother at birth
Check non-treponemal
titers in infant
Check treponemal test
in infant
Evaluate infant with
complete blood count,
liver function tests,
lumbar puncture, long
bone films, eye exam
Tx infant with PCN
Infectious Diseases & Immunology Question 17
Which of the following congenital infections increases the risk of spontaneous abortion?
A.Herpes simplex virus
B.Listeria
 C.Parvovirus B19
D.Syphilis
E.Toxoplasmosis
F.A, B, C
G.B, C, D
H.C, D, E
I.All of the above
Infectious Diseases & Immunology Question 18
Which of the following statements is TRUE about congenital syphilis?
A.Congenital syphilis is most often acquired via contact with an active vaginal lesion at delivery
B.Most infants with congenital syphilis are symptomatic at birth
C.Symptoms of congenital syphilis include persistent rhinitis, hepatosplenomegaly, desquamation
of the palms/soles, chorioretinitis, and indirect hyperbilirubinemia
D.All of the above
Infectious Diseases & Immunology Question 19
Which of the following statements is TRUE about varicella infection?
A.All infants with congenital varicella syndrome should be placed in airborne and contact
isolation
B.An infant born to a mother who develops varicella between 5 days before delivery until 2 days
after delivery should receive varicella immunoglobulin
C.If a mother develops varicella during pregnancy, she should receive varicella vaccine and
varicella immunoglobulin
D.All of the above
Infectious Diseases & Immunology Question 20
What is the most common congenital viral infection in the United States?
A.Adenovirus
B.Cytomegalovirus
C.Herpes simplex virus
D.Respiratory syncytial virus
E.Rubella virus
Infectious Diseases & Immunology Answers 11-20
Infectious Diseases & Immunology Answer 11
B. Group B Streptococcus is a more frequent cause of early-onset sepsis in preterm infants because of
unknown maternal Group B Streptococcus status
Early-onset sepsis is a neonatal infection occurring ≤72 hours of age. The incidence of early-
onset sepsis is approximately 1 per 1,000 live births. The risk in very low birthweight (VLBW)
infants is approximately 10-fold higher compared to term infants. Group B Streptococcus and
Escherichia coli are the two most common pathogens associated with early-onset sepsis. While
Group B Streptococcus remains the most common pathogen in term infants, Escherichia coli has
become the most common bacteria causing early-onset sepsis in VLBW infants. There are multiple
Group B Streptococcus serotypes, with Type III most often associated with late-onset sepsis.
References:
Puopolo K. Epidemiology of neonatal early-onset sepsis. NeoReviews. 2008;9(12):e571-e579
Stoll BJ, Hansen NI, Sanchez PJ, et al. Early-onset neonatal sepsis: The burden of Group B
Streptococcal and E. coli disease continues. Pediatrics. 2011;127(5):817-826
Infectious Diseases & Immunology Answer 12
D. All of the above vaccinations should be administered
All premature infants should be vaccinated based on their chronological age, rather than their
postmenstrual age. Thus, the infant in this vignette should receive a complete set of vaccinations at 2
months of age. Infants born in the US with human immunodeficiency virus (HIV) should not receive
oral polio vaccine or bacille Calmette-Guerin vaccine. An HIV-positive infant should not receive the
mumps, measles and rubella vaccine if the infant is severely immunocompromised and should not
receive the varicella vaccine if the infant’s CD4 counts are low. All other immunizations are
recommended.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Pickering LK, Baker CF, Long SS, McMillan JA (eds): 2009 Red Book: Report of the Committee on
Infectious Diseases. 28th edition. Elk Grove Village, IL; American Academy of Pediatrics; 2009
Infectious Diseases & Immunology Answer 13
D. IgG
Maternal immunoglobulin G (IgG) is the only antibody that crosses the placenta in significant
amounts. This intrauterine placental transfer occurs by endocytosis and provides passive immunity to
term neonates. IgG functions by binding and activating complement. IgA is a secretory
immunoglobulin that is found in saliva, colostrum, and respiratory & gastrointestinal secretions. IgD
appears to function as an antigen receptor and plays an important role in the regulation of B-cell
development. IgE is involved in allergic reactions by binding to basophils and mast cells, resulting
in histamine and leukotriene release. IgM binds and activates complement and is the first antibody
expressed after an infection.
Reference:
Stiehm ER, Ochs HD, Winklestein JA, Rich E (eds). Immunologic Disorders in Infants and Children.
5th edition. Philadelphia: WB Saunders Company; 2004
Infectious Diseases & Immunology Answer 14
E. Leukocyte adhesion deficiency
The infant in this vignette most likely as leukocyte adhesion deficiency. This disorder results from
abnormal neutrophil function despite increased neutrophil amounts. Affected individuals have
defective adhesion and migration, resulting in recurrent bacterial infections with poor wound healing
and necrotic lesions. They are at greater risk of developing an omphalitis and often have delayed
separation of their umbilical cord, sometimes beyond 21 days of life.
Chediak-Higashi is caused by abnormal neutrophil degranulation leading to partial oculocutaneous
albinism, nystagmus, peripheral neuropathy, and recurrent infections. Infants affected with chronic
granulomatous disease have abnormal phagocytic microbial ability leading to increased risk of
abscesses, poor wound healing, and granuloma formation. Individuals with Hyperimmunglobulin E
syndrome, also known as Job’s syndrome, have abnormal neutrophil chemotaxis, leading to recurrent
infections, particularly involving the skin. Infants often have coarse facial features and a broad nasal
bridge. Kostmann syndrome results from severe congenital neutropenia with infants developing
frequent infections in the first few months of life.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Medzhitov R, Janeway C. Innate immunity. N Engl J Med. 2000;343:338-344
Infectious Diseases & Immunology Answer 15
Infection Standard Contact Droplet Airborne
Cytomegalovirus X
Rubella x x
Herpes simplex virus x
Toxoplasmosis X
Human immunodeficiency virus X
Tuberculosis x x
Varicella x x
Respiratory syncytial virus x
Parvovirus B19 x
Listeria X
A brief description of these infections is described below:
a. Cytomegalovirus: double-stranded herpes DNA virus passed via secretions, sexual
intercourse, blood products, transplacental, intrapartum or via breastmilk→ standard
b. Rubella virus: RNA virus passed via respiratory secretions→ contact and respiratory
droplet
c.Herpes simplex virus: double-stranded herpes DNA virus passed via contact with lesions, or
rarely transplacental→ contact
d. Toxoplasmosis: intracellular parasite passed by poorly cooked meat, cat feces or
transplacental→ standard
e. Human immunodeficiency virus: RNA retrovirus passed via blood, sexual contact,
transplacental or via breastmilk→standard
f. Tuberculosis: slow-growing acid-fast bacillus passed most often by inhalation of infected
respiratory secretions or contamination of traumatized mucous membranes or skin; rarely it
is passed by hematogenous spread from an infected placenta or aspiration of infected
amniotic fluid→ airborne and contact
g. Varicella: DNA herpes virus passed via respiratory droplets, contact with rash or
transplacental→ airborne and contact
 h. Respiratory syncytial virus: RNA paramyxovirus passed by direct contact with secretions,
highly contagious→ contact
i. Parvovirus B19: single-stranded DNA passed via respiratory secretions, transplacental→
droplet
j. Listeria: gram-positive rod passed via unpasteurized milk and soft cheeses, uncooked meat
and unwashed raw vegetables→ standard
Definitions of the types of precautions are described below:
Standard precautions apply whenever contact with blood, other body fluids, non-intact skin,
mucous membranes, and secretions and excretions (except sweat) is likely or possible. The
precautions include hand hygiene, gloves, gowns and/or eye protection (when exposure to
body secretions or blood is possible), safe disposal of sharps, and properly disposing of
soiled lines and bloody or contaminated materials.
Contact precautions apply when microorganisms can be transmitted to patients via contact
between the patient and a healthcare worker, or by contact between the patient and a
contaminated object. Precautions include nonsterile gloves and gowns if there is substantial
direct contact with the patient or contaminated material.
Droplet precautions apply when microorganisms occur in particles of respiratory secretions
larger than 5 microns. These droplets remain suspended in the air for limited periods and
therefore human-to-human transmission can occur with exposure less than 3 feet (1 meter).
Precautions include a facemask for health care workers within six to ten feet of patients.
Airborne precautions apply when microorganisms occur in particles of respiratory secretions
smaller than 5 microns. These droplets can remain suspended in the air for extended
periods, and therefore human-to-human transmission can occur via inhalation. Precautions
include a placement of the patient in an airborne infection isolation room with negative
pressure for a minimum of 6 to 12 air changes per hour. Doors to the isolation rooms must
remain closed, and all persons entering must wear a respirator with a filtering capacity of
95% that allows a tight seal over the nose and mouth.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Friedman ND, Sexton DJ. General principles of infection control. UpToDate. Accessed January 8,
2012
Infectious Diseases & Immunology Answer 16
#1. Mother #2. Mother with + #3. Mother with #4.
with + RPR, + FTA-ABS, and + RPR, + FTA- Mother
RPR, received PCN > 4 wk ABS, and with -
persistently before birth with ≥ 4x received PCN < 4 RPR, +
- FTA-ABS drop in titers wk before birth FTA-
ABS
No treatment in mother X X X X
No treatment in infant X Depends; see below X
Check non-treponemal
consider X X X
titers in mother at birth
Check non-treponemal
X X X
titers in infant
 Check treponemal test in X X X
infant
Evaluate infant with
complete blood count,
liver function tests, Depends; see below X
lumbar puncture, long
bone films, eye exam
Tx infant with PCN Depends; see below X
Scenario #1: All women receive testing with a non-treponemal antibody (Ab) test (i.e., RPR or
VDRL) during early pregnancy. These tests measure a nonspecific IgG Ab to a cell membrane
cardiolipin. These tests are reported as titers and correlate with disease activity. There are many
causes of false-positive non-treponemal Ab tests including autoimmune disorders, tuberculosis,
Ebstein-Barr virus, and endocarditis. Women who have positive non-treponemal tests should have
treponemal tests sent. Treponemal tests (e.g., FTA-ATS) detect a specific Ab to Treponema
pallidum. After active syphilis disease, treponemal tests will remain positive for life. Treponemal
tests can also be falsely positive if antinuclear antibody is present. If a woman has a positive non-
treponemal Ab test and persistently negative treponemal antibody test, this indicates a false-positive
non-treponemal Ab test. In this case, further testing of the infant is not needed.
Scenario #2: Women with positive non-treponemal and treponemal Ab tests should be treated
during pregnancy. Treatment includes aqueous PCN G and desensitization to PCN if the pregnant
woman is allergic to PCN. Maternal titers should be monitored during pregnancy and re-treatment is
indicated if there is a 4-fold or greater increase in titers. Infants should receive non-treponemal and
treponemal Ab testing at birth. Further neonatal evaluation is indicated when mothers are not treated
with PCN; mothers are treated < 4 weeks prior to delivery; mothers have a ≥ 4-fold increase in titers;
and mothers were treated but did not have follow-up monthly serologies or infants have symptoms.
Infants should receive treatment if there are physical, laboratory or radiographic evidence of syphilis;
if spirochetes are visualized by darkfield microscopy; if CSF VDRL is reactive; if non-treponemal
test is 4-fold higher than the mother’s RPR or VDRL level; or if the mother was not adequately
treated.
In this case, the mother was appropriately treated. The mother should also have repeat titers sent at
birth. If the follow-up non-treponemal titers in the infant and mother are negative, this would indicate
successful treatment and no further evaluation or treatment of the infant would be necessary. This
infant should receive follow-up treponemal and non-treponemal Ab testing during the first year of
life. If the follow-up non-treponemal titers in the infant are ≥ 4-fold higher than the mother’s titers,
then the infant should receive a full evaluation and treatment if indicated (as described above). A
single intramuscular Benzathine PCN G injection can be given in the absence of active disease
(positive non-treponemal titers only). Aqueous intravenous PCN G (IV) for 10 to 14 days is
recommended if the infant has active disease.
Scenario #3: In this case, the mother did not receive adequate treatment for syphilis. Infants
should receive a full evaluation in addition to non-treponemal and treponemal testing. Because the
mother’s treatment was inadequate, this automatically meets criteria for treatment in the neonate.
Treatment with Benzathine PCN G or aqueous PCN G would depend on presence or absence of
active disease (see above). If an infant is treated, he/she should have follow-up non-treponemal
testing throughout the first year of life in addition to non-treponemal testing of the cerebrospinal fluid
at 6 months of life. If titers do not decrease, the infant may require re-treatment.
Scenario #4: A positive treponemal test with persistently negative non-treponemal tests in the
mother likely indicates a false-positive result, or previous syphilis infection that was treated in the
mother. Infants should receive non-treponemal and treponemal testing at birth. If the results match
those of the mother, this would confirm that the positive treponemal test result indicates past maternal
infection or a false-positive result.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Pickering LK, Baker CF, Long SS, McMillan JA (eds). 2009 Red Book: Report of the Committee on
Infectious Diseases. 28th edition. Elk Grove Village, IL: American Academy of Pediatrics; 2009
Infectious Diseases & Immunology Answer 17
G. Listeria, Parvovirus B19, Syphilis
Stillbirth or fetal loss is increased in congenital infections caused by Listeria, Parvovirus and
syphilis. Although fetal infection with varicella in the first 20 weeks of pregnancy leads to varicella
embryopathy or congenital varicella syndrome, it does not significantly increase the risk of
spontaneous abortion. Neonates with congenital toxoplasmosis are usually asymptomatic at birth and
are not at increased risk of intrauterine death.
References:
Satti KF, Ali SA, Weitkamp J-H. Congenital infections, Part 2: Parvovirus, listeria, tuberculosis,
syphilis, and varicella. 2010; NeoReviews. 11(12):e681-e695
Tian C, Ali SA, Weitkamp J-H. Congenital infections, Part I: Cytomegalovirus, toxoplasma, rubella,
and herpes simplex. 2010; NeoReviews. 11(8):e436-e446
Infectious Diseases & Immunology Answer 18
C. Symptoms of congenital syphilis include persistent rhinitis, hepatosplenomegaly, desquamation of
the palms/soles, chorioretinitis, and indirect hyperbilirubinemia
Syphilis infection usually occurs via the transplacental route, not during delivery. Approximately
30% to 40% of fetuses with congenital syphilis are stillborn. Most infants with congenital syphilis
are asymptomatic at birth and symptoms can develop by 3-14 postnatal weeks. Symptoms of early
congenital syphilis include pnuemonitis, persistent rhinitis, cutaneous bullous eruptions,
desquamation of the palms and soles, indirect hyperbilirubinemia, hemolytic anemia,
thrombocytopenia, nephritic syndrome, chorioretinitis, uveitis, osteochondritis, Erbs’ palsy, and
meningitis.
Late congenital syphilis occurs after 2 years of age. Symptoms represent “scarring” from earlier
disease and may include frontal bossing, Hutchinson teeth (peg-shaped and notched incisors with
marked thinning), mulberry molars, saddle nose, interstitial keratitis, glaucoma, corneal scarring,
intellectual disability, hydrocephalus, epilepsy and saber shins.
Reference:
Satti KF, Ali SA, Weitkamp J-H. Congenital infections, Part 2: Parvovirus, listeria, tuberculosis,
syphilis, and varicella. 2010; NeoReviews. 11(12):e681-e695
Infectious Diseases & Immunology Answer 19
B. An infant born to a mother who develops varicella between 5 days before delivery until 2 days
after delivery should receive varicella immunoglobulin
If a mother develops varicella during pregnancy, she should only receive varicella
immunoglobulin. Varicella vaccine is a live vaccine and administration is contraindicated during
pregnancy. The pregnant woman with a history of varicella should receive the vaccine after
delivering. Infants born to mothers who develop varicella between 5 days before delivery until 2
days after delivery are at greatest risk of varicella infection because there is insufficient time for
protective antibodies to cross to the fetus. Thus, these infants should receive varicella
immunoglobulin (VZIG). VZIG may also be given to infants who are exposed to varicella infection
postnatally if their mothers do not have a history of chicken pox and are seronegative, and the infants
are <28 weeks’ postmenstrual age regardless of the maternal history. Infants with congenital
varicella syndrome do not require airborne and contact isolation as long as there are no active
lesions.
Reference:
Satti KF, Ali SA, Weitkamp J-H. Congenital infections, Part 2: Parvovirus, listeria, tuberculosis,
syphilis, and varicella. 2010; NeoReviews. 11(12):e681-e695
Infectious Diseases & Immunology Answer 20
B. Cytomegalovirus
Cytomegalovirus (CMV) is the most common congenital viral infection in the United States,
affecting approximately 40,000 infants born each year. Congenital CMV infection is associated with
young maternal age, single marital status, non-white race, and women who have occupations
associated with increased exposure to young children. The most common sources of CMV infection
to pregnant women are infected young children in child care centers and sexual partners. Half of
seronegative-women acquire CMV within 1 year if they are exposed frequently to infected young
children.
Reference:
Tian C, Ali SA, Weitkamp J-H. Congenital infections, Part I: Cytomegalovirus, toxoplasma, rubella,
and herpes simplex. 2010; NeoReviews. 11(8):e436-e446
Infectious Diseases & Immunology Questions 21-30
Infectious Diseases & Immunology Question 21
True or False:
Most infants that acquire cytomegalovirus (CMV) via the transplacental route have evidence of
infection at birth including microcephaly, periventricular calcifications, chorioretinitis,
thrombocytopenia, petechiae/purpura and hearing loss. In contrast, infants that acquire CMV during
delivery (intrapartum route) are most often asymptomatic at birth.
Infectious Diseases & Immunology Question 22
Which of the following statements is TRUE about the association between hearing loss and
congenital cytomegalovirus infection?
A.Hearing loss is usually present at birth
B.Hearing loss is usually sensorineural
C.Hearing loss is usually unilateral
D.Treatment with gancyclovir can preserve hearing loss
E.A, B
F.A, B, C
G.B, D
Infectious Diseases & Immunology Question 23
Which of the following is TRUE about transmission of cytomegalovirus (CMV) via breast milk?
A.CMV transmission via breast milk is more likely to occur among preterm infants
B.Freezing breast milk reduces CMV transmission
C.Pasteurization (heat shocking) of breast milk reduces CMV transmission
D.A and B
E.A and C
F.All of the above
Infectious Diseases & Immunology Question 24
Which of the following medications is used to treat infants with congenital toxoplasmosis?
A.Ampicillin
B.Erythromicin
C.Gentamicin
D.Isoniazid, rifampin and pyrazinamide
E.Pyrimethamine and sulfadiazine
Infectious Diseases & Immunology Question 25
Please draw arrows to match the congenital infection with the risk of transmission and severity of
infection in neonatal life.
Organism Possible Answer
Toxoplasmosis Transmission to the fetus can occur at any time during the pregnancy, but
disease is more severe if acquired earlier in the pregnancy
Treponema Transmission to the fetus is most likely in early and late pregnancy (U-shaped
pallidum distribution), but disease is more severe if acquired in early pregnancy
Rubella Transmission to the fetus increases with gestation, but disease is more severe
if it is acquired earlier in pregnancy
Cytomegalovirus Transmission can occur any time during pregnancy, but disease is more severe
if acquired later in pregnancy
Infectious Diseases & Immunology Question 26
Which is the most common cardiac defect seen among infants with congenital rubella?
A.Coarctation of the aorta
B.Hypoplastic left heart syndrome
C.Patent ductus arteriosis
D.Tetralogy of Fallot
E.Ventricular septal defect
Infectious Diseases & Immunology Question 27
Although herpes simplex virus (HSV) is considered a member of the group of congenital infections
known as “TORCH,” transmission to neonates almost always occurs during contact with maternal
herpes lesions during delivery, rather than by the transplacental route.
Which of the following is (are) risk factors for the neonatal transmission of HSV?
A.Fetal-scalp monitoring
B.Precipitous delivery to a mother with no known herpes lesions
C.Prematurity
D.Vaginal delivery to a women who did not have HSV viral cultures sent with a history of HSV
lesions prior to index pregnancy
E.A, B and D
F.A and C
G.B and D
H.All of the above
Infectious Diseases & Immunology Question 28
Which of the following is TRUE about neonatal herpes simplex virus (HSV) infections?
A.Approximately 20% of infants with HSV encephalitis have long-term neurodevelopmental
impairments
B.Mortality rate of those with disseminated disease approaches 50% to 70%
C.SEM (skin, eye, mucous membrane) disease is usually present at birth
Infectious Diseases & Immunology Question 29
Evaluation for neonatal herpes simplex virus (HSV) in an asymptomatic infant includes obtaining
surface cultures (i.e., rectal, nasal, pharyngeal, and conjunctival cultures).
Which of the following statements is TRUE about this evaluation?
A.Infants born vaginally to mothers with vaginal lesions noted during labor should receive surface
cultures soon after birth
B.Infants born vaginally to mothers with vaginal lesions noted during labor should receive surface
cultures >12 hours after birth
C.Infants born vaginally to mothers with a history of HSV lesions during pregnancy, but without
lesions during labor should receive surface cultures soon after birth
D.Infants born vaginally to mother with a history of HSV lesions during pregnancy, but without
lesions during labor should receive surface cultures >12 hours after birth
Infectious Diseases & Immunology Question 30
Please indicate the environmental source of Listeria infection in pregnant women.
A.Cat feces
B.Contaminated water
C.Unpasteurized milk and cheese
D.Unwashed fruits
Infectious Diseases & Immunology Answers 21-30
Infectious Diseases & Immunology Answer 21
False
CMV transmission can occur transplacentally (all trimesters), intrapartum, through breast milk,
and via blood transfusions. Most infants are asymptomatic, regardless of the route of transmission.
Reference:
Tian C, Ali SA, Weitkamp J-H. Congenital infections, Part I: Cytomegalovirus, toxoplasma, rubella,
and herpes simplex. 2010; NeoReviews. 11(8):e436-e446
Infectious Diseases & Immunology Answer 22
G. Hearing loss is usually sensorineural
Treatment with gancylovir can preserve hearing loss
Congenital cytomegalovirus (CMV) infection is the most common non-genetic cause of congenital
sensorineural hearing loss in children. Hearing loss is often progressive and may not be detected until
after 1 year of life. Hearing loss is usually bilateral and moderate to profound. Treatment with
gancyclovir to infants with CMV infection has been associated with preservation of hearing.
However, infants receiving gancyclovir must be monitored for potential adverse side effects,
including nephrotoxicity, neutropenia and increased liver enzymes.
Reference:
Tian C, Ali SA, Weitkamp J-H. Congenital infections, Part I: Cytomegalovirus, toxoplasma, rubella,
and herpes simplex. 2010; NeoReviews. 11(8):e436-e446
Infectious Diseases & Immunology Answer 23
F. All of the above
CMV transmission via breast milk is more likely to occur among preterm infants
Freezing breast milk reduces CMV transmission
Pasteurization (heat shocking) of breast milk reduces CMV transmission
Cytomegalovirus (CMV) transmission via breast milk is more likely to occur among preterm
infants because term infants receive more passively transferred maternal antibodies. Both heat
shocking via pasteurization and freezing of breast milk reduces CMV transmission.
Reference:
Tian C, Ali SA, Weitkamp J-H. Congenital infections, Part I: Cytomegalovirus, toxoplasma, rubella,
and herpes simplex. 2010; NeoReviews. 11(8):e436-e446
Infectious Diseases & Immunology Answer 24
E. Pyrimethamine and sulfadiazine
Treatment with pyrimethamine and sulfadiazine is recommended for 1 year for infants with
congenital toxoplasmosis who are symptomatic at birth. Sulfadiazine administration can lead to bone
marrow suppression with associated neutropenia. Thus, supplementation with folinic acid is
recommended.
Reference:
Tian C, Ali SA, Weitkamp J-H. Congenital infections, Part I: Cytomegalovirus, toxoplasma, rubella,
and herpes simplex. 2010; NeoReviews. 11(8):e436-e446
Infectious Diseases & Immunology Answer 25
Organism Answer
Toxoplasmosis Transmission to the fetus increases with gestation, but disease is more severe
if it is acquired earlier in pregnancy
 Treponema Transmission can occur at any time during the pregnancy, but disease is more
pallidum severe if acquired later in the pregnancy
Rubella Transmission to the fetus is most likely in early and late pregnancy (U-shaped
distribution), but disease is more severe if acquired in early pregnancy
Cytomegalovirus Transmission to the fetus can occur any time during pregnancy, but disease is
more severe if acquired earlier in pregnancy
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Tian C, Ali SA, Weitkamp J-H. Congenital infections, Part I: Cytomegalovirus, toxoplasma, rubella,
and herpes simplex. 2010; NeoReviews. 11(8):e436-e446
Infectious Diseases & Immunology Answer 26
C. Patent ductus arteriosus
The severity of clinical symptoms of infants with congenital rubella is increased when
transmission occurs in the first trimester. There is a 50% chance of cardiac disease including patent
ductus arteriosis and pulmonary arterial hypoplasia. Other classic features of congenital rubella
syndrome include sensorineural hearing loss, cataracts, salt and pepper chorioretinitis, insulin-
dependent diabetes, and thyroid disease. Treatment is supportive only.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Tian C, Ali SA, Weitkamp J-H. Congenital infections, Part I: Cytomegalovirus, toxoplasma, rubella,
and herpes simplex. 2010; NeoReviews. 11(8):e436-e446
Infectious Diseases & Immunology Answer 27
F. Fetal-scalp monitoring and Prematurity
The most significant risk factor for neonatal herpes simplex virus (HSV) is primary genital
infection during pregnancy. Infants born to mothers who have a primary HSV lesion have a 50%
chance of developing HSV disease, compared to a less than 2% chance in mothers with a secondary
HSV infection. This is because of high viral replication and longer excretion of virus from primary
HSV lesions. Prematurity is also a risk factor for neonatal transmission of HSV probably because of
low transplacental passage of maternal antibodies. Fetal scalp monitoring increases the risk of
neonatal HSV infection because of breakdown in the skin barrier. Delivery after prolonged rupture of
membranes, rather than a precipitous delivery, will increase the exposure to maternal HSV lesions
and risk of ascending infection. Finally, sending viral cultures of mothers with previous HSV
infection in the absence of lesions is not indicated because viral shedding is brief and intermittent.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Tian C, Ali SA, Weitkamp J-H. Congenital infections, Part I: Cytomegalovirus, toxoplasma, rubella,
and herpes simplex. 2010; NeoReviews. 11(8):e436-e446
Infectious Diseases & Immunology Answer 28
B. Mortality rate of those with disseminated disease approaches 50% to 70%
Disseminated neonatal herpes simplex virus (HSV) disease is multisystemic and mortality rates
approach 50% for HSV-2 and 70% for HSV-1. Skin, eye and mucous membrane (SEM) disease
usually presents at approximately 1 week of age and is not present at birth. Skin findings that are
present at birth would represent intrauterine infection, but this is extremely rare. HSV encephalitis is
associated with a poor neurodevelopmental outcome; approximately 50% of those with encephalitis
suffer long-term sequelae, despite high-dose acyclovir treatment.
Reference:
Tian C, Ali SA, Weitkamp J-H. Congenital infections, Part I: Cytomegalovirus, toxoplasma, rubella,
and herpes simplex. 2010; NeoReviews. 11(8):e436-e446
Infectious Diseases & Immunology Answer 29
B. Infants born vaginally to mothers with vaginal lesions noted during labor should receive surface
cultures >12 hours after birth
Evaluation for neonatal herpes simplex virus (HSV) in the asymptomatic infant should occur at 12
to 24 hours of life. Positive cultures at that time may be interpreted as infection and not
contamination. It is not necessary to evaluate asymptomatic infants born to mothers with a history of
HSV lesions who do not have notable lesions at the time of delivery. Rather, close clinical
observation for signs of disease in these infants is adequate.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Tian C, Ali SA, Weitkamp J-H. Congenital infections, Part I: Cytomegalovirus, toxoplasma, rubella,
and herpes simplex. 2010; NeoReviews. 11(8):e436-e446
Infectious Diseases & Immunology Answer 30
C. Unpasteurized milk and cheese
Listeria monocytogenes is present in pasteurized milk and soft cheeses, uncooked meat, and raw
vegetables. Toxoplasma organisms are spread by cat feces. Bacterial gastroenteritis is often caused
by contaminated water.
Reference:
Satti KF, Ali SA, Weitkamp J-H. Congenital infections, Part 2: Parvovirus, listeria, tuberculosis,
syphilis, and varicella. 2010; NeoReviews. 11(12):e681-e695
Infectious Diseases & Immunology Questions 31-40
Infectious Diseases & Immunology Question 31
Which of the following statements about Listeria infection in neonates is TRUE?
A.Early-onset sepsis (<7 days) from Listeria occurs as a result of transplacental transfer
B.Late-onset sepsis (>7 days) from Listeria occurs as a result of an environmental contact
C.Listeria infection in the first two trimesters can be associated with stillbirth
D.Meningitis is the most frequent presentation of early-onset sepsis with Listeria
E.Pneumonia is the most frequent presentation of late-onset sepsis with Listeria
F.A and C
Infectious Diseases & Immunology Question 32
A neonatology fellow and neonatologist are discussing the immunoglobulin concentrations in
infants over time.
By what postnatal age does maternal IgG typically disappear in the neonatal circulation?
A. Birth
B. 2 months
C. 6 months
D. 9 months
E. 12 months
Infectious Diseases & Immunology Question 33
Which of the following is TRUE about congenitally-acquired toxoplasmosis?
A.Preterm infants are often symptomatic at birth, while term infants are not symptomatic
B.Less than half of affected infants will develop visual disabilities
C.More than half of affected infants will develop learning disabilities later in life
D.Periventricular calcifications can be seen in symptomatic neonates
E.A and B
F.A and C
G.A and D
H.All of the above
Infectious Diseases & Immunology Question 34
Please match the clinical scenario with the appropriate management of an infant with possible
congenital tuberculosis (TB) infection. (Check all that apply)
Management Mother with Mother with + PPD, Mother with + Congenital
+ PPD, - +CXR, no active PPD, active TB
CXR disease disease
Treat mother with
isoniazid (INH) x 9 mo
Treat mother with 4
anti-TB drugs
Must separate mother
and infant
Breastfeeding allowed
Infant needs PPD every
3 mo until 1 yr, then
yearly
 Treat infant with INH
Treat infant with 4 anti-
TB drugs
Infectious Diseases & Immunology Question 35
True or False. Limb hypoplasia with cicatricial scarring is a characteristic finding of congenital
varicella syndrome.
Infectious Diseases & Immunology Question 36
A 10-day old infant presents with a bilateral watery eye discharge. The next day, the discharge
appears purulent, the eyelids are red and swollen, and the conjunctivae are thickened.
What is the most likely pathogen causing this clinical presentation?
A.Chemical irritant
B.Chlamydia trachomatis
C.Herpes simplex virus
D.Neisseria gonorrhoeae
E.Streptococcus agalactiae group B
Infectious Diseases & Immunology Question 37
A 3-week old term infant presents to the Emergency Room with hepatosplenomegaly, respiratory
distress, fever, lethargy and skin papules. The mother reports that she had limited prenatal care and
recently immigrated to the United States from Africa. Testing reveals that this infant has a congenital
tuberculosis (TB) infection.
Of the following, the most preferred initial treatment for this infant includes:
A.Isoniazid alone
B.Isoniazid, rifampin and ethambutol
C.Isoniazid, rifampin, pyrazinamide and an aminoglycoside
D.Observation
E.Rifampin alone
Infectious Diseases & Immunology Question 38
A woman who is HIV-positive becomes pregnant. She is concerned that she will pass on the virus
to her infant.
Which of the following will reduce the risk of mother-to-child transmission of HIV?
A.Administration of IV Zidovudine during labor, unless the maternal viral load is undetectable at
that time
B.Administration of IV Zidovudine during labor, unless the pregnant woman has been adherent to
an antiretroviral regimen during pregnancy
C.Avoidance of a second antiretroviral medication to infants born to HIV-positive women to
reduce drug-resistant virus
D.Elective Cesarean section at or after 38 weeks gestation for all HIV-positive women
E.Initiation of Zidovudine prophylaxis to the infant within the first 12 to 48 hours of life
Infectious Diseases & Immunology Question 39
Which of the following statements about HIV infection and breastfeeding is TRUE?
A.Antiretroviral drugs have differential penetration in human milk, raising concerns about toxicity
to infants receiving breastmilk
B.Antiretroviral therapy reduces viral load in human milk making breastfeeding safe
C.Mothers who are HIV-positive should never breastfeed their infants
D.The risk of mother-to-child transmission of HIV through breastfeeding is between 30% to 50%
 E.The viral load of HIV in plasma is equal to that in human milk
Infectious Diseases & Immunology Question 40
For infants born to mothers who are HIV-positive, all of the following may be used as criteria for
presumptive exclusion of HIV infection EXCEPT:
A.One negative HIV antibody test result drawn at ≥6 months of age
B.One negative HIV RNA or DNA viral test result from a specimen drawn at ≥8 weeks of age
C.At least 2 negative HIV antibody test results from separate specimens drawn at ≥8 weeks of age
D.Two negative HIV RNA or DNA viral test results, from separate specimens, both of which
were drawn at ≥2 weeks of age and 1 of which was drawn at ≥4 weeks of age
Infectious Diseases & Immunology Answers 31-40
Infectious Diseases & Immunology Answer 31
F. Early-onset sepsis (<7 days) from Listeria occurs as a result of transplacental transfer.
Listeria infection in the first two trimesters can be associated with stillbirth.
Early-onset sepsis from Listeria is thought be transplacentally derived, while late-onset sepsis
from Listeria occurs after contact during delivery with vaginal flora colonized with Listeria. Listeria
infection in the first two trimesters can be associated with stillbirth.
Meningitis is the most frequent presentation of late-onset sepsis with Listeria. Pneumonia and sepsis
are the most frequent presentations of early-onset sepsis with Listeria.
Reference:
Satti KF, Ali SA, Weitkamp J-H. Congenital infections, Part 2: Parvovirus, listeria, tuberculosis,
syphilis, and varicella. 2010; NeoReviews. 11(12):e681-e695
Infectious Diseases & Immunology Answer 32
D. 9 months
During the 3rd trimester, maternal IgG crosses the placenta by endocytosis, conferring passive
immunity to the neonate. As shown in the Figure below, almost all of the maternal IgG disappears
from the infant’s circulation by 9 months of age. The postnatal concentrations of IgM and IgA are
summarized in the Figure as well.

References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Stiehm ER, Ochs HD, Winklestein JA, Rich E (eds). Immunologic Disorders in Infants and Children.
5th edition. Philadelphia: WB Saunders Company; 2004
Infectious Diseases & Immunology Answer 33
C. More than half of affected infants will develop learning disabilities later in life
Both term and preterm infants with congenital toxoplasmosis are usually asymptomatic at birth. Up
to 80% of affected infants develop learning and visual disabilities. These sequelae are often seen in
the first 3 months of life in preterm infants and later in term infants. Periventricular calcifications are
found in infants with congenital cytomegalovirus infection while cortical calcifications are observed
in infants with congenital toxoplasmosis.
Reference:
Tian C, Ali SA, Weitkamp J-H. Congenital infections, Part I: Cytomegalovirus, toxoplasma, rubella,
and herpes simplex. 2010; NeoReviews. 11(8):e436-e446
Infectious Diseases & Immunology Answer 34
Management Mother Mother with + Mother with + PPD, Congenital
with + PPD, +CXR, no active disease TB
PPD, - active disease
CXR
Treat mother with Depends
isoniazid (INH) x 9 on
X X
mo mother’s
status
Treat mother with 4 Depends
anti-TB drugs on
X
mother’s
status
Must separate mother Depends
X (once mother no
and infant on
longer with active
mother’s
disease, can re-unite)
status
Breastfeeding
X X X X
allowed
Infant needs PPD X
every 3 mo until 1 yr, (if –PPD at 3 mo, can d/c
X
then yearly INH, if +PPD, cont INH
x 9 mo)
Treat infant with
X
INH
Treat infant with 4
X
anti-TB drugs
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Pickering LK, Baker CF, Long SS, McMillan JA (eds). 2009 Red Book: Report of the Committee on
Infectious Diseases. 28th edition. Elk Grove Village, IL: American Academy of Pediatrics; 2009
Infectious Diseases & Immunology Answer 35
True
Limb hypoplasia with cicatricial scarring is a characteristic finding of congenital varicella
syndrome. In addition, congenital varicella syndrome is associated with chorioretinitis, cataracts,
and brain abnormalities that may include cortical atrophy, intellectual disability, and seizures. These
symptoms have been described in several other “TORCH” infections. However, limb hypoplasia is
unique to varicella infection.
Reference:
Satti KF, Ali SA, Weitkamp J-H. Congenital infections, Part 2: Parvovirus, listeria, tuberculosis,
syphilis, and varicella. 2010; NeoReviews. 11(12):e681-e695
Infectious Diseases & Immunology Answer 36
B. Chlamydia trachomatis
Chlamydia is the most common cause of conjunctivitis in the first month of life and occurs in ~8 in
1,000 births. Symptoms are typically evident in the first 5 to 14 days of life, but clinical findings can
be present earlier if there is premature rupture of membranes. Affected neonates typically present
with a bilateral watery discharge that becomes purulent and it can be associated with pneumonia. A
chlamydia infection can be diagnosed by Giemsa-stain of the conjunctival scrapings and can be
treated with oral erythromycin for 14 days. The Table provides a comparison of other causes of
conjunctivitis in a neonate.
Type of Onset Characteristics
Conjunctivitis
Chemical Within 24 hours Following prophylaxis
after exposure Decreased incidence because less usage of 1% silver
nitrate for prophylaxis
Negative culture
Spontaneously resolves within 48 hours
Acute 24-48 hours of Staph aureus (most frequent organism, golden crust around
purulent age (can be later eyelids), also due to Group B Streptococcus,
in life) Haemophilis influenzae (dacrocystitis), Strep
pneumoniae (dacrocystitis), Pseudomonas aeruginosa
Neisseria 2-5 days of life Abrupt onset of extremely copious, purulent bilateral
gonorrhoeae discharge
Medical emergency as can progress to cornea and
ulceration/perforation if untreated
Treat with 3rd generation cephalosporin
Can prevent with prophylaxis (0.5% erythromycin most
common, ideal if applied < 1 hour of age, decreases
incidence of gonorrheal conjunctivitis from 10 to 0.5%)
Chlamydia 5-14 days of life ~ 8/1000 births
(can be earlier if Most common cause of conjunctivitis in 1st month of life
premature In ~1/2 of infants with colonized mothers
rupture of Typically bilateral
membranes) Initially watery discharge that becomes purulent
Often associated with chlamydia pneumonia
Diagnose by Giemsa-stain of conjunctival scrapings
Treat with oral erythromycin x 14 days (20% require
second course)
Herpes Broad range (4 Most frequent viral etiology
simplex days to 3 weeks May also have keratitis, chorioretinitis, retinal dysplasia
of age ) Assess for systemic herpes and herpes encephalitis
Printed with permission from: Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010, p 226
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Martin, RJ, Fanaroff AA, Walsh MC. Fanaroff and Martin’s Neonatal-Perinatal Medicine: Diseases
of the Fetus and Infant. 8th Edition. 2006
Infectious Diseases & Immunology Answer 37
C. Isoniazid, rifampin, pyrazinamide and an aminoglycoside
Congenital tuberculosis (TB) infection can occur by:
•Hematogenous spread across an infected placenta
•Aspiration of infected amniotic fluid
•Ingestion of infected amniotic fluid
Affected infants typically present with symptoms during the 2nd or 3rd week of life. Management of
a neonate with a congenital TB infection includes initial treatment with a 4-drug broad medical
regimen including isoniazid, rifampin, pyrazinamide and an aminoglycoside. The length of treatment
depends on the sensitivities of the organism and extent of the disease.
Isoniazid alone is administered to an asymptomatic neonate who is born to a woman with an active
infection.
Isoniazid, rifampin and ethambutol is the therapeutic regimen recommended for pregnant women
with active disease. Pyridoxine is added to this regimen to prevent vitamin B6 deficiency.
Observation alone is recommended in cases of an asymptomatic neonate born to a woman with a
positive PPD, negative chest radiograph, and no evidence of active infection.
Rifampin alone is not recommended.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Martin, RJ, Fanaroff AA, Walsh MC. Fanaroff and Martin’s Neonatal-Perinatal Medicine: Diseases
of the Fetus and Infant. 8th Edition. 2006
Infectious Diseases & Immunology Answer 38
E. Initiation of Zidovudine prophylaxis to the infant within the first 12 to 48 hours of life
By following the current recommendations of antepartum management of an HIV-positive pregnant
woman and postnatal management of the infant, the risk of mother-to-child transmission of HIV is low
at about 1% to 2%. These recommendations include the following:
•All women who are HIV-positive should receive Zidovudine during labor, regardless of viral
load or adherence to antiretroviral therapy regimens.
•Elective Cesarean delivery is only indicated for women with viral loads >1000 copies per mL
prior to delivery.
•All infants born to HIV-positive women should be started on Zidovudine prophylaxis as soon
as possible, certainly within 12 to 48 hours of life.
There are certain scenarios in which infants might benefit from a second antiviral medication for
HIV prophylaxis. These include infants born to HIV-positive women with suboptimal viral
suppression at the time of delivery, who received antiretroviral therapy only during delivery, who did
not receive intrapartum Zidovudine, or those with known drug-resistant virus. However, there is no
clear research data supporting this approach.
Reference:
Havens PL, Mofenson LM, and the Committee on Pediatric AIDS. Evaluation and management of the
infant exposed to HIV-1 in the United States. Pediatrics. 2000;123:176-187
Infectious Diseases & Immunology Answer 39
A. Antiretroviral drugs have differential penetration in human milk, raising concerns about toxicity to
infants receiving breastmilk
The risk of mother-to-child HIV transmission via human milk is between 9% and 15%. The viral
load in human milk may not be the same as that in plasma. This is due to the fact that antiretroviral
drugs only reduce cell-free HIV virus, not cell-associated virus. Different antiretroviral drugs have
differential penetration in human milk, with some having levels in milk much higher than those in
plasma. Mothers who are HIV-positive should be discouraged from breastfeeding their infants if
sources of safe alternative nutrition are available. This is true in the United States, where infant
formula and safe drinking water are readily available.
Reference:
Havens PL, Mofenson LM, and the Committee on Pediatric AIDS. Evaluation and management of the
infant exposed to HIV-1 in the United States. Pediatrics. 2000;123:176-187
Infectious Diseases & Immunology Answer 40
C. At least 2 negative HIV antibody test results from separate specimens drawn at ≥8 weeks of age
According to the CDC, a presumptive exclusion of HIV infection in an infant born to an HIV-
positive mother can be made if the infant does not have any laboratory or clinical evidence of HIV
infection and any of the following:
1)Two negative HIV RNA or DNA viral test results, from separate specimens, both of which
were drawn at ≥2 weeks of age and one of which was drawn at ≥4 weeks of age
2)One negative HIV RNA or DNA viral test result from a specimen drawn at ≥8 weeks of age
3)One negative HIV antibody test result drawn at ≥6 months of age
In order to definitively rule out HIV infection, the infant must not have any laboratory or clinical
evidence of HIV infection and either of the following:
1)At least 2 negative HIV RNA or DNA viral test results, from separate specimens, both of
which were drawn at ≥1 months of age and 1 of which was drawn at ≥4 months of age
2)At least 2 negative HIV antibody test results from separate specimens drawn at ≥6 months of
age
Reference:
Havens PL, Mofenson LM, and the Committee on Pediatric AIDS. Evaluation and management of the
infant exposed to HIV-1 in the United States. Pediatrics. 2000;123:176-187
Infectious Diseases & Immunology Questions 41-50
Infectious Diseases & Immunology Question 41
You are asked to consult with a 26-year old G2P1 woman at 35 5/7 weeks’ gestation. Her
pregnancy has been uncomplicated until today when she presented with a fever to 102ºF, myalgia, and
a backache. She reports that her 2-year old daughter has recently been diagnosed with hand, foot and
mouth disease and was febrile today. Her husband too had a fever today. The patient’s complete
blood cell count revealed a leukocyte count of 7,700 cells/µL with a normal differential. She is
having regular and frequent contractions but no signs of rupture of membranes.
Of the following, the most appropriate management of this woman is to:
A.Administer betamethasone to the pregnant woman before induction to enhance fetal lung
maturation
B.Administer magnesium sulfate to the pregnant woman for neuroprotection of the infant
C.Deliver by Cesarean section to decrease the risk of disease transmission
D.Treat the woman with erythromycin for prevention of ascending infection
E.None of the above
Infectious Diseases & Immunology Question 42
You are taking care of a male infant born at 37 weeks’ gestation with a birthweight of 3 kg male
who is now 4 days old. He was admitted to the NICU yesterday with a fever to 38.6°C, tachypnea,
and cyanosis. He was evaluated for enteroviral sepsis because of a maternal history of a viral-like
illness with fever, abdominal pain, and diarrhea on the day of delivery. The infant is NPO, receiving
intravenous fluids and broad-spectrum antibiotics, and is on 40% oxygen via a hood. His BP has been
stable and his urine output is 1 ml/kg/hr for the last 12 hours.
His examination is significant for the following:
•Febrile
•Lethargy
•Tachypnea
•HR = 190 beats/minute
•Capillary refill = 3 seconds
His color appears jaundiced and he has multiple petechiae on his trunk. A CSF analysis done
yesterday show no pleocytosis with a glucose of 43 mg/dL and protein of 36 mg/dL. His CSF and
stool PCR for enterovirus just came back positive. Other viral studies have returned negative. Now
the lab calls you with the following results:
•WBC = 9,200 cells/µL
•Differential = polysegmented neutrophils 53%, lymphocytes 32%, monocytes 10%,
eosinophils 5%
•Hematocrit 30.5%
•Platelet = 39 cells/µL
•Aspartate aminotransferase = 240 units/L
•Alanine aminotransferase = 450 units/L
•Total bilirubin = 14.5 mg/dL with a direct bilirubin of 0.8 mg/dL
•Prothrombin time = 34 sec (12-14 range)
•Partial thromboplastin time = 50 sec (23-37 range)
You review the literature and find that all of the following management approaches is of possible
benefit to this patient EXCEPT:
A.Acyclovir
 B.Fresh frozen plasma (FFP) and packed red blood cell (PRBC) transfusions
C.Intravenous immunoglobulin (IVIG)
D.Pleconaril
E.Supportive management
Infectious Diseases & Immunology Question 43
A male infant, born at 28 weeks’ gestation with a birthweight of 820 g is recovering from surgical
necrotizing enterocolitis (NEC) that resulted in an ileostomy placement 12 days ago. He has a central
line in place for total parenteral nutrition. Over the last 24 hours he has become increasingly
hypotensive despite inotropic and fluid support and has had frequent apneic episodes requiring
intubation. His complete blood cell count is remarkable for neutropenia. He has been receiving
broad-spectrum antibiotics for the last 12 days as part of his NEC treatment. Given his clinical
picture you are worried about a systemic fungal infection and after sending fungal cultures from the
CSF and blood, you decide to empirically start treatment with an antifungal agent.
Which of the following drugs is the appropriate choice for empirical coverage in this infant?
A.Amphotericin B
B.Fluconazole PO
C.Fluconazole IV
D.Flucytosine
E.Liposomal Amphotericin B
Infectious Diseases & Immunology Question 44
You are called to review the complete blood cell count (CBC) results of an infant born at 28
weeks’ gestation. The pregnancy had been complicated by pregnancy-induced hypertension (PIH)
that was controlled with labetolol. The mother had presented 3 days earlier with rupture of amniotic
fluid. She had received 2 doses of betamethasone. On the day of delivery, the woman was noted to
have a fever of 100.6ºF and soon after the infant was born following unstoppable preterm labor.
After birth, the infant had appeared vigorous and required minimal resuscitation. She was noted to
have growth parameters at the 3rd percentile for her gestational age. Soon after birth she developed
retractions and cyanosis for which she was intubated and is currently stable on minimal ventilatory
settings. Blood cultures have been sent and she has been started on empirical antibiotics. The rest of
her laboratory results are as follows:
•White blood cell count = 7,000 cells/µL
•Differential: Polysegmented neutrophils 14%, Bands 14%, Lymphocytes 47%, Monocytes
6%, Eosinophils 3%, Basophils 0%
•Hematocrit = 29%
•Platelet count = 238,000 cells/µliter
44a. Which of the following values represent this infant’s absolute neutrophil count (ANC) and
immature to total neutrophil ratio (I:T ratio)?
A.ANC = 1,960; I:T ratio = 2.07
B.ANC = 1,960; I:T ratio = 0.5
C.ANC = 980; I:T ratio = 2.07
D.ANC = 980; I:T ratio = 0.5
E.ANC = 3,010; I:T ratio = 0.5
44b. For the ANC and I:T ratio calculated in the above question, which of the following is the most
appropriate interpretation for this infant’s bone marrow granulocyte kinetics?
A.Hyperregenerative bone marrow probably in response to antenatal steroid exposures
 B.Hyperregenerative bone marrow probably in response to infection
C.Hyporegenerative bone marrow probably secondary to a small for gestational age infant
D.Hyporegenerative bone marrow probably secondary to PIH in the mother
E.Increased neutrophil destruction secondary to congenital neutropenia syndrome
Infectious Diseases & Immunology Question 45
Recombinant granulocyte colony stimulating factor (rG-CSF) can stimulate production of
neutrophils in certain patients. Neutrophils are an important part of the body’s immune defense and
their deficiency can lead to life-threatening infections.
Of the following, the most appropriate scenario for use of rG-CSF as a standard therapy is:
A.Infant born at 24 weeks’ gestation with birthweight of 670 g with early-onset bacterial sepsis
and an absolute neutrophil count (ANC) of 2,000 at birth
B.Growth-restricted infant born at 26 weeks’ gestation with an ANC of 750 at birth who is born to
a mother with severe PIH
C.Infant with Kostmann syndrome
D.Infant born at 27 weeks’ gestation now 15 days old with stage IV necrotizing enterocolitis and
an ANC of 600
E.None of the above
Infectious Diseases & Immunology Question 46
Coagulase-negative Staphylococcus (CONS) includes over 30 species and is one of the most
common isolates found in nosocomial infections among NICU patients. While the distinction between
infection, contamination, and bacteremia are much debated, many studies have correlated a positive
CONS culture result from a normally sterile site with poor neurodevelopmental outcomes later in
life.
All of the following statements are true about CONS infections in the NICU EXCEPT:
A.90% of CONS isolates are Methicillin-resistant
B.CONS isolation is often related to the presence of foreign material in the body
C.CONS prevention is possible by weekly surveillance cultures and isolation of colonized
patients
D.Pathogenecity of CONS includes production of biofilms
E.Staph. epidermidis is the most common isolated CONS species
Infectious Diseases & Immunology Question 47
You are called by the laboratory about a positive blood culture growing Staphylococci
epidermidis from one of the two blood culture bottles sent 34 hours ago on a 24-day old male infant
born at 26 weeks’ gestation. The infant at the time of the evaluation was having increased apnea
episodes and after sending a CBC and blood culture, the infant was started on Nafcillin. The CBC
results are as follows:
•White blood cell count = 14,000 cells/µL
•Differential = Polysegmented neutrophils 45%, Bands 3%, Lymphocytes 32%, Eosinphils 8%,
Basophils 5%, and Monocytes 5%
•Hematocrit = 42%
•Platelet = 230,000 cells/µL
The infant was also loaded with caffeine and has since then stabilized to his respiratory baseline
of continuous positive airway pressure in room air.
In the past, the infant has had difficulty establishing full enteral feedings and has a Broviac catheter
that was placed 14 days ago that provides one-third of his total fluids.
 Deciding whether a CONS isolate is a true infection versus contamination can be difficult. Which
of the following factors in this vignette increases the likelihood that this is a TRUE infection?
A.CBC results at the time of evaluation
B.Growth from a single bottle
C.Isolate growing within 24-36 hours
D.Presence of a central line
E.Stabilization of clinical symptoms after starting Nafcillin
Infectious Diseases & Immunology Question 48
A 6-day old full-term male infant is noted to have abdominal erythema and oozing from the
umbilical cord.
Which of the following statements is FALSE?
A.Omphalitis is typically a polymicrobial infection
B.Risk factors for the development of omphalitis include prolonged labor and prolonged rupture of
membranes
C.The mortality rate of omphalitis is between 7% and 15%
D.The most common complication of omphalitis is necrotizing fasciitis
E.The reported incidence of omphalitis is approximately 0.7% in developed countries and up to
6% in developing countries
Infectious Diseases & Immunology Question 49
Which of the following statements about immunoglobulin levels in neonates is FALSE?
A.Maternal IgG is not usually detectable in an infant’s bloodstream at 4 months of age
B. Maternal IgG is transported across the placenta to the fetus by endocytosis
C. Neonatal IgA levels reach approximately 20% of adult levels by 1 year of age
D. Neonatal IgM levels reach approximately 75% of adult levels by 1 year of age
E. Peak maternal IgG levels in neonatal blood occur at approximately 40 weeks’ gestation
Infectious Diseases & Immunology Question 50
When does IgA production begin?
A. At 2 months’ gestation
B. At 4 months’ gestation
C. At 6 months’ gestation
D. At 8 months’ gestation
E. After birth
Infectious Diseases & Immunology Answers 41-50
Infectious Diseases & Immunology Answer 41
E. None of the above
The family history of exposure to hand, foot, and mouth disease (most commonly attributed to
Coxsackievirus A16 and Enterovirus 71), along with the onset of febrile viral syndrome in other
family members, is highly suggestive of enteroviral infection in the pregnant woman in this vignette.
Enteroviruses comprise 4 separate species of small, nonenveloped, single-stranded RNA viruses-
Human Enterovirus A, B, C and D. They include over 50 serotypes with a diverse range of clinical
manifestations ranging from non-specific illness to fatal meningoencephalitis. Over 44% of reported
enteroviral infections in the US occur in children <1 year of age.
Neonatal enteroviral sepsis ranges from a benign self-resolving illness to a severe life-threatening
illness. Clinical manifestations associated with high mortality include hepatic necrosis, mycoarditis
and meningoencephalitis. Risk factors for severity of illness have been found to correlate with early
birth and maternal illness around the time of delivery. The explanation for the latter is proposed to be
the absence of placental transfer of serotype specific antibodies. This is also one of the reasons for
use of IVIG as therapy in affected infants, providing a source of neutralizing antibodies. Other risk
factors include the serotype of enteroviral infection and early time of symptom onset in the affected
infant.
Enteroviral transmission has been documented antenatally via the placental circulation, perinatally
during vaginal delivery, and postnatally from close contact. Unlike herpes simplex virus infections,
no evidence exists to suggest decreased enteroviral transmission by avoiding vaginal delivery.
Betamethasone for fetal lung maturation is recommended for preterm deliveries <34 weeks’ gestation
and therefore is not appropriate for the woman in this vignette. Erythromycin is recommended for
treatment of latency between premature rupture of membrane and the onset of labor and is not
appropriate for this case. Use of magnesium sulfate for anticipated preterm birth has been mostly
studied in gestations less than 34 weeks and although the American Congress of Obstetricians and
Gynecologists does not provide firm guidelines for its use for preterm neuroprotection there is very
little evidence to use it above 34 weeks’ gestation (ACOG practice guideline, 2013).
References:
Abzug MJ, Levin MJ, Rotbart HA. Profile of enterovirus disease in the first two weeks of life.
Pediatr Infect Dis J. 1993 Oct;12(10):820-824
ACOG Committee Opinion: Magnesium sulfate before anticipated preterm birth for neuroprotection.
Number 455, March 2010. Accessed 10/24/2013
Khetsuriani N, LaMonte-Fowlkes A, Oberste MS, Pallansch MA. Centers for Disease Control and
Prevention. Enterovirus Surveillance-United States, 1970–2005. MMWR. 2006;55(No. SS-8)
http://www.cdc.gov/mmwr/PDF/ss/ss5508.pdf Accessed 10/24/2013
Modlin JF, Polk BF, Horton P, Etkind P, Crane E, Spiliotes A. Perinatal echovirus infection: risk of
transmission during a community outbreak. N Engl J Med. 1981;305:368-371
Tebruegge M, Curtis N. Enterovirus infections in neonates. Semin Fetal Neonatal Med. 2009;15:222-
227
Infectious Diseases & Immunology Answer 42
A. Acyclovir
The infant in this vignette most likely has enteroviral sepsis. Unfortunately, there is limited
evidence-based therapeutic options for the management of enteroviral neonatal sepsis. The infant in
this vignette is showing signs of hepatic involvement with coagulopathy and anemia and transfusions
with FFP and PRBC are appropriate. As for any infant with sepsis, supportive measures such as
temperature reduction, cardiorespiratory support, and close fluid monitoring is also appropriate.
High dose IVIG is thought to have a beneficial effect by providing neutralizing antibodies (albeit
in variable amount) against enterovirus as the IVIG is made from a pooled plasma sample of a
potentially enterovirus-exposed population who had mounted an adequate response. However,
despite the theoretical plausibility, the role of IVIG in clinical trials has not shown consistent benefit.
The role of hyperimmune IVIG is currently being investigated (Abzug).
Pleconaril is an antiviral capsid binding drug that inhibits the viral attachment to host cells.
Clinical trials to demonstrate its efficacy have not been conclusive and it is currently considered
experimental in the US (Abzug).
Acyclovir is a guanosine analogue and has a demonstrated efficacy in DNA viral infections such as
herpes simplex virus but does not have a role in RNA viral infections. It has known renal toxicity and
could aggravate renal failure if used in this case.
Reference:
Abzug MJ. The enteroviruses: Problems in need of treatments. J Infect. 2013 Oct 8. pii: S0163-
4453(13)00287-9
Infectious Diseases & Immunology Answer 43
A. Amphotericin B
Candidal infections account for a substantial portion of late-onset infections in the NICU,
specifically in the extremely low birthweight (ELBW) population. The infant in this vignette has many
of the major risk factors predisposing to fungal infections such as:
•Major abdominal surgery
•Presence of a central venous line
•ELBW
•Prematurity
•Exposure to broad-spectrum antibiotics for a prolonged duration
Systemic Candida infection in ELBW neonates can involve multiple organs and has a high
morbidity and mortality.
Among neonates, Amphotericin B remains the initial drug of choice for treatment of candidal
infections because of its superior penetrance through the blood brain barrier, renal system, and the
ocular orbit, regions that tend to be involved in neonatal systemic Candidiasis.
Efficacy of liposomal Amphotericin B is equivalent to Amphotericin B in adult studies. However,
because it is a larger molecule, it has less penetrance into the brain and kidney. Although it is
associated with fewer adverse effects in the kidney, it has additional liver toxicities that are not
observed with administration of Amphotericin B. Therefore its use in the neonatal and pediatric
populations is restricted to patients with renal toxicity or those that are non-responsive to
Amphotericin B.
Candida kruzii and some forms of Candida glabarata are resistant to fluconazole. Therefore,
these safer azole drugs can only be used once the sensitivity of the Candidal species is known. Both
IV and PO forms have equivalent bioavailability and can be used depending on the infant’s intestinal
function.
Flucytosine is rarely used alone because of rapid emergence of resistance but this medication has
been used with Amphotericin B in life-threatening forms of Candida meningitis and infection.
Reference:
American Academy of Pediatrics. Red Book: 2012 Report of the Committee on Infectious Diseases.
 Pickering LK, ed. 29th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2012
Infectious Diseases & Immunology Answer 44
44a. B. ANC = 1,960; I:T ratio = 0.5
The use of complete blood count indices in newborns can help elucidate the bone marrow kinetics
and provide information about the state of a newborn’s condition. The formulas for calculating the
ANC and I:T ratio are as below:
Absolute = [(% polysegmented neutrophils + % bands) x total white blood
neutrophil count, cells]/100
cells per µl
= [(14+14) x 7,000]/100 = 1,960
Immature to total =% bands/% polysegmented neutrophils
neutrophil ratio Alternatively I:T ratio = (bands + metamyelocytes + myelocytes)/
(polysegmented cells +bands+metamyelocytes+myelocytes)-note all
are %

=(14) / (14+14) = 0.5

The use of promyelocytes in the calculation of I:T ratio is unclear given that many laboratories do not
report it. According to Manroe et al in their original publication of reference values for newborns,
immature forms were defined as bands and all cells less immature than bands.
44b. B. Hyperregenerative bone marrow probably in response to infection
The life cycle of neutrophils begins with differentiation of myeloblasts → promyelocytes →
myelocytes (these 3 constituting the neutrophil proliferative pool) → metamyelocytes → bands →
segmented mature neutrophils (these last 3 constituting the post-mitotic neutrophil storage pool). The
immature to total ratio is a reflection of the rate of differentiation in the body. A high ratio is
suggestive of greater immature forms being pushed into the peripheral circulation with ongoing
production in the bone marrow. The interpretation of these indices is complicated by varying
definitions of neutropenia (1,000 to 2,000 neutrophils/µL) and a high I:T ratio (0.2-0.3). Also the
state of the marrow may be in transition between increased proliferation to subsequent suppression,
as seen in fulminate infection.
A simplistic interpretation of the I:T ratio in context with the ANC could be as follows:
ANC I/T Bone Marrow State
Ratio
Low High Increased production of immature forms but ongoing
(<1500) (>0.2- destruction/consumption of mature forms that is not matched
0.3) e.g., infection, autoimmune destruction
Low Low Suppression of production with or without associated consumption
e.g., infection, PIH, SGA status
Normal High Increased production of immature forms but ongoing
destruction/consumption of mature forms that is currently matched
e.g, infection, autoimmune state
Normal Low Normal state
In this vignette, the increased production of immature forms as seen by an elevated I:T ratio and
the low-normal ANC of >1500 suggests that the bone marrow is proliferating in response to stimuli
(most likely an infection). The infant in this vignette has multiple risk factors for infection including
prolonged preterm rupture of membrane, maternal fever before delivery, preterm labor, and a low
birthweight. There is no evidence to suggest that antenatal steroids increase immature cell production
in the bone marrow. Both PIH and small for gestational age (SGA) status are noted to cause transient
neutropenia that usually resolves in the first 3 to 4 days of life but in this case, the neutropenia is
marginal and there is a prominent left shift. Infants with congenital neutropenia syndrome, Kostmann
syndrome being the prototype, present with severe neutropenia in the 200s and usually later in life.
Thus, although the interpretation of neutrophil indices is ambiguous in many cases, for the infant in
this vignette, the most likely explanation is infection.
References:
Maheshwari A, Black V A practical approach to the neutropenic neonate. In: Hematology,
Immunology and Infectious Disease. Ohls R, Maheshwari A (Editors). Elsevier. 2012
Manroe BL, Weinberg AG, Rosenfeld CR, Browne R. The neonatal blood count in health and
disease. I. Reference values for neutrophilic cells. J Pediatr. 1979;95:89-98
Newman TB, Puopolo KM, Wi S, Draper D, Escobar GJ. Interpreting complete blood counts soon
after birth in newborns at risk for sepsis. Pediatrics. 2010;126:903-909
Infectious Diseases & Immunology Answer 45
C. Kostmann syndrome
Infants with neutropenia in the neonatal period can arise from a number of etiologies. Kostmann
syndrome is a congenital neutropenia that usually results from mutations in the neutrophil elastase
gene. Approximately 90% of affected patients respond to rG-CSF and the survival of these patients
has improved markedly with the use of this agent. Most patients are enrolled in a registry and the
potential long-term malignant and osteopenic outcomes of rG-CSF are under study.
Neutropenia in the preterm population can result from maternal PIH and those infants who are
small for gestational ag. In both scenarios, the neutropenia is commonly transient and resolves in the
first few days of life. Clinical trials studying the utility of rG-CSF in the management of neonatal
infection have been inconclusive. A Cochrane review found a reduction in mortality with rG-CSF
treatment among neonates with sepsis and severe neutropenia at the time of enrollment. There is no
evidence to recommend a role of rG-CSF in patients with NEC.
References:
Carr R, Modi N, Doré C. G-CSF and GM-CSF for treating or preventing neonatal infections.
Cochrane Database Syst Rev. 2003;(3):CD003066
Christensen R. The role of recombinant leukocyte colony stimulating factors. In: Hematology,
Immunology and Infectious Disease. Ohls R, Maheshwari A (Editors). Elsevier. 2012
Maheshwari A, Black V A practical approach to the neutropenic neonate. In: Hematology,
Immunology and Infectious Disease. Ohls R, Maheshwari A (Editors). Elsevier. 2012
Infectious Diseases & Immunology Answer 46
C. CONS prevention is possible by weekly surveillance cultures and isolation of colonized patients
Coagulase-negative Staphylococci (CONS) are widespread colonizers of skin and most babies
are colonized by 3 to 4 days of life. Staph. epidermidis is the most common isolated species.
Invasion by CONS to cause bacteremia and septicemia occurs in the setting of disruption of the
body’s defense barriers such as the presence of a central line or other foreign material, or
insufficiency of an infant’s immune response, as seen in the preterm population. One of the important
pathogenic mechanisms for a CONS infection is the production of a polysaccharide-based biofilm
that protects the bacteria from phagocytic activity of the host immune system. 90% of CONS isolates
are Methicillin-resistant and thus Vancomycin is the drug of choice for treating these bacterial
infections. As they are part of normal colonizing flora, surveillance cultures and isolation of such
widespread organisms would not be effective.
The main preventative approaches to decreasing CONS infections in a NICU include removal of
lines as soon as they not needed, ethanol and Vancomycin locks for central lines, and time-tested
methods of hand hygiene, use of protective equipment, and sterile procedure technique.
References:
American Academy of Pediatrics. Red Book: 2012 Report of the Committee on Infectious Diseases.
Pickering LK, ed. 29th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2012. Section
3. Staphlococcus Infections.
Nash C, Chu A, Bhatti M, Alexander K, Schreiber M, Hageman JR. Coagulase-negative
Staphylococci in the neonatal intensive care unit: Are we any smarter? NeoReviews.
2013;14:e284-e293
Infectious Diseases & Immunology Answer 47
D. Presence of a central line
CONS isolates constitute one of the most common causes of both late-onset bacteremia and
contaminant growth in NICUs. Discrepancy in the approach of physicians to a CONS isolate is wide
and ranges from treating all isolates to treating none. Attempts to distinguish between true bacteremia
and contamination have been made and the following criteria are proposed that occur more commonly
in true bacteremia rather than with contaminated samples:
•> 2 positive blood cultures from different collection sites
•Positive blood culture in combination with another sterile site (e.g., cerebrospinal fluid)
•Microbiological susceptibilities of isolates from multiple samples can be compared and if
identical suggest true infection. Similarly genotyping multiple positive isolates can confirm
that they are the same organism and increases the likelihood of true bacteremia versus
multiple contaminations.
•Colony forming units of >50 or in an automated system, growth within 15 hours (time to
positivity correlates with bacterial burden)
•Clinical examination consistent with sepsis
•Presence of a nidus for bacterial invasion, such as an intravascular catheter or other foreign
material
Use of Nafcillin is unlikely to have resulted in the infant’s improvement because 90% of CONS
infections are resistant to Methicillin. The infant’s clinical improvement could have equally been as a
result of the caffeine. However, a CONS infection can have a non-specific fluctuating course and in
the presence of a central line, a repeat peripheral blood culture should be sent. This infant’s CBC
shows no left shift and is not indicative of infection. The time to growth and the growth from a single
bottle are both consistent with contamination rather than infection.
References:
American Academy of Pediatrics. Red Book: 2012 Report of the Committee on Infectious Diseases.
Pickering LK, ed. 29th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2012. Section
3. Staphlococcus Infections.
Nash C, Chu A, Bhatti M, Alexander K, Schreiber M, Hageman JR. Coagulase-negative
Staphylococci in the neonatal intensive care unit: Are we any smarter? NeoReviews.
2013;14:e284-e293
Infectious Diseases & Immunology Answer 48
D. The most common complication of omphalitis is necrotizing fasciitis
 Omphalitis is an infection of the umbilical cord and surrounding tissues. The reported incidence is
approximately 0.7% in developed countries and up to 6% in developing countries, with a mortality
rate estimated between 7% and 15%. Risk factors for the development of omphalitis include low
birthweight, prolonged labor, prolonged rupture of membranes, maternal infection, non-sterile
delivery, umbilical catheterization, and home delivery. It is typically associated with a
polymicrobial infection, most commonly skin flora such as Staph. aureus, group A Streptococcal
species, and gram-negative species including E. coli. Clinical findings include erythema, induration,
and tenderness, along with purulent discharge from the umbilical cord stump. The most common
complication of omphalitis in infants is sepsis. Other less common complications include necrotizing
fasciitis, peritonitis, liver abscess, septic umbilical arteritis, and endocarditis.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Edwards M. The immune system: Postnatal bacterial infections. In: Martin R, Fanaroff A, and Walsh
M, eds. Neonatal-Perinatal Medicine: Diseases of the Fetus and Infant. 9th ed. St. Louis, Missouri:
Elsevier Press;2011:818
Palazzi D, Bradt M. Care of the umbilicus and management of umbilical disorders. In: UpToDate,
Basow, DS (Ed), UpToDate, Waltham, MA, 2013
Infectious Diseases & Immunology Answer 49
A. Maternal IgG is not usually detectable in an infant’s bloodstream at 4 months of age
Maternal IgG remains in an infant’s bloodstream for more than 6 months of age and is not usually
detectable at 9 months of age. Maternal IgG is transported across the placenta to the fetus by
endocytosis. Fetuses do not produce IgA and make only small amounts of IgM during gestation.
Neonatal IgA levels reach approximately 20% of adult levels by 1 year of age. Neonatal IgM levels
reach approximately 75% of adult levels by 1 year of age. Peak maternal IgG levels in neonatal
blood occur at approximately 40 weeks’ gestation.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Martin RJ, Fanaroff AA, Walsh M (eds). Neonatal and Perinatal Medicine: Diseases of the Fetus and
Newborn. 7th edition. St. Louis; Mosby, 2005
Infectious Diseases & Immunology Answer 50
E. After birth
Infectious Diseases & Immunology Questions 51-60
Infectious Diseases & Immunology Question 51
You are worried that a neonate in the NICU with frequent infections may have an immune
deficiency. Specifically, you are considering a disorder of B-lymphocytes.
All of the following is true about B-lymphocytes, EXCEPT:
A. Preterm infants have significantly lower B-lymphocyte numbers compared to term infants
B. The interaction of B-lymphocytes with antigen leads to production of specific antibodies
C. The number of B-lymphocytes peaks at 3 to 4 months of age
D. They mature within the bone marrow
E. X-linked agammaglobulinemia is caused by mutations in the Bruton tyrosine kinase that leads to
a block in B-lymphocyte development
Infectious Diseases & Immunology Question 52
A well appearing male neonate is brought to the NICU for a sepsis evaluation because of risk
factors for sepsis. The laboratory results show that the infant has neutropenia. You worry about his
infection risk.
Compared with neutrophils from adults, neutrophils from term neonates:
A. Adhere poorly to the endothelium
B. Have a decreased degranulation response
C. Have a higher chemotactic response
D. Have decreased phagocytosis
E. Have equal migration
Infectious Diseases & Immunology Question 53
A neonate has just been diagnosed with a Neisseria infection. You are worried about a
complement deficiency. All of the following is true about the complement system, EXCEPT:
A. C2 is the most common complement deficiency
B. C4 is part of the alternative pathway
C. Deficiency of late components results in an increased risk of a Neisseria infection
D. Most neonates reach adult complement levels at 3 to 6 months of age
E. The classical pathway requires antigen-antibody reaction
Infectious Diseases & Immunology Question 54
All of the following are components of the innate immune system, EXCEPT:
A. B-lymphocytes
B. Complement
C. Eosinophils
D. Neutrophils
E. Skin and mucous membranes
Infectious Diseases & Immunology Question 55
A male neonate is admitted to your NICU from the Emergency Room. He is two weeks old and
presented with a fever. Blood, urine, and CSF cultures were obtained. The catheterized urine culture
is growing 20,000 bacteria.
What is the most likely organism growing from this infant’s urine culture?
A. Candida
B. Coagulase-negative Staphylococcus
C. E. coli
D. Group B Streptococcus
 E. Listeria
Infectious Diseases & Immunology Question 56
A premature infant who is 32 weeks’ postmenstrual age has a diagnosis of Staph. aureus
bacteremia. A nurse in the NICU consults the neonatology fellow because of concern that the infant
has a swollen, erythematous knee with decreased motion.
Which of the following management steps is NOT indicated?
A.Antibiotic treatment for 4-6 weeks
B.Aspiration of fluid
C.Bone biopsy
D.Immobilization involved joint
E.Lumbar puncture
Infectious Diseases & Immunology Question 57
What is the most likely serotype of Group B Streptococcus to cause late-onset disease?
A. Serotype I
B. Serotype II
C. Serotype III
D. Serotype IV
E. Serotype V
Infectious Diseases & Immunology Question 58
A 3-month old infant presents with lethargy, constipation, poor feeding, a weak cry and hypotonia.
The infant’s mother reports that the infant’s weakness has been progressive. An electromyography is
performed, which shows an incremental response at high frequency and abnormal spontaneous
activity.
Of the following, the type of bacteria that is MOST likely to be the cause of the infant’s symptoms
is a(n):
A. Acid-fast bacillus
B. Gram-negative intracellular diplococcic in pairs
C.Gram-positive bacillus
D. Gram-positive diplococcic in chains
Infectious Diseases & Immunology Question 59
What is the most common form of immune dysfunction found in patients with chromosome 22q11.2
deletion?
A.Graft versus host disease
B.Oligoclonal peripheral T-cell proliferation (similar to Omenn syndrome)
C.Severe immunoglobulin deficiency
D.T cell hypoplasia and mild to moderate peripheral lymphopenia
E.Thymic aplasia and severe T-cell lymphopenia
Infectious Diseases & Immunology Question 60
You have been closely monitoring a neonate with erythema around the umbilicus for two days.
The erythema appears to be slowly worsening. You have been keeping the area clean and dry and
marking the erythema. Today, the neonate appears less active and has temperature instability. When
you arrive at the bedside you note purulent discharge from the umbilical cord and surrounding
induration. The erythema has spread rapidly and there is a bluish/black discoloration around the
umbilicus with areas of blistering.
All of the following are true about this infant’s condition EXCEPT:
A. A blood culture and complete blood cell count should be obtained
B. Intravenous antibiotic therapy should be started immediately
C. The prognosis is poor
D. There is no need to involve pediatric surgery
E. The etiology is frequently polymicrobial
Infectious Diseases & Immunology Answers 51-60
Infectious Diseases & Immunology Answer 51
A. Preterm infants have significantly lower B-lymphocyte numbers compared to term infants
B-lymphocytes are cells that recognize and bind to specific antigens via cell surface
immunoglobulin receptors. The B-cell interaction with antigen ultimately leads to production of
specific antibodies. These antibodies provide protection by recognizing a broad and ever-changing
array of foreign antigens and microbial pathogens.
In human fetuses, pre-B cells can be identified in the liver as early as 7 weeks of gestation and in
the bone marrow by 12 weeks’ gestation. By 30 weeks’ gestation, there are no detectable pre-B cells
in the fetal liver, and the bone marrow becomes the exclusive site for B-cell maturation. At birth, the
proportion of B cells is similar to that of adults, but the absolute number of B cells is significantly
higher. The number of B cells peaks at 3 to 4 months of age and declines to adult levels by 6 to 7
years of age. Preterm infants have B-cell numbers that are comparable to those in term infants.
Perturbations in B-cell development or maturation leads to well-characterized immunodeficiency
disease states, X-linked agammaglobulinemia, X-linked hyper IgM syndrome, and common variable
immunodeficiency. X-linked agammaglobulinemia is a profound immunodeficiency disease
accompanied by near absence of all immunoglobulins. Mutations in the Bruton tyrosine kinase lead to
a block in B-cell development of pre-B cells to the immature B cell stage. This B-cell developmental
arrest prevents B cells from differentiating and producing antibodies.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Schelonka R, Maheshwari A. The many faces of B cells: From generation of antibodies to immune
regulation. NeoReviews. 2013;14:e438-e447
Infectious Diseases & Immunology Answer 52
A. Adhere poorly to the endothelium
Neutrophils are the first-line defenders against bacterial and fungal pathogens. In the human fetus,
neutrophil development starts at 10 to 14 weeks’ gestation. Functional maturation of neutrophils
continues through the rest of the gestation. Circulating neutrophils leave the intravascular
compartment to enter the tissues in three major steps:
1.Margination and rolling on vascular endothelium
2.Attachment to the endothelial cells
3.Transendothelial migration
Compared with neutrophils from adults, neutrophils from both term and preterm neonates adhere
poorly to the endothelium. Once outside the blood vessel, neutrophils migrate along concentration
gradients of various chemoattractants. Neutrophils from both term and preterm neonates have an
impaired chemotactic response. Phagocytosis is a specific form of endocytosis directed at engulfing
solid particles into an internal phagosome. Neutrophils from preterm neonates have a developmental
defect in phagocytosis that corrects by the late third trimester or term gestation (to become
comparable to adult neutrophils). Neutrophil granules are involved in killing. Neutrophils from term
neonates have granule contents and degranulation responses similar to those from adults.
Reference:
Chandra S, Haines H, Michie C, Maheshwari A. Developmental defects in neutrophils from preterm
infants. NeoReviews. 2007;8:e368-e376
Infectious Diseases & Immunology Answer 53
B. C4 is part of the alternative pathway
 The complement system plays an important role as one of the principal components of the natural
immune system. Its major function is to facilitate the neutralization of foreign substances either in the
circulation or on mucous membranes. This function is accomplished by a series of plasma proteins
that are involved in specific and nonspecific host defense mechanisms. The classic pathway of
complement activation requires the presence of specific antibodies against a particular antigen,
leading to formation of immune complexes.
The order of component activation in the classic pathway is C1, C4, C2, and C3. The classical
and alternative pathways converge at C3. While the classical complement pathway requires antigen-
antibody reaction, the alternative pathway may be antibody-independent. Deficiency of early
components (C1-C4) leads to increased risk of infections (especially pneumococcal) and collagen
vascular disease. C2 is the most common deficiency. Deficiency of the late components (C5-C9)
leads to an increased risk of Neisseria infections.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Fanaroff AA, Martin RJ, Walsh M (eds). Neonatal-Perinatal Medicine. 9th edition. St. Louis: Mosby;
201
Infectious Diseases & Immunology Answer 54
A. B-lymphocytes
The immunologic system may be divided into two systems of host defense mechanisms: innate and
acquired immune mechanisms. Innate immunity includes host defense mechanisms that function
without prior exposure to a microorganism or its antigens. Some of these mechanisms include
physical barriers, such as intact skin and mucous membranes, and chemical barriers, such as gastric
acid and digestive enzymes. The innate immunity also includes neutrophils, monocytes, complement,
eosinophils, and cytokines. Innate immunity is a first-line, non-specific defense. It has rapid
availability. Acquired, or specific, immunity mostly consists of the cell-mediated (T-lymphocyte)
and humoral (B-lymphocyte and immunoglobulin) systems. The acquired immune response requires
memory.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Fanaroff AA, Martin RJ, Walsh M (eds). Neonatal-Perinatal Medicine. 9th edition. St. Louis: Mosby;
2010
Infectious Diseases & Immunology Answer 55
C. E. coli
The neonate in this vignette has a urinary tract infection. The organisms associated with a neonatal
urinary tract infection are similar to those that cause neonatal sepsis. Infection with E. coli is most
common. Although Group B Streptoccocus (GBS) can be isolated from the urine of infants with GBS
sepsis, primary urinary tract infection is rare. Pathogens causing health care–associated infections
include the following:
•E. coli
•Other gram-negative enteric bacilli such as Klebsiella and Enterobacter
•Enterococcus
•Candida
•coagulase-negative Staph
Empirical therapy for a neonatal urinary tract infection should include Ampicillin and an
aminoglycoside in dosages used for sepsis. Administration should be parenteral because of the high
incidence of sepsis in association with urinary tract infections in newborns, and because of the often
erratic oral antibiotic absorption in infants. Vancomycin and an aminoglycoside should be considered
for empirical therapy of health care–associated urinary tract infections.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Fanaroff AA, Martin RJ, Walsh M (eds). Neonatal-Perinatal Medicine. 9th edition. St. Louis: Mosby;
2010
Infectious Diseases & Immunology Answer 56
C. Bone biopsy
The infant in this vignette most likely has septic arthritis of the knee, probably from hematogenous
spread following bacteremia. While septic arthritis can be associated with osteomyelitis, a bone
biopsy is not indicated. Aspiration of the fluid is indicated for confirmation of diagnosis and relief of
increased pressure that results from a pus-filled joint. Immobilization of the involved joint may help
to minimize pain. Antibiotic treatment for 4 to 6 weeks is indicated in an infant with a Staph aureus
joint infection. A lumbar puncture is indicated to rule out meningitis. Infants with septic arthritis are
at greater risk of having a permanent abnormality compared with infants with osteomyelitis.
Reference:
Remington JS, Klein JO, Wilson CB. Nizet V, Maldonado Y (eds). Infectious Diseases of the Fetus
and Newborn Infant. 7th edition. Philadelphia: WB Saunders Company; 2010
Infectious Diseases & Immunology Answer 57
C. Serotype III
Serotype III is responsible for the majority of late-onset group B Streptococcus infections, with
symptoms typically occurring after days 7 of life. Approximately 30% to 40% of affected infants
have meningitis and half of affected infants have neurological sequelae. Mortality with late disease is
2% to 6%. Premature infants are not at increased risk for late-onset disease.
In contrast, early-onset disease (i.e., occurring less than 7 days of life) is more commonly
associated with pneumonia (35% to 55%) and less commonly associated with meningitis (5% to
10%). Typically, many serotypes are responsible (serotype III most likely) and premature infants are
at greater risk of disease.
References:
Brodsky D, Martin C. Neonatology Review. 2nd Edition. Lulu. 2010
Remington JS, Klein JO, Wilson CB. Nizet V, Maldonado Y (eds). Infectious Diseases of the Fetus
and Newborn Infant. 7th edition. Philadelphia: WB Saunders Company; 2010
Infectious Diseases & Immunology Answer 58
C. Gram-positive bacillus
The infant in this vignette presents with symptoms concerning for an infection with Clostridium
botulinum. This organism is a gram-positive anaerobic bacillus that emits a toxin, which inhibits the
release of acetylcholine from nerves. Infection can be acquired from airborne spores from soil, dust
or honey. A diagnosis is confirmed by identifying the toxin in stool culture and electromyography with
findings as follows:
•Incremental response at high-frequency
•Abnormal spontaneous activity
•Abundant, brief, small-amplitude action potentials
Mycobacterium tuberculosis is a slow-growing, acid fast bacillus. Neisseria gonorrhoeae is a
gram-negative intracellular diplococcus in pairs. Group B Streptococcus is a gram-positive
diplococcus in chains and Listeria monocytogenes is a gram-positive rod. These organisms are not
likely to cause the electromyography findings of the infant in this vignette.
Reference:
Remington JS, Klein JO, Wilson CB. Nizet V, Maldonado Y (eds). Infectious Diseases of the Fetus
and Newborn Infant. 7th edition. Philadelphia: WB Saunders Company; 2010
Infectious Diseases & Immunology Answer 59
D. T cell hypoplasia and mild to moderate peripheral lymphopenia
Chromosome 22q11.2 deletion is the most common chromosomal deletion syndrome. Multiple
names refer to the similar phenotypes including DiGeorge syndrome, velocardiofacial syndrome, and
CATCH 22 (Cardiac disease, Abnormal facies, Thymic hypoplasia, Cleft palate, Hypocalcemia). In
75% of patients with 22q11.2 deletion, the immune system is altered. This immunological effect is
thought to arise from thymic hypoplasia and manifests most commonly as mild to moderate peripheral
lymphopenia, specifically in a decreased CD3+ T-cell count. In a rare (1.5%) and extreme variant,
affected infants may have aplasia of the thymus resulting in extreme lymphopenia and increased risk
of viral infections. These cases will occasionally show a massive proliferation of the small number
of founder T-cells, resulting in infiltration of end organs with oligoclonal peripheral T lymphocytes.
Often associated with erythroderma and lymphadenopathy, this picture resembles Omenn syndrome
but is found infrequently. Infants with total thymic aplasia are also more sensitive to graft versus host
disease, unlike the milder and more common phenotype of thymic hypoplasia. In complete aplasia, the
absence of T-cells cannot support adequate B-cell proliferation, resulting in immunoglobulin
deficiency that mimics severe combined immunodeficiency. The treatment for severe aplasia
includes transplant.
References:
Gennery AR. Immunological aspects of 22q11.2 deletion syndrome. Cell Mol Life Sci. 2012;69:17-
27
McDonald-McGinn DM, Sullivan KE. Chromosome 22q11.2 deletion syndrome (DiGeorge
syndrome/velocardiofacial syndrome). Medicine (Baltimore). 2011;90:1-18
Infectious Diseases & Immunology Answer 60
D. There is no need to involve pediatric surgery
The infant in the above case has an omphalitis that appears to have progressed to necrotizing
fasciitis. Organisms that are found on the skin or that are introduced into the umbilical vessel by
catheterization can produce an omphalitis. Staph. aureus and E. coli are frequent pathogens, but
Group A Streptococci, anaerobic bacteria, and polymicrobial infections may occur. Direct bacterial
invasion of the umbilical cord and surrounding skin is common. Bacteria can invade the umbilical
artery and spread across its lumen, causing necrosis of the loose connective tissue of the arterial
wall. If the umbilical and iliac ends are occluded, a septic, loculated focus of infection may be found.
When the umbilical end remains patent, purulent material may drain through the umbilicus.
Necrotizing fasciitis is a life-threatening complication resulting from rapidly spreading destruction of
the fascia and subcutaneous tissue around the umbilicus by a polymicrobial infection.
In infants with an omphalitis and necrotizing fasciitis, purulent drainage can be noted from the
umbilical stump at its base of attachment to the abdominal wall or from the navel after the cord has
separated. The discharge can be foul-smelling. Periumbilical erythema and induration may be noted.
Parenteral administration of antibiotics is indicated if a neonate presents with periumbilical
erythema, edema, and tenderness with or without purulent drainage. Combination therapy should be
administered to provide broad-spectrum coverage. Vancomycin should be provided for gram-positive
coverage. An aminoglycoside, or a third-generation cephalosporin for better tissue penetration, can
be given to provide gram-negative coverage.
If there is extensive and rapidly spreading periumbilical erythema or involvement of the
abdominal wall, the complication of necrotizing fasciitis should be considered. Affected infants
frequently present with septic shock, areas of bluish or black discoloration, and induration.
Necrotizing fasciitis requires supportive care, pathogen-directed antibiotic therapy, and extensive
surgical debridement. Omphalitis complicated by necrotizing fasciitis can be associated with
bacteremia, coagulopathy, and shock, and frequently progresses to death despite surgical and
supportive measures. Septic embolization with metastasis to the lungs, kidneys, and skin can occur.
Reference:
Fanaroff AA, Martin RJ, Walsh M (eds). Neonatal-Perinatal Medicine. 9th edition. St. Louis: Mosby;
2010
Infectious Diseases & Immunology Questions 61-70
Infectious Diseases & Immunology Question 61
The Centers of Disease Control and Prevention (CDC) has published guidelines for the prevention
of perinatal Group B Streptococcus (GBS) disease, which are endorsed by the American Academy of
Pediatrics and the American Congress of Obstetricians and Gynecologists. The guidelines
recommend universal maternal screening for GBS, and treatment before delivery if the screening is
positive.
The impact of these practices is most accurately stated by which of the following:
A.There has been a decrease in the incidence of early and late-onset GBS disease
B.There has been a decrease in the incidence of early disease but an increase in the rate of late-
onset GBS
C.There has been a decrease in the incidence of early-onset GBS disease
D.There has been a decrease in the incidence of late-onset GBS disease
E.There has been no change in the incidence of early or late-onset disease but the severity of
disease has been reduce
Infectious Diseases & Immunology Question 62
A 1% solution of silver nitrate, 1% tetracycline ophthalmic ointment, or 0.5% erythromycin
ophthalmic ointment is approved for prophylaxis against ophthalmia neonatorum.
Of the following, the organism that is most likely to be targeted with this regimen is:
A.Candida albicans
B.Chlamydia trachomatis
C.Herpes simplex virus
D.Neisseria gonorrhoeae
E.Neisseria meningitides
Infectious Diseases & Immunology Question 63
You are examining a 10-day old infant with bilateral injected conjunctiva. His mother reports that
the redness started in the right eye 3 days ago and since yesterday has also involved the left eye.
There is scant mucopurulent discharge and worsening eyelid erythema. You learn that the maternal
history is significant for untreated chlamydia at delivery. You decide to treat the infant for
chlamydial conjunctivitis.
Of the following, the preferred treatment for neonatal chlamydial conjunctivitis is:
A.Intravenous Ceftriaxone
B.Oral Cotrimoxazole
C.Oral Erythromycin for 14 days
D.Oral Erythromycin for 7 days along with topical application for 7 days
E.Topical Erythromycin for 14 days
Infectious Diseases & Immunology Question 64
You attend the delivery of a full-term male neonate. The parents ask you about the eye ointment
(0.5% erythromycin) that is being applied.
You tell them that the prophylactic eye ointment has been shown to decrease the incidence of
conjunctivitis caused by:
A. Both Neisseria gonorrhoeae and chlamydia trachomatis
B. Chlamydia trachomatis only
C. Neisseria gonorrhoeae only
D. Neither Neisseria gonorrhoeae or chlamydia trachomatis
 E. Staphylococcus aureus
Infectious Diseases & Immunology Question 65
You are asked to meet with a pregnant woman at 36 weeks’ gestation. Her obstetrician reports
that she has an acute symptomatic hepatitis B infection. You review her laboratory findings.
Of the following, the set of laboratory findings that are most consistent with an acute symptomatic
hepatitis B infection is:
A. HepBsAg negative, anti-HepBc negative, anti-HepBs negative
B. HepBsAg negative, anti-HepBc negative, anti-HepBs positive
C. HepBsAg negative, anti-HepBc positive, anti-HepBs positive
D. HepBsAg positive, anti-HepBc positive, anti-HepBs negative, IgM anti-HepBc positive
E. HepBsAg positive, anti-HepBc positive, anti-HepBs negative, IgM anti-HepBc negative
Infectious Diseases & Immunology Question 66
Which of the following statements about the difference between neonatal and adult neutrophil
function is FALSE?
A. Neonates have a decreased baseline neutrophil proliferation rate but with an infection, the
neonatal bone marrow increases neutrophil production dramatically compared to the adult
B.Neonates have a decreased inflammatory response and have less ability to localize infection
compared to adults
C. Neutrophils of healthy infants have similar bacterial killing ability compared to the adult
D. The majority of neonatal neutrophils are in the bone marrow instead of in the plasma (as in
adults)
E.The neonate has decreased neutrophil migration compared to the adult
Infectious Diseases & Immunology Question 67
A woman is pregnant at 39 weeks’ gestation. She contacts her obstetrician because her primary
care provider has just diagnosed her with chickenpox.
Of the following, the timing of maternal infection that places the infant at greatest risk for a
Varicella infection is:
A. Between 5 days before delivery until 2 days after delivery
B. Between 20 days prior to delivery to 6 days before delivery
C. During the 2nd half of pregnancy and up to 21 days prior to delivery
D. During the first 20 weeks’ of gestation
E. There is equal risk to the infant at any point during gestation
Infectious Diseases & Immunology Question 68
You are taking care of a newborn with a congenital cytomegalovirus infection. The obstetrician
had sent the placenta to pathology for further evaluation and the results are now available.
Which is the most likely description in the pathology report of this newborn’s placenta?
A.Fibrosis of chorionic villi with placental edema
B.Massive hemorrhage involving the majority of the villi
C.Hydrops placentalis and round cell infiltration
D.Vacuolated cells observed in the majority of the villi
E.Villous damage with thrombosis and villitis with some villi containing inclusion body cells and
hemosiderin
Infectious Diseases & Immunology Question 69
Osteomyelitis is a relatively rare disease in neonates. However, early recognition of the symptoms
is important in order to initiate appropriate treatment and prevent long-term complications. There are
significant differences in presentation, severity of symptoms, and infecting organisms in children and
neonates with osteomyelitis.
Which one of the following statements about the differences between children and neonates is
FALSE?
A.Almost all affected neonates are infected by hematogenous spread while older children usually
develop osteomyelitis from spread of a contiguous infection
B.Bony destruction and sequestration is more common in older children than neonates
C.New bone formation is more rapid in neonates than older children
D.Osteomyelitis is more common in children than neonates
E.Septic arthritis often accompanies long bone osteomyelitis in neonates
Infectious Diseases & Immunology Question 70
The nurse calls you to the bedside of a 14-day old infant who was born at 27 weeks’ gestation. He
is requiring continuous positive airway pressure and is advancing on enteral feedings. Today, he
seems a bit more irritable, especially when the nurse is changing his diaper. The baby’s vital signs
are stable. On physical exam the infant is alert but you notice a slight swelling and redness of the
right hip. You are suspicious that this might be osteomyelitis and order a radiograph of the hips. The
right hip radiograph confirms your suspicion, showing soft tissue swelling and periosteal thickening
of the femur just below the head.
Of the following, the statement about osteomyelitis in a neonate that is most likely FALSE is:
A.Osteomyelitis in neonatal long bones often leads to epiphysitis
B.Septic arthritis is a common sequela, particularly in the hip joint
C.The bone marrow compartment is often involved in neonatal osteomyelitis
D.The femur and the tibia are the most frequently affected bones
E.The metaphyseal region of the long bones is most often the primary site
Infectious Diseases & Immunology Answers 61-70
Infectious Diseases & Immunology Answer 61
C. There has been a decrease in the incidence of early-onset GBS disease
Early-onset disease is defined as an infection occurring in an infant within the first 7 days of life.
A late-onset infection occurs after that period until about 3 months of age. In 2010, the CDC
published revised perinatal GBS prevention guidelines to decrease the risk of neonatal infection.
These recommendations are based on studies demonstrating that maternal recto-vaginal GBS
colonization around the time of delivery was a critical factor in neonatal GBS colonization and
subsequent invasive disease. Studies further showed that maternal intrapartum prophylaxis with
antimicrobials directed against GBS significantly decreased the risk of neonatal colonization and
early-onset GBS disease. Specifically, the guidelines recommend universal screening for GBS in all
pregnant women at 35 to 36 weeks’ gestation. For those women with positive GBS, intrapartum
prophylaxis at the time of delivery is recommended.
The impact of these guidelines has resulted in a dramatic fall (1.7 cases per 1,000 live births in the
early 1990s to 0.34–0.37 cases per 1,000 live births after 2004) in early-onset GBS neonatal sepsis.
However, the pathogenesis of late-onset disease is not altered by intrapartum antibiotics; the
incidence of late-onset GBS disease has remained constant at approximately 0.5 cases per 1000 live
births.
Reference:
Centers for Disease Control and Prevention. Prevention of Perinatal Group B Streptococcal Disease
Revised Guidelines from CDC. MMWR. 2010;59(No. RR-10):1-31
Infectious Diseases & Immunology Answer 62
D. Neisseria gonorrhoeae
Ophthalmia neonatorum is defined as neonatal conjunctivitis occurring in the first month of life.
Many organisms have been shown to cause neonatal conjunctivitis. Although gonococci contributes
less than 1% of the total burden, gonococci causes one of the most severe forms of conjunctivitis.
Gonoccocal conjunctivitis is also associated with systemic spread, making its prevention desirable.
Erythromycin 0.5% ophthalmic ointment is the only approved prophylaxis available in the United
States for prevention of gonococcal conjunctivitis. The use of this prophylactic ointment after birth
has been endorsed by the U.S. Preventive Services Task Force since 1996
(http://www.uspreventiveservicestaskforce.org/uspstf10/gonoculproph/gonocup.htm).
Chlamydia is a more frequent causative agent of neonatal conjunctivitis. However, chlamydial
conjunctivitis is associated with less severe eye manifestations. None of the approved
ophthalmologic medications for neonates has been shown conclusively to be effective against
maternal-to-infant transmission of chlamydia, although some reduction in neonatal conjunctivitis has
been reported (AAP, RedBook; Canadian Task Force). Herpes simplex virus is a cause of neonatal
ophthalmitis but it is not susceptible to antibacterial agents. Candida and Neisseria meningitidis are
not common causes of neonatal conjunctivitis.
References:
American Academy of Pediatrics. Red Book: 2012 Report of the Committee on Infectious Diseases.
Pickering LK, ed. 29th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2012
Canadian Task Force on the Periodic Health Examination. Prophylaxis for gonococcal and
chlamydial ophthalmia neonatorum. CMAJ. 1992;147:1449–1454
US Preventive Services Task Force Reaffirmation Recommendations. Ocular prophylaxis for
gonoccocal ophthalmia neonatorum. 2010. Available at:
http://www.uspreventiveservicestaskforce.org/uspstf10/gonoculproph/gonocup.htm
Infectious Diseases & Immunology Answer 63
C. Oral Erythromycin for 14 days
Vaginal Chlamydia trachomatis carriage in pregnant women can be asymptomatic and
transmission to an infant occurs during passage via the birth canal or by an ascending infection.
Mucosal surfaces of the neonate colonized with the bacteria include the conjunctiva, nasopharynx,
and lower respiratory tract. Neonatal conjunctivitis presents in the first 5 to 14 days of life with
mucopurulent discharge and a red eye. Conjunctival infection can be a predecessor of Chlamydia
pneumonia in newborns.
Topical therapy cannot eradicate systemic Chlamydia disease and therefore the recommended
treatment for neonatal conjunctivitis is oral erythromycin for 14 days (not 7 days). Erythromycin use
in the neonatal period has been associated with hypertrophic pyloric stenosis and parents should be
counseled about this before the medication is prescribed.
Intravenous ceftriaxone is the recommended therapy for newborns delivered to women with
untreated gonococcal infection. Oral sulfonamides (i.e., clotrimozaxole) can be used for treatment of
chlamydial conjunctivitis but because of increased toxicity in newborns, they are only recommended
after the neonatal period if erythromycin is not well-tolerated.
Reference:
American Academy of Pediatrics. Red Book: 2012 Report of the Committee on Infectious Diseases.
Pickering LK, ed. 29th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2012
Infectious Diseases & Immunology Answer 64
C. Neisseria gonorrhoeae only
Ophthalmia neonatorum is conjunctivitis in the first month of life with the most concerning
pathogens soon after birth caused by Neisseria gonorrhoeae or chlamydia trachomatis. Other
bacterial microbes and herpes simplex virus can also cause neonatal conjunctivitis. Eye ointment
choices for prophylaxis at birth include 0.5% erythromycin and 1% tetracycline. Silver nitrate is no
longer recommended. This prophylaxis is known to decrease the incidence of gonococcal
conjunctivitis. However, it does not prevent chlamydial conjunctivitis because colonization of the
nasopharynx can still occur.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Remington JS, Klein JO, Wilson CB. Nizet V, Maldonado Y (eds). Infectious Diseases of the Fetus
and Newborn Infant. 7th edition. Philadelphia: WB Saunders Company; 2010
Infectious Diseases & Immunology Answer 65
D. HepBsAg positive, anti-HepBc positive, anti-HepBs negative, IgM anti-HepBc positive

HepBsAg Anti- Anti- IgM anti- Maternal Diagnosis

HepBc HepBs HepBc
negative negative negative n/a Susceptible
negative negative positive n/a Immune as a result of hepatitis B vaccination
negative positive positive n/a Immune as a result of a remote natural
infection, not active
positive positive negative positive Acute infection
positive positive negative negative Chronic infection
negative positive negative n/a ? Resolved infection, susceptible, chronic or
resolving acute
Modified from: A Comprehensive Immunization Strategy to Eliminate Transmission of Hepatitis B Virus Infection in the United
States MMWR. 2005;54 (No. RR-16)
HepBsAg (hepatitis B surface antigen) is the first marker to appear during an acute infection. It is
present 1 to 3 months after exposure and typically before the onset of symptoms. The contribution of
antibodies against HepBcAg (i.e., Anti-HepBcAg) is initially of the IgM type and is specific for an
acute infection. Please see the Table and Graph on the next page for information about the timing of
specific markers and their relation to the disease state.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Remington JS, Klein JO, Wilson CB. Nizet V, Maldonado Y (eds). Infectious Diseases of the Fetus
and Newborn Infant. 7th edition. Philadelphia: WB Saunders Company; 2010
Infectious Diseases & Immunology Answer 66
A. Neonates have a decreased baseline neutrophil proliferation rate but with an infection, the
neonatal bone marrow increases neutrophil production dramatically compared to the adult
Neutrophils have the following functions: chemotaxis, phagocytosis, and bacterial killing.
Compared to adults, neonates have:
•Decreased migration
•Normal bacterial killing if healthy but decreased ability if ill
•A majority of neutrophils in the bone barrow instead of the plasma
•A HIGHER baseline proliferation rate of neutrophils and thus, with infection, the neonatal
bone marrow does not increase production as rapidly as it does in the adult.
References:
Brodsky D, Martin C. Neonatology Review. 2nd Edition. Lulu. 2010
Martin RJ, Fanaroff AA, Walsh MC (eds). Neonatal-Perinatal Medicine: Diseases of the Fetus and
Infant. 8th edition. Philadelphia: Mosby-Elsevier; 2006
Infectious Diseases & Immunology Answer 67
A. Between 5 days before delivery until 2 days after delivery
The Table summarizes the risk of varicella infection in an infant based on the timing of maternal
infection.
Timing of Maternal Risk of Varicella Infection in Infant
Infection
During first 20 weeks’ of High risk (~1-2%) of congenital varicella syndrome
gestation
During 2nd ½ of pregnancy Low risk of congenital varicella syndrome
up to 21 days prior to May develop varicella zoster early in life
delivery
Between 20 days prior to Mild symptoms, little risk of severe disease
delivery to 6 days before
delivery
Between 5 days before Greatest risk since insufficient time for protective antibodies to
delivery until 2 days after cross to fetus (17% chance of acute infection; if untreated, 30%
delivery mortality)
Printed with permission from: Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu.
2010;p 243
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Remington JS, Klein JO, Wilson CB. Nizet V, Maldonado Y (eds). Infectious Diseases of the Fetus
and Newborn Infant. 7th edition. Philadelphia: WB Saunders Company; 2010
Infectious Diseases & Immunology Answer 68
E. Villous damage with thrombosis, villitis with some villi containing inclusion body cells and
hemosiderin
Most placental infections are caused by ascending infections where pathogens ascend from the
vagina through the cervix and cause inflammation of the chorion and amnion, known as
chorioamnionitis. This can progress to involve the amniotic fluid, the surface of the umbilical cord,
and fetal umbilical vessels. Other infections are blood borne and can be acquired by traversing the
placental villous tissue.
The acronym TORCH (Toxoplasma, Other- syphilis, varicella, parvovirus, Rubella,
Cytomegalovirus, Herpes simplex) is commonly used to list the pathogens causing transplacental
infections. A cytomegalovirus infection causes the placenta to have villous damage with thrombosis
and villitis with some villi containing inclusion body cells and hemosiderin deposits.
Syphilis also causes a transplacental infection, however the histology of the placenta shows
hydrops and a marked round cell infiltration caused by maternal immunocytes. The microscopic
appearance of a transplacental infection attributable to Toxoplasma, varicella, parvovirus, and
rubella is more variable.
Reference:
Benirschke K. Abnormalities of the human placenta. NeoReviews. 2005;9:e414-e423
Infectious Diseases & Immunology Answer 69
D. Osteomyelitis is more common in children than neonates
Neonates, especially those who are treated in a NICU, are at higher risk of developing
osteomyelitis than older children. Bacteria typically reach the bone of a neonate by hematogenous
spread. Therefore, infants with central lines or indwelling catheters are at higher risk to develop
osteomyelitis as well as sepsis. Contiguous spread of bacteria to the bone occurs more commonly in
children. New bone formation and bone remodeling after osteomyelitis is more rapid in neonates
than in older children.
The vascular anatomy of the developing bone renders neonates more prone to develop septic
arthritis as a complication of osteomyelitis. During the first month after birth, the metaphysis of the
long bones lies within the joint capsule and capillaries connect the metaphysis with the joint space.
These connecting capillaries provide bacteria easy access to the joint space where they can cause
septic arthritis. In older children, long-bone infection is not associated with septic arthritis.
Bony destruction is less common in neonates with osteomyelitis because the thin periosteal tissues
allow for spontaneous drainage of the bony abscess into the subcutaneous spaces. Furthermore, the
periosteum is loosely attached to the bone, permitting the decompression of pus along the shaft.
References:
Fisher RG. Neonatal osteomyelitis. NeoReviews. 2011;12:e374-e380
Offiah AC. Acute osteomyelitis, septic arthritis and discitis: Differences between neonates and older
children. Eur J Radiol. 2006;60:221-232
Infectious Diseases & Immunology Answer 70
C. The bone marrow compartment is often involved in neonatal osteomyelitis
Due to the unique anatomy of the blood supply in the developing bone, most osteomyelitis
infections start in the metaphysis. The arterioles that are supplying the long bones make a sharp turn
just before reaching the physis where they connect with the veins. Because of this sharp turn, blood
flow slows down, making this location prone to hematogenous seeding of bacteria. From the
metaphysis, bacteria can spread to the epiphysis through transphyseal vessels, which cross the physis.
During development, these vessels are eventually obliterated and in older children, infections usually
do not spread across the growth plate to the epiphysis.
Neonatal osteomyelitis occurs most frequently in the long bones of the lower limb, followed by the
long bones of the upper limb. Osteomyelitis can occur in other bones as well (skull, maxilla, spine,
heel) but less frequently. Because the bone marrow compartment in a neonate is relatively protected
by thin periosteal tissue, early decompression of a metaphyseal abscess is common. However,
because neonates have vascular connections between the metaphysis and the joint space, bacteria can
reach the joint space and lead to septic arthritis. This risk of septic arthritis is also increased because
the metaphysis of most long bones in neonates is intracapsular.
References:
Fisher RG. Neonatal osteomyelitis. NeoReviews. 2011;12:e374-e380
Offiah AC. Acute osteomyelitis, septic arthritis and discitis. Eur J Radiol. 2006;60:221-232
Infectious Diseases & Immunology Questions 71-80
Infectious Diseases & Immunology Question 71
A pregnant woman has a vaginal herpes simplex virus (HSV) lesion at the time of delivery.
Of the following, the type of HSV that is possible in this lesion is:
A. HSV Type 1
B. HSV Type 2
C. Either HSV Type 1 or HSV Type 2
Infectious Diseases & Immunology Question 72
You are evaluating a 1-day old infant born at 38 3/7 weeks’ gestation. The mother is a 21-year old
primigravida woman who had been diagnosed with a primary herpes simplex virus (HSV) infection
at 20 weeks’ gestation. At that time, she received a course of acyclovir. She had a second episode of
genital HSV at 36 weeks’ gestation and received a second course of acyclovir.
At 38 3/7 weeks’ gestation, she presents to the hospital in spontaneous labor. On examination, she
does not have any active lesions or prodromal symptoms of genital HSV infection. She delivers the
infant by vaginal delivery 3 hours after rupture of membranes. Because she was positive for group B
Streptococcus (GBS), she received intrapartum antibiotic prophylaxis.
Of the following, the most accurate statement is:
A.Colonization with GBS facilitates HSV infection of the newborn
B.Neonates whose mothers receive suppressive acyclovir therapy do not develop HSV disease
C.Recurrent infections during pregnancy place the neonate at higher risk of developing HSV
disease
D.The infant in this vignette should have been delivered by Cesarean section (C/S)
E.The use of suppressive acyclovir therapy decreases the need for a C/S in women with a history
of genital herpes
Infectious Diseases & Immunology Question 73
You are evaluating a term infant born by Cesarean section (C/S) to a 22-year old primigravida
woman. Four days prior to delivery, the woman presented with her first genital herpes simplex virus
(HSV) lesion. The lesion was swabbed for HSV polymerase chain reaction (PCR) and culture and
she was prescribed acyclovir. Spontaneous labor started and she delivered a healthy infant by C/S. In
order to make appropriate management recommendations for the infant, you review the mother’s chart
to determine if she had a primary or recurrent infection. You find the following:
•Her genital lesion PCR is positive for HSV-Type 1
• Maternal IgG antibody status is positive for HSV-Type 2 and negative for HSV-Type 1
Of the following, the statement about the woman in this vignette that is most accurate is:
A.Determining the presence of anti-HSV IgG in maternal blood is a relatively new test and the
results are less reliable
B.The mother has a first-episode non-primary infection with HSV Type-1
C.The mother has a first-episode primary infection with HSV Type-1
D.The mother has a first-episode non-primary infection with HSV Type-2
E.The mother has a first-episode primary infection with HSV Type-2
Infectious Diseases & Immunology Question 74
You are taking care of a term infant who was delivered by Cesarean section (C/S) to a mother who
had active genital herpes simplex virus (HSV) lesions at the time of birth and no history of previous
lesions. The infant and mother are both evaluated and the infant is started on intravenous acyclovir.
The test results confirm that this woman had a first episode primary HSV Type-1 infection. The
infant’s cerebrospinal fluid (CSF) results are not indicative of infection (i.e., CSF and blood
polymerase chain reaction are negative for HSV) and the infant has a normal serum alanine
transaminase level. The infant remains clinically well.
Of the following, the most appropriate management of the infant in this vignette is to:
A.Change to oral acyclovir to finish a course of 10 days and discharge the infant with close
follow-up
B.Continue the intravenous acyclovir for 10 days
C.Stop the acyclovir and continue to observe the infant for an additional 48 hours
D.Stop the acyclovir and discharge the infant
E.None of the above
Infectious Diseases & Immunology Question 75
The state you practice in recently started a newborn screening program for severe combined
immunodeficiency (SCID).
What is the most likely molecular basis for the newborn screening test for SCID?
A.Detection by polymerase chain reaction (PCR) of DNA fragments that are excised during T-cell
receptor rearrangement
B.Detection of adenosine deaminase deficiency by mass spectrometry
C.Detection of adenylate kinase deficiency by mass spectrometry
D.Detection by PCR of recombinase activating genes
E.Identification of defects in the IL-2 receptor gamma-common chain
Infectious Diseases & Immunology Question 76
You are taking care of an infant diagnosed prenatally with tetralogy of Fallot. He was born at 39
weeks’ gestation by vaginal delivery. On postnatal evaluation, the infant has no radiographic thymic
shadow and a borderline low serum calcium level. You suspect that this infant might have DiGeorge
syndrome so you consult the Genetics team and send a fluorescent in situ hybridization to detect a
possible 22q11.2 deletion. While you are awaiting the results of the genetic testing, the newborn
screen results come back positive for severe combined immunodeficiency (SCID).
What is the next step to confirm the diagnosis of DiGeorge syndrome in this vignette?
A.Assess lymphocyte subsets by flow cytometry and T-cell function by proliferation assay
B.Send a complete blood cell count to assess the infant’s lymphocyte count
C.Send a repeat serum calcium level
D.Send blood for complement C3 and C4 levels
E.No further tests are needed at this point
Infectious Diseases & Immunology Question 77
You are taking care of a 7-day old infant born at term who was recently diagnosed with complete
DiGeorge (athymia) syndrome. The infant develops lymphadenopathy and an erythematous, diffuse
scaly rash covering his whole body. An oligoclonal T-cell population in the blood was identified and
T-cell receptor excision circles (TRECs) were not measurable.
What is the most appropriate treatment of the infant in this vignette?
A.Systemic antibiotics
B.Systemic antifungal agents
C.Systemic steroids and thymus transplantation
D.Topical treatment with hydrating cream
E.Topical treatment with steroids
Infectious Diseases & Immunology Question 78
 You are speaking with the parents of an infant who was recently diagnosed with DiGeorge
syndrome. You are explaining that most children with this syndrome have an impaired immune
system.
Which of the following statements is FALSE about the immunodeficiency in DiGeorge syndrome?
A.Patients are at high risk for the development of disseminated infections
B.Patients have a depressed T-cell function
C.Patients may present with graft-versus-host disease
D.Patients often have low immunoglobulin levels
E.The lack of T-cells in the periphery is explained by lack of precursor T-cells
Infectious Diseases & Immunology Question 79
A 2-week old neonate is brought to your attention because his umbilical cord is still attached and
the area around the cord is red. The pregnancy had been uncomplicated and the infant was born at
term by spontaneous vaginal delivery. The infant’s parents recently immigrated to the US and are
consanguineous. This is their first child. After obtaining a complete blood cell count (CBC) and a
blood culture in the infant, you start antibiotic therapy. The CBC returns with marked neutrophilia.
What is the most likely pathogenesis of this infant’s disease?
A.B-cell deficiency
B.Combined severe immune deficiency
C.Mutations in the β2 integrin gene leading to neutrophil dysfunction
D.T-cell deficiency
E.None of the above
Infectious Diseases & Immunology Question 80
You are taking care of a male infant born at 28 weeks’ gestation who has been intubated for more
than 2 weeks. Two days ago he developed increased respiratory secretions with need for frequent
suctioning, an increased oxygen requirement, and increased ventilator support. At that time, his
evaluation included a chest radiograph, a complete blood cell count, and a sputum and blood culture.
The radiograph did not show infiltrates. Because of a leukocytosis, he was started on empiric
antibiotics. Today, the blood culture results show gram-negative rods, with a possibility of
Pseudomonas aeruginosa.
Which of the following antibiotics would be a poor choice for treatment of this infant?
A.Cefepime
B.Cefotaxime
C.Gentamicin
D.Meropenem
E.Zosyn
Infectious Diseases & Immunology Answers 71-80
Infectious Diseases & Immunology Answer 71
C. Either HSV Type 1 or HSV Type 2
Genital herpes infections can be caused by both HSV Type 1 and HSV Type 2 and are common in
adults. Therefore, a substantial number of neonates can be exposed to either HSV Type 1 or HSV
Type 2 during birth. The risk of the neonate to acquire HSV infection depends largely on the mother’s
immunity to HSV. If the mother experiences a primary infection, she will be shedding HSV during
delivery and will have not have any circulating antibodies against HSV that could protect the infant.
The risk of transmission in this case is 57%. If the mother had a previous infection but with a different
serotype, the risk of transmitting the current virus decreases to 25%. In case of a recurrent infection
with the same serotype, the risk of transmission is much lower at ~2%. Since the risk of transmission
is so different, it is important to establish which type of infection the current outbreak represents in
order to determine the appropriate management.
References:
Pickering LK, Baker CJ, Kimberlin DW, Long SS, eds. Red Book: 2012 Report of the Committee on
Infectious Diseases. 29th edition, 2012
Infectious Diseases & Immunology Answer 72
E. The use of suppressive acyclovir therapy decreases the need for a C/S in women with a history of
genital herpes
If a primary infection with HSV occurs during pregnancy, women can be treated with acyclovir to
minimize the symptoms and to reduce the duration of the infection. Many women will have recurrent
episodes during the pregnancy. In order to prevent recurrent episodes near the end of the pregnancy,
acyclovir can be administered as suppressive therapy after 36 weeks’ gestation.
It is known that vaginal delivery in a pregnant woman with active genital lesions would expose the
infant to a higher risk of acquiring HSV infection. Therefore, in pregnant women who have active
genital lesions or prodromal symptoms at the time of delivery, a C/S is recommended. Suppressive
acyclovir therapy at the end of pregnancy reduces the risk of active lesions at delivery and thereby
reduces the need for a C/S in women with a history of genital herpes. However, this therapy does not
completely prevent viral shedding and therefore the potential for neonatal infection is not completely
eliminated.
The risk of neonatal transmission is much lower if the pregnant woman has a recurrent infection
(2% vs 57% with primary infection). However, if a pregnant woman with a recurrent HSV infection
has active genital lesions at the time of delivery, a C/S is recommended despite the low risk of
transmission given the severity of HSV disease in the neonate. In women with a history of recurrent
HSV lesions who do not have active lesions or prodromal symptoms at delivery, a C/S is not
recommended.
There is no evidence showing that GBS colonization has any effect on HSV transmission.
References:
ACOG Committee on Practice Bulletins. Clinical management guidelines for obstetrician-
gynecologists. No. 82 June 2007. Management of herpes in pregnancy. Obstet Gynecol.
2007;109:1489-1498
Brown ZA, Wald A, Morrow RA, et al. Effect of serologic status and cesarean delivery on
transmission rates of herpes simplex virus from mother to infant. JAMA. 2003;289:203–209
Kimberlin DW, Baley J. Committee on Infectious Disease and Committee on Fetus and Newborn.
Guidance on management of asymptomatic neonates born to women with active genital herpes
 lesions. Pediatrics. 2013;131:e635-e646
Infectious Diseases & Immunology Answer 73
B. The mother has a first-episode non-primary infection with HSV Type-1
It is important to reliably distinguish primary versus recurrent maternal HSV infection in order to
be able to manage exposed neonates according to their degree of risk. Making this distinction based
on clinical symptoms is unreliable. To aid with the diagnosis, viral and serological testing are
available. Viral studies (culture and PCR) help to detect the presence and serotype of HSV, while
serological tests identify antibodies (IgG) against HSV Type-1 or HSV Type-2. There are several
serological tests that reliably measure HSV Type-1 and HSV Type-2 IgG antibodies in maternal
blood and are FDA approved. The interpretation of these tests is summarized in the Table below.
Type of Maternal Infection Viral Test of Lesion (i.e., PCR or Serological Test
Culture) (i.e., IgG Antibody
Status)
First-episode primary Positive, for HSV-1 or HSV-2 Negative for HSV-1 and
infection HSV-2
First-episode non-primary Positive for HSV-1 Positive for HSV-2
infection AND
Negative for HSV-1
Positive for HSV-2 Positive for HSV-1
AND
Negative for HSV-2
Recurrent infection Positive for HSV-1 Positive for HSV-1
Positive for HSV-2 Positive for HSV-2
Modified from: Kimberlin DW, Baley J, Committee on Infectious Disease and Committee on Fetus and Newborn. Guidance on
management of asymptomatic neonates born to women with active genital herpes lesions. Pediatrics. 2013;131:641
References:
Diamond C, Selke S, Ashley R, et al. Clinical course of patients with serologic evidence of recurrent
genital herpes presenting with signs and symptoms of first episode disease. Sex Transm Dis.
1999;26:221-225
Kimberlin DW, Baley J. Committee on Infectious Disease and Committee on Fetus and Newborn.
Guidance on management of asymptomatic neonates born to women with active genital herpes
lesions. Pediatrics. 2013;131:e635-e646
Infectious Diseases & Immunology Answer 74
B. Continue the intravenous acyclovir for 10 days
The mother in this vignette was diagnosed with a first episode primary infection. In this type of
infection the transmission of HSV is 57%. Given this high risk of transmission, and given normal test
results in the neonate, the infant should be treated empirically with intravenous acyclovir for 10 days
to prevent progression from neonatal infection to disease.
If in this same vignette, the neonatal test results had been indicative of HSV disease, even if the
infant remains asymptomatic, the baby should be treated with intravenous acyclovir for 14 days (skin,
eye mouth disease) or 21 days (central nervous system disease). If the mother has a history of genital
HSV lesion preceding pregnancy, the likelihood of transmission to the infant is low. In this case, skin
and mucosal specimens should be sent for culture as well as blood for HSV polymerase chain
reaction and intravenous acyclovir is not necessary. If these tests are negative, the infant can be
discharged home with follow-up by the pediatric care provider. Parents should also be instructed to
watch for signs of possible HSV infection.
Reference:
Kimberlin DW, Baley J. Committee on Infectious Disease and Committee on fetus and Newborn.
Guidance on management of asymptomatic neonates born to women with active genital herpes
lesions. Pediatrics. 2013;131:e635-e646
Infectious Diseases & Immunology Answer 75
A. Detection by polymerase chain reaction (PCR) of DNA fragments that are excised during T-cell
receptor rearrangement
During T-cell development, T-cell precursor cells migrate from the bone marrow to the thymus,
where the precursor cells receive the appropriate signals to generate a unique T-cell receptor. In
order to generate this unique receptor bits of the germ-line, TCR genes are first excised, distant
segments are then brought together and the breaks are sealed. The intervening DNA between the
rearranged gene segments is looped out and joined together to form a circle, the T-cell receptor
excision circle (TREC). The process of gene segment recombinations results in an immense number
of unique T-cell receptors, making the T-cells capable of fighting the myriad pathogens the body
might encounter.
State newborn screening programs screen for SCID by measuring T-cell receptor excision circles
(TRECs), the fragments of DNA excised during T-cell receptor rearrangement. TRECs are present at
high levels in the blood of infants with normal T-cell development and can be detected by PCR.
Infants with SCID have a defective T-cell development and lack TRECs.
Reference:
Randolph DA, Routes JM, Verbsky JW. Newborn screening for severe combined immunodeficiency.
NeoReviews. 2013;14:e448-e455
Infectious Diseases & Immunology Answer 76
A. Assess lymphocyte subsets by flow cytometry and T-cell function by proliferation assay
Patients with DiGeorge syndrome can be diagnosed with an abnormal newborn screen for SCID.
The newborn screening program screens for SCID by measuring T-cell receptor excision circles
(TRECs), which are fragments of DNA excised during T-cell receptor rearrangement in the thymus.
Since patients with DiGeorge syndrome have an absent or hypoplastic thymus, the precursor T-cells
cannot undergo their maturation process in the thymus, during which the T-cell receptor is rearranged
and TRECs are formed.
Patients with DiGeorge syndrome might present with profoundly decreased T-cell numbers,
therefore lymphocyte subpopulations must be assessed by flow cytometry. Affected patients also can
have depressed T-cell function that can be measured with an in vitro stimulation assay; in this assay,
the patient’s T-cells are exposed to a mitogen and their proliferation is quantified.
Sending a complete blood cell count in the infant in this vignette would not provide information
about the different lymphocyte subsets. The complement system is not affected in DiGeorge
syndrome.
Not all patients with DiGeorge syndrome have hypocalcemia so a repeat serum calcium level
would not be helpful to confirm the diagnosis.
References:
Bobey-Wright NAM, Tcheurekdjian H, Wara D, Lewis DB. Immunologic aspects of DiGeorge
syndrome. NeoReviews. 2005; 6:e471-e478
Randolph DA, Routes JM, Verbsky JW. Newborn screening for severe combined immunodeficiency.
NeoReviews. 2013;14:e448-e455
Infectious Diseases & Immunology Answer 77
C. Systemic steroids and thymus transplantation
DiGeorge syndrome is a congenital syndrome characterized by congenital heart disease,
parathyroid aplasia leading to hypocalcaemia, thymic hypoplasia or aplasia, and facial dysmorphic
features. Infants with DiGeorge syndrome who do not have a thymus. and thus lack T cells. are
categorized as patients with complete DiGeorge syndrome. Infants with DiGeorge syndrome who
have a hypoplastic thymus and a low number of naïve T-cells that exhibit a fairly normal proliferative
function, are categorized as patients with partial DiGeorge syndrome.
The vast majority of patients with DiGeorge syndrome have partial DiGeorge syndrome. Within
the small group of patient with complete DiGeorge syndrome, some patients can develop an
eczematous rash associated with lymphadenopathy. These symptoms are caused by an oligoclonal
expansion of peripheral T-cells. This triad of findings (rash, lymphadenopathy and oligoclonal T-
cells) defines atypical complete DiGeorge syndrome.
It is important to distinguish atypical complete DiGeorge syndrome from partial DiGeorge
syndrome because the treatment of these two groups of patients is very different. Patients with
atypical complete DiGeorge syndrome need immuno-reconstitution with thymus transplantation.
While waiting for transplantation, they might require systemic corticosteroid therapy to suppress the
oligoclonal T-cells. In contrast, patients with partial DiGeorge syndrome usually have increasing T-
cell numbers over time and no intervention is necessary.
Although severe skin infections such as Staphylococcal scalded skin syndrome, candidiasis or
other fungal infections could present with a rash similar to the one described in this vignette, they
would not be associated with the presence of oligoclonal T-cells in the blood. Inflammatory skin
diseases such as psoriasis and atopic or seborrheic dermatitis could present with a similar rash,
however in a patient with Digeorge syndrome and the presence of oligoclonal T cells, this is less
likely.
References:
Bedocs LA, O’Regan GM, Bruckner A. Red, scaly babies: neonatal erythroderma. NeoReviews.
2011;12: e325-e334
Selim MA, Markert ML, Burchette JL, et al. The cutaneous manifestations of atypical complete
DiGeorge syndrome: a histopathologic and immunohistochemical study. J Cutan Pathol.
2008;35:380-385
Infectious Diseases & Immunology Answer 78
E. The lack of T-cells in the periphery is explained by lack of precursor T-cells
Patients with DiGeorge syndrome have absent or hyoplastic thymuses. Therefore, the precursor T-
cells formed in the bone marrow cannot undergo their maturation process in the thymus. So, the
immunodeficiency observed in patients with DiGeorge syndrome is explained by the deficiency of
non-hematopoietic cells rather than hematopoietic cells.
The spectrum of immune deficiency is broad, ranging from nearly normal to life-threatening
conditions. The immunodeficiency is mainly as a result of a reduced number of mature T-cells.
However, affected patients also have decreased T-cell proliferation after in vitro stimulation.
Since production of antibodies by B cells is dependent on CD4 T cell signals, affected patients
might have low immunoglobulin levels. Given their lack of cell-mediated immunity, patients with
DiGeorge syndrome are at risk for developing severe infections with Pneumocystis jiroveci,
cytomegalovirus and adenovirus. Some patients also can develop graft-versus-host disease as a result
of placental transfer and engraftment of maternal T-cells. These maternal T-cells can cause
inflammation leading to the typical rash and diarrhea seen in other forms of graft-versus-host disease.
Reference:
Bobey-Wright NAM, Tcheurekdjian H, Wara D, Lewis DB. Immunologic aspects of DiGeorge
syndrome. NeoReviews. 2005;6:e471-e478
Infectious Diseases & Immunology Answer 79
C. Mutations in the β2 integrin gene leading to neutrophil dysfunction
Leukocyte adhesion deficiency type 1 (LAD-1) is a rare autosomal recessive immunodeficiency
that is characterized by an adhesion defect of neutrophils. The disease is caused by mutations in the
β2 integrin gene (ITGB2) that results in absent or reduced expression of β2 integrins on leukocytes
(neutrophils, monocytes and other myeloid cells). β2 integrins are adhesion molecules that are
essential for normal endothelium-leukocyte interactions. In their absence, neutrophils are unable to
adhere to the endothelium and migrate to extravascular sites of infection or injury. Because the
neutrophils are unable to leave the circulation, patients often have neutrophilia during an infection.
Another characteristic of these patients is the absence of pus during an infection.
A delay in the natural detachment of the umbilical cord is often the first symptom of the LAD-1
because granulocyte influx and phagocytosis are involved in the resorption of the umbilical cord.
Infections in patients with LAD-1 require intensive antibiotic therapy. Despite careful management,
mortality is high and for several patients, hematopoietic stem cell transplantation is the treatment of
choice.
References:
Anderson JM, Philip AGS. Management of the umbilical cord: care regimens, colonization, infection,
and separation. NeoReviews. 2004;5:e155-e163
Parvaneh N, Mamishi S, Rezaei A, et al. Characterization of 11 new cases of leukocyte adhesion
deficiency type 1 with seven novel mutations in the ITGB2 gene. J Clin Immunol. 2010;30:756-
760
Infectious Diseases & Immunology Answer 80
B. Cefotaxime
Cefotaxime is a third-generation cephalosporin that is frequently used to treat respiratory
infections. It is active against most gram-negative bacteria. However, Pseudomonas aeruginosa is
resistant to Cefotaxime. Pseudomonas aeruginosa is naturally resistant to a large number of
antibiotics, and also can developed acquired resistance against antibiotics. Therefore, treatment
should be based on sensitivity results. Antibiotics that are effective against P. aeruginosa include:
Gentamicin, Zosyn, Cefepime and Meropenem.
References:
Gilbert DN, Moellering RC, Eliopoulos GM (eds). The Sanford guide to Antimicrobial Therapy. 43rd
edition. Sperryville, VA: Antimicrobial, Inc; 2013.
NeoFax Online. Available from Micromedex. Accessed on November 12, 2013. Available at
www.neofax.org
Infectious Diseases & Immunology Questions 81-90
Infectious Diseases & Immunology Question 81
You are caring for an infant with heterotaxy-asplenia. As a precaution, you initiate antibiotic
prophylaxis to prevent infection by encapsulated organisms.
Which of the following is NOT an encapsulated organism?
A.Haemophilus influenza
B.Neisseria meningitides
C.Pseudomonas aeruginosa
D.Salmonella typhi
E.Streptococcus pneumoniae
Infectious Diseases & Immunology Question 82
The spleen plays many important physiologic roles.
Of the following, the function that is NOT associated with the spleen is:
A.Assisting the functional maturation of antibodies
B.Helping the body excrete excess iron
C.Producing immunoglobulin (IgM) and complement
D.Removing abnormal red blood cells and platelets from the circulation
E.Supporting the proliferation of T-cells
Infectious Diseases & Immunology Question 83
Each of the following disorders can be associated with congenital asplenia EXCEPT:
A.Ivemark syndrome
B.Pearson syndrome
C.Sickle cell disease
D.Smith-Meyers-Fineman syndrome
E.Stormorken syndrome
Infectious Diseases & Immunology Question 84
You are concerned that an infant in the Neonatal Intensive Care Unit has an absent or non-
functioning spleen.
The finding on a peripheral blood smear MOST specific for splenic dysfunction is:
A.Heinz bodies
B.Howell-Jolly bodies
C.Pappenheimer bodies
D.Reticulocytes
E.Thrombocytosis
Infectious Diseases & Immunology Question 85
Infants and children lacking functioning spleens are at increased risk for infections.
Which of the following statements about immunizing children with asplenia is TRUE?
A.Asplenic children cannot receive any live virus immunizations
B.Asplenic infants should wait at least 6 months prior to receiving any vaccinations
C.Children should receive the 13-valent Pneumococcal vaccine as well as the 23-valent vaccine
after age 2
D.Children with asplenia are not at increased risk for viral infections and therefore should not
receive influenza vaccination
E.The meningococcal vaccine is only recommended for special subpopulations of children with
 asplenia, such as those living in shelters or dormitories
Infectious Diseases & Immunology Question 86
A growth-restricted infant is born by spontaneous vaginal delivery at 34 weeks’ gestation.
Following delivery, the infant is noted to have microcephaly, petechiae and hepatosplenomegaly. A
salivary sample confirms the presence of congenital cytomegalovirus (CMV) infection. Subsequent
audiology screening demonstrates unilateral sensorineural hearing loss.
What is the most appropriate treatment for this infant?
A.CMV-specific hyper-immunoglobulin
B.Six month course of Ganciclovir
C.Six month course of Valganciclovir
D.Six week course of Ganciclovir
E.Six week course of Valganciclovir
Infectious Diseases & Immunology Question 87
An ELBW infant, born at 24 weeks’ gestation and weighing 560 gm, is now 8 days old. The infant
remains on a mechanical ventilator, requires parenteral nutrition via an umbilical venous catheter
(UVC), and has not yet received any enteral nutrition. The infant develops hyperglycemia, becomes
more lethargic and has more frequent episodes of intermittent desaturations in oxygenation while on
the ventilator. A sepsis evaluation confirms the presence of a Central Line Associated Blood Stream
Infection (CLABSI).
What is the greatest single risk factor for a CLABSI in the infant in this vignette?
A.Birth weight
B.Delay in enteral feeding
C.Duration of UVC use
D.Duration of parenteral nutrition use
E.Post-natal age
Infectious Diseases & Immunology Question 88
Rotavirus vaccine is recommended for all infants. However, it is not routinely administered to
preterm neonates while they are in the NICU because of concern about the possibility of:
A.Feeding intolerance
B. Increased apnea
C. Intussusception
D.Irritability
E. Viral shedding
Infectious Diseases & Immunology Question 89
A multiparous woman presents at 38 1/7 weeks’ gestation in spontaneous labor. Her pregnancy
had been uneventful except for a recent recto-vaginal swab, which grew Group B Streptococcus.
Upon admission to the hospital, she receives Penicillin. She has a precipitous vaginal delivery 2
hours after initiation of antibiotic prophylaxis. She does not have any fever and the total duration of
membrane rupture is 9 hours. The infant emerges vigorous, and in no apparent distress.
Per CDC recommendations the most appropriate course of action for the infant in this vignette is:
A.Limited sepsis evaluation consisting of both blood culture and complete blood count with
differential. Antibiotics will need to be started with length of treatment dependent on culture
results. The infant can be discharged home if cultures are negative at 48 hours.
B.Limited sepsis evaluation consisting of both blood culture and complete blood count with
differential. Antibiotics will not need to be started. The infant can be discharged home if
 cultures are negative at 48 hours.
C.No sepsis evaluation required. Infant can go to the mother’s hospital room and can be
discharged home after 24 hours if remains well.
D.No sepsis evaluation required. Infant can go to the mother’s hospital room and can be
discharged home after 48 hours if remains well.
E.Sepsis evaluation consisting of blood culture, lumbar puncture and complete blood count.
Antibiotics will need to be started with length of treatment dependent on culture results. The
infant can be discharged home c if cultures are negative at 48 hours.
Infectious Diseases & Immunology Question 90
Early-onset sepsis (EOS) in newborns is defined by the CDC as blood or cerebrospinal fluid
culture-proven infection occurring within the first 7 postnatal days; though, it also has been defined as
before the third postnatal day in the epidemiology literature. Multiple potential pathogens are
associated with EOS.
Based on NICHD data, which of the following options lists the correct order of frequency for
pathogens causing EOS in neonates (starting with most frequent and going sequentially to least
frequent)?
A.Escherichia Coli, Group B Streptococcus, Enteroccocus, Listeria, Staphylococcus Aureus
B.Group B Streptococcus, Enteroccocus, Escherichia Coli, Staphylococcus Aureus
C.Group B Streptococcus, Escherichia Coli, Enteroccocus, Staphylococcus Aureus, Listeria
D.Group B Streptococcus, Escherichia Coli, Listeria, Staphylococcus Aureus
E.Group B Streptococcus, Staphylococcus Aureus, Escherichia Coli, Listeria
Infectious Diseases & Immunology Answers 81-90
Infectious Diseases & Immunology Answer 81
C. Pseudomonas aeruginosa
Certain bacteria are covered in a polysaccharide capsule, which helps them evade cell-mediated
immune response. Capsulated bacteria include the following:
•Haemophilus influenza
•Neisseria meningitides
•Salmonella typhi
•Streptococcus pneumoniae
Reference:
Styrt B. Infection associated with asplenia: Risks, mechanisms, and prevention. Am J Med.
1990;88:33N-42N
Infectious Diseases & Immunology Answer 82
B. Helping the body excrete excess iron
The spleen has many functions in the human body. It serves as a site of IgM and complement
production, assisting in the maturation of antibodies, and supporting the proliferation of T-cells. The
spleen also scavenges damaged or senescent red blood cells and platelets from the circulation and
serves as a reservoir of extra blood. In this process, the spleen recycles iron from hemoglobin for
use in hematopoeisis.
Reference:
Behrman RE, Kliegman RM, Jenson HB (eds). The hematopoietic system. In: Nelson’s Textbook of
Pediatrics. 17th edition. Philadelphia: Saunders, 2004
Infectious Diseases & Immunology Answer 83
C. Sickle cell disease
Ivemark syndrome is a rare, autosomal recessive disorder with features consisting of asplenia and
either dextrocardia or a right-sided aortic arch. It is also known as asplenia syndrome, heterotaxy
syndrome, cardiosplenic syndrome, right atrial isomerism, or bilateral right-sidedness. Pearson
syndrome is a bone marrow failure syndrome that causes sideroblastic anemia, thrombocytopenia,
and, in some cases, asplenia. Stormorken syndrome is also a rare disease that consists of asplenia
and thrombocytopenia, among other features. Smith-Meyers-Fineman syndrome is an X-linked
recessive disorder and involves asplenia, cryptorchidism, and severe intellectual impairment. Sickle
cell disease is a hemoglobinopathy that causes red blood cells to sickle under certain conditions.
Over time, the spleen autoinfarcts, making patients with sickle cell disease functionally asplenic.
References:
Adès LC, Kerr B, Turner G, Wise G. Smith-Fineman-Myers syndrome in two brothers. Am J Med
Genet. 1991;40:467-470
Behrman RE, Kliegman RM, Jenson HB (eds). The hematopoietic system. In: Nelson’s Textbook of
Pediatrics. 17th edition. Philadelphia: Saunders, 2004.
Chen H. Ivemark syndrome. Atlas of Genetic Diagnosis and Counseling. 2006, pp 549-552
Sjaastad O. The hereditary syndrome of thrombocytopathia, bleeding tendency, extreme miosis,
muscular fatigue, asplenia, headache, etc. (“Stormorken’s syndrome”): I. The headache. Headache.
1994;34:221-225
Infectious Diseases & Immunology Answer 84
B. Howell-Jolly bodies
Howell-Jolly bodies are small, round nuclear remnants that can be seen in red blood cells in
patients with non-functioning spleens. They can also be a normal finding in newborns up to 7 days of
life. Heinz bodies are denatured hemoglobin and Pappenheimer bodies are granules of iron. They
can both be seen in peripheral blood smears of patients with asplenia, though they are not specific to
this condition. Reticulocytosis and thrombocytosis may also be seen in the setting of asplenia, though
this is also non-specific.
Reference:
Behrman RE, Kliegman RM, Jenson HB (eds). The hematopoietic system. In: Nelson‘s Textbook of
Pediatrics. 17th edition. Philadelphia: Saunders, 2004
Infectious Diseases & Immunology Answer 85
C. Children should receive the 13-valent Pneumococcal vaccine as well as the 23-valent vaccine
after age 2
Children with no or non-functioning spleens should receive the typical schedule of childhood
vaccinations. Because they are at increased risk of infection form encapsulated bacteria, they should
also receive the 23-valent Pneumococcal vaccine after age 2. They should also receive the
meningococcal vaccine. All children older than 6 months of age with absent or poorly functioning
spleens should receive the influenza vaccine.
References:
CDC. MMWR. Use of 13-Valent Pneumococcal Conjugate Vaccine and 23-Valent Pneumococcal
Polysaccharide Vaccine for Adults with Immunocompromising Conditions: Recommendations of
the Advisory Committee on Immunization Practices (ACIP). October 12, 2012 / 61(40);816-819
Committee on Infectious Diseases. Policy Statement: Recommended Childhood and Adolescent
Immunization Schedule—United States, 2013. Pediatrics. 2013;131:397-398
Infectious Diseases & Immunology Answer 86
C. Six month course of Valganciclovir
A clinical trial by the Collaborative Antiviral Study Group found improved hearing outcomes in
infants with congenital CMV who received 6 weeks of intravenous Ganciclcovir compared to
placebo. Subsequent pharmacokinetic studies have demonstrated similar plasma levels of the active
drug if neonates are treated with either intravenous Ganciclovir or oral Valganciclovir (a prodrug of
Ganciclovir). The side effect profile was similar between the two drugs, with neutropenia being the
most common complication. More recent evidence found an improvement in both hearing and
developmental outcome among infants who were treated with a 6 month course of Valganciclovir,
compared to those treated for 6 weeks.
References:
Bialas KM, Swamy GK, Permar, SR. Perinatal cytomegalovirus infections: Epidemiology, prevention
and treatment. NeoReviews. 2015;16: e231-e235
Stehel EK, Sanchez PJ. Cytomegalovirus infection in the fetus and neonate. NeoReviews. 2005; 6:
e38 -e45
Infectious Diseases & Immunology Answer 87
A. Birth weight
Central Line Associated Blood Stream Infections (CLABSIs) account for approximately 70% of
hospital acquired infections in NICUs. The rate of CLABSIs in the US as of 2012 was 2.3 per 1000
line days for infants less than 750 gm. The greatest risk factor for a CLABSI is an infant’s gestational
age and birth weight. Other risk factors include, postnatal age, duration of hospital stay, duration of
central venous catheter placement, duration of parenteral nutrition, delay in initiation of enteral feeds,
and use of mechanical ventilation.
 To minimize the rate of CLABSIs, a bundled approach to prevention is taken. The specifics of care
bundles are unit-specific, but generally focus on hand hygiene techniques, optimization of central
catheter insertion, use and removal of central catheters, and infection surveillance.
Reference:
Garber SJ, Puopolo KM. Prevention of central line-associated bloodstream infections among infants
in the Neonatal Intensive Care Unit. NeoReviews. 2015;16: e211-220
Infectious Diseases & Immunology Answer 88
E. Viral Shedding
Administration of the rotavirus vaccine is recommended in stable preterm infants from 42 to 104
days of life. Currently there are 2 available rotavirus vaccines in the US: a pentavalent, reassortant
vaccine which requires 3 doses, and a monovalent vaccine which requires 2 doses. Both are live
vaccines, and viral shedding in the stool has been demonstrated for 15 days following administration
of the pentavalent vaccine, and 60 days following the monovalent vaccine. This has led to concern of
the possibility of vaccine-mediated transmission, and therefore the vaccine is typically administered
to hospitalized infants at or following discharge. However, a recent study found no increase in
adverse effects of rotavirus when administered to infants during their NICU stay.
The original tetravalent rotavirus vaccine was associated with increased risk of intussusception,
however neither the pentavalent or monovalent vaccines have shown an increased risk. Similarly no
increased risk for vomiting, diarrhea, irritability or apnea has been demonstrated with the vaccine.
Reference:
Shah SI. Immunization issues in preterm infants: Pertussis, Influenza, and Rotavirus. NeoReviews.
2014; 15: e439-448
Infectious Diseases & Immunology Answer 89
D. No sepsis evaluation required. Infant can go to the mother’s hospital room and can be discharged
home after 48 hours if remains well.
The 2010 CDC recommendations state that for intrapartum antibiotic prophylaxis (IAP) to be
considered adequate, treatment must consist of either Penicillin, Ampicillin or Cefazolin, and must be
initiated 4 hours prior to delivery. The mother of this infant received IAP for 2 hours prior to
delivery, and therefore received inadequate prophylaxis. However, in a change from previous
statements, the 2010 recommendations states that if an infant is greater than 37 weeks’ gestation, and
the membranes have been ruptured for less than 18 hours, even if the pregnant woman did not receive
adequate IAP, the infant does not need a laboratory evaluation or antibiotic coverage if clinically
well. However, the infant needs to be monitored for 48 hours prior to discharge to ensure they remain
clinically well. If an infant is either less than 37 weeks’ gestation, or if the membranes have been
ruptured for greater than 18 hours, then the infant should receive a limited evaluation and be
monitored for 48 hours.
Reference:
Prevention of Perinatal GBS Disease. http://www.cdc.gov/mmwr/pdf/rr/rr5910.pdf Accessed August
2015
Infectious Diseases & Immunology Answer 90
C. Group B Streptococcus, Escherichia Coli, Enteroccocus, Staphylococcus Aureus, Listeria
Group B Streptococcus (GBS) is the most common pathogen causing early-onset sepsis (EOS),
accounting for approximately 40% of cases. This is true despite a decline in the absolute national
incidence of GBS following the widespread implementation of intrapartum antibiotic prophylaxis
(1.8/1000 live births in 1990, to 0.24/1000 live births in 2013). E coli is the second most common
causal pathogen, accounting for 28% of all cases of EOS. Of note it is the leading cause of EOS
among preterm infants (accounting for 38%). The third most common pathogens to cause EOS are
Streptococcus species other than Group B Streptococcus. This category accounts for approximately
10% of EOS, and includes such organisms as S pneumoniae, S bovis, S mitis, and Group D
Streptococcus, to name a few. Staph aureus and Enteroccous species account for approximately 2%
to 3% of cases, respectively per NICHD figures, while Listeria accounts for less than 1% of cases of
EOS (0.5%).
Reference:
Stoll BJ, Hansen NI, Sánchez PJ, et al. Early onset neonatal sepsis: the burden of group B
Streptococcal and E. coli disease continues. Pediatrics. 2011;127:817-826
Infectious Diseases & Immunology Questions 91-100
Infectious Diseases & Immunology Question 91
In an effort to ensure the appropriate management of newborns at risk for early-onset sepsis
(EOS), you volunteer to develop practice guidelines to determine the need for a limited sepsis
evaluation (Blood culture and CBC with differential) and/or antibiotic coverage following delivery,
in infants over 35 weeks’ gestation.
Based on your review of the literature, which of the following statements regarding risk factors for
EOS is FALSE?
A.Group B Streptococcus (GBS) EOS in term infants most frequently occurs in infants whose
mothers had a negative GBS recto-vaginal screening swab.
B.Greater than 60% of cases of EOS will develop clinical symptoms in the first 24 to 48 hours of
life.
C.Maternal fever is associated with increased risk of EOS.
D.There is no reduction in risk of EOS if intrapartum antibiotic prophylaxis is given less than 4
hours prior to delivery.
E.The duration of membrane rupture correlates directly with increased risk of EOS.
Infectious Diseases & Immunology Question 92
A 7-day old female infant born at 37 weeks’ gestation is expected to be discharged from the
hospital. However, during the night prior to discharge, the baby develops a temperature of 100.6oF.
Her remaining vital signs are stable. On examination, the infant appears somewhat irritable. You
evaluate for sepsis, including viral studies for a possible herpes simplex virus (HSV) infection.
Which of the following statements about HSV is FALSE?
A.Blood HSV PCR is necessary to establish the diagnosis of disseminated disease.
B.Histological examination of skin lesions to assess for multinucleated giant cells and
eosinophilic intranuclear inclusions has low sensitivity.
C.Isolation of HSV by viral culture is the definitive laboratory method to establish active HSV
infection.
D.Presence of blood in the CSF may interfere with the CSF HSV PCR results.
E.Positive HSV surface cultures obtained at 12 to 24 hours of age is suggestive of infection rather
than contamination.
Infectious Diseases & Immunology Question 93
A term infant is born to a 22-year old woman following an uncomplicated pregnancy. After some
initial difficulty with breastfeeding, the infant does well in the nursery and is discharged home.
During follow-up at the pediatrician’s office, the newborn screening test results are reviewed, which
raises concern for toxoplasmosis. After the diagnosis is confirmed by PCR, the infant is treated with
pyrimethamine and sulfadiazine with folinic acid.
What long-term sequela is most common with asymptomatic infants with untreated congenital
toxoplasmosis?
A.Chorioretinitis
B.Deafness
C.Intellectual disability
D.Seizures
E. Spasticity
Infectious Diseases & Immunology Question 94
Neonatal pneumonias occur at an incidence of approximately 1% in term neonates, and frequently
present with non-specific findings. For this reason, clinicians typically have a high index of suspicion
of pneumonia among newborns with any signs of respiratory distress.
Which of the following statements about neonatal pneumonias is TRUE?
A.A congenital pneumonia is classified as any pneumonia presenting within the first 3 days of life.
B.Chlamydia trachomatis acquired during labor will typically cause late-onset pneumonia between
2 to 4 weeks of age.
C.Congenital pneumonia is only acquired during labor by aspiration of bacteria colonizing the
birth canal.
D.Cytomegalovirus is the major cause of early viral pneumonias.
E.Following the introduction of intrapartum prophylaxis for Group B Strep, E. coli is now the
most common cause of congenital pneumonia.
Infectious Diseases & Immunology Question 95
A term infant is just born via spontaneous vaginal delivery to a woman with a positive Venereal
Disease Research Laboratory test (VDRL). The infant is breathing comfortably in RA, has peeling
skin and a palpable liver 2 cm below the costal margin. The infant is admitted to the NICU and a
work-up is started.
Of the following, the most appropriate management of the infant in this vignette is:
A.Observation only
B.Evaluation with a complete blood count (CBC) and a blood culture
C.Evaluation with a CBC, liver function tests (LFTs), and VDRL
D.Evaluation with a CBC, LFTs, VDRL, and cerebrospinal fluid testing
Infectious Diseases & Immunology Question 96
During the delivery of an infant born at 32 weeks’ gestation, the neonatologist notices white spots
on the umbilical cord. The infant has severe respiratory distress and requires resuscitation with
intubation and positive-pressure ventilation. On further examination, the nurse observes a generalized
maculopapular rash on the infant’s skin.
Of the following, the management approach that is NOT indicated in this infant is:
A.Apply an antibacterial cream to the infant’s skin
B.Send the placenta for pathology
C.Send the tracheal aspirate for potassium hydroxide staining
D.Start treatment with antibiotics
E.Start treatment with fluconazole
Infectious Diseases & Immunology Question 97
With increased survival of very low birth weight infants and the use of wide-spectrum
antibacterial agents, systemic fungal infections are becoming more common in the newborn period.
Which of the following clinical features is LEAST likely to be found in a newborn with a
systemic fungal infection?
A.A high incidence of renal involvement
B.A low incidence of central nervous system involvement
C.Apnea, poor temperature control, and glucose intolerance
D.Endophthalmitis with white fluffy retinal deposits
E.Lethargy and feeding intolerance
Infectious Diseases & Immunology Question 98
The United Nations Millennium Development Goal 6 is attempting to halt the spread of HIV. One
of the primary ways to achieve this is to prevent the Mother to Child Transmission (MTCT) of HIV,
which can occur in utero, intrapartum or through breastfeeding.
Which of the following statements about the incidence and rates of transmission of HIV is
FALSE?
A.Children born to Hispanic mothers have the highest rates of perinatal MTCT of HIV in the US.
B.If a HIV-positive woman breastfeeds for over a year, the rate of MTCT of HIV approximately
doubles.
C.In the absence of preventive measures, the rate of perinatal MTCT of HIV would be up to 30%
in the US.
D.The current incidence of perinatally acquired HIV infection in the US is approximately 2 per
100,000 live births.
E.With the introduction of preventive measures (antiretroviral therapy, Cesarean section and
avoidance of breast feeding), the rate of MTCT of HIV in the US is less than 2%.
Infectious Diseases & Immunology Question 99
The use of maternal, antenatal, and neonatal prophylactic antiretroviral therapies has significantly
reduced the rates of perinatal HIV infection.
Which of the following statements about postnatal antiretroviral regimens is FALSE?
A.An infant born at 36 weeks’ gestation whose HIV-positive mother was treated with appropriate
antenatal antiretroviral therapy and had consistently low viral loads can receive 4 weeks of
Zidovudine alone.
B.An infant born at 36 weeks’ gestation whose HIV-positive mother was treated with appropriate
antenatal antiretroviral therapy will routinely receive 6 weeks of Zidovudine alone.
C.An infant born to a HIV-positive mother who received intrapartum antiretroviral therapy, but no
antenatal antiretroviral therapy, should receive 6 weeks of Zidovudine plus 3 doses of
Nevirapine.
D.The dose of Zidovudine is increased for preterm infants due to increased hepatic clearance.
E.Zidovudine and Nevirapine are the only antiretrovirals with dosing recommendations in preterm
infants.
Infectious Diseases & Immunology Question 100
An infant is born to a woman whose prenatal records are not available. At 6-hours of age, the
infant develops tachypnea and respiratory distress. A chest radiograph shows diffuse parenchymal
infiltrates. There is also a pleural effusion seen on the right costophrenic angle. Other than respiratory
distress, the infant is otherwise well appearing.
The most likely organism to cause this clinical picture is:
A. Chlamydia trachomatis
B. Cytomegalovirus
C. Group B Streptococcus
D. Herpes simplex
E. Listeria monocytogenes
Infectious Diseases & Immunology Answers 91-100
Infectious Diseases & Immunology Answer 91
D. There is no reduction in risk of EOS if intrapartum antibiotic prophylaxis is given less than 4 hours
prior to delivery.
The 2010 CDC recommendations state that for intrapartum antibiotic prophylaxis (IAP) to be
considered adequate, treatment must consist of either Penicillin, Ampicillin or Cefazolin, and must be
initiated 4 hours prior to delivery. However, evidence suggests that even IAP given <4 hours prior to
delivery does confer some protection (Odds Ratio for sepsis with GBS IAP given on-time or any
antibiotic given <4 hours is 0.35 (95% CI: 0.23-0.53).
Recognized risk factors for early-onset sepsis (EOS) include;
•Clinical condition of the newborn (60% to 90% of infants with EOS demonstrate clinical
symptoms within 24 to 48 hours after delivery)
•Duration of rupture of membranes
•Gestational age (increased risk associated with prematurity)
•Group B Streptococcus (GBS) positive recto-vaginal swab or bacteriuria (Of note, most
cases of GBS EOS among term infants now occur in infants whose mothers had a negative
screen)
•Intrapartum fever or chorioamnionitis
Reference:
Mukhopadhyay S, Puopolo KM. Neonatal early-onset sepsis: Epidemiology and risk assessment.
NeoReviews. 2015; 16: e221-230
Infectious Diseases & Immunology Answer 92
A. Blood HSV PCR is necessary to establish the diagnosis of disseminated disease.
The majority of neonatal herpes simplex virus (HSV) infections are acquired perinatally and
symptoms present usually within the first 2 weeks of life. The infection can be classified into three
groups: localized skin, eye, mouth (SEM) disease, central nervous system (CNS) disease with or
without SEM disease, and disseminated disease. In disseminated disease, there is systemic organ
involvement (e.g., hepatitis, pneumonitis) as well as SEM (~80%) or CNS (~60% to 75%) disease.
An infant with HSV hepatitis may have elevated liver transaminases and/or direct
hyperbilirubinemia. If there is a suspicion of neonatal HSV disease in an infant, sending an HSV
serum PCR could increase the chance of confirming the diagnosis, however a positive HSV PCR is
not necessary to make the diagnosis of disseminated disease. The diagnosis is established by
diagnostic or clinical signs of other organ involvement. Positive HSV surface cultures obtained at 12
to 24 hours of age is suggestive of infection rather than contamination. Histological examination of
skin lesions to assess for multinucleated giant cells and eosinophilic intranuclear inclusions (via
Tzanck smear) has low sensitivity.
References:
Kimberlin DW. Neonatal herpes simplex infection. Clin Microbiol Rev. 2004; 17:1-13
Knezevic A, Martic J, Stanojevic M, et al. Disseminated neonatal herpes caused by herpes simplex
virus types 1 and 2. Emerg Infect Dis. 2007;13:302-304
Infectious Diseases & Immunology Answer 93
A. Chorioretinitis
Chorioretinitis is the most common complicated of subclinical congenital toxoplasmosis that is
untreated. This inflammation of the retina can lead to scaring and visual deficits. While intellectual
disability, seizures, spasticity and deafness are common in patients with symptomatic congenital
toxoplasmosis, they are uncommon among asymptomatic individuals.
References:
Koppe JG, Loewer-Sieger DH, de Roever-Bonnet H. Results of 20-year follow-up of congenital
toxoplasmosis. Lancet. 1986;1:254
Mets MB, Holfels E, Boyer KM, et al. Eye manifestations of congenital toxoplasmosis. Am J
Ophthal. 1997;123:1-16
Wilson CB, Remington JS, Stagno S, et al. Development of adverse sequelae in children born with
subclinical congenital Toxoplasma infection. Pediatrics. 1980;66:767
Infectious Diseases & Immunology Answer 94
B. Chlamydia trachomatis acquired during labor will typically cause late-onset pneumonia between 2
to 4 weeks of age.
Neonatal pneumonias can be divided into early and late pneumonias, depending on whether the
infant presents before or after 3 days of age, respectively. Congenital pneumonia is a sub-type of
early pneumonia, which is acquired in utero. It can be secondary to aspiration of infected amniotic
fluid, ascending infection or hematogenous spread across the placenta. Infection acquired during
labor from aspiration of bacteria colonizing the birth canal is not defined as congenital as it is not
acquired in utero.
Despite intrapartum antibiotic prophylaxis, Group B Strep remains the most common cause of
early pneumonia, with E. coli being the second most common. Herpes simplex virus is the most
common viral pathogen causing early pneumonia, while cytomegalovirus rarely presents as an early
pneumonia.
Late neonatal pneumonias are most commonly secondary to nosocomial infections, and causative
organisms include coagulase-negative Staphylococcus, Staph aureus, Strep pyogenes, Strep
pneumonia, and E. coli. Chlamydia trachomatis can also cause late neonatal pneumonia. Although
chlamydia trachomatis infection is acquired during labor, pneumonia typically presents from week 2
to 4 of age due to its long incubation period.
Reference:
Martin RJ, Fanaroff AA, Walsh MC. Fanaroff and Martin’s Neonatal-Perinatal Medicine: Diseases
of the Fetus and Infant, 9th ed. Elsevier, 2011
Infectious Diseases & Immunology Answer 95
D. Evaluation with a CBC, LFTs, VDRL, and cerebrospinal fluid testing
Infants born to women with a positive Venereal Disease Research Laboratory test (VDRL) require
a thorough examination and a quantitative nontreponemal syphilis test. In order to be able to compare
results, the test performed on the infant should be the same as the one performed on the mother. If the
infant’s titer is four-fold greater than the mother’s titer or if the infant has clinical signs of congenital
syphilis, further tests should be sent. Because the infant in the vignette has signs of congenital syphilis
on physical examination, a lumbar puncture should be performed and cerebrospinal fluid should be
analyzed for cell count, protein content and VDRL.
Reference:
Kimberlin DW, Long SS, Brady MT, et al (eds). Red Book 2015: Report of the Committee on
Infectious Diseases. 13th edition. American Academy of Pediatrics, 2015
Infectious Diseases & Immunology Answer 96
A. Apply an antibacterial cream to the infant’s skin
The symptoms of the infant in this vignette suggest the diagnosis of congenital cutaneous
candidiasis. White spots on the umbilical cord and amniotic membranes are pathognomonic for
candidal chorioamnionitis. Prenatally acquired candida infections can result in a spectrum of disease
in the newborn, ranging from isolated cutaneous manifestations to systemic illness. Because this infant
has severe respiratory distress, an evaluation for a systemic fungal infection is needed. These tests
include the following: a complete blood cell count; tracheal aspirate for potassium hydroxide (KOH)
staining; and blood, urine and cerebrospinal fluid cultures. The placenta should also be sent for
further testing. While these tests are pending, the infant should be treated with antibiotics and
fluconazole. The skin lesions associated with a candida infection typically appear within the first 24
hours of age, and the typical rash consists of a generalized eruption with erythematous macules,
papules and/or pustules. Applying antibacterial cream to the infant’s affected skin is not an effective
treatment.
Reference:
Darmstadt GL, Dinulos JG, Miller Z. Congenital cutaneous candidiasis: clinical presentation,
pathogenesis, and management guidelines. Pediatrics. 2000;105:438-444
Infectious Diseases & Immunology Answer 97
B. A low incidence of central nervous system involvement
Most fungal infections in neonates are caused by Candida species. The presenting symptoms of
systemic fungal infections in an infant are usually non-specific and very similar to the symptoms of
bacterial infections. Involvement of the kidneys, central nervous system and eyes is common. Many
infants with systemic fungal infection will have a positive urine culture for Candida. Urinary tract
infections can result in renal parenchymal involvement and fungus ball formation. There is a high
incidence of central nervous system involvement with meningitis and other possible complications,
such as ventriculitis and cerebral abscess formation. If the candida infection involves the eyes, it can
result in blindness if untreated.
References:
Shane AL1, Stoll BJ. Recent developments and current issues in the epidemiology, diagnosis, and
management of bacterial and fungal neonatal sepsis. Am J Perinatol. 2013;30:131-14.
Tripathi N1, Watt K, Benjamin DK Jr. Treatment and prophylaxis of invasive candidiasis. Semin
Perinatol. 2012;36:416-423
Infectious Diseases & Immunology Answer 98
A. Children born to Hispanic mothers have the highest rates of perinatal MTCT of HIV in the US.
In the absence of preventative measures, there is a high rate of MTCT of HIV, with data suggesting
that MTCT of HIV in Europe would be up to 20%, up to 30% in the US, up to 40% in Africa, and up
to nearly 50% in South East Asia. MTCT of HIV can occur in utero, intrapartum or through breast
feeding. Not surprisingly, the rates of MTCT of HIV increase with prolonged breastfeeding (more
than 12 months duration). One randomized controlled trial from Kenya showed that HIV infection
rates almost doubled at 24 months among those who were breastfed rather than given formula (36%
versus 20% infection rate).
With the introduction of measures to prevent MTCT of HIV, the rates of infection have dropped
considerably. Currently, the rate of MTCT of HIV in the US is less than 2%. The most recent Center
for Disease Control (CDC) surveillance data on rates of perinatal HIV transmission in the US show
an incidence of 2.1 per 100,000 live births in 2009. This data was derived from 46 states rather than
the entire nation, as these 46 states had established confidential registries from at least 2007 such that
trends could be analyzed.
The data additionally highlights that there is a racial disparity in perinatal MTCT of HIV rates
within the USA, with children of African-American mothers having the highest rates at 9.9 per
100,000 live births; Hispanic mothers having a rate of 1.7 per 100,000 live births; and Caucasian
mothers having a rate of 0.1 per 100,000 live births.
References:
CDC. Monitoring selected national HIV prevention and care objectives by using HIV surveillance
data – United States and 6 U.S. dependent areas—2010. HIV Surveillance Supplemental Report
2012;17(No. 3, part A). Published June 2012
http://www.cdc.gov/hiv/pdf/2011_Monitoring_HIV_Indicators_HSSR_FINAL.pdf
Nduati RW, John GC, Ngacha DA, et al. Effect of breastfeeding and formula feeding on transmission
of HIV-1: a randomised clinical trial. JAMA. 2000;283:1167-1174
Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission.
Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal
health and interventions to reduce perinatal HIV transmission in the United States. Available at
http://aidsinfo.nih.gov/contentfiles/lvguidelines/perinatalgl.pdf
Prendergast AJ, Essajee S, Penazzato M. HIV and the Millennium Development Goals. Arch Dis
Child. 2015;100:S48-52l
Sturt AS, Dokubo EK, Sint TT. Antiretroviral therapy (ART) for treating HIV infection in ART-
eligible pregnant women. Cochrane Database Syst Rev. 2010;3:CD008440
Thorne C, Newell ML. HIV. Semin Fetal Neonatal Med. 2007;12:174-181
Infectious Diseases & Immunology Answer 99
D. The dose of Zidovudine is increased for preterm infants due to increased hepatic clearance.
Current recommendations for neonatal antiretroviral prophylaxis to prevent perinatal transmission
of HIV detail recommended regimens for both term and preterm infants. The only medications with
current dosing recommendations for preterm infants are Zidovudine and Nevirapine. The dose of both
medications is reduced in preterm infants because of their decreased clearance in this patient
population. Zidovudine is cleared by hepatic glucuronidation, however this pathway is immature in
preterm infants, and leads to reduced clearance and an extended half-life of Zidovudine in preterm
infants.
Recommended neonatal antiretroviral regimens to reduce perinatal transmission of HIV include:
Zidovudine- for all infants with HIV-positive mothers
Infants born at greater than or equal to 35 weeks’ gestation should be treated with:
•4 mg/kg/dose PO twice a day, as soon as possible after birth (ideally within 6 to 12 hours)
•If the infant is unable to take PO, 3 mg/kg/dose IV twice a day as soon as possible after birth
(ideally within 6 to 12 hours).
•A 6-week course of Zidovudine is routinely recommended, but a 4-week course may be
considered if the mother received standard antiretroviral therapy during pregnancy, there
were no concerns about maternal medication compliance, and the mother had consistent
viral suppression when checked.
Infants born between 30 to 35 weeks’ gestation should be treated with:
•2 mg/kg/dose PO twice a day, as soon as possible after birth (ideally within 6 to 12 hours)
•If the infant is unable to take PO, 1.5 mg/kg/dose IV twice a day as soon as possible after birth
(ideally within 6 to 12 hours).
•At 15 days of age, the dose should be increased to either 3 mg/kg/dose PO twice a day, or 2.3
mg/kg/dose IV twice a day
•A 6-week course of Zidovudine is recommended.
Infants born at less than 30 weeks’ gestation should be treated with:
 •2 mg/kg/dose PO twice a day, as soon as possible after birth (ideally within 6 to 12 hours)
•If the infant is unable to take PO, 1.5 mg/kg/dose IV twice a day as soon as possible after birth
(ideally within 6 to 12 hours).
•After 4 weeks of age, the dose should be increased to either 3 mg/Kg/dose PO twice a day, or
2.3 mg/Kg/dose IV twice a day
•A 6-week course of Zidovudine is recommended.
Nevirapine-for infants whose HIV-positive mothers did not receive antenatal antiretrovirals
(including those who just received intrapartum antiretrovirals). The use of this agent can be
considered for those babies born to women who received antenatal therapy but had a persistently
high viremia, however there is no specific data to support its use in this setting.
•Infants with a birth weight greater than or equal to 2 kg should receive 12 mg/dose PO and
those with a birth weight between 1.5 to 2kg, should receive 8 mg/dose.
•A total of 3 doses should be administered. The first within 48 hours of delivery, the second 48
hours after the first, and the third 96 hours after the second.
Reference:
Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission.
Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal
health and interventions to reduce perinatal HIV transmission in the United States. Available at
http://aidsinfo.nih.gov/contentfiles/lvguidelines/perinatalgl.pdf
Infectious Diseases & Immunology Answer 100
C. Group B Streptococcus
Pneumonia is an important cause of neonatal infection. It can occur early (< 7 days of age) or late
onset (>7 days of age). Bacteria are the principal pathogens for each type. Early-onset pneumonia can
occur by intrauterine aspiration of infected amniotic fluid, transplacental transmission of organisms,
or aspiration during birth of infected amniotic fluid. Chest radiograph findings of pleural effusion and
diffuse parenchymal infiltrates support the diagnosis. Intrauterine infection is usually the result of
maternal infection, which may be transmitted transplacentally and involves many organs (including
blood, liver, central nervous system, lungs). Pathogens include rubella, cytomegalovirus, herpes
simplex virus, mumps, adenovirus, Varicella, and Listeria. Pneumonias that are acquired at birth most
often are caused by Group B Streptococcus, but Escherichia coli, Klebsiella, and Chlamydia
trachomatis also are seen. Chlamydia trachomatis pneumonia typically presents at a later age of
approximately three weeks.
Reference:
Flidel-Rion O, Shinwell E. Respiratory distress in the term and near-term infant. NeoReviews.
2005;6:e289-297
Infectious Diseases & Immunology Questions 101-107
Infectious Diseases & Immunology Question 101
An infant is been monitored in the NICU for several months with recurrent, severe purulent
bacterial and fungal infections. The nitroblue tetrazolium (NBT) test is performed and is negative.
The infant described in this vignette most likely has:
A. Chediak-Higasi syndrome
B. Chronic granulomatous disease
C. Leukocyte adhesion deficiency
D. Neutropenia
E. Severe combined immunodeficiency
Infectious Diseases & Immunology Question 102
A term neonate without sepsis risk factors is born by vaginal delivery.
If this infant’s concentration of circulating neutrophils was plotted by age, the curve would be
most similar to:

A. Curve A
B. Curve B
C. Curve/Line C
D. Curve D
E. None of the above
Infectious Diseases & Immunology Question 103
All of the following compounds are collectins, EXCEPT:
A. Conglutinin
B. Mannan-binding lectin (MBL)
C. Surfactant protein (SP)-A
D. SP-B
E.SP-D
Infectious Diseases & Immunology Question 104
You are reviewing the prenatal labs of a mother who just had a term infant via vaginal delivery.
You note that the mother tested positive for hepatitis B surface antigen.
Which of the following statements about hepatitis is TRUE?
A. If the maternal hepatitis B e antigen is negative, there is a higher risk for hepatitis transmission
to the infant.
B. The infant should be started on anti-retroviral therapy for hepatitis B.
C. The infant should not be allowed to breastfeed.
 D. The infant should receive hepatitis B immune globulin but not the hepatitis B vaccine.
E. Transmission to the infant is associated with maternal HBV viral load.
Infectious Diseases & Immunology Question 105
A teacher is pregnant and is exposed to a male student who has an infection that caused his cheeks
to turn red. Three weeks later, she presents at 20 weeks’ gestation with an erythematous rash on her
face and joint pain. Her fetus is monitored throughout pregnancy and found to develop hydrops fetalis.
The cause of the hydrops in this case is most likely:
A. Anemia
B. Chromosomal abnormality
C. Congenital heart disease
D. Immune-mediated process
E. Vein of Galen aneurysm
Infectious Diseases & Immunology Question 106
A Sudanese refugee gives birth two days after arrival into the United States. Her infant, likely
late-preterm based on birth weight and Ballard scoring, is admitted to the NICU because of
respiratory distress. Of note, the infant has a “blueberry muffin” rash on physical exam.
Which of the following physical exam findings will help differentiate congenital rubella from
congenital cytomegalovirus?
A.Cataracts
B.Deafness
C.Hepatosplenomegaly
D.Microcephaly
E.Small for gestational age
Infectious Diseases & Immunology Question 107
A 23-year old G5P0040 woman presents to the Obstetric unit in active labor, without having
received prenatal care. Based on fundal height and ultrasound measurements, it is estimated that she
is 34 weeks’ gestation. The NICU is called to attend the delivery and assess the neonate for
admission.
The infant emerges with fair cry and tone, and is brought to the radiant warmer. A full physical
exam is complete, prompting concern for an intrauterine infection.
Which of the following physical findings is specific to congenital syphilis?
A.Blueberry muffin rash
B.Cataracts
C.Clustered vesicles on erythematous base
D.Early-onset jaundice
E.Vesiculobullous mucocutaneous lesions
Infectious Diseases & Immunology Answers 101-107
Infectious Diseases & Immunology Answer 101
B. Chronic granulomatous disease
Chronic granulomatous diseases (CGDs) are inherited disorders resulting from mutations in the
genes encoding the phagocyte NADPH oxidase. Phagocytic cells, such as neutrophils, cannot generate
superoxide that is necessary to kill bacteria. Affected individuals present with multiple recurrent and
severe infections, frequently with uncommon organisms. Common infections in CGD include
pneumonia, lymphadenitis and impetigo. The diagnosis of CGD is made by demonstrating an absent
or greatly decreased neutrophil respiratory burst. One of the simplest tests to show this is the
nitroblue tetrazolium test (NBT) test. Neutrophils isolated from the patient are stimulated to undergo a
respiratory burst in the presence of NBT. When reduced, the dye is converted to deep blue. If the
NBT is negative, or does not turn blue, neutrophil respiratory burst is impaired.
Reference:
Orkin S, Nathan D, Ginsburg D, et al. Nathan and Oski’s Hematology of Infancy and Childhood. 8th
edition. Philadelphia, Saunders Elsevier. 2014
Infectious Diseases & Immunology Answer 102
B. Curve B
Neutrophils are part of the innate immune system and are the first responders to infection. They
play a major role in phagocytosis. There are many differences in the neutrophils in neonates as
compared to adults. The neonate’s neutrophils, or polymorphonuclear monocytes (PMNs) as they are
also called, are less deformable. They also have less migratory ability and poorer aggregation. In
addition, they are less prone to apoptosis after becoming activated and can contribute to
inflammation. The number of neutrophils undergoes changes in the first few days after birth in healthy
infants with an initial increase after birth that peaks at 12 to 24 hours. There is then a decline that
reaches steady state by 72 hours and remains stable. These changes are best represented on Curve B.
Preterm neonates do not have as much of an increase at 12 to 24 hours. It is abnormal for term infants
to have a neutrophil level below 3000 m3 in the first 3 days of life or below 1500 m3 after that the
first 3 days of life. Low neutrophil levels may be associated with infection.
Reference:
Blackburn ST (ed). Maternal, Fetal and Neonatal Physiology: A Clinical Perspective. 4th edition. St.
Louis: Elsevier Health Sciences; 2012
Infectious Diseases & Immunology Answer 103
D. SP-B
The collectins are a family of soluble oligomeric proteins that play a part in host defense of the
neonate. They contain polypeptide chains with a collagenous region and a C-type lectin domain. They
are related in structure to the complement protein C1q. In mammals, the collectins include: mannose-
binding lectin (MBL), conglutinin, and surfactant proteins A and D (SP-A, SP-D). MBL is present
mostly in blood and in the upper respiratory tract. It can bind directly to invading microorganisms and
activate the complement system. MBL deficiency is associated with susceptibility of the neonate to
infection. SP-A and SP-D are also most abundant in the lungs and also bind to microorganisms and
inhaled particles. They do not activate the complement system. Conglutinin is another mammalian
collectin that was originally identified in bovine serum.
Reference:
Novartis Foundation. Innate Immunity to Pulmonary Infection. 1st Edition. Hoboken: John
Wiley&Sons Inc, 2006
Infectious Diseases & Immunology Answer 104
E. Transmission to the infant is associated with maternal HBV viral load.
People acutely infected with hepatitis B virus (HBV) may be asymptomatic or symptomatic. The
spectrum of signs and symptoms is varied and includes subacute illness with nonspecific symptoms,
clinical hepatitis with jaundice, or fulminant hepatitis. Extrahepatic manifestations, such as arthralgia,
arthritis, macular rashes, thrombocytopenia, polyarteritis nodosa, and glomerulonephritis can occur.
Perinatal transmission of HBV is highly efficient and can occur from blood exposures during
delivery. Without post exposure prophylaxis, the risk of an infant acquiring HBV from an infected
mother is very high in women who are hepatitis B e antigen (HBeAg)-positive. The risk is much
lower in infants born to HBeAg-negative mothers. Transmission is also associated with maternal
viral load. Post-exposure prophylaxis of infants born to mothers who are positive for hepatitis B
surface antigen has significantly decreased transmission. Prophylaxis consists of active and passive
immunization. Hepatitis B immune globulin (HBIG) provides short-term protection and should be
administered with the Hepatitis B vaccine. Subsequent doses of the Hepatitis B vaccine should then
be administered per the normal immunization schedule. The goal is to give this therapy within 12
hours of birth to infants born to affected mothers. Infants born to HBsAg-positive women should be
tested for anti-HBs and HBsAg at 9 to 18 months of age. No specific therapy for acute hepatitis B
infection is available. Breastfeeding by an HBsAg-positive mother poses no additional risk of
acquisition of hepatitis B infection as long as proper immunoprophylaxis is given.
Reference:
Kimberlin DW, Long SS, Brady MT, et al. Red Book: Report of the Committee on Infectious Disease.
30th Edition. 2015
Infectious Diseases & Immunology Answer 105
A. Anemia
Parvovirus B19 commonly causes a “slapped-cheek” rash on the face and, less commonly, fever,
headaches, sore throat and joint pain. In adults, it may cause arthralgias in addition to the
characteristic skin rash. About 35% to 53% of pregnant women have been reported to have
measurable concentrations of IgG to parvovirus, suggestive of prior immunity. The placenta contains
a parvovirus receptor, and transplacental transmission may occur at any time during pregnancy, with
the risk of transmission being the highest in the first and second trimesters. Fetal parvovirus infection
is characterized by nonimmune hydrops fetalis, ascites, pleural effusion, hypertrophic
cardiomyopathy, placentomegaly, and ventriculomegaly. Parvovirus attacks not only the maternal red
blood cells but also fetal erythrocyte precursors. Destruction of fetal red blood cells leads to
nonimmune hydrops fetalis. Hydrops can develop within 2 weeks and may resolve spontaneously or
cause fetal death.
References:
Fanaroff AA, Martin RJ, Walsh M (eds). Neonatal-Perinatal Medicine. 10th edition. St. Louis:
Mosby; 2014
Kumar M, Abughali N. Perinatal parvovirus B19 infection. NeoReviews. 2005;6:e32-37
Infectious Diseases & Immunology Answer 106
A. Cataracts
Dermal hematopoiesis is the histologic basis for blueberry muffin skin lesions. Prior to 34 weeks’
gestation, the skin serves as the hematopoietic center for the fetus. Blueberry muffin lesions are due
to either the persistence or recurrence of this fetal potential. The disseminated blue-purple nodules
can be seen in congenital rubella and congenital cytomegalovirus (CMV).
 These two diseases have many overlapping physical exam findings. In addition to the blueberry
muffin rash, both diseases can be associated with growth restriction or small for gestational age,
microcephaly, congenital deafness, and hepatosplenomegaly. CMV can present with chorioretinitis
and intracranial calcifications. Congenital rubella can present with congenital heart disease, diffuse
adenopathy, jaundice within the first 24 hours, and ocular anomalies, including microphthalmia,
glaucoma, cataracts, and pigmented retinopathy.
References:
Gleason CA, Devaskar SU. Avery’s Diseases of the Newborn. 9th Ed. Philadelphia: Elsevier; 2012
Krowchuk DP, Mancini AJ. Pediatric Dermatology. 2nd Ed. AAP Section on Dermatology; 2011
Zitelli BJ, Davis HW. Atlas of Pediatric Physical Diagnosis. 5th Ed. Philadelphia: Elsevier; 2007
Infectious Diseases & Immunology Answer 107
E. Vesiculobullous mucocutaneous lesions
Toxoplasmosis, rubella, cytomegalovirus, herpes simplex virus and syphilis are well-known
sources of pathology when acquired prenatally or perinatally. There are many overlapping physical
findings amongst these diseases, including small for gestational age (SGA), microcephaly, early-onset
jaundice, hepatosplenomegaly, diffuse adenopathy, and petechiae.
Infants who are symptomatic at birth from syphilis tend to have evidence of intrauterine growth
restriction, hepatosplenomegaly, direct and indirect hyperbilirubinemia, Coombs-negative hemolytic
anemia, thrombocytopenia, generalized lymphadenopathy, and mucocutaneous lesions. The typical
lesions in congenital syphilis are vesicular or bullous, and ultimately rupture to form superficial
crusted erosions or ulcerations. The rash is generalized, and classically involves the palms and
soles.
References:
Gleason CA, Devaskar SU. Avery’s Diseases of the Newborn. 9th Ed. Philadelphia: Elsevier; 2012
Krowchuk DP, Mancini AJ. Pediatric Dermatology. 2nd Ed. AAP Section on Dermatology; 2011
Zitelli BJ, Davis HW. Atlas of Pediatric Physical Diagnosis. 5th Ed. Philadelphia: Elsevier; 2007
VII. FLUIDS, ELECTROLYTES, NUTRITION & RENAL
Fluids, Electrolytes, Nutrition & Renal Questions 1-10
Fluids, Electrolytes, Nutrition & Renal Question 1
Which of the following vitamins is important for pulmonary epithelial growth and cellular
differentiation?
A. Biotin
B. Thiamine
C. Vitamin A
D. Vitamin C
E. Vitamin D
Fluids, Electrolytes, Nutrition & Renal Question 2
A family of a 2-day old infant born at 27 weeks’ gestation is interested in giving donor human milk
to their infant. The pediatric resident is uncertain about the components of human milk that are and
are not preserved by the pasteurization process.
Which of the following components is NOT preserved in the pasteurization process?
A. Immunoglobulin M
B. Oligosaccharides
C. Vitamin A
D. Vitamin D
E. Vitamin E
Fluids, Electrolytes, Nutrition & Renal Question 3
A 1 kg male infant was born at 27 weeks’ gestation via Cesarean section following concerns for
placental abruption. At 10 days of age, he is receiving a parenteral nutrition solution infusing at a
rate of 3.5 mL/hour, which contains 3.5 g/100 mL of amino acids and 20% glucose. In addition, he is
receiving a 20% lipid solution infusing at a rate of 0.3 mL/hour.
Of the following, the CLOSEST estimate of the number of kilocalories (kcal) he is receiving per
kilogram per day is:
A. 60 kcal/kg/day
B. 80 kcal/kg/day
C. 100 kcal/kg/day
D. 120 kcal/kg/day
E. 140 kcal/kg/day
Fluids, Electrolytes, Nutrition & Renal Question 4
A female infant was born at 35 weeks’ gestation with hydrops fetalis associated with an
arrhythmia. She has significant abdominal distension that is compromising her respiratory status.
After performing a paracentesis, the peritoneal fluid is sent for analysis.
The type of fluid that is MOST likely to be found in this infant’s peritoneal lavage is:
A. Blood
B. Chylous
C. Exudative
D. Transudative
E. Urine
Fluids, Electrolytes, Nutrition & Renal Question 5
A 6-week old term male infant has Pierre-Robin sequence; he has had poor weight gain over the
past several weeks and has recently changed from breastfeeding to formula feeding. He develops a
severe diaper dermatitis, hypoalbuminemia, and a crusted erythematous rash around his perioral area.
 Which trace element is most likely to be deficient in this infant?
A.Chromium
B.Copper
C.Manganese
D.Selenium
E.Zinc
Fluids, Electrolytes, Nutrition & Renal Question 6
Please complete the Table to indicate the characteristics of each type of renal tubular acidosis
(RTA)
RTA Type Etiology Urine pH Serum Potassium Hypercalciuria
Type 1 (Distal)
Type 2 (Proximal)
Type 4
Fluids, Electrolytes, Nutrition & Renal Question 7
A term female infant is seen by her pediatrician at 3 weeks of age. The infant’s mother has
mastitis and she is being treated with Dicloxacillin.
Which of the following recommendations is appropriate for the woman in this vignette?
A. Continue breastfeeding and/or using a breast pump
B. Temporarily stop breastfeeding and avoid use of a breast pump
C. Temporarily stop breastfeeding and provide pumped breast milk
D. Temporarily stop breastfeeding, use a breast pump, and disregard pumped milk until antibiotic
course is finished
Fluids, Electrolytes, Nutrition & Renal Question 8
In general, the term neonate has adequate carbohydrate absorption.
By what approximate gestational age does the fetus’ concentration of lactase reach the lactase
concentration of an adult?
A. 18 weeks’ gestation
B. 24 weeks’ gestation
C. 28 weeks’ gestation
D. 36 weeks’ gestation
E. 40 weeks’ gestation
Fluids, Electrolytes, Nutrition & Renal Question 9
The mother of a 1-month old infant born at 30 weeks’ gestation is an adult dietician and has been
providing her infant with breast milk. She asks the neonatologist to compare preterm infant formula
to mature breast milk because she is considering supplementing with preterm infant formula. She is
specifically interested in the whey-to-casein ratio in preterm infant formula.
The neonatologist informs the mother that preterm formula has a whey-to-casein ratio of:
A. 20:80
B. 40:60
C. 60:40
D. 80:20
Fluids, Electrolytes, Nutrition & Renal Question 10
An infant is born at 24 weeks’ gestation by vaginal delivery following unstoppable preterm labor.
Which of the following is the most accurate description of the ratio of extracellular fluid (ECF) to
intracellular fluid (ICF) in this infant?
A. ECF 25%: ICF 65%
B. ECF 65%: ICF 25%
C. ECF 45%: ICF 35%
D. ECF 35%: ICF 45%
E. ECF 20%: ICF 40%
Fluids, Electrolytes, Nutrition & Renal Answers 1-10
Fluids, Electrolytes, Nutrition & Renal Answer 1
C. Vitamin A
Vitamin A (also known as retinol) is important for pulmonary epithelial growth and cellular
differentiation. Vitamin A deficiency may play a role in the development of chronic lung disease.
Deficiency of Vitamin A can also lead to photophobia, conjunctivitis, failure to thrive, generalized
scaling, abnormal epiphyseal bone formation, and/or abnormal tooth enamel. Features associated
with other vitamin deficiencies are summarized in the Table below.
Vitamin Associated Features of Vitamin Deficiency
Vitamin B1 Beriberi (symptoms include fatigue, irritability, constipation, cardiac failure)
(thiamine) Associated with pyruvate dehydrogenase complex deficiency and maple
syrup urine disease
Vitamin B2 Failure to thrive, photophobia, blurred vision, dermatitis, mucositis
(riboflavin) Associated with glutaric aciduria type I

Vitamin B6 Dermatitis, mucositis

(pyridoxine) Hypochromic anemia, possible seizures
Associated with homocystinuria
Biotin Alopecia, dermatitis, scaling, seborrhea
Associated with biotinidase deficiency, beta-methylcrotonyl glycinuria,
propionic acidemia, and pyruvate dehydrogenase complex deficiency
Vitamin C Poor wound healing and bleeding gums
(ascorbic Associated with transient tyrosinemia
acid)
Vitamin D Rickets
Failure to thrive
Possible tetany
Modified from: Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010, p 303
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Committee on Nutrition. Pediatric Nutrition Handbook. 6th ed. Elk Grove, IL: American Academy of
Pediatrics; 2008
Fluids, Electrolytes, Nutrition & Renal Answer 2
A. Immunoglobulin M
Several important components of human milk are preserved through the process of pasteurization.
These retained components include oligosaccharides; vitamins A, D, and E; lactose; long-chain
polyunsaturated fatty acids; and epidermal growth factor. However, the Holder pasteurization process
impacts the immunological properties of human milk. Lymphocytes, alkaline phosphatase, cytokines,
some growth factors, lipoprotein, and some lipases are destroyed. Lactoferrin and lysozyme
concentrations are reduced by at least 50% and 25%, respectively. Immunoglobulins are impacted
differently: while most of the immunoglobulins A and G are preserved, all of the immunoglobulin M
is typically destroyed.
References:
Donor milk. American Academy of Pediatrics. NeoReviewsPlus. 2011;July, 8:Q7
Quigley M, Henderson G, Anthony MY, McGuire W. Formula milk versus donor breast milk for
feeding preterm or low birthweight infants. Cochrane Database of Systematic Reviews.
2007;4:CD002971
Fluids, Electrolytes, Nutrition & Renal Answer 3
B. 80 kcal/kg/day
The infant in this scenario is receiving parenteral nutrition solution containing 3.5 g/100 mL of
amino acids and 20% glucose at a rate of 3.5 mL/hour. In addition, he is receiving a 20% lipid
solution infusing at a rate of 0.3 mL/hour. Based on the amount of kilocalories per gram of nutrient
shown in the Table below, his total amount of calories can be calculated.
Component Kcals per gram
Carbohydrate (Dextrose) 3.4
Protein 4
Fat 9
Carbohydrate: 20% = 20 g/100 mL
20 g/100 mL x 3.4 kcal/g=68 kcal/100 mL or 0.68 kcal/mL
3.5 mL/hr x 24 hours/day=84 mL/day
.68 kcal/mL x 84 mL/day= 57 kcal/day
Protein: 3.5 g/100 mL x 4 kcal/g=14 kcal/100 mL or 0.14 kcal/mL
3.5 mL/hr x 24 hours/day=84 mL/day
.14 kcal/mL x 84 mL/day= 11 kcal/day
Lipid: 20% = 20 g/100 mL
20 g/100 mL x 9 kcal/g=180 kcal/100 mL=1.8 kcal/mL
1.8 kcal/mL x 0.3 mL/hour x 24 hours/day =13 kcal/day
Total calories per day: 57 + 11 + 13 = 81 kcal/day divided by 1 kg=81 kcal/kg/day
Fluids, Electrolytes, Nutrition & Renal Answer 4
D. Transudative
The peritoneal fluid in a newborn with hydrops fetalis complicated by congestive heart failure or
cardiac arrhythmia is usually transudative. Peritoneal blood can be found if an infant has
hepatosplenic trauma. Chylous fluid is evident if there is a lymphatic obstruction or malformation.
An exudative fluid is identified in neonates with meconium peritonitis. The peritoneal fluid can be
urine if the infant has posterior urethral valves or a bladder perforation.
Urine Posterior urethral valves (most common urinary cause), bladder perforation,
neurogenic bladder
Possible mechanisms for urinary ascites include: transudation through
bladder wall and/or rupture of fetal bladder
Chylous Lymphatic obstruction or malformation
Transudative Congestive heart failure/cardiac arrhythmias
Exudative Meconium peritonitis
Blood Hepatosplenic trauma
Hepatic failure Congenital infections (cytomegalovirus, rubella, toxoplasmosis, syphilis),
familial cirrhosis
Gastrointestinal Intestinal obstruction and perforation (atresia, malrotation, volvulus)
Modified from: D’ Alessandro MP. Neonatal Ascites. www.virtualpediatrichospital.org; Griscom NT et al. Diagnostic aspects of
neonatal ascites: report of 27 cases. Am J Roentgenol. 1977;128:961-970
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
D’ Alessandro MP. Neonatal Ascites. www.virtualpediatrichospital.org Accessed August 5, 2015
Griscom NT et al. Diagnostic aspects of neonatal ascites. Am J Roentgenol. 1977;128:961-970
Fluids, Electrolytes, Nutrition & Renal Answer 5
E. Zinc
Zinc deficiency may result from malabsorption, as occurs in acrodermatitis enteropathica, or more
rarely, from inadequate intake. Acrodermatitis enteropathica is a rare autosomal recessive disorder
that results from defective zinc uptake in the duodenum and jejunum because of an abnormality in the
zinc transporter protein ZIP4. Noncutaneous findings include failure to thrive, irritability, and
photophobia. Alkaline phosphatase is a zinc-dependent enzyme, and low serum concentrations may
suggest the possibility of this diagnosis. Secondary infection with Staphylococcus aureus or Candida
is common. Response to zinc supplementation is dramatic, with resolution of the dermatitis within
days. The dermatologic findings observed in other deficiencies are described in the Table below.
Trace Function Clinical Effects of Deficiency
Element
Chromium Regulates glucose levels In animals – diabetes
because of role in In humans – unknown
insulin metabolism
Copper Critical for production Anemia
of red blood cells as Osteoporosis
well as hemoglobin Depigmentation of hair and skin
formation Neutropenia
Important for absorption Poor weight gain
of iron Hypotonia, ataxia later in life
Associated with multiple
enzyme activities
Iron Component of Anemia (microcytic, hypochromic)
hemoglobin and Failure to thrive
myoglobin required for
transport of O2 and CO2
Absorbed predominantly
in the duodenum and
proximal jejunum
Vitamin C enhances
absorption
Manganese Role in enzyme Unknown
activation (e.g.,
superoxide dismutase)
Important for normal
bone structure
Role in CHO
metabolism
Selenium Cofactor for glutamine In animals – muscle disease
 peroxidase In humans – cardiomyopathy
Zinc Important component of Acrodermatitis enteropathica
several enzymes (e.g., Autosomal recessive disorder in which there is an
carbonic anhydrase and abnormality of zinc absorption or transport
carboxypeptidase) Failure to thrive, alopecia, diarrhea, dermatitis
Important for growth (commonly perianal), ocular changes, rash (crusted,
erythematous, involving face, extremities and
anogenital areas), nail hypoplasia or dysplasia
Acquired zinc deficiency
Premature infants receiving inadequate amounts of zinc
Maternal zinc deficiency can lead to fetal growth
restriction, congenital anomalies
Infants with malabsorption, poor weight gain poor
wound healing, anemia (iron deficiency)
Printed with permission from: Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu.
2010, p 303
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Bedocs LA, O’Regan GM, Bruckner AL. Red, scaly babies: Neonatal erythroderma. NeoReviews.
2011;12:e325-34
Kleigman RM, et al. Nelson Textbook of Pediatrics. 18th ed. Philadelphia: WB Sanders Co; 2007
Fluids, Electrolytes, Nutrition & Renal Answer 6
RTA Type Etiology Urine pH Serum Hypercalciuria
Potassium
Type 1 Diminished acid Low-
> 6.5 Yes
(Distal) secretion in distal tubule normal
Type 2 < 6.5;
(Proximal) Diminished bicarbonate (but can be > 6.5 before Low-
No
resorption the acidosis is normal
established)
Type 4 Aldosterone deficiency
or aldosterone <6.5 High No
resistance
Type 1 (Distal) or Classic RTA: This is the most severe type and occurs because of diminished
acid secretion in the distal tubule, and therefore it presents with a high urine pH. Affected infants
have a low serum potassium concentration because potassium is lost in the urine as a cation
replacement for hydrogen. Although the cause of the hypercalcuria is not completely clear, it likely
results from increased calcium release from bone as a buffer, downregulation of calcium transport
proteins in the kidney, and high distal sodium delivery leading to more calcium excretion. Treatment
involves bicarbonate administration.
Type 2 (Proximal) RTA: This type of RTA results from a reduction in the threshold for
bicarbonate reabsorption in the proximal tubule to 15 mEq/L. This leads to profound urinary
bicarbonate losses. Initially this leads to a high urine pH. With time, the kidney compensates and
distal acidification occurs leading to a lower urine pH. Hypercalciuria does not occur. Treatment is
bicarbonate administration.
Type 4 RTA: This type of RTA results from aldosterone deficiency or aldosterone resistance
(psuedohypoaldosteronism). This leads to severe hyperkalemia, hyponatremia and metabolic
acidosis. Hypercalciuria does not occur.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Ringer SA. Renal tubular acidosis. NeoReviews. 2010;11(5):e252-e256
Fluids, Electrolytes, Nutrition & Renal Answer 7
A. Continue breastfeeding and/or using a breast pump
Mastitis affects 1/3 of breastfeeding women in the US. Symptoms usually arise in the 3rd to 4th
week postpartum and typically involve one breast. Breast engorgement is followed by systemic
inflammation with chills, fever, and tachycardia. The breast can be firm and tender. Notably, 10% of
affected woman may develop an abscess. The expressed breast milk can be cultured and the mother
should be treated empirically with Dicloxacillin. If the organism is penicillin-resistant, erythromycin
can be used; alternatively, if the organism is resistant to Dicloxacillin and Erythromycin, Vancomycin
is usually prescribed. Breastfeeding can be continued but if breastfeeding is too painful for the
mother, pumped breast milk can be given to the infant.
References:
Cunningham FG, Leveno KJ, Bloom SL, Hauth JC, Gilstrap LC, Wenstrom KD (eds): Williams
Obstetrics. 22nd edition. New York: McGraw-Hill; 2005
Fluids, Electrolytes, Nutrition & Renal Answer 8
D. 36 weeks’ gestation
Carbohydrate digestion and absorption in the term neonate is adequate because of the colonic
salvage pathway, adequate concentrations of glucosidases/disaccharidases, and normal glucoamylase
concentration. Although the intestinal disaccharidases (i.e., sucrase, maltase, and isomaltase) reach
adult amounts at 28 weeks’ gestation, lactase concentration reaches an adult concentration by
approximately 36 weeks’ gestation. The Table below summarizes carbohydrate digestion and
absorption in the term neonate.
Gastrointestinal Characteristics
Enzyme/Function
Pancreatic amylase Present at 22 weeks’ gestation
Adequate amounts produced
Decreased secretion at birth
Glucoamylase Normal action at birth
Located in the intestinal brush border
Removes glucose from end of starch
Intestinal All except lactase reach adult levels at 28 weeks’ gestation
disaccharidases Glucosidases = sucrase, maltase, isomaltase
Colonic bacteria Helps ferment malabsorbed CHO to acids, which are absorbed in
colon (system called colonic savage pathway)
Glucose transport Transport across intestine
Less efficient in the newborn, especially the premature infant
 Lactase Adult levels at 36 weeks’ gestation
Colonic salvage pathway helps limit CHO malabsorption
Printed with permission from: Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu.
2010, p 313
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Fanaroff AA, Martin RJ, Walsh MC (eds). Neonatal-Perinatal Medicine: Diseases of the Fetus and
Infant. 8th ed. Philadelphia: Mosby-Elsevier; 2006
Fluids, Electrolytes, Nutrition & Renal Answer 9
C. 60:40
Whey and casein are major protein sources in neonates. Whey has greater cysteine and less
methionine than casein. Colostrum has a whey-to-casein ratio of 80:20, mature breast milk has a
whey-to-casein ratio of 55:45, and preterm formulas have a whey-to-casein ratio of 60:40.
References:
Kliegman RM, Stanton BMD, St Geme J, Schor N, Behrman RE (eds). Nelson Textbook of
Pediatrics. 19th edition. Philadelphia: WB Saunders; 2011
Fluids, Electrolytes, Nutrition & Renal Answer 10
B. ECF 65%: ICF 25%
At 24 weeks’ gestation, the infant’s total body water (TBW) is comprised mostly of extracellular
fluid (ECF). As shown in the graph on the next page, TBW and ECF decrease with increasing
gestational age, while intracellular fluid (ICF) increases with age.

References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Fanaroff AA, Martin RJ (eds). Neonatal and Perinatal Medicine: Diseases of the Fetus and Newborn.
6th Edition. St. Louis: Mosby; 1997, p 623
Fluids, Electrolytes, Nutrition & Renal Questions 11-20
Fluids, Electrolytes, Nutrition & Renal Question 11
A 3-month old male infant born at 24 weeks’ gestation has a history of necrotizing enterocolitis
complicated by bowel resection and a continued dependence on parenteral nutrition. His physical
examination is notable for hair loss, seborrhea and a scaly dermatitis.
What vitamin is most likely to be deficient in this infant?
A.Ascorbic acid
B.Biotin
C.Retinol
D.Riboflavin
E.Thiamine
Fluids, Electrolytes, Nutrition & Renal Question 12
A 1-week old newborn, has a non-anion gap metabolic acidosis, but is otherwise stable in room
air. After infectious and metabolic testing is negative, the possibility of a renal tubular acidosis
(RTA) is considered.
All of the following statements about Type I and II RTA is correct, EXCEPT:
A. Both Type I and Type II RTA are associated with nephrocalcinosis
B. The diagnosis of Type I RTA is confirmed by a high urine pH
C. Type I RTA is associated with a defect in renal acid secretion and Type II RTA is related to
abnormal renal bicarbonate reabsorption
D. Type I RTA is typically caused by a problem in the distal tubule as compared to Type II RTA,
which is typically associated with a proximal tubule abnormality
E. Type II RTA can be transient in newborns because of short-lived failure of bicarbonate
reabsorption in the proximal convoluted tubule
Fluids, Electrolytes, Nutrition & Renal Question 13
A pregnant woman presents with oligohydramnios at 26 weeks’ gestation. The neonatologist
meets with the family.
In discussing fetal renal development and intrauterine urine production, all of the following are
true, EXCEPT:
A.Fetal urine production increases with gestational age
B. Fetal urine rate is approximately 5 mL/hr at 20 weeks’ gestation and up to 50 mL/hr at term
gestation
C. The first fetal glomeruli develop at approximately 9 weeks’ gestation
D. The vast majority (90%) of amniotic fluid at 20 weeks’ gestation is composed of fetal urine
E. All of the above are true
Fluids, Electrolytes, Nutrition & Renal Question 14
A neonatologist is managing a 1-week old male infant born at 25 weeks’ gestation. The infant is
requiring moderate ventilatory settings. He is hypotensive, requiring dopamine and epinephrine
infusions. He is receiving indomethacin to treat a large patent ductus arteriosus. He has now
developed oliguria.
All of the following options can explain this infant’s oliguria, EXCEPT:
A.Administration of indomethacin for treatment of the patent ductus arteriosus
B. Decreased renal blood flow in the setting of hypotension and poor cardiac output
C. Inadequate renal perfusion pressure because cardiac output to the kidneys is decreased to 25%
D. Increased endothelin production by the renal vascular endothelial cells
 E. Physiologic response to low intravascular volume
Fluids, Electrolytes, Nutrition & Renal Question 15
You are taking care of a 3-month old male infant born at 24 weeks’ gestation who had surgical
necrotizing enterocolitis (NEC), resulting in significant short gut syndrome and malabsorption. He is
receiving complete total parenteral nutrition. Based on his clinical symptoms, you suspect that he
might have copper deficiency.
All of the following are true about copper metabolism and copper deficiency in a preterm neonate,
EXCEPT:
A.Ceruloplasmin is a more reliable marker of copper stores than serum copper concentrations
B.Classic symptoms of copper deficiency include hypochromic anemia, neutropenia and
osteoporosis
C.Copper deficiency in an infant born at 28 weeks’ gestation may not be apparent until 2 months of
age
D.Copper is primarily stored in the liver
E.Fetal copper accumulation begins during the 3rd trimester
Fluids, Electrolytes, Nutrition & Renal Question 16
As the rounding physician in the Newborn Nursery, you speak with a mother who is concerned
about her medication intake and the risk to her infant if she decides to breastfeed. The mother has a
history of depression and has been maintained on a selective serotonin reuptake inhibitor throughout
her pregnancy. In addition, she has been taking methadone to help with chronic back pain. She is
currently receiving fentanyl and morphine for pain control after her Cesarean delivery.
Which of the following medications is an absolute contraindication to breastfeeding in this infant?
A.Fentanyl
B.Methadone
C.Morphine
D.Sertraline
E.None of the drugs listed is an absolute contraindication to breastfeeding
Fluids, Electrolytes, Nutrition & Renal Question 17
Of the following, Vitamin E deficiency is associated with:
A.Coagulopathy
B.Hemolysis, anemia, reticulocytosis
C.Macrocytic anemia, hypersegmented neutrophils
D.Photophobia, conjunctivitis
E.Poor wound healing, bleeding gums
Fluids, Electrolytes, Nutrition & Renal Question 18
Compared to cow’s milk formula, human milk contains:
A.Less carnitine
B.Less cholesterol
C.Less docosahexaenoic acid
D.More amino acids
E.More long-chain unsaturated fatty acids
Fluids, Electrolytes, Nutrition & Renal Question 19
Compared to term breastmilk, preterm breastmilk contains:
A.Fewer amino acids
B.Less sodium and chloride
 C.More lactose
D.More cholesterol
E.More long-chain polyunsaturated fatty acids
Fluids, Electrolytes, Nutrition & Renal Question 20
Compared to foremilk, hindmilk contains:
A.Equal amount of protein
B.Less fat
C.Less protein
D.More lactose
E.More protein
Fluids, Electrolytes, Nutrition & Renal Answers 11-20
Fluids, Electrolytes, Nutrition & Renal Answer 11
B. Biotin
Biotin deficiency is associated with biotinidase deficiency, beta-methylcrotonylglycinuria, propionic
academia, and pyruvate dehydrogenase complex deficiency. Symptoms of biotin deficiency include
alopecia, scaling dermatitis, and seborrhea. Ascorbic acid deficiency leads to wound healing and
bleeding gums and is associated with transient tyrosinemia. Retinol is important for pulmonary
epithelial growth and cellular differentiation and if deficient, may be associated with chronic lung
disease. Riboflavin deficiency may be associated with failure to thrive, photophobia, blurred vision,
dermatitis and mucositis; this may be found in individuals with glutaric aciduria type 1. Thiamine
deficiency can cause beriberi with fatigue, irritability, constipation and cardiac failure. Thiamine
deficiency is associated with pyruvate dehydrogenase complex deficiency and maple syrup urine
disease. Symptoms of vitamin A deficiency include photophobia, conjunctivitis, abnormal epiphyseal
bone formation and tooth enamel, generalized scaling, and failure to thrive.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Kliegman RM, Stanton BMD, St Geme J, Schor N, Behrman RE (eds). Nelson Textbook of
Pediatrics. 19th edition. Philadelphia: WB Saunders; 2011
Fluids, Electrolytes, Nutrition & Renal Answer 12
A. Both Type I and Type II RTA are associated with nephrocalcinosis
Renal tubular acidosis (RTA) is a cause of non-anion gap metabolic acidosis. There are generally
three types of RTA:
1.Type I (distal) RTA is associated with a defect in acid secretion in the distal tubule
2.Type II (proximal) RTA is associated with a defect in bicarbonate reabsorption in the proximal
tubule
3.Type IV (hyperkalemic/hypoaldosteronism) is associated with aldosterone deficiency or
insensitivity
The diagnosis of RTA can be confirmed by a high urine pH in the setting of a non-anion gap
metabolic acidosis. The pH is typically >6.5 in Type I RTA and high or low in Type II RTA (>7.6).
Type I RTA can be attributable to autosomal dominant and recessive forms; the recessive form can
be associated with hearing loss. Type II RTA can occur transiently in premature and term infants as a
result of immaturity of renal bicarbonate reabsorption. There are other types of Type II RTA that can
be associated with autosomal recessive disorders, including Fanconi syndrome. Type I RTA is the
only RTA typically associated with nephrocalcinosis. The cause of the nephrocalcinosis is unknown
but possibly associated with increased bone breakdown and calcium release to help buffer the extra
acid.
Reference:
Ringer SA. Renal tubular acidosis. NeoReviews. 2010;11(5):e252-e255
Fluids, Electrolytes, Nutrition & Renal Answer 13
E. All of the above are true
The fetal kidney begins to develop with formation of the pronephros as early as 2 to 3 weeks of
gestation. The first glomeruli develop at approximately 9 weeks’ gestation. The formation of the
metanephros eventually leads to the mature kidney, while the pronephros and mesonephros
disappear. Once complete, the kidney contains approximately 1 million nephrons. Nephrogenesis is
usually complete by 34 to 36 weeks’ gestation.
Urine production in the fetus begins as early as 10 to 12 weeks’ gestation, and gradually increases
from approximately 5 mL/hr at 20 weeks’ gestation to ~50 mL/hr by 40 weeks’ gestation.
Approximately 90% of amniotic fluid is composed of fetal urine at 20 weeks’ gestation. Absent or
diminished intrauterine fetal urine production, as occurs in renal agenesis or posterior urethral
valves, leads to severe oligohydramnios and pulmonary hypoplasia.
Reference:
Su SW, Stonestreet BS. Core concepts : Neonatal glomerular filtrate rate. NeoReviews.
2010;11(12):e714-e721
Fluids, Electrolytes, Nutrition & Renal Answer 14
C. Inadequate renal perfusion pressure because cardiac output to the kidneys is decreased to 25%
The etiology of oliguria in a neonate can be multifactorial and always requires a thorough
evaluation, especially if it occurs acutely. Renal output depends on renal blood flow. Unlike adults,
where 25% of the total cardiac output is dedicated to the kidney, infant kidneys receive only ~10% of
the total cardiac output. Renal blood flow is dependent on renal perfusion pressure (systemic blood
pressure can be used as a proxy) and indirectly correlated with renal vascular resistance. Multiple
etiologies can result in decreased renal perfusion pressure, including hypovolemia and systemic
hypotension.
There are multiple factors in the renal circulation that can result in either local vasodilation or
vasoconstriction. Prostaglandins (PG) and nitric oxide are two examples of renal vasodilators, while
indomethacin acts by inhibiting PG synthesis, thus resulting in reduced renal blood flow and urine
output. Endothelin is a renal vasoconstrictor; it is produced by the renal vascular endothelial cells
and its release can be stimulated by angiotensin II, bradykinin, epinephrine (potential etiology in this
infant), or stress.
Reference:
Su SW, Stonestreet BS. Core concepts : Neonatal glomerular filtrate rate. NeoReviews.
2010;11(12):e714-e721
Fluids, Electrolytes, Nutrition & Renal Answer 15
A. Ceruloplasmin is a more reliable marker of copper stores then serum copper concentrations
Copper is a mineral necessary for energy production because it is a component of the cytochrome
oxidase complex. The fetus begins to accumulate copper stores during the 3rd trimester, although
infants born at approximately 28 weeks’ gestation or later often have enough copper stores so that a
copper deficiency would not become apparent until 2 months of life. Up to 50% to 60% of copper is
stored in the liver.
Copper deficiency is rare in neonates, with the exception of those infants who have Menkes
disease (X-linked recessive disorder attributable to inability of cellular absorption of copper,
resulting in severe copper deficiency and usually infantile death). Copper deficiency is also difficult
to diagnose given the lack of normal values for serum copper concentrations and the large variation in
copper and ceruloplasmin concentrations in healthy preterm neonates. Some infants with copper
deficiency may actually have falsely elevated serum concentrations of copper and cerulopasmin,
possibly from an extra source of ceruloplasmin, such as blood transfusions. Therefore, one must have
a high index of suspicion to diagnose copper deficiency. Risk factors include extremely low
birthweight or extremely low gestational age infants, as well as prolonged total parenteral nutrition
without supplementation of copper, particularly in the setting of poor intestinal reabsorption. Copper
is typically absorbed in the small intestine and may be decreased as a result of competitive
absorption of iron and/or zinc.
Common symptoms of copper deficiency in infancy include: hypochromic anemia, neutropenia
and osteoporosis. Affected infants may also have: failure to thrive, pallor, hypotonia, and additional
bone changes, such as metaphyseal irregularities and wormian bones.
Reference:
Giles E, Doyle LW. Copper in extremely low-birthweight or very preterm infants. NeoReviews.
2007;8:e159-e163
Fluids, Electrolytes, Nutrition & Renal Answer 16
E. None of the drugs is an absolute contraindication for breastfeeding
The use of maternal medications during pregnancy for the management of pain, as well as
depression and other mood disorders, is becoming increasingly more common. While these
medications increase the risk of an infant developing neonatal abstinence syndrome (NAS), maternal
use of these medications is not an absolute contraindication to breastfeeding. Because safety
information about medication use during pregnancy and lactation is frequently revised, clinicians
should refer to an updated source prior to making recommendations about usage.
Selective serotonin reuptake inhibitors are generally considered safe in breastfeeding, although
there are some case reports of increased colic and prolonged crying with fluoxetine. However,
because women with a history of depression have a higher risk of developing postpartum depression,
the risks and benefits of stopping this medication must be weighed against the adverse consequences
of postpartum depression. Opiates, including morphine, fentanyl, codeine and hydrocodone, are
believed to be safe with breastfeeding. All are expressed in breastmilk, but in small amounts. The
use of meperedine has been associated with increased sedation in the newborn. Methadone is not a
contraindication to breastfeeding; only small amounts have been detected in breast milk.
Breastfeeding is contraindicated for women who continue to use illicit substances postpartum.
Reference:
Burgos AE, Burke Jr BL. Neonatal abstinence syndrome. NeoReviews. 2009;10(5):e222-e228
Fluids, Electrolytes, Nutrition & Renal Answer 17
B. Hemolysis, anemia, reticulocytosis
Vitamins E, A, D, and K are fat-soluble vitamins. Vitamin E is an antioxidant and is administered
when an infant is receiving iron supplementation to prevent iron-induced hemolysis. Vitamin E
deficiency can cause hemolytic anemia, reticulocytosis, thrombocytosis, acanthocytosis, and
neurologic sequelae.
Vitamin K deficiency causes bleeding diathesis because of effects on the clotting factors II, VII,
IX, and X. Vitamin B12 and folate deficiency cause macrocytic anemia with hypersegmented
neutrophils. Photophobia and conjunctivitis are effects of Vitamin A deficiency. Vitamin C
deficiency can cause poor wound healing and mucosal bleeding.
Reference:
Martin RJ, Fanaroff AA, Walsh MC. Fanaroff and Martin’s Neonatal-Perinatal Medicine Diseases of
the Fetus and Infant. St. Louis: Mosby, 9th edition, 2010
Fluids, Electrolytes, Nutrition & Renal Answer 18
E. More long-chain unsaturated fatty acids
 Human milk contains a greater amount of long-chain unsaturated fatty acids compared to cow’s
milk. Human milk also contains greater amounts of carnitine, cholesterol, and docosahexaenoic acid
compared with cow’s milk. Most amino acid amounts are lower in breastmilk compared with cow’s
milk.
References:
American Academy of Pediatrics Committee on Nutrition. Pediatric Nutrition Handbook. 6th
edition. Elk Grove, IL: American Academy of Pediatrics, 2008
Adamkin DH. Nutritional Strategies for the Very Low Birthweight Infant. Cambridge, UK:
Cambridge University Press, 2009
Fluids, Electrolytes, Nutrition & Renal Answer 19
E. More long-chain polyunsaturated fatty acids
Preterm breastmilk is different than term breastmilk. Premature milk contains more protein,
sodium, and chloride than term human milk. However, the amount of protein supplied is still
insufficient for adequate growth in a premature infant and protein supplementation is still required.
The amount of lactose is lower in premature breastmilk.
References:
American Academy of Pediatrics Committee on Nutrition. Pediatric Nutrition Handbook. 6th
edition. Elk Grove, IL: American Academy of Pediatrics, 2008
Adamkin DH. Nutritional Strategies for the Very Low Birthweight Infant. Cambridge, UK:
Cambridge University Press, 2009
Bitman J, Wood L, Hamosh M, Hamosh P, Mehta NR. Comparison of the lipid composition of breast
milk from mothers of term and preterm infants. Am J Clin Nutr. 1983;38:300-312
Kovács A, Funke S, Marosvölgyi T, Burus I, Decsi T. Fatty acids in early human milk after preterm
and full-term delivery. J Pediatr Gastro Nutr. 2005;41:454-459
Saarela T, Kokkonen J, Koivisto M. Macronutrient and energy contents of human milk fractions
during the first six months of lactation. Acta Paediatrica. 2005;94:1176-1181
Fluids, Electrolytes, Nutrition & Renal Answer 20
A. Equal amount of protein
Foremilk contains higher amounts of lactose but lower concentrations of fat than hindmilk; the
protein content is the same.
Reference:
American Academy of Pediatrics Committee on Nutrition. Pediatric Nutrition Handbook. 6th
edition. Elk Grove, IL: American Academy of Pediatrics, 2008
Fluids, Electrolytes, Nutrition & Renal Questions 21-30
Fluids, Electrolytes, Nutrition & Renal Question 21
Which of the following statements about the fat content of human milk is INCORRECT?
A.Cholesterol is a negligible component of breast milk and varies by maternal diet
B.Fat is responsible for 50% of the caloric content of breast milk
C.Human milk contains lipases to aid in fat digestion and absorption
D.Human milk contains substantial amounts of long-chain polyunsaturated fatty acids
E.Triglycerides are the most variable component of breast milk, dependent on gestational age and
maternal diet
Fluids, Electrolytes, Nutrition & Renal Question 22
In order to prevent negative nitrogen balance, negative energy balance, and catabolic metabolic
state, protein should provide what percentage of kilocalories in parenteral nutrition?
A.< 5%
B.7% to 15%
C.20% to 25%
D.30% to 50%
E.> 50%
Fluids, Electrolytes, Nutrition & Renal Question 23
Of the following, energy expenditure in a neonate is highest for:
A.Activity
B.Cold stress
C.Fecal losses
D. Nutritional storage and synthesis
E. Resting metabolic rate
Fluids, Electrolytes, Nutrition & Renal Question 24
Which of the following statements about trace metals and iron is INCORRECT?
A.Chromium plays a role in carbohydrate and lipid metabolism, though clinical deficiency remains
to be described
B.Copper is critical for red blood cell production
C.Iron should not be included routinely in parenteral nutrition preparations because of its potential
to suppress immune function and generate free oxygen radicals
D.Selenium is important for proper axonal development in the central nervous system
E.Zinc is a vital trace element important for bone development
Fluids, Electrolytes, Nutrition & Renal Question 25
Which of the following is a TRUE statement about preterm infant formula?
A.All preterm formulas are hyperosmolar as a result of increased nutrient content
B.Preterm formula contains about 50% more protein than term formula
C.Preterm formula contains higher lactose amounts compared with term formula
D. Preterm formula is higher in iron content than term formula
E.The sodium content of preterm formula is the same as term formula and human milk
Fluids, Electrolytes, Nutrition & Renal Question 26
Which of the following statements about short bowel syndrome is FALSE?
A.Loss of the ileocecal valve may lead to diarrhea as a result of reflux of bacteria from the colon
B.Resection of the colon can result in dehydration and loss of electrolytes
 C.Resection of the jejunum leads to malabsorption of protein, fat, and carbohydrate
D.Steatorrhea can result from complete jejunal resection along with fat-soluble vitamin and zinc
deficiencies
E. The ileum can compensate for the absorptive capacity of the jejunum
Fluids, Electrolytes, Nutrition & Renal Question 27
An infant has a primary metabolic acidosis caused by a proximal renal tubular acidosis, Type II.
Which of the following is the most likely urine profile in this infant?
H+ HCO3- pH K+
A. High Low Low Low
B. High Normal Low Normal/high
C. Low Normal High Normal/high
D. Low High High Low
E. Normal/high High Normal/low High
Fluids, Electrolytes, Nutrition & Renal Question 28
Infants with renal tubular acidosis often have failure to thrive; this is caused by which of the
following?
A.Cardiac dysfunction as a result of chronic hypocalcemia
B.Chronic dehydration as a result of polyuria and inability to concentrate urine
C.Chronic hypocalcemia leading to bone demineralization and impaired long bone growth
D.Decreased secretion of growth hormone as a result of low serum pH
E.Direct effect of hypochloremia
Fluids, Electrolytes, Nutrition & Renal Question 29
The reduced ability of the preterm infant to concentrate urine is related to all of the following
EXCEPT:
A.Low serum urea concentration
B.More permeable glomerular basement membrane
C.Reduced Na+ absorption in the thick ascending loop leading to low medullary osmolality
D.Short loop of Henle
E.Tubule insensitivity to vasopressin
Fluids, Electrolytes, Nutrition & Renal Question 30
A male fetus is found to be small for gestational age with a large placenta. The maternal serum
and amniotic fluid alpha-fetoprotein concentrations are elevated. The infant is born preterm and
admitted to the neonatal intensive care unit with severe proteinuria, hypoproteinemia, and
hyperlipidemia.
Which of the following is the most likely cause of the findings described above?
A.Congenitally acquired human immunodeficiency virus
B.Congenital nephrotic syndrome, Finnish type
C.Diffuse mesangial sclerosis
D.Membranous nephropathy
Fluids, Electrolytes, Nutrition & Renal Answers 21-30
Fluids, Electrolytes, Nutrition & Renal Answer 21
A. Cholesterol is a negligible component of breast milk and varies by maternal diet
Cholesterol is necessary for somatic growth and production of bile salts and steroid hormones; it
has a constant concentration in breast milk and is independent of maternal diet. Fat is responsible for
50% of the caloric content of breast milk. Human milk contains lipases to aid in fat digestion and
absorption. Human milk contains substantial amounts of long-chain polyunsaturated fatty acids. The
most variable component of human milk is triglycerides, which is dependent on gestational age and
maternal diet. Other components of human milk include: carnitine, inositol (cell membrane synthesis,
surfactant production, and retinal development), and choline (central nervous system development).
References:
Adamkin DH. Nutritional Strategies for the VLBW Infant. Cambridge, UK: Cambridge University
Press, 2009
American Academy of Pediatrics Committee on Nutrition. Pediatric Nutrition Handbook. 6th
edition. Elk Grove, IL: American Academy of Pediatrics, 2008
Fluids, Electrolytes, Nutrition & Renal Answer 22
B. 7% to 15%
Administration of protein is critical for the maintenance of positive energy, a positive nitrogen
balance, and avoiding catabolism. To avoid a negative nitrogen balance, protein should provide
between 7% and 15% of kilocalories. One gram of protein yields 4 kcals of energy. Minimal goals
for protein administration are 2.5 to 3.5 g/kg/day for preterm infants and 2 to 2.5 g/kg/day for term
infants.
Reference:
Committee on Nutrition. Pediatric Nutrition Handbook. 6th ed. Elk Grove, IL: American Academy of
Pediatrics; 2008
Fluids, Electrolytes, Nutrition & Renal Answer 23
E. Resting metabolic rate
Resting metabolic rate requires the greatest amount of energy expenditure in a neonate, expending
40 to 60 kcals/kg/day. A summary of caloric expenditure in the neonate is summarized in the Table.
Form of Energy Caloric Expenditure in Neonate
Resting metabolic rate 40-60 kcals/kg/day
Activity 0-5 kcals/kg/day
Cold stress 0-5 kcals/kg/day
Nutrition processing Excretion: 15 kcals/kg/day
Storage: 20-30 kcals/kg/day
Synthesis: 15 kcals/kg/day
Total 90-120 kcals/kg/day
Note: 1 kcal = 1 cal and is defined as the amount of heat required to raise the temperature of 1 kg of water from 14.5ºC to
15.5ºC; Modified from: Martin RJ, Fanaroff AA, Walsh MC. Fanaroff and Martin’s Neonatal-Perinatal Medicine
Diseases of the Fetus and Infant. St. Louis: Mosby, 9th edition, 2010
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Martin RJ, Fanaroff AA, Walsh MC. Fanaroff and Martin’s Neonatal-Perinatal Medicine Diseases of
the Fetus and Infant. St. Louis: Mosby, 9th edition, 2010
Fluids, Electrolytes, Nutrition & Renal Answer 24
D. Selenium is important for proper axonal development in the central nervous system
Selenium is an essential component of glutathione peroxidase, protecting the body from oxidant
damage. Along with zinc, copper, chromium, manganese, molybdenum, and iodine, selenium is an
essential trace element that needs to be included in parenteral nutrition (PN) preparations. Selenium
is not involved in axonal development. Chromium plays a role in carbohydrate and lipid metabolism,
though clinical deficiency remains to be described. Copper is critical for red blood cell production,
hemoglobin formation, and iron absorption. Iron is not routinely included in PN because of concerns
about iron overload, suppression of immune function, and the propagation of free oxygen radicals.
Iron may be safely given enterally once feedings are established. Zinc is a vital trace element
important for bone development, and is important for the function of transcriptional factors and
steroid receptors.
References:
Adamkin DH. Nutritional Strategies for the Very Low Birthweight Infant. Cambridge, UK:
Cambridge University Press, 2009
Vincent JB. Recent advances in the nutritional biochemistry of trivalent chromium. Proc Nutr Soc.
2004;63(1):41-47
Fluids, Electrolytes, Nutrition & Renal Answer 25
B. Preterm formula contains about 50% more protein than term formula
Compared to term infant formula, preterm formula has a high protein concentration, lower lactose
concentration, and higher sodium content. Preterm formula generally has lower iron content, though
most formulas are offered with and without iron fortification. Despite being enriched nutritionally,
preterm formulas are iso-osmolar unless concentrated beyond 24 kcals/ounce.
Reference:
Adamkin DH. Nutritional Strategies for the Very Low Birthweight Infant. Cambridge, UK:
Cambridge University Press, 2009
Fluids, Electrolytes, Nutrition & Renal Answer 26
D. Steatorrhea can result from complete jejunal resection along with fat-soluble vitamin and zinc
deficiencies
The jejunum is responsible for the absorption of protein, fat, and carbohydrate in addition to iron,
calcium, and magnesium. The ileum is responsible for uptake of vitamin B12; the release of
neurologically important hormones; and the absorption of bile salts, fats, fat-soluble vitamins, and
zinc. The ileocecal valve is crucial for the regulation of transit time and prevention of colonic
bacteria from entering the small intestine. The colon is responsible for water and electrolyte
reabsorption. Though the jejunum is responsible for some fat absorption, the ileum is responsible for
the absorption of fat-soluble vitamins and zinc. The ileum has the ability to compensate for some of
the functions of the jejunum.
Reference:
Adamkin DH. Nutritional Strategies for the Very Low Birthweight Infant. Cambridge, UK:
Cambridge University Press, 2009
Fluids, Electrolytes, Nutrition & Renal Answer 27
E. Normal/high H+, high HCO3-, normal/low pH, high Ca++, high K+
There are three main types of renal tubular acidosis (RTA): I, II, and IV.
Type I RTA (also known as distal or classic RTA) is characterized by the inability of the distal
tubule to secrete hydrogen ion, leading to a lower serum pH and higher urine pH. Type I RTA can be
primary (mostly autosomal dominant) or attributable to a secondary cause, such as interstitial renal
disease, autoimmune disease, or drug-induced. Infants affected by Type I RTA can be treated
effectively with administration of bicarbonate. This is represented by answer Option A.
Type II, or proximal, RTA is a consequence of excessive bicarbonate loss in the proximal tubule.
It can also be primary (autosomal recessive or dominant) or secondary, often found in preterm infants
or infants with Fanconi syndrome, Lowe syndrome, cystinosis, or tyrosinemia. Urine bicarbonate
concentrations are extremely elevated, but urine pH may be low or normal as a result of the preserved
renal ability to excrete hydrogen ion in the distal tubule. These results are represented by Option E.
Infants affected by Type II RTA can be treated with administration of base (bicarbonate or citrate);
recovery is typical.
Type IV RTA is related to aldosterone deficiency or resistance. It has five subtypes, with 1, 4,
and 5 being most common. Individuals affected with subtype 1 are aldosterone-deficient, with salt-
wasting and hyperchloremia; this subtype is related to Addison’s disease and congenital adrenal
hyperplasia. Subtype 4 (pseudohypoaldosteronism) is rare and also has salt-wasting. Subtype 5
(early childhood RTA) is the most common subtype; it does not have salt-wasting. This is
represented by answer Option B.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Chan JC, Scheinman JI, Roth KS. Consultation with the nephrologist: renal tubular acidosis. Pediatr
Rev. 2001;22:277-287
Fluids, Electrolytes, Nutrition & Renal Answer 28
D. Decreased secretion of growth hormone as a result of low serum pH
The poor growth in patients with renal tubular acidosis (RTA) is related to the direct effects of
serum acid leading to a decreased release of growth hormone. In addition, affected individuals have
less interest in feeding, presumably because of the metabolic acidosis. While RTA is associated with
polyuria, hypocalcemia, and hypokalemia, none of these are associated with failure to thrive.
Typically RTA is associated with hyperchloremia, rather than hypochloremia, as a result of
preferential excretion of sodium bicarbonate and reabsorption of sodium chloride in the setting of
acidic urine.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Chan JC, Scheinman JI, Roth KS. Consultation with the nephrologist: renal tubular acidosis. Pediatr
Rev. 2001;22:277-287
Fluids, Electrolytes, Nutrition & Renal Answer 29
B. More permeable glomerular basement membrane
The concentrating ability of the human kidney increases with increasing gestational age. The
maximum urine osmolality in preterm infants is 500 mOsm/L, while term infants can attain a urine
osmolality of 800 mOsm/L. Older children and adults can reach an osmolality of 1200 mOsm/L. The
premature infant’s reduced ability to concentrate urine is related to: 1) tubule insensitivity to
vasopressin; 2) low serum urea concentration; 3) reduced Na+ absorption in the thick ascending loop
leading to low medullary osmolality; and 4) a short loop of Henle. The permeability of the premature
infant’s glomerular basement membrane increases with advancing gestational age.
References:
Fanaroff AA, Martin RJ, Walsh M (eds.). Neonatal-Perinatal Medicine: Diseases of the Fetus and
 Infant. 8th edition. Philadelphia: Mosby-Elsevier, 2006
Fluids, Electrolytes, Nutrition & Renal Answer 30
B. Congenital nephrotic syndrome, Finnish type
Congenital nephrotic syndrome is characterized by proteinuria, hypoproteinemia, hyperlipidemia,
and edema. The vast majority of affected infants have clinical symptoms in the first month of life.
The Finnish type is most common. This type has an autosomal recessive pattern of inheritance and is
caused by a mutation in the NPHS1 gene coding for the nephrin protein. Fetal findings include small
for gestational age, a large placenta, and an elevated maternal serum or amniotic fluid alpha-
fetoprotein. Proteinuria can lead to impaired immune function with loss of immunoglobulins. As a
result of urinary losses of anti-coagulant proteins, infants are at increased risk of thrombosis.
Individuals affected by congenital nephrotic syndrome require dialysis and renal transplant.
Infants affected by diffuse mesangial sclerosis have similar clinical findings as congenital nephrotic
syndrome, though the fetal findings are absent. Clinical onset typically occurs later in infancy and
may be associated with hypertension. Infection with toxoplasmosis, rubella, syphilis,
cytomegalovirus, or herpes simplex viruses, human immune deficiency, and Hepatitis B have all been
associated with congenital nephrotic syndrome.
Reference:
Kliegman RM, Behrman RE, Jenson HB, Stanton B (eds). Nelson Textbook of Pediatrics. 18th
edition. Philadelphia: Saunders, 2007
Fluids, Electrolytes, Nutrition & Renal Questions 31-40
Fluids, Electrolytes, Nutrition & Renal Question 31
A male fetus is suspected of having Lowe syndrome, an X-linked disorder impacting the enzymatic
function of the cellular Golgi apparatus.
Which of the following organ systems is NOT involved in Lowe syndrome?
A.Endocrine/metabolic
B.Neurologic
C.Ophthalmologic
D.Renal
E.Reproductive
Fluids, Electrolytes, Nutrition & Renal Question 32
A neonatologist is caring for a female infant with dysmorphic facial features, including triangular
facies, protruding ears, large eyes with strabismus, and a drooping mouth. A history of
polyhydramnios is noted. The neonatologist is concerned that this infant has Bartter syndrome.
The most likely laboratory findings in this infant with presumed Bartter syndrome is:
A.Hyperkalemia, metabolic acidosis, high urine sodium chloride
B.Hyperkalemia, metabolic acidosis, hypercalciuria
C.Hypokalemia, metabolic acidosis, high urine sodium chloride
D.Hypokalemia, metabolic alkalosis, hypercalciuria
E.Hypokalemia, normal serum pH, hypercalciuria
Fluids, Electrolytes, Nutrition & Renal Question 33
Preterm infants have higher serum creatinine concentrations in the first weeks of life compared to
term infants because:
A.Preterm infants have a greater creatinine clearance because of impaired glomerular filtration
B.Preterm infants have greater reabsorption of filtered creatinine in leaky renal tubules
C.Both
D.Neither
Fluids, Electrolytes, Nutrition & Renal Question 34
True or False.
Autosomal recessive polycystic kidney disease can be seen with prenatal ultrasonography as early
as 16 weeks’ gestation and rarely presents with associated congenital hepatic fibrosis and some
degree of biliary dysgenesis.
Fluids, Electrolytes, Nutrition & Renal Question 35
Which of the following sequelae is most common among infants with autosomal recessive
polycystic kidney disease?
A.Chronic lung disease
B.Death
C.Hypernatremia
D.Hypertension
E.Poor growth
Fluids, Electrolytes, Nutrition & Renal Question 36
Which of the following statements is TRUE about multicystic dysplastic kidney disease in the
newborn?
A.Always presents as an abdominal mass on physical examination
B.Bilateral disease is usually severe, and presents with severe oligohydramnios and pulmonary
hypoplasia
C.Most newborns have an associated urinary tract abnormality, such as vesicoureteral reflux
D.Unilateral disease usually presents with elevated creatinine concentrations
E.B, C, and D
F.B and C
Fluids, Electrolytes, Nutrition & Renal Question 37
A 6-week old infant born at 24 weeks’ gestation has required continuous parenteral nutrition
because of multiple episodes of necrotizing enterocolitis. Recent laboratory evaluation demonstrates
significant anemia.
Which of the following has a critical role in red blood cell production and hemoglobin formation?
A.Chromium
B.Copper
C.Manganese
D.Selenium
E. Zinc
Fluids, Electrolytes, Nutrition & Renal Question 38
Renal agenesis occurs as a result of failure of development of the:
A.Early pronephros
B.Mesonephros
C.Metanephros
D.Ureteric bud
Fluids, Electrolytes, Nutrition & Renal Question 39
True or False.
Renal tubular acidosis can be a transient developmental problem in the neonate and young infant.
Fluids, Electrolytes, Nutrition & Renal Question 40
True or False.
The prenatal diagnosis of hydronephrosis is almost always indicative of a renal or urological
pathology in the newborn.
Fluids, Electrolytes, Nutrition & Renal Answers 31-40
Fluids, Electrolytes, Nutrition & Renal Answer 31
A. Endocrine/metabolic
Lowe syndrome is an X-linked recessive disorder affecting the enzymatic function of the cellular
Golgi apparatus. It is also known as oculocerebrorenal syndrome. As such, the organs affected
include: eyes (cataracts, glaucoma), nervous system (hypotonia, areflexia, severe mental deficiency),
kidneys (tubular dysfunction, proteinuria, aminoaciduria, possible congenital nephrotic syndrome),
and the reproductive system (cryptorchidism). Lowe syndrome can be prenatally diagnosed by
elevated maternal and amniotic alpha-fetoprotein concentrations with increased nucleotide pyro-
phosphatase in skin fibroblasts.
Reference:
Kliegman RM, Behrman RE, Jenson HB, Stanton B (eds). Nelson Textbook of Pediatrics. 18th
edition. Philadelphia: Saunders, 2007
Fluids, Electrolytes, Nutrition & Renal Answer 32
D. Hypokalemia, metabolic alkalosis, hypercalciuria
Bartter syndrome is a clinical disease caused by a number of defects in sodium, chloride, and
potassium transport in the loop of Henle. It manifests as either a severe antenatal or classic form
presenting in later infancy or childhood. Antenatal history may be notable for polyhydramnios.
Physical examination findings include triangular facies, protruding ears, large eyes with strabismus,
and drooping mouth. Common electrolyte derangements include hypokalemic metabolic alkalosis
with hypercalciuria. Affected infants may develop dehydration and hypotension related to severe
salt-wasting. Management requires replacement of sodium and potassium and close attention to fluid
balance.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Kliegman RM, Behrman RE, Jenson HB, Stanton B (eds). Nelson Textbook of Pediatrics. 18th
edition. Philadelphia: Saunders, 2007
Fluids, Electrolytes, Nutrition & Renal Answer 33
B. Preterm infants have greater reabsorption of filtered creatinine in leaky renal tubules
Preterm infants have a lower creatinine clearance because of impaired glomerular filtration and
they have greater reabsorption of filtered creatinine in leaky renal tubules. The range of serum
creatinine concentrations based on postnatal age and birth gestational age and shown in the Table.
Normal Serum Creatinine (mg/dL) Based on Gestational Age (mean ± SD)
Postnatal Age 25-28 Weeks 29-34 Weeks 38-42 Weeks
Week 1 1.4±0.8 0.9±0.3 0.5±0.1
Week 2-8 0.9±0.5 0.7±0.3 0.4±0.1
> Week 8 0.4±0.2 0.35* 0.4±0.1
* n= 1, no SD
Modified from: Su SW, Stonestreet BS. Core Concepts: Neonatal glomerular filtration rate. NeoReviews. 2010;e71-e721
Reference:
Su SW, Stonestreet BS. Core Concepts: Neonatal glomerular filtration rate. NeoReviews.
2010;e714-e721
Fluids, Electrolytes, Nutrition & Renal Answer 34
False
 Autosomal recessive polycystic kidney (ARPKD) disease can be diagnosed by prenatal
ultrasonography with findings of large echogenic kidneys with numerous cysts. However, these
findings are not present until later in gestation. In contrast, fetuses with multicystic dysplastic kidneys
have large echogenic kidneys with thin-walled cysts that are visible with prenatal ultrasonography by
20 weeks’ gestation. ARPKD is associated with congenital hepatic fibrosis and some degree of
biliary dysgenesis.
Reference:
Cohen JN, Ringer SA. Congenital kidney abnormalities: Diagnosis, management, and palliative
care. NeoReviews. 2010;11(5):e226-e235
Fluids, Electrolytes, Nutrition & Renal Answer 35
D. Hypertension
A recent large cohort of infants with autosomal recessive polycystic kidney disease showed that
65% developed hypertension. Almost all had hyponatremia as a result of underlying dysregulation of
sodium reabsorption in the abnormally formed collecting ducts. This hyponatremia leads to
intravascular volume expansion followed by severe hypertension. In this cohort, 25% died, 12% of
survivors had chronic lung disease, 42% of survivors had chronic renal insufficiency, and 25% of
survivors had poor growth.
Reference:
Cohen JN, Ringer SA. Congenital kidney abnormalities. NeoReviews. 2010;11(5):e226-e235
Fluids, Electrolytes, Nutrition & Renal Answer 36
F. Bilateral disease is usually severe, and presents with severe oligohydramnios and pulmonary
hypoplasia. Most newborns have an associated urinary tract abnormality, such as vesicoureteral
reflux
Multicystic dysplastic kidney is the most common cause of an abdominal mass in the newborn.
However, many dysplastic kidneys involute, even in the prenatal period so an abdominal mass may
NOT be present at birth in an affected infant. Bilateral disease is usually severe, and presents with
severe oligohydramnios and pulmonary hypoplasia, but those with unilateral disease usually lack
signs or symptoms, other than a possible abdominal mass. Approximately 20% to 43% have a
urinary tract abnormality such as vesicoureteral reflux.
Reference:
Cohen JN, Ringer SA. Congenital kidney abnormalities. 2010;11(5):e226-e235
Fluids, Electrolytes, Nutrition & Renal Answer 37
B: Copper
Copper is critical for red blood cell production and hemoglobin formation. It is also important for
absorption of iron and contributes to the activity of multiple enzymes. Clinical effects of copper
deficiency include anemia, osteoporosis, depigmentation of hair and skin, neutropenia, poor weight
gain, hypotonia, and ataxia in later life. The Table summarizes the function of 6 trace elements and
their clinical manifestations if the element is deficient.
Trace Function Clinical Effects of Deficiency
Element
Chromium Regulates glucose levels In animals – diabetes
because of role in insulin In humans – unknown
metabolism
Copper Critical for production of Anemia
red blood cells as well as Osteoporosis
 hemoglobin formation Depigmentation of hair and skin
Important for absorption Neutropenia
of iron Poor weight gain
Associated with multiple Hypotonia, ataxia later in life
enzyme activities
Iron Component of Anemia (microcytic, hypochromic)
hemoglobin and Failure to thrive
myoglobin required for
transport of oxygen and
carbon dioxide
Absorbed predominantly
in the duodenum and
proximal jejunum
Vitamin C enhances
absorption
Manganese Role in enzyme activation Unknown
(e.g., superoxide
dismutase)
Important for normal bone
structure
Role in CHO metabolism
Selenium Cofactor for glutamine In animals – muscle disease
peroxidase In humans – cardiomyopathy
Zinc Important component of Acrodermatitis enteropathica
several enzymes (e.g., Autosomal recessive disorder in which there is an
carbonic anhydrase and abnormality of zinc absorption or transport
carboxypeptidase) Failure to thrive, alopecia, diarrhea, dermatitis
Important for growth (commonly perianal), ocular changes, rash (crusted,
erythematous, involving face, extremities and
anogenital areas), nail hypoplasia or dysplasia
Acquired zinc deficiency
Premature infants receiving inadequate amounts of zinc
Maternal zinc deficiency can lead to fetal growth
restriction, congenital anomalies
Infants with malabsorption, poor weight gain poor
wound healing, anemia (iron deficiency)
Modified from Behrman RE, Kliegman RM, Arvin AM (eds). Nelson Textbook of Pediatrics.
15th edition. Philadelphia: WB Saunders Co; 1996, p 146-147; and Printed with permission
from Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010, p 303
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Kleigman RM, et al. Nelson Textbook of Pediatrics. 18th ed. Philadelphia: WB Sanders Co; 2007
D. Ureteric bud
The development of the kidney involves multiple stages. First, the pronephros forms but then
regresses by 4 weeks’ gestation. Next, the mesonephros forms, which gives rise to the mesonephric
tubule and duct. The mesonephric duct gives rise to the ureteric bud, which eventually becomes the
collecting ducts after interacting with undifferentiated mesoderm. These eventually become the
nephrons. Renal agenesis occurs when the ureteric bud fails to develop. If the ureteric bud forms, but
there is no interaction with the undifferentiated mesoderm, renal dysplasia occurs.
Reference:
Cohen JN, Ringer SA. Congenital kidney abnormalities: Diagnosis, management, and palliative
care. 2010;11(5):e226-e235
Fluids, Electrolytes, Nutrition & Renal Answer 39
True
Type 2 (Proximal) Renal Tubule Acidosis (RTA) associated with diminished bicarbonate
reabsorption in the proximal tubule is a transient developmental problem in the neonate and young
infant. Term infants may have a mild RTA with serum bicarbonate concentrations of 20 to 24 mEq/L
and if preterm infants are affected, serum bicarbonate concentrations may be as low as 15 mEq/L.
This transient failure of bicarbonate reabsorption usually improves progressively during infancy.
Reference:
Ringer SA. Renal tubular acidosis. NeoReviews. 2010;11(5):e252-e256
Fluids, Electrolytes, Nutrition & Renal Answer 40
False
The prenatal diagnosis of hydronephrosis is not usually associated with a specific cause and often
resolves before birth.
Reference:
Ringer SA. Hydronephrosis in the fetus and neonate. NeoReviews. 2010;11(5):e236-242
Fluids, Electrolytes, Nutrition & Renal Questions 41-50
Fluids, Electrolytes, Nutrition & Renal Question 41
True or False.
Prenatal hydronephrosis that resolves prior to delivery does not require postnatal evaluation.
Fluids, Electrolytes, Nutrition & Renal Question 42
Which of the following statements about intrauterine vesicoamniotic shunt placement is accurate?
A.This procedure is indicated for fetuses with severe oligohydramnios that presents in the 3rd
trimester
B.This procedure poses great risk because infections and preterm birth can occur
C.Shunt failure rarely occurs
D.A and B
E.All of the above
Fluids, Electrolytes, Nutrition & Renal Question 43
The most common cause of prenatal hydronephrosis is:
A.Megaureter
B.No specific anomaly
C.Ureteropelvic junction obstruction
D.Vesiculoureteral reflux
Fluids, Electrolytes, Nutrition & Renal Question 44
The most common cause of acute renal failure in the neonate is:
A.Cardiac surgery
B.Dehydration
C.Hypoxic-ischemic encephalopathy
D.Sepsis
Fluids, Electrolytes, Nutrition & Renal Question 45
Please complete the Table below that compares the urine indices of prerenal renal failure with
intrinsic renal failure.
Urine
Urine Fractional Excretion of Sodium
Sodium
Osmolality (FeNa)
(high or
(high or low) <2 % or >2 %
low)
Prerenal Failure
Renal Tubular
Injury
Fluids, Electrolytes, Nutrition & Renal Question 46
Which hormone plays the biggest role in fetal growth?
A.Chorionic gonadotropin
B.Growth hormone
C.Insulin-like growth factor
D.Thyroid hormone
Fluids, Electrolytes, Nutrition & Renal Question 47
Which hormone plays the biggest role in placental regulation of fetal nutrient supply?
A.Growth hormone
B.Insulin-like growth factor
 C.Placental lactogen
D.Thyroid hormone
Fluids, Electrolytes, Nutrition & Renal Question 48
Please match the whey: casein protein ratio of the following milk sources:
Milk Source Whey: Casein Ratio
Colostrum 20:80
Mature milk 60:40
Predominately casein formula 55:45
Predominantly whey formula 80:20
Fluids, Electrolytes, Nutrition & Renal Question 49
Which of the following is thought to play a role in brain and retinal development?
A.Linolenic acid
B.Long-chain polyunsaturated fatty acids
C.Short and medium-chain triglycerides
D.Stearic acid
Fluids, Electrolytes, Nutrition & Renal Question 50
Which of the following are contraindications to breastfeeding in the United States?
A.Known maternal cytomegalovirus infection
B.Herpes simplex viral lesion on the breast
C.Hepatitis C
D.Human immunodeficiency virus
E.Mastitis
F.PPD positive, chest radiograph negative
G.A, B, C, D
H.A, B, D
I.B, D
Fluids, Electrolytes, Nutrition & Renal Answers 41-50
Fluids, Electrolytes, Nutrition & Renal Answer 41
False
Prenatal management of hydronephrosis includes serial ultrasonography to identify resolution or
disease progression. Monitoring should also include evaluation for oligohydramnios. Postnatal
management should ALWAYS include at least one renal ultrasound, even if the hydronephrosis
resolves prenatally. Most practitioners wait until 7-10 days of life to ensure that normal water losses
have occurred and hydration status is stable.
Reference:
Ringer SA. Hydronephrosis in the fetus and neonate. NeoReviews. 2010;11(5):e236-242
Fluids, Electrolytes, Nutrition & Renal Answer 42
B. This procedure poses great risk because infections and preterm birth can occur
Vesicoamniotic shunt placement may be indicated when severe oligohydramnios is present in the
fetus during the second trimester (~20 weeks’ gestation) because of the high risk of lung hypoplasia if
the oligohydramnios is untreated. The procedure poses great risk because of the possibilities of
infection and preterm birth. Shunt failure or displacement is common, but the procedure can decrease
oligohydramnios and preserve lung function.
Fluids, Electrolytes, Nutrition & Renal Answer 43
B. No specific anomaly
Hydronephrosis is one of the most commonly diagnosed prenatal findings. The incidence ranges
from 1% to 5%. Approximately half are not associated with a specific cause and resolve before
birth.
Reference:
Ringer SA. Hydronephrosis in the fetus and neonate. NeoReviews. 2010;11:e236-242
Fluids, Electrolytes, Nutrition & Renal Answer 44
C. Hypoxic-ischemic encephalopathy
Hypoxic-ischemic encephalopathy has been described as the most frequent cause of acute renal
failure in the neonate. Both oliguric and non-oliguric renal failure have been described in association
with severe asphyxia.
Reference:
Ringer SA. Acute renal failure in the neonate. NeoReviews. 2010;11:e243-e251
Fluids, Electrolytes, Nutrition & Renal Answer 45
Urine Fractional Excretion of Sodium
Urine Sodium
Osmolality (FeNa)
(high or low)
(high or low) <2 % or >2 %
Prerenal Failure High (> 350 Low (< 20 to 30
<2 %
mOsm/L) mEq/L)
Renal Tubular Low (<350 High (>30 to 40
>2 %
Injury mOsm/L) mEq/L)
Glomerular filtration rate depends on 4 parameters:
1. Flow in the afferent arteriole
2. Transcapillary hydraulic pressure
3. Colloid osmotic pressure
4. Permeability of the glomerular capillaries
 Prerenal failure occurs because of decreased plasma flow rate. When renal perfusion decreases,
catecholamines are released, which causes systemic vasoconstriction with dilation of the afferent
arteriole and constriction of the efferent arteriole, thereby preserving renal blood flow. Urine
osmolality is increased and urine sodium concentration is low because the kidney tries to absorb as
much sodium and water to increase systemic blood pressure. The fractional excretion of sodium
(FeNa) is usually <2 % in a newborn (and <1 % in a child with more mature kidneys). Renal tubular
injury causes the kidney to inappropriately excrete sodium and water, leading to a low urine
osmolality and high urine sodium.
Reference:
Ringer SA. Acute renal failure in the neonate. NeoReviews. 2010;11:e243-e251
Fluids, Electrolytes, Nutrition & Renal Answer 46
C. Insulin-like growth factor
Insulin-like growth factors I and II are important regulators of both placental and fetal growth.
Growth hormone and thyroid hormone are important factors involved in postnatal growth. Chorionic
gonadotropin and placental lactogen are placental hormones.
Reference:
Regnault TRH, Limesand SW, Hay WW. Factors influencing fetal growth. NeoReviews. 2(6):e119-
e128
Fluids, Electrolytes, Nutrition & Renal Answer 47
C. Placental lactogen
Placental lactogen plays a pivotal role in the growth and development of the fetus by coordinating
metabolic and nutrient supply from the pregnant woman to the developing fetus. Insulin-like growth
factors I and II are important regulators of both placental and fetal growth. Growth hormone and
thyroid hormone are important for postnatal growth.
Reference:
Regnault TRH, Limesand SW, Hay WW. Factors influencing fetal growth. NeoReviews. 2(6):e119-
e128
Fluids, Electrolytes, Nutrition & Renal Answer 48
Milk Source Whey: Casein Ratio
Colostrum 80:20
Mature milk 55:45
Predominately casein formula 20:80
Predominantly whey formula 60:40
Preterm formulas usually have an even higher protein content than term formulas. The whey:casein
ratio is 60:40.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Committee on Nutrition. Pediatric Nutrition Handbook. 6th ed. Elk Grove, IL: American Academy of
Pediatrics; 2008
Fluids, Electrolytes, Nutrition & Renal Answer 49
B. Long-chain polyunsaturated fatty acids
Long-chain polyunsaturated fatty acids, such as omega-6 and omega-3, are believed to be
important in brain and retinal development. Linolenic and linoleic acids are essential fatty acids;
stearic acid is also a fatty acid but is not essential. These fatty acids and short and medium-chain
triglycerides have not been associated with brain and retinal development.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Committee on Nutrition. Pediatric Nutrition Handbook. 6th ed. Elk Grove, IL: AAP; 2008
Fluids, Electrolytes, Nutrition & Renal Answer 50
I. Herpes simplex viral lesion on the breast and Human immunodeficiency virus
A herpes simplex viral (HSV) lesion on the breast is a contraindication to breastfeeding because
of the possibility of passage of HSV to the neonate. Similarly, in the United States, it is
contraindicated to breastfeed if the mother has human immunodeficiency virus (HIV). (This is not a
contraindication in other countries where the risk of mortality from dehydration is much higher than
the risk of acquiring HIV). Known active cytomegalovirus disease is a relative contraindication to
breastfeeding. Most recommend continuing breastfeeding, even in preterm infants because the
maternal antibodies, which pass through the breast milk may improve the severity of the infection.
Only active tuberculosis disease (PPD and chest radiograph positive with symptoms) is a
contraindication to breastfeeding. While a breast abscess is a contraindication for breastfeeding, a
woman with mastitis can still breastfeed. Maternal hepatitis C infection is not a contraindication to
breastfeed.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Pickering LK, Baker CF, Long SS, McMillan JA (eds). 2009 Red Book: Report of the Committee on
Infectious Diseases. 28th edition. Elk Grove Village, IL: American Academy of Pediatrics; 2009
Fluids, Electrolytes, Nutrition & Renal Questions 51-60
Fluids, Electrolytes, Nutrition & Renal Question 51
While managing the fluids and electrolytes of a 600 gram infant born at 26 weeks’ gestation, the
neonatology fellow notes that the infant’s 6-hour sodium concentration is 150 mEq/L.
Possible contributing factors to this infant’s hypernatremia include all of the following EXCEPT:
A. A higher insensible water loss (IWL) than expected
B.A lower glomerular filtration rate (GFR) for the preterm neonate than the full-term neonate
C.Hyper-osmotic urine osmolality
D.A and B
E.None of the above
Fluids, Electrolytes, Nutrition & Renal Question 52
An infant born at 24 weeks’ gestation is receiving 70% humidity in an isolette. The neonatology
fellow is involved in teaching a group of pediatric residents about extreme prematurity at this baby’s
bedside. One of the residents asks the fellow to explain the factors that contribute to insensible water
loss (IWL).
Of the following, the factor LEAST likely associated with increased IWL in an extremely
premature infant is:
A.Antenatal steroid exposure
B.Earlier postnatal age
C.Increased upper airway epithelial fluid loss
D.Placement on a radiant warmer compared with an isolette
E.Younger gestational age
Fluids, Electrolytes, Nutrition & Renal Question 53
A 6-day old full-term large-for-gestational-age infant with a birthweight of 4,000 grams presents
to the Emergency Room with seizures. The infant had been exclusively breastfeeding and had started
to appear jaundiced the day prior to presentation. The mother reported that the infant had been
breastfeeding for 5 minutes each feeding and had 1 wet diaper over the past 36 hours. The infant
currently weighs 2,800 grams. The Emergency Room physician orders several laboratory tests.
53a. All of the following laboratory values will likely be INCREASED in the infant in this vignette
EXCEPT:
A.Blood urea nitrogen
B.Calcium
C.Glucose
D.Potassium
E.Sodium
53b. This infant’s sodium concentration is 160 mEq/L. The Emergency Room team discusses the
approach to correct this infant’s free water deficit to a desired sodium concentration of 145 mEq/L.
Which of the following MOST closely represents this infant’s free water deficit?
A.150 mL
B.180 mL
C.210 mL
D.240 mL
E.270 mL
Fluids, Electrolytes, Nutrition & Renal Question 54
A 2-week old term infant is brought to the Emergency Room with seizures and is quickly
transferred to the Neonatal Intensive Care Unit. The grandmother reports that the mother has been
breastfeeding and supplementing the feedings with apple tea, which is mostly free water. The astute
medical student is concerned that the infant has water intoxication and suggests specific laboratory
testing, including a sodium concentration. The sodium concentration is 117 mEq/L. Although the risk
is low, the neonatologist asks the medical student to present an overview of cerebral demyelination.
Of the following, the most accurate statement about cerebral demyelination is:
A.In most cases of cerebral demyelination, the infant is symptomatic
B.It is associated with a rapid correction of the plasma sodium concentration by more than 25
mmol/L in 24 to 48 hours
C.It is not associated with hypoxemia
D.It is not associated with severe liver disease
E.The most sensitive test to diagnose cerebral demyelination is cranial ultrasonography
Fluids, Electrolytes, Nutrition & Renal Question 55
A female infant born at 24 weeks’ gestation has a birth weight of 500 grams. After admission to
the Neonatal Intensive Care Unit, the infant is placed in a humidified environment to address
insensible water loss (IWL).
Of the following, the primary mechanism of IWL in an extremely premature infant is:
A.Increased ambient humidity
B.Increased glomerular filtration rate
C.Increased urinary dilution
D.Transepidermal loss
E.Upper airway epithelial loss
Fluids, Electrolytes, Nutrition & Renal Question 56
A male newborn with prenatally diagnosed polycystic kidney disease is now 10 days old and has
anuria. A peritoneal catheter has been placed. While waiting for the catheter site to heal, the infant is
being managed with maximal medical therapy including fluid restriction and frequent monitoring of
his electrolytes.
Which of the following is NOT an indication for initiation of dialysis?
A.Creatinine > 5.0 mg/dL
B.Hyperkalemia
C.Hyperphosphatemia
D.Hyponatremia with volume overload
E.Persistent metabolic acidosis
Fluids, Electrolytes, Nutrition & Renal Question 57
A 1,000 gram female infant born at 29 weeks’ gestation infant is receiving total fluids of 140
mL/kg/day with 3 g/kg/day of protein and 2 g/kg/day of 20% Intralipids in D15W.
Approximately how many calories is this infant receiving per day?
A. 80 kcal/day
B. 90 kcal/day
C. 100 kcal/day
D. 110 kcal/day
E. 120 kcal/day
Fluids, Electrolytes, Nutrition & Renal Question 58
A 2-day old male infant born at 30 weeks’ gestation is noted to have gross hematuria,
thrombocytopenia, and laboratory evidence of acute renal dysfunction. A renal ultrasound
demonstrates a left renal vein thrombosis.
Which of the following statements about renal vein thrombosis in a neonate is TRUE?
A.Inherited prothrombotic conditions are rare in neonates with renal vein thrombosis
B.Polycythemia and maternal diabetes are risk factors for renal vein thrombosis
C.Renal vein thrombosis is the etiology for the majority of venous thromboses in neonates
D. Surgical thrombectomy is associated with lower morbidity and mortality rates compared with
conservative management
E.The majority of infants present with the classic findings of hematuria, thrombocytopenia,
renal failure, and a palpable flank mass
Fluids, Electrolytes, Nutrition & Renal Question 59
In regards to fetal composition, all of the following decrease with advancing gestational age and
birth weight, EXCEPT:
A.Chloride content
B. Extracellular water
C. Phosphorous
D. Sodium content
E. Total body water
Fluids, Electrolytes, Nutrition & Renal Question 60
You are giving a lecture to medical students about the amino acid requirements for neonates. One
student asks you about essential amino acids. All of the following are essential amino acids,
EXCEPT:
A. Aspartate
B. Leucine
C. Lysine
D. Methionine
E. Phenylalanine
Fluids, Electrolytes, Nutrition & Renal Answers 51-60
Fluids, Electrolytes, Nutrition & Renal Answer 51
C. Hyper-osmotic urine osmolality
Although preterm infants can dilute their urine similar to term infants, they cannot concentrate their
urine to the same degree. Adults can reach a maximum urine osmolality of 1500 mOsm/L; term
infants can concentrate their urine to 600 mOsm/L; and preterm infants can reach a urine osmolality of
500 mOsm/L. Thus, the preterm infant has a limited ability to conserve free water and often has a
hypo-osmotic urine osmolality.
Although extremely preterm neonates can maintain water and sodium balance within a relatively
narrow range over a broad range of water and sodium intakes, the ability of the preterm kidney to
compensate for changes in water and electrolyte intake is limited. Glomerular filtration rate is lower
in the preterm neonate than the term neonate and increases with advancing gestational and postnatal
age. In addition, the sodium reabsorptive capacity of the proximal nephron is limited in the preterm
neonate, hindering the preterm infant’s ability to conserve sodium with a normal extracellular
volume. Extremely preterm infants can also have a higher insensible water loss than expected, further
contributing to the risk of hypernatremia.
References:
Gallini F, Maggio L, Romagnoli C, Marrocco G, Tortorolo G. Progression of renal function in
preterm neonates with gestational age < 32 weeks. Pediatr Nephrol. 2000;15:119-124
Lorenz JM. Fluid and electrolyte therapy in very low-birthweight neonates. NeoReviews.
2008;9(3):102-108
Vanpee M, Herin P, Zetterstrom R, Aperia A. Postnatal development of renal function in very low
birthweight infants. Acta Paediatr Scand. 1988;77:191-197
Fluids, Electrolytes, Nutrition & Renal Answer 52
A. Antenatal steroid exposure
Insensible water loss (IWL) is a major factor in fluid/electrolyte loss in extremely preterm
neonates. Intrauterine exposure to maternal antenatal steroids decreases IWL at any given gestational
age. This is most likely as a result of greater skin maturation and better perfusion in infants exposed
to maternal steroids. IWL occurs transepidermally and across upper airway epithelium.
Transepidermal fluid loss plays a greater role and increases in the following scenarios:
1) Younger gestational age
2) Earlier postnatal age
3) Ambient water vapor pressure
4) Radiant warmer (Studies have shown that IWL is 15-35% higher during the first 3 weeks of
age for infants placed under a radiant warmer compared with a humidified environment.)
References:
Dmitriou G, Kavvadia V, Marcou M, Greenough A. Antenatal steroids and fluid balance in very low
birth weight infants. Arch Dis Child Fetal Neonatal Ed. 2005;90:F509-513
Kjartanson S, Arsan S, Hammarlund K, Sjors G, Sedin G. Water loss from the skin of term and
preterm infants nursed under a radiant warmer. Pediatr Res. 1995;37:233-238
Lorenz JM. Fluid and electrolyte therapy in very low-birthweight neonates. NeoReviews.
2008;9(3):102-108
Fluids, Electrolytes, Nutrition & Renal Answer 53
53a. B. Calcium
The infant in this vignette has evidence of dehydration (i.e., decreased urine output, poor oral
intake, significant weight loss). Because of this free water deficit, this infant is likely to have a
relative increase in serum sodium concentration. To maintain an osmotic equilibrium, hypernatremia
leads to an efflux of fluid from the intracellular space to the extracellular space. In the brain, cerebral
cellular dehydration and cell shrinkage can then occur. Cerebral dehydration from hypernatremia can
lead to a physical separation of the brain from the meninges resulting in rupture of the fragile bridging
veins and possible intracerebral hemorrhage. Infants with hypernatremia often have hyperglycemia,
elevated potassium secondary to rhabdomyolysis, and an elevated blood urea nitrogen. Although
earlier reports suggested that hypocalcemia was related to hypernatremia, this has not been found in
more recent studies.
53b. D. 240 mL
Free water deficit can be calculated as follows:

Thus, in this case, the free water deficit is 240 mL (4 mL x 4 kg x 15 mEq/L).

Reference:
Moritz ML, Ayus JC. Disorders of water metabolism in children: Hyponatremia and hypernatremia.
Pediatr Rev. 2002;23:371-379
Fluids, Electrolytes, Nutrition & Renal Answer 54
B. It is associated with a rapid correction of the plasma sodium concentration by more than 25
mmol/L in 24 to 48 hours
Cerebral demyelination (CDM) can develop if there is an excessive change in serum sodium
concentrations. CDM lesions are a rare complication of hyponatremic encephalopathy. These lesions
typically occur several days after the correction of hyponatremia and affected patients can present
with quadriplegia, confusion, pseudobulbar palsy, and a pseudocoma with a “locked in” stare.
However, many affected patients are asymptomatic. The lesions are best diagnosed by magnetic
resonance imaging at least 2 weeks after the hyponatremia correction. Recent data suggest that CDM
lesions are associated with the magnitude of the absolute correction. Hyponatremic patients who
develop CDM lesions may also have a history of a hypoxemic period and/or severe liver disease.
Reference:
Moritz ML, Ayus JC. Disorders of water metabolism in children: Hyponatremia and hypernatremia.
Pediatr Rev. 2002;23:371-379
Fluids, Electrolytes, Nutrition & Renal Answer 55
D. Transepidermal loss
Insensible water loss (IWL) occurs transepidermally and across upper airway epithelium.
Transepidermal fluid loss plays a more significant role than upper epithelium loss.
The preterm kidney cannot compensate for changes in water and electrolyte intake. The
glomerular filtration rate is lower in the preterm than the term neonate and does not contribute to
IWL. Although preterm infants can dilute their urine as much as term infants and adults, this does not
contribute to IWL. Increased ambient humidity will lead to a decrease in IWL.
References:
Kjartanson S, Arsan S, Hammarlund K, Sjors G, Sedin G. Water loss from the skin of term and
preterm infants nursed under a radiant warmer. Pediatr Res. 1995;37:233-238
Lorenz JM. Fluid and electrolyte therapy in very low-birthweight neonates. NeoReviews.
2008;9(3):102-108
Fluids, Electrolytes, Nutrition & Renal Answer 56
A. Creatinine > 5.0 mg/dL
The indications for renal replacement therapy, or dialysis, in a newborn include the following:
•Hyperkalemia
•Hyponatremia with symptomatic volume overload
•Hyperphosphatemia
•Metabolic acidosis
•Hypocalcemia
•Uremic symptoms
•An inability to provide adequate nutrition due to need for fluid restriction
A significantly elevated creatinine concentration is not an indication for dialysis; although, often, with
elevated creatinine levels, the resulting electrolyte abnormalities and fluid overload can be indicators
for dialysis.
Reference:
Fanaroff AA, Martin RJ, Walsh M (eds). Neonatal-Perinatal Medicine. 9th edition. St. Louis: Mosby;
2010
Fluids, Electrolytes, Nutrition & Renal Answer 57
C. 100 kcal/day
To calculate the caloric content of parenteral nutrition, one must know the amount of calories per
component, as shown in the Table below:
Component Kcals per gram
Carbohydrate (Dextrose) 3.4
Protein 4
Fat 9
General calculations are as follows:
(g/100 mL) x (mL/kg/day) x (kcals/g) = total kcals/kg/day
g/100 mL = % solution of dextrose, protein; e.g., D10W solution = 10% = 10 g/100 mL
mL/kg/day = total 24 hour intake in mL for the specific component
kcals/gram = kcal constant that the specific nutritional component contributes per gram
Thus, for the infant in this vignette:
Total grams of protein: 3 g/kg/day x 4 kcal/g x 1 kg = 12 kcal/day
Total grams of lipid: 2 g/kg/day x 9 kcal/g x 1 kg = 18 kcal/day
Total grams of glucose: 15 g/100 mL x 140 mL/kg/day x 3.4 kcal/g x 1 kg = 71 kcal/day
Total kcal/day = 101 kcal/day
Reference:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Fluids, Electrolytes, Nutrition & Renal Answer 58
B. Prematurity, polycythemia, and maternal diabetes represent risk factors for renal vein thrombosis.
Approximately 10% of venous thromboses in neonates occur in the renal vein. Inherited
prothrombotic conditions, including factor V Leiden mutation, protein C deficiency, protein S
deficiency, methylenetetrahydrofolate reductase mutation, and elevated lipoprotein (a) levels, are
more commonly identified in infants with renal vein thrombosis than the general population.
Additional risk factors for renal vein thrombosis include:
•Cyanotic congenital heart disease
 •Dehydration
•Maternal diabetes
•Perinatal asphyxia
•Polycythemia
•Prematurity
•Sepsis
•Shock
The minority of neonates present with the complete constellation of hematuria, thrombocytopenia,
renal failure, and palpable flank mass. Conservative management has been shown to have similar
morbidity and mortality rates compared to invasive surgical thrombectomy.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Chan A. Pathogenesis, clinical features, and diagnosis of thrombosis in the newborn. In: UpToDate,
Basow, DS (Ed), UpToDate, Waltham, MA, 2013
Fluids, Electrolytes, Nutrition & Renal Answer 59
C. Phosphorous
At birth, the body composition of the neonate varies based on the length of pregnancy and
intrauterine complications that affect fetal growth. With increasing gestational age, all fetuses undergo
changes in body composition. These changes are summarized in the Table below:
Decreases with Advancing GA and Birth Increases with Advancing GA and Birth
Weight Weight
Total body water Intracellular water
Extracellular water Protein
Sodium content Fat
Chloride content Calcium, phosphorous, magnesium
Iron
Printed with permission from: Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010; p 299
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Polin RA, Fox WW, Abman SH (eds). Fetal and Neonatal Physiology. 3rd edition. Philadelphia: WB
Saunders Co; 2004
Fluids, Electrolytes, Nutrition & Renal Answer 60
A. Aspartate
Amino acids play crucial roles as precursors for proteins and neurotransmitters, as transport
molecules, and in cell signaling. Amino acids can be divided into essential and nonessential,
depending on whether they are completely derived from the diet or they can be produced
endogenously from other substrates in sufficient amounts. Classically, isoleucine, leucine, valine,
lysine, methionine, phenylalanine, threonine, tryptophan, and histidine are considered essential amino
acids for adults. However, several metabolic processes are not fully developed in infants. Therefore,
the following amino acids are conditionally essential for the infant:
•Arginine
•Glutamine
•Glycine
•Proline
 •Taurine
•Tyrosine
Cysteine was historically defined as conditionally essential, but recent studies have demonstrated
that this is not the case for enterally fed infants. Aspartate is a nonessential amino acid. Aspartate
plays a key function in transamination and in the urea cycle and has a crucial role in purine and
pyrimidine synthesis, which depends on the donation of its amino group. In addition, aspartate is an
excitatory neurotransmitter and is involved in gluconeogenesis.
References:
Blaardingerbroek H, Van den Akker CHP, de Groof F, et al. Amino acids for the neonate: Search for
the ideal dietary composition. NeoReviews. 2011;12:e506-e516
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Fluids, Electrolytes, Nutrition & Renal Questions 61-70
Fluids, Electrolytes, Nutrition & Renal Question 61
You obtain a chest radiograph on a preterm infant and notice an incidental fracture. The infant had
been born at 24 weeks’ gestation and has been receiving a prolonged course of parenteral nutrition
after a diagnosis of medical necrotizing enterocolitis. You review the components of this infant’s
parenteral nutrition.
Of the following, the ideal Ca:P ratio by weight for neonates receiving parenteral nutrition is:
A. 0.3:1
B. 1:1
C. 1.3:1
D. 5:1
E. 3:1
Fluids, Electrolytes, Nutrition & Renal Question 62
All of the following statements are true about antidiuretic hormone (ADH), EXCEPT:
A. It acts directly on the late distal tubule as well as cortical and medullar collecting ducts
B. It has an extrarenal effect of arterial vasodilation
C. It is present in the fetus at 11 weeks’ gestation
D. It is produced in cell bodies of neurons located in the hypothalamus
E. It is the primary determinant of water excretion in kidney
Fluids, Electrolytes, Nutrition & Renal Question 63
You prescribe chlorothiazide to an infant with chronic lung disease. All of the following are true
about this medication, EXCEPT:
A. It acts mainly at the proximal tubule
B. It can displace bilirubin from albumin so must be used cautiously if indirect hyperbilirubinemia
is present
C. It inhibits NaCl reabsorption
D. It inhibits pancreatic release of insulin leading to hyperglycemia
E. It leads to decreased renal excretion of Ca
Fluids, Electrolytes, Nutrition & Renal Question 64
Which of the following compounds is an essential fatty acid?
A.Glycerol
B.Linoleic acid
C.Oleic acid
D.Palmitic acid
E.Stearic acid
Fluids, Electrolytes, Nutrition & Renal Question 65
A 6-day old term infant presents to the Emergency Room with lethargy and weight loss. The
mother reports that the infant has been exclusively breastfeeding. Over the past several days, the
infant has had fewer wet diapers and is not waking to feed. The infant’s present weight is 20%
below birthweight.
Which of the following values is LEAST consistent with this infant’s history and clinical
findings?
A.Creatinine: 1.5 mg/dL
B.Hematocrit: 25%
C.Serum bicarbonate: 15 mEq/L
 D.Serum sodium: 171 mEq/L
E.Urine specific gravity: > 1.015
Fluids, Electrolytes, Nutrition & Renal Question 66
Which of the following would be LEAST likely to present with a hypochloremic metabolic
alkalosis?
A.Bartter syndrome
B.Cystic fibrosis
C.Diuretic therapy
D.Galactosemia
E.Pyloric stenosis
Fluids, Electrolytes, Nutrition & Renal Question 67
All of the following factors have been implicated in causing cholestasis associated with parenteral
nutrition (PN), EXCEPT:
A.Dextrose content
B.Lipid content
C.Longer duration of parenteral nutrition
D.Ongoing trophic feedings
E.Protein content
Fluids, Electrolytes, Nutrition & Renal Question 68
Mothers of very low and extremely low birthweight infants admitted to the NICU are more likely
to have inadequate breast milk production compared to mothers of term infants. The milk production
of the mothers of these preterm infants relies on the quality and frequency of pumping.
The factors leading to inadequate breast milk production in women of preterm infants include all
of the following, EXCEPT:
A.Altered colostrum composition after premature delivery precluding its use
B.Delayed lactogenesis
C.Lack of appreciation of volume and frequency of pumping needed to be established in the first 2
weeks after delivery
D.Lack of hospital-grade electric pumps
E.Prescription of progestin-based birth control pills
Fluids, Electrolytes, Nutrition & Renal Question 69
You are meeting with the mother of a 1-day old infant born at 36 weeks’ gestation in the Newborn
Nursery. The mother is uncertain about whether she wants to breastfeed. To help with her decision,
she would like to know more about the immunoglobulins in human milk.
Which of the following statements is TRUE?
A.Colostrum contains a lower concentration of immunoglobulins
B.IgA represents 90% of all immunoglobulins in human milk
C.Immunoglobulins in human milk do not refer protection against Enterobacteriaceae bacteria
D.The concentration of IgA in human milk decreases over time
E.There is no IgM in human milk
Fluids, Electrolytes, Nutrition & Renal Question 70
Which of the following fetal body composition components DECREASES with advancing
gestational age and weight?
A.Fat
B.Intracellular water
C.Iron
D.Protein
E.Sodium
Fluids, Electrolytes, Nutrition & Renal Answers 61-70
Fluids, Electrolytes, Nutrition & Renal Answer 61
C. 1.3:1
Inadequate calcium and phosphorus intake has been associated with diminished bone
mineralization in premature infants receiving total parenteral nutrition for a prolonged period. This
deficiency occurs when protein and energy are adequate for growth but calcium and phosphorus are
insufficient to sustain appropriate skeletal mineralization. Calcium and phosphorus cannot be
provided through parenteral solutions at high concentrations because of the increased risk of
precipitation. The solubility of calcium and phosphorus in parenteral solutions depends on the
following:
•Temperature
•Type and concentration of amino acids
•Dextrose concentration
•pH of the calcium salt
•Sequence of the addition of calcium and phosphorus to the solution
•Calcium-to-phosphorus ratio
•Presence of lipids
With a range of fluid intake of 120 to 150 mL/kg per day, it is advisable to supply a calcium
content of 50 to 60 mg/dL and a phosphorus content of 40 to 45 mg/dL corresponding to a calcium-to-
phosphorus ratio of 1.3:1 by weight. This quantity of calcium provided by the parenteral route is
about 60% to 75% of that deposited by the fetus during the last trimester of gestation.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Fanaroff AA, Martin RJ, Walsh M (eds). Neonatal-Perinatal Medicine. 9th edition. St. Louis: Mosby;
2010
Fluids, Electrolytes, Nutrition & Renal Answer 62
B. It has an extrarenal effect of arterial vasodilation
Antidiuretic hormone (ADH) is also known as arginine vasopressin or AVP. Its two main actions
are mediated by two different classes of receptors:
•V1 receptors stimulate peripheral vasoconstriction, glycogenolysis, platelet aggregation, and
vascular smooth muscle hypertrophy
•V2 receptors increase water permeability of the renal collecting ducts by inducing aquaphorins;
this results in greater water retention and decreased urine volume
The main stimulus for the antidiuretic effects of ADH is an elevation in plasma osmolality,
primarily the extracellular fluid concentration of sodium chloride. ADH is produced in cell bodies of
neurons located in supraoptic and paraventricular nuclei of the hypothalamus. It is stored in secretory
granules in the posterior pituitary gland and released when small increases in plasma osmolality
occur. It acts directly on the late distal tubule as well as cortical and medullary collecting ducts. It is
the primary determinant of water excretion in the kidney.
ADH is present in the fetus at 11 weeks’ gestation. During development, ADH aids in regulating
the proliferation and morphogenesis of target cells in the brain, pituitary, kidney, and liver. Because
the fetus contributes significantly to modulation of fluid fluxes among the maternal, fetal, and amniotic
fluid compartments, fetal ADH action is an important component of adaptive responses to changes in
the environment in utero.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Polin RA, Fox WW, Abman SH (eds). Fetal and Neonatal Physiology. 3rd edition. Philadelphia: WB
Saunders Co; 2004
Fluids, Electrolytes, Nutrition & Renal Answer 63
A. It acts mainly at the proximal tubule.
Diuretics represent one of the most common classes of drugs administered to sick neonates. One
class of diuretics are the thiazide agents, such as chlorothiazide. Thiazide diuretics are delivered to
the renal tubular lumen via the organic acid transport system. Thiazides exert their diuretic effect by
blocking the electroneutral sodium chloride transporter and inhibiting NaCl reabsorption. They act
primarily at the distal tubule. Because only 5% of filtered sodium reabsorption occurs within the
distal tubule, thiazide diuretic efficacy is limited. Chlorothiazide promotes increased urinary losses
of sodium, potassium, magnesium, chloride, bicarbonate, and phosphate. It also leads to decreased
renal excretion of calcium. It can induce a hypochloremic alkalosis and can also cause hyperuricemia.
Chlorothiazide must be used cautiously if indirect hyperbilirubinemia is present as it displaces
bilirubin from albumin. Another potential side effect of chlorothiazide is that it can inhibit the
pancreatic release of insulin leading to hyperglycemia.
References:
Bestic M. Reed M. Pharmacology review: Common diuretics used in the preterm and term infant.
NeoReviews. 2005;6:e392-398
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Fluids, Electrolytes, Nutrition & Renal Answer 64
B. Linoleic acid
Linoleic and linolenic acid are essential fatty acids. The most common nonessential fatty acids
include stearic acid, oleic acid and palmitic acid. Neutral fat is composed of three long-chain fatty
acids and one glycerol.
References:
Brodsky D, Martin C. Neonatology Review. 2nd Edition. Lulu. 2010
Fanaroff AA, Martin RJ, Walsh M (eds). Neonatal-Perinatal Medicine. 8th ed. St. Louis: Mosby;
2005
Fluids, Electrolytes, Nutrition & Renal Answer 65
B. Hematocrit: 25%
The infant described in this vignette has findings consistent with dehydration. Hydration status can
be assessed by weight loss, degree of hypernatremia, urine output, urine osmolality, and urine
specific gravity. Infants with dehydration can have a low serum bicarbonate concentration with a high
creatinine concentration. Affected patients may have an elevated hematocrit; anemia is not typical.
Reference:
Brodsky D, Martin C. Neonatology Review. 2nd Edition. Lulu. 2010
Fluids, Electrolytes, Nutrition & Renal Answer 66
D. Galactosemia
Infants with galactosemia typically present with a metabolic acidosis with an increased anion gap.
Diuretic therapy, pyloric stenosis, cystic fibrosis and Bartter syndrome can all present with
hypochloremic metabolic alkalosis.
Reference:
Brodsky D, Martin C. Neonatology Review. 2nd Edition. Lulu. 2010
Fluids, Electrolytes, Nutrition & Renal Answer 67
D. Ongoing trophic feedings
Parenteral nutrition-associated cholestasis (PNAC) is commonly found in infants who require a
prolonged duration of PN (usually >7 days), lack enteral feeding, and have an associated surgery. The
pathogenesis of PNAC is unclear and multiple alterations of PN have been trialed to attempt to
reduce the incidence of cholestasis. All major constituents of PN have been implicated in causation
or aggravation of cholestasis including the following:
•High dextrose concentration related to hepatic steatosis
•High protein concentration related to canalicular dysfunction
•Toxic effects of intralipid on hepatic cells
No one component has been identified as the sole cause of PNAC. The only treatment that has been
consistently effective in treating infants with PNAC has been the introduction of enteral feedings.
Even a small amount of feedings, such as trophic feedings, has been shown to decrease the incidence
of PNAC. Therefore, all the options listed in this case have been implicated in PNAC expect trophic
feedings, which is considered protective.
Reference:
Colby C, Hartman T, Lang T. Pharmacotherapy for the treatment of parenteral nutrition-associated
cholestasis. NeoReviews. 2007;8:e547-e550
Fluids, Electrolytes, Nutrition & Renal Answer 68
A. Altered colostrum composition after premature delivery precluding its use
Colostrum is produced by the paracellular entry of maternal immune components into the mammary
ducts. The content of colostrum after a preterm delivery consists of high concentrations of immune
protective substances and is considered physiologically key to the preterm infant’s health.
Acquisition of colostrum can help reassure mothers that despite the initial small volume, the contents
are essential for their baby.
Delayed lactogenesis is the onset of breast milk production after the third postnatal day and is
associated with preterm delivery. It is important to inform women of premature infants to anticipate
this delay to minimize maternal frustration. As the volume of nasogastric feedings provided to a
VLBW or ELBW infant can be small during the first weeks, some mothers may have a false sense of
reassurance that those small volumes are adequate. However, in order to establish the volume that
will ultimately be required by the infant, mothers should pump frequently (at least 8 times per day)
with a target of about 350 mL per day by the end of the second week. Maintaining a milk diary can
help mothers and care providers identify problems with milk production early. As the milk
production is dependent on the quality of pumping, hospital grade electric pumps are recommended
and poor quality pumps can result in painful pumping with low milk volumes. Progestin-based birth
control pills have been associated with a fall in milk production and alternatives should be discussed
before such medications are prescribed.
Reference:
Paula P. Meier PP. Engstrom JL. Evidence-based practices to promote exclusive feeding of human
milk in very low-birthweight infants. NeoReviews. 2007;8:e467-e477
Fluids, Electrolytes, Nutrition & Renal Answer 69
B. IgA represents 90% of all immunoglobulins in human milk
Immunoglobulins form an important component of the immunological activity found in breast milk
and colostrum. Approximately 90% of all immunoglobulins in human milk contain IgA. Newborns
lack secretory IgA at birth and infants who receive human milk have higher concentrations of IgA
compensating for this deficit. Secretory IgA binds specifically to respiratory and enteric pathogens,
thereby immobilizing them and preventing their adherence to epithelial cells.
Other immunoglobulins found in human milk are IgM and IgG. The concentrations of secretory IgA
remains consistently high, while levels of IgM in human milk decrease over time in lactating mothers.
References:
Labbok MH, Clark D, Goldman AS. Nat Rev Immunol. 2004;4:565-572
McElroy S, Weitkamp JH. Innate immunity in the small intestine of the preterm infant. NeoReviews.
2012;12:e517-e526
Peitersen B, Bohn L, Andersen H. Quantitative determination of immunoglobulins, lysozyme, and
certain electrolytes in breast milk during the entire period of lactation, during a 24-hour period,
and in milk from the individual mammary gland. Acta Paediatr Scand. 1975;64:709-717
Fluids, Electrolytes, Nutrition & Renal Answer 70
E. Sodium
Sodium content decreases with advancing gestational age and weight. Other factors that decrease
include total body water, extracellular water and chloride content. Factors that increase with
advancing gestational age and weight include intracellular water, protein, fat, iron, calcium,
phosphorus and magnesium.
References:
Brodsky D, Martin C. Neonatology Review. 2nd Edition. Lulu. 2010
Fanaroff AA, Martin RJ, Walsh M (eds). Neonatal-Perinatal Medicine. 8th ed. St. Louis: Mosby;
2005
Fluids, Electrolytes, Nutrition & Renal Questions 71-80
Fluids, Electrolytes, Nutrition & Renal Question 71
A female infant is admitted to the NICU with an antenatal history of bilateral enlarged, cystic
kidneys. She has a normal respiratory rate and is breathing comfortably in room air. Her abdominal
examination is notable for distention and two large masses. A postnatal renal ultrasound reveals
bilateral large hyperechoic kidneys.
71a. The differential diagnosis of the infant in this vignette includes all of the following, EXCEPT:
A.Autosomal dominant polycystic kidney disease
B.Autosomal recessive polycystic kidney disease
C.Diffuse cystic dysplasia
D.Glomerulocystic kidney disease
E.Potter’s syndrome
71b. The neonatologist suspects that the infant in this vignette has autosomal recessive polycystic
kidney disease (ARPKD).
Patients with ARPKD are at risk for all of the following complications, EXCEPT:
A.Cholangitis
B.Hepatic tumors
C.Portal hypertension
D.Systemic hypertension
E.Urinary incontinence
71c. The parents of the infant in this vignette ask the neonatologist about the prognosis for their
daughter.
Of the following, that most likely response by the neonatologist is:
A. The condition is so rare that information on prognosis is unknown
B.The prognosis depends on the results of genetic testing
C.The prognosis is dismal, with mortality rates up to 90% in the newborn period
D.The prognosis is guarded, with 30% of affected newborns not surviving the neonatal period
E.Survival is almost assured, with mortality only about 10%
Fluids, Electrolytes, Nutrition & Renal Question 72
A term infant with malrotation is now 10 days old after surgical correction on day 3. The infant
has been maintained on IV fluids consisting of Dextrose 10% with electrolytes. Total parenteral
nutrition was not initiated as the intention was to feed the infant, however the infant has not tolerated
repeated attempts at enteral feedings. Now the infant has developed a scaly dermatitis, and alopecia.
The infant’s complete blood count shows thrombocytopenia. You suspect this is secondary to a
dietary deficiency, and you check the Holman index, which is raised at 0.4.
What is the most likely nutritional deficiency in this infant in this vignette?
A.Essential fatty acid deficiency
B.Niacin deficiency
C.Selenium deficiency
D.Thiamine deficiency
E.Zinc deficiency
Fluids, Electrolytes, Nutrition & Renal Question 73
Lipids are essential to the developing newborn. Lipids have the following functions:
•Provide a source of high calorie energy
•Are an essential component of cell membrane structure
 •Involved in neural and retinal development, organogenesis, angiogenesis, regulation of the
immune system and inflammation.
Triglycerides are the most common form of dietary fat.
Which of the following statements about triglyceride absorption in newborns is TRUE?
A.Bile salts are amphiphilic molecules.
B.Chylomicrons aid in the absorption of free fatty acids and monoglycerides from the intestinal
lumen into the enterocyte.
C.Lipases are hydrophobic enzymes.
D.Micelles are secreted into the lymphatic circulation to disperse triglycerides around the body.
E.Triglycerides are esterified by lipases to form monoglycerides and free fatty acids.
Fluids, Electrolytes, Nutrition & Renal Question 74
A male infant born at 23 6/7 weeks’ gestation without benefit of antenatal steroids is requiring
high frequency oscillatory ventilation to manage his severe respiratory distress syndrome. His
mother had been in a car accident, and there had been some hemorrhage at delivery. On the first day
of life, the infant’s urine output is 0.6 mL/kg/hr and he is receiving 160 mL/kg/day of IV fluids plus
multiple boluses. He has the following laboratory results:
•Serum sodium=130 mEq/L, potassium=5.2 Eq/L, bicarbonate 15 Eq/L
•Serum creatinine=1.3 mg/dL
•Urine electrolytes with a sodium=5 mEq/L and urine creatinine=2.5 mg/dL.
The fractional excretion of sodium (FENa) for the infant in this vignette is:
A. 0.2%
B. 0.5%
C. 2%
D. 5%
E. 20%
Fluids, Electrolytes, Nutrition & Renal Question 75
A male infant is born at 24 weeks’ gestation. On the third day of life, his urine output is calculated
at 12 mL/kg/day for the past 12 hours. His total fluids had been restricted to 120 mL/kg/day due to
concern for a patent ductus arteriosus. His most recent serum electrolytes were notable for a sodium
of 154 mEq/L, potassium 4.6 mEq/L, chloride 110 mEq/L, bicarbonate 17 mEq/L, BUN 28 mg/dL,
creatinine 1.3 mg/dL, glucose 90 mg/dL.
Based on this data, the estimated serum osmolality of the infant in this vignette is:
A.275 mOsm/kg
B.304 mOsm/kg
C.309 mOsm/kg
D.314 mOsm/kg
E.319 mOsm/kg
Fluids, Electrolytes, Nutrition & Renal Question 76
A mother is visiting her 7-day old son in the NICU. He was born at 33 weeks’ gestation because
of premature rupture of membranes and preterm labor following an automobile accident. He is doing
well and has just weaned off of CPAP. The mother has been pumping and is planning to breastfeed
for the first time today. Her supply has been increasing, but she describes a difficulty with milk
ejection when she uses the pump.
Which hormone is responsible for milk ejection?
A.Estrogen
 B.Feedback inhibitor of lactation
C.Progesterone
D.Prolactin
E.Oxytocin
Fluids, Electrolytes, Nutrition & Renal Question 77
Twin female infants are born at 39 weeks’ gestation. The pregnancy was spontaneous, and the
fetuses had dichorionic placentation. There were no complications during the pregnancy other than
hyperemesis in the first trimester. Fetal cell DNA testing did not identify any aneuploidy. The first
twin born weighs 2400 g, while the second weighs 3200 g. They both appear non-dysmorphic and
have Apgar scores of 8 and 9 at 1 and 5 minutes, respectively.
What is different about the body composition of the two twins at birth?
A.The larger infant has a lower content of glycogen in the liver
B.The larger infant has a higher nitrogen content
C.The smaller infant has more bone mineral content
D.The smaller infant has more total body fat
E.The smaller infant has more total lean mass
Fluids, Electrolytes, Nutrition & Renal Question 78
A male infant is born at 27 weeks’ gestation following unstoppable preterm labor. His birth
weight is 800 g, and by day of life 12 his weight is 730 g. He has been receiving total parenteral
nutrition to achieve calories of 108 kcal/kg/day with a total fluid of 140 mL/kg/day.
What changes have occurred in this infant’s body composition in the first 12 days of life?
A.Decrease in total body water, extracellular and interstitial volumes
B.Decrease in total body water and extracellular volume, increase in interstitial volume
C.Decrease in total body water, increase in extracellular and interstitial volumes
D.Increase in total body water, decrease in extracellular and interstitial volumes
E.Increase in total body water, extracellular and interstitial volumes
Fluids, Electrolytes, Nutrition & Renal Question 79
A male infant is born at 32 weeks’ gestation by Cesarean section as a result of worsening maternal
hypertension with proteinuria. The infant’s birth weight is 1400g. He is placed on CPAP. At 6
hours of age, he starts to receive enteral feedings and he reaches full volume feedings by the 5th day of
life. He is receiving expressed breast milk supplemented with human milk fortifier. At the time of
discharge, he is continued on breast milk but is now being supplemented with a transitional formula.
What are the daily protein requirements for the infant in this vignette during the first week of life
and at discharge, respectively?
A.3 g/kg/d and 2 g/kg/d
B.3 g/kg/d and 3 g/kg/d
C.4 g/kg/d and 3 g/kg/d
D.4 g/kg/d and 4 g/kg/d
E.5 g/kg/d and 4 g/kg/d
Fluids, Electrolytes, Nutrition & Renal Question 80
A male infant is born at 23 3/7 weeks’ gestation following premature rupture of membranes and
unstoppable preterm labor. He is intubated and receives 3 doses of surfactant. On day of life 15, he
is extubated to CPAP. He reaches full enteral feedings on day of life 21, after intermittent periods of
feeding intolerance. At 6 weeks of age, he suddenly develops apnea. He is intubated, and has
radiographic evidence of free air below the diaphragm. He is diagnosed with necrotizing
enterocolitis complicated by perforation, and is surgically managed with creation of an ileostomy.
He is started on total parenteral nutrition (PN) with intra-lipids, but because of PN-associated liver
disease, his lipids are restricted. At 10 weeks of life, he continues to receive all of his nutrition by
PN because of large volume outputs from his ostomy with any attempts at enteral feedings. By 12
weeks of life his platelets are 40,000/uL and his weight gain is poor. A red scaly rash is noted in his
diaper region.
What is the most likely reason that the infant in this vignette has developed these new symptoms at
12 weeks of life?
A.Caloric deficiency
B.Deficiency of linoleic aid
C.Deficiency of oleic acid
D.Deficiency of zinc
E.Deficiency of cysteine
Fluids, Electrolytes, Nutrition & Renal Answers 71-80
Fluids, Electrolytes, Nutrition & Renal Answer 71
71a. E. Potter’s syndrome
There are many types of renal cystic disease. Polycystic kidney disease (PKD) is a group of
inherited disorders in which cysts grow in the kidneys, severely affecting their function. Autosomal
dominant is the most common inherited form of the disease and symptoms typically develop in early
to mid adulthood. Autosomal recessive PKD is much rarer, comprising only about 10% of cases.
Onset of symptoms is typically in the newborn period. Both types have renal ultrasound findings of
large, cystic, hyperechoic kidneys. Diagnosis is confirmed by genetic testing. Diffuse cystic
dysplasia is a poorly understood, though well-characterized, form of cystic renal disease with large,
cystic, dysplastic kidneys. Glomerulocystic kidney disease is a rare condition that causes large,
hyperechoic kidneys with cysts located mostly in the glomeruli. It may be seen as part of many genetic
syndromes associated with an underlying dysfunction of cilia. Potter’s syndrome is a constellation of
findings caused by prolonged oligohydramnios in the fetus, which leads to pulmonary hypoplasia and
physical deformities of the face and extremities. It is caused by renal agenesis, hypoplasia, or
bladder outlet obstruction. Typical ultrasound findings at birth show small or absent kidneys.
71b. E. Urinary incontinence
ARPKD is a rare, genetic disorder affecting between 1/10,000 and 1/40,000 live births. It is
caused by several different mutations in the fibrocystic gene PKHD1. ARPKD typically presents at
birth with enlarged cystic kidneys that have abnormal function. Non-renal complications include
pulmonary hypoplasia and systemic hypertension. About 45% of patients also have liver
involvement, with dysgenesis of the portal triad and resultant portal hypertension, varices, and
recurrent cholangitis. There is also increased risk for both benign and malignant liver tumors.
71c. D. The prognosis is guarded, with 30% of affected infants not surviving the neonatal period
Infants with ARPKD have a high mortality rate with 30% of affected newborns not surviving
beyond the neonatal period. Pulmonary hypoplasia and renal failure are poor prognostic signs.
Genetic markers are not yet available to help predict survival. Survivors require renal replacement
therapy in childhood or adolescence.
References:
Bissler JJ, Siroky BJ, Hong Y. Glomerulocystic kidney disease. Pediatr Nephrol. 2010;25:2049-
2059
Bonsib SM. The classification of renal cystic diseases and other congenital malformations of the
kidney and urinary tract. Arch Pathol Lab Med. 2010;134:554-568
Büscher R, Büscher AK, Weber S, et al. Clinical manifestations of autosomal polycystic kidney
disease (ARPKD): Kidney-related and non-kidney-related phenotypes. Pediatr Nephrol.
2013;October 10 [Epub ahead of print]:1-11
Slovi TL, Bernstein J, Bruskin A. Hyperechoic kidneys in the newborn and young infant. Pediatr
Nephrol. 1993;7:294-302
Fluids, Electrolytes, Nutrition & Renal Answer 72
A. Essential fatty acid deficiency
Linoleic acid and alpha-linoleic acid are essential fatty acids, which cannot be endogenously
derived. The absence of these essential fatty acids in the diet for as little as 3 to 7 days, can lead to
Essential Fatty Acid Deficiency (EFAD). Clinically, EFAD is characterized by a scaly dermatitis,
alopecia, increased susceptibility to infection, and failure to thrive. Affected infants often have an
associated thrombocytopenia. Diagnosis of EFAD is confirmed by a raised Holman index. This is the
ratio of triene (mead acid) to tetraene (arachidonic acid). A ratio of greater than 0.2 is considered
diagnostic for EFAD.
References:
Friedman Z, Danon A, Stahlman MT, Oates JA. Rapid onset of essential fatty acid deficiency in the
newborn. Pediatrics. 1976;58:640-649
Martin CR. Lipids and Fatty Acids in the Preterm Infant, Part 1: Basic Mechanisms of Delivery,
Hydrolysis, and Bioavailability. NeoReviews. 2015;16;e160-168
Fluids, Electrolytes, Nutrition & Renal Answer 73
A. Bile salts are amphiphilic molecules.
Triglycerides are hydrophobic, and therefore poorly soluble in an aqueous solution. Therefore, a
multistep process is required to aid in their absorption. First, the lipids are emulsified (broken into
smaller droplets). This occurs secondary to the mechanical forces in the stomach and intestine, and
the detergent properties of bile salts. Given the hydrophobic qualities of lipids, the emulsified
particles would coalesce if they were formed purely by mechanical stress. Bile salts are amphiphilic
molecules (contain both hydrophilic and hydrophobic components). They coat the emulsified
particles, and with phospholipids, stabilize the emulsification. The next step is the hydrolysis of
triglycerides by lipases, to form monoglycerides and free fatty acids. Lipases are water-soluble, and
act at the water-lipid interface. Emulsification therefore greatly increases the surface area for lipases
to function on the lipid particles.
The free fatty acids, bile salt and monoglycerides form a micelle (fat soluble vitamins,
phospholipids, and cholesterol are also incorporated into the micelle). When the micelle comes in
contact with the intestinal wall, the free fatty acids and monoglycerides then diffuse across the plasma
membrane into the enterocyte.
Within the enterocyte, the free fatty acids and monoglycerides are transported to the endoplasmic
reticulum, and are then re-esterified into triglycerides, and then incorporated into chylomicrons. The
chylomicrons are packaged into exocytic vesicles by the Golgi apparatus. The vesicles fuse with the
plasma membrane, and the chylomicrons are secreted into the lymphatic system. From the lymphatic
system, they enter into the blood stream and are distributed around the body.
References:
Martin CR. Lipids and Fatty Acids in the Preterm Infant, Part 1: Basic Mechanisms of Delivery,
Hydrolysis, and Bioavailability. NeoReviews. 2015;16:e160-168
Sherwood L. Fundamentals of Human Physiology. 4th edition. Belmont, Brooks Cole 2011
Fluids, Electrolytes, Nutrition & Renal Answer 74
C. 2%
FENa is calculated as the plasma ratio of creatinine to sodium, divided by the urine ratio of
creatinine to sodium.

A FeNa less than 1% is normal, while a FENa between 1% and 2.5% suggests a pre-renal
etiology and a FENa greater than 3% is consistent with intrinsic renal failure. In this vignette, this
infant’s FENa is 2%.
 This infant has a FENa consistent with pre-renal cause of oliguria.
Reference:
Andreoli SP. Acute renal failure in the newborn. Semin Perinatol. 2004;28:112-123
Fluids, Electrolytes, Nutrition & Renal Answer 75
E. 319 mOsm/kg
Serum or plasma osmolality is the density of electrolytes per kg of water. It can be measured
directly or estimated from electrolyte values:

For this patient: serum osmolality = (2 x 154) + (90/18) + (28/2.8) = 319 mOsm/kg
This value is elevated above the normal 285-295 mOsm/kg, likely as a result of the infant’s
hypovolemia.
Reference:
Davis JA, Harvey DR, Stevens JF. Osmolality as a measure of dehydration in the neonatal period.
Arch Dis Child. 1966;41:448-450
Fluids, Electrolytes, Nutrition & Renal Answer 76
E. Oxytocin
Oxytocin is released in response to tactile stimulation of the nipple, and leads to contraction of
myoepithelial cells of the mammary gland. This results in milk ejection.
Prolactin and feedback inhibitor of lactation (FIL) are also released during breastfeeding. Nipple
stimulation leads to prolactin release, but prolactin levels do not correlate with volume of milk
produced. FIL is made by mammary epithelial cells in response to pressure and reduces milk
production when the breast is full. Estrogen and progesterone stimulate breast development and
maturation, but do not change during breastfeeding sessions.
Reference:
Neville MC, McFadden TB, Forsyth I. Hormonal regulation of mammary differentiation and milk
secretion. J Mammary Gland Biol Neoplasia. 2002;7:49
Fluids, Electrolytes, Nutrition & Renal Answer 77
B. The larger infant has a higher nitrogen content
Infants are small for gestational age (SGA) if their birth weight is below the 10th percentile for
gestational age, as represented by the smaller twin in this vignette. SGA infants have a different body
composition at birth compared to appropriate for gestational age (AGA) infants. SGA infants have
reduced total body mass, lean mass, and bone mineral content. Because of the reduced muscle mass,
there is lower nitrogen content in SGA infants. Lower fetal plasma glucose and lower fetal insulin
result in lower glycogen content in the liver and muscle of SGA infants.
References:
Anderson MS, Hay WW. Intrauterine growth restriction and the small-for-gestational-age infant. In:
Neonatology Pathophysiology and Management of the Newborn, 5th ed, Avery GB, Fletcher MA,
MacDonald MG (Eds), Lippincott Williams & Wilkins, Philadelphia, 1999
Lapillonne A, Braillon P, Claris O, et al. Body composition in appropriate and in small for
gestational age infants. Acta Paediatr. 1997;86:196
Fluids, Electrolytes, Nutrition & Renal Answer 78
A. Decrease in total body water, extracellular and interstitial volumes
Total body water is composed of extracellular water and intracellular water. Extracellular water
includes interstitial and intravascular volumes. Preterm infants have a higher total body water
percentage compared to term infants. In the first two weeks of life, preterm infants have significant
fluid losses that coincide with weight loss. During this process, there is a decrease in total body
water, extracellular volume and specifically the interstitial component of extracellular fluid.
Intracellular water increases during this same time.
References:
Bauer K, Boveermann G, Roithmaier A, et al. Body composition, nutrition, and fluid balance during
the first two weeks of life in preterm neonates weighing less than 1500 grams. J Pediatr.
1991;118:615-620
Friis-Hansen B. Body water compartments in children: Changes during growth and related change in
body composition. Pediatrics. 1961.28:169-181
Fluids, Electrolytes, Nutrition & Renal Answer 79
C. 4 g/kg/d and 3 g/kg/d
Several studies have demonstrated improved weight gain for VLBW infants who receive 4 g/kg/d
protein, compared to less than 3.5 g/kg/d protein. Protein and energy intake in preterm infants during
the first week of age has been correlated with improved developmental outcomes at age 18 months.
Intake higher than 4 g/kg/d of protein in this population is not generally recommended. Once a preterm
infant reaches term gestational age, protein intake of 3 g/kg/d has been shown to result in appropriate
weight gain.
References:
Brumberg HL, Kowalski L, Troxell-Dorgan A, et al. Randomized trial of enteral protein and energy
supplementation in infants less than or equal to 1250 g at birth. J Perinatol. 2010;30:517
Cooke R, Embleton N, Rigo J, et al. High protein pre-term infant formula: effect on nutrient balance,
metabolic status and growth. Pediatr Res. 2006;59:265
Dusick AM, Poindexter BB, Ehrenkranz RA, Lemons JA. Growth failure in the preterm infant: can we
catch up? Semin Perinatol. 2003;27:302-310
Stephens BE, Walden RV, Gargus RA, et al. First-week protein and energy intakes are associated
with 18-month developmental outcomes in extremely low birth weight infants. Pediatrics.
2009;123:1337-1343
Fluids, Electrolytes, Nutrition & Renal Answer 80
B. Deficiency of linoleic acid
Prolonged PN without adequate intra-lipids can lead to deficiencies in essential fatty acids
(EFAs), which manifest as dermatitis, thrombocytopenia, increased infection and failure to thrive.
Less than 0.5 mg/kg/d of EFA intake can lead to a deficiency. The two essential amino acids are
linoleic and linolenic acids.
Oleic acid, an omega-9 fat, is a non-essential fatty acid. Deficiency is rare as the body can
synthesize these fats. Caloric deficiency would likely appear as failure to thrive with catabolic
metabolism and is less likely to cause thrombocytopenia and dermatitis. Cysteine is not an essential
amino acid for adults but synthesis is limited in neonates. However, cysteine is typically provided in
PN and a randomized trial demonstrated no benefit to higher amounts of cysteine. Zinc deficiency can
occur with prolonged PN and is characterized by dermatitis, but less likely to cause
thrombocytopenia and failure to thrive.
References:
Centers for Disease Control and Prevention. Notes from the field: Zinc deficiency dermatitis in
cholestatic extremely premature infants after a nationwide shortage of injectable zinc -
 Washington, DC, December 2012. MMWR Morb Mortal Wkly Rep. 2013;62:136
Friedman Z, Danon A, Stahlman MT, Oates JA. Rapid onset of essential fatty acid deficiency in the
newborn. Pediatrics. 1976;58:640-649
Gutcher GR, Farrell PM. Intravenous infusion of lipid for the prevention of essential fatty acid
deficiency in premature infants. Am J Clin Nutr. 1991;54:1024
te Braake FW, Schierbeek H, Vermes A, et al. High-dose cysteine administration does not increase
synthesis of the antioxidant glutathione preterm infants. Pediatrics. 2009;124:e978
Fluids, Electrolytes, Nutrition & Renal Questions 81-90
Fluids, Electrolytes, Nutrition & Renal Question 81
A vegan woman seeks nutritional counseling advice from her obstetrician prior to conception. Her
diet strictly avoids all animal products. She is currently taking a vitamin B12 supplement.
It may be beneficial to recommend to the woman in the vignette all of the following supplements
except:
A.Calcium
B.Fiber
C.Iron
D.Vitamin D
E.Zinc
Fluids, Electrolytes, Nutrition & Renal Question 82
A preterm infant is delivered at 24 weeks’ gestational age with a birth weight of 500 gm. The
neonatology fellow wants to optimize this infant’s post-natal growth.
Which of the following statements about the daily caloric requirements is the MOST appropriate
for this infant’s growth and development?
A.If parenterally fed, the energy expenditure from fecal losses is calculated at 10 kcal per kg per
day.
B.Providing twice the resting energy expenditure is appropriate to maintain growth in a preterm
infant.
C.The resting energy expenditure in a preterm infant is approximately 70 kcal per kg per day.
D.To maintain growth on full enteral feedings, the infant in this vignette will require approximately
55 kcal per day.
E.While receiving full parenteral nutrition, the infant should receive at least 55 kcal per day.
Fluids, Electrolytes, Nutrition & Renal Question 83
Lipids are an important dietary requirement that function as a source of calories in an infant, but
are also involved in a wide range of activities including cell signaling and formation of cell
membranes.
Which of the following statements about lipid requirements and administration is LEAST
accurate?
A.Intralipid is a soybean-based oil, rich in omega-6 fatty acids.
B.Lipid infusion should be advanced to 3 to 4 gm per kg per day.
C.Omega-6 fatty acids are considered more pro-inflammatory than omega-3 fatty acids.
D.Soy-based oils are rich in phytosterols, which are associated with a greater risk of liver
cholestasis.
E.There is an increased frequency of elevated serum triglyceride levels when using 20% lipid
solutions instead of 10% lipid solutions
Fluids, Electrolytes, Nutrition & Renal Question 84
Adequate protein intake is essential to ensure appropriate growth and development of the
newborn.
Which of the following statements about the protein requirements of the fetus and newborn is
LEAST accurate?
A.A newborn who is commenced on intravenous fluids that do not contain protein has sufficient
reserves to prevent a catabolic state for the first 48 hours.
B.A protein intake of 2.8 gm per kg per day in a preterm infant is the minimum amount required to
 maintain intrauterine rates of weight gain and nitrogen retention.
C.Current recommendations state that very low birth weight (VLBW) infants require 3.5 to 4 gm
per kg per day of protein.
D.For each gram of protein supplied enterally to a newborn, there is a 0.4 cm per week increase in
the head circumference.
E.The placenta supplies 3.5 gm per kg per day of amino acids to the developing fetus.
Fluids, Electrolytes, Nutrition & Renal Question 85
It is important to understand the physiology behind breastfeeding.
Which of the following statements about the hormonal control of lactation is FALSE?
A.Oxytocin causes contraction of myoepithelial cells.
B.Oxytocin is released from the posterior pituitary.
C.Oxytocin levels increase with suckling.
D.Progesterone promotes milk production.
E.Prolactin is essential for milk secretion.
Fluids, Electrolytes, Nutrition & Renal Question 86
Maternal nutrition influences fetal growth.
What are potential consequences of maternal malnutrition?
A.Increased risk of heart disease later in life
B.Increased risk for hyperlipidemia and obesity later in life
C.Low birth weight
D.All of the above
Fluids, Electrolytes, Nutrition & Renal Question 87
Acute renal injury in neonates is common and can be associated with long-term morbidity.
Which group of patients is at high risk for acute renal injury?
A.Neonate with indirect hyperbilirubinemia
B.Neonate with structural heart disease requiring surgery
C.Neonate with perinatal hypoxic-ischemic injury
D.Neonate with sepsis
E.B+C+D
F.All of the above
Fluids, Electrolytes, Nutrition & Renal Question 89
As the neonatologist on service, you are treating a male infant born at 28 weeks’ gestation with
indomethacin for a large hemodynamically significant patent ductus arteriosus. Twenty-four hours
after the initiation of indomethacin, you notice that the baby’s urine output is significantly decreased
and his serum creatinine is elevated.
Of the following, the most likely mechanism by which indomethacin causes acute renal injury is:
A.An unknown mechanism
B.Distal tubular toxicity
C.Generation of reactive oxygen species
D.Inhibition of prostaglandin production and thus, a decrease in afferent arteriole dilatation
E.Precipitation and obstruction of the renal tubular system
Fluids, Electrolytes, Nutrition & Renal Question 90
Vitamin D deficiency and insufficiency is a global problem.
Which of the following statements about the fetal implications of maternal vitamin D deficiency is
TRUE?
A.An increased maternal intestinal absorption provides calcium to the fetus without requiring
vitamin D.
B.Maternal vitamin D deficiency only causes hypocalcemia in the fetus if the pregnant woman is
vitamin deficient in the third trimester.
C.The infant will be born with a low blood calcium level.
D.The infant will be born with osteomalacia.
E.The pregnant woman cannot provide enough calcium to the fetus.
Fluids, Electrolytes, Nutrition & Renal Answers 81-90
Fluids, Electrolytes, Nutrition & Renal Answer 81
B. Fiber
Vegan diets can be successful during pregnancy, but require close evaluation, surveillance and
counseling. Avoidance of all animal products can result in vitamin B12 deficiency, and this
supplement is recommended for vegans regardless of pregnancy status. In addition to vitamin B12,
vegan women are likely to benefit from a multi-vitamin and mineral supplement when planning for
pregnancy. Specifically, a diet that lacks dairy products may be low in calcium and vitamin D. The
important gestational nutrients of folic acid, iron and zinc intake may be low in pregnant vegan
woman. However, plant-based diets are typically rich in fiber in this group of women.
References:
Creasy RK, Resnik R, Iams JD. Maternal-Fetal Medicine. 5th edition. Philadelphia: Saunders; 2004
Institute of Medicine: Nutrition during pregnancy, weight gain, and nutrient supplements. Washington,
DC: National Academy Press; 1990
Fluids, Electrolytes, Nutrition & Renal Answer 82
D. To maintain growth on full enteral feedings, the infant in this vignette will require approximately
55 kcal/day.
The resting energy expenditure (REE) of a VLBW or ELBW infant is 50 kcal per kg per day. To
achieve growth, sufficient calories must be provided to account for both the REE and additional
energy losses due to metabolic activity. An example of energy loss due to metabolic activity is the
fecal loss of energy, which occurs when enterally fed, which is 10 kcal per kg per day.
The caloric requirements to maintain growth in a preterm infant are calculated from the formula:
(REE x 2) + energy losses
Therefore, for an enterally fed infant, this is (REE x 2) + fecal energy loss = 110-120 kcal/kg/day. If
parenterally fed, there is less energy loss from metabolic activity, and the approximate caloric
requirements are 80-100 kcal/kg/day.
Reference:
Torrazza RM, Neu J. Evidence-based guidelines for optimization of nutrition for the very low
birthweight infant. NeoReviews. 2013;14:e340-349
Fluids, Electrolytes, Nutrition & Renal Answer 83
E. There is an increased frequency of elevated serum triglyceride levels when using 20% lipid
solutions instead of 10% lipid solutions
Lipids are an important requirement for the appropriate growth and development of an infant. In
ELBW and VLBW infants, lipids are typically commenced parenterally. By convention, the lipid
content of infusions is increased in a stepwise fashion; however, this practice is not evidence-based.
Therefore, some clinicians have advocated for starting lipid infusions of 3 gm per kg per day.
Independent of the method of starting infusions, the target lipid infusion in an ELBW and VLBW infant
should be 3 to 4 gm per kg per day.
Serum triglycerides are routinely monitored in infants receiving a lipid infusion and if the
triglyceride level is greater than 200 mg/dL, the lipid infusion rate is either reduced or stopped for up
to 24 hours. Elevated levels of serum triglycerides are less common now with the use of 20% lipid
solutions rather than 10% solutions. The reason for the higher serum triglycerides associated with the
10% solutions is not entirely clear, but these solutions did contain more phospholipids. It has been
proposed that the phospholipids potentially inhibited hydrolysis, leading to the increased serum
triglycerides measured.
 In the US, the only product currently licensed for lipid infusions in infants is Intralipid. This is a
soy-based oil, which contains both omega-6 (including linoleic acid) and omega-3 (including
linolenic acid) fatty acids. Omega-6 fatty acids are more abundant in Intralipid and are considered
more pro-inflammatory than Omega-3 fatty acids. In addition, the phytosterols in soy-based oils are
associated with a greater risk of liver cholestasis. Long-term use (usually greater than 2 weeks) of
Intralipid has been associated with cholestasis and parenteral nutrition-associated liver disease
(PNALD). If either of these conditions develop, the usual practice is to reduce the lipid infusion to 1
gm/kg/day. This is done to limit the insult to the liver, but will not meet all the nutritional
requirements of the infant. Therefore, the aim should be to establish the infant on full enteral feedings
as soon as safely possible. This will allow for adequate lipid intake and the discontinuation of
Intralipid.
Reference:
Torrazza RM, Neu J. Evidence-based guidelines for optimization of nutrition for the very low
birthweight infant. NeoReviews. 2013;14:e340-349
Fluids, Electrolytes, Nutrition & Renal Answer 84
A. A newborn who is commenced on intravenous fluids that do not contain protein, has sufficient
reserves to prevent a catabolic state for the first 48 hours.
Adequate protein intake is essential for growth and development of the fetus and newborn, with
studies showing that for each gram of protein supplied enterally to a newborn, there is a 6.5 gm per
day increase in weight and a 0.4 cm per week increase in head circumference.
Prenatally, the placenta provides approximately 3.5 gm per kg per day of amino acids to the
developing fetus. This approximately matches the fetus’ protein utilization with a 26 week gestational
age infant thought to accrete 2.5 gm per kg per day of protein, and losing approximately 1 gm per kg
per day. Following delivery, there is an abrupt disruption to the protein intake, and the infant enters
into a catabolic state. If commenced on only dextrose-containing fluids, the infant will lose protein
stores at approximately 0.6 to 1 gm per kg per day. Therefore, protein must be supplied either
intravenously through parenteral nutrition, or through enteral feedings if appropriate, as soon as
possible following delivery, to prevent the infant entering into a negative nitrogen balance.
For VLBW infants, a minimum of 2.8 gm per kg per day of protein is required to maintain
intrauterine rates of weight gain and nitrogen retention. This is the bare minimum requirements and an
intake of 3.5 to 4 gm per kg per day of protein has been shown to result in rates of weight gain and
nitrogen accretion in excess of the intrauterine rates, and is the current recommended protein
requirements for these infants.
References:
de Boo HA and Harding JE. Protein metabolism in preterm infants with particular reference to
intrauterine growth restriction. Arch Dis Child Fetal Neonatal Ed. 2007;92:F315–F319
Polin RA, Fox WW, Abman SH. Fetal and Neonatal Physiology. 4rd Edition. Saunders, Philadelphia.
2011
Torrazza RM, and Neu J. Evidence-Based Guidelines for Optimization of Nutrition for the Very Low
Birthweight Infant. NeoReviews. 2013;14:e340-349
Fluids, Electrolytes, Nutrition & Renal Answer 85
D. Progesterone promotes milk production.
During pregnancy, there is development of glandular and ductal tissue secondary to the influence
of progesterone and estrogen, respectively. In addition to these structural changes, progesterone also
inhibits milk production during pregnancy. The placenta is a rich source of progesterone, and
therefore following delivery, there is a precipitous fall in maternal progesterone levels. At the same
time as there is removal of the inhibitory effect of progesterone, there is an increase in prolactin
levels.
Prolactin is produced by the anterior pituitary and increased levels are essential for milk
production and secretion. Following delivery, there is an initial surge in prolactin levels. These
levels decrease, but remain above basal levels while breastfeeding is continued. The actual volume
of milk produced does not correlate with prolactin levels, but is rather thought to be regulated by
local mechanisms including autocrine and mechanical stretch responses. When the infant suckles,
there is a neuro-endocrine reflex which results in a further short-term increase in prolactin and the
release of oxytocin from the posterior pituitary. The oxytocin travels in the bloodstream to the
mammary glands, where it interacts with receptors on myoepithelial cells leading to their contraction
and the ejection of milk from the alveoli.
References:
Polin RA, Fox WW, Abman SH. Fetal and Neonatal Physiology. 4rd Edition. Saunders, Philadelphia.
2011
Rhoades RA, Bell DR. Medical Physiology Principles for Clinical Medicine. 4th Edition. North
American Edition, Lippincott, Williams & Wilkins, Philadelphia. 2012
Fluids, Electrolytes, Nutrition & Renal Answer 86
D. All of the above
The adverse perinatal outcomes of maternal underweight include preterm delivery and low birth
weight. In addition to perinatal adverse outcomes, there are lifelong metabolic changes associated
with severe maternal nutrition restriction. Follow-up studies of adults with mothers exposed to
famine during World War II, have shown an increased incidence of hyperlipidemia, obesity and heart
disease in those exposed to maternal malnutrition early in gestation. Exposure during mid and late
gestation resulted in glucose intolerance. Interestingly, the long-term outcomes were dependent on the
timing of in utero exposure to maternal undernutrition but not on actual birth weight achieved. So,
some have hypothesized that mechanisms that allow fetal adaptation to restricted maternal nutrient
intake and growth might have adverse health consequences later in life.
Reference:
Bloomfield FH, Spiroski A-M, Harding JE. Fetal growth factors and fetal nutrition. Semin Fet Neonat
Med. 2013;18:118-123
Fluids, Electrolytes, Nutrition & Renal Answer 87
E. B+C+D
Neonates are vulnerable to the same factors that cause acute renal injury in older children, such as
sepsis and hypotension. However, given the dynamic changes in renal physiology after birth and the
immaturity of the kidneys of preterm infants, acute renal injury in the neonatal period results from the
combination of harmful exposure and developmental vulnerability. Sepsis is one of the most
important risk factors for acute renal injury in the neonatal period. Neonates with sepsis are at higher
risk for hypotension and are frequently treated with nephrotoxic antibiotics. In addition, the systemic
inflammation might directly damage the kidneys. Perinatal hypoxic-ischemic events place infants at
significantly higher risk for acute kidney injury, and those who developed acute kidney have a more
complicated course (longer hospital stay, worse neurodevelopmental outcomes). Another group of
neonates at increased risk for acute kidney injury are those with congenital heart disease requiring
surgery and/or ECMO.
Reference:
Selewski DT, Charlton JR, Jetton JG, et al. Neonatal acute kidney injury. Pediatrics. 2015, July
13:2014-3819
Fluids, Electrolytes, Nutrition & Renal Question 88
Which of the following statements about neonatal renal physiology is FALSE?
A.Glomerular filtration rate gradually increases and reaches adult levels by 2 years of life.
B.Nephrogenesis continues until 34 to 36 weeks’ gestation.
C.Premature infants have a decreased ability to concentrate urine.
D.Renal blood flow increases during the first 2 months of life.
E.The cardiac output to the kidney increases after birth.
Fluids, Electrolytes, Nutrition & Renal Answer 88
E. The cardiac output to the kidney increases after birth.
Nephrogenesis starts during the fifth week of pregnancy and is not complete until 34 to 36 weeks
of gestation. In utero, the kidneys receive about 25% of the fetal cardiac output; this decreases
dramatically to less than 5% during birth as a result of hemodynamic changes. During the first two
months of age, renal blood flow gradually increases because of increased systemic arteriolar
resistance and decreased renal vascular resistance. During the first day of age, a term infant’s
glomerular filtration rate is about half of the adult value. Glomerular filtration rate gradually
increases after birth to reach adult values after 2 years. Compared to term infants, premature infants
have an even lower glomerular filtration rate and are slower to reach adult values. In addition,
premature infants have immature renal tubular function with decreased ability to reabsorb electrolytes
and concentrate urine.
Reference:
Selewski DT, Charlton JR, Jetton JG, et al. Neonatal acute kidney injury. Pediatrics. 2015, July
13:2014-3819
Fluids, Electrolytes, Nutrition & Renal Answer 89
D. Inhibition of prostaglandin production and thus, a decrease in afferent arteriole dilatation
Indomethacin is a nonsteroidal anti-inflammatory drug frequently used to treat a patent ductus
arteriosus in a premature infant. Indomethacin inhibits prostaglandin production and while its
vasoconstrictive effects are desirable for the closure of the patent ductus arteriosus, this effect also
results in the inhibition of the compensatory dilation of the afferent arteriole with a decrease in
glomerular filtration rate and as a consequence, decreased urine output.
Reference:
Selewski DT, Charlton JR, Jetton JG, et al. Neonatal acute kidney injury. Pediatrics. 2015, July
13:2014-3819
Fluids, Electrolytes, Nutrition & Renal Answer 90
A. An increased maternal intestinal absorption provides calcium to the fetus without requiring
vitamin D.
The majority of the fetal skeletal calcium is acquired during the third trimester of the pregnancy
when the placenta actively transports calcium. However, an increased intestinal calcium absorption
in the pregnant woman begins in the first trimester and is maintained throughout the pregnancy. This
increased intestinal calcium absorption is independent of vitamin D. Therefore, even in pregnant
women with severe vitamin D deficiency, the fetus will have normal calcium blood levels and a
normal skeleton at birth.
Reference:
Kovacs CS. Maternal vitamin D deficiency: Fetal and neonatal implications. Semin Fetal Neonatal
Med. 2013 Feb 13
Fluids, Electrolytes, Nutrition & Renal Questions 91-100
Fluids, Electrolytes, Nutrition & Renal Question 91
Growth and bone mineralization are dependent on adequate mineral supply.
Which of the following statements about the differences in calcium homeostasis between the fetus
and infant is FALSE?
A.After birth, intestinal calcium absorption becomes an active process.
B.During pregnancy, the placenta actively transports calcium to the fetus.
C.Fetal mineral homeostasis requires parathyroid hormone.
D.Fetal mineral homeostasis requires vitamin D and calcitriol.
E.The infant’s calcium homeostasis is dependent on vitamin D.
Fluids, Electrolytes, Nutrition & Renal Question 92
Which of the following statements about the mechanisms of mineral homeostasis during the
transition from intrauterine to extrauterine life is FALSE?
A.After birth, initial intestinal calcium absorption is a passive process facilitated by lactose.
B.Calcium levels are lower in the fetal circulation than in the maternal blood.
C.Calcium levels drop significantly after birth.
D.Calcium levels reach normal values within 48 hours after birth.
E.In the neonatal period, a sequential increase in parathyroid hormone and calcitriol facilitates
intestinal calcium absorption.
Fluids, Electrolytes, Nutrition & Renal Question 93
The mother of a healthy, term, exclusively breastfed infant asks about the need to supplement her
child’s diet with calcium.
Which of the following statements about breast milk and calcium is TRUE?
A.Human breast milk meets the calcium requirements for the first 6 months of an infant’s life.
B.Formula contains more calcium than breast milk.
C.The recommended daily calcium allowance in the first 6 months of life is 200 mg/day.
D.There is no data to support long-term benefits of calcium supplementation in breast fed infants.
E.All of the above
Fluids, Electrolytes, Nutrition & Renal Question 94
What are the factors that contribute to the reduced feeding tolerance in premature infants?
A.Decreased absorptive capacity
B.Decreased production of digestive enzymes
C.Lack of coordinated gut motility
D.All of the above
E.None of the above
Fluids, Electrolytes, Nutrition & Renal Question 95
A male term infant is being managed in the NICU because of severe perinatal depression. He is
currently 2-days old and is receiving only intravenous fluid. He has had very low urine output and the
analysis of his urine shows it to be very concentrated. In addition, his serum sodium value is 128
mEq/L and has dropped from 130 mEq/L 4 hours ago even though there have not been any changes in
his management. He is not having any seizures or neurologic symptoms at this time. His serum
osmolality is very low. His weight has also increased 200 g from the day prior.
The most appropriate next step in the management of the infant in this vignette is to:
A. Decrease the infant’s total fluid volume
B. Increase the amount of potassium in the IV solution
 C. Increase the amount of sodium in the IV solution
D. No adjustment is required
E. Provide a bolus of hypertonic saline
Fluids, Electrolytes, Nutrition & Renal Question 96
A male infant born at 28 weeks’ gestation has been receiving intravenous fluid containing only
dextrose and electrolytes for one week because of inability to obtain central access. The infant is not
receiving any other infusions and is not being fed because of concerns about his abdominal
examination. During the neonatology fellow’s examination at 1 week of age, the infant’s skin appears
to be very dry and scaly. The fellow also notes that the baby has had very poor growth. His complete
blood cell count is remarkable for thrombocytopenia.
What is the most appropriate next step in the management of this infant?
A. Begin an intravenous lipid emulsion
B. Begin iron supplementation
C. Begin vitamin supplementation
D. Increase the infant’s glucose infusion rate
E. Screen for infection and begin antibiotic and antifungal treatment
Fluids, Electrolytes, Nutrition & Renal Question 97
All of the following statements about fat digestion are true, EXCEPT:
A. Fat malabsorption results in enteric losses of the fat-soluble vitamins A, D, E, and K.
B. Mammary lipase is present in human milk and works in the duodenum.
C. Pancreatic lipases account for the majority of fat digestion.
D. Preterm infants have lower levels of bile acids and salts as compared to term infants.
E. Short-chain and medium-chain triglycerides are not dependent on micelle formation for
digestion.
Fluids, Electrolytes, Nutrition & Renal Question 98
The pediatric senior resident is helping the new intern write total parenteral nutrition (TPN)
orders for a 5day old infant born at 28 weeks’ gestation. The infant is not receiving any enteral
nutrition and is not requiring any other medications or infusions.
Which of the following TPN order most appropriately meets the recommended requirements for
the infant described in this vignette?
Volume (ml/kg/day) Dextrose Amino Acids (g/kg/day) Lipid
(mg/kg/min) (g/kg/day)
A. 130 4 1 0.5
B. 130 10 3.5 3
C. 90 5 2 5
D. 140 20 3 2
E. 140 4 4 3
Fluids, Electrolytes, Nutrition & Renal Question 99
A newborn is intubated because of respiratory distress. A post-intubation chest radiograph shows
that the infant’s bones appear to be very osteopenic. Questions about his calcium status arise.
Which of the following statements about calcium balance in the fetus and neonate is TRUE?
A. Phosphorous is the major constituent of bones in the neonate.
B. The fetus is hypercalcemic relative to the mother.
C. The majority of total body calcium of the neonate is found in the extracellular fluid or soft
tissues.
D. The transfer of calcium across the placenta is regulated by the pregnant woman.
E. Total body calcium content of the fetus is highest at the end of the first trimester.
Fluids, Electrolytes, Nutrition & Renal Question 100
As the neonatology fellow, you attend the delivery of a term infant with prenatal diagnosis of
severe unilateral hydronephrosis. You order a baseline creatinine concentration, which is 1.2 mg/dL.
The baby’s father is a nephrologist. He asks you if this value can reliably be used to predict the
infant’s glomerular filtration rate (GFR).
Of the following, the most appropriate statement in response to the father in this vignette is:
A. Determination of creatinine is the “gold standard” for assessing GFR.
B. In the neonate, creatinine can be reabsorbed by the tubules, whereas in the adult it is minimally
absorbed.
C. It takes 1 to 2 months postnatally in term infants for creatinine to reach stable levels.
D. The concentration of creatinine checked at birth is accurate in a newborn.
E. The GFR is highest at birth and then declines.
Fluids, Electrolytes, Nutrition & Renal Answers 91-100
Fluids, Electrolytes, Nutrition & Renal Answer 91
D. Fetal mineral homeostasis requires vitamin D and calcitriol.
There are significant differences between the fetal and neonatal mineral homeostasis. The fetus
receives minerals, including calcium from the placenta. After birth, the intestines absorb calcium.
While the fetal calcium homeostasis is independent of vitamin D and calcitriol, postnatal vitamin
D/calcitriol deficiency will impair calcium absorption and result in abnormal skeletal mineralization.
Several studies indicated that fetal calcium homeostasis is dependent on parathyroid hormone.
Reference:
Kovacs CS. Bone development and mineral homeostasis in the fetus and neonate: roles of the
calciotropic and phosphotropic hormones. Physiol Rev. 2014;94:1143-1218
Fluids, Electrolytes, Nutrition & Renal Answer 92
B. Calcium levels are lower in the fetal circulation than in the maternal blood.
During pregnancy, the placenta supplies the fetus with calcium. An active placental transport
maintains calcium levels in the fetal circulation that are higher than in the maternal blood. These
higher calcium levels are necessary for optimal fetal skeletal development. After birth, when the
placental calcium supply is cut off, there is a transient drop and calcium levels return to normal
within the first 48 hours of life. In the neonate, calcium is absorbed from the intestine. Initially this is
a passive process facilitated by lactose, later it becomes an active process and it is facilitated by
parathyroid hormone and calcitriol.
Reference:
Kovacs CS. Bone development and mineral homeostasis in the fetus and neonate: roles of the
calciotropic and phosphotropic hormones. Physiol Rev. 2014;94:1143-1218
Fluids, Electrolytes, Nutrition & Renal Answer 93
E. All of the above
The calcium content of human milk meets the requirements needed for optimal bone growth during
the first 6 months of life. Long-term benefits of supplementing breast milk with additional calcium
have not been shown. The National Academy of Sciences, Institute of Medicine 2011 Guidelines for
calcium and vitamin D intake recommend 200 mg/day of calcium for healthy infants during the first 6
months of life. In contrast to calcium, breast milk is deficient in vitamin D and exclusively breastfed
infants require supplementation with vitamin D. Infant formula provided 30% to 100% more calcium
than breast milk. However, formula also has a higher phosphorus content. This higher phosphorus
content will result in higher blood phosphorus levels, which in turn could result in lower calcium
levels in formula-fed infants when compared to breastfed infants.
References:
Abrams SA. What are the risks and benefits to increasing dietary bone minerals and vitamin D intake
in infants and small children? Annu Rev Nutr. 2011;31:285-297
Ross AC, Taylor CL, Yaktine AL, Del Valle HB, editors. Dietary Reference Intakes for Calcium and
Vitamin D. Institute of Medicine (US) Committee to Review Dietary Reference Intakes for Vitamin
D and Calcium. Washington (DC): National Academies Press (US); 2011
Fluids, Electrolytes, Nutrition & Renal Answer 94
D. All of the above
During the first weeks of life, premature infants receive the majority of calories needed for growth
through parenteral nutrition. However, establishing enteral nutrition is very important and should
begin early. Given the immaturity of the gut, enough time should be allowed for the gut to adapt.
Factors that contribute to reduced feeding tolerance in premature infants are: a decreased absorptive
capacity, decreased production of digestive enzymes, and a lack of coordinated gut motility.
Reference:
Leaf A. Introducing enteral feeds in the high-risk preterm infant. Sem Fet Neonat Med. 2013;18:150-
154
Fluids, Electrolytes, Nutrition & Renal Answer 95
A. Decrease the infant’s total fluid volume
The infant in this case has findings that are consistent with the syndrome of inappropriate secretion
of antidiuretic hormone (SIADH). It is characterized by renal retention of water, hyponatremia,
decreased osmolality, and oliguria. Treatment is fluid and sodium restriction even though affected
infants have hyponatremia and oliguria. Total body sodium is normal, but total body water is
elevated. As a result, large amounts of sodium should not be given to treat the hyponatremia.
Reference:
Gleason CA, Devaskar SU (eds). Avery’s Diseases of the Newborn. 9th edition. Philadelphia:
Elsevier Saunders; 2011
Fluids, Electrolytes, Nutrition & Renal Answer 96
A. Begin an intravenous lipid emulsion
Fats and other dietary lipids play a major role in neonatal nutrition. They provide energy to
support growth and development. They also deliver essential fatty acids. A fatty acid is a long
hydrocarbon chain capped by a carboxyl group. Essential fatty acids are those fatty acids that cannot
be synthesized endogenously and are required from the diet. They include alpha-linolenic acid and
linoleic acid. A dietary lack of these essential fatty acids even for only 3 to 7 days can elicit the
clinical syndrome of essential fatty acid deficiency, which is characterized by a dry, scale-like
dermatitis, alopecia, thrombocytopenia, susceptibility to bacterial infection, and failure to thrive. If
fat containing formulas or breast milk cannot be given, it can be prevented with as little as 0.25 to 0.5
g/kg/day of lipid emulsion.
Reference:
Fanaroff AA, Martin RJ, Walsh M (eds). Neonatal-Perinatal Medicine. 10th edition. St. Louis:
Mosby; 2014
Fluids, Electrolytes, Nutrition & Renal Answer 97
C. Pancreatic lipases account for the majority of fat digestion.
The majority of dietary fat is in the form of triglycerides, which is composed of fatty acids. Fat
digestion in the adult relies on pancreatic lipase to break down triglycerides and bile acids to
emulsify fat droplets during lipolysis. These processes are decreased in infants, especially preterm
infants. Bile acid levels are low, especially in preterm infants, as a result of lower bile synthesis and
poor ileal absorption. Alternative pathways to compensate for the decreased levels of pancreatic
lipase and bile acids include human milk bile salt-stimulated lipase, gastric lipase, and lingual lipase.
Gastric and lingual lipase have high activity at birth. Mammary lipase is also present in the milk of
term and preterm mothers and functions in the duodenum. This enzyme is able to hydrolyze
triglycerides at low concentrations of bile salts. Long-chain fatty acids are dependent on bile salts for
proper micellization and uptake into the intestinal lymphatics. Medium-chain fatty acids do not
require micellization and can be directly absorbed into the blood stream. The absorption of fat-
soluble vitamins is closely associated with the absorption and transport of lipids.
References:
Blackburn ST (ed). Maternal, Fetal and Neonatal Physiology: A Clinical Perspective. 4th edition. St.
 Louis: Elsevier Health Sciences; 2012
Gleason CA, Devaskar SU (eds). Avery’s Diseases of the Newborn. 9th edition. Philadelphia:
Elsevier Saunders; 2011
Fluids, Electrolytes, Nutrition & Renal Answer 98
B. Volume: 130 ml/kg/d; 10 mg/kg/min Dextrose, 3.5 g/kg/day Amino Acids; 3 g/kg/d Lipids
If optimized appropriately, total parenteral nutrition (TPN) can be used as the main source of
nutrition and energy requirements for critically ill neonates. Energy is essential for body maintenance
and growth. Each gram of weight gain for growth requires between 3 and 4.5 kcal. As a result, an
ideal daily weight gain of 15 g/kg requires calories of 45 to 67 kcal/kg. Neonates also need total
fluids of 120 to 150 ml/kg/day to allow for growth and compensate for insensible water losses, stool
output, and renal solute load. Neonates require up to 3.5 to 4 g/kg/day of amino acids to maintain
stores and promote growth. Glucose is a type of carbohydrate and is the main energy source of the
neonatal brain. Endogenous glucose production is about 6 mg/kg per minute in the preterm infant. This
should be the minimum rate. The maximum rate is guided by the maximal glucose oxidative capacity
for energy production. If glucose is given in excess, it is inefficiently converted to lipid and can lead
to carbon dioxide accumulation. The maximum glucose oxidation capacity is 12 mg/kg/min. It is
crucial to provide lipid emulsions at a minimum rate of 0.5 to 1 g/kg/day to prevent essential fatty
acid deficiency. Lipids are the primary source of energy supply in TPN and should be provided at a
rate of 3 g/kg/day.
Reference:
ElHassan N, Kaiser JR. Parenteral nutrition in the neonatal intensive care unit. NeoReviews.
2011;12:e130-e140
Fluids, Electrolytes, Nutrition & Renal Answer 99
B. The fetus is hypercalcemic relative to the mother.
Calcium and phosphorous are the key elements required for bone mineralization. Calcium is the
most abundant mineral in the body and the major component of bone. Approximately 99% of total
body calcium in the neonate is either in bone or in a calcium phosphate form. A minimal percentage is
contained in the extracellular fluid and soft tissue. Fetal accretion rates of calcium peak during the
third trimester, with upwards of 80% of fetal skeletal mineralization taking place during this period.
The transfer of calcium across the placenta is regulated largely by the fetus. The fetus is
hypercalcemic relative to the mother, particularly in the third trimester. Placental
syncytiotrophoblasts have a relatively low calcium concentration, allowing facilitative diffusion from
the pregnant woman. An active adenosine triphosphate-dependent calcium pump transfers calcium
from the basal surface of the syncytium to the fetus. This calcium ion pump is integral to fetal calcium
metabolism. Maternal calcium status also directly affects transplacental calcium flux.
References:
Polin RA, Fox WW, Abman SH (eds). Fetal and Neonatal Physiology. 4th ed. Philadelphia: WB
Saunders Co; 2010
Vachharajani A, Mathur A, Rao R. Metabolic bone disease of prematurity. NeoReviews.
2009;10:e402-e411
Fluids, Electrolytes, Nutrition & Renal Answer 100
B. In the neonate, creatinine can be reabsorbed by the tubules, whereas in the adult it is minimally
absorbed.
Until 35 to 36 weeks of gestation, the number of glomeruli is increasing, and the glomerular
filtration rate (GFR) is largely dependent on the number of glomeruli. After reaching the full
complement of glomeruli, GFR increases in conjunction with the increase in renal mass. The gold
standard assessment of GFR in adults and children is the inulin clearance. Inulin works well as it is a
freely filtered substance that is not reabsorbed. However, it is a difficult test to perform on a neonate.
As serum creatinine concentration is measured easily and is accessible in an infant, it is used to
assess renal function in the neonate. However, serum creatinine values must be used cautiously to
assess GFR in the neonate because their use is based largely on the finding that, in adults, creatinine
behaves similarly to inulin, as a freely filtered and minimally absorbed substance. In the neonate,
however, creatinine is reabsorbed due to the leaky tubules, especially at lower urine flow rates.
Also, the creatinine value soon after birth is elevated and primarily represents maternal serum
creatinine. Therefore, a single creatinine value does not provide an accurate assessment of neonatal
renal function until serum creatinine concentrations have reached steady state, which may take 1 to 2
weeks for the term infant. Mostly due to incomplete nephrogenesis, GFR in preterm neonates is
significantly lower than in term infants. In the term infant, the GFR at birth typically doubles in the
first two postnatal weeks.
References:
Gleason CA, Devaskar SU (eds). Avery’s Diseases of the Newborn. 9th edition. Philadelphia:
Elsevier Saunders; 2011
Kelly L, Seri I. Renal developmental physiology. NeoReviews. 2008;9:e150-161
Fluids, Electrolytes, Nutrition & Renal Questions 101-104
Fluids, Electrolytes, Nutrition & Renal Question 101
All of the following amino acids can be converted into glucose through gluconeogenesis,
EXCEPT:
A. Alanine
B. Glutamate
C. Glycine
D. Leucine
E. Valine
Fluids, Electrolytes, Nutrition & Renal Question 102
The pediatric resident is called to the delivery of a term infant that has been complicated by
intrauterine growth restriction. After the infant is born, the resident notes that the infant has
microcephaly and hypotonia. Upon further exam, the resident observes that the infant has epicanthic
folds, a broad nasal tip, micrognathia, a cleft palate, and low-set ears. The neonatology fellow
examines the infant and agrees with the resident’s finding and also notes that the infant has syndactyly
of the second and third toes and hypospadias. The infant is admitted to the NICU for management of
hypoglycemia and hypothermia. Throughout the infant’s NICU course, the infant continues to have
severe hypotonia and feeding difficulties.
The disorder that is most likely present in the infant in this vignette belongs to which of the
following classes of metabolic disease?
A. Disorder of amino acid metabolism
B. Disorder of carbohydrate metabolism
C. Disorder of cholesterol synthesis
D. Disorder of fatty acid metabolism
E. Mitochondrial disorder
Fluids, Electrolytes, Nutrition & Renal Question 103
During sign-out about an infant in the Neonatal Intensive Care Unit, the day fellow informs that
night-time covering fellow that the infant likely has syndrome of inappropriate secretion of anti-
diuretic hormone (SIADH).
If the diagnosis of SIADH is correct for the infant in this vignette, all of the following is expected
in this infant, EXCEPT:
A. Decreased serum sodium concentration
B. Increased serum osmolality
C. Increased urine concentration
D. Oliguria
E. Weight gain
Fluids, Electrolytes, Nutrition & Renal Question 104
A male infant born at 27 weeks’ gestation is now 5 weeks old. He is receiving full enteral
feedings with fortified breast milk.
In order to achieve optimal bone mineralization in preterm infants, which of the following is
important??
A.Breast milk should be fortified as breast milk alone does not meet the mineral requirements of a
premature infant.
B.If alkaline phosphatase activity peaked at levels <800 IU/L and the infant achieved full enteral
feedings with fortified breast milk or formula, serial measurements of alkaline phosphatase
 activity can be stopped.
C.Preterm, high mineral content formula should be used.
D.Screening with alkaline phosphatase activity and serum phosphorus should be started at 4 to 6
weeks after birth and continued biweekly.
E.All of the above
Fluids, Electrolytes, Nutrition & Renal Answers 101-104
Fluids, Electrolytes, Nutrition & Renal Answer 101
D. Leucine
Based on the nature of their metabolic end products, amino acids are classified as ketogenic,
glucogenic, or both ketogenic and glucogenic. Ketogenic amino acids yield acetyl-CoA or
acetoacetyl-CoA as metabolic end products. Glucogenic amino acids give rise to glucose or glycogen
and pyruvate or any of the intermediates of the tricarboxylic acid (TCA) cycle. Gluconeogenesis from
amino acids occurs mainly in the liver and the kidney. Alanine, glycine, and glutamate are the main
glucogenic amino acids. Other glucogenic amino acids include aspartate, cysteine, and proline. The
glucogenic and ketogenic amino acids include tyrosine, isoleucine, phenylalanine and tryptophan. The
ketogenic amino acids include leucine and lysine.
Reference:
Gleason CA, Devaskar SU (eds). Avery’s Diseases of the Newborn. 9th edition. Philadelphia:
Elsevier Saunders; 2011
Fluids, Electrolytes, Nutrition & Renal Answer 102
C. Disorder of cholesterol synthesis
The infant described in this vignette most likely has Smith-Lemli-Opitz syndrome. This syndrome
is a disorder of cholesterol synthesis associated with dysmorphic features, cleft palate, congenital
heart disease, hypospadias, polydactyly, and syndactyly of the second and third toe. Serum
cholesterol concentrations may be abnormally low or normal. An elevated plasma 7-
dehydrocholesterol value is diagnostic. In Smith-Lemli-Opitz, the enzyme that converts this compound
to cholesterol is missing and 7-dehydrocholesterol accumulates to toxic levels. In addition, as
cholesterol is a key part of cell membranes and myelin, a defect in cholesterol has serious
implications.
References:
Blackburn ST (ed). Maternal, Fetal and Neonatal Physiology: A Clinical Perspective. 4th Edition. St.
Louis: Elsevier Health Sciences; 2012
Dagli A, Zori R, Heese B. Testing strategy for inborn errors of metabolism in the neonate.
NeoReviews. 2008;9:e291-298
Fluids, Electrolytes, Nutrition & Renal Answer 103
B. Increased serum osmolality
The main action of the hormone vasopressin (or anti-diuretic hormone, ADH) is to regulate the
osmolality of the extracellular compartment. The primary renal action of ADH is to selectively raise
free water reabsorption via the insertion of water channels into the distal tubular and collecting duct
epithelium. Under certain pathologic conditions, the dysregulated release of ADH can occur. This
significantly affects renal function. One example of this occurs in the syndrome of inappropriate
secretion of anti-diuretic hormone (SIADH). SIADH can be associated with birth hypoxia-ischemia,
intracranial hemorrhage, pulmonary abnormalities, or positive-pressure ventilation. It is
characterized by free water retention by the kidneys with decreased serum sodium and osmolality.
Affected infants also have oliguria, increased urine concentration, and weight gain/edema.
Reference:
Gleason CA, Devaskar SU (eds). Avery’s Diseases of the Newborn. 9th edition. Philadelphia:
Elsevier Saunders; 2011
Fluids, Electrolytes, Nutrition & Renal Answer 104
E. All of the above
Calcium accretion peaks during 32-36 weeks of gestation when the fetus accretes 100-130 mg/kg
of calcium per day. In comparison, a breastfed term infant’s daily calcium retention is 90 mg.
Therefore, in order to meet the increased needs of preterm infants, breast milk should be fortified or
preterm formula with high mineral content should be used. In addition, biochemical studies should be
routinely performed to follow bone mineralization. Measurements of alkaline phosphatase activity
and serum phosphorus should be obtained once a premature infant is 4 to 6 weeks old. Measurements
can be stopped when the alkaline phosphatase activity peaks at levels <800 IU/L and the infant
achieves full enteral feedings with fortified breast milk or formula.
Reference:
Abrams SA; Committee on Nutrition. Calcium and vitamin D requirements of enterally fed preterm
infants. Pediatrics. 2013;131:e1676-83
VIII. GASTROENTEROLOGY
Gastroenterology Questions 1-10
Gastroenterology Question 1
A term female infant develops bilious vomiting at 48 hours of age. She has not passed meconium
and her abdomen is extremely distended. Physical examination shows a normal-appearing perineum.
Abdominal radiograph shows dilated small and large bowel with absence of rectal air. No other
anomalies are apparent.
Of the following, the MOST likely diagnosis in this infant is:
A.Annular pancreas
B.Duodenal atresia
C.Hirschsprung disease
D.Ileal atresia
E.Pyloric stenosis
Gastroenterology Question 2
A male fetus with an intestinal atresia has an intrauterine intestinal perforation at 28 weeks’
gestation.
What is the most likely postnatal radiographic finding?
A. Dilated bowel loops
B. Intra-abdominal calcifications
C. Paucity of bowel gas
D. Pneumatosis
E. Portal venous gas
Gastroenterology Question 3
A 10-day old 1000 gram infant presents with increased abdominal distension and bilious
aspirates. The abdominal radiograph is shown below.

Radiograph kindly provided by Dmitry Dukhovny, MD

The most appropriate initial management of this infant is to:
A.Administer a fluid bolus to improve intestinal perfusion
B.Intubate the infant in anticipation of apnea
C.Obtain an abdominal ultrasound to confirm the diagnosis
D.Sedate the infant to minimize abdominal movements
E.Stop feedings and place a replogle to continuous suction to provide bowel rest
Gastroenterology Question 4
Of the following, the most likely long-term issue in an infant who had medical necrotizing
enterocolitis (NEC) is:
 A.Chronic diarrhea
B.Encopresis
C.Failure to thrive
D.Gastroesophageal reflux disease
E.Intestinal stricture
Gastroenterology Question 5
A 3-day old term infant develops abdominal distension and has not passed meconium. A barium
contrast enema study reveals a narrowed segment of the colon with dilated bowel proximal to the
involved segment.
Which of the following diseases is associated with a small left colon or microcolon?
A. Maternal diabetes
B. Maternal hypothyroidism
C. Maternal lupus
D. Maternal myasthenia gravis
E. A and B
Gastroenterology Question 6
A 12-hour old full-term male infant has an episode of bilious emesis. His physical examination is
unremarkable. His upper gastrointestinal series is similar to an infant’s study found at:
http://www.virtualpediatrichospital.org/providers/CAP/Case04/Images/Case04.02.jpg
The infant undergoes emergency surgery to correct the underlying problem.
Which of the following is NOT part of this procedure?
A.Appendectomy
B.Placement of the cecum in the left lower abdominal quadrant
C.Placement of the small and large intestines in anatomically correct positions
D.Rotation of the intestines counterclockwise
E.Separation of Ladd’s bands
Gastroenterology Question 7
A 2-day old infant born at 26 weeks’ gestation has a spontaneous intestinal perforation.
All of the following are risk factors, EXCEPT:
A.Initiation of feedings with formula instead of breast milk
B.Mechanical ventilation for surfactant deficiency
C. Postnatal steroid exposure
D. Prior indomethacin to close a patent ductus arteriosus
E.Use of vasopressors
Gastroenterology Question 8
A former 29-week gestational age infant now with a postmenstrual age of 36 weeks’ gestation has
persistent postprandial emesis and has been treated twice for aspiration pneumonia. You are
concerned about pathologic gastroesophageal reflux disease (GERD) and would like to confirm the
diagnosis.
Which of the following will most reliably diagnose GERD in this infant?
A.Esophageal endoscopy
B. Esophageal manometry
C. Impedance monitoring
D.Nuclear scintigraphy
E.Upper gastrointestinal series
Gastroenterology Question 9
A 1-month old male infant who was born full-term has bi-phasic stridor that worsens when he
cries. He is well-appearing and afebrile. Chest radiograph shows a normal cardiothymic silhouette.
Bronchoscopy reveals a large mass compressing the trachea above and below the glottis. A
computed tomography scan of his neck and chest reveals a cystic mass in the superior mediastinum.
The mass is removed surgically and determined by pathology to be an esophageal duplication
cyst.
In additional to airway obstruction and respiratory compromise, which of the following is another
potential complication of an esophageal duplication cyst?
A.Acid secretion by gastric epithelium, leading to ulceration and erosion into contiguous structures
B.Dysphasia and epigastric pain
C.Malignant transformation
D.None of the above
E.All of the above
Gastroenterology Question 10
A 2-week old former 29 week gestational age neonate develops feeding intolerance and
abdominal distension. Radiographic findings demonstrate pneumatosis intestinalis and free intra-
abdominal air, which is consistent with necrotizing enterocolitis (NEC). The pediatric surgeon
recommends a laparotomy. While obtaining consent for the procedure, the parents ask the surgeon
about potential complications.
Which of the following statements is TRUE?
A.Laparotomy has been shown to have lower morbidity and mortality rates compared to primary
peritoneal drain placement for the surgical management of NEC
B.Medically and surgically managed patients with NEC have similar long-term
neurodevelopmental outcomes
C.Recurrent NEC occurs in 25% of cases
D.The mortality rate of surgical NEC is greatest in infants of lower gestational age
E. The most common delayed complication of NEC is the formation of an intestinal stricture
involving the right colon
Gastroenterology Answers 1-10
Gastroenterology Answer 1
C. Hirschsprung disease
The features of the infant in the vignette are consistent with a distal intestinal obstruction, such as
Hirschsprung disease. The typical neonatal presentation of Hirschsprung disease includes: delay or
failure to pass meconium, bilious emesis, and abdominal distension. The disease is characterized by
congenital absence of the intramural ganglia in the affected bowel segment. Radiographic findings
demonstrate distention of small and large bowel with lack of rectal air. An annular pancreas may
lead to a duodenal atresia with finding of a double-bubble appearance radiographically and limited
distal air. An ileal atresia may show a triple-bubble or multiple dilated bowel loops with air-fluid
levels. Infants with a pyloric stenosis will not have bilious emesis but rather, present with projectile
non-bilious vomiting.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Hansen A, Puder M (eds). Manual of Surgical Neonatal Intensive Care. 2nd edition. Hamilton,
Ontario: BC Decker; 2009
Loening-Baucke V, Kimura K. Failure to pass meconium: diagnosing neonatal intestinal
obstruction. Am Fam Physician. 1999; 60(7):2043-2050
Gastroenterology Answer 2
B. Intra-abdominal calcifications
An intrauterine intestinal perforation can lead to a meconium peritonitis. Meconium peritonitis is
demonstrated radiographically by intra-abdominal calcifications scattered throughout the peritoneum.
Eighty-six percent of fetuses with meconium peritonitis have intra-abdominal calcifications, which
are visible approximately 8 days after the perforation. Mixed meconium and urine calcifications are
present in cases such as recto-urethral fistulas.
Reference:
Ali SW, ul Hassan M. Meconium peritonitis-a leading case of neonatal peritonitis. Indian J
Pediatr. 1996;63:229-232
Gastroenterology Answer 3
E. Stop feedings and place a replogle to continuous suction to provide bowel rest
The clinical and radiographic findings of the infant in this vignette are most consistent with
necrotizing enterocolitis (NEC). Anteroposterior abdominal and left lateral recumbent radiographs
are the ideal studies to assess the intestinal gas pattern and identify free abdominal air. Intestinal ileus
is the most common early finding of infants affected with NEC. Other early findings include intestinal
dilation and thickening of bowel loops; air-fluid levels may also be evident in the decubitus view.
The pathognomonic radiographic finding in NEC is intramural gas, also known as pneumatosis
intestinalis and shown in the vignette’s radiograph. The gas is located between the subserosal and
muscularis layers of the bowel and is attributable to hydrogen production from pathogenic bacteria
within the bowel wall. Two radiographic patterns of pneumatosis are described: cystic and linear.
The cystic type results from air bubbles in the submucosal layer and may appear similar to fecal
material in the large bowel. The linear pattern is formed by coalesced air bubbles and runs parallel to
the bowel lumen. Additional radiographic findings in infants with NEC include: portal venous gas
(also shown in this infant’s radiograph), thickened bowel walls, fixed bowel loop, and
intraperitoneal air.
Initial management of NEC requires decompression of the bowel gas by placement of a replogle
tube to low continuous suction. Feedings should be discontinued to ensure bowel rest and antibiotics
should be started. Serial monitoring of electrolytes, platelets, hematocrit, and abdominal radiographs
are helpful to determine the progression of the disease. Surgical bowel resection may sometimes be
warranted.
References:
Caplan MS, Jilting T. The pathophysiology of necrotizing enterocolitis. NeoReviews.
2001;2(5):c103-c108
Dimmitt RA and Moss RL. Clinical management of necrotizing enterocolitis. NeoReviews,
2001;2:e110-e117
Kleigman RM, Walsh MC. Neonatal necrotizing enterocolitis: Pathogenesis, classification, and
spectrum of disease. Curr Prob Pediatr. 1987;17:213
Gastroenterology Answer 4
E. Intestinal stricture
Neonates with a history of medical necrotizing enterocolitis (NEC) are at increased risk of
developing intestinal strictures. If a large portion of the bowel is surgically removed, infants are at
risk for short bowel syndrome and failure to thrive.
Most post-NEC intestinal strictures (80%) occur in the large intestine. Within the large bowel, the
left colon is the most common site for a stricture (49%), followed by the right colon (22%), terminal
ileum (15%), and transverse colon (13%). However, the ileum and jejunum may also be affected.
Strictures occur as the intestinal tissue heals and granulation tissue forms leading to subsequent
fibrosis and stricture formation.
Reference:
Jesse N, Neu J. Necrotizing enterocolitis: Relationship to innate immunity, clinical features, and
strategies for prevention. NeoReviews. 2006;7:e143 - e150
Gastroenterology Answer 5
E. A and B – Maternal diabetes and maternal hypothyroidism
Microcolon in a newborn can be associated with maternal diabetes (most common association),
maternal hypothyroidism, maternal toxemia, and prematurity. It can be a rare complication of cecal
perforation. The pathogenesis of small left colon is postulated to result from a functional immaturity
of the ganglion cells, primarily affecting the descending and rectosigmoid colon. This functional
obstruction leads to abdominal distention and inability to pass meconium. A barium contrast enema
study will show a small colon segment with dilated proximal bowel.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Fanaroff AA, Martin RJ, Walsh MC (eds). Neonatal-Perinatal Medicine: Diseases of the Fetus
and Infant. 8th ed. Philadelphia: Mosby-Elsevier; 2006
Gastroenterology Answer 6
C. Placement of small and large intestines in anatomically correct positions
The infant in the vignette has a malrotation with midgut volvulus causing the bowel to rotate
around the mesentery and kinking off its blood supply. It is the consequence of abnormal fetal
intestinal rotation and fixation in the abdomen. Infants may present with bilious emesis alone, or with
signs of acute peritonitis and bloody stools. Plain radiographs reveal dilated bowel loops with air-
fluid levels. Contrast studies show an abnormal course of the duodenum and either a “bird’s beak”
(complete obstruction) or an “apple core” (partial obstruction) configuration.
Treatment is with emergent surgery. The Ladd’s procedure consists of the following:
 Reducing the volvulus by turning the bowel in a counterclockwise fashion
Separating the Ladd’s bands that connect the intestine to the mesentery
Removing the appendix
Situating the bowel in the abdomen with the cecum in the left lower quadrant and the
duodenum on the right. This is an important step to avoid recurrences.
References:
Hansen A, Puder M (eds). Manual of Surgical Neonatal Intensive Care. 2nd edition. Hamilton,
Ontario: BC Decker, 2009
Virtual Pediatric Hospital. Available at: http://www.virtualpediatrichospital.org/ Accessed on:
August 5, 2015
Gastroenterology Answer 7
A. Initiation of feedings with formula instead of breast milk
Spontaneous intestinal perforation (SIP) is a localized intestinal perforation in small, preterm
infants. It typically involves the terminal ileum and occurs earlier in life (often in the first week) than
a perforation associated with necrotizing enterocolitis. Risk factors associated with SIP include the
following:
• Exposure to indomethacin
• Exposure to postnatal steroids
• Treatment with vasopressors
• Mechanical ventilation and receipt of surfactant
• Maternal chorioamnionitis
Infants may be asymptomatic or present with hypotension and abdominal discoloration. An
abdominal radiograph reveals pneumoperitoneum without pneumatosis or portal venous gas.
Treatment involves bowel rest, antibiotics, and potentially surgical repair, though often the
perforation will heal without intervention.
References:
Attridge JT, Clark R, Walker MW, Gordon PV. New insights into spontaneous intestinal
perforation using a national data set: (1) SIP is associated with early indomethacin exposure. J
Perinatol. 2006;26:93-99
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Gastroenterology Answer 8
C. Impedance monitoring
There is much controversy surrounding the diagnosis and treatment of gastroesophageal reflux
disease in newborn. Most newborns have some degree of physiologic reflux resulting from poor
lower esophageal sphincter tone, prolonged sphincter relaxation, and poor esophageal motility. A
smaller proportion of infants have symptomatic reflux disease (6% to 7% of term infants, 7% to 10%
of preterm infants). Symptoms include emesis, respiratory problems such as wheezing and aspiration,
pain, and back arching. Long-term complications include oral aversion and esophageal stricture as a
result of esophagitis.
A diagnosis of GERD is typically based on clinical signs and symptoms. Esophageal pH
monitoring can provide additional information by measuring the frequency and duration of acid reflux
episodes. This study also helps to assess the temporal relationship between acid reflux and clinical
symptoms and helps determine the adequacy of anti-acidic reflux medications. However, pH probes
must be placed in the correct position for the entire test period and they only measure acid-related
reflux. Most recently, studies have found that non-acid reflux is a common cause of reflux.
Impedance monitoring is a pH-independent method of measuring reflux by assessing change in
resistance to electrical current flow between sensors located throughout the esophagus. One of the
sensors is a distal pH sensor that categorizes the episode as acid or non-acid. This test can assess for
the presence of reflux, the time that the liquid is in the esophagus and how long it takes for the bolus
to be cleared from the esophagus. Impedance monitoring is the most reliable method currently used to
diagnose GERD in an infant.
Endoscopy can visualize the esophagus and allow for biopsy of the esophageal epithelium. It can
be helpful to discriminate between reflux and eosinophilic or allergic esophagitis. However, it is an
invasive procedure requiring sedation and not a first-line method to diagnose GERD in an infant.
Esophageal manometry is technically difficult to perform and does not provide information about
reflux itself, only sphincter tone and function.
The role of nuclear scintigraphy in the evaluation of pediatric GERD is unclear. A nuclear scan
can detect non-acid and acid reflux, evaluate gastric emptying, and may demonstrate aspiration.
However, a lack of standardized techniques and the absence of age-specific normative data limit the
value of scintigraphy in infants.
Upper gastrointestinal series can provide information regarding motility, though it is time-limited
and cannot distinguish between physiologic and pathologic reflux. It is ideal for detecting anatomic
abnormalities such as strictures, achalasia and malrotation.
References:
Brodsky D. Gastroesophageal reflux in the premature infant. In: Primary Care of the Premature
Infant. Brodsky D, Ouellette MA (eds). Philadelphia: WB Saunders, 2008
Lundell LR, Dent J, Bennett JR, et al. Endoscopic assessment of esophagitis: clinical and
functional correlates and further validation of the Los Angeles classification. Gut. 1999;45:172-80
Rosen R. GERD in the preterm infant. Primary Care of the Preterm Infant Conference.
Massachusetts Medical Society, Waltham, MA. March 4, 2011
Gastroenterology Answer 9
E. Acid secretion by gastric epithelium, leading to ulceration and erosion into contiguous structures
Dysphasia and epigastric pain
Malignant transformation
Esophageal duplication cysts are rare congenital abnormalities occurring in 1 in 8,200 births.
These cysts results from foregut budding in early embryonic life. They can be spherical or tubular
and contain smooth muscle, skeletal muscle, columnar, squamous, or gastric epithelium, or a
combination of the above. Most affected infants are asymptomatic and the diagnosis is made
incidentally, with 22% presenting before the age of 2 years. Those with symptoms usually have
respiratory problems related to airway obstruction. Others may have dysphasia and epigastric pain.
If esophageal duplication cysts are not removed, they can undergo malignant transformation. If they
contain gastric epithelium, acid production may cause ulceration and erosion into neighboring
structures. Resection is definitive treatment, with removal of intrathoracic cysts presenting potential
risk to the recurrent laryngeal nerve.
Reference:
Nayan S, Nguyen LH, Nguyen VH, Daniel SJ, Emil S. Cervical esophageal duplication cyst: Case
report and review of the literature. J Pediatr Surg. 2010;45:e1-e5
Gastroenterology Answer 10
D. The mortality rate of surgical NEC is greatest in infants of lower gestational age
NEC is the most common surgical emergency in neonates and has significant associated mortality
and morbidities. Stricture formation is the most common delayed complication after recovery from
acute NEC and occurs in both medically and surgically managed patients. Up to 36% of affected
infants may develop a stricture, with the majority occurring in the left colon. The overall incidence of
recurrent NEC is approximately 6% and most recurrences can be managed medically. While patients
who have medically managed NEC have similar neurodevelopmental and growth outcomes compared
to patients without NEC, surgically managed patients with NEC have been shown to have worse long-
term neurodevelopmental and growth outcomes. However, similar rates of morbidity and mortality
have been shown with patients who receive laparotomy or primary peritoneal drain placement for the
management of NEC. The mortality rate of surgical NEC is dependent upon the severity of disease
and is greatest in infants of lower gestational age.
Reference:
Raval M, Moss RL. Surgical necrotizing enterocolitis: A primer for the neonatologist. NeoReviews.
2013;14:e393-e401
Gastroenterology Questions 11-20
Gastroenterology Question 11
An omphalocele is a congenital abdominal wall defect resulting from incomplete body wall
folding during embryogenesis.
Which of the following statements is FALSE?
A.Approximately 10% of infants with omphaloceles will have also have gigantism, macroglossia,
and hypoglycemia secondary to pancreatic hyperplasia
B.Associated genes include pituitary homeobox 2, insulin-like growth factor 2, cyclin-dependent
kinase inhibitor 1C, and a methylenetetrahydrofolate reductase gene polymorphism
C.Congenital anomalies are noted in 50% to 70% of patients with an omphalocele
D.The incidence of omphalocele is 1 to 3 per 10,000 live births
E.The presence of an omphalocele is associated with young maternal age
Gastroenterology Question 12
A 36 week gestational age male infant is born with an abdominal wall defect 1 cm to the right of
the umbilicus. Eviscerated abdominal contents, including large and small bowel, are not covered in a
protective sac, and the infant is diagnosed with a gastroschisis.
Which of the following statements is TRUE?
A. Gastroschisis is associated with advanced maternal age
B. Gene polymorphisms of endothelial nitric oxide synthase, intracellular adhesion molecule 1,
and atrial natriuretic peptide have been associated with a ten-fold increased risk of developing
an omphalocele
C. Intrauterine growth restriction is more likely to occur in infants born with an omphalocele than
in infants born with a gastroschisis
D.Prolonged ileus, catheter-related infection, and sepsis are the most common complications of
gastroschisis and affect 15% to 30% of patients
E.The majority of infants born with gastroschisis will have an associated intestinal atresia or
stenosis
Gastroenterology Question 13
Neonatal hemochromatosis, now known as gestational alloimmune liver disease, is the most
common cause of neonatal liver failure.
Which of the following statements is FALSE?
A. Neonatal hemochromatosis typically begins in utero
B.Neonatal hemochromatosis is characterized by massive iron deposition in the liver and extra-
hepatic tissues
C. The pathogenesis of neonatal hemochromatosis results from transplacental passage of maternal
IgG antibodies with subsequent injury of the fetal liver
D. The recurrence risk of neonatal hemochromatosis in pregnancies subsequent to the index case
is approximately 25%
E. Without exchange transfusion or intravenous immunoglobulin (IVIG), survival of infants with
neonatal hemochromatosis is approximately 10% without liver transplantation
Gastroenterology Question 14
Which of the following statements about neonatal protein digestion is MOST accurate?
A.Amino acid transport capacity is not developed until 6 months of age
B.Chymotrypsin and trypsin are present in duodenal fluid and decreased in both preterm and full-
term infants
 C.Decreased secretory IgA levels increase intestinal uptake of intact protein in neonates compared
to adults
D.Gastric pH is decreased in neonates (compared to adults) as a result of increased HCl secretion
E.Neonates have decreased absorption of nitrogen compared to adults
Gastroenterology Question 15
A 1-day old full-term male neonate presents with bilious emesis and a distended abdomen. He had
a water-soluble contrast enema that shows a transition zone in the distal portion of the sigmoid colon
with marked dilatation of the descending and transverse colon.
Of the following, the complication that is most likely to occur in this infant is:
A.Acute bacterial enterocolitis
B.Malrotation
C.Necrotizing enterocolitis
D.Spontaneous intestinal perforation
E.Volvulus
Gastroenterology Question 16
You are called to see a male infant with a prenatal diagnosis of a gastroschisis who has become
tachypneic in the last 30 minutes. The baby was born 5 hours ago after an elective Cesarean section at
39 weeks’ gestation with a birthweight of 3.5 kg. Apgar scores were 9 and 9 at 1 and 5 minutes,
respectively. The mother’s pregnancy, general health, and delivery course are unremarkable. Besides
the gastroschisis, the neonate had a normal physical exam, with an initial respiratory rate of 35 to 45
breaths per minute and no increased work of breathing. A peripheral IV line was inserted late at 3
hours of life due to some difficulty in placement and IV fluids were ordered at 60 mL/kg/day and are
awaited. The exposed bowel was examined and found intact and viable and left wrapped in saline
soaked gauze.
At 5 hours of life, the baby is sleeping and does not awaken during your exam. His heart rate is
180 beats/min, mean BP is 40 mm Hg and respiratory rate is 60 to 70 breaths per minute. He is not in
respiratory distress and has an oxygen saturation of 100% in room air. His tone is decreased. His
glucose is 68 mg/dL. He has an orogastric tube in place that has drained 30 mL of bile-stained fluid.
The team has already sent a complete blood count (CBC) and blood culture and has ordered a chest
radiograph and antibiotics.
What should be the initial management of this infant?
A.Give a bolus of 10 mL/kg of normal saline and start maintenance fluids
B.Give a glucose bolus of 2 mg/kg STAT
C.Replace his orogastric tube
D.Take him to the OR immediately to explore new-onset gut ischemia
E.Transilluminate his chest to look for a pneumothorax
Gastroenterology Question 17
A 1-day old full-term infant with respiratory distress and abdominal distension has an abdominal
radiograph that shows dilated bowel loops with air-fluid levels and peritoneal calcifications. The
infant is taken to the operating room for an exploratory laparotomy and is noted to have ileal
atresia.
Which of the following statements about jejunal-ileal atresia is TRUE?
A. A greater degree of intraluminal air noted on an abdominal radiograph postnatally generally
correlates with a more proximal obstruction
B. Duodenal atresia is more common than jejunal or ileal atresia
 C. Ileal atresias most commonly occur in the proximal ileum and rarely occur in the distal ileum
D.Polyhydramnios occurs in approximately 1/3 of fetuses with jejunal atresia and is less common
in fetuses with ileal atresia
E. The obstruction associated with jejunal-ileal atresia occurs during intestinal development
Gastroenterology Question 18
A 6-week old male infant born at 39 weeks’ gestation presents to the Emergency Room with
nonbilious vomiting and dehydration. An abdominal ultrasound reveals pyloric stenosis.
Which of the following statements about pyloric stenosis is FALSE?
A.Pyloric stenosis is more common in males than in females
B. The classic metabolic derangement associated with pyloric stenosis is hypochloremic
hyperkalemic metabolic acidosis
C. The recurrence risk of pyloric stenosis for a family with one child who has pyloric stenosis is
3%
D. The risk of having a child with pyloric stenosis is greater if the mother has a prior history of
pyloric stenosis instead of the father having a prior history of pyloric stenosis
E. Pyloric stenosis has been associated with blood types O and B
Gastroenterology Question 19
8-month old infant presents with a history of failure to thrive, diarrhea with fatty, foul-smelling
stools, and recurrent infections. The pediatrician suspects that the infant might have Shwachman-
Diamond syndrome (SDS).
Which of the following statements about SDS is FALSE?
A. Patients with SDS are at increased risk of acute myeloid leukemia and aplastic anemia
B. SDS is a rare autosomal recessive disorder, most commonly associated with a mutation in a
gene located on chromosome 7q11
C. SDS often presents in infancy with pancreatic dysfunction, bone marrow failure, and skeletal
abnormalities
D.The gene associated with this disorder plays an important role in the maturation of the 60S
ribosomal subunit and ribosomal assembly
E.Thrombocytopenia is the most common hematologic abnormality associated with SDS
Gastroenterology Question 20
A 1-day old full term female infant presents with bilious emesis. The infant’s abdominal
radiograph is shown below:

Radiograph kindly provided by Dmitry Dukhovny, MD

Which of the following statements about this infant’s most likely diagnosis is FALSE?
A.Bilious emesis in the first 24 hours of life is the most common postnatal clinical presentation
B.Greater than 30% of infants with this diagnosis have trisomy 21
C.Intrauterine ischemia is the most common etiology
D. It is associated with congenital heart disease (30%) and esophageal atresia (10%)
E.Polyhydramnios is a common prenatal ultrasonographic finding
Gastroenterology Answers 11-20
Gastroenterology Answer 11
E. The presence of an omphalocele is associated with young maternal age
Omphalocele is a midline defect characterized by eviscerated abdominal contents typically
covered by a protective sac. It is associated with advanced maternal age and approximately 30% of
affected infants have an abnormal karyotype, including trisomy 13, 18, and 21. Approximately 50%
to 70% of affected patients have associated congenital anomalies, including 10% of cases with
Beckwith-Wiedemann syndrome characterized by omphalocele, gigantism, macroglossia, and
hypoglycemia secondary to pancreatic hyperplasia. Several genes including pituitary homeobox 2,
insulin-like growth factor 2, cyclin-dependent kinase inhibitor 1C, and a methylenetetrahydrofolate
reductase gene polymorphism (677C-T) have been associated with an omphalocele, however their
roles in the pathogenesis remain unclear.
Reference:
Kastenberg Z, Dutta S. Ventral abdominal wall defects. NeoReviews. 2013;14:e402-e411
Gastroenterology Answer 12
E. The presence of an omphalocele is associated with young maternal age
Omphalocele is a midline defect characterized by eviscerated abdominal contents typically
covered by a protective sac. It is associated with advanced maternal age and approximately 30% of
affected infants have an abnormal karyotype, including trisomy 13, 18, and 21. Approximately 50%
to 70% of affected patients have associated congenital anomalies, including 10% of cases with
Beckwith-Wiedemann syndrome characterized by omphalocele, gigantism, macroglossia, and
hypoglycemia secondary to pancreatic hyperplasia. Several genes including pituitary homeobox 2,
insulin-like growth factor 2, cyclin-dependent kinase inhibitor 1C, and a methylenetetrahydrofolate
reductase gene polymorphism (677C-T) have been associated with an omphalocele, however their
roles in the pathogenesis remain unclear.
Reference:
Kastenberg Z, Dutta S. Ventral abdominal wall defects. NeoReviews. 2013;14:e402-e411
Gastroenterology Answer 13
D. The recurrence risk of neonatal hemochromatosis in pregnancies subsequent to the index case is
approximately 25%
The recurrence risk of neonatal hemochromatosis approaches 90% in pregnancies subsequent to
the index case, consistent with the mechanism of fetal alloimmune injury. Studies have demonstrated
that IVIG, when given to a pregnant woman weekly beginning at 18 weeks’ gestation, significantly
decreases the risk of severe neonatal hemochromatosis in at-risk pregnancies.
References:
Shanmugam NP, Bansal S, Greenough A, Verma A, Dhawan A. Neonatal liver failure: Aetiologies
and management – State of the art. Eur J Pediatr. 2011;170:573-581
Squires R. Acute liver failure in children. In: UpToDate, Basow, DS (Ed), UpToDate, Waltham,
MA, 2013
Gastroenterology Answer 14
B. Chymotrypsin and trypsin are present in duodenal fluid and decreased in both preterm and full-
term infants
In general, protein digestion in neonates is adequate because of normal nitrogen absorption and
increased intestinal uptake of intact protein compared with adults. This increased uptake is a result
of increased secretory IgA levels and increased mucosal permeability. Gastric pH is increased in
neonates due to decreased HCl secretion. Dipeptidase in the mucosa and amino acid transport
capacity are both well-developed early in life. Chymotrypsin and trypsin are present in the duodenal
fluid and while amounts are decreased in infants, these compounds remain important for protein
digestion in neonates.
Reference:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Gastroenterology Answer 15
A. Acute bacterial enterocolitis
The clinical presentation and contrast enema findings of the infant in this vignette are consistent
with Hirschsprung disease (congenital intestinal aganglionosis), which occurs in 1 in 5,000 births. A
contrast enema radiograph in affected patients typically reveals a transition zone in the distal portion
of the sigmoid colon with marked dilatation of the proximal descending and transverse colon.
Hirschsprung disease can be complicated by acute bacterial enterocolitis, which is associated with a
mortality rate of 25% to 30%. Affected patients may present with vomiting, bloody stools, ulceration
of the intestinal mucosa, necrosis of the bowel wall, and/or sepsis.
The other potential complications listed as options are not usually associated with Hirschsprung
disease. Necrotizing enterocolitis typically occurs in premature infants and clinical findings include
abdominal distention, feeding intolerance, abdominal wall erythema, and systemic instability.
Affected infants have pneumatosis intestinalis, portal venous air, and/or intestinal perforation visible
on abdominal radiographs. Infants with a spontaneous intestinal perforation can present with
abdominal distention and pneumoperitoneum. Volvulus is a complication associated with malrotation
that can lead to intestinal ischemia.
The Table below summarizes the radiographic findings of specific gastrointestinal disorders.
Disorder Possible Radiographic Features
Diaphragmatic Plain radiograph: bowel loops in thoracic cavity
hernia
Duodenal Plain radiograph: double-bubble
atresia
Hirschsprung Plain radiograph: distended bowel loops, absence of rectal gas
disease Barium enema: transition zone with aganglionic segment appearing relatively
narrow compared with the proximally dilated bowel
Ileal atresia Plain radiograph: triple-bubble or multiple dilated loops with air-fluid
levels
Malrotation Barium swallow:
with volvulus if volvulus with complete obstruction dilated proximal duodenum tapers
distally to point of obstruction (viewed as a “bird’s beak”)
if volvulus with partial obstruction spiral or corkscrew appearance
duodenum
Meconium Plain radiograph: varying distended small bowel loops; bubbly appearance
ileus of contents (meconium mixed with air); no air-fluid levels
Meconium Plain radiograph: peritoneal calcifications
peritonitis
Microcolon Barium enema: small left colon with dilated bowel proximal to involved
segment
 Necrotizing Plain radiograph: pneumatosis intestinalis, ileus, portal venous gas,
enterocolitis persistent bowel loop, pneumoperitoneum
Pyloric Barium swallow or ultrasound: “string sign”
stenosis
Printed with permission from: Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010, p 336-337
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Loening-Baucke V, Kimura K. Failure to pass meconium: Diagnosing neonatal intestinal
obstruction. Am Fam Physician. 1999;60:2043-2050
Martin, RJ, Fanaroff AA, Walsh MC. Fanaroff and Martin’s Neonatal-Perinatal Medicine:
Diseases of the Fetus and Infant. 8th Edition. 2006
Gastroenterology Answer 16
A. Give a bolus of 10 mL/kg of normal saline and start maintenance fluids
Infants with gastroschisis can have massive evaporative and third space fluid losses via their
exposed intestines despite moist barriers. Coupled with fluid loss due to gastric decompression,
babies with gastroschisis can become dehydrated quickly. In the absence of retractions or hypoxia,
the tachypnea of the infant in this vignette is probably secondary to rapid dehydration and acidosis
and is likely to respond to a normal saline bolus with immediate initiation of maintenance IV fluid.
Newborns with gastroschisis initially may require up to double the usual maintenance fluid volume,
approximately 120 ml/kg/day in term infants.
The blood glucose of the infant in this vignette is normal for a newborn and additional glucose
administration is not needed. A blocked orogastric tube can cause distress and tachypnea in an infant
due to bowel dilatation but in this case, the orogastric tube seems to be functioning well with
continued output. The recent exam of the infant’s bowel was satisfactory and therefore, a new-onset
perforation or volvulus is less likely. Even if that was the case, the initial management should include
fluid resuscitation and re-examination of the bowel. Gastroschisis is usually an isolated defect, unlike
the other abdominal wall defect, omphalocele. Lung hypoplasia and pneumothorax are more prevalent
in infants with a giant omphalocele.
Reference:
Ledbetter DJ. Congenital abdominal wall defects and reconstruction in pediatric surgery:
gastroschisis and omphalocele. Surg Clin North Am. 2012;92:713-727
Gastroenterology Answer 17
D. Polyhydramnios occurs in approximately 1/3 of fetuses with jejunal atresia and is less common in
fetuses with ileal atresia
Jejunal-ileal atresia is more common than duodenal or colonic atresia with an incidence of 1 per
1,500 to 5,000 births. The frequency is similar between males and females. The frequency with
which jejunal-ileal atresias occur in particular small bowel locations is distal ileum (36%) >
proximal jejunum (31%) > distal jejunum (30%) > proximal ileum (13%). Jejunal-ileal atresia is
most commonly single, however multiple atresias occur in 6% to 20% of cases. Polyhydramnios
occurs in approximately 1/3 of infants with jejunal atresia and is less common in fetuses with ileal
atresia. Intrauterine ischemia is the most common etiology, which can be caused by any of the
following:
Volvulus
Malrotation
 Intestinal strangulation at the umbilical ring
Intestinal perforation
Vasoconstrictive drugs including cocaine, pseudoephedrine, and nicotine
The presence of bile droplets, meconium, and lanugo distal to the jejunal-ileal atresia result in
obstruction after intestinal development, unlike duodenal atresia in which the obstruction occurs
during development. Postnatally, a greater degree of intraluminal air evident on an abdominal
radiograph generally correlates with a more distal obstruction.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Hansen A, Puder M. Manual of Neonatal Surgical Intensive Care. 2nd edition. People’s Medical
Publishing House. 2009A
Gastroenterology Answer 18
B. The classic metabolic derangement associated with pyloric stenosis is hypochloremic
hyperkalemic metabolic acidosis
The incidence is approximately 1 per 3,000 births and is greater in males than females,
particularly first-born males. The recurrence risk of pyloric stenosis for a family with one child who
has pyloric stenosis is 3% for subsequent children (4% if male, 2.4% if female). The risk of having a
child with pyloric stenosis if the mother has a history of pyloric stenosis is 19% for a son and 7% for
a daughter. The risk of having a child with pyloric stenosis with a paternal history of pyloric stenosis
is 5.5% for a son and 2.4% for a daughter. Pyloric stenosis has been associated with blood types O
and B. The classic metabolic derangement associated with pyloric stenosis is a hypochloremic
hypokalemic metabolic alkalosis. This occurs as a result of electrolyte losses from gastric outlet
obstruction and repeated vomiting.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Fanaroff AA, Martin RJ, Walsh MC (eds). Neonatal-Perinatal Medicine: Diseases of the Fetus
and Infant. 8th ed. Philadelphia: Mosby-Elsevier; 2006
Jorde LB, Carey JC, Bamshad MJ. Medical Genetics. 3rd edition. St. Louis: Mosby; 2009
Gastroenterology Answer 19
E. Thrombocytopenia is the most common hematologic abnormality associated with SDS
Shwachman-Diamond syndrome is a rare autosomal recessive disorder with an estimated
incidence of 1 in 75,000. 90% of cases of SDS are associated with a mutation in the SDS gene
located on chromosome 7q11, which plays an important role in the maturation of the 60S ribosomal
subunit and ribosomal assembly.
SDS often presents in infancy with the following:
•Bone marrow failure (neutropenia, anemia, thrombocytopenia or general pancytopenia)
•Pancreatic dysfunction (steatorrhea, failure to thrive)
•Recurrent infections
•Skeletal abnormalities (metaphyseal dystosis, thoracic dystrophies, low turnover osteopenia)
Neutropenia is the most common hematologic abnormality associated with SDS. Patients with
SDS are at increased risk of myelodysplastic syndromes and leukemia, including acute myeloid
leukemia and aplastic anemia.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Shimamura A. Shwachman-Diamond syndrome. In: UpToDate, Basow, DS (Ed), UpToDate,
Waltham, MA, 2013
Gastroenterology Answer 20
C. Intrauterine ischemia is the most common etiology
The infant in this vignette most likely has duodenal atresia. Duodenal atresia occurs in
approximately 1 in 20,000 to 40,000 births. It is commonly associated with other congenital
anomalies including malrotation (20%), congenital heart disease (30%), esophageal atresia (10%),
genitourinary anomalies (11%), and annular pancreas (20%). One-third of infants with duodenal
atresia will also have trisomy 21. Duodenal atresia occurs as a result of failure of recanalization of
the intestinal tube during the 8-10th weeks of gestation after obliteration of the lumen by epithelial
proliferation during the 6-7th weeks of gestation. This most commonly occurs in the second portion
of the duodenum. In contrast, jejunal and ileal atresias are thought to result from intrauterine ischemic
injury. Prenatally, fetal ultrasonographic often reveals polyhydramnios or intestinal distention.
Bilious emesis in the first 24 hours of life is the most common postnatal presentation. The classic
abdominal radiographic findings are the “double bubble” sign (as found in this infant’s abdominal
radiograph), an air-fluid level, and a lack of distal intestinal air.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Hansen A, Puder M. Manual of Neonatal Surgical Intensive Care. 2nd edition. People’s Medical
Publishing House. 2009
Gastroenterology Questions 21-30
Gastroenterology Question 21
Identify the most common etiology (1-5) associated with the gastrointestinal abnormalities listed
(A-E).
1. Failure of normal rotation with abnormal fixation
2. Failure of recanalization of the intestinal tube after obliteration of the lumen by epithelial
proliferation
3. Intrauterine ischemia
4.In utero intestinal perforation with meconium spillage
5.Obstruction with hyperviscous secretions from mucous glands of the small intestine
A.Duodenal atresia
B. Jejunal-ileal atresia
C. Malrotation
D. Meconium ileus
E. Meconium peritonitis
Gastroenterology Question 22
Which of the following is the most common cause of a neonatal abdominal flank mass?
A.Adrenal hemorrhage
B.Dysplastic kidney
C.Hydronephrosis
D. Renal vein thrombosis
E. Wilms’ tumor
Gastroenterology Question 23
Biliary atresia is the leading cause of pediatric liver transplantation. The pathogenesis of this
disorder is not yet completely understood and the disorder may be an end phenotype for different
disease processes.
Of the following, the most likely mechanism of biliary atresia in infants is:
A.Deficiency of the ATP-dependent bile acid transporter
B.Failure to release proteins from the liver with resultant cirrhosis
C.Lipid-induced damage to hepatic cells
D.Mutation in the JAGGED1 gene
E.Viral infection followed by exaggerated inflammation and bile duct destruction
Gastroenterology Question 24
A male infant born at 32 weeks’ gestation with a congenital diaphragmatic hernia is 56 days old
today (i.e., postmenstrual age 40 weeks’ gestation) and is being evaluated for cholestasis noted 2
weeks ago. The first 2 weeks of his life were tumultuous because he required a significant amount of
respiratory support. However, he was successfully repaired 4 weeks ago. He remained nil per os
(NPO) for the first 4 weeks of his life, receiving total parenteral nutrition but has been receiving full
enteral feedings for the last 10 days.
Two weeks ago, he was noted to appear jaundiced on examination and his laboratory data showed
a serum bilirubin of 9.8 mg/dL with a direct fraction of 5.0 mg/dL. His state newborn screen
including a screen for toxoplasmosis was normal. A cytomegalovirus urine shell vial is negative. His
abdominal ultrasound revealed a collapsed gallbladder. His stool color has been normal although for
the past 3 days, he has had clay-colored stools. His current laboratory tests are as follows:
AST = 88 U/L
 ALT = 50 U/ L
Tot bilirubin = 7.8 mg/dL
Direct bilirubin = 5.7 mg/dL
Gamma-glutamyl transpeptidase (GGT) = 406 U/L (normal range 12-132 U/L)
Alpha fetoprotein = 50,000 ng/mL
His prothrombin time and complete blood count are within normal limits.
Of the following, the preferred next step in the evaluation of this infant is to:
A.Obtain a hepatobiliary scintigraphy to assess for an obstructive biliary condition
B.Obtain a magnetic resonance imaging of the liver to evaluate for neonatal hemochromatosis
C.Obtain a liver biopsy to assess for progressive familial intrahepatic biliary hypoplasia
D.Send serum cytomegalovirus (CMV) IgG levels to assess for a CMV-related hepatitis
E.Wait and repeat these laboratory tests in a week to determine the trend
Gastroenterology Question 25
A 32-day old male infant born at term gestational age is brought to the Emergency Room after his
parents had observed a mass on his left thigh. His parents report that he has otherwise been well,
although he has had slow weight gain. He is exclusively breastfeeding.
On examination, he appears jaundiced and the mass looks like a hematoma. He also has scattered
bruising on his extremities. The nurse shows you his stool and it is pale-colored without much yellow
coloring. On further questioning, the infant’s parents report that his stools have been pale-colored for
some time now.
Laboratory testing reveals the following:
•Total bilirubin = 10.5 mg/dL
•Direct bilirubin = 7.8 mg/dL
The Emergency Room physician speaks to the parents about the need for admission and initial
management.
Of the following, the most appropriate initial management of this infant includes initiation of:
A.Intravenous prednisolone
B.Intravenous Vitamin K
C.Oral ursodiol
D.Oral Vitamin K
E.Phototherapy
Gastroenterology Question 26
A 4-week old male infant is admitted to the hospital with two days of nonbilious vomiting and
dehydration.
Of the following, the most likely diagnosis in this infant is:
A. Duodenal atresia
B. Hirschsprung disease
C. Jejunal atresia
D. Pyloric stenosis
E. Volvulus
Gastroenterology Question 27
You are asked by an obstetrical nurse to evaluate a term infant with a large amount of oral
secretions noted soon after birth. After suctioning the mouth and nose, you find that you are unable to
advance an orogastric tube into the infant’s stomach. On examination, you note that the infant’s
abdomen has a scaphoid appearance. The infant’s babygram is shown below:
Radiograph kindly provided by Dmitry Dukhovny, MD
Of the following, the most likely diagnosis in this infant is a(n):
A. Double tracheoesophageal fistula
B. Esophageal atresia with distal tracheoesophageal fistula
C. Esophageal atresia with proximal tracheoesophageal fistula
D. Isolated esophageal atresia
E. Isolated tracheoesophageal fistula
Gastroenterology Question 28
A pregnant woman at 30 weeks’ gestation asks to speak with a neonatologist. She is concerned
because her first child had meconium plug syndrome. You meet with her to review the pathogenesis,
clinical findings, management and outcomes of an infant with this condition.
All of the following statements about meconium plug syndrome are true, EXCEPT:
A. It can be complicated by intestinal perforation
B. It is associated with functional immaturity of the distal ileum
C. It is likely to result from immaturity of myenteric plexus nerve cells
D. It presents as failure to pass meconium in the first 24 to 48 hours
E. There is an increased incidence in infants of diabetic mothers
Gastroenterology Question 29
The neonatology team is called to the delivery of a term infant who has an abdominal wall defect.
The neonatology fellow speaks with the pediatric resident about the differences between an
omphalocele and a gastroschisis.
Of the following, the characteristic most likely to be consistent with a gastroschisis is:
A. An abnormal insertion of the umbilical cord
B. A normal appearance of the bowel
C. Association with older maternal age
D. Association with other gastrointestinal anomalies
E.Presence of a covering sac
Gastroenterology Question 30
One of the largest surface areas of the human body exposed to the external world is the
gastrointestinal tract. A sophisticated barrier defense system comprising both the innate and adaptive
immune system helps protect this large surface area from potentially harmful stimuli.
The components of the cellular innate immune system that help to protect the small intestine
include all of the following, EXCEPT:
 A.Dendritic cells that help to determine the type of immune response needed by sampling luminal
antigens
B.Macrophages located in the lamina propria
C.Natural killer T-cells that have the capacity to respond within minutes after antigen recognition
D.Neutrophils that can infiltrate the mucosa during infections
E.T-regulatory cells that are located in the lamina propria
Gastroenterology Answers 21-30
Gastroenterology Answer 21
A. 2. Dudodenal atresia – Failure of recanalization of the intestinal tube after obliteration of the
lumen by epithelial proliferation
B. 3. Jejunal-ileal atresia – Intrauterine ischemia
C. 1. Malrotation – Failure of normal rotation with abnormal fixation
D. 5. Meconium ileus – Obstruction with hyperviscous secretions from mucous glands of the small
intestine
E. 4. Meconium peritonitis – In utero intestinal perforation with meconium spillage
Duodenal atresia is the result of failure of recanalization of the intestinal tube during the 8th to
10th week of gestation after obliteration of the lumen by epithelial proliferation between the 6th and
7th weeks of gestation. This most commonly occurs in the second part of the duodenum.
Jejunal-ileal atresia occurs as the result of intestinal ischemia, often secondary to volvulus,
malrotation, intestinal strangulation at the umbilical ring, intestinal perforation, peritonitis, or
vasoactive drugs, including cocaine, pseudoephedrine, and nicotine.
Malrotation is the result of failure of normal rotation with abnormal fixation with the presence of
Ladd’s bands (fibrous bands between the cecum and right posterior retroduodenal peritoneum).
Meconium ileus occurs in the setting of hyperviscous secretions produced by the mucous glands of
the small intestine resulting in obstruction.
Meconium peritonitis occurs after an intrauterine intestinal perforation associated with a
meconium ileus, intestinal atresia, volvulus, or gastroschisis. The spillage of meconium into the
peritoneal cavity induces a peritonitis.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Fanaroff AA, Martin RJ, Walsh MC (eds). Neonatal-Perinatal Medicine: Diseases of the Fetus
and Infant. 8th ed. Philadelphia: Mosby-Elsevier; 2006
Gastroenterology Answer 22
C. Hydronephrosis
Renal masses account for the majority of abdominal masses. Hydronephrosis is the most common
cause of an abdominal flank mass and can be caused by:
•A ureteropelvic junction obstruction
•A ureterovesicular junction obstruction
•Posterior urethral valves
•A neurogenic bladder
The remaining options listed in the vignette are possible causes of an abdominal mass, yet they are
less common than hydronephrosis.
Reference:
Brodsky D, Martin C. Neonatology Review. 2nd Edition. Lulu. 2010
Gastroenterology Answer 23
E. Viral infection followed by exaggerated inflammation and bile duct destruction
Biliary atresia (BA) occurs in 1 in 6,000 to 1 in 18,000 infants with a higher incidence in Asian
populations such as Taiwan. Pathologically progressive inflammatory damage to the biliary ducts
results in fibrotic obliteration affecting both the intra- and extrahepatic biliary ducts in varying
degrees. BA is classified into 3 structural types by the Japanese Association of Pediatric Surgeons.
More than 90% of cases of BA are Type 3, notable for diffuse aberration in the structure of extra- and
intrahepatic biliary ducts. Types 1 and 2 have greater sparing of the intrahepatic biliary structures,
although some degree of blunting and pruning is present (Davenport et al). BA can also be classified
into an embryonic variant (higher incidence of associated anomalies, such as splenic malformation)
or a perinatal/acquired form with progressive inflammation.
Since the 1970’s, isolation of viral genetic material from the liver of a large number of infants
with BA has led to the hypothesis that viral-triggered immune reactions at a specific developmental
time during the perinatal period could give rise to BA. Cytomegalovirus, reovirus and rotavirus are
potential triggering agents.
Deficiency of the ATP-dependent bile acid transporter is associated with Progressive Familial
Intrahepatic Cholestasis type 2. Failure to release protein from the liver is the mechanism leading to
liver injury in patients with alpha 1-antitrypsin deficiency. Lipid-induced damage to the liver is one
of the mechanisms for cholestasis associated with parenteral nutrition. Alagille syndrome is
attributable to a mutation in the JAGGED1 gene. Although all these diseases are associated with
neonatal cholestasis, they are distinct from BA and have different management and outcomes.
References:
Davenport M. Biliary atresia: Clinical aspects. Semin Pediatr Surg. 2012;21:175-184
Feldman AG, Mack CL. Biliary atresia: Cellular dynamics and immune dysregulation. Semin
Pediatr Surg. 2012;21:192-200
Feldman AG, Sokol RJ. Neonatal cholestasis. NeoReviews. 2013;14:e63-e73
Gastroenterology Answer 24
A. Obtain a hepatobiliary scintigraphy to assess for an obstructive biliary condition
The diagnosis of biliary atresia (BA) is challenging in preterm infants. However, it is critical to
diagnose because the success of surgery is dependent on the timing of the intervention. Indeed, there
is a success rate of less than 20% if an infant with BA has surgery after 90 days of age.
Hepatobiliary scintigraphy is a highly sensitive non-invasive test to diagnose BA. However, the test
has a low specificity, resulting in false-positive results. Therefore, patients often require further
confirmation (e.g., percutaneous liver biopsy or cholangiopancreatography) before undergoing
surgery.
Although this infant is at risk for cholestasis caused by prolonged parenteral nutrition, the new
finding of acholic stools requires an urgent evaluation to exclude BA because of the time-sensitive
nature of its intervention. Therefore, waiting for resolution would also not be appropriate.
Neonatal hemochromatosis (NH) is associated with perinatal liver injury as a result of maternally
acquired transplacental antibodies that cause an alloimmune-mediated injury against fetal/neonatal
liver cells. NH classically presents soon after birth with a presentation of liver failure and
coagulopathy. The alpha-fetoprotein levels are often >80,000 ng/mL. The infant in this vignette does
not have clinical findings consistent with NH.
Progressive familial intrahepatic biliary hypoplasia is a group of autosomal recessive disorders
with impaired bile acid formation. Both Types 1 and 2 can present in the neonatal period and both
are notable for normal GGT levels, unlike the patient in this vignette.
CMV IgG levels correspond with maternal antibodies transferred across the placenta to the fetus
and postnatal levels cannot be used to determine active infection in a neonate.
References:
Davenport M. Biliary atresia: clinical aspects. Semin Pediatr Surg. 2012;21:175-184
Feldman AG, Sokol RJ. Neonatal cholestasis. NeoReviews. 2013;14:e63-e73
Lopriore E, Mearin ML, Oepkes D, Devlieger R, Whitington PF. Neonatal hemochromatosis:
management, outcome, and prevention. Prenat Diagn. 2013;Sept 13:1-5
Mourier O, Franchi-Abella S, Ackermann O, et al. Delayed postnatal presentation of biliary
atresia in 2 premature neonates. J Pediatr Gastroenterol Nutr. 2011;52:489-491
Gastroenterology Answer 25
B. Intravenous Vitamin K
The infant in this vignette has clinical and laboratory findings that are most consistent with a
diagnosis of biliary atresia. Affected infants typically present with cholestasis after 2 weeks of life
in an otherwise healthy child. A definitive diagnosis requires a biopsy. Biliary atresia is
characterized by inflammatory panductular biliary system obliteration that prevents secretion of bile
acid into the gut. As a consequence, infants can develop a deficiency in substances that require bile
acids for absorption such as lipid-soluble vitamins (e.g., Vitamin K). Because breast milk has low
amounts of Vitamin K, infants with biliary atresia who are exclusively breastfeeding can have a more
significant Vitamin K deficiency. Bleeding as a result of Vitamin K deficiency can have serious
consequences, such as intracranial bleeding. Because the infant in this vignette has evidence of
bleeding in his muscle, urgent replenishment of Vitamin K should be a priority. Fortunately,
aberrations in the coagulation pathway that result from Vitamin K deficiency can be reversed a few
hours after parenteral administration. Because the primary reason for Vitamin K deficiency in this
infant occurs because of poor enteral absorption, oral administration is not a good alternative for
urgent replenishment.
Phototherapy converts unconjugated (i.e., the indirect portion of total bilirubin) into a water-
soluble isomer that does not require liver conjugation. Phototherapy leads to a structural
isomerization of indirect bilirubin into lumirubin and a configurational isomerization, decreasing
indirect bilirubin concentrations. Phototherapy does not decrease levels of conjugated (i.e., the
direct component) bilirubin and is not a therapeutic option for the infant in this vignette.
Prednisolone can be administered to patients with biliary atresia to decrease inflammation.
Before treating the infant in this vignette with prednisolone, the diagnosis of biliary atresia will need
to be confirmed. Ursodiol is a hydrophilic bile acid that improves biliary clearance by adding to the
bile acid pool. Because ursodiol is slow-acting with effects that are observed only after chronic
therapy, this agent would not be helpful in the infant in this vignette who requires urgent action to
prevent further bleeding. Although prednisolone and ursodiol are used as adjuvants in the treatment
of biliary atresia, the therapy of choice remains surgery (i.e., a Kasai procedure).
References:
Burke CW. Vitamin K deficiency bleeding: overview and considerations. J Pediatr Health Care.
2013;27:215-221
Davenport M. Biliary atresia: clinical aspects. Semin Pediatr Surg. 2012;21:175-184
Gastroenterology Answer 26
D. Pyloric stenosis
Of the possible options listed in this vignette, pyloric stenosis is the only diagnosis that presents
with nonbilious emesis. Pyloric stenosis occurs in 3 of 1,000 births and there is a greater incidence in
males. Most affected patients present during the first week to age five months with nonbilious
vomiting and dehydration. Electrolyte abnormalities are common and include hypochloremic,
hypokalemic metabolic alkalosis. The diagnosis of pyloric stenosis is made by ultrasound.
Management of patients with pyloric stenosis includes correction of the electrolyte abnormalities and
pyloromyotomy.
Duodenal atresia, jejunal atresia, and volvulus all present with bilious emesis. Infants with
Hirschsprung disease may present with lack of meconium passage in the first 48 hours, constipation,
abdominal distention, and failure to thrive.
Reference:
Fanaroff AA, Martin RJ, Walsh M (eds). Neonatal-Perinatal Medicine. 9th edition. St. Louis:
Mosby; 2010
Gastroenterology Answer 27
D. Isolated esophageal atresia
The infant in this vignette has increased oral secretions and a scaphoid abdomen with radiographic
findings that show coiling of the orogastric tube in the upper esophageal pouch and lack of air in the
stomach and intestines. This is most consistent with an isolated esophageal atresia (EA) without a
tracheoesophageal fistula (TEF). There are 5 variants of EA/TEF, compared in the Table below.

References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Fanaroff AA, Martin RJ, Walsh M (eds). Neonatal-Perinatal Medicine. 9th edition. St. Louis: Mosby;
2010
Gastroenterology Answer 28
B. It is associated with functional immaturity of the distal ileum
Meconium plug syndrome is a transient disease that results from a functional immaturity and
hypomotility of the colon (note: this is in contrast to neonates with a meconium ileus, which involves
the distal ileum). The pathogenesis is thought to be secondary to immaturity of myenteric plexus
nerve cells. This diagnosis is more common in infants of diabetic mothers, those exposed to
magnesium sulfate prenatally, and infants with cystic fibrosis. Neonates with meconium plug
syndrome have a delayed passage of meconium and typically present with abdominal distention and
failure to pass meconium in the first two days of life. Bilious vomiting may be present. Despite these
initial clinical findings, the course is typically benign. Complications are rare but include electrolyte
imbalance and intestinal perforation. An abdominal radiograph of an affected infant typically shows
multiple dilated loops of bowel without rectal gas. A contrast enema demonstrates an “empty” distal
colon, dilated proximal bowel, and filling defects caused by plugs.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Fanaroff AA, Martin RJ, Walsh M (eds). Neonatal-Perinatal Medicine. 9th edition. St. Louis: Mosby;
2010
Gastroenterology Answer 29
E. Association with other gastrointestinal anomalies
The most common abdominal wall defects found in neonates are omphalocele and gastroschisis.
An omphalocele is a central abdominal wall defect of variable size that is covered by a membrane
composed of amnion. The umbilical cord connects to the central portion of this membrane. In
contrast, a gastroschisis is usually smaller and located to the right of the normally inserted umbilical
cord. A gastroschisis does not have any protective membranous covering. Although the bowel in
infants with a gastroschisis appears matted, foreshortened, and edematous, the bowel in infants with
an omphalocele appears normal. It is common for infants with an omphalocele to have other
anomalies. However, these anomalies are rarely gastrointestinal. While it is less likely for
gastroschisis to be associated with other anomalies, when they are present, there is a high incidence
that the anomalies are related to the gastrointestinal system. Gastroschisis is associated with a
younger maternal age.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Hansen A, Puder M (eds). Manual of Surgical Neonatal Intensive Care. Hamilton Ontario: BC
Decker; 2003
Gastroenterology Answer 30
E. T-regulatory cells that are located in the lamina propria
The barrier defense system of the gastrointestinal system includes both the adaptive and the innate
immune system. The components of the innate immunity in the intestines include the following:
•Secretory IgA
•Intestinal mucins
•Antimicrobial peptides
•Pathogen recognition receptors
•Immune cells
Innate immune cells are present in both the outer epithelial layer and inner lamina propria. In the
outer layer, T-cells expressing the gamma delta T-cell receptor are present between the epithelial
cells. The functional relevance of gamma delta T-cells is not fully determined yet. However, studies
suggest that these cells can be rapidly mobilized during infections or after epithelial damage.
Furthermore, animal experiments have shown that these cells have an important role in mucosal
repair by producing keratinocyte growth factor.
Macrophages are located in the lamina propria and are present in high numbers. One of their
primary roles is to eliminate bacteria that pass the epithelial barrier by phagocytosis. In addition they
also help to restore epithelial barrier function by secreting growth factors that promote enterocyte
proliferation. Other innate immune cells that are present in the lamina propria are natural killer cells
and natural killer T-cells. Both cells are capable of responding within minutes to invading pathogens,
making them ideal sentinels in the intestine.
T-regulatory cells are cells of the adaptive immune system and can be found in both the epithelial
layer and the lamina propria. They have an important role in regulating the immune response against
the commensal flora in the intestine.
References:
Ismail AS, Behrendt CL, Hooper LV. Reciprocal interactions between commensal bacteria and
gamma delta intraepithelial lymphocytes during mucosal injury. J Immunol. 2009;182:3047-3054
McElroy S, Weitkamp JH. Innate immunity in the small intestine of the preterm infant.
NeoReviews 2012;12:e517-e526
Gastroenterology Questions 31-40
Gastroenterology Question 31
During her rotation in the NICU, a medical student asks you about the intestinal microbiota and the
mechanisms by which a homeostasis is maintained between the host and the millions of bacteria that
colonize a newborn.
Some of the mechanisms to achieve this balance include all of the following, EXCEPT:
A.Expression of innate immune receptors on the epithelial surface
B.Intestinal mucins produced by goblet cells that provide a physical barrier and facilitate removal
of bacteria
C.Production of antimicrobial peptides by Paneth cells
D.Secretion of IgA by plasma cells
E.Tight junctions between epithelial cells that do not permit the presence of lymphocytes in the
epithelial layer
Gastroenterology Question 32
You are called to the bedside of a 10-day old infant born at 27 3/7 weeks’ gestation because the
infant has become progressively less active, mottled and had an episode of bilious emesis. The infant
requires continuous positive airway pressure and had been advancing on enteral feedings. The
infant’s abdominal radiograph shows areas of pneumatosis intestinalis.
You stop the enteral feedings and start antibiotic treatment.
Of the following, the most likely preterm infant characteristic that increases the risk of this disease
is:
A.Few Paneth cells
B.Loose tight junction
C.Thin goblet cell secretions and decreased IgA concentrations
D.None of the above
E.All of the above
Gastroenterology Question 33
The mechanisms by which the body decreases bilirubin levels include all of the following,
EXCEPT:
A.Conjugation by glucuronyl transferase in the liver
B.Deconjugation by heme oxygenase
C.Excretion of urobilin and stercobilin in stool
D.Isomerization of bilirubin in the skin
Gastroenterology Question 34
Elevated direct hyperbilirubinemia may be associated with all of the following conditions,
EXCEPT:
A.Biliary atresia
B.Gilbert syndrome
C.Hepatitis
D.Portal vein thrombosis
E.Sepsis
Gastroenterology Question 35
An infant is born with evidence of liver failure. The differential diagnosis of overt liver failure in
a newborn includes neonatal hemochromatosis and hemophagocytic lymphohistiocytosis (HLH).
Of the following laboratory test abnormalities, the one that distinguishes a diagnosis of HLH from
neonatal hemochromatosis is:
A.Anemia
B.High ferritin
C.Low fibrinogen
D.Neutropenia
E.Thrombocytopenia
Gastroenterology Question 36
You are asked to evaluate a 2-week old infant with jaundice, pale colored stools, and dark urine.
The infant’s mother is hepatitis B surface antigen negative and the infant received the Hepatitis B
vaccine at birth. You are concerned about cholestasis and order fractionated bilirubin levels, hepatic
enzyme levels, and a coagulation panel. The infant has an elevated direct bilirubin level, mildly
elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and abnormal
coagulation parameters. You suspect that the infant has biliary atresia.
What is the next step in the evaluation of the infant in this vignette?
A.Abdominal computed tomography
B.Hepatobiliary iminodiacetic acid (HIDA) scan
C.Liver ultrasonography
D.Open liver biopsy
E.Percutaneous liver biopsy
Gastroenterology Question 37
Which of the following statements about treatment of an infant with biliary atresia is TRUE?
A.Bacterial cholangitis, ascites, and pruritis are common complications after
hepatoportenterostomy
B.Children who have appropriately timed hepatoportenterostomy procedures will not require liver
transplantation
C.Infants with biliary atresia should wait at until at least 6 months of age before undergoing
hepatoportenterostomy (i.e., Kasai procedure) because of improved success in older children
D.Liver transplantation requires a size-matched donor organ (i.e., a liver from an infant or child)
E.Portal hypertension can be avoided with prompt hepatoportenterostomy
Gastroenterology Question 38
Which of the following gastrointestinal hormones or enteric neuropeptides is responsible for
pancreatic enzyme secretion and gallbladder contraction?
A. Cholecystokinin
B. Gastrin
C. Glucose-dependent insulinotropic peptide
D. Motilin
E. Secretin
Gastroenterology Question 39
All of the following statements about gastric acid are true, EXCEPT:
A. Gastric acid affects drug absorption.
B. Gastric acid is a barrier to microorganisms.
C. Gastric acid secretion reaches adult levels by 2 years of age.
D. Gastrin is the principal mediator of gastric acid secretion.
E. The newborn’s initial gastric pH is neutral or slightly alkaline.
Gastroenterology Question 40
The digestion and absorption of medium and long-chain fatty acids are different.
Compared to long-chain fatty acids, medium-chain fatty acids:
A. Are able to directly enter the portal venous system from the enterocyte
B. Are all unsaturated
C. Are resynthesized into triglycerides and packaged into chylomicrons
D. Can be further metabolized to terminal metabolites that regulate inflammation
E. Contain 12 to 24 carbons
Gastroenterology Answers 31-40
Gastroenterology Answer 31
E. Tight junctions between epithelial cells that do not permit the presence of lymphocytes in the
epithelial layer
Intestinal bacteria have several functions that are beneficial for the host as long as they are
contained in the intestinal lumen and penetration of the epithelial barrier is prevented. To maintain
intestinal homeostasis, an intestinal defense system evolved that comprises both the innate and the
adaptive immune system. The components of the innate immunity of the gut include the following:
1. Intestinal mucins: secreted by goblet cells and form a thick physical barrier against bacteria
and facilitate their removal.
2.Secretory IgA: produced by plasma cells that are immobile and located in the lamina propria.
Once secreted, IgA is transported across the epithelial cells to the luminal side where it can bind to
bacteria, preventing them from penetrating the epithelial layer
3.Antimicrobial peptides: mainly produced by Paneth cells, but also goblet cells and epithelial
cells ; comprised of defensins, C-type lectins and lysozyme. These peptides can kill bacteria by
disrupting the cell wall or inner membrane.
4.Pathogen recognition receptors: located either on the surface or in the cytoplasm of epithelial
cells. These receptors recognize pathogen-associated molecular patterns and damage-associated
molecular patterns. They include the membrane-bound Toll-like receptors and the cytoplasmic Nod-
like receptors.
5.Immune cells: includes dendritic cells, macrophages, natural killer (NK) cells, NK T-cells,
gamma delta T-cells; they are found in both the outer epithelial layer and inner lamina propria
References:
Hooper LV, Macpherson AJ. Immune adaptations that maintain homeostasis with the intestinal
microbiota. Nat Rev Immunol. 2010;10:159-169
McElroy S, Weitkamp JH. Innate immunity in the small intestine of the preterm infant.
NeoReviews. 2012;12:e517-e526
Santaolalla R, Abreau MT. Innate immunity in the small intestine. Curr Opin Gastroenterol.
2012;28:124-129
Gastroenterology Answer 32
E. All of the above
The infant described in this vignette most likely has necrotizing enterocolitis (NEC). NEC is a
complex disease and its pathogenesis is not fully understood. Several hypotheses have been
formulated to explain the unique susceptibility of premature infants to develop NEC. Frequently cited
contributing factors include the following:
•Loose tight junctions between the intestinal epithelial cells
•Thin goblet cell secretions that form a less effective physical barrier
•Few Paneth cells that could produce antimicrobial peptides
•Decreased IgA concentrations
•Increased production of inflammatory cytokines after exposure to commensal and pathogenic
bacteria
•Altered TLR4 signaling resulting in enterocyte apoptosis
References:
McElroy S, Weitkamp JH. Innate immunity in the small intestine of the preterm infant.
NeoReviews. 2012;12:e517-e526
 Salzman NH, Underwood MA, Bevins CL. Paneth cells, defensins, and the commensal microbiota:
A hypothesis on intimate interplay at the intestinal mucosa. Semin Immunol. 2007;19:70-83
Gastroenterology Answer 33
B. Deconjugation by heme oxygenase
Heme oxygenase converts heme to biliverdin, which is then converted to bilirubin by biliverdin
reductase. There are multiple mechanisms for the removal of bilirubin from the circulation. Initially,
unconjugated bilirubin is taken up by the liver and conjugated with glucuronic acid by glucuronyl
transferase. The conjugated bilirubin is water-soluble and is excreted in bile. Most (95%) is then
reabsorbed in the terminal ileum and returned to the liver in a process called enterohepatic
circulation. That which is not recirculated is converted by colonic bacteria to urobilin or stercobilin
and excreted in the stool.
Reference:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Gastroenterology Answer 34
B. Gilbert syndrome
All of the options listed in this question are associated with direct (i.e., conjugated)
hyperbilirubinemia except for Gilbert syndrome. This syndrome is a mild and relatively common
genetic condition, affecting 3% to 7% of Americans. It is caused by an impairment in the conjugation
process of bilirubin, resulting in intermittent increases in indirect (i.e., unconjugated) bilirubin.
References:
National Library of Medicine. Genetics Home Reference. Gilbert syndrome. February, 2012
Tiker F, Tarcan A, Kilicdag H, Gurakan B. Early onset conjugated hyperbilirubinemia in newborn
infants. Ind J Ped. 2006;73:409-412
Gastroenterology Answer 35
D. Neutropenia
Neonatal hemochromatosis is a disorder in which iron is deposited in the liver and other tissues in
abnormally large quantities. It can result in stillbirth, intrauterine growth restriction, and preterm
birth. In the newborn, it can result in liver failure and cardiac impairment. Laboratory evaluation
yields normal or elevated hepatic enzymes, coagulation abnormalities including low fibrinogen,
anemia and thrombocytopenia, and high ferritin levels. HLH is a rare disease with a high mortality.
It is caused by abnormally hyper-activated T-cells and macrophages. Though the same laboratory
profile as hemochromatosis may be seen, patients with HLH may also have neutropenia and low
national killer cell counts. The diagnosis of HLH is confirmed by finding hemophagocytosis in
samples of bone marrow, spleen, or lymph node tissue.
References:
Murray FK, Kowdley KV. Neonatal hemochromatosis. Pediatrics. 2001;108:960-964
Suzuki N, Morimoto A, Ohga S, et al. HLH/LCH Committee of the Japanese Society of Pediatric
Hematology. Characteristics of hemophagocytic lymphohistiocytosis in neonates: A nationwide
survey in Japan. J Pediatr. 2009 Aug;155:235-238
Gastroenterology Answer 36
C. Liver ultrasonography
Biliary atresia is a congenital absence of bile ducts either within or outside the liver. Untreated,
the accumulation of bile in the liver causes hepatic failure. Diagnostic imaging for biliary atresia
typically begins with an abdominal ultrasound to look for evidence of bile ducts, a gallbladder, and
possible obstructions to bile flow, such as tumors. The next step is a HIDA scan, a radionuclide test
that evaluates the flow of bile in the liver and gallbladder. There may be a role for a computed
tomography scan, though this is less likely to add much information. Percutaneous biopsy is typically
performed prior to surgery.
Reference:
Hartley JL, Davenport M, Kelly DA. Biliary atresia. Lancet. 2009;374:1704–1713
Gastroenterology Answer 37
A. Bacterial cholangitis, ascites, and pruritis are common complications after
hepatoportenterostomy
Therapy for biliary atresia centers on restoration of bile flow to the small intestines. In a
hepatoportenterostomy, or Kasai procedure, a loop of small bowel is brought up to the liver in order
to create a conduit for bile flow. This is associated with significant morbidities, including portal
hypertension, cholangitis, ascites, and pruritis. Hepatoportenterostomy should be performed as early
as possible, prior to 3 months of age if possible, in order to prevent irreversible liver damage.
However, even a child with an appropriately timed operation can develop cirrhosis and liver failure,
necessitating liver transplantation by adulthood. Transplantation is curative, and may be performed
using part of an adult liver (i.e., split-liver transplant).
Reference:
National Digestive Diseases Information Clearinghouse, National Institute of Diabetes and
Digestive and Kidney Diseases, National Institutes of Health. Biliary atresia. August 1, 2012
http://digestive.niddk.nih.gov/ddiseases/pubs/atresia/#6
Gastroenterology Answer 38
A. Cholecystokinin
Gastrointestinal peptide hormones play an important role in the structural and functional
development of the gut. Production of gastrin, secretin, somatostatin, motilin, and glucose-dependent
insulinotropic peptide begins very early in gestation. Surges of these hormones occur after birth and
appear to be responsible for the major growth and functional change of the GI tract in early neonatal
life. The surges of many of these hormones only occur after oral feedings are initiated. Gastrin is an
important regulator of gastric secretion and is trophic to the gastric mucosa. Secretin is a duodenal
hormone. Cholecystokinin is released from the small intestine and stimulates pancreatic enzyme
secretion and contracts the gallbladder. It has trophic effects on the pancreas, as well. Motilin is also
released by the small intestine and has powerful motor functions including acceleration of gastric
emptying. Glucose-dependent insulinotropic peptide is a jejunal hormone and plays a role in the
postprandial release of insulin levels. Neurotensin is an ileal peptide that has inhibitory effects on
gastric secretion and motility. It is important for the adaptation of the neonate to enteral nutrition.
Reference:
Gleason CA, Devaskar SU (eds). Avery’s Diseases of the Newborn. 9th edition. Philadelphia:
Elsevier Saunders; 2011
Gastroenterology Answer 39
C. Gastric acid secretion reaches adult levels by 2 years of age.
At birth, the gastric pH is neutral to alkaline which may be partially caused by the alkaline nature
of amniotic fluid. By several hours of age, the neonatal stomach begins to secrete acid and the pH
falls. Acid production slowly increases toward adult levels by about 3 months of age. Circulating
gastrin is the main mediator of postprandial gastric secretion. It stimulates secretion by a direct effect
on the parietal cell. Decreased gastric acid secretion can increase the risk of nosocomial infection as
gastric acid is a barrier to microorganisms. The absorption of several drugs is affected by gastric
acid.
Reference:
Fanaroff AA, Martin RJ, Walsh M (eds). Neonatal-Perinatal Medicine. 10th edition. St. Louis:
Mosby; 2014
Gastroenterology Answer 40
A. Are able to directly enter the portal venous system from the enterocyte
There are several types of fatty acids. Fatty acids that have carbon-carbon double bonds are
known as unsaturated. Fatty acids without double bonds are saturated. Another approach to
classifying fatty acids is based on their length. Short-chain fatty acids are fatty acids with tails of
fewer than six carbons. Medium-chain fatty acids have tails of 6 to 12 carbons. Long-chain fatty acids
have tails of 13 to 21 carbons.
The process of lipid digestion occurs in two major steps involving bile acids and lipases. The first
step involves the breakdown of lipid into smaller particles via micellar emulsification. Once inside
the enterocyte, different chain length fatty acids are metabolized in distinct ways. Longer chain fatty
acids are resynthesized into triglycerides and packaged into chylomicrons. The chylomicrons are
packaged into vesicles, which are exocytosed into the lymphatic system. Long-chain fatty acids can be
further metabolized to terminal metabolites that play a role in the resolution of inflammation.
Medium-chain fatty acids are able to directly enter the portal venous system.
Reference:
Elzouki A, Harfi H, Nazer H, et al. Textbook of Clinical Pediatrics. 2nd Edition. New York:
Springer; 2012
Gastroenterology Questions 41-44
Gastroenterology Question 41
A neonatologist is asked to evaluate a 12-hour old male infant in the nursery who has had several
episodes of non-bloody, bright green emesis. He is receiving formula.
The most appropriate next step in the management of the infant in this vignette is to:
A. Change to a pre-digested formula
B. Continue feeding
C. Perform an exploratory laparotomy
D. Obtain an abdominal ultrasound
E. Obtain an upper gastrointestinal series
Gastroenterology Question 42
A 3-week old infant born at 25 weeks’ gestation presents with abdominal distention and bloody
stools. The infant is diagnosed with necrotizing enterocolitis and perforation based on the abdominal
radiographs. The infant requires surgical intervention with resection of the distal ileum.
Of the following, the most likely deficiency to be found in the infant described in this vignette is:
A. Fatty acid
B. Iron
C. Protein
D. Vitamin B12
E. Vitamin E
Gastroenterology Question 43
A term infant has prolonged conjugated hyperbilirubinemia with an ultrasound that reveals a cystic
dilatation of the common bile duct.
Which of the following statements about this infant’s condition is TRUE?
A. It does not cause acholic stools.
B.It is more frequent in boys.
C. It is more frequently diagnosed in the Caucasian population.
D. One complication is malignancy.
E. There is no treatment.
Gastroenterology Question 44
A 6-day old newborn with jaundice has a total bilirubin of 4 mg/dL and a direct bilirubin of 2.5
mg/dL.
Of the following, the most likely diagnosis in the infant in this vignette is:
A. ABO incompatibility
B. Alagille syndrome
C. Crigler-Najjar syndrome
D. Gilbert disease
E. Physiologic jaundice
Gastroenterology Answers 41-44
Gastroenterology Answer 41
E. Obtain an upper gastrointestinal series
Midgut malrotation can lead to an upper intestinal obstruction. It is caused by abnormal rotation in
utero of the midgut that results in abnormal mesenteric fixation. This can lead to a short mesenteric
base that may allow twisting of the bowel and mesentery around the axis of the superior mesenteric
artery. This twisting is known as volvulus, which can lead to severe vascular compromise, bowel
ischemia, and necrosis. The major presenting symptom of malrotation with volvulus is bilious emesis
in the first month of life.
Because of the potential for bowel ischemia and loss, bilious emesis in an infant should be
considered a potential surgical emergency and further evaluation undertaken to rule out malrotation.
The abdominal radiograph is not always a useful evaluation for malrotation as it may be normal.
Abdominal ultrasound is also limited. The diagnostic exam of choice is the upper gastrointestinal
series. In this exam, dye is ingested into the stomach and the location of the duodenum is seen and
predicts the mesenteric attachment. An abnormal course of the duodenum and an abnormal location of
the duodenal-jejunal junction is diagnostic of malrotation. Volvulus may also be captured on the
upper gastrointestinal series or it may be transient in nature. Once the diagnosis of a malrotation is
confirmed, surgery is required to reposition the bowel via the Ladd’s procedure.
Reference:
Fanaroff AA, Martin RJ, Walsh M (eds). Neonatal-Perinatal Medicine. 10th edition. St. Louis:
Mosby; 2014
Gastroenterology Answer 42
D. Vitamin B12
Vitamin B12 is widely present in the diet. It combines with a glycoprotein, called intrinsic factor,
prior to its absorption. It is a unique vitamin in that it is only absorbed at specific sites in the terminal
ileum. If the terminal ileum is resected or impaired, vitamin B12 deficiency can occur and affected
individuals must receive replacement with intramuscular injections. Deficiency can lead to
hematologic (megaloblastic, macrocytic anemia) and to neurologic abnormalities (neural
degeneration). The hematologic abnormalities respond to folate but the neurologic impairment does
not. The terminal ileum also has a critical role in bile acid absorption. The absorption of protein, fat,
carbohydrates, iron and other vitamins occurs throughout the duodenum, jejunum, and ileum.
References:
Blackburn ST (ed). Maternal, Fetal and Neonatal Physiology: A Clinical Perspective. 4th edition.
St. Louis: Elsevier Health Sciences; 2012
Kleinman R, Goulet OJ, Mieli-Vergani G, et al (eds). Walker’s Pediatric Gastrointestinal Disease.
Volume Two. 5th edition. Ontario: BC Decker Inc; 2008
Gastroenterology Answer 43
D. One complication is malignancy.
Choledochal cysts are congenital anomalies of the biliary tract and have varying degrees of cystic
dilatation. This diagnosis mainly refers to cystic abnormalities of the common bile duct. Choledochal
cysts occur much more frequently in girls than in boys and are more frequently diagnosed in the Asian
population. Anatomic classification of type is based on location and extent of dilatation as well as
number of cysts. Affected infants typically present with conjugated hyperbilirubinemia. Acholic
stools may be observed and an abdominal mass may be palpable. Ultrasound is the preferred method
for screening. The treatment involves complete surgical resection. Unfortunately, affected individuals
may develop a malignancy in any remaining cystic tissue.
References:
Fanaroff AA, Martin RJ, Walsh M (eds). Neonatal-Perinatal Medicine. 10th edition. St. Louis:
Mosby; 2014
Kleinman R, Goulet OJ, Mieli-Vergani G, et al (eds). Walker’s Pediatric Gastrointestinal Disease.
Volume Two. 5th edition. Ontario: BC Decker Inc; 2008
Gastroenterology Answer 44
B. Alagille syndrome
While jaundice may be benign, it is also a common sign of neonatal hepatobiliary and metabolic
disease. The jaundiced infant should be evaluated by serum bilirubin levels that are fractionated into
a conjugated (direct) and unconjugated (indirect) portion. The type of hyperbilirubinemia, either
direct or indirect can help narrow the differential diagnosis. Indirect hyperbilirubinemia is the most
common cause of hyperbilirubinemia. Conjugated hyperbilirubinemia is generally defined as a
conjugated or direct bilirubin level greater than 1 mg/dL when the total bilirubin is less than 5 mg/dL
or more than 20% of the total bilirubin if the total bilirubin is greater than 5 mg/dL. Conjugated
hyperbilirubinemia is never physiologic or normal. Unconjugated hyperbilirubinemia, conversely, is
a common finding and can result from physiologic jaundice, breastfeeding and human milk–associated
jaundice, red blood cell hemolysis, hypothyroidism, Gilbert syndrome, or Crigler-Najjar syndrome.
Alagille syndrome is an autosomal dominant multisystem disorder characterized by a paucity of
intralobular bile ducts. It is characterized by a conjugated or direct hyperbilirubinemia. Individuals
may also have congenital heart disease, dysmorphic features, and short stature. Affected neonates and
children may require liver transplantation.
Reference:
Feldman A, Sokol R. Neonatal cholestasis. NeoReviews. 2013;14:e63-73
IX. HEMATOLOGY & BILIRUBIN
Hematology & Bilirubin Questions 1-10
Hematology & Bilirubin Question 1
When does the bone marrow become the primary site of hematopoiesis in the fetus?
A. 1 to 2 weeks’ gestation
B. 5 to 10 weeks’ gestation
C. 11 to 15 weeks’ gestation
D. 16 to 20 weeks’ gestation
E. 22 to 25 weeks’ gestation
Hematology & Bilirubin Question 2
Which of the following medications may induce indirect hyperbilirubinemia?
A. Ampicillin
B. Ceftriaxone
C. Isoniazid
D. Phenobarbital
E. Rifampin
Hematology & Bilirubin Question 3
A pediatrician identifies petechiae over the chest of a 1-hour old term female infant. Laboratory
studies reveal that she has a platelet count of 15,000/μL. The infant’s mother has Crohn’s disease and
is being treated with azathioprine.
Which of the following laboratory studies is most consistent with neonatal autoimmune
thrombocytopenia?
A. High maternal platelet count
B. Low maternal platelet count
C. Normal maternal platelet count
D. Spontaneous resolution of neonatal thrombocytopenia within 24 hours of age
Hematology & Bilirubin Question 4
A term infant is brought to the Neonatal Intensive Care Unit because of prolonged bleeding after a
circumcision. A coagulation evaluation reveals normal prothrombin and partial thromboplastin
times. The infant’s complete blood count is normal.
Which one of the following hematological disorders is most likely in this infant?
A. Factor II deficiency
B.Factor V deficiency
C. Factor IX deficiency
D. Factor XIII deficiency
E. Von Willebrand’s disease
Hematology & Bilirubin Question 5
A 2-month old female infant with ileal atresia has developed worsening heart failure over the past
several days. She has a single superficial hemangioma on her left shin, which has been rapidly
growing over the past 2 weeks.
Which of the following abnormalities is most likely to be present in this vignette?
A.Anemia
B.Leukopenia
C. Polycythemia
D.Thrombocytopenia
E.Thrombocytosis
Hematology & Bilirubin Question 6
You are asked to evaluate a plethoric newborn male infant born at 40 weeks’ gestation with a
birthweight of 2,100 grams. The mother is a 45-year old primagravida female who conceived by in
vitro fertilization and declined fetal testing. The pregnancy was also complicated by gestational
diabetes and pre-eclampsia. The infant has subtle features of trisomy 18. You obtain a complete
blood count to assess the plethoric infant and the venous hematocrit is 68%, which is confirmed by
repeat testing.
All of the following are possible explanations for polycthemia in this infant, EXCEPT:
A.Intrauterine growth restriction
B.Maternal diabetes
C.Pre-ecclampsia
D.Trisomy 18
E.All of the above are true
Hematology & Bilirubin Question 7
You are evaluating a plethoric, full-term, growth-restricted newborn. The infant’s venous
hematocrit is measured at 67%. You obtain a repeat value, which confirms the polycythemia.
Which of the following symptoms is LEAST likely related to polycythemia?
A.Apnea
B.Hypocalcemia
C.Hypoglycemia
D.Hypoxia
E.Thrombocytosis
Hematology & Bilirubin Question 8
A female term newborn with a birthweight of 3 kg has a hematocrit of 71%, which is confirmed
with repeat testing. She is in mild respiratory distress, plethoric, and hypoglycemic. The neonatology
team plans to perform a partial exchange transfusion with normal saline to decrease the infant’s
hematocrit to 55%.
Assuming that this infant’s total body blood volume is 90 mL/kg, how much blood is needed for
the partial exchange transfusion to attain this goal?
A.30 mL
B.60 mL
C.90 mL
D.120 mL
E.150 mL
Hematology & Bilirubin Question 9
Of the following, which is the most prevalent hemoglobinopathy in the world?
A.Alpha-thalassemia
B. Beta-thalassemia
C. Hemoglobin E
D. Hereditary spherocytosis
E. Sickle cell disease
Hematology & Bilirubin Question 10
A male Amish infant is brought to his pediatrician’s office because his mother is concerned by his
yellow color. His physical examination is remarkable only for jaundice. Laboratory evaluation
reveals an elevated indirect bilirubin, normal NADPH level, and normal liver function studies. His
blood smear shows a normocytic, normochromic anemia with reticulocytosis.
The hemolytic anemia in this infant is most likely caused by:
A.A defect in the enzymatic activity of glucose-6-phosphate dehydrogenase
B.Chromosomal instability leading to breakage
C.Defective proteins in the erythrocyte cell membrane
D. Disordered activity of pyruvate kinase
E. Substitution of valine for glutamic acid at position 6 of the beta-globin gene
Hematology & Bilirubin Answers 1-10
Hematology & Bilirubin Answer 1
E. 22 to 25 weeks’ gestation
The bone marrow becomes the primary site of hematopoiesis after 22 weeks’ gestation. Before
that time, the secondary yolk sac hematopoiesis is active between 2.5 and 10 weeks’ gestation and
fetal liver hematopoiesis is active between 6 and 22 weeks’ gestation.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Fanaroff AA, Martin RJ, Walsh MC (eds). Neonatal-Perinatal Medicine: Diseases of the Fetus and
Infant. 8th edition. Philadelphia: Mosby-Elsevier; 2006
Hematology & Bilirubin Answer 2
B. Ceftriaxone
By binding albumin and displacing unconjugated bilirubin from albumin, ceftriaxone can induce
indirect hyperbilirubinemia. Similarly, sulfonamides and indomethacin can also increase indirect
bilirubin concentrations. Alternatively, phenobarbital and rifampin can decrease bilirubin
concentrations by increasing P450 metabolism, and thereby enhancing the conjugation of bilirubin.
Ampicillin does not impact bilirubin concentrations.
References:
Beers MH, Porter RS, Jones TV (eds): The Merck Manual of Diagnosis and Therapy. 18th edition.
New Jersey: Merck Research Laboratories; 2006
Benitz WE, Tatro DS. The Pediatric Drug Handbook. St. Louis: Mosby; 1995
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Hematology & Bilirubin Answer 3
B. Low maternal platelet count
The Table provides a differential diagnosis of abnormal infant and maternal platelet count
abnormalities.
Infant Maternal Differential Diagnosis
Platelet Platelet
Count Count
Decreased Normal Neonatal alloimmune
Neonatal drug
Hemangioma
Congenital thrombocytopenia
Maternal idiopathic thrombocytopenic purpura in remission
Decreased Decreased Maternal idiopathic thrombocytopenic purpura – autoimmune,
increased platelet associated IgG levels
Maternal drug
Pregnancy-induced hypertension
Familial
Modified from Cloherty JP, Stark AR (ed). Manual of Neonatal Care. 4th Edition. Philadelphia: Lippincott-Raven; 1998, p 471
Neonatal autoimmune thrombocytopenia occurs in women with idiopathic thrombocytopenic
purpura, lupus, and other autoimmune diseases. Maternal anti-platelet antibodies destroy maternal
platelets and then cross the placenta to decrease fetal platelets, leading to both maternal and
fetal/neonatal thrombocytopenia. In contrast, infants affected with neonatal alloiummune
thrombocytopenia are born to women with normal platelet counts.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Cloherty JP, Stark AR (ed). Manual of Neonatal Care. 4th Edition. Philadelphia: Lippincott-Raven;
1998
Christensen RD (ed). Hematologic Problems in the Neonate. Philadelphia: WB Saunders; 2000
Hematology & Bilirubin Answer 4
D. Factor XIII deficiency
The cause of bleeding in an infant can be determined by testing the infant’s coagulation studies and
platelet count. If an infant has an isolated elevation of the prothrombin time, which measures the
extrinsic pathway, the infant may have Vitamin K deficiency (leading to deficiencies in factors II, VII,
IX and X). If these infants also have elevated prothromboplastin times, primary deficiencies may
exist in factors II, V and X. Isolated prothromboplastin times (measures the intrinsic pathway) occurs
in patients with von Willebrand’s disease, or isolated factor VIII and IX deficiencies. In contrast,
infants with factor XIII deficiency will have normal prothrombin and partial thromboplastin times.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Nuss R, Manco-Johnson M. Bleeding disorders in the neonate. NeoReviews. 2008;9:e162-e169
Hematology & Bilirubin Answer 5
D. Thrombocytopenia
The infant described in this vignette likely has Kasabach-Merritt (KM) syndrome. Infants with
KM may have multiple skin lesions that resemble hemangiomas or a single, large, rapidly growing
hemangioma-like lesion. Some affected infants may have retroperitoneal or mediastinal vascular
abnormalities without displaying a dermatologic lesion. Recent studies suggest that these internal or
external hemangiomas are Kaposi-like and consistent with hemangioendotheliomas. The lesions can
lead to high output cardiac failure, disseminated intravascular coagulation, and thrombocytopenia.
Reference:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Hematology & Bilirubin Answer 6
E. All of the above are true
Polycythemia in the newborn is defined as a venous hematocrit above 65% or a hemoglobin above
22 g/dL. It is thought to affect 0.4% to 5% of newborns. There are many causes of polycythemia in the
newborn period. Polycythemia can often represent a normal physiologic response to fetal hypoxia.
Pathophysiologic causes of polycythemia can result from an increase in red blood cell production or
an increase in transfusion of red blood cells.
Increased red blood cell production can result from:
•Placental insufficiency (e.g., preeclampsia and other hypertensive disorders of pregnancy,
placental abruption, maternal smoking)
•Genetic disorders (e.g., trisomy 13, 18, 21 and Beckwith-Wiedemann syndrome)
•Endocrine abnormalities (e.g., thyrotoxicosis or maternal diabetes with poor glucose control)
The mechanism of polycythemia in women with diabetes is thought to result from increased fetal
red blood cell production associated with fetal hyperinsulinemia, tissue hypoxia, and increased
erythropoietin concentrations. However, some infants born to a diabetic woman may be exposed to
severe placental vasculopathy, which can be associated with erythropoietin resistance and anemia.
The mechanism of genetic disorders and polycythemia is not well understood, but up to 30% of
patients with trisomy 21, 17% of patients with trisomy 18, and 8% with trisomy 13, can have
polycythemia.
Increased red cell transfusion can result from a placental-fetal transfusion, such as delayed cord
clamping, or twin-twin transfusion syndrome.
Reference:
Remon JI, Raghavan A, Maheshwari A. Polycythemia in the newborn. NeoReviews. 2011; 12
(1):e20-e27
Hematology & Bilirubin Answer 7
E. Thrombocytosis
Polycythemia in the newborn is defined as a venous hematocrit above 65% or a hemoglobin above
22 g/dL. The clinical signs and symptoms that are associated with polycythemia are thought to result
from the “hyperviscosity” syndrome, whereby resistance (R) to blood flow is measured by
Poiseuille’s Law:

This formula shows that the effects of hyperviscosity are thought to be more prominent in the
microcirculation because the smaller radius leads to a greater resistance to blood flow.
There are multiple neonatal effects of polycythemia as a result of the sluggish circulation:
•Neurologic symptoms, including lethargy, irritability, apnea, and seizures
•Respiratory effects, such as hypoxia and increased work of breathing
•Hypoglycemia (the mechanism is not well understood, but occurs in up to 40% of infants)
•Hypocalcemia, which is found in 1 to 11% of infants with polycythemia and thought to be
related to elevated concentrations of calcitonin gene-related peptide (CFRG), although the
entire mechanism is not completely understood
•Necrotizing enterocolitis as a result of the increased viscosity
•Reduced glomerular filtration
•Thrombocytopenia, possibly as a result of platelet consumption in the microvasculature where
the resistance to blood flow is the highest
Reference:
Remon JI, Raghavan A, Maheshwari A. Polycythemia in the newborn. NeoReviews. 2011; 12
(1):e20-e27
Hematology & Bilirubin Answer 8
B. 60 ml
The management of polycythemia in the newborn can be controversial, and includes adequate
hydration and management of symptoms. A partial exchange transfusion is usually recommended for
asymptomatic infants with a hematocrit greater than 70% and possibly for symptomatic infants with a
hematocrit greater than 65%. The partial exchange transfusion can be performed using normal saline
(in a 1:1 exchange), as clinical advantage has not be found with use of albumin or fresh frozen
plasma.
For the patient in this vignette:
partial exchange amount = [(71%-55%)/71%] x 90 mL/kg= 20.3 mL/kg = 60.8 mL
Reference:
Remon JI, Raghavan A, Maheshwari A. Polycythemia in the newborn. NeoReviews. 2011;12:e20-
e27
Hematology & Bilirubin Answer 9
C. Hemoglobin E
Hemoglobin E is the most prevalent hemoglobin abnormality in the world. This hemoglobinopathy
results from a gene mutation causing decreased production of beta chains. Children affected by
Hemoglobin E disease can have variable clinical presentations ranging from asymptomatic, mild
microcytic anemia, or severe transfusion-dependent anemia. The severest manifestation occurs in
individuals with co-inherited beta-thalassemia. Those affected with Hemoglobin E can also have
sickle cell disease and alpha-thalassemia.
Alpha-thalassemia is a group of conditions caused by the disordered production of alpha chains and
is common in people of Asian and African descent. Beta-thalassemia is a spectrum of hereditary
anemias caused by either quantitative or qualitative abnormalities in beta chain production. It is also
prevalent in Asia, Africa, and the Mediterranean. Sickle cell disease is caused by qualitatively
abnormal beta chains and is common in people of African and Mediterranean descent. Hereditary
spherocytosis is not a hemoglobinopathy, but rather a defect in the cell membrane of erythrocytes.
References:
Kliegman RM, Behrman RE, Jenson HB, Stanton B (eds). Nelson Textbook of Pediatrics. 18th
edition. Philadelphia: Saunders, 2007
Vichinsky E. Hemoglobin E syndromes. Hematology Am Soc Hematol Educ Program. 2007:79-83
Hematology & Bilirubin Answer 10
D. Disordered activity of pyruvate kinase
The infant in this vignette most likely has pyruvate kinase deficiency. This disorder is caused by
an autosomal recessive defect in the enzyme that converts phosphoenolpyruvate to pyruvate with
release of ATP (see below). The subsequent lack of ATP leads to a hemolytic anemia that is both
normocytic and normochromic with an appropriate reticulocyte response. Although people of all
ethnicities can be affected by pyruvate kinase deficiency, some populations, such as the Amish, are at
greater risk.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency presents similarly, though with decreased

NADPH levels (see equation below). While G6PD deficiency is common in individuals from
Mediterranean, African, and Asian descent, it is not often found in the Amish population.

Chromosomal fragility and breakage is the etiology of congenital aplastic anemia, or Fanconi’s
anemia, an autosomal recessive disorder of erythrocyte production. This anemia is not associated
with hemolysis and a reticulocytosis is not present. Defects in membrane proteins of the erythrocyte,
such as hereditary elliptocytosis, spherocytosis, and pyropoikilocytosis, leads to hemolysis. In all of
these defects, a blood smear will show abnormally shaped red blood cells corresponding to the
disorder. Substitution of valine for glutamic acid at position 6 of the beta-globin gene is the classic
mutation found in individuals with sickle cell disease.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Kliegman RM, Behrman RE, Jenson HB, Stanton B (eds). Nelson Textbook of Pediatrics. 18th
edition. Philadelphia: Saunders, 2007
Hematology & Bilirubin Questions 11-20
Hematology & Bilirubin Question 11
A well-appearing full-term infant born to a 27-year old G2P1 now P2 healthy woman is brought to
the NICU for a sepsis evaluation as a result of a maternal intrapartum fever. Complete blood count
reveals a white blood cell count of 17,000/µl with a normal differential, hematocrit of 56%, and
platelet count of 22,000/µl. The infant’s liver function studies are normal. The mother’s platelet
count is normal.
Of the following, the most likely cause of this infant’s thrombocytopenia is:
A.Congenital cytomegalovirus
B. Maternal alloantibodies against fetal human platelet antigen-1a
C. Maternal gestational thrombocytopenia
D. Maternal idiopathic thrombocytopenic purpura
E. Maternal lupus autoantibodies
Hematology & Bilirubin Question 12
Vitamin K is an essential cofactor for all of the following, EXCEPT:
A.Factor II
B.Factor VII
C.Factor IX
D.Protein C
E. Tissue factor
Hematology & Bilirubin Question 13
Classic hemorrhagic disease of the newborn is characterized by which of the following?
A.Inadequate Vitamin K stores and intake, especially in breastfeeding infants
B. More common in girls if late-onset form
C. Occurs more commonly during winter months
D. Onset within first 24 hours of age
E.Typically asymptomatic unless the infant undergoes an invasive procedure
Hematology & Bilirubin Question 14
A male newborn with a prenatal diagnosis of trisomy 21 is admitted to the Neonatal Intensive Care
Unit with respiratory distress. His vital signs demonstrate normothermia, tachypnea, tachycardia,
normal blood pressure, and normal oxygen saturations in room air. He has mild subcostal retractions
and occasional grunting. Complete blood count reveals a white count of 55,000/µL with neutrophil
predominance and the presence of blasts; hematocrit of 52%; and platelet count of 76,000/µL. Chest
radiograph reveals bilateral pleural effusions.
Which of the following statements about the infant in this vignette is MOST ACCURATE?
A.Though typically asymptomatic, infants with transient myeloproliferative disease may present
with hepatosplenomagaly, effusions, and bleeding
B. Transient myeloproliferative disease occurs in more than 30% of in infants with trisomy 21
C.Transient myeloproliferative disease usually resolves by 2 years of age
D.Transient myeloproliferative disease is rarely diagnosed in the neonatal period
E. Treating transient myeloproliferative disease with chemotherapy prevents the occurrence of
secondary leukemias
Hematology & Bilirubin Question 15
A 48-hour old full-term well-appearing infant has an indirect bilirubin concentration of 16 mg/dL
and receives treatment with phototherapy.
 The dose of phototherapy administered to the infant in this vignette is dependent upon all of the
following, EXCEPT:
A.Distance of infant from the light source
B.Duration of light exposure
C.Irradiance of light
D.Spectrum of light
E.Surface area of infant exposed
Hematology & Bilirubin Question 16
Which of the following statements about sacrococcygeal teratomas is INCORRECT?
A.Almost all occur sporadically
B.There is a 4:1 female:male incidence
C.The risk of malignancy is low, about 1%
D.Surgical removal of the coccyx may reduce the risk of recurrence
E.Weakness, paralysis, or other neurologic symptoms indicate extension of the teratoma into the
spine
Hematology & Bilirubin Question 17
An infant born at 32 weeks’ gestation with a birth weight of 1600 g has the following laboratory
findings:
Laboratory Finding Birth 1 week of age
White blood count (x 10 /µL) 3.2
3 5.6
Hematocrit (%) 45 42
Platelet count (x 103/µL) 78 115
The infant has not received any intervention between these 2 time periods.
The etiology for these hematological abnormalities mostly likely results from:
A.Birth trauma
B.Congenital cytomegalovirus
C.Group B Streptococcus sepsis
D.Maternal pre-eclampsia
Hematology & Bilirubin Question 18
A full-term infant presents with several hemangiomas (external and visceral) and
thromobocytopenia.
Which of the following disorders is most likely?
A.Fanconi anemia
B.Kasabach-Merritt syndrome
C.Thrombocytopenia with absent radius syndrome
D.Trisomy 18
Hematology & Bilirubin Question 19
True or False:
Neonatal allommune thrombocytopenia is unlikely to occur during the first pregnancy because
women have not yet been exposed to fetal platelets.
Hematology & Bilirubin Question 20
What is the preferred first-line management of severe neonatal alloimmune thrombocytopenia
(platelet <20,000/µL)?
A.Human platelet antigen-1a negative platelet transfusion
B.Intravenous immunoglobulin
C.Random donor platelet transfusion
Hematology & Bilirubin Answers 11-20
Hematology & Bilirubin Answer 11
B. Maternal alloantibodies against fetal human platelet antigen-1a
The infant in this vignette has isolated thrombocytopenia that is most likely the result of neonatal
alloimmune thrombocytopenia (NAIT) resulting from placentally transferred maternal antibodies to
paternally inherited human platelet antigen (HPA)-1a on the infant’s platelets. HPA-1a negative
women may become sensitized to fetal HPA-1a during a first pregnancy, increasing the likelihood of
NAIT in subsequent pregnancies. Infants may be asymptomatic or have bleeding diathesis, petechiae,
and intracranial hemorrhage as the result of severe thrombocytopenia. Mothers of affected infants
have a normal platelet count. Affected infants can be treated with platelet transfusions from a random
donor and if ineffective, from a HPA-1a negative donor. Intravenous immune globulin and
corticosteroids may reduce this immune-mediated platelet destruction.
Approximately 10% to 15% of infants with congenital cytomegalovirus are symptomatic at birth.
Affected infants usually are growth-restricted with physical examination findings of
hepatosplenomegaly, jaundice, dermal hematopoiesis, and microcephaly. Laboratory findings include
thrombocytopenia, and abnormal liver function studies. Mothers are not typically symptomatic
because congenital cytomegalovirus is typically acquired from a primary maternal infection acquired
at the time of conception.
Unlike NAIT, neonatal autoimmune thrombocytopenia results from maternal anti-platelet
antibodies caused by maternal autoimmune disease, such as lupus or idiopathic thrombocytopenia
purpura. Maternal platelet counts are usually low. Neonatal autoimmune thrombocytopenia is
associated with a less severe thrombocytopenia than NAIT, though some infants may need treatment
with platelet transfusions.
Maternal gestational thrombocytopenia is an isolated thrombocytopenia in pregnant women of
unknown etiology. This thrombocytopenia does not impact the fetus or infant and resolves post-
partum.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Martin RJ, Fanaroff AA, Walsh MC. Fanaroff and Martin’s Neonatal-Perinatal Medicine Diseases of
the Fetus and Infant. St. Louis: Mosby, 9th edition, 2010
Hematology & Bilirubin Answer 12
E. Tissue factor
Vitamin K is essential for the proper functioning of Factors II, VII, IX, and X and proteins C and
S. Vitamin K does not impact tissue factor function.
Hematology & Bilirubin Answer 13
A. Inadequate Vitamin K stores and intake, especially in breastfeeding infants
Hemorrhagic disease of the newborn is a bleeding diathesis caused by Vitamin K deficiency.
There are 3 forms of this disease: classic, early-onset, and late-onset. The classic form presents
between 2 and 7 days of life with bleeding from the umbilical stump; gastrointestinal bleeding;
intracranial hemorrhage; and prolonged bleeding after invasive procedures, such as circumcision. It
is caused by inadequate Vitamin K stores and poor Vitamin K intake; exclusively breastfeeding
infants are at greater risk of acquiring this disease. Early-onset disease occurs within 24 hours of
birth and is typically the result of placentally transferred drugs that inhibit Vitamin K production, such
as anticonvulsants, cephalosporin antibiotics, and warfarin. Late-onset disease occurs between age 2
weeks and 6 months of life, is more common in boys, occurs more often during the summer, and is
caused by either poor enteral intake of Vitamin K or liver disease. It can cause life-threatening
bleeding and infants are at high risk for intracranial hemorrhage. All forms of hemorrhagic disease of
the newborn are responsive to treatment with Vitamin K.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Orkin SH, Nathan DG, Ginsburg D, Look AT, Fisher DE, Lux SE. Nathan and Oski’s Hematology of
Infancy and Childhood. 7th edition. Philadelphia: Saunders, 2009
Hematology & Bilirubin Answer 14
A. Though typically asymptomatic, infants with transient myeloproliferative disease may present with
hepatosplenomagaly, effusions, and bleeding
Transient myeloproliferative disease, or transient leukemia, occurs in roughly 5% to 10% of
infants with trisomy 21 and is usually diagnosed in the neonatal period. Affected individuals are
typically asymptomatic but may present with hepatosplenomegaly, effusions, and bleeding or
petechiae. The hallmark of this disease is leukocytosis with neutrophilia, thrombocytopenia, and
blasts detected on a blood smear. Transient myeloproliferative disease is usually self-limited, with
60% to 70% of cases resolving spontaneously by two months of age. Treatment with
chemotherapeutic agents is reserved for infants with hyperviscosity as a result of persistently
elevated white count or life-threatening bleeding from liver involvement. Though effective, therapy
does not prevent the occurrence of subsequent leukemia. About 20% of affected infants with trisomy
21 will develop myeloid leukemia.
Reference:
Zwaan CM, Reinhardt D, Hitzler J, Vyas P. Acute leukemias in children with Down syndrome.
Hematol Oncol Clin North Am. 2010;24:19-34
Hematology & Bilirubin Answer 15
B. Duration of light exposure
Phototherapy lowers indirect bilirubin concentrations mostly by the irreversible conversion of
bilirubin to the structural isomer lumirubin, which is water-soluble and easily excreted. The dose of
phototherapy is dependent on the light spectrum (wavelength of 425 to 475 nanometers is most
effective), irradiance of light (i.e., power of electromagnetic radiation per unit area), distance of the
infant from the light source, and surface of skin exposed. The dose of phototherapy that is
administered does not depend on the duration of light exposure.
References:
American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of
hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics.
2004;114:297-316
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Ruud Hansen TW. Phototherapy for neonatal jaundice – therapeutic effects on more than one level?
Semin Perinatol. 2010;34:231-234
Hematology & Bilirubin Answer 16
C. The risk of malignancy is low, about 1%
Sacrococcygeal teratomas (SCT) are benign germ cell tumors composed of all three embryonic
layers. They may arise anywhere along the midline, but over half occur in the sacrococcygeal
region. They are classified as mature (most neonatal and infant teratomas) or immature (high
malignant potential). These tumors are more common in girls (>80%) and almost always occur
sporadically. In utero, large teratomas may cause high output heart failure and non-immune hydrops.
The affected fetus and infant may develop a consumptive coagulopathy and thrombocytopenia. The
SCT may also involve the dura of the spinal cord and thus cause neurologic symptoms. Treatment is
with complete surgical excision, including the coccyx, in order to prevent recurrence. The risk of
recurrence is about 10%, while risk of malignant transformation is between 15% and 20%. It is
recommended that affected individuals be followed with regular imaging and measurement of the
tumor markers alpha-fetoprotein (elevated levels associated with endodermal sinus tumor) and beta
human chorionic gonadotropin (elevated levels associated with choriocarcinoma).
Reference:
Barksdale EM, Obokhare I. Teratomas in infants and children. Curr Opin Pediatr. 2009;21:344-349
Hematology & Bilirubin Answer 17
D. Maternal pre-eclampsia
Maternal pre-eclampsia is associated with mild thrombocytopenia that rarely drops lower than
50,000/µL and recovers to normal levels by 7 to 10 days of life. Pre-eclampsia can also be
associated with neutropenia and an elevated hematocrit.
Reference:
Wong W, Glader B. Approach to the newborn with thrombocytopenia. NeoReviews. 2004;5:e444-
450
Hematology & Bilirubin Answer 18
B. Kasabach-Merritt syndrome
Kasabach-Merritt syndrome is characterized by hemangiomas and thrombocytopenia. Coagulation
is activated locally within the hemangiomas and platelets are sequestered in the vascular
malformation, leading to shortened platelet survival and thrombocytopenia. Only 50% of infants have
visible hemangiomas. Because hemangiomas increase in size during infancy, infants with these
lesions are at risk for bleeding.
Etiology of Thrombocytopenia in the Neonate
Ill-appearing Hypoxic-ischemic encephalopathy
Chronic intrauterine hypoxia
Sepsis (bacterial, viral)
Congenital infection (viral)
Disseminated intravascular coagulation
Congenital anomalies or dysmorphic Thrombocytopenia with absent radius (TAR)
features syndrome
Fanconi anemia
Chromosomal disorders (trisomy 13, 18, 21 or
Turner syndrome)
Well-appearing Occult infection
Maternal autoimmune thrombocytopenia
Neonatal alloimmune thrombocytopenia
Amegakaryocytic thrombocytopenia
Hereditary macrothrombocytopenias
Maternal pre-eclampsia
Kasabach-Merritt syndrome
Modified from: Wong W, Glader B. Approach to the newborn with thrombocytopenia. NeoReviews. 2004;5:e444-450
Reference:
Wong W, Glader B. Approach to the newborn with thrombocytopenia. NeoReviews. 2004;5:e444-
450
Hematology & Bilirubin Answer 19
False
Unlike Rh hemolytic disease, neonatal immune thrombocytopenia (NAIT) occurs in 50% of infants
during the woman’s 1st pregnancy of an at-risk couple. The recurrence rate is >75% in subsequent
pregnancies.
Reference:
Wong W, Glader B. Approach to the newborn with thrombocytopenia. NeoReviews. 2004;5:e444-
450
Hematology & Bilirubin Answer 20
C. Random donor platelet transfusion
Previously, infants affected by neonatal alloimmune thrombocytopenia (NAIT) received human
platelet antigen-1a negative platelets. Recent evidence suggests that most infants with NAIT respond
to random donor platelet transfusions and thus, this is now the first-line treatment for severe
thrombocytopenia. Intravenous immunoglobulin is administered to affected infants to prevent further
platelet destruction.
References:
Saxonhouse MA, Sola-Visner MC. Thrombocytopenia in the neonatal intensive care unit.
NeoReviews. 2009;10:e435-e445
Wong W, Glader B. Approach to the newborn with thrombocytopenia. NeoReviews. 2004;5:e444-
450
Hematology & Bilirubin Questions 21-30
Hematology & Bilirubin Question 21
As you are rounding in the Newborn Nursery with a group of interns and medical students, you
evaluate an African-American infant with jaundice. The infant is 24-hours old.
Of the following, the MOST accurate statement(s) about noninvasive bilirubin measurement
is(are):
A.The difference between a total serum bilirubin (TSB) value of 5 mg/dL and 8 mg/dL can be
perceived by the eye
B.Transcutaneous bilirubin (TcB) measurement provides valuable information about trends and a
TSB measurement should be obtained when the TcB measurement is above the 75th percentile
C.Visual assessment of jaundice is equally reliable in light and darkly pigmented infants
D.A and C
E.All of the above
Hematology & Bilirubin Question 22
While rounding in the Newborn Nursery, the medical students ask about the approach to evaluate a
2-day old term infant for indirect hyperbilirubinemia prior to discharge.
Of the following, the MOST accurate statement about preventing and managing indirect
hyperbilirubinemia is (are):
A.Determine the infant’s risk factors for indirect hyperbilirubinemia
B.Evaluate the risk for severe indirect hyperbilirubinemia based on the nomogram constructed by
Bhutani, et al.
C.Interpret all total serum bilirubin (TSB) values based on hour of age, instead of days of life
D.Measure a total TSB or transcutaneous bilirubin (TcB) concentration prior to discharge
E.All of the above
Hematology & Bilirubin Question 23
A male infant is born at 39 weeks’ gestation. The neonatologist explains the mechanisms of
physiologic jaundice to the rotating third-year medical student.
Of the following, the most likely mechanism involved in physiologic jaundice is:
A.Decreased amount of ligandin
B.Decreased enterohepatic circulation of bilirubin
C.Decreased erythrocyte volume
D.Increased bilirubin conjugation
E.Increased erythrocyte survival
Hematology & Bilirubin Question 24
The neonatology fellow explains non-feeding breast milk jaundice that occurs in the first few days
of a newborn’s life. Because it often takes a few days to establish an adequate supply of breast milk,
breastfed infants may receive a lower amount of calories during this period.
Of the following, the most likely impact of decreased caloric intake in these affected infants is
(are):
A.Decreased amount of ligandin
B.Decreased bilirubin conjugation
C.Decreased bilirubin excretion
D.Increased enterohepatic circulation of bilirubin
E.All of the above
Hematology & Bilirubin Question 25
 After deciding that an infant born at 38 weeks’ gestation requires phototherapy, the pediatrician
meets with the pediatric residents to review the factors that can influence the efficacy of this
phototherapy.
Of the following, the factor that most likely LIMITS the efficacy of phototherapy is:
A.A light source that has output in the blue-green spectrum
B.A light source placed as close to the infant as possible to increase irradiance
C.An extremely high concentration of total serum bilirubin (TSB)
D.Hemolysis as a cause of the indirect hyperbilirubinemia
E.Maximal surface area exposure of an infant to phototherapy
Hematology & Bilirubin Question 26
Erythropoietin (EPO) is the primary hormone responsible for regulating erythropoiesis throughout
gestation.
Which of the following statements is FALSE?
A. After birth, erythropoiesis is suppressed in term infants as a result of improved postnatal tissue
oxygenation and decreased circulating EPO levels
B. EPO does not cross the placenta in humans and fetal production increases with gestational age
C.EPO production is regulated by the transcription factor hypoxia inducible factor-1 (HIF-1)
D.In term infants, hemoglobin typically reaches an average nadir of 11 g/dL at approximately 8 to
12 weeks after birth
E. In the fetus, EPO is produced primarily by the kidneys
Hematology & Bilirubin Question 27
A 6-week old former 24 week gestational age female infant is noted to have a hemoglobin of 7
g/dL.
Which of the following statements is FALSE?
A. Blood loss from phlebotomy increases with lower gestational age and greater illness severity
B. Delayed cord clamping may augment the initial red blood cell volume by 10% to 15%
C. Insufficient iron availability may inhibit the efficacy of erythropoietin (EPO) in prematurity
D. Red blood cell survival is approximately 45 to 50 days in extremely low birth weight infants,
compared to 60 to 80 days in term newborns
E. Studies to date examining the administration of recombinant human EPO have demonstrated a
decrease in the number of blood donors to which infants are exposed
Hematology & Bilirubin Question 28
Iron stores in premature infants increase in proportion to gestational age and birth weight.
Premature infants have increased iron utilization and are at risk for iron depletion and anemia.
Which of the following statements is FALSE?
A. Approximately 80% of total body iron is contained in hemoglobin
B.Erythrocyte expansion needs are more rapid for preterm than term infants secondary to a
relatively faster growth rate
C. Most iron transfer from a pregnant woman to the fetus occurs prior to 26 weeks’ gestation
D. Prenatally, fetal iron is accrued at 1.6-2.0 mg/kg daily
E. The healthy term infant’s total body iron content is 75 mg/kg body weight
Hematology & Bilirubin Question 29
A full-term male infant is admitted to the Neonatal Intensive Care Unit with respiratory distress.
His physical examination is notable for hepatosplenomegaly and a red/brown nodular rash with
confluent purpura. His white blood cell count at the time of admission is 110,000 cells/μL.
 Of the following, the disorder that is LEAST likely to be associated with an INCREASED risk of
congenital leukemia is:
A.Beckwith-Wiedemann syndrome
B.Bloom’s syndrome
C.Diamond-Blackfan syndrome
D.Fanconi’s anemia
E.Trisomy 21
Hematology & Bilirubin Question 30
Match the coagulation factor deficiencies (A-E) with their respective inheritance patterns (1-6).
1.Autosomal dominant
2.Autosomal recessive
3.Autosomal dominant or recessive
4.Mitochondrial
5.X-linked dominant
6.X-linked recessive
A.Factor VIII deficiency
B.Factor IX deficiency
C.Factor XI deficiency
D.Factor XIII deficiency
E.Von Willebrand disease
Hematology & Bilirubin Answers 31-40
Hematology & Bilirubin Answer 31
B. Transcutaneous bilirubin (TcB) measurement provides valuable information about trends and a
total serum bilirubin (TSB) measurement should be obtained when the TcB measurement is above the
75th percentile.
Visual Assessment: Traditional identification of jaundice in a newborn relied on blanching of the
skin to reveal the underlying color of the skin and subcutaneous tissue. Although the clinical
examination remains important, it has its limitations and is unreliable, especially in darkly pigmented
infants. The difference between a total serum bilirubin (TSB) value of 5 mg/dL (85.5 µmol/L) and 8
mg/dL (136.8 µmol/L) cannot be distinguished by visual examination. The potential errors associated
with the clinical examination have led experts to recommend that all newborns have a TSB or TcB
measurement prior to discharge from the hospital.
Noninvasive Measurement: Electronic devices can provide estimates of TSB concentrations and a
close correlation has been found between TcB and TSB values. TcB measurements provide valuable
information about trends and it is recommended that a TSB measurement be obtained when the TcB
measurement is above the 75th percentile.
References:
Maisels MJ. Neonatal jaundice. Pediatr Rev. 2006;27:443-453
Maisels MJ, Ostrea EM, Touch S et al. Evaluation of a new transcutaneous bilirubinometer.
Pediatrics 2004;113:1628-1635
Hematology & Bilirubin Answer 22
E. All of the above
Before discharge, every newborn needs to be assessed for the risk of subsequent severe indirect
hyperbilirubinemia. In addition to determining specific risk factors in each infant, clinicians need to
measure a total serum bilirubin (TSB) or transcutaneous bilirubin (TcB) concentration prior to the
infant’s discharge. Bhutani, et al. established “Risk Zones” for the prediction of indirect
hyperbilirubinemia in neonates. These nomograms are based on hour-specific bilirubin values
obtained from 2,840 newborns who had a gestational age ≥ 36 weeks and birthweights ≥ 2,000 grams
or infants with a birth gestational age ≥ 35 weeks and birthweights ≥ 2,500 grams. For each enrolled
infant, the peak serum indirect bilirubin concentration was measured before discharge. Infants with
bilirubin values that are at or above the 75th percentile for hours of age are at increased risk for
developing severe indirect hyperbilirubinemia after discharge. Thus, these infants require
phototherapy, close monitoring of hydration status, evaluation for isoimmune hemolytic disease, and
follow-up bilirubin measurements.
References:
Bhutani VK, Johnson L, Sivieri EM. Predictive ability of a predischarge hour specific serum
bilirubin for subsequent significant hyperbilirubinemia in healthy term and near term newborns.
Pediatrics 1999;103:6-14
Maisels MJ. Neonatal jaundice. Pediatr Rev. 2006;27:443-453
Hematology & Bilirubin Answer 23
A. Decreased amount of ligandin
After separation from the placenta, the neonate must dispose of the bilirubin load that previously
had been cleared by the placenta. Because indirect hyperbilirubinemia is an almost universal finding
in the first week of life, this transient elevation of the serum bilirubin has been termed physiologic
jaundice.
 Physiologic mechanisms of neonatal jaundice include the following:
Increased bilirubin load on the liver cell. Contributing factors include:
1) increased erythrocyte volume
2) decreased erythrocyte survival
3) increased bilirubin that does not come from the turnover of red blood cells. This
bilirubin is derived from ineffective erythropoietin and the turnover of nonhemoglobin
heme in the liver
4) increased enterohepatic circulation of bilirubin
Decreased hepatic uptake of bilirubin from plasma. Contributing factors include decreased
amount of ligandin.
Decreased bilirubin conjugation. Contributing factors include decreased uridine
diphosphoglucouronysl transferase activity.
Defective bilirubin excretion. Excretion is impaired but not rate-limiting.
Reference:
Maisels MJ. Neonatal jaundice. Pediatr Rev. 2006;27:443-453
Hematology & Bilirubin Answer 24
D. Increased enterohepatic circulation of bilirubin
The jaundice associated with breastfeeding in the first 2 to 4 postnatal days has been called “non-
feeding breast milk jaundice” or “breastfeeding-associated jaundice.” This jaundice is caused by an
increased enterohepatic circulation of bilirubin because the decrease in caloric intake stimulates the
enterohepatic circulation.
Reference:
Maisels MJ. Neonatal jaundice. Pediatr Rev. 2006;27:443-453
Hematology & Bilirubin Answer 25
D. Hemolysis as a cause of the indirect hyperbilirubinemia
When reviewing factors that impact the efficacy of phototherapy, it is important to review the
following:
•Distance of the light source from the patient: increased irradiance leads to a greater rate of
decline in total serum bilirubin (TSB) concentrations; it is important to bring the light source
as close as possible to the infant to increase irradiance.
•Etiology of the indirect hyperbilirubinemia: phototherapy is likely to be less effective if
jaundice is caused by hemolysis or if cholestasis is present.
•Light source: the blue-green spectrum is most effective in lowering TSB; light at this
wavelength penetrates the skin well and is absorbed maximally by bilirubin.
•Surface area of exposed skin: the more the surface area that is exposed, the greater the rate of
decline of TSB.
•TSB concentration at the start of phototherapy: the higher the initial concentration of the TSB,
the more rapid the decline in TSB with phototherapy.
Reference:
Maisels MJ. Neonatal jaundice. Pediatr Rev. 2006;27:443-453
Hematology & Bilirubin Answer 26
E. In the fetus, EPO is produced primarily by the kidneys.
EPO is produced by the fetal liver and the cortical interstitial cells of the kidney in response to
hypoxia. In the fetus, EPO is produced primarily by the liver, which is thought to be less sensitive to
hypoxia compared to the kidneys. Erythropoiesis decreases after birth as a result of marked
improvement in postnatal oxygen delivery and relatively depressed plasma EPO levels. This leads to
a “physiologic nadir” of hemoglobin around 8 to 12 weeks after birth. In premature infants, this
decline is referred to as anemia of prematurity, and occurs earlier, is generally more severe, and
often requires transfusion. EPO does not cross the placenta in humans and fetal production increases
with gestational age. The production of EPO is regulated by the transcription factor HIF-1 and its
primary function is to regulate erythrocyte production.
References:
Garcia-Prats J. Anemia of prematurity. In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA,
2013
Kling P. Anemia of prematurity and erythropoietin therapy. In: de Alarcon P, Werner W, Christensen
R, eds. Neonatal Hematology. 2nd ed. Cambridge, UK: Cambridge University Press; 2013:37-46
Hematology & Bilirubin Answer 27
E. Studies to date examining the administration of recombinant human EPO have demonstrated a
decrease in the number of blood donors to which infants are exposed
Anemia of prematurity is a common complication of preterm delivery, the etiology of which is
multifactorial. The following factors contribute to the development of anemia of prematurity:
•Insufficient EPO production
•Small circulating blood volume
•Iatrogenic blood loss
•Hemorrhage
•Hemolysis
•Shortened red blood cell survival
Phlebotomy volume correlates directly with transfused red blood cell volume. Delayed cord
clamping has been shown to increase the initial red blood cell volume by 10% to 15% and improve
an infant’s long-term iron status. Red blood cell survival in extremely low birthweight infants is
significantly shorter than red blood cells of term infants. Inadequate iron stores in preterm infants
may limit the efficacy of EPO and subsequent recovery of red blood cell volume. Importantly, studies
of recombinant human EPO administration have not demonstrated a decrease in the number of blood
donors to which infants are exposed and EPO administration is not currently routinely recommended
in neonates.
References:
Garcia-Prats J. Anemia of prematurity. In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA,
2013
Kling P. Anemia of prematurity and erythropoietin therapy. In: de Alarcon P, Werner W, Christensen
R, eds. Neonatal Hematology. 2nd ed. Cambridge, UK: Cambridge University Press; 2013:37-46
Hematology & Bilirubin Answer 28
C. Most iron transfer from a pregnant woman to the fetus occurs prior to 26 weeks’ gestation.
Maternal iron deficiency in pregnancy has been associated with decreased fetal iron stores,
preterm birth, and low birthweight. Transfer of iron from a pregnant woman to the fetus is supported
by a substantial increase in maternal iron absorption during pregnancy and is regulated by the
placenta. For each gram of hemoglobin synthesized, 3.47 mg of elemental iron is required. Most iron
transfer to the fetus occurs after 30 weeks’ gestational age and corresponds with peak efficiency of
maternal iron absorption. Prenatally, fetal iron is accrued at a rate of 1.6 to 2.0 mg/kg daily. A
healthy term infant’s total body iron content is 75 mg/kg body weight, approximately 80% of which is
contained in hemoglobin. Iron requirements are generally greater in preterm compared to term infants
secondary to relatively faster growth rates.
References:
Allen L. Anemia and iron deficiency: Effects on pregnancy outcome. Am J Clin Nutr. 2000;71:1280-
1294
Garcia-Prats J. Anemia of prematurity. In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA,
2013
Gillen-Goldstein J, Funai E, Roque H, Ruvel J. Nutrition in pregnancy. In: UpToDate, Basow, DS
(Ed), UpToDate, Waltham, MA, 2013
Kling P. Anemia of prematurity and erythropoietin therapy. In: de Alarcon P, Werner W, Christensen
R, eds. Neonatal Hematology. 2nd ed. Cambridge, UK: Cambridge University Press; 2013:37-46
Hematology & Bilirubin Answer 29
A. Beckwith-Wiedemann syndrome
Congenital leukemia is a rare disease with an incidence of less than 5 per 1,000,000. Infants
classically present within the first 4 weeks of life with hepatosplenomegaly, petechiae, ecchymoses,
and “leukemia cutis”. This rash is typically red/brown in color and nodular with confluent purpura
and is caused by leukemic infiltration of the skin. Beckwith-Wiedemann syndrome is an autosomal
dominant disorder associated with a gene defect at chromosome 11p15.5. It is classically associated
with macrosomia, large tongue, omphalocele, and hypoglycemia, as well as an increased incidence of
intra-abdominal malignancies (e.g. Wilms tumor, hepatoblastoma). Beckwith-Wiedemann is not
associated with an increased risk of congenital leukemia.
Bloom’s syndrome (characterized by hypopigmented and hyperpigmented skin lesions,
photosensitive malar rash, mild craniofacial dysmorphisms, and a high-pitched voice), Diamond-
Blackfan syndrome (characterized by a congenital macrocytic hypoplastic anemia), Fanconi’s anemia
(characterized by short stature, bone marrow failure with cytopenias, radial and other anomalies),
and trisomy 21 are all associated with an increased risk of congenital leukemia.
References:
Kuter D. Megakaryocyte biology and the production of platelets. In: UpToDate, Basow, DS (Ed),
UpToDate, Waltham, MA, 2013
Seif A. Pediatric leukemia predisposition syndromes: Clues to understanding leukemogenesis. Cancer
Genet. 2011;204:227-244
Hematology & Bilirubin Answer 30
A. 6. Factor VIII deficiency - X-linked recessive
B. 6. Factor IX deficiency - X-linked recessive
C. 2. Factor XI deficiency - Autosomal recessive
D. 2. Factor XIII - Autosomal recessive
E. 3. Von Willebrand disease - Autosomal dominant or recessive
Hemophilia A (Factor VIII deficiency) has an X-linked recessive inheritance pattern and accounts
for approximately 70% of cases of hemophilia. Approximately 10% of cases of Hemophilia A
present in the neonatal period and most children develop symptoms by 18 months of life.
Hemophilia B (Factor IX deficiency), also known as Christmas disease, has an X-linked recessive
inheritance pattern and accounts for approximately 30% of cases of hemophilia.
Hemophilia C (Factor XI deficiency) has an autosomal recessive inheritance pattern and can be
associated with Noonan syndrome. Patients with Factor XI deficiency have an increased risk of
genitourinary bleeding.
Factor XIII deficiency, also known as fibrin stabilizing factor deficiency, has an autosomal
recessive inheritance pattern and is classically diagnosed in the setting of prolonged bleeding of the
umbilical cord or after a circumcision.
Von Willebrand disease rarely presents in the newborn period. The types of von Willebrand
disease are described below:
•Type I: most common, mildest form; decreased von Willebrand factor and factor VIII levels
•Type IIa: abnormal von Willebrand factor, platelet clumping ability is decreased
•Type IIb: abnormal von Willebrand factor, platelet clumping ability is increased
•Type III: severe disease with total absence of von Willebrand factor and extremely low factor
VIII levels
Types I, IIa, and IIb have an autosomal dominant pattern of inheritance while the inheritance pattern
of Type III von Willebrand disease is autosomal recessive.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
National Hemophilia Foundation. http://www.hemophilia.org/NHFWeb/MainPgs/MainNHF.aspx?
menuid=182&contentid=47&rptname=bleeding Accessed August 5, 2015
Hematology & Bilirubin Questions 31-40
Hematology & Bilirubin Question 31
A 3-day old male infant has prolonged bleeding after his circumcision. Of note, his parents had
declined his Vitamin K injection at birth.
Which of the following statements about hemorrhagic disease of the newborn is FALSE?
A.Bleeding symptoms typically improve approximately 4 hours after Vitamin K administration
B.Maternal intake of anticonvulsants during pregnancy has been associated with early-onset (<24
hours of life) neonatal disease
C.Neonatal risk factors for Vitamin K deficiency include liver disease and breastfeeding
D.The diagnosis is suggested by a normal prothrombin time, prolonged partial thromboplastin
time, and normal platelet count
E.Vitamin K is an essential cofactor for Factors II, VII, IX, X, protein C, and protein S
Hematology & Bilirubin Question 32
Which of the following statements is TRUE about fetal and neonatal platelets?
A.Congenital thrombocytopenia is a common cause of neonatal thrombocytopenia
B.Fetal megakaryocytes are generally larger in size than adult megakaryocytes
C.Low platelet counts associated with Thrombocytopenia-Absent Radius (TAR) syndrome are the
result of low thrombopoietin levels
D.Megakaryocytes account for only 0.03% to 0.1% of nucleated cells in the bone marrow
E.Platelets have been detected in the fetal liver and circulatory system as early as the second
trimester
Hematology & Bilirubin Question 33
An infant noted to have an adrenal mass by fetal ultrasonography is diagnosed with a
neuroblastoma.
Which of the following statements about neuroblastoma in infants is FALSE?
A.It is associated with a worse prognosis if it presents at less than 12 months of age
B.Neuroblastoma develops from primitive sympathetic ganglion cells
C.Neuroblastoma has been associated with central hypoventilation, Hirschsprung’s disease, and
neurofibromatosis type I
D.Symptoms can include Horner’s syndrome and orbital ecchymoses
E.The adrenal glands are the most common primary site in approximately 70% of cases
Hematology & Bilirubin Question 34
Of the following, the syndrome that has the LOWEST risk of Wilms tumor is:
A.Beckwith-Wiedemann syndrome
B.Denys-Drash syndrome
C.Pearlman syndrome
D.WAGR syndrome
E. Wiscott-Aldrich syndrome
Hematology & Bilirubin Question 35
Of the following, the most likely area of the brain that has yellow-staining and bilirubin deposition
in infants with kernicterus is:
A.Basal ganglia
B.Corpus callosum
C. Globus pallidus
D.Insular cortex
 E. Pons
Hematology & Bilirubin Question 36
A neonate with ABO incompatibility and hemolysis has rising indirect bilirubin levels despite
fluid administration, phototherapy, and intravenous immunoglobulin (IVIG) administration. The team
prepares for a double-volume exchange transfusion and the neonatologist meets with the family.
Of the following, the LEAST likely risk associated with a double-volume exchange transfusion is:
A. Graft versus host disease
B. Hypercalcemia
C. Infection
D. Necrotizing enterocolitis
E. Thrombosis
Hematology & Bilirubin Answer 37
A full-term infant born by Cesarean section appears jaundiced at 3 days of age. The infant’s
parents are both internists and would like to learn more about jaundice in a neonate. They ask the
baby’s pediatrician several questions.
All of the following statements about bilirubin are true, EXCEPT:
A. Bilirubin binds tightly to albumin in plasma
B. Bilirubin bound to albumin does not cross the blood-brain barrier
C. Free unconjugated bilirubin is the form that most readily crosses the blood-brain barrier
D. Heme oxygenase converts heme to biliverdin
E. The placenta can remove indirect bilirubin and biliverdin
Hematology & Bilirubin Question 38
A full-term infant who has been exclusively breastfeeding is noted to have grossly bloody stools at
3 days of age. Of note, the family had declined the Vitamin K medication soon after birth. The
following laboratory tests are sent:
•Prothrombin time (PT)
•Partial thromboplastin time (PTT)
•Platelet count
•Hematocrit
The infant’s laboratory findings are most consistent with a diagnosis of Vitamin K deficiency.
Of the following, the most likely laboratory results in this infant with Vitamin K deficiency are:
A. Decreased platelet count, increased PT, increased PTT
B. Decreased platelet count, normal PT, normal PTT
C. Normal platelet count, increased PT, normal PTT
D. Normal platelet count, normal PT, increased PTT
E. Normal platelet count, normal PT, normal PTT
Hematology & Bilirubin Question 39
A male newborn has increased bleeding after a circumcision, which requires a prolonged period
of local pressure to stop the bleeding. An initial laboratory evaluation reveals a prolonged partial
thromboplastin time.
What is the inheritance pattern of the MOST likely disorder in this infant?
A.Autosomal dominant
B.Autosomal recessive
C.Mitochondrial
D.X-linked dominant
 E. X-linked recessive
Hematology & Bilirubin Question 40
The hemoglobin chains are different in a fetus compared with an adult.
Which of the following statements about the development of hemoglobin types is TRUE?
A. Embryonic hemoglobin consists of a combination of ζ-globin, ε-globin, and δ-globin chains.
B. Embryonic hemoglobin is the predominant form of hemoglobin until 20 weeks’ gestation.
C. Hemoglobin A2 (α2δ2) accounts for only 2% to 3% of hemoglobin by 1 year, due to a decrease
in the production of δ-globin after birth.
D. The percentage of β-globin chain synthesis begins to increase at approximately 30 weeks’
gestation, with a concomitant decline in the percentage of γ-globin chain synthesis.
E . There are 2 forms of embryonic hemoglobin (Hemoglobin Gower 1, and Hemoglobin Gower
2).
Hematology & Bilirubin Answers 31-40
Hematology & Bilirubin Answer 31
D. The diagnosis is suggested by a normal prothrombin time, prolonged partial thromboplastin time,
and normal platelet count
Hemorrhagic disease of the newborn is the result of Vitamin K deficiency leading to inadequate
production of essential coagulation factors including Factors II, VII, IX, X; protein C; and protein S.
Neonatal risk factors include liver disease, malabsorption, antibiotic therapy, breastfeeding, and
maternal intake with placental transfer of several classes of medications including anticonvulsants
(e.g. carbamazepine, phenytoin), barbiturates, cephalosporins, rifampin, isoniazid, and warfarin. A
prolonged prothrombin time (PT), normal partial thromboplastin time (PTT), and normal platelet
count are classic laboratory findings; however, the PTT may also be increased if the infant has
prolonged Vitamin K deficiency. Bleeding symptoms improve rapidly (often within 4 hours) after
Vitamin K administration.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Christensen RD (ed). Hematologic Problems in the Neonate. Philadelphia: WB Saunders; 2000
Hematology & Bilirubin Answer 32
D. Megakaryocytes account for only 0.03% to 0.1% of nucleated cells in the bone marrow
Megakaryocytes account for only 0.03% to 0.1% of nucleated cells in the bone marrow and have
been detected in the fetal liver and circulatory system as early as 8 weeks’ gestation. Fetal
megakaryocytes are generally smaller and of lower ploidy than adult megakaryocytes. However there
is a greater number of megakaryocytes circulating in fetuses compared to adults.
Congenital thrombocytopenia is a rare cause of low platelet counts in infants, accounting for less
than 1% of cases of neonatal thrombocytopenia. The low platelet count associated with
Thrombocytopenia-Absent Radius (TAR) syndrome is the result of a blockage in differentiation of an
early megakaryocyte precursor resulting in decreased platelet production. Thrombopoietin and
thrombopoietin receptor levels are normal in patients with TAR syndrome.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Fernandes C. Neonatal thrombocytopenia. In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA,
2013
Kuter D. Megakaryocyte biology and the production of platelets. In: UpToDate, Basow, DS (Ed),
UpToDate, Waltham, MA, 2013
Hematology & Bilirubin Answer 33
A. It is associated with a worse prognosis if it presents at less than 12 months of age
Neuroblastoma, the second most common tumor in the neonatal period, develops from primitive
sympathetic ganglion cells. The adrenal glands are the most common primary site in approximately
70% of cases. Symptoms can include the following:
•Abdominal mass
•Diarrhea
•Flushing
•Heterochromia iridis
•Horner’s syndrome
•Hypertension
•Opsomyoclonus
 •Orbital ecchymoses
•Subcutaneous nodules
Central hypoventilation, Hirschsprung’s disease, and neurofibromatosis type I have been associated
with neuroblastoma. Children less than 12 months of age with advanced metastatic disease (i.e.,
Stage IV-S, which involves a localized primary tumor and liver, skin, and/or bone marrow
metastases) is associated with a favorable prognosis.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Shohet J, Nuchtern J. Clinical presentation, diagnosis, and staging evaluation of neuroblastoma. In:
UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, 2013
Hematology & Bilirubin Answer 34
E. Wiscott-Aldrich syndrome
Wilms tumor is the most common renal malignancy of children under 15 years of age and two-
thirds of cases are diagnosed less than 5 years of age. Wilms tumor can be bilateral in approximately
5% of cases and often metastasizes to lung, liver, and bone. Several malformation syndromes have
been associated with an increased risk of Wilms tumor including the following:
•Beckwith-Wiedemann syndrome
•Denys-Drash syndrome
•Pearlman syndrome
•WAGR syndrome
Beckwith-Wiedemann syndrome is classically associated with macrosomia, large tongue,
omphalocele, and hypoglycemia, as well as an increased incidence of intra-abdominal malignancies
including Wilms tumor in 5% to 10% of patients. Denys-Drash syndrome is notable for progressive
renal disease, male pseudohermaphroditism, and Wilms tumor in most patients. Pearlman syndrome
is associated with fetal gigantism, visceromegaly, abnormal facies, bilateral renal hamartomas, and
Wilms tumor secondary to a germline mutation resulting in an autosomal recessive overgrowth
syndrome. WAGR syndrome is characterized by Wilms tumor, aniridia, genitourinary anomalies, and
mental retardation. Approximately 20% of children with WAGR syndrome develop a Wilms tumor.
Wiscott-Aldrich is an X-linked disorder associated with immune deficiency, thrombocytopenia, and
eczema. Patients with Wiscott-Aldrich have an increased risk of malignancies, such as leukemia and
B cell lymphoma, but rarely have a Wilms tumor.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Chintagumpala M, Muscal J. Presentation, diagnosis, and staging of Wilms tumor. In: UpToDate,
Basow, DS (Ed), UpToDate, Waltham, MA, 2013
Hematology & Bilirubin Answer 35
A. Basal ganglia
Acute bilirubin encephalopathy, also known as kernicterus, leads to deposition of bilirubin in the
basal ganglia, cranial nerve nuclei, and hippocampus. The yellow-staining has been correlated
microscopically to necrosis, neuronal loss and gliosis. Surviving children develop choreoathetosis,
sensorineural hearing loss, gaze palsies, dental dysplasia, and mild intellectual deficits.
References:
Brodsky D, Martin C. Neonatology Review. 2nd Edition. Lulu. 2010
Kliegman RM, Behrman RM, Jansen HB, Stanton B. Nelson Textbook of Pediatrics. 18th edition.
Philadelphia: WB Saunders; 2007
Hematology & Bilirubin Answer 36
B. Hypercalcemia
The morbidity rate associate with a double-volume exchange transfusion in neonates ranges from
7% to 25%. Potential complications include the following:
•HYPOcalcemia
•Necrotizing enterocolitis
•Thrombosis
•Infection
•Thrombocytopenia
•Graft versus host disease
The incidence of mortality associated with a double-volume exchange transfusion is extremely low,
but some studies have reported mortality rates associated with the procedure of 0.3%.
References:
Brodsky D, Martin C. Neonatology Review. 2nd Edition. Lulu. 2010
Wong RJ, Bhutani VK. Treatment of unconjugated hyperbilirubinemia in term and late preterm infants.
In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, 2013
Hematology & Bilirubin Answer 37
E. The placenta can remove indirect bilirubin and biliverdin
Bilirubin is a byproduct of heme metabolism. Only a small proportion of bilirubin produced in the
newborn results from ineffective erythropoiesis; most is produced from the breakdown of circulating
red blood cells. Conversion of heme to biliverdin is catalyzed by heme oxygenase, which is widely
distributed in tissues throughout the body. Biliverdin reductase then catalyzes the conversion of
biliverdin to bilirubin. The placenta can remove indirect bilirubin but not biliverdin, so there is a
fetal advantage to make bilirubin.
In the bloodstream, unconjugated bilirubin can be bound tightly to albumin or it can exist in a free
form. The free unconjugated bilirubin is the form that most readily crosses the blood-brain barrier
while bilirubin bound to albumin does not cross the blood-brain barrier. In the liver, bilirubin
becomes conjugated with glucuronic acid by the enzyme glucuronyltransferase, making it soluble in
water.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Polin RA, Fox WW, Abman SH (eds). Fetal and Neonatal Physiology. 3rd edition. Philadelphia: WB
Saunders Co; 2004
Hematology & Bilirubin Answer 38
C. Normal platelet count, increased PT, normal PTT
Vitamin K is necessary for the production of functional key coagulation proteins such as Factor II,
VII, IX and X, as well as proteins C and S. Without Vitamin K supplementation at birth, Vitamin K
deficiency can worsen, especially in infants receiving breastmilk exclusively, resulting in bleeding
that can be life-threatening. The bleeding usually manifests itself 2 to 5 days after birth. The most
common site of bleeding is the gastrointestinal tract. Infants with Vitamin K deficiency have the
following laboratory findings:
•Normal platelet count
•Increased PT
•Normal PTT initially; with prolonged Vitamin K deficiency, PTT will also be prolonged
Infants with disseminated intravascular coagulation (DIC) and liver disease will also have elevated
PT and PTT values. While infants with liver disease typically have a normal platelet count, infants
with DIC have a low platelet count. Deficiencies of hereditary clotting factors that are independent of
Vitamin K are associated with a normal platelet count, normal PT, and prolonged PTT.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Christensen RD (ed). Hematologic Problems in the Neonate. Philadelphia: W.B. Saunders; 2000
Hematology & Bilirubin Answer 39
E. X-linked recessive
The infant described most likely has Hemophilia A (i.e., Factor VIII deficiency), which has an X-
linked recessive pattern of inheritance and accounts for ~70% of cases of hemophilia. It can present
in the neonatal period and most affected infants develop symptoms by age 18 months. Laboratory
evaluation of Factor VIII levels can help determine the severity of hemophilia and management
includes Factor VIII replacement.
References:
Brodsky D, Martin C. Neonatology Review. 2nd Edition. Lulu. 2010
Christensen RD (ed). Hematologic Problems in the Neonate. Philadelphia: WB Saunders; 2000
Hematology & Bilirubin Answer 40
D. The percentage of β-globin chain synthesis begins to increase at approximately 30 weeks’
gestation, with a concomitant decline in the percentage of γ-globin chain synthesis
Embryonic hemoglobin predominates in the yolk sac-derived erythrocytes during the first 8 weeks
of gestation. It has 3 forms, Gower 1 (ζ2ε2), Gower 2 (ζ2γ2), and Poland (α2ε2). As the fetus matures
there is a switch from the production of ζ-globin to α-globin, and then from ε-globin to γ-globin. This
leads to an increase in fetal hemoglobin (α2γ2) synthesis, which becomes the predominant form of
hemoglobin throughout the remainder of the pregnancy.
The percentage of β-globin synthesis begins to increase at around 30 weeks’ gestation, with a
concomitant decrease in the percentage of γ-globin chain synthesis. Despite this, fetal hemoglobin
still accounts for 70% to 90% of the neonate’s total hemoglobin at term gestational age. After birth,
there is a rapid decline in γ-globulin production, a further increase in β-globin production, and also
an increase in δ-globin synthesis as the infant transitions from fetal to adult hemoglobin. By 1 year of
age, the infant’s hemoglobin is similar to an adult, consisting of approximately 95% Hemoglobin A
(α2 β 2),1-2% Hemoglobin F (α2γ2), and 3-4% Hemoglobin A2 (α2δ2).
References:
De Alarco P, Werner E, Christensen RD (eds). Neonatal Hematology- Pathogenesis, Diagnosis, and
Management of Hematologic Problems. 2nd Edition. Cambridge University Press. 2013
Nguyen T. Hemoglobinopathies in the neonate. NeoReviews. 2015:16; e278-286
Hematology & Bilirubin Questions 41-50
Hematology & Bilirubin Question 41
Thalassemias are the most common form of hemoglobinopathy, occurring secondary to a
quantitative abnormality in the globin chains that form hemoglobin.
Which of the following statements about thalasemias is TRUE?
A. α -thalassemia carriers typically have a normal clinical exam, but a low mean corpuscular
volume, and mean corpuscular hemoglobin on testing.
B. β-Thalassemia trait leads to a decrease in Hemoglobin A2.
C. Frontal bossing and maxillary hypertrophy, secondary to increased erythopoeisis, is found in
children with Cooley’s anemia.
D. Hemoglobin H is classically associated with hydrops fetalis and early neoantal death.
E. Homozygous β-thalassemia frequently presents with hepatosplenomegaly on routine newborn
examination.
Hematology & Bilirubin Question 42
An infant is born to a mother with known sickle cell anemia. The infant’s father has a normal
phenotype but has homozygous β+ thalassemia (β-thalassemia intermedia).
Based on these results, what would you expect to be the hemoglobin designation on this infant’s
state newborn screening test?
A. FA
B. FAS
C. FC
D. FS
E. FSA
Hematology & Bilirubin Question 43
An ELBW infant, now 6 weeks post-natal age, has a hematocrit of 27%.
Which of the following statements about the management of anemia of prematurity is TRUE?
A.ELBW infants have a greater risk of developing necrotizing enterocolitis if they receive a
transfusion within 2 weeks of age.
B.Irradiated blood is used for transfusions to reduce the transmission of CMV.
C.Milking the umbilical cord is associated with an increased hematocrit compared to delayed cord
clamping.
D.There is a direct correlation in neonates between the volume of blood drawn for lab tests, and
the volume of blood that is transfused.
E.Transfusion of 10ml/kg should increase the hemoglobin concentration by approximately 3 to4
g/dL.
Hematology & Bilirubin Question 44
The oxyhemoglobin saturation curve describes the relationship between the partial pressure of
oxygen in arterial blood, and the hemoglobin-oxygen saturation.
Which of the following statements about the oxyhemoglobin saturation curve is LEAST
ACCURATE?
A.Alkalosis increases the affinity for oxygen to hemoglobin.
B.An increase in 2,3-Diphosphoglycerate (2,3-DPG) leads to an increase in oxygen affinity to
hemoglobin.
C.Increased temperature reduces the oxygen binding affinity to hemoglobin.
D.The Bohr effect causes the oxyhemoglobin curve to be shifted to the right.
 E.The oxyhemoglobin curve in a fetus is shifted to the left of the adult oxyhemoglobin curve.
Hematology & Bilirubin Question 45
Since the use of Rhogam, the incidence of hydrops fetalis due to Rh incompatibility has
significantly decreased.
What are other hematologic causes of hydrops fetalis?
A.Chronic fetomaternal hemorrhage
B.Homozygous alpha-thalassemia
C.Homozygous glucose-6-phosphate dehydrogenase (G6PD) deficiency
D.Maternal iron deficiency anemia
E.A+B+C
Hematology & Bilirubin Question 46
Physiological jaundice commonly occurs in newborns.
Which of the following is LEAST consistent with physiologic jaundice?
A.A full-term African American newborn with a cord blood bilirubin of 1.5 mg/dL.
B.A full-term African American newborn with a bilirubin of 6 mg/dL on day 3.
C.A full-term Asian American newborn with a peak bilirubin of 14 mg/dL on day 3.
D.A full-term Asian American newborn with a serum bilirubin of 3 mg/dL on day 10.
E.A full-term Caucasian newborn with a peak bilirubin of 14 mg/dL on day 3.
Hematology & Bilirubin Question 47
Red blood cell (RBC) storage lesion is the name given to the various alterations to the RBC’s
function and integrity, which occur during preservation. The RBC storage lesion is thought to impact
tissue oxygenation and has been implicated in several transfusion-associated injuries, including
transfusion-associated gut injury (TRAGI).
Which of the following is NOT a component of the RBC storage lesion?
A.Cytokine release during filtering of white blood cells
B.Increased blood viscosity due to a high hematocrit
C.Increased hemoglobin oxygen affinity due to reduced PaO2
D.Increased nitric oxide levels leading to production of reactive oxidative species
E.Stacking of RBCs leading to microaggregates
Hematology & Bilirubin Question 48
A 43-year old woman without any prior pregnancies underwent successful intrauterine
insemination. The woman is blood type A-negative and the sperm donor is blood type A-positive.
This pregnancy has been followed closely for development of Rh antibody, with negative screens in
the first trimester, and again at 28 weeks’ gestation.
The pregnancy was otherwise uncomplicated and the infant is delivered at term via vaginal
delivery followed by manual removal of the placenta. The infant was admitted to the Newborn
Nursery. The results of blood work on admission include blood type A-positive, hematocrit 52% and
reticulocytes 0.4%.
Of the following, the most appropriate NEXT step in the management of the woman in this vignette
is:
A.Administer one standard prophylactic dose of Rh immune globulin
B.Initiate iron supplementation
C.Order maternal complete blood cell count
D.Recommend pre-implantation Rh screening for subsequent pregnancies
E.Screen for a fetal-maternal transplacental hemorrhage
Hematology & Bilirubin Question 49
A term infant is born in an ambulance en-route to the hospital. The paramedics assign an Apgar
score of 8 at 1 minute and 9 at 5 minutes, with both deductions due to the infant’s color. The
neonatology team is called to assess the infant prior to admission to the Newborn Nursery. The infant
is noted to be alert and active, but with significant pallor. Serum blood work is ordered at 1-hour of
age, with the following results:
Hemoglobin-8.2 g/dL
Reticulocytes-0.3%
Bilirubin-0.7 mg/dL
DAT-negative
The laboratory findings in this clinical vignette are consistent with which of the following
diagnoses?
A.Enclosed hemorrhage with resorption of blood
B.Hemorrhagic anemia
C.Hereditary red blood cell defect
D.Immune-mediated hemolysis
E.Physiologic anemia of infancy
Hematology & Bilirubin Question 50
You are asked to perform a prenatal consultation on a pregnant woman at 18 weeks’ gestation.
This is her second pregnancy with the same father. Her prenatal screens show a B positive, Rh
negative blood type. The father of the baby has a blood type of B positive, Rh positive. The woman
asks you for information about the implications of this blood type difference on her pregnancy.
All of the following statements are true, EXCEPT:
A. In addition to the D antigen, the Rh system contains numerous other antigens.
B. The fetal middle cerebral artery peak systolic velocity is the best noninvasive tool for
predicting fetal anemia in at-risk pregnancies.
C. The frequency of Rhesus antigens varies among populations.
D. The indirect Coombs titer for maternal anti-D is only used to detect the presence, not the degree
of alloimmunization.
E. This pregnancy is at higher risk of complications from hemolytic disease as compared to her
prior one.
Hematology & Bilirubin Answers 41-50
Hematology & Bilirubin Answer 41
C. Frontal bossing and maxillary hypertrophy, secondary to increased erythopoeisis, is found in
children with Cooley’s anemia.
There are 4 alpha globin genes. α-Thalassemia carriers have a mutation in a single gene, and
typically have no phenotypic manifestations. A person with α-thalassemia trait has mutations in two
genes. Affected individuals typically have a low mean corpuscular volume and mean corpuscular
hemoglobin, and may have a mild anemia. Hemoglobin H (β4) occurs when there are mutations in 3
genes, and Hemoglobin Barts (γ 4) when all 4 genes are mutated or silent. Hemoglobin H can result
in a chronic hemolytic anemia, raised total and direct bilirubin levels, cholelithiasis,
hepatosplenomegaly, and skeletal abnormalities. Hemoglobin Barts classically leads to fetal hydrops
and neonatal death. Intrauterine transfusions have been attempted to treat fetuses with hemoglobin
Barts with some success.
There are 2 β-globin genes. Individuals with β-thalssemia trait have a mutation in a single gene.
Affected individuals typically have target cells visible on their peripheral smear, a mild microcytic
hypochromic anemia, and an increase in Hemoglobin A2. Individuals with homozygous β0-
thalassemia (Cooley’s anemia) have a chronic hemolytic anemia, raised total and direct bilirubin
levels, cholelithiasis, hepatosplenomegaly, skeletal abnormalities (such as frontal bossing, maxillary
hypertrophy), and a delay in growth.
Both α- and β-thalassemias are associated with increased iron absorption. This coupled with the
increased iron load received if the infant is transfusion-dependent, can lead to iron overload.
Hemoglobin F is the predominant form of hemoglobin during the fetal and neonatal periods.
Therefore, disruption to the α-globin chains with α-thalassemia can present in utero (Hemoglobin
Barts hydrops fetalis), or during the neonatal period (Hemoglobin H), while infants with β-
thalassemia do not typically have any signs or symptoms during the neonatal period.
Reference:
Nguyen T. Hemoglobinopathies in the neonate. NeoReviews. 2015:16;e278-286
Hematology & Bilirubin Answer 42
E. FSA
Hemoglobin designations on state newborn screening tests and their interpretations are shown below:
FANormal
FVEither homozygous for hemoglobin variant or double heterozygote for hemoglobin variant
and β0 thalassemia
FAVHeterozygote for hemoglobin variant
FVADouble heterozygote for hemoglobin variant and β+ thalassemia
FV1V2Double heterozygote for 2 different hemoglobin variants
Of note, V represents any hemoglobin variant
β+- Indicates that there is some production of the β globin chain
β0 - Indicates that there is no production of the β globin chain
Using Sickle Cell as an Example
FANormal
FSEither sickle cell disease (SS) or sickle cell S- β0 thalassemia
FASSickle cell trait
FSASickle cell S- β+ thalassemia
FSVDouble heterozygote for sickle cell and alternate hemoglobin variant, example FSC-
 Hemoglobin SC disease
In this example, the infant’s mother is known to have sickle cell anemia, and as such, has homozygous
mutations in the HBB genes, leading to production of hemoglobin SS. Similarly, the father has
homozygous β+ thalassemia (β+ β+). Therefore, the infant will inherit both sickle cell trait from the
mother, and a single β+ globin gene from the father- FSA- sickle cell- β+ thalassemia.
Reference:
Nguyen T. Hemoglobinopathies in the neonate. NeoReviews. 2015:16;e278-286
Hematology & Bilirubin Answer 43
C. There is a direct correlation in neonates between the volume of blood drawn for lab tests, and the
volume of blood that is transfused.
Anemia of prematurity occurs secondary to a decreased red blood cell life span, reduced
erythropoietin production, and phlebotomization. Studies have found that there is a direct correlation
between the blood volume that is phlebotomized, and the volume of blood that the infant is transfused,
highlighting the importance of judicious blood draws.
Anemia of prematurity is treated by reducing the blood volume drawn, ensuring adequate iron
intake, and when necessary, by transfusing the infant. For neonatal transfusions, irradiated blood is
used, which prevents Graft versus Host disease. The blood may also be leucodepleted to limit the
risk of CMV transmission. When ordering a red cell transfusion, a dose of 10 to 15 ml/kg is typically
requested. This is estimated to raise the hemoglobin concentration by 2-3 g/dL. There are numerous
adverse outcomes that have been described in association with transfusions, including BPD, ROP and
necrotizing enterocolitis (NEC); however, whether the association reflects sicker infants requiring
transfusions, or if there is a causal link is not clear. Some but not all studies have shown an increased
incidence of NEC following RBC transfusions. When this observation is made, it usually occurs later
in post-natal life, at a mean PMA of 31 weeks’ gestation.
Other proposed methods to reduce the severity of anemia of prematurity include prophylactic
measures such as delayed cord clamping and cord milking. While studies are still evaluating the true
benefits of these techniques, current data supports that the two methods are comparable, and result in
an increased initial hemoglobin level. There have been conflicting reports if this results in a
decreased need for transfusion or not.
References:
Al-Wassia H, Shah PS. Efficacy and safety of umbilical cord milking at birth: a systematic review
and meta-analysis. JAMA Pediatr. 2015;169:18-25
Hensch LA, Indrikovs AJ, Shattuck KE. Transfusion in extremely low-birth-weight premature
neonates. NeoReviews. 2015; 16: e287-296
Rabe H, Jewison A, Alvarez RF, et al. Milking compared with delayed cord clamping to increase
placental transfusion in preterm neonates: a randomized controlled trial. Obstet Gynecol.
2011;117:205-211
Hematology & Bilirubin Answer 44
B. An increase in 2,3-Diphosphoglycerate (2,3-DPG) leads to an increase in oxygen affinity to
hemoglobin.
The oxyhemoglobin saturation curve can be altered by changes in the physiological state of the
infant to meet alterations in oxygen demands. An increase in hemoglobin-oxygen affinity shifts the
oxyhemoglobin saturation curve to the left, and a decrease in affinity shifts the curve to the right.
Factors associated with a shift of the curve to the left include: fetal hemoglobin, increased
intracellular pH, decreased carbon dioxide, decreased 2,3-DPG, and decreased temperature. Factors
associated with a shift to the right include: increased 2,3-DPG, increased temperature, and the Bohr
effect. The Bohr effect is the shift of the curve to the right in response to an increased partial pressure
of carbon dioxide, or a decrease in intracellular pH, or both.
2,3-DPG is an organic phosphate that reduces the hemoglobin-oxygen affinity. It shifts the curve to
the right: 1) directly by stabilizing deoxyhemoglobin through cross linking β-globin chains; and 2)
indirectly by reducing the intra-erythrocyte pH (Bohr effect). Following delivery, there are
insufficient 2,3-DPG levels to explain the rapid decrease in the blood’s oxygen affinity by its direct
cross linking of β-globin chains, rather 2,3-DPG helps mediate the rapid decrease in affinity
indirectly by reducing the intracellular pH.
Reference:
Polin R, Fox W, Abman S. Fetal and Neonatal Physiology, 3rd Edition. Philadelphia, Saunders. 2004
Hematology & Bilirubin Answer 45
E. A+B+C. Chronic fetomaternal hemorrhage + Homozygous alpha thalassemia + Homozygous G6PD
deficiency
The pathogenesis of hydrops fetalis includes multiple diseases including hematologic,
cardiovascular, renal, infectious and chromosomal disorders. Hematologic disorders are the cause of
hydrops fetalis in about 10% of the cases. In addition to Rh incompatibility, homozygous alpha-
thalassemia, homozygous glucose-6-phosphate dehydrogenase (G6PD) deficiency, chronic
fetomaternal hemorrhage, thrombosis, and bone marrow failure can be a hematologic cause of
hydrops fetalis.
Reference:
Cloherty JP, Eichenwald EC, Hansen AR et al. Manual of Neonatal Care, 6th edition. Lippincott,
Williams & Wilkins, 2011
Hematology & Bilirubin Answer 46
E. A full-term Caucasian newborn with a peak bilirubin of 14 mg/dL on day 3.
Physiological jaundice commonly occurs in newborns. It is an unconjugated hyperbilirubinemia
that is characterized by a cord blood total bilirubin level of 1.5 to 2 mg/dL, which then increases to
peak concentrations between days 3 to 5 in full-term newborns before declining to adult levels. It
should be recognized that there is variability in the bilirubin levels, impacted by factors including
race, method of feeding, and genetics.
The typical peak total serum bilirubin levels in Caucasian and African American newborns are
between 5 to 6 mg/dL at 48 to 120 hours of age. Asian American newborns typically develop higher
values of 10 to 14 mg/dL at 72 to 120 hours of age. After the bilirubin peaks, it slowly declines to
adult levels (2 mg/dL) by day 10.
References:
Lauer BJ, Spector ND. Hyperbilirubinemia in the newborn. Pediatr Rev. 2011;32:341-349
Martin RJ, Fanaroff AA, Walsh MC. Fanaroff and Martin's Neonatal-Perinatal Medicine: Diseases of
the Fetus and Infant, 10th ed. Elsevier, 2015
Hematology & Bilirubin Answer 47
D. Increased nitric oxide levels leading to production of reactive oxidative species
Red blood cell (RBC) storage lesion is due to multiple changes in the physicochemical nature of
the RBC. These changes include;
Changes in the RBC physical structure
•RBC stacking, leading to microaggregates and obstruction to flow
•Increased adhesiveness of RBCs
 •Less deformability of RBCs
•A higher hematocrit leading to increased viscosity
•Free membrane lipids, which are vasoactive
•RBC fragmentation leading to free hemoglobin (a nitric oxide scavenger)
Altered RBC metabolism
•Higher affinity for oxygen due to a low PaO2 and 2,3-diphosphoglycerate
•Altered vascular resistance due to increased lactate, low pH, large base deficit, and increased
potassium
•Lower ATP
•Increased free iron, which can cause oxidative injury
Depletion of nitric oxide
•Free hemoglobin acts as a scavenger for nitric oxide and has a much higher affinity than RBC
hemoglobin
•Reduced RBC nitric oxide during storage
Humoral factors
•Cytokines released from white blood cells during leucodepletion
•Infused humoral factors activate endothelial receptors, and increase platelet activating factor
Although causality remains unclear, there is increasing evidence for the association between blood
transfusion and transfusion-associated gut injury (TRAGI) in preterm infants. The RBC storage lesion
has been implicated in this process. TRAGI itself has recently been described in the extremely low
birth weight neonate and is distinct from typical necrotizing enterocolitis (NEC) in that it occurs in
the following: scenarios
•Within 48 hours of a blood transfusion
•Typically among infants born less than 28 weeks’ gestation but at 31 to 32 weeks’
postmenstrual age
•In infants who aside from the transfusion, have a low risk for NEC
•In infants with significant anemia prior to transfusion
References:
Christensen RD, Baer VL, Del Vecchio A, Henry E. Unique risks of red blood cell transfusions in
very-low-birth-weight neonates. J Matern Fetal Neonatal Med. 2013;26:60-63
La Gamma EF, Feldman A, Mintzer J, et al. Red blood cell storage in transfusion-related acute gut
injury. NeoReviews. 2015:16;e420-430
Hematology & Bilirubin Answer 48
E. Screen for a fetal-maternal transplacental hemorrhage
An Rh-negative woman with an Rh-positive fetus is at risk of developing an Rh antibody, putting
her fetus at risk for hemolytic disease. Fetal red blood cells have been discovered in the maternal
circulation as early as the 10th week of gestation and following abortion. Women with a history of
spontaneous and therapeutic abortions, in addition to known previous Rh positive pregnancies, are at
risk for Rh immunization.
If an Rh antibody develops during pregnancy as a result of a primary or secondary immune
response, this usually occurs after 20 weeks’ gestation. The minimum recommendation in at risk
woman, therefore, is for first trimester screening for Rh antibody, followed by repeat screening at
28weeks’ gestation.
Peripartum factors that can increase the risk and volume of a fetal-maternal transplacental
hemorrhage include Cesarean delivery and manual removal of the placenta. After delivery, cord
blood can be sent for ABO group, Rh type, and direct antiglobulin testing. Maternal blood should be
sent for presence of Rh antibody, and if testing is available, for a fetal-maternal transplacental
hemorrhage. Most instances of Rh immunization follow a small or undetectable fetal-maternal
hemorrhage. However, quantitative testing (Kleihauer-Betke test) can detect the rare maternal cases
that require additional units of Rh immune globulin, which typically follow exposure to more than 30
mL of fetal blood (15 mL of fetal red blood cells). Given the manual removal of the placenta in the
vignette above, this woman is at risk for a peripartum fetal-maternal transplacental hemorrhage.
References:
Creasy RK, Resnik R. Maternal Fetal Medicine. 3rd edition. Philadelphia: Elsevier; 1994
Moise KJ. Prevention of Rh(D) alloimmunization. In: UpToDate, Post TW (Ed), UpToDate,
Waltham, MA (Accessed on July 15, 2015)
Hematology & Bilirubin Answer 49
B. Hemorrhagic anemia
Anemia is a common problem in the newborn period. The etiology can often be identified by
medical history and physical examination. It is important to assess family history, maternal medical
history, obstetric history, and the age of onset of the anemia in the neonate. An initial diagnostic
approach to assess the differential of anemia in the newborn period includes assessing hemoglobin
(and/or hematocrit), reticulocytes, bilirubin and DAT.
Significant anemia at birth is often due to blood loss or alloimmune hemolysis. In the first 24
hours, in addition to clinical history, the direct antiglobulin test (DAT) will be helpful in
differentiating hemorrhagic anemia and immune-mediated hemolysis. In alloimmune hemolysis, the
DAT is expected to be positive. In hemorrhagic anemia, the DAT will be negative. Hemorrhagic
anemia in newborns can be subcategorized into fetal hemorrhage, placental hemorrhage, umbilical
cord bleeding and postpartum neonatal hemorrhage.
Typically, internal hemorrhages and other hemolytic processes become evident after 24 hours of
age. Several weeks after birth is a typical timeframe for presentation of anemias due to abnormalities
in the synthesis of hemoglobin beta chains, hypoplastic RBC disorders and physiologic anemia of
infancy or prematurity.
On physical examination, an infant with chronic blood loss may appear pale, without any evidence
of distress. Acute severe blood loss can present with hypovolemic shock. Neonates with hemolytic
anemia often show jaundice to a greater degree than expected for age, in addition to
hepatosplenomegaly.
Reference:
Gleason CA, Devaskar SU. Avery’s Diseases of the Newborn. 9th Edition. Philadelphia: Elsevier;
2012
Hematology & Bilirubin Answer 50
D. The indirect Coombs titer for maternal anti-D is only used to detect the presence, not the degree of
alloimmunization.
Hemolytic disease of the fetus and newborn is the result of immune-mediated destruction of fetal
or newborn red blood cells. It occurs when fetal or newborn red blood cells (RBC) contain antigens
that are not present in the maternal blood. Rhesus (Rh) status frequently refers to the D antigen.
However, in addition to D, the Rh blood system consists of C, c, D, E, e, and G antigens. Rh D
incompatibility is the best described cause of hemolytic disease of the fetus and newborn. RhD-
negative refers to the lack of D antigen on the RBC surface. An algorithm is available to manage
affected pregnancies with intrauterine transfusions and timed delivery by using antibody titers and
fetal middle cerebral artery and velocities.
There have been great efforts focused on the prevention of hemolytic disease in infants of Rh-
negative mothers. However, RhD remains the most commonly identified red blood cell antigen
causing hemolytic disease of the fetus and the newborn. 11% to 35% of Caucasian populations are
RhD-negative because of a gene deletion. In contrast, most East Asian and African populations that
lack RBC surface expression of RhD have a grossly intact gene. The most commonly used diagnostic
test is the indirect Coombs test; the steps of this test are shown below. This test is used to detect not
only the presence, but also the degree of alloimmunization, which helps guide obstetrical management
of allo-immunized pregnancies. A critical titer refers to the titer associated with a risk for fetal
hydrops.

References:
Fanaroff AA, Martin RJ, Walsh M (eds). Neonatal-Perinatal Medicine. 10th edition. St. Louis:
Mosby; 2014
Ross MB, Alacron P. Hemolytic disease of the fetus and newborn. NeoReviews. 2013;14:e83-e88
Hematology & Bilirubin Questions 51-60
Hematology & Bilirubin Question 51
Which of the following changes leads to a decrease oxygen affinity?
A. Decreased 2,3-diphosphoglycerate
B. High pH
C. Increased fetal hemoglobin
D. Increased temperature
E. Low CO2
Hematology & Bilirubin Question 52
A term infant has a presumptive diagnosis of alpha-Thalassemia trait based on the state newborn
screening test.
Which of the following statements about alpha-Thalassemia trait is TRUE?
A. α-globin gene expression does not begin until after birth.
B. Affected individuals have a high mean corpuscular volume.
C. Affected individuals have impaired growth and development.
D. Only one α-globin gene is mutated.
E. This finding is more frequent in Asia, the Mediterranean, and Africa.
Hematology & Bilirubin Question 53
Which of the following characteristics is consistent with an infant who has iron deficiency
anemia?
Transferrin Mean Cell Volume Total Iron Binding Capacity
Ferritin
Receptor (MCV) (TIBC)
A. Normal Normal High Increased
B. Increased High Low Increased
C. Increased Low Low Increased
D. Increased Low High Decreased
E. Low High Low Decreased
Hematology & Bilirubin Question 54
Following an uncomplicated pregnancy, an appropriate for gestational age male infant is born at
38 weeks’ gestation via Cesarean section following failure to progress. There are no sepsis risk
factors, and the infant is well appearing. The baby is exclusively breastfeeding, with weight on day
of life two down 5% from birth weight. A 48-hour total serum bilirubin concentration is 16 mg/dL
with a direct bilirubin concentration 0.3 mg/dL. The infant has blood type A+. His mother has blood
type O+, antibody negative. His family history is notable for hereditary spherocytosis.
Which of the following laboratory tests is the most appropriate NEXT step in differentiating the
potential cause of this infant’s hyperbilirubinemia?
A.Blood culture
B.Complete blood count
C.Direct Coombs test
D.Osmotic fragility test
E.Peripheral smear
Hematology & Bilirubin Question 55
A 32-year old G2P1 woman at 34 weeks’ gestation is undergoing induction of labor for worsening
symptoms of preeclampsia. After an uncomplicated term delivery, her first infant required a 7-day
hospital stay for indirect hyperbilirubinemia, treated with phototherapy. The likely etiology of
jaundice for this infant was a large cephalohematoma and weight loss of 12% while exclusively
breastfeeding. During her prenatal consult, this woman is concerned about the risk of indirect
hyperbilirubinemia if she were to deliver at 34 weeks’ gestation.
In addition to concerns for suboptimal breastfeeding, which of the following factors contributes to
an INCREASED risk for neonatal jaundice in late preterm infants compared to term infants?
A.Decreased enterohepatic circulation
B.Delayed signs of bilirubin neurotoxicity
C.Increased hematocrit at birth
D.Increased red blood cell turnover
E.Lower uridine diphosphate glucuronosyltransferase 1A1 enzyme activity
Hematology & Bilirubin Question 56
A 27-year old G5P4 had a successful home delivery of a 3700 g male infant at 39 2/7 weeks’
gestation following an uneventful pregnancy with adequate prenatal care. The infant’s exam is
notable for a cephalohematoma. He is scheduled for pediatric follow-up at 36-hours of age for
critical congenital heart disease screening, newborn screening, and a weight check.
What advice about jaundice is appropriate in this infant’s initial 36-hour period?
A.Arrange for serum bilirubin screening at 6 to 8 hours of age
B.Phototherapy is indicated only if jaundice extends to the infant’s lower extremities
C.Place the bassinette in direct sunlight as prophylaxis
D.Provide formula until lactation is established
E.Seek care for any jaundice noticed in the first 24 hours of age
Hematology & Bilirubin Question 57
A 1400g neonate closely followed prenatally for isoimmune hemolytic disease is born via
Cesarean section at 33 weeks’ gestation for worsening fetal anemia. At 18-hours of age, the infant’s
total serum bilirubin is nearing exchange levels, having not responded to initial phototherapy
treatment. A serum albumin concentration is ordered to assist in the clinical decision-making.
Which of the following statements about albumin and jaundice is TRUE?
A.A bilirubin to albumin (B/A) ratio ≥ 6.8 mg/g is an indication for an exchange transfusion.
B.A B/A ratio is a surrogate for unbound bilirubin.
C.An albumin ≥ 2.5 g/dL is a risk factor for developing indirect hyperbilirubinemia.
D.Due to lower serum albumin levels, preterm infants have a higher B/A ratio threshold to initiate
therapy.
E.There is an increased albumin binding affinity for bilirubin in sick infants.
Hematology & Bilirubin Question 58
A 4-day old full-term female infant presents to the Emergency Department with a fever to 102°F.
She is tachypneic, tachycardic, and appears listless. Her examination is notable for a systolic
murmur and jaundice to the umbilicus. Her capillary blood gas analysis is: pH=7.18, pCO2=58 mm
Hg. An evaluation for sepsis is completed, with the remainder of her laboratory results pending. A
peripheral IV is placed and the infant is given IV Ampicillin, Cefotaxime and Acyclovir.
In assessing this infant’s risk for bilirubin-associated brain damage, which of the following factors
would contribute to an increased unbound bilirubin fraction?
A.Acidosis
B.Acyclovir
C.Cefotaxime
 D.High serum albumin levels
E.Low total serum bilirubin level
Hematology & Bilirubin Question 59
An African American female infant born at 32 weeks’ gestation with intrauterine growth
restriction is being treated in the NICU for feeding intolerance. Maternal blood type is A+ antibody
negative; infant blood type is O+ direct antiglobulin test (i.e., Coombs) negative. Currently, the baby
is day of life 8, requiring CPAP for respiratory support and caffeine citrate for apnea of prematurity.
Her most recent capillary blood gas is pH=7.45, pCO2=32 mm Hg. She is receiving total fluids of
150 ml/kg/day, of which 100 ml/kg/day is TPN and 50 ml/kg/day is unfortified donor breast milk.
Her total serum bilirubin is 4 mg/dL and albumin is 3 g/dL. She has no sepsis risk factors, is
otherwise well appearing, and has not received any antibiotic treatment.
Which of the following factors increase the risk of development of kernicterus in the infant in this
vignette?
A.Bilirubin/albumin ratio
B.Blood group incompatibility
C.Gestational age
D.pH
E.Race
Hematology & Bilirubin Question 60
A mother brings her 3-day old infant to the Emergency Department because of decreased feeding.
On physical exam, the infant is noted to have severe jaundice. Family history is notable for glucose-
6-phosphate dehydrogenase deficiency. Phototherapy is started immediately while further history is
taken and laboratory investigations are ordered.
What sign on physical exam would alert the clinician that some bilirubin-associated irreversible
central nervous system damage has already occurred?
A.Backward arching of the trunk
B.Decreased activity
C.Hypotonia
D.Poor sucking
E.Slightly high-pitched cry
Hematology & Bilirubin Answers 51-60
Hematology & Bilirubin Answer 51
D. Increased temperature
Oxygen from the lung diffuses into the blood where it is predominantly bound to hemoglobin in red
blood cells. Hemoglobin oxygen affinity, which refers to the ability of hemoglobin to bind or release
oxygen, is modulated by pH, CO2, temperature, and fetal hemoglobin. 2,3-diphosphoglycerate (DPG)
is an organic phosphate normally found in the human erythrocyte. 2,3-DPG reduces oxygen affinity by
stabilizing deoxyhemoglobin. Lower pH, higher CO2, increased temperature, and a decreased
proportion of fetal hemoglobin reduces oxygen affinity. These shifts in affinity promote oxygen uptake
in the pulmonary capillaries and release into the tissues.
Reference:
Polin RA, Fox WW, Abman SH (eds). Fetal and Neonatal Physiology. 4th edition. Philadelphia: WB
Saunders Co; 2010
Hematology & Bilirubin Answer 52
E. This finding is more frequent in Asia, the Mediterranean, and Africa.
Hemoglobin consists of 2 α-like and 2 β-like globins. The thalassemias are an example of a
hemoglobinopathy. There are 2 α-like chains per chromosome 16 and as a result, 4 α-globin genes. α-
Thalassemia results from defects in the α-globin gene, whereas β-thalassemia occurs from mutations
in the β-globin gene. α-Thalassemias result from mutations of 1 or more of the 4 α-globin genes. α-
globin gene expression begins in utero, and as a result, mutations can have very severe clinical
consequences.
α-Thalassemia carrier occurs when one α-globin gene is mutated. There are 3 other normal-
functioning α-globin genes. Carriers have no clinical manifestations. Mutations of 2 α-globin genes
lead to α-thalassemia trait. Individuals with alpha Thalassemia trait have low mean corpuscular
volume, low mean corpuscular hemoglobin, and normal or a very mild anemia. They are otherwise
well and have normal growth and development. Mutations in 3 α-globin genes cause hemoglobin H
disease. The most severe form of α-thalassemia occurs when all 4 α-globin genes are mutated and no
α-globin chains are produced. Most affected individuals develop hemoglobin Bart hydrops fetalis and
die in utero. α-Thalassemias occur with greater frequency in Asia, the Mediterranean, and Africa.
Reference:
Nguyen T. Hemoglobinopathies in the neonate. NeoReviews. 2015;16:e278-286
Hematology & Bilirubin Answer 53
C. Increased Transferrin Receptor, Low MCV, Low Ferritin, Increased TIBC
Iron is essential for growth and development and as a result, a deficiency in iron can have several
clinical effects. Iron is necessary for oxygen transport, cellular functioning, and cell proliferation.
Iron status of the neonate is a balance between iron accretion during gestation, iron utilization and
loss, and iron acquired postnatally, either through enteral or parenteral routes. The uptake of iron by
the enterocyte is an important regulatory step in body iron content. Iron is initially taken up by the
enterocyte. It is then released into the intracellular iron pool and used for cellular metabolism, stored
as ferritin, or transferred out of the enterocyte. Iron is transported through the bloodstream bound
primarily to transferrin, a protein that has two iron-binding sites.
Potential tests to evaluate an infant’s iron status include hematocrit, hemoglobin, red cell indices,
serum ferritin, serum iron, and total iron binding capacity (TIBC). Each test identifies iron
availability at a different point in iron metabolism. Hemoglobin and hematocrit are the least sensitive
measures of iron deficiency. Iron deficiency anemia is microcytic and hypochromic. Low mean cell
volume (MCV) is consistent with iron deficiency. Serum ferritin reflects iron stores. Low serum
ferritin is specific for iron deficiency. However, ferritin is an acute-phase protein and may increase
during infection, masking low stores. Serum iron concentration identifies advanced iron deficiency
but has low sensitivity. The TIBC primarily reflects the amount of available unbound transferrin and
is elevated in iron deficiency. Synthesis of the soluble transferrin receptor is increased when
intracellular iron is insufficient.
Reference:
Cheng C, Juul S. Iron balance in the neonate. NeoReviews. 2011;12:e148-158
Hematology & Bilirubin Answer 54
C. Direct Coombs test
The infant in this vignette has indirect hyperbilirubinemia. The history is notable for different
maternal and infant blood types and a family history of hereditary spherocytosis placing the infant at
risk for ABO incompatibility or hereditary spherocytosis.
Of the many red blood cell membrane defects that lead to hemolysis, the only diagnoses that
manifest themselves in the newborn period include hereditary spherocytosis, elliptocytosis,
stomatocytosis, and infantile pyknocytosis. It is difficult to correctly establish a diagnosis in the
neonatal period, as neonates typically exhibit marked variation in red cell membrane size and shape.
However, the peripheral smears of hematologically normal newborns lack spherocytes. Therefore,
when this morphologic abnormality is apparent, a diagnosis of hereditary spherocytosis is often
considered. This diagnosis can be confirmed with the incubated osmotic fragility test after the first
weeks of life, coupled with fetal red cell controls.
The most appropriate next test in the evaluation of the infant in this vignette is the Direct Coombs
test, as ABO hemolytic disease must be investigated. Infants affected by ABO hemolytic disease may
also manifest prominent microspherocytosis. In addition, hereditary spherocytosis and ABO
hemolytic disease can occur simultaneously, and lead to severe anemia and indirect
hyperbilirubinemia.
Reference:
Gleason CA, Devaskar SU. Avery’s Diseases of the Newborn. 9th Ed. Philadelphia: Elsevier; 2012
Hematology & Bilirubin Answer 55
E. Lower uridine diphosphate glucuronosyltransferase 1A1 enzyme activity
Full-term and late preterm infants become jaundiced by similar mechanisms: increased hepatic
bilirubin load and decreased hepatic bilirubin clearance.
The increased hepatic bilirubin load seen in neonates is a result of decreased erythrocyte survival
of neonatal red cells (70 to 90 days, compared to 120 days in adults). Neonates also have increased
red blood cell mass compared to adult values. The average hemoglobin values at birth are 17 mg/dL
at term (range 14 to 20 mg/dL), 16.4 mg/dL in preterm infant with BW 1.2 to 2.5 kg (range 13.5 to 19
mg/dL) and 16 mg/dL in preterm infants with BW <1.2 kg (range 13 to 18 mg/dL). Late preterm
infants have a similar degree of red blood cell turnover and heme degradation as term infants.
Decreased hepatic bilirubin clearance is related to impaired hepatic bilirubin uptake, disorders of
bilirubin conjugation, and enhanced enterohepatic circulation. Impaired hepatic uptake of bilirubin
can be seen with a patent, or partially patent, ductus venosus, which allows blood to bypass the
liver. The bilirubin conjugating capacity of neonates is dependent on the activity of hepatic uridine
diphosphate glucuronosyltransferase 1A1 (UGT1A1). The enzyme expression is modulated in a
developmental manner, with 0.1% of adult levels at 17 to 30 weeks’ gestation, 1% adult values at 30
to 40 weeks’ gestation, and reaching adult levels by 14 weeks postnatal age. Although there is a
marked increase in enzyme activity following birth, this maturation appears to be slower in late
preterm infants during the first week of life, causing an exaggerated hepatic immaturity. Late preterm
infants are also at risk for increased enterohepatic circulation. Inadequate enteral intake, in addition
to dehydration, can contribute to indirect hyperbilirubinemia by increasing the hepatic bilirubin load.
The U.S. Pilot Kernicterus Registry, a database of voluntarily reported cases of kernicterus, is
over-represented by late preterm infant cases. This registry has demonstrated that late preterm infants
show signs of bilirubin neurotoxicity at an earlier postmenstrual age than term newborns. Of note,
this indirectly suggests a greater vulnerability to bilirubin-induced brain injury in late preterm
infants.
References:
Gleason CA, Devaskar SU. Avery’s Diseases of the Newborn. 9th Ed. Philadelphia: Elsevier; 2012
Maisels MJ, Watchko JF, Bhutani VK, Stevenson DK. An approach to the management of
hyperbilirubinemia in the preterm infant less than 35 weeks of gestation. J Perinatol. 2012;32:660-
664
Hematology & Bilirubin Answer 56
E. Seek care for any jaundice noticed in the first 24 hours of age
Physiologic jaundice typically applies to jaundice in newborns as a result of the normal processes
of increased breakdown of red blood cells in the setting of reduced capacity for uptake, conjugation
and excretion of bilirubin in the liver. The distinction between physiologic and nonphysiologic
jaundice, at times, can be difficult to make clinically. Thus, nonphysiologic jaundice typically refers
to jaundice attributed to exaggerated hepatic bilirubin load or decreased hepatic bilirubin clearance
beyond that expected in the newborn period. Nonphysiologic jaundice may result from a pathologic
process.
Cephalohematomas, internal hemorrhages, ecchymoses, and other extravascular blood collections
will increase the bilirubin load on the liver. Extravascular red cells have a markedly shortened life
span, and their heme fraction is quickly catabolized to bilirubin by tissue macrophages that contain
heme oxygenase and biliverdin reductase. Thus, these extravascular blood collections can be
associated with increased serum bilirubin levels, with typical manifestations 48 to 72 hours after the
extravasation of blood.
Jaundice appreciated within the first 24-hours of birth is heralded as a sign of nonphysiologic, or
pathologic, jaundice. It is important for these infants to seek care. Based on historical evidence,
these infants are more likely to receive phototherapy, and to develop a serum bilirubin ≥ 25 mg/dl.
Any infant exhibiting clinical jaundice in the first 24-hours of age warrants an evaluation for
pathologic causes, including hemolytic processes.
There is recent evidence that the pattern and intensity of clinically apparent jaundice on physical
exam may not be as reliable an indicator of indirect hyperbilirubinemia as previously thought.
However, the absence of jaundice has excellent negative predictive value for developing a serum
bilirubin level requiring phototherapy. Current recommendations include a transcutaneous or total
serum bilirubin measurement to complement the clinical assessment for jaundice on every neonate,
prior to discharge. For births occurring outside the hospital, this should be completed at the initial
pediatric evaluation between 24 and 48 hours of age.
References:
AAP Policy Statement: Planned home birth. Pediatrics. 2013;131:1016-1020
Gleason CA, Devaskar SU. Avery’s Diseases of the Newborn. 9th Ed. Philadelphia: Elsevier; 2012
Hansen TWR. Bilirubin metabolism. NeoReviews. 2011;11:e316
Hematology & Bilirubin Answer 57
C. A B/A ratio is a surrogate for unbound bilirubin.
Chronic bilirubin encephalopathy, including kernicterus, is currently a rare event in the United
States. However, it is believed that preterm infants are at greater risk for the development of
bilirubin-associated brain damage than term infants. In addition, there is a paucity of data to quantify
this risk, and limited diagnostic techniques to accurately predict the infants at highest risk.
Unbound, or free, bilirubin is more likely to cross the blood-brain barrier and cause neurologic
injury. However, to-date, there is no commercially available method to test and quantify unbound
bilirubin. Most bilirubin is normally bound to albumin, resulting in low concentrations of unbound
bilirubin. For patients who have high bilirubin concentrations, the capacity of albumin to bind
bilirubin is exceeded, leading to higher concentrations of unbound bilirubin. The ratio of bilirubin to
albumin (B/A) can be used as a surrogate for unbound bilirubin, in conjunction with measurement of
bilirubin concentration, birth weight (or gestational age), and clinical status.
In 1994, Ahlfors published criteria for exchange transfusion in jaundiced low-birthweight (BW)
infants utilizing the B/A ratio in conjunction with total bilirubin, categorizing the infants as standard
or high risk. The recommended threshold to initiate therapy ranged from 4 mg/g for high risk infants
with BW < 1250 g, and increased up to 7.2 mg/g for standard risk infants with BW 2000-2499 g. Of
note, this is one expert’s recommendations, and not evidence-based.
The limitations of using the B/A ratio relate to the necessity of using this tool as a complement to
the multifactorial assessment of the infant’s risk of pathologic jaundice. It is known that premature
and sick infants often have a decreased serum albumin concentration. Albumin ≤ 2.5 g/dL is cited as
a risk factor. The albumin binding affinity for bilirubin may also be decreased in the presence of
sepsis, acidosis, hypoxia, free fatty acids and various albumin-binding drugs. As a result, these
infants are likely to have a higher proportion of unbound bilirubin for a given total serum bilirubin
value compared to healthy term infants. Thus, a lower B/A ratio or bilirubin threshold is often used
to initiate therapy. A single threshold for treatment, taken out of context, is an inaccurate tool in the
prevention of bilirubin-associated brain damage.
References:
Ahlfors CE. Criteria for exchange transfusion in jaundiced newborns. Pediatrics. 1994;93:488-494
Gleason CA, Devaskar SU. Avery’s Diseases of the Newborn. 9th Ed. Philadelphia: Elsevier; 2012
Maisels MJ, Watchko JF, Bhutani VK, Stevenson DK. An approach to the management of
hyperbilirubinemia in the preterm infant less than 35 weeks of gestation. J Perinatol. 2012;32:660-
664
Wong, RJ, Stevenson DK, Ahlfors CE, Vreman HJ. Neonatal jaundice: bilirubin physiology and
clinical chemistry. NeoReviews. 2007;8:e58
Hematology & Bilirubin Answer 58
A. Acidosis
Unbound, or free, bilirubin is more likely to cross the blood-brain barrier, potentially leading to
bilirubin-associated encephalopathy and neurologic injury. Most bilirubin is normally bound to
albumin, resulting in low concentrations of unbound bilirubin. At high total serum bilirubin
concentrations, the capacity of albumin to bind bilirubin is exceeded, leading to higher concentrations
of unbound bilirubin. The ratio of bilirubin to albumin (B/A) can be used as a surrogate for unbound
bilirubin, in conjunction with measurement of bilirubin level, birth weight (or gestational age), and
clinical status.
Sick infants often have a decreased serum albumin concentration. Albumin ≤ 2.5 g/dL is cited as a
risk factor. The albumin binding affinity for bilirubin may also be decreased in the presence of
sepsis, acidosis, hypoxia, free fatty acids and various albumin-binding drugs. As a result, these
infants are likely to have a higher proportion of unbound bilirubin for a given total serum bilirubin
value compared to healthy term infants. Therefore, a lower B/A ratio or bilirubin threshold is often
used to initiate therapy.
Ceftriaxone, a third-generation cephalosporin, displaces bilirubin bound to serum albumin. It
simultaneously was shown to decrease the unconjugated bilirubin and increase the erythrocyte-bound
bilirubin. Ampicillin, acyclovir and cefotaxime do not have this property.
References:
Gleason CA, Devaskar SU. Avery’s Diseases of the Newborn. 9th Ed. Philadelphia: Elsevier; 2012
Gulian JM, Dalmasso C, Pontier F, Gonard V. Displacement effect of ceftriaxone on bilirubin bound
to human serum albumin. Chemotherapy. 1986;32:399-403
Wong, RJ, Stevenson DK, Ahlfors CE, Vreman HJ. Neonatal jaundice: bilirubin physiology and
clinical chemistry. NeoReviews. 2007;8:e58
Hematology & Bilirubin Answer 59
C. Gestational age
It is generally believed that infants < 35 weeks’ gestation are at greater risk for the development of
bilirubin-associated brain damage than term infants, although data is lacking to truly quantify the
magnitude of this risk. In 2012, the Section on Perinatal Pediatrics of the American Academy of
Pediatrics published consensus-based (rather than evidence-based) recommendations. They
recommended treatment levels for phototherapy and exchange transfusion, assuming that treatment at
these levels would do more good than harm. Based on available evidence, and expert consensus, the
levels recommended are based on gestational age, and are lower than treatment thresholds for term
infants.
The U.S. Pilot Kernicterus registry is over-represented by preterm and late-preterm infants. The
registry demonstrates that these infants show signs of bilirubin neurotoxicity at earlier postnatal ages
than term newborns, indirectly suggesting a greater vulnerability to kernicterus.
When evaluating an infant’s risk for kernicterus, it is important to note their gestational age, risk
factors for increasing hepatic bilirubin load, including hemolysis, risk factors for decreased hepatic
bilirubin clearance, risk factors for increasing unbound bilirubin, in addition to noting their total
serum bilirubin level.
Blood group incompatibility with positive direct antiglobulin testing (DAT, i.e., Coombs test) is a
major risk factor of severe indirect hyperbilirubinemia. The mother-infant dyad in this vignette does
not have a blood group set-up, and DAT is negative. The infant’s serum albumin level of 3 g/dL and
bilirubin/albumin (B/A) ratio of 1.3 mg/g are reassuring. Serum albumin < 2.5 g/dL is a risk factor.
Depending on gestational age and clinical status, a B/A ratio > 4 mg/g may be considered a risk
factor. Racial risk factors to note are East Asian ancestry, listed as a major risk factor for severe
hyperbilirubinemia in the 2004 AAP clinical practice guideline. The capillary blood gas of this
infant does not confer an increased risk based on pH. Importantly, acidosis can decrease the albumin
binding affinity for bilirubin, contributing to an increased unbound bilirubin.
References:
AAP Clinical Practice Guideline: Management of hyperbilirubinemia in the newborn infant 35 or
more weeks of gestation. Pediatrics. 2004;114:297-316
Gleason CA, Devaskar SU. Avery’s Diseases of the Newborn. 9th Ed. Philadelphia: Elsevier; 2012
Maisels MJ, Watchko JF, Bhutani VK, Stevenson DK. An approach to the management of
 hyperbilirubinemia in the preterm infant less than 35 weeks of gestation. J Perinatol. 2012;32:660-
664
Hematology & Bilirubin Answer 60
A. Backward arching of the trunk
Acute bilirubin encephalopathy typically progresses through three stages. Stage 1 is characterized
by an infant with decreased activity, poor suck, hypotonia, and a slightly high-pitched cry. If the total
serum bilirubin level is rapidly decreased, as with an exchange transfusion, these nonspecific
abnormalities can be reversed. Stage 2 is characterized by the findings of stage 1, with the addition
of rigid extension of all four extremities, tight-fisted posturing of the arms, crossed extension of the
legs, and a high-pitched irritable cry. These changes may be accompanied by seizure activity,
retrocollis (backward arching of the neck), opisthotonos (backward arching of the trunk) and fever.
Stage 3 is characterized by hypertonia with marked retrocollis and opisthotonos, stupor, coma and a
shrill cry. Available evidence and the medical literature suggest that once an infant demonstrates
signs of opisthotonos, some damage to the central nervous system has occurred.
Reference:
Gleason CA, Devaskar SU. Avery’s Diseases of the Newborn. 9th Ed. Philadelphia: Elsevier; 2012
Hematology & Bilirubin Questions 61-64
Hematology & Bilirubin Question 61
A 3-day old infant born at 35 weeks’ gestation is admitted to the Special Care Nursery because of
indirect hyperbilirubinemia. The infant is exclusively breastfeeding and has had two wet diapers in
the past 24 hours. The infant’s weight is down 8% from birth weight. A serum glucose on admission
is 74 mg/dL. There is no evidence of hemolysis, and the infant is well-appearing. A peripheral IV is
placed, intravenous fluids are started, and the infant is placed under phototherapy.
What is the clinical reason to administer intravenous fluids to this infant?
A.Account for an increase in oxygen consumption
B.Account for the infant’s increased insensible water loss through the respiratory tract
C.Account for the infant’s increased insensible water loss through the skin
D.Ensure adequate urine output
E.Ensure normothermia is maintained
Hematology & Bilirubin Question 62
A 1000 g male infant was born at 27 weeks’ gestation via emergent Cesarean section for the
indication of cord prolapse following artificial rupture of membranes. He was born to a 24-year old
G1P0 woman with pre-eclampsia and evolving HELLP syndrome. His admission physical exam was
notable for significant bruising over his entire body, and prophylactic phototherapy was initiated. He
is receiving breastmilk and intravenous total parenteral nutrition. His serum bilirubin level rose from
5.2 mg/dL at 24 hours of age to 9.3 mg/dL at 48 hours of age.
What is the most appropriate NEXT step in the management of the infant in this vignette?
A.Administer intravenous immunoglobulin
B.Bring the halogen phototherapy lamp closer to the infant
C.Perform an exchange transfusion
D.Place a light source beneath the infant
E.Stop oral feedings
Hematology & Bilirubin Question 63
A 4-day large-for-gestational age female infant, born at 41 weeks’ gestation via Cesarean section
for the indication of failure to progress following induction, is being evaluated for discharge
readiness in the Newborn Nursery.
This pregnancy was notable for class A1 gestational diabetes, with a normal fetal
echocardiogram. The infant is exclusively formula feeding and has maintained euglycemia. She has
evidence of adequate stool and urine output. Her transcutaneous (TcB) bilirubin is assessed in the
low-intermediate risk zone. Family history is notable for a previous sibling born at 37 weeks’
gestation, who required admission to the NICU for transient tachypnea of the newborn treated with
CPAP, hypoglycemia treated with dextrose-containing IV fluid, and indirect hyperbilirubinemia
treated with phototherapy.
In the clinical vignette above, which of the following is a major risk factor for the development of
severe indirect hyperbilirubinemia?
A.Discharge from the hospital after 72 hours
B.Gestational age ≥ 41 weeks’ gestation
C.Exclusive bottle feeding
D.Macrosomic infant of a diabetic mother
E.Previous sibling received phototherapy
Hematology & Bilirubin Question 64
 You are medical control for a transport coming from a rural birthing center in which there is
concern for significant fetal blood loss. The pediatrician had contacted the city hospital from the
delivery room of a term infant. The pediatrician had placed a low-lying umbilical venous catheter,
and had given the infant two 10 mL/kg normal saline bolus with minimal response. O-negative blood
is not currently available. The infant is pale with poor perfusion, weak peripheral pulses, and
tachycardic.
Of the following, what would be appropriate advice for the resuscitation team while they await the
arrival of the transport team?
A.Administer intramuscular Vitamin K
B.Await complete blood cell count results prior to transfusing
C.Transfuse blood collected from the father
D.Transfuse blood collected from the placenta
Hematology & Bilirubin Answers 61-64
Hematology & Bilirubin Answer 61
D. Ensure adequate urine output
Previously some studies suggested that phototherapy increased insensible water loss, particularly
in preterm infants. More recently, it has been shown that as long as normothermia is maintained
(through servo-control) and infants are not subjected to heat stress, phototherapy does not lead to an
increase in oxygen consumption or insensible water loss through the skin or the respiratory tract.
However, adequate hydration is important, and an essential element in the bilirubin-lowering function
of phototherapy. The bilirubin isomer, lumirubin, is excreted in the bile and urine, and is therefore
dependent on adequate urine output.
Reference:
Gleason CA, Devaskar SU. Avery’s Diseases of the Newborn. 9th Ed. Philadelphia: Elsevier; 2012
Hematology & Bilirubin Answer 62
D. Place a light source beneath the infant
Extravascular blood collections, seen with severely bruised or ecchymotic infants, enhance the
hepatic bilirubin load. Clinically, this typically manifests with elevated total serum bilirubin levels
48 to 72 hours after extravasation of blood. This can also lead to a prolonged indirect
hyperbilirubinemia.
For indirect hyperbilirubinemia that continues to rise in spite of phototherapy, management options
include ensuring phototherapy is optimized by increasing the irradiance of the phototherapy or
increasing the body surface area of the infant exposed to phototherapy. Caution must be used when
attempting to increase the irradiance of phototherapy units. If halogen lights are used, they must not
be positioned closer to the infant than recommended by the manufacturer due to the risk of burn. In
addition, if two halogen lamps are used, they must always focus on different surfaces of the infant to
reduce the risk of burn. Irradiance increases dramatically as the distance between the light source
and the infant decreases. This is an important point when the special blue tube phototherapy units are
used. A bank of these blue tubes may be placed about 10 cm above the infant safely.
Safe options to increase the surface area of the infant exposed to phototherapy include minimizing
the skin covered by clothing and diapers, placing a light source beneath the infant, and using reflecting
material around the isolette or radiant warmer bed.
Although an evidence-based exchange-transfusion level for preterm infants is lacking, the 2012
consensus-based recommendation from the AAP Section on Perinatal Pediatrics includes a threshold
of 11 to 14 mg/dl for exchange transfusion for infants < 28 weeks’ gestation.
There are theories, but lacking evidence for an unidentified factor in human milk that increases
enterohepatic circulation in the delayed “breast milk jaundice”. In “breast milk jaundice”, the infant is
receiving an adequate amount of enteral nutrition from breast milk. This typically becomes apparent
after the first postnatal week, and can persist for weeks. During the first few days of age, exclusively
breastfeeding infants can develop fasting indirect hyperbilirubinemia (also known as “breast
nonfeeding jaundice”). In fasting hyperbilirubinemia, there is increased enterohepatic circulation
resulting from enhanced intestinal reabsorption of unconjugated bilirubin during times of inadequate
enteral nutritional intake.
Intravenous immunoglobulin (IVIG), which may be considered in cases of immune-mediated
hemolysis, will not confer a benefit to this infant with extravascular blood collection as the source of
his indirect hyperbilirubinemia.
References:
de Almeida MF, Draque CM. Neonatal jaundice and breastfeeding. NeoReviews. 2007;8(7):e282
Gleason CA, Devaskar SU. Avery’s Diseases of the Newborn. 9th Ed. Philadelphia: Elsevier; 2012
Maisels MJ, Watchko JF, Bhutani VK, Stevenson DK. An approach to the management of
hyperbilirubinemia in the preterm infant less than 35 weeks of gestation. J Perinatol. 2012;32:660-
664
Hematology & Bilirubin Answer 63
E. Previous sibling received phototherapy
As recommended in the 2004 American Academy of Pediatrics (AAP) clinical practice guideline
for the management of indirect hyperbilirubinemia, every newborn should be assessed for the risk of
developing severe indirect hyperbilirubinemia prior to discharge from the hospital. The AAP
recommends a systematic assessment of risk, utilizing a predischarge measurement of bilirubin level,
assessment of clinical factors, and arranging appropriate follow-up care.
The important risk factors most frequently associated with severe indirect hyperbilirubinemia are
exclusive breastfeeding, preterm or late-preterm gestation (<38 weeks’ gestation), previous sibling
received phototherapy, and jaundice noted before hospital discharge. The complete list of risk
factors, in order of importance are as follows (adapted from AAP 2004):
Major Risk Factors Minor Risk Factors Decreased Risk
(associated with
decreased risk of
significant jaundice)
Predischarge bilirubin (TSB or TcB) Predischarge bilirubin (TSB or Bilirubin (TSB or
level in the high-risk zone TcB) level in the high TcB) level in the
Jaundice observed in the first 24 hours intermediate-risk zone low-risk zone
after birth Gestational age 37 – 38 weeks Gestational age ≥ 41
Blood group incompatibility with Jaundice observed before weeks
positive direct antiglobulin test (or discharge Exclusive bottle
other hemolytic disease) Previous sibling with jaundice feeding
Gestational age 35 to 36 weeks Macrosomic infant of a diabetic Black race
Previous sibling received phototherapy mother Discharge from
Cephalohematoma or significant Maternal age ≥ 25 years hospital after 72
bruising Male gender hours
Exclusive breastfeeding (particularly if
nursing is not going well and weight
loss is excessive)
References:
AAP Clinical Practice Guideline: Management of hyperbilirubinemia in the newborn infant 35 or
more weeks of gestation. Pediatrics. 2004;114:297-316
Gleason CA, Devaskar SU. Avery’s Diseases of the Newborn. 9th Ed. Philadelphia: Elsevier; 2012
Hematology & Bilirubin Answer 64
D. Transfuse blood collected from the placenta
An infant who has signs of hypovolemia, and has not responded quickly to initial resuscitative
efforts should have IV access established. A UVC should be placed in the low-lying position for
resuscitative volume replacement therapy. Currently recommended fluid is isotonic saline for initial
efforts, at a trial volume of 10 mL/kg. This may be repeated if necessary. If significant blood loss has
occurred, the infant may require infusion of RBCs to improve the circulating O2-carrying capacity.
Often, this is accomplished with transfusion of emergent non-crossmatched O-negative blood. If this
is unavailable, blood collected from the placenta may be utilized. Sterile removal of blood drawn
from the placenta is shown on this video: https://www.youtube.com/watch?
v=5niR8Y9XB_M&noredirect=1. The mother will have a compatible antibody profile with her infant
at the time of birth and thus, maternal blood can be used as well. The father of the infant may not be a
suitable donor.
In a hypovolemic infant requiring resuscitation, the priority is establishing hemodynamic stability.
Anemia does not need to be confirmed with laboratory results prior to treatment. Vitamin K and
Lactated Ringer’s Solution will not increase the O2-carrying capacity, and are unlikely to provide
acute clinical improvement.
Reference:
Gleason CA, Devaskar SU. Avery’s Diseases of the Newborn. 9th Edition. Philadelphia:
Elsevier;2012
X. ENDOCRINOLOGY
Endocrinology Questions 1-10
Endocrinology Question 1
Which of the following does NOT cross the placenta?
A.Iodide
B.Thyroid-releasing hormone
C.Thyroid-stimulating hormone
D.Thyroxine
E.Triiodothyronine
Endocrinology Question 2
A full-term infant born to parents from Saudi Arabia is noted to have ambiguous genitalia and
elevated blood pressures. The rest of the physical examination is unremarkable. Laboratory
evaluation reveals normal serum electrolytes with elevated serum androgens and
deoxycorticosterone.
Of the following, which enzymatic defect is responsible for this infant’s congenital adrenal
hyperplasia?
A.Aromatase
B.5 alpha-reductase
C.11 beta-hydroxylase
D.17 alpha-hydroxylase
E.21-hydroxylase
Endocrinology Question 3
Of the following, the most likely congenital cardiac defect in an infant of a diabetic mother is:
A.Ebstein’s anomaly
B.Tetrology of Fallot
C.Transposition of the great vessels
D.Tricuspid atresia
E.Truncus arteriosus
Endocrinology Question 4
How does gestational diabetes impact a woman’s health?
A.Increases the likelihood of developing metabolic syndrome
B.Increases the risk of pregnancy-related hypertension
C.Significantly increases the lifetime risk of developing diabetes mellitus
D.All of the above
E.None of the above; gestational diabetes is a benign, self-limited condition
Endocrinology Question 5
A full-term male infant has prolonged indirect hyperbilirubinemia, a large posterior fontanel,
hypotonia, and feeding difficulties.
The neonatology fellow suspects that the infant has congenital hypothyroidism. Laboratory
evaluation reveals a low thyroxine concentration and elevated thyroid-stimulating hormone.
The most likely cause for this infant’s hypothyroidism is:
A.Deiodase deficiency
B.Organification defect
C. Panhypopituitarism
D. Thyroid dysgenesis
E.Thyroid-stimulating hormone resistance
Endocrinology Question 6
A 1-week old full-term infant has an intraparenchymal cerebral hemorrhage. His urine output is
10 mL/kg/hour. Laboratory evaluation reveals Na+=158 mEq/L, K+=4.1 mEq/L, Cl-=118 mEq/L,
HCO3-=30 mEq/L, and serum and urine osmolality of 310 mOsm and 125 mOsm, respectively.
Upon administration of exogenous vasopressin (anti-diuretic hormone), the MOST likely impact
on this infant’s osmolality is:
A.Decrease in serum and urine osmolality
B.Decrease in serum osmolality and increase in urine osmolality
C.Increase in serum and urine osmolality
D.Increase in serum osmolality and decrease in urine osmolality
E.No change in serum or urine osmolality
Endocrinology Question 7
A female infant born at 26 weeks’ gestation is now 10 weeks of age. Her course was complicated
by severe respiratory distress syndrome requiring exogenous surfactant administration and high
frequency mechanical ventilation. She also developed necrotizing enterocolitis requiring an
exploratory laparotomy and several weeks of bowel rest. A chest radiograph to evaluate the
percutaneous central line placement reveals bilateral humeral fractures. The cardiothymic silhouette
is noted to be normal.
The most likely etiology to explain the fractures of the infant in this vignette is:
A.Hypoparathyroidism
B.Non-accidental trauma
C.Osteopenia of prematurity
D.Pseudohypoparathyroidism
E.Vitamin D-dependent rickets
Endocrinology Question 8
Which of the following statements is TRUE about the physiologic effects of parathyroid hormone?
A.Decreases renal calcium reabsorption
B.Increases hydroxylation of vitamin D in the kidney, indirectly increasing intestinal absorption of
calcium and phosphorus
C.Increases renal phosphorus reabsorption
D.Inhibits renal calcitriol production
E.Inhibits the release of calcium and phosphorus from bone
Endocrinology Question 9
A female infant of a diabetic mother is admitted to the Neonatal Intensive Care Unit with
irritability, tremulousness, and concern for seizure activity. Physical examination reveals a jittery
full-term infant with laryngospasm and episodes of rhythmic left lower extremity jerking. Her chest
radiograph reveals a normal cardiothymic silhouette. Her electrocardiogram reveals a prolonged QT
interval. Her blood glucose is 80 mg/dL.
Serum electrolyte evaluation of this infant would most likely reveal:
A.Hypercalcemia
B.Hyperkalemia
C.Hypermagnesemia
D.Hypocalcemia
E.Hypomagnesemia
Endocrinology Question 10
All of the following hormones are produced by the anterior pituitary, EXCEPT:
A.Adrenocorticotropic hormone
B.Growth hormone
C.Oxytocin
D.Prolactin
E.Thyroid-stimulating hormone
Endocrinology Answers 1-10
Endocrinology Answer 1
C. Thyroid-stimulating hormone
The placenta is a hormonally active organ, producing estrogens and human chorionic gonadotropin
that stimulates triidodothyronine (T3) and thyroxine (T4). Both maternal T3 and T4 are partially
permeable across the placenta. Although the amount of hormones transferred is low, this transfer is
critical for the fetus because the fetal hypothalamic-pituitary axis is not well-developed in the first
trimester and the fetus is not able to produce thyroid hormone until 18 to 20 weeks’ gestation.
Thyroid-releasing hormone, thyroid-stimulating hormone receptor antibodies, and iodide all freely
cross the placenta. In contrast, thyroid-stimulating hormone does not cross the placenta.
Reference:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Belfort MB, Brown RS. Hypothyroidism in the preterm infants. In: Primary Care of the Premature
Infant. Brodsky D, Ouellette MA (eds). Philadelphia: WB Saunders, 2008
Endocrinology Answer 2
C. 11 beta-hydroxylase
11 beta-hydroxylase deficiency is the second most common cause of congenital adrenal
hyperplasia, occurring particularly in individuals of Middle Eastern descent. It results from an
inability to convert deoxycorticosterone to aldosterone and 11-deoxycortisol to cortisol. There is a
resulting excess of 17 hydroxy-progesterone, which leads to increased serum androgen production.
There is no salt-wasting because deoxycorticosterone acts as a mineralocorticoid. Male infants have
normal external genitalia at birth while females may have ambiguous genitalia of variable severity
because of increased androgen exposure. Diagnosis is confirmed with increased deoxycorticosterone
and deoxycortisol concentrations. Therapy includes glucocorticoid replacement and genital
reconstruction.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Kliegman RM, Behrman RE, Jenson HB, Stanton B (eds). Nelson Textbook of Pediatrics. 18th
edition. Philadelphia: Saunders, 2007
Endocrinology Answer 3
C. Transposition of the great vessels
Effects of maternal diabetes on the fetus are well-known and include congenital heart disease
(hypertrophic cardiomyopathy, ventricular septal defect, transposition of the great vessels), renal
anomalies, caudal regression, neural tube defects, central nervous system anomalies, and small left
colon. The risk of congenital malformations correlates with the degree of uncontrolled maternal
diabetes. If a woman with diabetes achieves glycemic control after conception, the risk of fetal
anomalies is 7.8%; however, if glycemic control is attained prior to pregnancy, the risk of fetal
anomalies decreases to 2.5%.
Reference:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Endocrinology Answer 4
D. All of the above
Gestational diabetes affects ~2% of pregnant women. It may be controlled by manipulations to the
maternal diet or may require insulin therapy. Effects of maternal diabetes on the fetus are well-
known and include congenital heart disease (hypertrophic cardiomyopathy, ventricular septal defect,
transposition of the great vessels), renal anomalies, caudal regression neural tube defects, central
nervous system anomalies, and small left colon. Recent evidence has demonstrated long-term effects
of gestational diabetes on the mother, notably a significant increase in the risk of diabetes, with some
estimates as high as 50% of those affected developing diabetes within 20 years of pregnancy.
Women with a history of gestational diabetes are also at risk of cardiovascular disease, obesity, and
metabolic syndrome. In addition, these women are at increased risk of pregnancy-induced
hypertension, although this relationship is not clearly understood.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Kliegman RM, Behrman RE, Jenson HB, Stanton B (eds). Nelson Textbook of Pediatrics. 18th
edition. Philadelphia: Saunders, 2007
Metzger BE. Long-term outcomes in mothers diagnosed with gestational diabetes mellitus and their
offspring. Clin Obstet Gynecol. 2007;50:972-979
Endocrinology Answer 5
D. Thyroid dysgenesis
Congenital hypothyroidism can present with prolonged jaundice, a large posterior fontanel,
umbilical hernia, macroglossia, hoarse cry, abdominal distention, hypotonia, feeding difficulties,
lethargy, mottled skin, hypothermia, and goiter. Long-term consequences include delayed growth,
cognitive deficits, and delayed puberty. The most common etiology of congenital hypothyroidism is
thyroid dysgenesis (occurring in ~75% of cases), which results from partial or complete absence of
the thyroid gland.
Thyroid dyshormonogenesis occurs in ~10% of infants with congenital hypothyroidism and leads
to inadequate thyroid hormone production. It can be caused by thyroid-stimulating hormone
resistance, defects in iodide transport, thyroglobulin abnormality, deiodase deficiency, or an
organification defect.
Defects in the hypothalamic-pituitary axis, such as panhypopituitarism, are much less common,
occurring in ~5% of individuals affected by congenital hypothyroidism. It is associated with other
hormone deficiencies.
Neonatal hypothyroidism can also be caused by transient hypothyroidism (~10%), which is
attributable to maternal medications, maternal antibodies, or neonatal iodine exposure. Preterm
infants commonly have transient hypothyroxinemia of prematurity of unknown etiology but may be
related to an immature hypothalamic-pituitary axis. Sick euthyroid presents as temporarily low
thyroid hormone levels with normal thyroid-stimulating hormone in the setting of an acute or chronic
illness.
References:
Belfort MB, Brown RS. Hypothyroidism in the preterm infants. In: Primary Care of the Premature
Infant. Brodsky D, Ouellette MA (eds). Philadelphia: WB Saunders, 2008
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Grasberger H, Refetoff S. Genetic causes of congenital hypothyroidism due to dyshormonogenesis.
Curr Opin Pediatr. 2011;23:421-428
Endocrinology Answer 6
B. Decrease in serum osmolality and increase in urine osmolality
The infant in this vignette likely has neurogenic or central diabetes insipidus (DI) caused by a
decrease in anti-diuretic hormone (ADH) production as a result of his intracerebral hemorrhage.
Other intracranial lesions, such as tumors and arterio-venous malformations, can also lead to central
DI. About 10% of cases are idiopathic. The inadequate ADH production causes free water loss from
the kidney resulting in hypernatremia, an increase in serum osmolality, and inappropriately dilute
urine. Treatment with exogenous ADH will lead to a decrease in serum osmolality and an increase in
urine osmolality.
In contrast to central DI, individuals affected by nephrogenic DI have an inadequate renal response
to ADH. Similar to central DI, the disease is associated with increased serum osmolality and
decreased urine osmolality. However, serum ADH levels are normal or elevated. After
administration of exogenous ADH, serum and urine osmolalities are not altered.
References:
Kliegman RM, Behrman RE, Jenson HB, Stanton B (eds). Nelson Textbook of Pediatrics. 18th
edition. Philadelphia: Saunders, 2007
Knoers N. Nephrogenic diabetes insipidus. In: GeneReviews. Pagon RA, Bird TD, Dolan CR,
Stephens K (eds). Seattle (WA): University of Washington, Seattle, 2010
Porterfield SP. Endocrine Physiology. 2nd edition. St Louis: Mosby; 2001
Endocrinology Answer 7
C. Osteopenia of prematurity
The infant in the vignette is at high risk for developing osteopenia of prematurity. She was born
very prematurely, preventing the placental transfer of calcium and phosphorus during the third
trimester. She is also severely ill, requiring immobility, and has not been receiving maximal enteral
nutrition. These factors led to osteopenia, with demineralized bones susceptible to fracture.
Osteopenia of prematurity is best prevented by early establishment of enteral feedings with
appropriate calcium and phosphorus supplementation for age, physical therapy, and supplementation
with Vitamin D.
Hypoparathyroidism manifests as hypocalcemia with low serum parathyroid hormone (PTH)
levels. Hypoparathyroidism can be attributable to glandular hypoplasia, neonatal glandular
suppression as a result of maternal hyperparathyroidism, autoimmune parathyroiditis, and mutations
in the calcium receptor. Vitamin D-dependent rickets causes pathologic fractures, rachitic rosary, and
moth-eaten metaphases on radiograph. It is caused by decreased calcium absorption mediated by
Vitamin D. Pseudohypoparathyroidism is caused by defects in peripheral PTH receptors, leading to
hypocalemia in the setting of elevated PTH. Non-accidental trauma is unlikely to occur in a
hospitalized preterm infant, though infants with complex medical problems are at high-risk of non-
accidental traumatic fractures once they are discharged from the hospital.
References:
Kliegman RM, Behrman RE, Jenson HB, Stanton B (eds). Nelson Textbook of Pediatrics. 18th
edition. Philadelphia: Saunders, 2007
Lothe A, Sinn J, Stone M. Metabolic bone disease of prematurity and secondary hyperparathyroidism.
J Paediatr Child Health. 2011;47:550-553
Endocrinology Answer 8
B. Increases hydroxylation of vitamin D in the kidney, indirectly increasing intestinal absorption of
calcium and phosphorous
Parathyroid hormone (PTH) is produced by the parathyroid gland and is secreted in response to
low serum calcium concentrations. It stimulates the activity of renal 1-alpha-hydroxylase, increasing
the active form of vitamin D and indirectly increasing intestinal calcium and phosphorus absorption.
PTH increases renal calcium absorption and decreases renal phosphorus absorption. PTH also acts
directly on bone, mobilizing calcium and phosphorus. This hormone also increases renal calcitriol
production.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Kliegman RM, Behrman RE, Jenson HB, Stanton B (eds). Nelson Textbook of Pediatrics. 18th
edition. Philadelphia: Saunders, 2007
Endocrinology Answer 9
D. Hypocalcemia
Maternal diabetes can lead to neonatal hypocalcemia, hypoglycemia and hypomagnesemia.
Although jitteriness most commonly reflects hypoglycemia in an infant of a diabetic mother, the infant
in this vignette has a normal glucose concentration, heightening suspicion for another electrolyte
problem. Although infants with hypocalcemia and hypomagnesemia may be asymptomatic, both can
induce jitteriness. Classic signs of hypocalcemia include Chvostek and Trousseau signs, irritability,
laryngospasm, tetany, seizures, and prolonged QT interval. Infants with hypomagnesemia may have
muscle weakness, increased deep tendon reflexes, irritability, jitteriness, seizures, and a prolonged
QT interval. Hypocalcemia and hypomagnesemia are both treated with careful monitoring and
replacement of the deficient electrolyte.
Reference:
Kliegman RM, Behrman RE, Jenson HB, Stanton B (eds). Nelson Textbook of Pediatrics. 18th
edition. Philadelphia: Saunders, 2007
Endocrinology Answer 10
C. Oxytocin
The anterior pituitary is derived from Rathke’s pouch of the embryonic oropharynx. It is
responsible for producing growth hormone, prolactin, adrenocorticotropic hormone, thyroid-
stimulating hormone, leutinizing hormone, follicle-stimulating hormone, and pro-opiomelanocortin.
The posterior pituitary originates from the floor of the forebrain and is responsible for storing and
secreting anti-diuretic hormone and oxytocin, both of which are produced in the hypothalamus.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Kliegman RM, Behrman RE, Jenson HB, Stanton B (eds). Nelson Textbook of Pediatrics. 18th
edition. Philadelphia: Saunders, 2007
Endocrinology Questions 11-20
Endocrinology Question 11
A neonatologist meets with a pregnant woman at 36 weeks’ gestation with Graves disease. Her
condition has been well-controlled and there have been no signs of fetal distress.
Which of the following statements about the effects of maternal Graves disease on the fetus or
infant is FALSE?
A.A small number of infants may develop primary hypothyroidism
B.Exophthalmos can occur in affected infants
C.Fetal hydrops can occur in affected fetuses
D.Fetal hyperthyroidism typically develops during the 2nd half of gestation
E.Half of the neonates born to mothers with Graves disease develop hyperthyroidism
Endocrinology Question 12
You are asked to evaluate an otherwise healthy, well appearing 4-day old term newborn because
of an abnormal thyroid-stimulating hormone (TSH) concentration measured on the infant’s newborn
state screen. The screen had been erroneously sent shortly after birth. The infant is breastfeeding
well, with normal voiding and stooling patterns.
You speak with the family and tell them that you plan to repeat the newborn screen but are not
worried because:
A.The infant is well appearing, without clinical signs of hypothyroidism
B. The infant’s reverse triiodothyronine (rT3) is also elevated
C. There is a TSH surge after birth, with markedly elevated TSH concentrations compared to
older infants
D. The TSH concentration is suppressed at birth and takes several days to reach a normal level
E. The TSH measurement is not as reliable as measuring thyroxine (T4)
Endocrinology Question 13
A neonatologist is evaluating an infant of a diabetic mother who was born at term weighing 4.6
kg. The infant appears plethoric and is admitted to the NICU for management of hypoglycemia. The
family asks the neonatologist to discuss neonatal complications of maternal diabetes.
Which of the following findings in the newborn is NOT associated with maternal diabetes?
A.Hypoglycemia
B. Hypercalcemia
C. Increased intracardiac septal thickening
D.Mild surfactant deficiency
E. Polycythemia
Endocrinology Question 14
A neonatologist is asked to consult with a pregnant woman with hyperthyroidism. The woman
inquires if her own thyroid hormone crosses the placenta to the fetus.
All of the following can cross the placenta, EXCEPT for:
A.Maternal thyroid-releasing hormone (TRH)
B.Maternal thyroid-stimulating hormone (TSH)
C.Maternal thyroxine (T4)
D.Radioactive iodide
E.TSH receptor antibodies (TRAb)
Endocrinology Question 15
 A neonatologist is called to the Delivery Room of a term infant with respiratory distress. The
infant’s initial physical examination reveals mild respiratory distress and an unexpected finding of
ambiguous external genitalia. Review of the maternal records reveals that an amniocentesis had been
done showing a 46 XX karyotype.
Which of the following etiologies is LEAST likely to be attributed to an overvirilized female?
A. 5-alpha reductase deficiency
B. 11-beta hydroxylase deficiency
C. 21-hydroxylase deficiency
D. Aromatase deficiency
E. Maternal androgen and progesterone therapy
Endocrinology Question 16
A 14-day old male infant is brought to the Emergency Department because of difficulty feeding,
vomiting, and lethargy. Physical examination reveals temperature=37°C, heart rate=190 beats per
minute, blood pressure=55/30 (mean=34) mm Hg, and respiratory rate=60 breaths per minute. The
infant’s anterior fontanel is sunken and his skin turgor is poor with a capillary refill time of 5
seconds.
Which of the following laboratory findings are MOST consistent with the diagnosis of congenital
adrenal hyperplasia resulting from 21-hydroxylase deficiency?
A. Sodium=124 mEq/L, potassium=6.2 mEq/L, chloride=86 mEq/L
B. Sodium=132 mEq/L, potassium=5.5 mEq/L, chloride 92=mEq/L
C. Sodium=124 mEq/L, potassium=3.2 mEq/L, chloride 86=mEq/L
D. Sodium=142 mEq/L, potassium=3.2 mEq/L, chloride 100=mEq/L
E. Sodium=158 mEq/L, potassium=5.5 mEq/L, chloride 120=mEq/L
Endocrinology Question 17
Which of the following statements is TRUE about infants of diabetic mothers?
A.Fetal hyperinsulinemic state restricts substrate availability for surfactant biosynthesis
B.Fetal hyperinsulinism decreases erythropoeisis
C.Infants of diabetic mothers with a small left colon have chronic difficulty with intestinal
obstruction
D.Infants of diabetic mothers with cardiomyopathy frequently have clinical signs of heart failure
Endocrinology Question 18
True or False:
The metabolic abnormalities in infants of diabetic mothers resolve in the neonatal period.
Endocrinology Question 19
Which hormone contributes to the development of macrosomia among infants of diabetic mothers?
A.Adiponectin
B.Cortisol
C.Growth hormone
D.Insulin-like growth factor
E.Leptin
Endocrinology Question 20
Choose the correct statement about hyperglycemia in the preterm neonate.
A.Correlated with birth weight
B.Correlated with glycosuria and osmotic diuresis
C.Correlated with sepsis
D.All of the above
Endocrinology Answers 11-20
Endocrinology Answer 11
E. Half of the neonates born to mothers with Graves disease develop hyperthyroidism
Thyroid disease is a common entity in pregnancy. Graves disease occurs in 0.1% to 0.4% of all
pregnancies, although only about 1% of neonates born to women with Graves will be clinically
affected. The fetus/neonate is affected as a result of transplacental passage of thyroid-stimulating
hormone (TSH) receptor-stimulating and receptor-blocking antibodies during the 2nd half of
pregnancy. Because stimulating antibodies are more often produced, most affected neonates will
develop hyperthyroidism. However, a small number of infants may develop hypothyroidism if the
amount of blocking antibodies crossing the placenta is greater than the amount of stimulating
antibodies. Evidence of fetal disease can be apparent even if the pregnant woman has inactive
Graves disease (e.g., following removal or destruction of the thyroid gland) because the fetus is still
exposed to maternal antibodies. Intrauterine signs of fetal disease include fetal tachycardia, growth
restriction, and fetal hydrops. A fetal goiter may also be present. Post-birth, the symptoms of
hyperthyroidism in a newborn are usually apparent within the first 10 days of life, although clinical
symptoms can present up to 4 to 6 weeks of life. Thyrotoxicosis usually resolves by 2 months of age
but may last as long as 5 months of life.
The signs and symptoms of neonatal hyperthyroidism is variable and include the following:
•Increased irritability and jitteriness
•Periorbital edema and exophthalmos
•Tachycardia
•Pulmonary hypertension
•Weight loss
•Diarrhea
•Sweating and flushing
•Advanced bone age
•Hepatosplenomegaly
•Bruising and petechiae
•Goiter
Infants with evidence of thyrotoxicosis should be managed immediately with anti-thyroid therapies
and symptomatic relief can be provided by beta-blockade. Anti-thyroid options include
propylthiouracil and carbimazole.
Reference:
Hernandez MI, Lee KW. Neonatal Graves disease caused by transplacental antibodies. NeoReviews.
2008; 9(7):e305-e208
Endocrinology Answer 12
C. There is a TSH surge after birth, with markedly elevated TSH concentrations compared to older
infants
The timing of the newborn state screen is critical to interpret the results of thyroid function studies.
Typically the newborn screen is performed 36 to 72 hours after birth in a healthy term infant.
Because the state screen of the infant in this vignette was obtained shortly after birth, it may reflect
normal physiologic changes that would be considered abnormal in a different situation.
After birth, there is a dramatic increase in serum thyroid-stimulating hormone (TSH)
concentrations with levels as high as 60 to 70 mU/L. While not completely understood, this process is
thought to result from the infant’s initial exposure to the relatively cold atmosphere compared with the
intrauterine environment. This TSH surge results in an increase in serum thyroxine (T4) and
triiodothyronine (T3) concentrations. The concentration of T4 in the first week of life is usually the
highest than at any other time during life. The T3 levels tend to rise after the first week of life and
continue to increase during the first month of life. In contrast, concentrations of reverse T3 (rT3) tend
to decrease postnatally because of the increased action of deiodinase D, as well as loss of placental
deiodinase D3. Free T4 and thyroid-binding globulin follow a similar path as T4, usually exhibiting a
peak in the first week of life followed by a gradual decline. While an abnormally high TSH value
would be concerning for congenital hypothyroidism, the infant in this vignette most likely has an
elevated TSH because the screen was performed immediately after birth when the TSH is expected to
be high because of normal physiologic adaptation.
Reference:
Feingold SB, Brown RS. Neonatal thyroid function. NeoReviews. 2010;11(11):e640-e645
Endocrinology Answer 13
B. Hypercalcemia
Infants of a diabetic mother (IDM) are at increased risk for multiple problems after birth.
Hypoglycemia typically occurs as a result of attenuation of the maternal supply of glucose once the
umbilical cord is clamped. The fetal hyperinsulinemic state continues in the short-term and lack of
maturity of the counter-regulatory hormones may result in persistent neonatal hypoglycemia. In
addition, the effect of insulin as a growth factor may result in intracardiac septal and ventricular wall
thickening, which can lead to a transient cardiomyopathy.
IDMs are at increased risk of having respiratory distress syndrome, although the risk has
decreased over the years; this is probably because of more accurate fetal assessment of gestational
age. The mechanism for surfactant deficiency may result from increased fetal insulin inhibitory action
on fibroblast-pneumocyte factor, which normally acts on type II alveolar cells to produce surfactant.
IDMs are at increased risk of polycythemia, although the mechanism is not understood. In addition.
IDMs are also at an increased risk for hypocalcemia (NOT HYPERcalcemia), possibly as a result of
a delay in the neonatal parathyroid hormone surge due to urinary magnesium losses (which can
decrease parathyroid hormone secretion, thus resulting in hypocalcemia)
References:
Dailey TL, Coustan DR. Diabetes in pregnancy. NeoReviews. 2010;11(11):e619-e625
Ogata, ES. Problems of the infant of the diabetic mother. NeoReviews. 2010;11(11):e627-e630
Endocrinology Answer 14
B. Maternal thyroid-stimulating hormone (TSH)
Thyroid gland embryogenesis is completed by 10 to 12 weeks of gestation and the gland begins to
secrete thyroid hormone at approximately 12 weeks’ gestation. The fetal thyroid-stimulating hormone
(TSH) receptors, however, do not become responsive to TSH and TSH receptor antibodies (TRAbs)
until ~20 weeks’ gestation. There is a progressive increase in thyroxine (T4) and thyroxine-binding
globulin (TBG) in the fetus, as well as an increase in free T4 (fT4) between 18 and 36 weeks’
gestation.
In the first half of pregnancy, small amounts of maternal T4 cross the placenta when fetal T4
remains low. Additionally, maternal thyroid-releasing hormone (TRH) can cross the placenta but only
in small amounts because the maternal serum TRH concentration is low. However, maternal TSH
does not cross the placenta. TRAb (both stimulating and blocking) are immunoglobulin G antibodies
that readily cross the placenta. Additionally, anti-thyroid medications and iodide both can cross the
placental barrier. Iodide placental passage can affect the fetus in the first half of pregnancy when the
fetal thyroid hormone production is increasing.
Reference:
Hernandez MI, Lee KW. Neonatal Graves disease caused by transplacental antibodies. NeoReviews.
2008;9(7):e305-e208
Endocrinology Answer 15
A. 5-alpha reductase deficiency
5-alpha reductase deficiency is an autosomal recessive disorder that limits the conversion of
testosterone to dihydrotesterone (see Figure).

Males with 5-alpha reductase deficiency have ambiguous genitalia with appropriately
differentiated Wolffian structures, absence of Müllerian-derived structures, small phallus, urogenital
sinus with perineal hypospadias, and a blind vaginal pouch. Later in life, males have progressive
virilization with decreased facial hair and small prostates. “Testicles at twelve” is sometimes used
in reference to 5-alpha reductase deficiency because of virilization and descent of testes to the labial
location at the time of puberty. Females have a normal phenotype. Thus, the infant in this vignette
with a 46 XX chromosomal analysis is not likely to have 5-alpha reductase deficiency.
Aromatase deficiency prevents conversion of testosterone to estradiol, thus androstenedione is not
ultimately converted to estrone (see Figure above). Affected females have Müllerian duct structures
and absent Wolffian duct structures, evident by ambiguous genitalia or cliteromegaly. Affected
females may also have multicystic ovaries, tall stature, virilization at puberty, and delayed bone age.
If the fetus is exposed to maternal androgen and progesterone therapy between 8 to 13 weeks’
gestation, the female fetus is at risk for ambiguous genitalia, including posterior fusion of the vagina,
scrotalization of the labia and some fusion of the urethral folds. If the female fetus is exposed to these
maternal hormones after 13 weeks’ gestation, the fetus may develop cliteromegaly.
Congenital adrenal hyperplasia encompasses a group of enzymatic disorders that leads to
ambiguous genitalia. These are summarized in the Table below. Deficiencies in 21-hydroxylase, 11
beta-hydroxylase, and 3 beta-hydroxysteroid dehydrogenase lead to ambiguous external genitalia in
females.
Enzyme Effect on Effect on Effect on Laboratory
Deficiency Males Females Blood
Pressure
(BP) and
Salt
Retention
21-hydroxylase Normal Ambiguous Normal Elevated 17-0H
deficiency external external BP progesterone
genitalia genitalia (some Elevated 17-0H
May have Milder form may may have progesterone following
rapid growth present later in low BP) adrenocorticotropic
 or life with Salt- hormone administration
virilization hirsutism, wasting
menstrual
irregularities
and decreased
fertility
11-beta Normal Ambiguous High BP Increased
hydroxylase external external No salt- deoxycorticosterone
deficiency genitalia genitalia wasting and deoxycortisol
Postnatal Postnatal (note:
virilization virilization may have
salt-
wasting
in
neonatal
period)
17-alpha Ambiguous Normal external High BP Elevated
hydroxylase male genitalia but No salt- deoxycorticosterone
deficiency genitalia there is no wasting and corticosterone
development of Low 17-0H progesterone
secondary and low 17-0H
sexual traits pregnenolone
3 beta- Incomplete Ambiguous Normal Elevated 17-0H
hydroxysteroid male external BP pregnenolone,
dehydrogenase development genitalia Salt- pregnenolone and
deficiency with small (cliteromegaly, wasting dehydroepiandrosterone
(rare) phallus and mild
severe virilization)
hypospadias
Printed with permission from: Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010, p 378
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Fanaroff AA, Martin RJ, Walsh MC (eds). Neonatal-Perinatal Medicine: Diseases of the Fetus and
Infant. 8th edition. Philadelphia: Mosby-Elsevier; 2006
Sperling MA. Pediatric Endocrinology. 3rd edition. Philadelphia: WB Saunders; 2008
Endocrinology Answer 16
A. Sodium=124 mEq/L, potassium=6.2 mEq/L, chloride=86 mEq/L
Infants with 21-hydroxylase deficiency have the following abnormalities:
1. Aldosterone deficiency because patients cannot convert progesterone to deoxycorticosterone
2. Cortisol deficiency because patients cannot convert 17-OH progesterone to 11-
deoxycortisol
3. Increased testosterone production because of increased precursors of 17-OH progesterone
Approximately 50% to 75% of affected infants present with salt-wasting usually in the 2nd week of
life with vomiting, dehydration, hyperkalemia and hyponatremia. Symptoms may progress to
hypotension and shock. Thus, the infant in this vignette will most likely have a low serum sodium
concentration, elevated serum potassium concentration, and low serum chloride concentration.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Chi C, Chong Lee H, Neely EK. Ambiguous genitalia in the newborn. NeoReviews. 2008;9:e78-e84
Endocrinology Answer 17
A. Fetal hyperinsulinemic state restricts substrate availability for surfactant biosynthesis
Infants of diabetic mothers have a 4- to 6-fold increase in surfactant deficiency as a result of
decreased surfactant production. Fetal hyperinsulinism is associated with increased erythropoeisis,
resulting in polycythemia and indirect hyperbilirubinemia. Thickening of the interventricular septum
and left or right ventricular wall that occurs in cardiomyopathy of infants of diabetic mothers is
usually asymptomatic and regresses in the first postnatal year. A small left colon that can occur in
infants of diabetic mothers is a transient anomaly.
Reference:
Ogata ES. Problems of the infant of the diabetic mother. NeoReviews. 2010;11:e627-e631
Endocrinology Answer 18
False
The metabolic effects that occur in infants of diabetic mothers, such as transient hypoglycemia,
hypocalcemia and hypomagnesemia, do resolve. However, offspring of mothers with diabetes
mellitus have higher rates of obesity, impaired glucose tolerance, and hypertension in childhood and
adulthood.
Reference:
Ogata ES. Problems of the infant of the diabetic mother. NeoReviews. 2010;11:e627-e631
Endocrinology Answer 19
D. Insulin-like growth factor
There are two main types of insulin-like growth factor present in intra-uterine life: insulin-like
growth factor binding protein-3 and insulin growth factor-1. These are both increased in the fetuses
of diabetic women, leading to macrosomia.
Reference:
Ogata ES. Problems of the infant of the diabetic mother. NeoReviews. 2010;11:e627-e631
Endocrinology Answer 20
C. Correlated with sepsis
Neonatal hyperglycemia is associated with stress and septicemia. Glucose concentrations vary
inversely with birth weight. Preterm infants with hyperglycemia have glycosuria that is NOT
associated with osmotic diuresis.
Reference:
Rozance PJ, Hay WW. Neonatal hyperglycemia. NeoReviews. 2010;11:e632-e639
Endocrinology Questions 21-30
Endocrinology Question 21
Which of the following is NOT a risk factor for hyperglycemia in the preterm neonate?
A.Early and high rates of intravenous lipid infusions
B.Insufficient pancreatic insulin secretion
C.Intrauterine growth restriction
D.Lack of enteral feedings, leading to increased incretin secretion and action, which limits insulin
secretion
Endocrinology Question 22
The most common approach to the treatment of neonatal hyperglycemia includes the:
A.Initiation of enteral feedings
B.Initiation of intravenous insulin
C.Reduction of glucose infusion rates
D.Reduction of lipid infusion rates
Endocrinology Question 23
You are reviewing the newborn state screening results of a 14-day old infant born at 26 weeks’
gestation who is currently maintained on room air continuous positive airway pressure (CPAP)
and receiving full enteral feedings. The screen identifies a low thyroxine (T4) concentration
with a normal thyroid-stimulating hormone (TSH).
All of the following may be consistent with this infant’s findings, EXCEPT:
A.Although thyroxine (T4) levels are decreased, free T4 (fT4) level may be normal
B. Decreased stores of thyroid iodine
C. Increased production of reverse triiodothyronine (rT3) because of illness with correspondingly
lower amounts of T4
D.Infants born less than 31 weeks’ gestation may not have an increase in T4 levels, and may
actually have a decrease in T4 in the first 1 to 2 weeks of life
E. All of the above are true
Endocrinology Question 24
What is the most common clinical presentation of an infant with congenital hypothyroidism?
A.Asymptomatic
B.Feeding intolerance
C.Hoarse cry
D.Hypotonia
E. Widened anterior fontanel
Endocrinology Question 25
Which of the following is TRUE about iodine and neonatal thyroid function?
A.Iodine deficiency can lead to hypothyroidism
B.Iodine deficiency is the most common cause of maternal-fetal hypothyroidism worldwide
C.Iodine excess can lead to hypothyroidism
D.A and B
E. All of the above
Endocrinology Question 26
Which of the following medications can inhibit thyroid-stimulating hormone secretion and lead to
depressed thyroxine concentrations?
A.Albuterol
 B.Dopamine
C.Metoclopramide
D.Omeprazole
Endocrinology Question 27
Which of the following is TRUE about thyroid function in small-for-gestational age infants
compared to appropriate-for-gestational age (AGA) infants?
A.The surge in thyroid-stimulating hormone (TSH) and thyroxine (T4) is the same as AGA infants
B.The surge in TSH and T4 is higher than AGA infants
C.The surge in TSH and T4 is lower than AGA infants
D.The surge in TSH is higher and T4 is lower than AGA infants
E.The surge in TSH is lower and T4 is higher than AGA infants
Endocrinology Question 28
Which is the dominant thyroid hormone in NEONATAL life?
A.Free thyroxine (T4)
B.Reverse triiodothyronine (rT3)
C.Triiodothyronine (T3)
Endocrinology Question 29
Which of the following thyroid hormones is INCREASED during times of critical illness among
preterm infants?
A.Free thyroxine (T4)
B.Reverse triiodothyronine (rT3)
C.Triiodothyronine (T3)
Endocrinology Question 30
A 2-month old male infant born at term presents to his pediatrician for a routine follow-up
appointment. He was born by emergent Cesarean section because of a concern for placental
abruption. He had perinatal depression at the time of delivery with an Apgar score of 1 at 1 minute, 3
at 5 minutes, and 5 at 10 minutes. He required mechanical ventilation for the first 48 hours of life and
received therapeutic hypothermia. He did well through the remainder of his NICU course and was
discharged home on day of life 12.
At this visit, his examination is remarkable for palpable, non-tender, non-erythematous,
subcutaneous nodules on his arms, thighs, and buttocks. The mother reports that these lesions have
been there for several weeks.
The most appropriate next step in the management of this infant is:
A.Administer an IV fluid bolus and furosemide
B.Obtain a CBC and blood culture
C.Obtain total and ionized calcium levels
D.Routine care
E.Use a fine needle to aspirate the lesions
Endocrinology Answers 21-30
Endocrinology Answer 21
D. Lack of enteral feedings, leading to increased incretin secretion and action, which limits insulin
secretion
Hyperglycemia (and hypoglycemia) can occur in growth-restricted infants. Hyperglycemia often
results from insufficient pancreatic insulin secretion in both preterm and growth-restricted infants.
Intravenous lipid infusions lead to high circulating free fatty acid concentrations that promote
gluconeogenesis, leading to hyperglycemia. Lack of enteral feedings leads to diminished incretin
secretion, a hormone that promotes insulin secretion from the pancreas.
Reference:
Rozance PJ, Hay WW. Neonatal hyperglycemia. NeoReviews. 2010;11:e632-e639
Endocrinology Answer 22
C. Reduction of glucose infusion rates
There is no consensus about the management of hyperglycemia in the neonate. Most commonly,
clinicians try to reduce glucose infusion rates. There is no concrete data to suggest that hyperglycemia
has harmful affects but further research is warranted.
Reference:
Rozance PJ, Hay WW. Neonatal hyperglycemia. NeoReviews. 2010;11:e632-e639
Endocrinology Answer 23
E. All of the above are true
There are multiple etiologies for low thyroxine (T4) concentrations in a premature infant. Similar
to term infants, premature infants have a surge in thyroid-stimulating hormone (TSH) with an
associated increase in T4 concentrations. However, the premature infant’s peak levels may not be as
high.
Some premature infants may have low T4 levels but the free T4 (fT4) may be normal as a result of
lower levels of thyroid-binding globulin or abnormal protein binding. Decreased thyroidal iodine
stores can also be a contributing factor of a low T4 in premature infants, although this is more
common in regions with iodine deficiency. Premature infants may have an increase in reverse
triiodothryonine (rT3) because of increased activity of de-iodinase D3 associated with illness; this
may lead to correspondingly lower amounts of T4. Sometimes infants born below 31 weeks’
gestation may exhibit a decrease in T4 levels during the first few weeks of life. Clearance of
maternal T4 from the neonatal circulation can also contribute to the initially low T4 levels in
premature infants. Finally, small for gestational age infants can have lower fT4 levels, possibly
related to the cause of their growth restriction.
Reference:
Feingold SB, Brown RS. Neonatal thyroid function. NeoReviews. 2010;11(11):e640-e645
Endocrinology Answer 24
A. Asymptomatic
90% of infants with congenital hypothyroidism are asymptomatic at birth. This may be because
some maternal thyroxine (T4) is transferred across the placenta and brain triiodiothyronine (T3)
concentrations are preserved during fetal life. In contrast, if both the pregnant woman and the fetus
have hypothyroidism, most infants have permanent cognitive delay, despite early postnatal therapy.
Reference:
Feingold SB, Brown RS. Neonatal thyroid function. NeoReviews. 2010;11:e640-e646
Endocrinology Answer 25
E. All of the above
Iodine deficiency can lead to hypothyroidism
Iodine deficiency is the most common cause of maternal-fetal hypothyroidism worldwide
Iodine excess can lead to hypothyroidism
Iodine is an essential element of thyroid hormone synthesis, comprising 65% of thyroxine (T4) and
59% of triiodothyronine (T3) by weight. Fetal and neonatal iodine stores are critically dependent on
maternal iodine status in-utero and on the iodine content of formula or human milk postnatally. Iodine
deficiency can lead to hypothyroidism. This is the most common cause of maternal-fetal
hypothyroidism worldwide.
Excess iodine also has a thyroid-suppressive effect and can be dangerous. Causes of excess iodine
include drugs such as potassium iodide, amiodarone, iodinated contrast agents, and topical antiseptic
solutions, such as povidone-iodine.
Reference:
Feingold SB, Brown RS. Neonatal thyroid function. NeoReviews. 2010;11:e640-e646
Endocrinology Answer 26
B. Dopamine
Dopamine and steroids, and possible caffeine, inhibit the secretion of thyroid-stimulating
hormone. Maternal administration of propylthiouracil or methimazole for treatment of Graves
disease also causes congenital hypothyroidism by inhibiting thyroid hormonogenesis.
Reference: Feingold SB, Brown RS. Neonatal thyroid function. NeoReviews. 2010;11:e640-e646
Endocrinology Answer 27
D. The surge in TSH is higher and T4 is lower than AGA infants.
Small-for-gestational age (SGA) infants have significantly higher thyroid-stimulating hormone
(TSH) and lower total and free thyroxine (T4) concentrations than appropriate-for-gestational age
infants. This may occur because of the severity of intrauterine malnutrition in SGA fetuses as well as
fetal hypoxemia and acidemia. This pattern differs from the response to starvation in adults where
TSH is reduced.
Reference:
Feingold SB, Brown RS. Neonatal thyroid function. NeoReviews. 2010;11:e640-e646
Endocrinology Answer 28
C. Triiodothyronine (T3)
After birth, thyroid-stimulating hormone (TSH) secretion increases, leading to increased thyroxine
(T4) secretion. Deiodinase (D1) found in the placental and fetal tissues is activated and converts T4
to triiodothyronine (T3). After birth, when placental D3 is no longer present, concentrations of
reverse T3 are significantly decreased.

Reference:
Feingold SB, Brown RS. Neonatal thyroid function. NeoReviews. 2010;11:e640-e646
Endocrinology Answer 29
B. Reverse triiodothyronine (rT3)
During critical illness, activating deiodinase (D1) is decreased, resulting in decreased conversion
of free thyroxine (T4) to triiodothyronine (T3). Inactive deiodinase, D3, in turn converts T4 to rT3.
Concentrations of T4 are also lower during a critical illness.

Reference:
Feingold SB, Brown RS. Neonatal thyroid function. NeoReviews. 2010;11:e640-e646
Endocrinology Answer 30
C. Obtain total and ionized calcium levels
Subcutaneous fat necrosis is uncommon and usually occurs in the first few weeks of life. It can be
diagnosed based on clinical appearance. Subcutaneous fat necrosis is characterized by firm nodules
and plaques on the back, buttocks, thighs, forearms, and cheeks. The nodules and plaques may be
erythematous, flesh colored, or blue in color. A CBC and blood culture are not required unless there
is a high suspicion for infection. Fine needle aspiration of classic lesions is rarely required.
The pathophysiology of subcutaneous fat necrosis is not completely known. Potential etiologies
include a primary defect in subcutaneous fat, birth hypoxia associated with skin ischemia,
hypothermia, local trauma, or maternal factors. A granulomatous reaction is noted on histologic
examination of skin biopsy specimens. Hypercalcemia is a potential complication of these lesions.
Hypercalcemia most likely results from increased production of 1,25-dihydroxyvitamin D by the
granulomatous lesions that subsequently stimulates intestinal uptake of calcium.
The differential diagnosis of hypercalcemia in an infant includes primary and tertiary
hyperparathyroidism, hyperthyroidism, familial hypocalciuric hypercalcemia, Williams syndrome,
and increased intake of calcium or vitamin D. Infants with hypercalcemia can present with failure to
thrive, anorexia, constipation, polyuria, hypotonia, vomiting, dehydration, or irritability. Potentially
life-threatening complications include seizures, cardiac arrest, and renal failure.
Hypercalcemia in infants requires immediate treatment. Measurement of the infant’s total and
ionized calcium levels is necessary. Dietary intake of supplemental calcium should be stopped and a
diet low in calcium and vitamin D should be started. Intravenous fluid hydration should be
administered and furosemide can be given to increase calciuresis. If hypercalcemia persists,
alternative therapies include corticosteroids, calcitonin, and/or bisphosphonates.
References:
Schiller J, Chang J. Index of suspicion in the nursery. NeoReviews. 2006;7:e160
Strohm B, Hobson A, Brocklehurst P, et al. Subcutaneous fat necrosis after moderate therapeutic
hypothermia in neonates. Pediatrics. 2011;128:e450-452
Zifman E, Mouler M, Eliakim A, et al. Subcutaneous fat necrosis and hypercalcemia following
therapeutic hypothermia – A patient report and review of the literature. J Pediatr Endocrinol
Metab. 2010;23:1185-1188
Endocrinology Questions 31-40
Endocrinology Question 31
A male infant is born at 26 weeks’ gestation. At 12 hours of age, his blood culture that had been
sent on admission is positive for Candida albicans. After discussing the case with the Infectious
Diseases consultation service, the team orders liposomal amphotericin B. At 3 days of age, the infant
has a spontaneous intestinal perforation. A penrose drain is placed to manage the perforation and two
days later, the infant has a seizure. His serum potassium, glucose and calcium concentrations are all
within the normal range.
Of the following, the electrolyte or mineral that is most likely responsible for this infant’s seizure
is:
A.Chloride
B.Magnesium
C.Phosphorus
D.Sodium
E.Zinc
Endocrinology Question 32
An infant is delivered at 38 weeks’ gestation by vaginal delivery. He has a micropenis (phallic
length < 2.5 cm) but has palpable testes. The infant also has a cleft palate and a narrow nasal bridge.
Which of the following would be unexpected in this infant’s clinical course?
A.Hyperglycemia
B.Hypernatremia
C.Hypotension
D.Polyuria
E.Prolonged jaundice
Endocrinology Question 33
An infant is born at 39 weeks’ gestation. On exam, the infant has ambiguous genitalia with a
microphallus and non-palpable testes.
33a. Which of the following contributes most to phallic enlargement and testicular descent?
A.Estradiol
B.Fetal follicle-stimulating hormone (FSH)
C.Fetal luteinizing hormone (LH)
D.Müllerian inhibiting substance (MIS)
E.Placental human chorionic gonadotropin (hCG)
33b. Undervirilization of the male infant can be caused by decreased testosterone production or
androgen insensitivity.
Which of the following is an example of a defect in testosterone production?
A.3-beta hydroxysteroid dehydrogenase deficiency
B.5-alpha reductase deficiency
C.21-alpha hydroxylase deficiency
D.Luteoma of pregnancy
E.Placental aromatase deficiency
33c. Which of the following is usually NOT associated with undervirilization of the male infant?
A.Bifid scrotum
B.Blind vaginal pouch
C.Cryptorchidism
 D.Hypospadias
E.Uterus
33d. Because of this infant’s physical exam findings, the neonatologist orders a newborn state screen,
electrolytes, and a biochemical panel to assess for congenital adrenal hyperplasia (CAH). All of
these tests are normal. The neonatologist orders an abdominal ultrasound, which identifies testes in
the inguinal canal.
Which of the following laboratory tests would be LEAST useful in determining the etiology of this
undervirilized male?
A.Dihydrotestosterone (DHT)
B.Luteinizing hormone (LH)
C.Müllerian inhibiting substance (MIS)
D.Renin level
E.Testosterone
33e. Which of the following findings are most consistent with 5-alpha reductase deficiency?
A.Normal testosterone, normal DHT
B.Normal testosterone, low DHT
C.Normal testosterone, high DHT
D.High testosterone, high DHT
E.Low testosterone, normal DHT
Endocrinology Question 34
Sexual differentiation generally begins between the 6th and 7th week of gestation.
Which of the following activates events that lead to the differentiation of the gonad to testes?
A.5-alpha reductase
B.Human chorionic gonadotropin (hCG)
C.Müllerian inhibiting substance (MIS)
D.Sex-determining region Y (SRY) gene
E.Testosterone
Endocrinology Question 35
A term infant is admitted to the NICU for observation and evaluation because of a prenatal
diagnosis of a goiter. The infant has a tachyarrhythmia at 10 hours of age.
35a. The pediatric resident rotating in the NICU is curious about the incidence of neonatal
hyperthyroidism.
What is the incidence of thyroid disease in an infant born to a woman with Graves’ disease?
A.1% to 5%
B.5% to 10%
C.10% to 15%
D.15% to 30%
E.30% to 50%
35b. The infant in the vignette has clinical and laboratory findings that are consistent with
hyperthyroidism.
Which of the following laboratory findings are most likely in this infant?
A.High TSH, low T4
B.High TSH, normal T4
C.Low TSH, low T4
D.Low TSH, high T4
 E.Normal TSH, high T4
35c. Upon further history, the neonatology team learns that the infant’s mother has inactive Graves’
disease and has had her thyroid gland removed several years ago.
What is the most plausible scenario to explain this infant’s hyperthyroidism?
A.Decreased transplacental passage of TSH receptor stimulating and blocking antibodies
B.Increased transplacental passage of TSH receptor blocking antibodies compared with
stimulating antibodies
C.Increased transplacental passage of TSH receptor stimulating antibodies compared with
blocking antibodies
D.Increased transplacental passage of TSH receptor stimulating and blocking antibodies in equal
amounts
E.No passage of TSH receptor antibodies
35d. Maternal hyperthyroidism can result in adverse fetal/neonatal outcomes.
Of the following, the preferred management of a pregnant woman with hyperthyroidism is:
A.Iodide therapy
B.Methimazole
C.Propranolol
D.Propylthiouracil
E.Thyroidectomy
35e. Which of the following has been shown to be associated with intrauterine exposure to
methimazole?
A.Congenital diaphragmatic hernia
B.Cutis aplasia congenita
C.Ebstein’s anomaly
D.Gastroschisis
E.Omphalocele
35f. Which of the following is not typically associated with neonatal hyperthyroidism?
A.Congestive heart failure
B.Craniosynostosis
C.Goiter
D.Hypertension
E.Large for gestational age
Endocrinology Question 36
An infant is about to be delivered at 38 weeks’ gestation by Cesarean delivery. A pediatric
resident interested in pursuing endocrinology is attending the delivery with a neonatologist. She is
interested in learning more about the physiological function of the thyroid gland and asks about
normal thyroid-stimulating hormone (TSH) levels after birth.
Of the following, the pattern that most likely corresponds to an infant’s serum TSH concentration
is:
A.Peaks at 5 minutes of age
B.Peaks at 30 minutes of age
C.Peaks at 24 hours of age
D.Peaks at 48 hours of age
E.Peaks at 1 week of life
Endocrinology Question 37
 An infant is delivered prematurely at 28 weeks’ gestation. At a few hours of age, the infant has
hypotension and the neonatology fellow orders a calcium level. The infant’s calcium level is 5.7
mg/dL. The fellow postulates that the infant’s hypocalcemia results from low mineral levels because
peak intrauterine transfer of calcium occurs late in pregnancy.
Which of the following is most useful in the management of hypocalcemia in an infant?
A.Bisphosphonate
B.Calcitonin
C.Calcitriol
D.Corticosteroid
E.Furosemide
Endocrinology Question 38
A 4-month old male infant born at 24 weeks’ gestation had a clinical course complicated by
necrotizing enterocolitis requiring an ileostomy and prolonged parenteral nutrition. A radiograph
demonstrates a fracture of the left humerus. The neonatologist recalls the distinction between
osteopenia and osteomalacia.
38a. Of the following, the description that is most consistent with osteomalacia is:
A.Decreased osteoid production, normal mineralization
B.Increased matrix resorption, normal mineralization
C.Increased osteoid production, decreased mineralization
D.Increased matrix resorption, normal mineralization
E.Normal osteoid production, decreased mineralization
38b. Which of the following positively influences mineral accretion in the fetus?
A.Fetal parathyroid hormone
B.Intrauterine growth restriction (IUGR)
C.Maternal estrogen
D.Maternal Vitamin D deficiency
E.Preeclampsia
38c. Which of the following is NOT a risk factor in the development of osteopenia of prematurity?
A.Aluminum contamination of parenteral nutrition
B.Arthrogryposis
C.Corticosteroid treatment
D.Early enteral feedings
E.Furosemide treatment
38d. Which of the following is elevated in an infant with osteomalacia?
A.25 (OH) Vitamin D
B.Alkaline phosphatase
C. Calcitonin
D.Serum calcium
E.Serum phosphate
Endocrinology Question 39
The anatomic development of the thyroid gland begins at 3 weeks’ gestation.
The thyroid gland develops from thickening of which of the following layers?
A.Ectoderm
B.Endoderm
C.Mesoderm
 D.Endoderm and mesoderm
E.Ectoderm, endoderm and mesoderm
Endocrinology Question 40
Which of the following compounds cannot cross the placenta?
A.Iodide
BThyroxine (T4)
C.Triiodothyronine (T3)
D. Thyroid-releasing hormone (TRH)
E.Thyroid-stimulating hormone (TSH)
Endocrinology Answers 31-40
Endocrinology Answer 31
B. Magnesium
Amphotericin B administration is known to lead to hypomagnesemia. Other etiologies of
hypomagnesemia include the following:
•Maternal illness such as diabetes or preeclampsia
•A growth restricted fetus
•Prematurity
•Malabsorption
•Chronic diarrhea
•Liver disease
•Perinatal depression
Clinical manifestations of neonatal hypomagnesemia include irritability, tremors, muscle weakness,
and seizures.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Index of Suspicion in the Nursery. NeoReviews. 2006;7(3):e160-e162
Endocrinology Answer 32
A. Hyperglycemia
The infant in this vignette has hypoplastic genitalia and midline facial abnormalities, which is
consistent with hypopituitarism. Hypoglycemia is a classic finding in an infant with hypopituitarism;
affected infants do not have hyperglycemia. This hypoglycemia can result from impaired
adrenocorticotropic hormone (ACTH) secretion or growth hormone (GH) deficiency.
Additionally, an infant with hypopituitarism can have hypotension, as a result of ACTH
deficiency. Hypothermia, lethargy, poor feeding, prolonged jaundice, and constipation are common
nonspecific findings in infants with hypopituitarism. Impaired prolactin and gonadotropin secretion
do not cause acute illness but an infant with a microphallus may have ACTH or GH deficiency.
Polyuria and hypernatremia may indicate antidiuretic hormone (ADH) deficiency.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Dempsher D. Adrenal and pituitary insufficiency in the neonate. NeoReviews. 2008;9:e72-77
Endocrinology Answer 33
33a. C. Fetal luteinizing hormone (LH)
Testosterone and Müllerian inhibiting substance (MIS, also called anti-Müllerian hormone or
Müllerian inhibiting factor) are produced by the testis and stimulate Wolffian duct differentiation and
Müllerian duct regression, respectively. Local conversion of testosterone to dihydrotestosterone
(DHT) by 5-alpha reductase leads to the fusion of the labioscrotal folds and formation of the scrotum
and penis. In the first trimester, testosterone production from the Leydig cell is driven by placental
hCG. Fetal LH secretion increases during the second trimester and stimulates phallic enlargement
and testicular descent. Estradiol and fetal FSH secretion are not involved in phallic and testicular
development.
33b. A. 3-beta hydroxysteroid dehydrogenase deficiency
The Figure provides a summary of the androgen/estrogen pathways.
 An infant with a deficiency in 3-beta hydroxysteroid dehydrogenase (noted as A in the Figure
above), will have decreased ability to convert pregnenolone to progesterone; 17-OH pregnenolone to
17-OH progesterone; and DHEA to androstenedione. Lower amounts of androstenedione result in
decreased testosterone production. Clinically, an infant with 3-beta hydroxysteroid dehydrogenase
deficiency may have incomplete male development evident by a small phallus and severe
hypospadias.
In contrast, 21-hydroxylase deficiency results in an excessive amount of androgen production and
actually leads to normal male external genitalia. 5-alpha reductase deficiency does not impact
testosterone production; rather, it leads to abnormal testosterone metabolism. Luteoma of pregnancy
and placental aromatase deficiency also lead to excess androgen production.
33c. Uterus
Undervirilization of a male infant can be caused by androgen receptor insensitivity or inadequate
testosterone production. While an infant with complete androgen insensitivity syndrome can have
normal female external genitalia, Müllerian structures (such as the uterus) are usually absent. Testes
may be found intra-abdominally or in the inguinal canal. Similarly, 5-alpha reductase deficiency,
which decreases the amount of testosterone converted to DHT, can lead to varying degrees of
ambiguity—from a blind vaginal pouch to bifid scrotum. Hypospadias can be associated with
undervirilization and results from failure of urethral differentiation leading to placement of the meatus
proximal to the tip of the glans penis.
33d. D. Renin level
Laboratory testing in an undervirilized male includes evaluating for inadequate testosterone
production or androgen receptor insensitivity. Laboratory testing includes measurements of
testosterone, DHT, LH, and FSH in the first 24 hours as well as MIS to evaluate for testicular
function. A renin level should be sent when CAH is strongly suspected.
33e. B. Normal testosterone, low DHT
Testosterone is converted to dihydrotestosterone (DHT) by the enzyme 5-alpha reductase. An
infant with a low DHT level and a normal testosterone level, most likely has 5-alpha reductase
deficiency. Because DHT is the primary hormone responsible for differentiation of male external
genitalia, patients with decreased 5-alpha reductase activity will have various degrees of ambiguous
genitalia, ranging from a blind vaginal pouch to mild hypospadias with bifid scrotum.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Chi C, Chong Lee H, Neely EK. Ambiguous genitalia in the newborn. NeoReviews. 2008;9:e78-e84
Endocrinology Answer 34
D. Sex-determining region Y (SRY) gene
During normal embryogenesis, the fetus contains both female (Müllerian) and male (Wolffian)
genital ducts. Wolffian ducts develop into the vas deferens, epididymis and seminal vesicles. The
SRY gene in males activates events that lead to the differentiation of the gonad to testes. The Table
below summarizes the steps involved in the development of a male or female fetus.
Male Development Female Development
Wolffian duct (derived from excretory Müllerian duct (or paramesonephric duct,
mesonephros duct) develops into epididymis, derived from coelomic epithelium) develops into
vas deferens, ejaculatory duct, and seminal fallopian tubes, uterus, cervix, and upper third of
vesicles vagina
Lower portion of vagina from canalization of
vaginal plate
Urethral folds fuse corpus spongiosum and Urethral folds do not fuse labia minora
penile urethra
Genital tubercle corpora cavernosa of Genital tubercle clitoris
penis/phallus
Labioscrotal folds fuse scrotum Labioscrotal swellings do not fuse labia
majora
Printed with permission from: Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010, p 379
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Chi C, Chong Lee H, Neely EK. Ambiguous genitalia in the newborn. NeoReviews. 2008;9:e78-e84
Endocrinology Answer 35
35a. A. 1% to 5%
Women with Graves’ disease or with a history of Graves’ disease treated with thyroidectomy
produce high amounts of thyroid-stimulating immuoglobulins (TSIs). However, there is a low
incidence of neonatal hyperthyroidism in neonates born to mothers with Graves’ disease. There are
several pregnancy-related immunologic events that work concomitantly to lower the fetal/neonatal
risk for hyperthyroidism. Although the TSH receptor is present in the fetus at 12 weeks of gestation,
fetal immunoglobulins are only 5% to 8% of maternal levels prior to 15 weeks’ gestation so very
little TSI actually crosses the placenta in the first trimester. At 30 weeks’ gestation, when fetal
immunoglobulin levels are equal to maternal levels, there is a decrease in maternal TSI
concentrations as a result of immune suppression during pregnancy.
35b. D. Low TSH, high T4
The infant in this vignette has hyperthyroidism and is most likely to have the following laboratory
findings:
•Extremely low TSH
•Normal or elevated T4
•Normal or elevated T3
If the infant’s hyperthyroidism is caused by maternal Graves’ disease, the infant will also have
increased TSH-receptor antibodies (TRAbs).
35c. C. Increased transplacental passage of TSH receptor stimulating antibodies compared with
blocking antibodies
A woman with Graves’ disease or a history of Graves’ disease treated with thyroidectomy
typically produces both TSH receptor stimulating and blocking antibodies. The clinical
manifestations in the infant depend on the quantity of transplacental passage of these antibodies as
well as the ratio of blocking to stimulating antibodies that cross into the fetus. Increased
transplacental passage of TSH receptor stimulating antibodies compared with blocking antibodies
will lead to transient hyperthyroidism. Conversely, increased transplacental passage of TSH
receptor blocking antibodies compared with stimulating antibodies will lead to hypothyroidism.
35d. D. Propylthiouracil
Propylthiouracil is the preferred medication for the treatment of pregnant woman with
hyperthyroidism. Fetal exposure to methimazole has been associated with fetal anomalies.
Propranolol is not recommended during pregnancy because of potential neonatal morbidities such as
hypoxia, respiratory depression, and hypoglycemia. Iodide therapy during pregnancy is
contraindicated because of the association with neonatal goiter and hypothyroidism. Thyroidectomy
is rarely performed during pregnancy.
35e. B. Cutis aplasia
Cutis aplasia congenita has been associated with methimazole. Fetal exposure to methimazole has
also been associated with choanal atresia, esophageal atresia and tracheoesophageal fistula.
35f. E. Large for gestational age
Most newborns with hyperthyroidism have a history of intrauterine growth restriction (IUGR) and
prematurity. Affected newborns can also have a goiter, craniosynostosis, and hypertension. Beta-
adrenergic stimulation in the infant can lead to high output heart failure.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Buckingham B. The hyperthyroid fetus and infant. NeoReviews. 2000;1:e103-e109
Endocrinology Answer 36
B. Peaks at 30 minutes of age
An infant usually has a large increase in TSH serum concentrations soon after birth (the peak is at
approximately 30 minutes of age) partly as a result of extrauterine cold exposure. Persistently
elevated serum TSH values after 24 hours is consistent with primary hypothyroidism. The Figure
below shows the intrauterine and postnatal changes in TSH and thyroid hormones.

References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Feingold SB, Brown RS. Neonatal thyroid function. NeoReviews. 2010;11:e 640-e646
Endocrinology Answer 37
C. Calcitriol
Vitamin D (in the form of calcitriol) supplementation can help to treat hypocalcemia in an infant,
specifically if it is caused by hypoparathyroidism. Ergocalciferol can also be used if the infant’s
parathyroid function is normal. Oral intake of a low phosphate formula will also help to increase
calcium absorption.
The other options are helpful in the management of an infant with hypercalcemia. Corticosteroids
can be used to inhibit reabsorption of calcium. Bisphosphonates can inhibit osteoclasts (leading to a
decrease in bone turnover) and increase calciuresis. Calcitonin has been shown to inhibit intestinal
reabsorption of calcium while furosemide can increase calciuresis.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Index of Suspicion in the Nursery. NeoReviews. 2006;7(3):e160-e162
Endocrinology Answer 38
38a. E. Normal osteoid production, decreased mineralization
Osteopenia of prematurity, also known as metabolic bone disease of prematurity, is characterized
by decreased bone matrix as a result of either decreased deposition or increased matrix resorption.
In contrast, infants with osteomalacia have decreased mineralization but continued to have adequate
osteoid production. The distinctions between osteopenia of prematurity and osteomalacia are
summarized in the Table below.
Characteristic Osteopenia of Osteomalacia
 Prematurity
General Decreased bone Decreased mineralization
definition matrix because of Osteoid production is spared
decreased
deposition or
increased matrix
resorption
Pathophysiology Mineralization is not Because osteoblasts are still able to make matrix, the
affected mineral content of bone is decreased and the bones
are soft and more radiolucent; bones bend more
easily when exposed to force
Causes Severe systemic Decreased supply of calcium and phosphate
disease (inadequate accretion of calcium and phosphate in
(bronchopulmonary utero, fluid restriction, total parenteral nutrition,
dysplasia, sepsis, enteral feedings, human milk, unsupplemented
necrotizing formula, soy formula)
enterocolitis Decreased intestinal absorption of calcium and
Medications phosphate (Vitamin D deficiency, abnormal vitamin
(diuretics, postnatal D metabolism, intestinal malabsorption)
systemic steroids) Increased mineral losses associated with medications
Prolonged such as diuretics, methylxanthines, postnatal systemic
immobilization steroids
Radiographic No changes in growth Widening of growth plate with fraying
features plate Radiolucent bones as a result of demineralization
Thinner bones,
fractures
Printed with permission from: Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010, p 390
38b. C. Maternal estrogen
Estrogen has an anabolic effect on bone growth and positively influences mineral accretion in the
fetus. The placenta transfers calcium from the mother to fetus throughout pregnancy with the greatest
amount of transfer occurring during the 3rd trimester. The high fetal serum calcium levels lead to
increased fetal calcitonin and suppressed fetal parathyroid function. High fetal calcitonin
concentrations inhibit bone resorption. A fetus who is growth restricted or born to a woman with
Vitamin D deficiency or preeclampsia may have decreased mineral accretion.
38c. D. Early enteral feedings
Delayed enteral feedings and feeding restriction increases the risk for metabolic bone disease of
prematurity. Additionally, circumstances of limited movements, such as sedation, paralysis and
infants with syndromes such as spina bifida, arthrogryposis, osteogenesis imperfecta, increase an
infant’s risk of developing osteopenia of prematurity. Aluminum toxicity and medications such as
furosemide and corticosteroids, are also risk factors for developing osteopenia of prematurity.
38d. B. Alkaline phosphatase (ALP)
The Table below summarizes the laboratory findings in a premature infant with bone disease. As
noted in the Table, infants with osteomalacia often have elevated alkaline phosphatase levels because
of increased osteoblast activity to produce bone matrix. Elevated alkaline phosphatase values can
also be found in infants with:
•Normal growth
•Healing after a fracture
•Copper deficiency
Affected infants with osteomalacia have decreased supply of both calcium and phosphate but serum
levels may be normal if infants have appropriate increases in PTH and adequate phosphate
supplementation, respectively. Infants with osteomalacia may have normal or low (OH) Vitamin D
levels. Calcitonin levels are usually normal.
Laboratory Expected Result of Bone Disease in Premature Infant
Finding
Serum calcium Usually within normal range because PTH is functional
May be elevated in hypophosphatemia or low in severe Vitamin D
deficiency
May also be decreased
Serum phosphate Normal or low in infants who are not receiving adequate phosphate
supplementation
Alkaline Elevated if osteomalacia (because of increased osteoblast activity, which
phosphatase leads to an increase in osteoblast-derived alkaline phosphatase)
25 (0H) Vitamin Best measure of body Vitamin D stores
D Normal but may be low in unsupplemented infants, infants born to mothers
with low stores, and/or infants receiving anticonvulsants
1,25 (0H)2 Usually elevated
Vitamin D
Parathyroid Usually normal but may be elevated if Vitamin D deficiency or if significant
hormone urinary calcium losses
Note: calcitonin concentration normal
Urine Broad variability during first weeks of life; if ratio > 1.5 near postmenstrual
calcium/creatinine term gestational age, very elevated
ratio
Modified from: Diaz R. Osteopenia of prematurity. In: Primary Care of the Premature Infant. Brodsky D, Ouellette MA (eds).
Philadelphia: WB Saunders; 2008, p 219; Printed with permission from: Brodsky D, Martin C. Neonatology Review. 2nd edition.
Lulu. 2010; p 390
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Vaccharajani AV, Mathur AM, Rao R. Metabolic bone disease of prematurity. NeoReviews.
2009;10:e402-e411
Endocrinology Answer 39
B. Endoderm
The thyroid gland develops from a median endodermal thickening. Thyroid follicles form and
produce thyroglobulin at 8 weeks’ gestation. Fetal thyroid hormone can accumulate at 10 weeks’
gestation. Thyroid stimulating hormone production by the pituitary gland begins at 12 weeks’
gestation, as does thyroid hormone secretion.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Endocrinology Answer 40
E. Thyroid-stimulating hormone (TSH)
Thyroid-stimulating hormone is unable to cross the placenta. In contrast, iodide, T3, T4, TRH,
and TSH-receptor stimulating and blocking antibodies are all able to cross the placenta.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Endocrinology Questions 41-50
Endocrinology Question 41
Thyroid function in preterm infants partly reflects the relative immaturity of the hypothalamic-
pituitary thyroid axis.
Which of the following is elevated in the preterm infant compared to the term infant?
A.Iodide stores
B.Thyroglobulin
C.Thyroid binding globulin
D.Thyroxine (T4)
E. Triiodothyronine (T3)
Endocrinology Question 42
During embryogenesis, Wolffian ducts develop into the epididymis, vas deferens, ejaculatory duct,
and seminal vesicles. The SRY gene activates differentiation of the bi-potential gonad into testes.
42a. Which of the following is the first compound to stimulate Wolffian duct differentiation?
A.Dihydrotestosterone (DHT)
B.Estradiol
C.Insulin-like growth factor 3 (INSL3)
D.Testosterone
E.5-alpha reductase
42b. Which structure is the Wolffian ducts derived from?
A.Coelomic epithelium
B.Genital tubercle
C.Labioscrotal folds
D.Mesonephros duct
E.Paramesonephros duct
42c. When is the critical period of external virilization of the male fetus?
A.1-6 weeks of gestation
B.6-12 weeks of gestation
C.12-18 weeks of gestation
D.18-24 weeks of gestation
E.Third trimester of pregnancy
Endocrinology Question 43
Which of the following is MOST CONSISTENT with the laboratory values found in an infant
with hypopituitarism?
A.High growth hormone (GH), high cortisol, high free thyroxine (T4), normal thyroid-stimulating
hormone (TSH)
B.High GH, low cortisol, low free T4
C.Low GH, high cortisol, low free T4
D.Low GH, low cortisol, low free T4
E.Normal GH, low cortisol, low free T4
Endocrinology Question 44
On morning rounds, the neonatology team is discussing a 3-week old female infant born at 39
weeks’ gestation with a history of hypoxic-ischemic encephalopathy treated with therapeutic
hypothermia. The infant’s course was complicated by pulmonary hypertension that was responsive to
inhaled nitric oxide. She was successfully extubated to room air at 1 week of life.
 At present, the infant is maintaining her temperature in a crib. Her physical exam is notable for
palpable, subcutaneous nodular non-tender lesions ranging from 0.5 cm to 1.5 cm on her upper back,
arms and buttocks that had been observed several weeks ago but have remained the same size. She
remains in the NICU because of drug withdrawal and poor oral feeding skills. She is receiving 20
kcal/oz breastmilk and taking about 50% of her feedings by mouth. She is also receiving
supplemental oral vitamin D. Last night, she had some non-bilious emesis, prompting the resident to
send blood tests, including a calcium level, which is 17.9 mg/dL. The neonatology team discusses the
cause of this infant’s hypercalcemia.
44a. What is the MOST likely etiology of hypercalcemia in the infant in this vignette?
A.Decreased vitamin D intake
B.History of pulmonary hypertension
C.Hyperphosphatasia
D.Hypoparathyroidism
E.Subcutaneous fat necrosis
44b. Which of the following is NOT a typical feature of hypercalcemia?
A.Constipation
B.Emesis
C.Hyperphagia
D.Irritability
E.Polyuria
44c. Which of the following imaging modalities would be the most useful to demonstrate the potential
sequelae of an infant with chronic hypercalcemia?
A.Computerized tomography of the brain
B.Cranial ultrasound
C.Echocardiogram
D.Magnetic resonance imaging of the brain
E.Renal ultrasound
44d. The Neonatology team decides to consult with the Endocrinology team about how to best
evaluate and manage this infant’s hypercalcemia. The Endocrinology team recommends sending the
following tests:
•Parathyroid hormone (PTH) level
•25 (OH) Vitamin D level
•1,25 (OH)2 Vitamin D level
Of the following, the most likely laboratory findings in this infant are:
A.High PTH, high 25 (OH) Vitamin D, high 1,25 (OH)2 Vitamin D
B.High PTH, low 25 (OH) Vitamin D, high 1,25 (OH) 2 Vitamin D
C.Low PTH, normal 25 (OH) Vitamin D, low 1,25 (OH) 2 Vitamin D
D.Low PTH, low 25 (OH) Vitamin D, low 1,25 (OH) 2 Vitamin D
E.Low PTH, normal 25 (OH) Vitamin D, normal 1,25 (OH) 2 Vitamin D
44e. Which of the following is NOT recommended in the management of an infant with
hypercalcemia?
A.200 mL/kg/day normal saline intravenous fluid
B.Bisphosphonate
C.Corticosteroid
D.Furosemide
 E.Low phosphate formula
Endocrinology Question 45
Soon after birth, a full-term male newborn is noted to have hypospadias.
Which of the following statements about hypospadias is FALSE?
A.Advanced maternal age, pre-existing maternal diabetes mellitus, and maternal smoking have
been associated with hypospadias
B.Delayed circumcision is recommended in case the foreskin may be required for repair
C.Hypospadias is estimated to occur in approximately 1 in 500 births
D.If associated with bilateral undescended testes, congenital adrenal hyperplasia must be
considered
E.The majority of cases of hypospadias are in a sub-coronal location
Endocrinology Question 46
Which of the following statements is FALSE about cryptorchidism in premature male infants?
A.Approximately 90% of premature male infants with cryptorchidism will have descended testes
by 9 months of age
B.Premature infants are more likely to require surgical correction of cryptorchidism than term
male infants
C.Risk factors associated with cryptorchidism include small for gestational age and prenatal
exposure to endocrine disruptors, including diethylstilbestrol and pesticides
D.Testes begin to descend through the inguinal canal at approximately 28 weeks’ gestation
E.The incidence of cryptorchidism is higher in preterm than term male infants
Endocrinology Question 47
Which of the following laboratory and/or radiographic evaluations (1-5) are most indicated in the
initial evaluation of a phenotypically male infant born with bilateral non-palpable testes?
1.Abdominal and pelvic ultrasonography
2.Adrenal hormone and metabolite levels
3.Adrenal ultrasonography
4.Karyotype
5.Luteinizing hormone, follicle-stimulating hormone, Müllerian inhibiting substance, and
testosterone levels
A.1 and 2
B.1, 2, and 3
C.1, 2, and 4
D.1, 2, and 5
E.4 only
Endocrinology Question 48
Which of the following statements about the embryological development of the thyroid gland is
FALSE?
A.Accumulation of iodide for thyroid hormone production begins during the second trimester
B. Development of the thyroid gland begins at approximately 3 weeks’ gestation
C. The thyroid gland develops from a median endodermal thickening in the primitive pharyngeal
floor
D. Thyroglobulin production from thyroid follicles begins at approximately 8 weeks’ gestation
E. Secretion of thyroid-stimulating hormone from the fetal pituitary gland and thyroid hormone
from the fetal thyroid gland begins at approximately 12 weeks’ gestation
Endocrinology Question 49
You are examining a neonate with genitalia that appears to be consistent with a female. However,
you palpate bilateral masses in the labia. A karyotype reveals 46 XY.
Of the following, the most likely disorder in this neonate is:
A. 5-alpha-reductase deficiency
B. 11 beta-hydroxylase deficiency
C. 21-hydroxylase deficiency
D. Androgen insensitivity syndrome
E. Aromatase deficiency
Endocrinology Question 50
Of the following, the most likely change in neonatal carbohydrate physiology soon after birth is a
DECREASE in:
A. Catecholamine secretion
B. Glucagon levels
C. Glycogenolysis
D. Insulin production
E. Ketogenesis
Endocrinology Answers 41-50
Endocrinology Answer 41
B. Thyroglobulin
In contrast to low circulating T3 and T4 that are found in preterm infants, serum concentrations of
thyroglobulin are higher in preterm infants compared with term infants. Additionally, preterm infants
have lower iodide stores and decreased thyroid binding globulin levels compared with term infants.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Feingold SB, Brown RS. Neonatal thyroid function. NeoReviews. 2010;11:e 640-e646
Endocrinology Answer 41
42a. D. Testosterone
During embryogenesis, the fetus contains both female (Müllerian) and male (Wolffian) genital
ducts. Wolffian ducts develop into the vas deferens, epididymis and seminal vesicles. The SRY
gene in males activates events that lead to the differentiation of the gonad to testes. Subsequently, two
hormones, testosterone and Müllerian inhibiting substance (MIS, also known as anti-Müllerian
hormone or Müllerian inhibiting factor) are produced by the testis and stimulate Wolffian duct
differentiation and Müllerian duct regression, respectively. Local conversion of testosterone to DHT
by 5-alpha reductase leads to the fusion of the labioscrotal folds and formation of the scrotum and
penis. INSL3 promotes testicular development. Estradiol is not involved in Wolffian duct
differentiation. The schematic below provides an overview of gonadal differentiation.

42b. D. Mesonephros duct

The Wolffian ducts are derived from the excretory mesonephros duct, which differentiates into the
epididymis, vas deferens, ejaculatory duct, and seminal vesicles. The Müllerian duct, also known as
the paramesonephric duct, is derived from the coelomic epithelium, which develops into the
Fallopian tubes, uterus, cervix, and upper third of the vagina. The genital tubercle develops into the
corpus cavernosa of the penis/phallus in the male and clitoris in the female. The labioscrotal folds
fuse into the scrotum in the male and do not fuse in the female (leading to the labia majora). Refer to
the Table in Question 34.
42c. B. 6-12 weeks of gestation
Sexual differentiation begins by the 6th-7th week of gestation and the critical period of external
virilization is between 6 and 12 weeks of gestation.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Chi C, Chong Lee H, Neely EK. Ambiguous genitalia in the newborn. NeoReviews. 2008;9:e78-
Endocrinology Answer 43
D. Low growth hormone, low cortisol, low free T4
In a healthy newborn, plasma concentrations of GH are persistently elevated but in a newborn who
has hypopituitarism, the GH level is generally less than 5 ng/mL (normal 8-15 ng/mL). Also, random
and stimulated cortisol levels are low. Infants with hypopituitarism have free T4 levels that are low
and TSH is usually low but can be normal.
References:
Dempsher D. Adrenal and pituitary insufficiency in the neonate. NeoReviews. 2008;9:e72-77
Endocrinology Answer 44
44a. E. Subcutaneous fat necrosis
The history and skin findings of the infant in this vignette are consistent with subcutaneous fat
necrosis (SFN), which can be associated with hypercalcemia. The cause of SFN is unknown.
However, possible etiologies include the following:
•Defects in subcutaneous fat
•Hypothermia
•Birth hypoxia
•Local trauma
•Maternal factors such as diabetes or preeclampsia
Histologic examination of a SFN lesion reveals a granulomatous reaction of the fat. The
pathogenesis of hypercalcemia associated with SFN is not well-established. However, one proposed
mechanism is that the granulomas of the SFN secrete increased 1,2 (OH)2 vitamin D, stimulating the
uptake of calcium especially in the intestine. The hypercalcemia found in affected patients is typically
observed several weeks after the skin findings.
There is no known association between pulmonary hypertension and hypercalcemia.
Hypoparathyroidism decreases calcium levels and leads to hypocalcemia. Similarly,
hyperphosphatasia increases alkaline phosphatase activity and decreases serum calcium levels.
44b. C. Hyperphagia
Hyperphagia is NOT commonly associated with hypercalcemia. Symptoms of hypercalcemia in
an infant are non-specific and include the following:
•Poor feeding
•Failure to thrive
•Constipation
•Polyuria
•Dehydration
•Vomiting
•Irritability
Fatal complications include seizures, cardiac arrest, and renal failure.
44c. E. Renal ultrasound
Long standing hypercalcemia can cause nephrocalcinosis, which can be detected with a renal
ultrasound. Head imaging is not likely to be useful because intracranial calcifications are uncommon
in infants with hypercalcemia. Intra-cardiac calcifications would also be uncommon unless there is
concern for generalized arterial calcifications.
44d. C. Low PTH, normal 25 (OH) Vitamin D, low 1,25 (OH)2 Vitamin D
The infant in this vignette most likely has a low PTH level in response to an elevated serum
calcium. Because she is receiving supplemental oral vitamin D, the infant’s 25 (OH) Vitamin D level
should be normal. However, because of the low PTH, the infant may have decreased conversion of
inactive Vitamin D [25 (OH) Vitamin D] to the active form - 1,25 (OH)2 Vitamin D. The regulation
of calcium and phosphorus metabolism is described in the Table.
Intestine Kidney Bone
Ca ~20-60% absorption Filters free Ca and ~98% Enters bone when
(tightly- Majority occurs in proximal reabsorbed (~60% in Ca levels are
regulated) small intestine proximal tubule, ~25% in high and exits
loop of Henle and fine when Ca levels
regulation in distal nephron) are low
Cortisol and
thyroid hormones
increase release
from bone
P ~70-90% absorption Filters free P and ~90% Cortisol and
(daily reabsorbed (majority in thyroid hormone
levels proximal tubule) increase release
vary from bone
widely)
PTH Increases renal production of Increases Ca reabsorption in Increases release
action active form of Vitamin D (or thick ascending loop of of Ca and P from
calcitriol) and thus, indirectly Henle bone (i.e.,
increases Ca and P intestinal Decreases P reabsorption increases bone
absorption (this is PTH’s greatest effect resorption)
on P) Also increases
Decreases renal HCO3 bone remodeling
reabsorption (and thus, Requires Vitamin
increases Cl reabsorption) D for these
Increases renal calcitriol actions
production
Vitamin D 1,25 (0H)2 Vitamin D Conversion of inactive form Calcitriol
action increases absorption of Ca to active form [25(0H) increases PTH
and slightly increases Vitamin D /calcidiol to effect on bone
intestinal absorption of P 1,25(0H)2 Vitamin
D/calcitriol]
PTH and low serum P levels
increase calcitriol
production
Calcitonin No direct effect Small increase in Ca and P Calcitonin inhibits
 action renal excretion release of Ca and
Site of inactivation of P from bone (i.e.,
calcitonin decreases bone
resorption)
No effect on bone
remodeling
Printed with permission from: Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010, p 387-88
44e. E. Low phosphate formula
Intake of low phosphate formula will actually lead to an increase in calcium absorption.
When an infant has hypercalcemia, any exogenous calcium should be discontinued. Subsequently,
intravenous fluid hydration with normal saline at twice the maintenance volume and treatment with
furosemide should help to increase calciuresis. Corticosteroids can be used to inhibit calcium
reabsorption. Finally, bisphosphonates can inhibit osteoclasts (leading to decreased bone turnover)
and increase calciuresis. Calcitonin has also been shown to inhibit intestinal reabsorption of
calcium.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Index of Suspicion in the Nursery. NeoReviews. 2006;7(3):e160-e162
Endocrinology Answer 45
E. The majority of cases of hypospadias are in a sub-coronal location
Hypospadias is the result of incomplete folding or partial closure of the urethra in males and is
estimated to occur in approximately 1 in 500 births. The final position of the urethral opening is
determined by the extent of incomplete folding or closure. The location of the displaced urethral
occurs in the glans or corona in 50% of cases, sub-coronal or penile shaft in 30% of cases, and
scrotum or perineum in 20% of cases. In a rare variant, the foreskin may appear normal and the
urethral abnormality is only noted after circumcision when the glans of the penis becomes visible.
Advanced maternal age, pre-existing maternal diabetes mellitus, gestational age less than 37 weeks,
history of paternal hypospadias, maternal smoking, and pesticide exposure have been associated with
hypospadias. Delayed circumcision is recommended in case the foreskin may be required for repair.
If hypospadias is noted with bilateral undescended testes, congenital adrenal hyperplasia must be
ruled out.
References:
Baskin L. Hypospadias. In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, 2013
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Endocrinology Answer 46
B. Premature infants are more likely to require surgical correction of cryptorchidism than term male
infants.
The incidence of cryptorchidism is higher in preterm infants at (approximately 30%), compared to
3% to 6% in full-term infants. Risk factors associated with cryptorchidism include small for
gestational age, birth weight < 2.5 kilograms, and prenatal exposure to endocrine disruptors (e.g.,
diethylstilbestrol, pesticides). Developmentally, testes begin to descend through the inguinal canal
into the scrotum at approximately 28 weeks’ gestation. Approximately 90% of preterm and 75% of
full-term infants with cryptorchidism will have descended testes by 9 months of age. Thus, term
infants are more likely to require surgical correction than preterm infants.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Cooper C, Docimo S. Undescended testes (cryptorchidism) in children: Clinical features and
evaluation. In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, 2013
Endocrinology Answer 47
C. 1, 2 and 4
A phenotypically male infant born with bilateral non-palpable testes requires evaluation for
congenital adrenal hyperplasia presenting as a female pseudohermaphrodite. Prior to discharge
home, the infant’s evaluation should include imaging to characterize the anatomy and confirm the
presence and location of the testes by abdominal and pelvic ultrasonography. Adrenal hormone and
metabolite levels are required to evaluate for congenital adrenal hyperplasia and a karyotype helps
identify disorders of sexual differentiation.
An adrenal ultrasound is not required in the evaluation of this infant. It is a more useful test in the
setting of an infant with ambiguous genitalia being evaluated for congenital adrenal hyperplasia with
equivocal hormonal levels. Luteinizing hormone, follicle-stimulating hormone, Müllerian inhibiting
substance, and testosterone levels are most helpful when obtained at approximately 6 weeks of life
during the peak of the “mini-puberty of infancy”.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Cooper C, Docimo S. Undescended testes (cryptorchidism) in children: Clinical features and
evaluation. In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, 2013
Endocrinology Answer 48
A. Accumulation of iodide for thyroid hormone production begins during the second trimester
The development of the thyroid gland begins at approximately 3 weeks’ gestation. The thyroid
gland develops from a median endodermal thickening in the primitive pharyngeal floor.
Thyroglobulin production from thyroid follicles begins at approximately 8 weeks’ gestation.
Accumulation of iodide for thyroid hormone production begins as early as 10 weeks’ gestation.
These steps enable secretion of thyroid-stimulating hormone from the fetal pituitary gland and thyroid
hormone from the fetal thyroid gland, which starts at approximately 12 weeks’ gestation.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Sperling MA. Pediatric Endocrinology. 3rd edition. Philadelphia: WB Saunders; 2008
Endocrinology Answer 49
D. Androgen insensitivity syndrome
The infant in the above vignette likely has androgen insensitivity syndrome. The androgen
insensitivity syndromes are disorders in which peripheral tissues are partially to completely
incapable of responding to stimulation by any androgen because of an androgen receptor or
postreceptor defect. In complete androgen insensitivity syndrome, affected individuals have a 46 XY
karyotype with bilateral testes but a failure in Wolffian duct development and complete absence of
any masculinization of the external genitalia. Affected infants have female-appearing external
genitalia with a distal vaginal pouch. The Müllerian structures are absent. The testes are of normal
size and may be descended into the inguinal canal or labia majora, and more than half of these
individuals have an inguinal hernia, which may lead to their clinical recognition in infancy.
Infants with androgen insensitivity syndrome typically have an elevated leutinizing hormone level,
a normal follicle-stimulating hormone level, and an increased testosterone level. In partial androgen
insensitivity syndrome, there are similar clinical and laboratory findings as in complete androgen
insensitivity syndrome. However, there is usually some virilization at the time of puberty.
Aromatase deficiency is an inability to convert testosterone to estradiol and androstenedione to
estrone. Females have Müllerian duct structures and absent Wolffian duct structures. The female
exam is significant for ambiguous genitalia or cliteromegaly.
5 alpha-reductase deficiency is an autosomal recessive disorder leading to the inability to convert
testosterone to dihydrotestosterone. Males have ambiguous genitalia with appropriately
differentiated Wolffian structures, absence of Müllerian derived structures, a small phallus, a
perineal hypospadias at the urogenital sinus, and a blind vaginal pouch. Females have a normal
phenotype.
Deficiencies in the enzymes 21-hyroxylase and 11 beta-hydroxylase lead to congenital adrenal
hyperplasia. Individuals may exhibit postnatal virilization with males having a normal appearance
and females having ambiguous external genitalia.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Fanaroff AA, Martin RJ, Walsh M (eds). Neonatal-Perinatal Medicine. 9th edition. St. Louis: Mosby;
2010
Endocrinology Answer 50
D. Insulin production
At birth, the maternal glucose supply is acutely interrupted and the neonate accommodates by
increasing glucagon levels (3- to 5-fold) within minutes to hours after birth. The neonate also
decreases insulin production and rapidly increases catecholamine secretion. All of these changes lead
to an increase in glycogenolysis, gluconeogenesis, lipolysis, and ketogenesis. Glucose concentration
is lowest 30 to 90 minutes after birth in a full term-infant.
Reference:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Fanaroff AA, Martin RJ, Walsh M (eds). Neonatal-Perinatal Medicine. 9th edition. St. Louis: Mosby;
2010
Endocrinology Questions 51-58
Endocrinology Question 51
All of the following are true about calcium and phosphate homeostasis in the neonate, EXCEPT:
A. Calcitonin increases immediately after birth
B. Calcitriol levels increase during the first day of life
C. Calcium levels increase in the first six hours after delivery
D. Phosphate is high in the first few days of life
E. Parathyroid hormone (PTH) levels increase during the first day of life
Endocrinology Question 52
You are called to the bedside of a 2-week old female infant who had been born at 33 weeks’
gestation. The infant is currently being treated with Amphotericin B for a fungal infection. The nurse
has witnessed seizure activity. Upon your arrival, the seizure has stopped but you observe that the
infant is very irritable with tremors and hyperreflexia. She also has a weak respiratory effort. You
ask the nurse to send blood for specific laboratory tests.
Of the following, the most likely abnormality in this infant is:
A. Hypercalcemia
B. Hyperkalemia
C. Hypernatremia
D. Hypomagnesemia
E. Hypophosphatemia
Endocrinology Question 53
A neonate presents with ambiguous external genitalia, hypertension, normal electrolytes, and
increased deoxycorticosterone and deoxycortisol concentrations.
What is the most appropriate management of this infant?
A. Glucocorticoid and mineralocorticoid replacement and reconstructive surgery of abnormal
female genitalia
B.Glucocorticoid and mineralocorticoid replacement, salt supplementation, and reconstructive
surgery of abnormal female genitalia
C. Glucocorticoid replacement and reconstructive surgery of abnormal female genitalia
D.Mineralocorticoid replacement and reconstructive surgery of abnormal female genitalia
E. Salt supplementation and reconstructive surgery of abnormal female genitalia
Endocrinology Question 54
Of the following, the most likely time period that the fetal thyroid gland begins secreting thyroid
hormones is
A. 3 weeks’ gestation
B. 8 weeks’ gestation
C. 12 weeks’ gestation
D. 6 months’ gestation
E. 8 months’ gestation
Endocrinology Question 55
You are taking care of a 1-week old female infant born at 31 weeks’ gestation. You just heard that
the newborn state screen revealed a slightly elevated 17-hydroxyprogesterone (17-OHP) level. The
baby is clinically stable and receiving feedings with unfortified maternal milk via a nasogastric tube.
Reviewing her laboratory results, you notice that the infant has mild hyponatremia. On physical
examination, you notice a slightly enlarged clitoris.
 The most preferred approach in managing the infant in this vignette is to:
A.Immediately start the baby on stress steroids
B.Discuss with the parents that the infant’s mild hyponatremia is likely related a low sodium
concentration in the breast milk
C.Not take any further action as the newborn state screen often yields false-positive results for
congenital adrenal hyperplasia in premature babies
D.Reassure the parents that the slightly enlarged clitoris is a normal variant of prematurity
E.Send a repeat newborn state screen as well as electrolytes and a 17-OHP level
Endocrinology Question 56
A male infant is born at 39 weeks’ gestation to a mother with no significant medical history. The
pregnancy was notable for conception with a sperm donor due to paternal infertility.
At delivery, the infant appears vigorous without any respiratory distress. During a detailed
physical exam, the infant’s phallus is noted to be 1 cm when fully extended. His testes are descended
bilaterally. A karyotype reveals he is 46 XY.
Which hormone was responsible for his phallic development prior to the 8th week of gestation?
A.Dihydrotestosterone
B.Follicle-stimulating hormone
C.Human chorionic gonadotropin
D.Luteinizing hormone
E.Testosterone
Endocrinology Question 57
A term infant is born to parents who are expecting a male infant as the free fetal DNA analysis had
identified a XY genotype. The infant’s birth weight is 3400g and the birth length is 50 cm. On
examination, the neonatology fellow is concerned about a micropenis with a urethral meatus at the
base. The infant’s testes are palpable in the inguinal canal bilaterally. The father of the child is known
to have a mutation in the DNA-binding domain of the androgen receptor.
Which laboratory test is most likely to have an abnormally-high result for this infant?
A.Cortisol
B.Follicle-stimulating hormone
C.Serum potassium
D.Serum sodium
E.Testosterone
Endocrinology Question 58
Congenital adrenal hyperplasia is the most common cause of virilization in females. 21 α-
hydroxylase deficiency accounts for 95% of these cases.
Which of the following plasma steroid profiles is MOST TYPICAL of the salt wasting form of 21
α-hydroxylase deficiency?
A.Elevated: 11-deoxycorticosterone and aldosterone; Variable: 17-hydroxyprogesterone;
Decreased: dehydroepiandrosterone and renin
B.Elevated: 17-hydroxyprogesterone dehydroepiandrosterone and 11-deoxycorticosterone;
Decreased: aldosterone, and renin
C.Elevated: 17-hydroxyprogesterone, dehydroepiandrosterone, and renin: Decreased: 11-
deoxycorticosterone and aldosterone
D.Elevated: 17-hydroxyprogesterone, dehydroepiandrosterone, and renin: Normal: 11-
deoxycorticosterone and aldosterone
E.Elevated: dehydroepiandrosterone and renin: Decreased: 17-hydroxyprogesterone, 11-
deoxycorticosterone and aldosterone
Endocrinology Answers 51-58
Endocrinology Answer 51
C. Calcium levels increase in the first six hours after delivery
Fetal skeletal growth and cell growth is dependent upon maternal calcium and phosphorous
supply. Calcium increases throughout gestation with the greatest increase during the third trimester.
Calcium levels decrease rapidly in the first six hours after delivery and are at the lowest levels at
~24 hours of age. Following the initial decrease in calcium, PTH increases during the first day of life
and peaks at ~48 hours of life.
Calcitriol [1,25(OH)2 vitamin D3] levels also increase initially. Phosphate is high in the first few
days of life and slowly declines with age. Calcitonin is secreted primarily by the parafollicular cells
of the thyroid gland. Its main biologic effect is to inhibit osteoclastic bone resorption. Secretion of
calcitonin varies with acute changes in serum calcium concentration. Calcitonin increases
immediately after birth and then slowly decreases.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Polin RA, Fox WW, Abman SH (eds). Fetal and Neonatal Physiology. 3rd edition. Philadelphia: WB
Saunders Co; 2004
Endocrinology Answer 52
D. Hypomagnesemia
Hypomagnesemia occurs when serum magnesium concentrations fall below 1.6 mg/dL (0.66
mmol/L), although clinical signs often do not develop until they fall below 1.2 mg/dL (0.49 mmol/L).
The signs of hypomagnesemia are the same as those of hypocalcemia: irritability, tremors, and
seizures. They can also include hyperreflexia, muscle weakness (especially of the respiratory
muscles) and a prolonged QT interval. The causes of hypomagnesemia in a neonate include the
following:
•Maternal magnesium deficiency
•Malabsorption
•Chronic diarrhea
•Drug-induced (of which Amphotericin is a cause)
•Hypoparathyroidism
•Perinatal depression
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Fanaroff AA, Martin RJ, Walsh M (eds). Neonatal-Perinatal Medicine. 9th edition. St. Louis: Mosby;
2010
Endocrinology Answer 53
C. Glucocorticoid replacement and reconstructive surgery of abnormal female genitalia
The infant described in this vignette most likely has 11 beta-hydroxylase deficiency, the second
most common cause of congenital adrenal hypoplasia. In this enzyme deficiency, 11-deoxycortisol
cannot be converted to cortisol and deoxycorticosterone cannot be converted to corticosterone,
resulting in cortisol and aldosterone deficiency, respectively. In addition, affected infants have an
increase in testosterone production. Despite the deficiency in aldosterone, affected infants do not
have salt-wasting because deoxycorticosterone functions as a mineralocorticoid. Thus,
glucocorticoid replacement and reconstructive surgery of abnormal female genitalia are appropriate
management strategies in infants with 11 beta-hydroxylase deficiency.
21-hydroxylase deficiency is the most common cause of congenital adrenal hyperplasia. Affected
patients have salt-wasting, cortisol and mineralocorticoid deficiency, and elevated 17-OH
progesterone levels.
References:
Brodsky D, Martin C. Neonatology Review. 2nd Edition. Lulu. 2010
Sperling MA. Pediatric Endocrinology. 3rd edition. Philadelphia: WB Saunders; 2008
Endocrinology Answer 54
C. 12 weeks’ gestation
The anatomic development of the thyroid gland begins at 3 weeks’ gestation. The thyroid gland
develops from a median endodermal thickening in the primitive pharyngeal floor. Thyroid follicles
form and begin thyroglobulin production at ~ 8 weeks’ gestation. The fetal thyroid can accumulate
iodide at ~ 10 weeks’ gestation. Thyroid stimulating hormone production from the pituitary gland
begins at ~12 weeks’ gestation. Thyroid hormones are secreted from the fetal thyroid gland beginning
at ~12 weeks’ gestation.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Sperling MA. Pediatric Endocrinology. 3rd edition. Philadelphia: WB Saunders; 2008
Endocrinology Answer 55
E. Send a repeat newborn state screen as well as electrolytes and a 17-OHP level
Premature infants have a high false-positive rate of diagnosing congenital adrenal hyperplasia
(CAH) based on a newborn state screening test in premature infants In addition, most affected
neonates with CAH have an extremely elevated 17-OHP value, rather than a mild elevation as the
infant in this vignette. However, this infant’s mildly elevated 17-OHP still warrants further
investigation in the setting of abnormal laboratory findings and an enlarged clitoris. It is also
important to note that prenatal steroids might result in false-negative results. Therefore, the clinician
needs to send a repeat newborn state screen and further confirmatory tests to assess for CAH.
Because 21-hydroxylase deficiency is the cause in more than 95% of infants with CAH, this infant’s
17-OHP (i.e., the substrate of this enzyme) should be measured. If the level of 17-OHP remains high,
the infant should be immediately referred to a pediatric endocrinologist. Electrolytes should be
measured as well, since CAH can present in two clinical syndromes: a salt-losing form or a non-salt-
losing form. Although supplying enough glucocorticoids to reduce hyperplasia is the mainstay of
therapy, this therapy is not yet warranted in the patient in this vignette because a diagnosis of CAH
has not been confirmed.
References:
Cavarzere P, Samara-Boustani D, Flechtner I, et al. Transient hyper-17-hydroxyprogesteronemia: a
clinical subgroup of patients diagnosed at neonatal screening for congenital adrenal hyperplasia.
Eur J Endocrinol. 2009;161:285-292
Gatelais F, Berthelot J, Beringue F, et al. Effect of single and multiple courses of prenatal
corticosteroids on 17-hydroxyprogesterone levels: implication for neonatal screening of
congenital adrenal hyperplasia. Pediatr Res. 2004;56:701-705
Varness TS, Allen DB, Hoffman GL. Newborn screening for congenital adrenal hyperplasia has
reduced sensitivity in girls. J Pediatr. 2005;147:493-498
Endocrinology Answer 56
C. Human chorionic gonadotropin
This infant described in this vignette most likely has partial adrenal insensitivity syndrome (PAIS),
whereby mutations in the androgen receptor (AR) lead to a reduction in androgen signaling. More
severe forms, such as complete androgen insensitivity syndrome (CAIS), may lead to female external
genitalia.
PAIS retains some androgen signaling due to less severe mutations in the AR. Therefore, normal
signals are able to induce development of external male genitalia, though to varying degrees. Prior to
production of androgens by the fetal testes, maternal hCG provides sufficient stimulation for
testosterone synthesis in the adrenal glands. Normal penile development, without bifid scrotum or
hypospadias, requires early hCG stimulation and sufficient levels of signaling through the AR.
Phallic development in the second and third trimester requires luteinizing hormone (LH) receptor
activity of the Leydig cells. By the 8th week of gestation, LH triggers production of testosterone by
the Leydig cells. Testosterone can be converted to dihydrotestosterone by 5-alpha-reductase starting
in the 12th week of gestation. Lack of adequate testosterone signaling in the third trimester results in
micropenis.
Follicle-stimulating hormone acts on Sertoli cells to assist with spermatogenesis but does not
participate in androgen signaling.
References:
Hiort O. Clinical and molecular aspects of androgen insensitivity. Endocr Dev. 2013;24:33-40
Massanyi EZ, Dicarlo HN, Migeon CJ, Gearhart JP. Review and management of 46,XY disorders of
sex development. J Pediatr Urol. 2013;9:368-379
Endocrinology Answer 57
E. Testosterone
Disorders of sexual development may lead to ambiguous genitalia. Dihydrotestosterone drives the
virilization process in both male and female fetuses. Undervirilization in infants with 46XY can be
attributed to congenital adrenal hyperplasia (CAH), including a deficiency of 5-alpha-reductase,
which completes the final conversion of testosterone to active dihydrotestosterone.
A mutation of the androgen receptor (AR), which is encoded on the X chromosome, can also lead
to a disorder of sexual development, as is the case with this family. Lack of androgen signaling
results in decreased virilization. In patients with AR mutations, testosterone is usually upregulated
due to lack of gondatropin releasing hormone inhibition by testosterone. Therefore, testosterone
levels are elevated. Patients with AR mutations do not have any adrenal defects, and thus cortisol
and electrolyte abnormalities are not expected. Follicle-stimulating hormone (FSH) elevations have
been observed in some males with hypogonadism, but not specifically for males with AR mutations.
Disorders of sexual development can be due to chromosomal abnormalities, assessed by
karyotype. The most frequently observed abnormal karyotypes in patients with these disorders are 45
XO and 47 XXY. Affected infants are unlikely to present with ambiguous genitalia but rather,
typically present with hypogonadism.
Initial studies to evaluate an infant with ambiguous genitalia include electrolytes to monitor for salt
wasting due to CAH, a karyotype, and FISH for SRY. At greater than 48 hours of life, serum levels
of 17-hydroxyprogesterone, FSH, leutinizing hormone, testosterone and estradiol are useful.
Consultation with the Endocrinology team can be helpful for gender assignment decisions.
References:
Arboleda VA, Sandberg DE, Vilain E. DSDs: Genetics, underlying pathologies and psychosexual
differentiation. Nat Rev Endocrinol. 2014;10:603-615
Hiort O, Holterhus PM, Horter T, et al. Significance of mutations in the androgen receptor gene in
males with idiopathic infertility. J Clin Endocrinol Metab. 2000;85:2810-2815
Endocrinology Answer 58
C. Elevated: 17-hydroxyprogesterone, dehydroepiandrosterone, and renin; Decreased: 11-
deoxycorticosterone and aldosterone
21 α-Hydroxylase catalyzes the conversion of progesterone to deoxycorticosterone in the
aldosterone synthesis pathway and 17-hydroxyprogesterone to 11-deoxycorticosterone in the cortisol
synthesis pathway. The disruption of these pathways leads to the accumulation of precursor steroids
(progesterone and 17-hydroxyprogesterone), the loss of downstream steroids (11-
deoxycorticosterone, cortisol, corticosterone and aldosterone), and the shunting of these precursors to
the testosterone synthesis pathway (increased dehydroepiandrosterone, androstenedione, and
testosterone), which is independent of the 21 α-Hydroxylase enzyme.
The other options listed in this question are associated with the following enzymatic defects:
21 α-hydroxylase deficiency (simple virilizing form, has some 21 hydroxylase activity)-
Elevated: 17-hydroxyprogesterone, dehydroepiandrosterone, and renin
Normal: 11-deoxycorticosterone, and aldosterone
11 β-Hydroxylase deficiency-
Elevated: 17-hydroxyprogesterone, dehydroepiandrosterone, and 11-deoxycorticosterone
Decreased: aldosterone and renin
3β hydroxysteroid deficiency-
Elevated; dehydroepiandrosterone, and renin
Decreased: 17-hydroxyprogesterone, 11-deoxycorticosterone, and aldosterone
17 α-Hydroxylase deficiency-
Elevated: 11-deoxycorticosterone, and aldosterone
Variable: 17-hydroxyprogesterone
Decreased: dehydroepiandrosterone and renin
References:
Chi C, Lee HC, Nelly EK. Ambiguous genitalia in the newborn. NeoReviews. 2008;9:e78-84
Martin RJ, Fanaroff AA, Walsh MC. Fanaroff and Martin's Neonatal-Perinatal Medicine: Diseases of
the Fetus and Infant, 10th ed. Elsevier, 2015
X. INBORN ERRORS OF METABOLISM &
THERMOREGULATION
Inborn Errors of Metabolism & Thermoregulation Questions 1-10
Inborn Errors of Metabolism & Thermoregulation Question 1
A male infant born at 36 weeks’ gestation presents to the Neonatal Intensive Care Unit at six hours
of age with a profound metabolic acidosis, elevated pyruvate and lactate concentrations,
hyperammonemia, and ketonuria. A diagnosis of pyruvate carboxylase deficiency is suspected.
Which of the following is MOST likely to improve this infant’s status?
A. Biotin
B. Carnitine
C. D-penicillamine
D. Glycine
E. Restriction of methionine
Inborn Errors of Metabolism & Thermoregulation Question 2
An infant presents in the newborn period with lactic acidosis, hypoglycemia, and hepatomegaly.
Further testing reveals that the infant has a glycogen storage disease.
Of the following, the enzyme that is most likely to be deficient in this infant is:
A.Branching enzyme
B.Debranching enzyme
C.Glucose-6-phosphatase
D.Lysosomal alpha-glucosidase
E.Phosphorylase kinase
Inborn Errors of Metabolism & Thermoregulation Question 3
A two-day old infant is found to have poor feeding, vomiting, and lethargy. Laboratory evaluation
reveals significant hyperammonemia, elevated urine organic acids, a respiratory alkalosis, and a
normal serum glucose. Based on these findings, a urea cycle defect is suspected and the infant is
diagnosed with ornithine carbamyl transferase deficiency.
Which is the typical inheritance pattern of ornithine carbamyl transferase deficiency?
A.Autosomal dominant
B.Autosomal recessive
C.X-linked dominant
D.X-linked recessive
E.No genetic transmission has been established
Inborn Errors of Metabolism & Thermoregulation Question 4
A previously healthy male infant is being evaluated at 2-months of age because of
hepatosplenomegaly and poor muscle tone. Ophthalmologic examination reveals clear corneas with
macular cherry red spots.
Bone marrow biopsy would reveal which of the following findings?
A. Foam cells
B. Gaucher cells
C. Marrow fibrosis
D. Normal bone marrow
E. White blood cell inclusions
Inborn Errors of Metabolism & Thermoregulation Question 5
A previously healthy female infant is brought to the Emergency Room at 4-months of life because
of seizures. He is hypotonic and has subtle facial dysmorphisms. Laboratory evaluation reveals
normal sodium, potassium, and calcium with an anion-gap metabolic acidosis. Her serum lactate and
pyruvate concentrations are both elevated. A sepsis evaluation is unremarkable. Head imaging
reveals global cerebral and cerebellar atrophy and absence of the corpus callosum. A metabolic
disorder is suspected, most likely a deficiency in pyruvate dehydrogenase.
Which of the following type of inheritance pattern is associated with this disorder?
A. Autosomal dominant
B. Autosomal recessive
C. Mitochondrial
D. X-linked dominant
E. X-linked recessive
Inborn Errors of Metabolism & Thermoregulation Question 6
A neonate is suspected of having a urea cycle defect after presenting with hyperammonemia, a
primary respiratory alkalosis, and a normal serum glucose. The infant’s serum amino acids and urine
organic acids are measured. The infant has elevated serum glutamine and alanine amounts with low
serum citrulline and arginine. The infant’s urine orotic acid concentrations are low.
Of the following, the most likely enzyme that is deficient in the infant in this vignette is:
A. Arginase
B. Argininosuccinic acid synthetase
C. Ornithine carbamyl transferase
D. Carbamyl phosphate synthetase
E.N-acetylglutamate synthetase
Inborn Errors of Metabolism & Thermoregulation Question 7
The Newborn State Screening Laboratory reports the newborn screening results of a 2-week old
former 28 week gestational age infant. The testing reveals an elevated tyrosine concentration with a
normal phenylalanine concentration. The infant’s serum glucose and liver function studies are
normal.
What is the most appropriate next step?
A.Begin a tyrosine-free diet to decrease the likelihood of liver failure and future malignancy
B.Decrease protein intake while awaiting repeat state screening results
C.Immediately initiate treatment with nitisinone to decrease toxic metabolite production
D.Repeat the newborn state screen to confirm results before intervening
E.Send serum and urine succinylacetone levels and urine reducing substances
Inborn Errors of Metabolism & Thermoregulation Question 8
Biotinidase deficiency causes all of the following, EXCEPT:
A. Alopecia
B. Ataxia
C. Blindness
D. Nystagmus
E. Seizures
Inborn Errors of Metabolism & egulation Question 9
A five-month old male infant has sagging lips, joint laxity, and brittle, steely hair. The pregnancy
was remarkable for premature rupture of membranes. He is at risk for developmental delay, seizures,
neurological decline, and osteoporosis.
His disorder is caused by a defect in the transport of what metal?
A. Chromium
B. Copper
 C. Iron
D. Selenium
E. Zinc
Inborn Errors of Metabolism & Thermoregulation Question 10
A three-day old female newborn suffers from lethargy, hypotonia, and seizures. She has
respiratory failure and hiccups with need for intubation and mechanical ventilation. Head imaging
reveals an absent corpus callosum. An electroencephalogram shows a burst suppression pattern.
There are elevated glycine concentrations in the infant’s urine, blood, and cerebrospinal fluid.
The diagnosis most consistent with the findings in this infant is:
A.Familial glycinuria
B.Hartnup disease
C.Maple syrup urine disease
D.Non-ketotic hyperglycinemia
E.Propionic acidemia
Inborn Errors of Metabolism & Thermoregulation Answers 1-10
Inborn Errors of Metabolism & Thermoregulation Answer 1
A. Biotin
Pyruvate carboxylase deficiency is an autosomal recessive mitochondrial disorder. Infants may
present in the neonatal period with neurological abnormalities (seizures, coma, hypotonia,
hypertonia) and hepatomegaly. More commonly, affected children present at a few months of age with
developmental delay, failure to thrive, lethargy, seizures, feeding difficulty, and renal dysfunction.
Presenting laboratory abnormalities include a metabolic acidosis, elevated pyruvate and lactate
concentrations, ketonuria, and hyperammonemia. Citrullinemia may occur in severe cases because of
low oxaloacetate levels that lead to decreased aspartate and decreased arginosuccinic acid. Biotin
may help in this potentially fatal disease.

D-penicillamine and methionine restriction are management options for treating infants with
cystinuria. Glycine administration can be used in the management of isovaleric acidemia to increase
non-toxic isovalerylglycine production. Carnitine can be used to increase isovalerylglycine
excretion. Carnitine can also be used to supplement patients with carnitine deficiency.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Fernandes J, Saudubray JM, Van den Berghe G, Walter JH (eds). Inborn Metabolic Diseases:
Diagnosis and Treatment. 4th edition. Berlin and New York: Springer-Verlag; 2006
Scriver CR, Sly WS, Childs B, et al (eds). The Metabolic and Molecular Bases of Inherited Disease.
8th edition. McGraw-Hill; 2000
Inborn Errors of Metabolism & Thermoregulation Answer 2
C. Glucose-6-phosphatase
There are 8 known types of glycogen storage disease. Only two types (Type I and Type II) have
symptoms in the neonatal period. Type I, known as von Gierke’s disease, results from a deficiency in
glucose-6-phosphatase. This leads to impaired breakdown of glucose-6-phosphate resulting in
decreased production of glucose and glycogen. It is the only glycogen storage disease that causes
lactic acidosis. It is also associated with hypoglycemia, hepatomegaly, neutropenia, diarrhea, failure
to thrive, increased infection risk, and possible bleeding diathesis secondary to liver failure. Thus,
the infant in this vignette most likely has glucose-6-phosphatase deficiency.
Type II glycogen storage disease, known as Pompe disease, is caused by a deficiency in the
lysosomal alpha-glucosidase. Neonatal symptoms include severe, symmetric muscle weakness and
cardiomegaly with congestive heart failure.
A summary of the glycogen storage diseases is provided below:
Enzyme Deficiency Clinical Prognosis
Type I Glucose-6-phosphatase Lactic acidosis (only this Poor prognosis
von type), low glucose Early death if no treatment
Gierke Hepatomegaly, neutropenia Possible hematomas in late
FTT, diarrhea childhood
Bleeding disorder (results
from liver failure)
Increased risk for infection
Type II Lysosomal -glucosidase Symmetric severe muscle Poor prognosis
Pompe weakness Usually death < age 1 year
Cardiomegaly, CHF
Type III Debranching enzyme- Low glucose, ketonuria No signs in neonatal period
Forbes amylo-1,6-glucosidase Hepatomegaly Good prognosis
Muscle fatigue
Type IV Branching enzyme Cirrhosis beginning at No signs in neonatal period
Andersen several months of age Very poor prognosis
Hypotonia Death from liver failure less
Muscle weakness than 4 years of age
Type V Muscle phosphorylase Muscle fatigue in No signs in neonatal period
McArdle adolescence Good prognosis
Type VI Liver phosphorylase Mild hypoglycemia No signs in neonatal period
Hers Hepatomegaly, Ketonuria Usually good prognosis
Type VII Muscle Similar to type V No signs in neonatal period
Tarui phosphofructokinase Muscle fatigue in Good prognosis
adolescence
Type Phosphorylase kinase Similar to type III yet No signs in neonatal period
VIII without myopathy Good prognosis
Low glucose
Ketonuria, Hepatomegaly
GI = gastrointestinal; FTT = failure to thrive; CHF = congestive heart failure
Modified from lecture by JF Nicholson, MD: Inborn errors of metabolism. Children's Hospital of New York-Presbyterian Medical
Center, 1994 and printed with permission from: Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010, p 397
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Fernandes J, Saudubray JM, Van den Berge G, Walter JH (eds). Inborn Metabolic Diseases:
Diagnosis and Treatment. 4th edition. Berlin and New York: Springer-Verlag, 2006
Inborn Errors of Metabolism & Thermoregulation Answer 3
D. X-linked recessive
There are many enzymes involved in the urea cycle, any of which can cause defects leading to
clinical disease. Most neonates affected with urea cycle defects present in the first few days of life
with poor feeding, vomiting, apnea, and changes in mental status. All defects involve some degree of
hyperammonemia, primary respiratory alkalosis, and normal serum glucose. Ornithine carbamyl
transferase deficiency is the most common urea cycle defect and is typically inherited in an X-linked
recessive pattern. Interestingly, heterozygote females are also severely affected as a result of random
X inactivation of the abnormal gene. Other laboratory findings include elevated urine orotic acid;
increased serum glutamine and alanine; and decreased serum citrulline and arginine.
Treatment for this and other urea defects involves removing the infant’s nitrogen load by limiting
protein intake, administration of sodium benzoate or sodium phenylacetate, or, in severe cases,
hemodialysis. Avoidance of catabolism is important. Depending on the type of urea cycle defect,
citrulline supplementation may also be warranted.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Fernandes J, Saudubray JM, Van den Berge G, Walter JH (eds). Inborn Metabolic Diseases:
Diagnosis and Treatment. 4th edition. Berlin and New York: Springer-Verlag, 2006
Inborn Errors of Metabolism & Thermoregulation Answer 4
A. Foam cells
The child described in the vignette most likely has Niemann-Pick disease, Type A. This disease is
a congenital lipidosis, caused by a lysosomal storage disease. It typically presents in the first month
of life with hepatosplenomagaly and nervous system deterioration. Hallmarks include macular cherry
red spots, clear corneas, and foam cells on bone marrow biopsy. Niemann-Pick disease Type B does
not have ophthalmologic or central nervous system involvement. Both disorders result from a
sphingomyelinase defect.
Other lipidoses include Types I and II Gaucher disease, which affects people of Ashkenazi Jewish
descent. This disease affects children of any age and results from defects in the enzyme
glucocerebrosidase. While affected individuals do not have ophthalmological abnormalities,
hepatosplenomegaly and neurologic manifestations (Type II) are present. Bone marrow evaluation
reveals Gaucher cells. White blood cell bone marrow inclusions are found in both generalized
gangliosidosis and Wolman disease, while the bone marrow is normal in Tay-Sachs disease,
metachromatic leukodystrophy, Fabry disease, and Krabbe disease.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Nicholson JF. Inborn Errors of Metabolism. Children’s Hospital of New York-Presbyterian Medical
Center, 1994
Inborn Errors of Metabolism & Thermoregulation Answer 5
C. Mitochondrial
Pyruvate dehydrogenase deficiency is a mitochondrial disorder. It presents in childhood with
delays in development, poor muscle tone and weakness, seizures, ataxia or choreoathetosis, and
global cerebral atrophy. It is associated with an absent corpus callosum and subtle facial
dysmorphology, including a narrow head with frontal bossing, wide nasal bridge, long philtrum, and
flared nostrils. Serum chemistries reveal anion-gap metabolic acidosis with elevated lactate and
pyruvate levels. Pyruvate dehydrogenase deficiency is diagnosed by assessing abnormal enzyme
activity in white blood cells or skin fibroblasts. This disease does not have a treatment and is
uniformly fatal.
References:
Brown GK, Otero LJ, LeGris M, Brown RM. Pyruvate dehydrogenase deficiency. J Med Genet.
1994;31:875–9
Nicholson JF. Inborn Errors of Metabolism. Children’s Hospital of New York-Presbyterian Medical
Center, 1994
Inborn Errors of Metabolism & Thermoregulation Answer 6
D. Carbamyl phosphate synthetase
The urea cycle pathways are shown in the Figure below. The specific serum amino acid and urine
organic acid abnormalities in each urea cycle defect is also summarized below. Based on this
infant’s laboratory findings, carbamyl phosphate synthetase is the most like enzyme that is deficient in
the infant in this vignette.

Urine Orotic
Disorder Glutamine/Alanine Citrulline Arginine
Acid
N-acetylglutamate High Low Low Low
synthetase
Carbamyl phosphate High Low Low Low
synthetase
Ornithine carbamyl High High Low Low
transferase
Argininosuccinic acid High High High Low
 synthetase
Argininosuccinic lyase High High High Low
Arginase High High High High
Printed with permission from: Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010, p 400
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Fernandes J, Saudubray JM, Van den Berge G, Walter JH (eds). Inborn Metabolic Diseases:
Diagnosis and Treatment. 4th edition. Berlin and New York: Springer-Verlag, 2006
Inborn Errors of Metabolism & Thermoregulation Answer 7
E. Send serum and urine succinylacetone levels and urine reducing substances
Tyrosine is produced from phenyalanine and breaks down into fumarate and acetoacetate (shown
below).

An elevated serum tyrosine corresponds to tyrosinemia or transient tyrosinemia of the newborn.

The results of the abnormal screening tests of the premature infant in this vignette are most consistent
with transient tyrosinemia of the newborn. This condition results from immaturity of hepatic enzymes
involved in tyrosine metabolism, affects up to 10% of preterm infants, and resolves spontaneously
with age. Transient tyrosinemia is a diagnosis of exclusion. Both transient tyrosinemia of the
newborn and tyrosinemia have elevated tyrosine and normal phenylalanine. Tyrosinemia may be
distinguished from the benign transient tyrosinemia because tyrosinemia also has elevated serum and
urine succinylacetone levels and positive urine reducing substances.
It is important to distinguish between the two entities (tyrosinemia and transient tyrosinemia of the
newborn) because they have distinct therapies and prognoses. Individuals affected with tyrosinemia
are treated with nitisinone to decrease toxic metabolite production as well as a diet low in tyrosine,
phenylalanine, and methionine. Despite these interventions, infants with tyrosinemia may progress to
hepatic failure and require a liver transplant. In contrast, transient tyrosinemia of the newborn is
benign and self-limited. Infants may respond to supplemental ascorbic acid and decreased protein
intake.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Fernandes J, Saudubray JM, Van den Berge G, Walter JH (eds). Inborn Metabolic Diseases:
Diagnosis and Treatment. 4th edition. Berlin and New York: Springer-Verlag, 2006
Inborn Errors of Metabolism & Thermoregulation Answer 8
D. Nystagmus
Biotinidase deficiency is an autosomal recessive condition. Symptoms are the result of decreased
available biotin for enzymatic reactions. Symptoms present during infancy and include immune
dysfunction, alopecia, and skin rash. If untreated, biotinidase deficiency may lead to neurologic
dysfunction, including seizures, hypotonia, lethargy, ataxia, blindness, and hearing loss. Affected
individuals have an abnormal newborn state screen with low serum biotinidase. Treatment is with
oral biotin supplementation.
Reference:
Martin RJ, Fanaroff AA, Walsh MC. Fanaroff and Martin’s Neonatal-Perinatal Medicine Diseases of
the Fetus and Infant. St. Louis: Mosby, 9th edition, 2010
Inborn Errors of Metabolism & Thermoregulation Answer 9
B. Copper
Menkes disease is an X-linked recessive disorder of copper transport, the hallmark of which is
brittle, steely, and kinky hair. It also disrupts nervous system and bone development. The diagnosis
of Menkes disease may be confirmed by low serum ceruloplasmin and copper levels. Treatment
involves daily copper injections, which may increase life expectancy to the teen years.
Reference: NCBI Bookshelf: Menkes Syndrome. http://www.ncbi.nlm.nih.gov/books/NBK22216/
Inborn Errors of Metabolism & Thermoregulation Answer 10
D. Non-ketotic hyperglycinemia
Non-ketotic hyperglycinemia is an autosomal recessive disease resulting from defective cleavage
of glycine to ammonia.

Most infants demonstrate symptoms within the first 48 hours of life, including lethargy, hypo- or
hypertonia, seizures, obtundation, respiratory failure, and hiccups. This disorder is associated with
an absent corpus callosum and an electroencephalographic burst suppression pattern that evolves to
hypsarrhythmia during the second month of life. Laboratory analysis reveals elevated urine, blood,
and cerebrospinal glycine concentrations. There is no reliably effective treatment; prognosis is poor.
Familial glycinuria is a disorder of defective renal glycine reabsorption, variably accompanied by
oxalate urolithiasis. It has an autosomal dominant inheritance pattern. Hartnup disease is an
autosomal recessive condition resulting from amino acid transport defect causing skin disease, ataxia,
dystonia, and seizures. Maple syrup urine disease is a group of autosomal recessive defects in the
enzymes responsible for the metabolism of branched-chain amino acids (leucine, isoleucine, and
valine). It presents at birth with neurological abnormalities, though the hallmark is an odor of maple
syrup in the urine. It is treated by restricting intake of branched-chain amino acids. Propionic
aciduria, also known as ketotic hyperglycinemia, is an autosomal recessive disease caused by
propionyl-CoA carboxylase deficiency. It has a similar clinical presentation as non-ketotic
hyperglycinemia, however ketones are present in the urine and blood.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Fernandes J, Saudubray JM, Van den Berge G, Walter JH (eds). Inborn Metabolic Diseases:
Diagnosis and Treatment. 4th edition. Berlin and New York: Springer-Verlag, 2006
Inborn Errors of Metabolism & Thermoregulation Questions 11-20
Inborn Errors of Metabolism & Thermoregulation Question 11
A newborn infant presents with lethargy and poor feeding in the first day of life. A work-up for an
infectious etiology, including a complete blood count, urinalysis, and cerebrospinal fluid chemistries,
cell count, and gram stain, are normal. Serum electrolytes are normal. Head imaging shows no
evidence of intraventricular hemorrhage, stroke, or mass. Serum ammonia level is 300 mmols/L with
normal concentrations of lactate and amino acid. The urine does not contain ketones and has normal
organic acids levels.
Of the following, the infant in this vignette most likely has:
A. Arginase deficiency
B. Glutaric aciduria
C. Methylmalonic acidemia
D. Ornithine transcarboxylase deficiency
E. Transient neonatal hyperammonemia
Inborn Errors of Metabolism & Thermoregulation Question 12
The newborn state screen results for a healthy full-term infant reveals elevated methionine
concentrations. Laboratory analysis shows increased serum and urine homocysteine. Confirmatory
testing is positive for homocystinuria.
The child is at risk for all of the following, EXCEPT:
A.Downward dislocated lens
B.Osteoporosis
C.Short stature
D.Seizures
E.Thrombosis
Inborn Errors of Metabolism & Thermoregulation Question 13
A male infant is born at 28 weeks’ gestation. After observation for 24 hours, he is transitioned
from a radiant warmer to an isolette to minimize heat loss.
All of the following provide an explanation for this infant’s risk for heat loss, EXCEPT:
A. Decreased epidermal and dermal thickness
B. Decreased subcutaneous fat
C. Decreased surface area to body weight ratio
D. Immature nervous system
Inborn Errors of Metabolism & Thermoregulation Question 14
A late preterm infant becomes hypothermic when placed on a cold blanket.
Of the following, which type of heat loss best explains this infant’s hypothermia?
A. Conductive
B. Convective
C. Evaporative
D. Radiant
Inborn Errors of Metabolism & Thermoregulation Question 15
A 15-year old boy has an ophthalmologic examination and is noted to golden-brown granular
pigmentations on his cornea. He also has difficulty speaking and abnormal jerky movements of his
extremities. His mother reports that he also has liver disease.
What is the treatment of choice for this child’s condition?
A.Biotin
 B.Copper injections
C.D-penicillamine
D.Sodium benzoate
E.Sodium phenylacetate
Inborn Errors of Metabolism & Thermoregulation Question 16
An infant presents at 7-days of age with significant hepatosplenomegaly. Metabolic screening
suggests that the infant has the lipidosis Gaucher-Type I.
Which of the following enzymes is affected in individuals with Gaucher-Type I?
A. Arylsulfatase
B. Beta galactosidase
C. Glucocerebrosidase
D. Hexosamindase
E. Sphingomyelinase
Inborn Errors of Metabolism & Thermoregulation Question 17
Which of the following urea cycle defects will result in low serum orotic acid concentrations?
A.Argininosuccinic acid synthetase deficiency
B.Argininosuccinic lyase deficiency
C.Ornithine carbamyl transferase deficiency
D.N-acetylglutamate synthetase deficiency
Inborn Errors of Metabolism & Thermoregulation Question 18
A 1-month old baby girl is brought to the Emergency Room by ambulance after a new onset of
seizure activity with whole body shaking. The parents report that she had been vomiting for the past
week and has not been interested in eating. She was born at 41 weeks’ gestation by repeat Cesarean
section and had been exclusively breastfed until 3 weeks of age when formula supplementation was
started.
The parents report that the infant had been doing well and had demonstrated weight gain at the
most recent visit to the pediatrician two weeks ago. Initial laboratory findings include hypoglycemia,
elevated liver function tests, and the presence of urine reducing substances.
Which of the following enzymes is most likely absent in this infant?
A.Carbamyl phosphate synthetase
B.Fructose 1-phosphate aldolase
C.Galactose-1-phosphate-uridyltransferase
D.Phenylalanine hydroxylase
E.Pyruvate carboxylase
Inborn Errors of Metabolism & Thermoregulation Question 19
You are called to provide a consultation for a pregnant woman whose prior infant died at 2 days
of life. Genetic testing was performed during this pregnancy; an amniocentesis showed absence of
the enzyme galactose-1-phosphate-uridyltransferase.
If this infant does not receive treatment postnatally, all of the following laboratory markers will be
abnormal, EXCEPT for:
A.Coagulation factors
B.Glucose
C.Lactate
D.Liver function tests
Inborn Errors of Metabolism & Thermoregulation Question 20
 Which of the following presentations is more consistent with a diagnosis of an inborn error of
metabolism than a diagnosis of hypoxic-ischemic encephalopathy?
A.Absence of dysmorphic features
B.Hyperammonemia
C.Hypoglycemia
D.Metabolic abnormalities occur after an interval period of good health
E.Metabolic acidosis
F.Perinatal distress at birth requiring resuscitation
G.Seizures
Inborn Errors of Metabolism & Thermoregulation Answers 11-20
Inborn Errors of Metabolism & Thermoregulation Answer 11
E. Transient neonatal hyperammonemia
The differential diagnosis for neonatal hyperammonemia is extensive, but can be simplified into
disorders with 1) acidosis and ketonuria; 2) acidosis without ketonuria, or 3) absence of acidosis and
ketonuria. The infant described above falls into the last category. In the presence of normal serum
amino acids and urine organic acids, the infant most likely has transient neonatal hyperammonemia.
This is a benign disorder of unknown etiology. It typically occurs in preterm infants and is thought to
be related to immaturity of N-acetylglutamate synthetase enzyme activity. Therapy is supportive,
possibly involving dialysis if ammonia levels persist at dangerously high levels. Prognosis is good
with no long-term sequelae.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Nicholson JF. Inborn Errors of Metabolism. Children’s Hospital of New York-Presbyterian Medical
Center, 1994
Inborn Errors of Metabolism & Thermoregulation Answer 12
C. Short stature
Homocystinuria is an autosomal recessive condition caused by a deficiency in either Vitamin B12
dependent
betaine-homocysteine methyltransferase, methyltetrahydofolate-homocysteine methyltransferase, or
pyridoxine-dependent cystathionine synthetase, the latter of which is more common. The pathway is
shown below.

Homocystinuria is typically asymptomatic in infancy but can lead to multi-organ dysfunction,

including:
•Ophthalmologic abnormalities: downward dislocated lenses, glaucoma, myopia
•Bony abnormalities: osteoporosis, scoliosis, increased tendency to fracture bones, tall stature,
arachnodactyly, decreased joint mobility
•Neurological abnormalities: developmental delay, cognitive impairment, seizures
•Hematological issues: increased thrombosis and bleeding risk
Homocystinuria can be successfully treated by supplementing with pyridoxine, cysteine, and folate
and limiting dietary methionine. Prognosis is good if normal homocysteine levels are attained.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Fernandes J, Saudubray JM, Van den Berge G, Walter JH (eds). Inborn Metabolic Diseases:
Diagnosis and Treatment. 4th edition. Berlin and New York: Springer-Verlag, 2006
Inborn Errors of Metabolism & Thermoregulation Answer 13
C. Decreased surface area to body weight ratio
Premature neonates are more prone to heat loss because they have:
1. Decreased epidermal and dermal thickness → increased radiant and conductive heat loss
2. Minimal subcutaneous fat → decreased response to cooling
 3. Immature nervous system → decreased response to cooling
4. Increased surface area to body weight ratio (3X greater than adult ratio)
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Fanaroff AA, Martin RJ, Walsh MC (eds). Neonatal-Perinatal Medicine: Diseases of the Fetus and
Infant. 8th edition. Philadelphia: Mosby-Elsevier; 2006
Inborn Errors of Metabolism & Thermoregulation Answer 14
A. Conductive
Conductive heat loss indicates transfer of heat from a neonate to a contacting solid object. An
infant will become cold if he/she is placed on a cold blanket or mattress because of conductive heat
loss. The four types of heat loss are compared in the next Table.
Conductive Convective Evaporative Radiant
Definition Transfer of Transfer of heat from Transfer of heat Transfer of heat
heat from neonate to surrounding from skin and between neonate
neonate to gas respiratory tract to and surface that
a The heated air expands a drier is not in contact
contacting and then travels upwards environment with neonate
solid Heat loss is in the
object form of
electromagnetic
waves
Examples Cold blanket Cool air Prematurity leading Incubator walls,
or mattress Air currents will lead to to immature windows, chairs,
more turbulence and stratum corneum light bulbs, other
displacement of heated and poor people
gas epidermal barrier
~40-50% of function
nonevaporative neonatal Younger postnatal
heat loss age
High velocity of
surrounding air
Prevention Place infant Limit air currents; plastic Plastic cover Protect incubator
on warm cover Increase incubator walls from
blanket or May require environmental humidity excess cooling
mattress temperature to be greater Double walled
than skin temperature to isolette
maintain a normal core Plastic cover
temperature
Printed with permission from: Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010, p 425
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Fanaroff AA, Martin RJ, Walsh M (eds). Neonatal-Perinatal Medicine. 9th edition. St. Louis: Mosby;
2010
Inborn Errors of Metabolism & Thermoregulation Answer 15
C. D-penicillamine
 The patient in this vignette most likely has Wilson Disease, an autosomal recessive disorder
resulting from the inability to transport copper in the liver. This abnormality leads to copper
deposition in the liver, cornea, basal ganglia, and renal tubules. Deposition in the cornea causes
golden brown pigmentations called Kayser-Fleischer rings. Neurological symptoms such as
dysarthria and extrapyramidal movements, as noted in this patient, result from copper deposition in
the basal ganglia. The treatment of choice is D-penicillamine, which chelates copper to reduce serum
levels.
Biotin is a ubiquitous vitamin that binds to carboxylases and enhances its function. Individuals
affected with biotinidase deficiency are treated with biotin supplementation. Biotinidase is an enzyme
that allows release of biotin from carboxylase so that it can be reutilized. Affected patients present
during infancy with immune deficits, alopecia, and rash.
Copper injections are the treatment for Menkes Disease, a disorder caused by a defect in the
membrane copper transport channel leading to poor absorption and cellular distribution of copper.
Brittle, kinky, steely hair is a characteristic physical finding in affected patients.
Sodium benzoate and sodium phenylacetate are scavengers for ammonia that allow nitrogen
precursors to be excreted in the urine. They are used to treat infants with severe hyperammonemia
that results from urea cycle defects.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Fernandes J, Saudubray JM, Van den Berghe G, Walter JH (eds). Inborn Metabolic Diseases:
Diagnosis and Treatment. 4th edition. Berlin and New York: Springer-Verlag; 2006
Inborn Errors of Metabolism & Thermoregulation Answer 16
C. Glucocerebrosidase
There are many types of lipidoses (summarized in the Table below). These disorders are caused
by distinct enzymatic abnormalities, and have varying onset and clinical manifestations. Gaucher-
Type I is caused by an abnormality in the glucocerebrosidase enzyme.
Type Defect Onset Ophtho CNS, Liver
Findings Spleen
Glucosylceramide Glucocerebrosidase Any Normal HSM Gaucher cells in b
Lipidosis I = age Normal CNS Increased risk of
Gaucher I Common in Ashke
Glucosylceramide Glucocerebrosidase Infant- Normal HSM Gaucher cells in b
Lipidosis II = 2 yo Profound Common in Ashke
Gaucher II CNS loss
Sphingomyelin Sphingomyelinase First Clear HSM Foam cells in bon
Lipidosis A month cornea Profound
Niemann-Pick A Cherry CNS loss
red
spots in
1/2
Sphingomyelin Sphingomyelinase First Normal HSM Foam cells in bon
Lipidosis B month Normal CNS
Niemann-Pick B or
later
 GM 2- Hexosaminidase A 3–6 Clear No HSM Normal bone mar
gangliosidosis months cornea Profound
Tay-Sachs Cherry CNS loss
red
spots
Generalized galactosidase Infant Clear HSM Inclusions in WBC
gangliosidosis cornea Profound
Infantile GM 1 Cherry CNS loss
red
spots in
1/2
Metachromatic Arylsulfatase A 1–2 yo Normal No HSM Normal bone
leukodystrophy Profound marrow
CNS loss
Fabry disease galactosidase Early Cloudy +/- Normal bone mar
or late cornea hepatomegaly X-linked
child- Normal Normal CNS Incidence ~1:80,0
hood retina
Galactosyl- galactosidase First Normal No HSM Normal bone mar
ceramide lipidosis few cornea Profound Storage is not lyso
= Krabbe disease months Optic CNS loss
atrophy
Wolman Disease Acid lipase Infant Normal Hepatomegaly Inclusions in WBC
Profound
CNS loss
Adrenal
calcifications
Ophtho= ophthalmologic; CNS=central nervous system; HSM=hepatosplenomegaly; WBC=white blood cells. Modified from lecture b
nd
Printed with permission from: Brodsky D, Martin C. Neonatology Review. 2 . Lulu. 2010, p 412
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Fernandes J, Saudubray JM, Van den Berghe G, Walter JH (eds). Inborn Metabolic Diseases:
Diagnosis and Treatment. 4th edition. Berlin & New York: Springer-Verlag; 2006
Inborn Errors of Metabolism & Thermoregulation Answer 17
D. N-acetylglutamate synthetase deficiency
The urea cycle is shown in the Figure. Of the choices listed in this vignette, only N-
acetylglutamate synthetase deficiency would lead to low orotic acid concentrations because the
enzyme defect occurs prior to the formation of orotic acid. The remaining enzyme deficiencies occur
after the formation of orotic acid and thus the absence of any of these enzymes would lead to the
diversion of the urea cycle pathway toward the creation of orotic acid and thus cause elevated serum
concentrations. The Table following shows the abnormalities of glutamine, alanine, urine orotic acid,
citrulline, and arginine associated with urea cycle defects.
A N-acetylglutamate synthetase if deficiency → normal or low orotic acid, inconsistent amino
acid profile
B Carbamyl phosphate synthetase
If deficiency → congenital hyperammonemia type I, autosomal recessive, hyperammonemia,
normal or low orotic acid, increased glutamine and alanine, decreased citrulline, decreased
arginine
C Ornithine carbamyl transferase
If deficiency → congenital hyperammonemia type II, X-linked recessive (yet many
heterozygote females are also severely affected depending on type of mutation and result of
random X inactivation of the abnormal gene)
Most common of all urea cycle abnormalities; incidence of 1:70,000
Severe/lethal in males, partially defected females (with unaffected fathers)
Extremely elevated urine orotic acid, hyperammonemia, increased glutamine and alanine,
decreased citrulline, decreased arginine
D Argininosuccinic acid synthetase if deficiency → citrullinemia, brittle hair
Hyperammonemia, very high citrulline, orotic aciduria, decreased arginine
E Argininosuccinic lyase if deficiency → argininosuccinic aciduria
Autosomal recessive, brittle hair
Orotic aciduria, some increased citrulline, decreased arginine
If severe deficiency, leads to hyperammonemia
F Arginase if deficiency → argininemia
Autosomal recessive, typically presents with spastic diplegia that progresses, orotic aciduria
Urine Orotic
Disorder Glutamine/Alanine Citrulline Arginine
 Acid
N-acetylglutamate synthetase High Low Low Low
Carbamyl phosphate High Low Low Low
synthetase
Ornithine carbamyl High High Low Low
transferase
Argininosuccinic acid High High High Low
synthetase
Argininosuccinic lyase High High High Low
Arginase High High High High
Printed with permission from: Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010, p 400
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Fernandes J, Saudubray JM, Van den Berghe G, Walter JH (eds). Inborn Metabolic Diseases:
Diagnosis and Treatment. 4th edition. Berlin and New York: Springer-Verlag; 2006
Lee B. Management of urea cycle disorders. UpToDate.com (Subscription required). Accessed on
October 9, 2011
Inborn Errors of Metabolism & Thermoregulation Answer 18
B. Fructose 1-phosphate aldolase
This infant most likely has fructosemia as result of a deficiency in fructose 1-phosphate aldolase,
leading to an inability to break down fructose. This enzyme is found only in the liver, kidney, and
intestine. Infants who are exclusively breastfed are asymptomatic until formula is introduced.
Breastmilk contains lactose, which is made up of galactose and glucose while cow’s milk formula
contains sucrose, which is made up of fructose and glucose. Clinical symptoms of fructose 1-
phosphate aldolase deficiency include vomiting, lethargy, and seizures. If prolonged, infants may
exhibit failure to thrive, liver disease, and renal dysfunction. The pathway of hereditary fructose
intolerance is shown below:

Deficiency of carbamyl phosphate synthetase leads to congenital hyperammonemia Type I, a urea

cycle disorder characterized by elevated ammonia levels. Although this disorder is affected by
protein intake, it is not affected by exposure to fructose or other types of carbohydrates.
Deficiency of galactose-1-phosphate-uridyltransferase leads to galactosemia, which typically
presents soon after any type of feeding is introduced. Both breastmilk and formula contain lactose,
which is made up of galactose and glucose.
Deficiency of phenylalanine hydroxylase leads to phenylketonuria (PKU). Affected infants cannot
convert phenylalanine to tyrosine. Neonates are asymptomatic prior to feedings. Similar to
galactosemia, both breastfed and formula-fed infants will be affected.
Deficiency of pyruvate carboxylase leads to pyruvate dehydrogenase complex deficiency, a
mitochondrial disorder characterized by an inability to convert pyruvate to oxaloacetate. The onset
of symptoms is not affected by the type of infant feeding.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Fernandes J, Saudubray JM, Van den Berghe G, Walter JH (eds). Inborn Metabolic Diseases:
Diagnosis and Treatment. 4th edition. Berlin and New York: Springer-Verlag; 2006
Inborn Errors of Metabolism & Thermoregulation Answer 19
C. Lactate
This infant will have classic galactosemia, which results from the absence of the galactose-1-
phosphate-uridyltransferase enzyme leading to an inability to break down galactose into glucose (see
Figure below). Clinical findings include poor feeding, vomiting within the first 2 to 3 days of life,
lethargy, jaundice, hepatomegaly, liver failure and renal tubular dysfunction. Because of liver failure,
liver function tests will be elevated and production of coagulation factors will be decreased.
Affected infants will not be able to convert galactose to glucose, and thus, will have hypoglycemia.
Although these infants will have a metabolic acidosis, it results from renal tubular dysfunction and not
from excessive lactate concentrations.

References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Fernandes J, Saudubray JM, Van den Berghe G, Walter JH (eds). Inborn Metabolic Diseases:
Diagnosis and Treatment. 4th edition. Berlin and New York: Springer-Verlag; 2006
Inborn Errors of Metabolism & Thermoregulation Answer 20
D. Metabolic abnormalities occur after an interval period of good health
The following criteria are necessary to diagnose hypoxic-ischemic encephalopathy (HIE):
1. Evidence of metabolic acidosis with fetal or early neonatal blood sample (pH <7.00 and
base deficit ≥12 mmol/L)
2. Early-onset of moderate or severe encephalopathy (infants ≥ 34 weeks’ gestation)
3. Spastic quadriplegia or dyskinetic cerebral palsy
4. Exclusion of other causes, such as trauma, coagulopathies, infection and genetic disorders.
Other characteristics of HIE include:
•A sentinel hypoxic event, which occurs immediately before or during labor
•Sudden, rapid deterioration of fetal heart rate
•Apgar scores of 0 to 3 for longer than 5 minutes
•Early evidence of multisystem involvement
•Early imaging evidence of an acute cerebral abnormality
•Metabolic and respiratory acidosis, hypoglycemia, hypocalcemia, hyponatremia (results from
SIADH) and hyperammonemia (results from hepatic dysfunction)
In contrast, inborn errors of metabolism (IEM) usually present postnatally, after an interval period
of apparent good health, following a normal pregnancy. An infant with IEM can also present with
metabolic acidosis, hyperammonemia, hypoglycemia, and seizures. In general, IEM is more likely
when the degree of metabolic abnormalities appear out of proportion to the obstetrical and birth
history and when there is a report of consanguinity. Infants with HIE usually do not have dysmorphic
features. Similarly, most IEMs are not usually associated with dysmorphic features. Some exceptions
include Smith-Lemli-Opitz syndrome, (a disorder of cholesterol synthesis), Zellweger syndrome (a
peroxisomal disorder), and Menkes disease (a disorder of copper metabolism).
Reference:
Enns GM. Inborn errors of metabolism masquerading as hypoxic-ischemic encephalopathy.
NeoReviews. 2005;6(12):e549-558
Inborn Errors of Metabolism & Thermoregulation Questions 21-30
Inborn Errors of Metabolism & Thermoregulation Question 21
Please match the following laboratory findings with the inborn error of metabolism among infants
who have hypoglycemia.
Inborn Error of Metabolism Possible Diagnoses
Galactosemia Abnormal urine organic acids
Disorders of amino acid metabolism Abnormal acylcarnitine profile
Organic acidemias Increased serum ketones and lactate
Fatty acid oxidation defects Urine non-glucose reducing substances
Glycogen storage diseases Abnormal serum amino acids
Inborn Errors of Metabolism & Thermoregulation Question 22
Which of the following statements is TRUE about testing for an inborn error of metabolism?
A.Ammonia concentrations can be falsely low if the sample is not immediately rushed on ice to the
laboratory and analyzed
B.Free and total carnitine concentrations should be ordered in order to test for fatty acid oxidation
defects
C.Lactate and pyruvate concentrations should be obtained simultaneously for comparison
D.Results from an expanded newborn screening are sufficient to make a diagnosis of an inborn
error of metabolism
E.All of the above
Inborn Errors of Metabolism & Thermoregulation Question 23
Which of the following features are consistent with galactosemia?
A.Abnormal urine organic acids
B.Cataracts
C.Hyperbilirubinemia
D.Klebsiella sepsis
E.A, B, C
F.B, C
G.B, C, D
Inborn Errors of Metabolism & Thermoregulation Question 24
True or False:
Metabolic etiologies for non-immune hydrops are usually caused by lysosomal and glycogen
storage diseases and are therefore easily diagnosed with post-natal testing for these disorders.
Inborn Errors of Metabolism & Thermoregulation Question 25
Please select the laboratory findings that are found in the following inborn errors of metabolism
among infants who have hyperammonemia.
Organic Pyruvate metabolism defects or Urea Transient
acidemias mitochondrial energy metabolism cycle hyperammonemia of
defects defects the newborn
Metabolic
acidosis
Lactic
acidosis
Abnormal
 urine organic
acids
Abnormal
plasma
amino acids
Inborn Errors of Metabolism & Thermoregulation Question 26
Please select the laboratory findings that are found in the following inborn errors of metabolism
among infants with a metabolic acidosis.
Glycogen storage Pyruvate Mitochondrial energy Organic
diseases, hereditary metabolism metabolism defects, acidemias, fatty
fructose intolerance defects pyruvate carboxylase acid oxidation
deficiency disorders
Lactic acidosis
Elevated
lactate/pyruvate
ratio
Hypoglycemia
Abnormal urine
organic acids
Inborn Errors of Metabolism & Thermoregulation Question 27
A 9-month old male infant presents to the Emergency Room with lethargy and difficulty breathing.
His mother provides you with a discharge summary from his last hospital admission, which states that
he suffers from a glycogen storage disease. His examination is significant for hypotonia, inability to
sit on his own, and minimal head control. A chest radiograph shows significant cardiomegaly.
Which of the following enzymes is most likely absent in this infant?
A.Debranching enzyme-amylo-1,6-glucosidase
B.Glucose-6-phosphatase
C.Liver phosphorylase
D.Lysosomal alpha-glucosidase
E.Muscle phosphorylase
Inborn Errors of Metabolism & Thermoregulation Question 28
A neonatal nurse is instructing new parents of a baby born at 24 weeks’ gestation about the
preferred use of the isolette portholes during routine care of their infant.
What type of neonatal heat loss is decreased by use of the portholes during care times?
A.Condensation
B.Conductive
C.Convective
D.Evaporative
E. Radiant
Inborn Errors of Metabolism & Thermoregulation Question 29
Which of the following is an accurate definition of a thermoneutral zone in a newborn?
A.Environmental temperature between 36.5°C and 37.5°C
B.Environmental temperature between 36.5°C and 37.5°C with 60% to 70% humidity
C.Environmental temperature in which the newborn has minimal metabolic demands in the form of
 oxygen consumption and maintains a temperature in the normal range
D.Environmental temperature range in which the newborn can maintain a body temperature
between 36.5°C and 37.5°C
E.Newborn body temperature between 36.5°C and 37.5°C in which the infant’s metabolic activity
is most efficient
Inborn Errors of Metabolism & Thermoregulation Question 30
He has a history of chronic lung disease but has been in room air for the past week. He has very
infrequent desaturation episodes and has been off caffeine for 10 days. He is receiving most of his
feedings by a nasogastric tube, although he is beginning to exhibit oral cues to feed.
He has recently been transitioned from an incubator to a crib. The ambient temperature of the
NICU is about 20.5°C (68.9°F). Over the next 3 days his weight plateaus without any gain during the
first 2 days and weight loss on the third day. He has increased desaturation episodes for which he is
placed back in oxygen. Soon after transition to a crib, his temperature ranges were normal between
36.5°C and 36.8°C but this morning, his temperature has been 36°C despite extra bundling.
His examination is significant for some decreased activity compared to his baseline. The
neonatology team is considering obtaining a sepsis evaluation to find a cause for his clinical changes.
The parents ask if these changes could be related to a premature transition out of the incubator.
Which of the following statements is an accurate answer to the question posed by the parents in
this vignette?
A.As the ambient temperature of the NICU is within the thermoneutral zone of the infant these
changes cannot be a result of the transition
B.Newborns respond to thermal stress by agitation and the decreased activity on exam makes
transition from the incubator an unlikely cause of this infant’s condition
C.The changes in this infant’s condition could result from a premature transition out of the
incubator
D.The increased oxygen requirement is not a feature of thermal stress and therefore the changes in
his condition must be caused by something else
E.The normal body temperature range of the infant soon after transition to a crib suggests that his
condition cannot be a result of this transition
Inborn Errors of Metabolism & Thermoregulation Answers 21-30
Inborn Errors of Metabolism & Thermoregulation Answer 21
Inborn Error of Metabolism Diagnosis
Galactosemia Urine non-glucose reducing substances
Disorders of amino acid metabolism Abnormal serum amino acids
Organic acidemias Abnormal urine organic acids
Fatty acid oxidation defects Abnormal acylcarnitine profile
Glycogen storage diseases Increased serum ketones and lactate
In the setting of severe hypoglycemia, the initial screening laboratory tests previously mentioned
should be ordered to assess for an inborn error of metabolism, in addition to urine for reducing
substances. Urine for reducing substances can be abnormal in the setting of galactosemia as well as
hereditary fructose intolerance and tyrosinemia. Fatty acid oxidation defects usually present with low
serum/urine ketones and hypoglycemia with an abnormal acylcarnitine profile. Glycogen storage
diseases usually present with hypoglycemia during a period of fasting, and thus it is often missed in
the newborn period because infants feed regularly. Laboratory findings associated with glycogen
storage disease Type 1 include hypoglycemia, lactic acidosis, elevated serum ketones and
hyperuricemia.
Reference:
Dagli AI, Zori RT, Heese BA. Testing strategy for inborn errors of metabolism in the neonate.
NeoReviews. 2008;9(7):e291-e298
Inborn Errors of Metabolism & Thermoregulation Answer 22
C. Lactate and pyruvate concentrations should be obtained simultaneously for comparison
Ammonia concentrations can be significantly elevated if the sample is not rushed on ice to the
laboratory and analyzed. Results for ammonia, pyruvate and lactate values are most accurate when
obtained from a free-flowing blood sample without the use of a tight tourniquet and then rushed to the
lab on ice. Lactate and pyruvate concentrations should be obtained simultaneously for comparison.
An acylcarnitine profile is more informative in diagnosing fatty oxidation defects than total and free
carnitine concentrations alone. Abnormal results from an expanded newborn screen should always be
confirmed by more definitive testing; the newborn screen is a screening test.
Reference:
Dagli AI, Zori RT, Heese BA. Testing strategy for inborn errors of metabolism in the neonate.
NeoReviews. 2008;9(7):e291-e298
Inborn Errors of Metabolism & Thermoregulation Answer 23
F. Cataracts and Hyperbilirubinemia
Classic galactosemia is caused by a deficiency of galactose-1-phosphate-urdyltransferase, an
enzyme involved in the breakdown of lactose. The pathway is shown below:

Infants with galactosemia usually present with poor feeding, vomiting, lethargy, and
hyperbilirubinemia, which can progress to liver failure with hepatomegaly, coagulopathy and
hypoalbuminemia. Cataracts occur at birth or, more commonly, after 2 weeks of age as a result of
excess galactitol, but regress with good dietary control of lactose. Infants are at increase risk of
infection with Escherichia coli. The presence of a nonglucose urine reducing substance is indicative
of galactosemia.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Dagli AI, Zori RT, Heese BA. Testing strategy for inborn errors of metabolism in the neonate.
NeoReviews. 2008;9(7):e291-e298
Inborn Errors of Metabolism & Thermoregulation Answer 24
False
Etiologies for non-immune hydrops include cardiac, hematologic, endocrine, infectious, pulmonary
and metabolic. Inborn errors of metabolism that can lead to non-immune hydrops include the
following:
Inborn Error of Metabolism Laboratory Test
Lysosomal storage diseases Urine screen for mucopolysaccarides and
oligosaccharides
Smith-Lemli-Opitz syndrome 7-dehydrocholestrol
Mevalonic aciduria urine organic acids
Zellweger syndrome Plasma very long chain fatty acids
Congenital disorders of glycosylation Serum transferring isoforms
Mitochondrial disorders Serum lactate
Glycogen storage disease type IV Enzyme studies, liver biopsy
Glucose 6-phopsphate dehydrogenase Complete blood count with peripheral smear for
(G6PD) hemolytic anemia
Pyruvate kinase deficiency Complete blood count with peripheral smear for
hemolytic anemia
Despite an extensive evaluation, the metabolic evaluation of infants with hydrops does not usually
yield a diagnosis.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Dagli AI, Zori RT, Heese BA. Testing strategy for inborn errors of metabolism in the neonate.
NeoReviews. 2008;9(7):e291-e298
Inborn Errors of Metabolism & Thermoregulation Answer 25
Organic Pyruvate metabolism defects or Urea Transient
acidemias mitochondrial energy metabolism cycle hyperammonemia of
defects defects the newborn
Metabolic
X X
acidosis
Lactic
X
acidosis
Abnormal
urine organic X
acids
Abnormal
plasma X
 amino acids
An infant with hyperammonemia often presents with encephalopathy. If an infant is
encephalopathic, the laboratory studies listed above can help to differentiate the potential causing
condition. It is important to differentiate these disorders with transient hyperammonemia of the
newborn, which presents with elevated ammonia concentration in the first 24 hours of life with
normal plasma amino acids and no acidosis.
Reference:
Dagli AI, Zori RT, Heese BA. Testing strategy for inborn errors of metabolism in the neonate.
NeoReviews. 2008;9(7):e291-e298
Inborn Errors of Metabolism & Thermoregulation Answer 26
Glycogen storage Pyruvate Mitochondrial energy Organic
diseases, hereditary metabolism metabolism defects, acidemias, fatty
fructose intolerance defects pyruvate carboxylase acid oxidation
deficiency disorders
Lactic acidosis X X X X (or none)
Elevated
lactate/pyruvate X X
ratio
Hypoglycemia X X (or none)
Abnormal urine
X
organic acids
When metabolic acidosis is present, it is important to determine whether or not there is an
increased anion gap. Lactic acidosis usually occurs because of mild cardiovascular instability and
associated anaerobic metabolism. If the degree of lactic acidosis appears to be out of proportion to
the cardiovascular instability, an inborn error of metabolism that leads to an increase in lactate
should be considered. In addition, acylcarnitine profiles can be considered during the evaluation to
assess for organic acidemias and fatty acid oxidation disorders.
Reference:
Dagli AI, Zori RT, Heese BA. Testing strategy for inborn errors of metabolism in the neonate.
NeoReviews. 2008;9(7):e291-e298
Inborn Errors of Metabolism & Thermoregulation Answer 27
D. Lysosomal alpha-glucosidase
A comparison of the glycogen storage diseases is shown in the Table below.
Enzyme Deficiency Organ Clinical Prognosis
Type I Glucose-6- Liver Lactic acidosis Poor prognosis
von Gierke phosphatase Kidney (only this type), Early death if no
GI low glucose treatment
Hepatomegaly, Possible
neutropenia hematomas in
FTT, diarrhea late childhood
Bleeding
disorder
(results from
liver failure)
 Increased risk
for infection
Type II Lysosomal alpha- All organs Symmetric Poor prognosis
Pompe glucosidase (especially severe muscle Usually death
skeletal muscle weakness less than age 1
and nerves) Cardiomegaly, year
CHF

Type III Debranching enzyme- Liver Low glucose, No signs in

Forbes amylo-1,6- Muscle ketonuria neonatal period
glucosidase Hepatomegaly Good prognosis
Muscle fatigue
Type IV Branching enzyme Liver Cirrhosis No signs in
Andersen Nerves beginning at neonatal period
several months Very poor
of age prognosis
Hypotonia Death from liver
Muscle failure less than
weakness 4 years of age
Type V Muscle Muscle Muscle fatigue No signs in
McArdle phosphorylase in adolescence neonatal period
Good prognosis
Type VI Liver phosphorylase Liver Mild No signs in
Hers hypoglycemia neonatal period
Hepatomegaly Usually good
Ketonuria prognosis
Type VII Muscle Muscle Similar to type No signs in
Tarui phosphofructokinase V neonatal period
Muscle fatigue Good prognosis
in adolescence
Type VIII Phosphorylase kinase Liver Similar to type No signs in
III yet without neonatal period
myopathy good prognosis
Low glucose
Ketonuria
Hepatomegaly
GI = gastrointestinal; FTT = failure to thrive; CHF = congestive heart failure
Modified from lecture by JF Nicholson, MD: Inborn errors of metabolism. Children's Hospital of New York-Presbyterian Medical
Center, 1994
The infant in this vignette most likely has Pompe’s Disease, a Type II glycogen storage disease
(GSD). This is a disorder caused by the deficiency of lysosomal -glucosidase. All organs,
especially skeletal muscle and nerves are affected. Affected infants demonstrate marked symmetric
muscle weakness, cardiomegaly, and congestive heart failure. The prognosis is very poor with death
occurring at less than age 1 year.
Debranching enzyme-amylo-1,6-glucosidase deficiency leads to Type III GSD, also known as
Forbes Disease, which typically affects the liver and muscle. Affected children do not exhibit
clinical signs during the neonatal period and the prognosis is good.
Glucose-6-phosphatase deficiency leads to Type I GSD (von Gierke disease), the most common
type of GSD. It affects the liver, kidney, and gastrointestinal system while the brain and muscle are
spared. Neonates can be severely affected without treatment and prognosis is very poor.
Liver phosphorylase deficiency leads to Type VI GSD (Hers disease). This disease affects mainly
the liver with resulting hypoglycemia, hepatomegaly and ketonuria. There are no signs in the neonatal
period and prognosis is good.
Muscle phosphorylase deficiency leads to Type V GSD (McArdle Disease). Affected children
show no signs in the neonatal period. The onset of muscle fatigue occurs during adolescence with
good overall prognosis.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Staretz-Chacham O, Lang TC, LaMarca ME, Krasnewich D, Sidransky E. Lysosomal storage disease
in the newborn. Pediatrics. 2009; 123:1191-120627.
Inborn Errors of Metabolism & Thermoregulation Answer 28
C. Convective
Convective heat loss is the transfer of heat from the neonate to the surrounding gas. During this
process, heated air expands and then travels upwards. The utilization of portholes helps to decrease
convective heat loss by minimizing air currents and thus decreasing turbulence and displacement of
heated air. Prevention of convective heat loss can be accomplished by the use of a plastic cover and
limitation of air currents.
Conductive heat loss is the transfer of heat from the neonate to a contacting solid object.
Conductive heat loss can be prevented by placing an infant on a rubber foam mattress. Evaporative
heat loss is the transfer of heat from the skin and respiratory tract to the environment. Plastic covers
and increased incubator humidity help prevent evaporative heat loss. Radiant heat loss is the transfer
of heat between the neonate and a surface that is not in contact with the infant. Double-walled
incubators help decrease radiant heat loss. Condensation is not a type of heat loss, but instead a
phase change when vapor is cooled and changes its phase to a liquid.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Dollberg S, Hoath SB. Temperature regulation in preterm infants: Role of the skin-environment
interface. NeoReviews. 2001;2:e282-e291
Inborn Errors of Metabolism & Thermoregulation Answer 29
C. Environmental temperature in which the newborn has minimal metabolic demands in the form of
oxygen consumption and maintains a temperature in the normal range
The thermoneutral zone is the environmental temperature that allows a baby to have minimal
metabolic demands and maintain a normal body temperature. The concept of a thermoneutral zone or
environment is important when caring for newborns, particularly those that are preterm. Humans are
homeothermic, which means that they have an ability to maintain their temperature within a narrow
range (36.5°C and 37.5°C) over a wide range of environmental temperatures. However, outside a
certain range of environmental temperatures, the body has to increase its metabolic rate to produce
energy to maintain this narrow range of body temperatures. The thermoneutral zone is influenced by
birthweight and postnatal age and is considerably higher in preterm infants compared with term
infants. Humidity influences the ability of the body to retain heat, especially in preterm infants.
 If the environmental temperature is lower than the thermoneutral zone, the infant’s metabolic
demands increase. For severe temperature abnormalities, the metabolic activities may become
exhausted, leading to an increase in morbidity and mortality. Although metabolic activities are most
efficient in the normal body temperature range, this is not the definition of a thermoneutral zone. An
important implication of this concept is that an infant may have a normal temperature range for some
time even though the infant is placed outside the thermoneutral environment. This period of euthermia
can vary, depending on the infant’s metabolic resources and the extremes of temperature. However,
after some time, a persistent abnormal thermoneutral environment would lead to a metabolic stress on
the infant, leading to an increase in oxygen consumption and shifting of energy away from growth.
Reference:
Ringer SA. Core Concepts: Thermoregulation in the newborn Part I: Basic mechanisms. NeoReviews
2013;14:e161-e167
Inborn Errors of Metabolism & Thermoregulation Answer 30
C. The changes in this infant’s condition could result from a premature transition out of the incubator
A thermoneutral environment is defined as an environmental temperature in which the newborn has
minimal metabolic demands (in the form of oxygen consumption) and one that allows the newborn to
maintain a temperature in the normal range. The thermoneutral zone is influenced by birthweight and
postnatal age and is considerably higher in preterm infants compared to term infants. An important
implication of this concept is that an infant can have a normal temperature range for some time after
being placed in an environment outside the thermoneutral range, depending on the infant’s metabolic
resources and the extremes of temperature. However, this could lead to a metabolic stress on the
infant with an associated increase in oxygen consumption and shifting of energy away from growth.
In this vignette, the ambient temperature of the NICU at 20.5°C is lower than the thermoneutral
zone for most infants, including full-term infants. The World Health Organization recommends a
delivery room temperature of 25°C. Term infants with an inadequate environmental temperature
usually have an initial sympathetic response resulting in agitation. In contrast, preterm infants in this
situation often become lethargic.
Transitioning from the incubator to a crib is a critical requirement towards an infant’s discharge
goals. There are no clear rules about the timing of this transition but most institutions rely on an
infant’s weight to determine when to transition an infant to a crib. After an initial period of
maintaining a normal temperature, the infant in this vignette may have a low temperature as a result of
failing to adjust to a crib because of an immaturity in thermoregulation. Sepsis is another possible
cause of this infant’s clinical findings.
Reference:
Ringer SA. Core Concepts: Thermoregulation in the newborn Part I: Basic mechanisms. NeoReviews
2013;14:e161-e167
Inborn Errors of Metabolism & Thermoregulation Questions 31-33
Inborn Errors of Metabolism & Thermoregulation Question 31
A female infant born at 24 weeks’ gestation is placed in a convective incubator. All of the
following will decrease heat loss, EXCEPT:
A. Adding plastic heat shields
B. Decreasing humidity
C. Using a double-walled incubator instead of a single-walled incubator
D. Using a rubber foam mattress
E. Utilizing portholes during care of the neonate
Inborn Errors of Metabolism & Thermoregulation Question 32
Heat loss in the infant can be categorized into 4 types: evaporative, convective, conductive and
radiant heat loss. Preterm infants are more likely to have an acute and rapid response associated with
heat loss.
Of the following, the most likely device that optimally decreases heat loss in a neonate by all 4
mechanisms is:
A.Double-walled incubators with humidification
B.Exothermic mattress
C.Occlusive plastic wrapping
D.Radiant warmer
E.Single-walled incubators with humidification
Inborn Errors of Metabolism & Thermoregulation Question 33
An infant was just delivered at 34 weeks’ gestation and is being admitted to the NICU. The
admission temperature was 36oC. The neonatology fellow discusses with the team the importance of
avoiding hypothermia in the newborn.
Which of the following statements about hypothermia in the newborn is FALSE?
A.Hypothermia can lead to increased mortality.
B.Hypothermia can lead to increased risk for several comorbidities.
C.Maintaining normothermia is an integral part of newborn life support algorithms.
D.Since the use of increased environmental temperature was introduced in the delivery room,
hypothermia in newborn infants is extremely rare.
E.There are several techniques to maintain normothermia in newborn infants.
Inborn Errors of Metabolism & Thermoregulation Answers 31-33
Inborn Errors of Metabolism & Thermoregulation Answer 31
B. Decreasing humidity
Convective incubators use servocontrol of forced air by using skin or air temperature as a
temperature control. Even with their use, the infant can still have a large amount of heat loss. This
heat loss can be evaporative, radiant, convective, or conductive heat loss. If humidity is increased or
the infant is swaddled, this will decrease evaporative heat loss. If a double-walled incubator is used
instead of a single-walled incubator, this will decrease radiant heat loss. If plastic heat shields are
added, this will also decrease radiant heat loss. Convective heat loss can be minimized by utilizing
portholes during care of the infant. A rubber foam mattress will decrease conductive heat loss.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Fanaroff AA, Martin RJ, Walsh M (eds). Neonatal-Perinatal Medicine. 9th edition. St. Louis: Mosby;
2010
Inborn Errors of Metabolism & Thermoregulation Answer 32
A. Double-walled incubators with humidification
As stated in this vignette, there are 4 mechanisms of heat loss in newborns. Because preterm
infants have an exaggerated loss of heat through all of these mechanisms and lower energy resources
to generate heat, they are particularly vulnerable to hypothermia. Below is a description of each type
of heat loss.
1.Conductive heat loss: as a result of direct contact between the body and an object with a
lower temperature. Conductive heat loss is increased in preterm infants as a result of
increased skin surface area compared to weight. Exothermic mattresses decrease
conductive heat loss by providing a warm surface for contact with the infant’s skin.
2.Convective heat loss: as a result of movement of air with a lower temperature around the
infant’s exposed body. Convective heat loss is increased in preterm infants as a result of
increased skin surface area compared to weight. The only method to decrease convection is
to decrease the movement of air over the infant, which is achieved in closed incubators.
3.Radiant heat loss: as a result of colder objects that are not in direct contact with the body.
Single-walled incubators can continue to allow radiant heat loss as there is poor insulation
between the infant’s environment in the incubator and the outside environment.
4.Evaporative heat loss: as a result of evaporation of water on the body or through highly
permeable skin of preterm infants in a dry environment. Occlusive plastic wrapping can help
to decrease evaporative losses by providing a water-proof barrier and this approach is
recommended by the American Academy of Pediatrics Neonatal Resuscitation Program for
delivery room management of extremely low birthweight infants. Humidification provided in
incubators can help to decrease evaporative losses that result from loss of water through the
thin permeable skin of preterm infants.
Double-walled incubator with humidification can decrease all forms of heat loss and are
commonly employed in NICUs. Single-walled incubators with humidification can also decrease most
forms of heat loss but are susceptible to radiant heat losses if the outside environment is cold.
Exothermic mattresses and occlusive wrappings are helpful for minimizing conductive and
evaporative heat loss, respectively but not for other types of heat loss. Newborns placed on radiant
warmers are still at risk for convective and evaporative heat loss.
Reference:
Ringer SA. Core Concepts: Thermoregulation in the newborn Part I: Basic mechanisms. NeoReviews
2013;14:e161-e167
Inborn Errors of Metabolism & Thermoregulation Answer 33
D. Since the use of increased environmental temperature was introduced in the delivery room,
hypothermia in newborn infants is extremely rare.
Maintaining normothermia is an integral part of newborn resuscitation. Several studies have
shown the effectiveness of thermoregulatory techniques such as skin-to-skin contact, drying and
wrapping, radiant warmers, plastic coverings, and hats. However, maintaining a newborn’s
temperature in a desired range can be challenging and is a worldwide problem. Preventing
hypothermia is of outmost importance since a low body temperature is associated with increased risk
to develop several comorbidities (hypoglycemia, respiratory distress, intraventricular hemorrhage,
coagulation abnormalities) and some studies even suggest that there is an increased mortality.
References:
Chitty H, Wyllie J. Importance of maintaining the newly born temperature in the normal range from
delivery to admission. Semin Fetal Neonatal Med. 2013;18:362-8
Reilly MC, Vohra S, Rac VE, et al. Vermont Oxford Network Heat Loss Prevention (HeLP) Trial
Study Group. Randomized trial of occlusive wrap for heat loss prevention in preterm infants. J
Pediatr. 2015;166:262-8.e2
XII. PHARMACOLOGY & STATISTICS
Pharmacology & Statistics Questions 1-10
Pharmacology Question 1
The major purpose of random assignment in a clinical trial is to:
A. Ensure that the study groups have comparable baseline characteristics
B. Facilitate double blinding
C. Facilitate the measurement of outcome variables
D. Help ensure that study subjects are representative of the general population
E. Reduce selection bias in the allocation of treatment
Pharmacology & Statistics Question 2
In a population of 1,000 neonates, it is found that 100 newborns have a specific disease and 900
do not have this disease. 180 babies have positive test results even though 100 of these infants do not
have actually have the disease.
2a. What is the sensitivity of this screening test?
A. 44%
B. 50%
C. 80%
D. 89%
E. 97%
2b. What is the specificity of this screening test?
A. 44%
B. 50%
C. 80%
D.89%
E. 97%
2c. What is the positive predictive value of this test?
A. 44%
B. 50%
C. 80%
D. 89%
E. 97%
2d. What is the negative predictive value of this test?
A. 44%
B. 50%
C. 80%
D. 89%
E. 97%
Pharmacology & Statistics Question 3
In a small pilot study, the data from 12 neonates who had a previous diagnosis of necrotizing
enterocolitis (NEC) was compared with the data of 12 neonates without NEC. The study was
focused primarily on determining if the use of probiotics was associated with NEC. Each neonate
with NEC was matched by age, race, weight and co-morbidities with a neonate without NEC.
What type of study design is this?
A. Case-control
B. Concurrent cohort
C. Cross-sectional
 D. Randomized control trial
E. Retrospective cohort
Pharmacology & Statistics Question 4
A preterm male infant born at 31 weeks’ gestation is placed on a proton pump inhibitor (PPI) for
treatment of pathologic gastroesophageal reflux disease. Proton pump inhibitors are metabolized
mostly in the liver through the cytochrome P450 system.
Which of the following proton pump inhibitors has been found to have the least interaction with the
cytochrome P450 system?
A. Esomeprazole
B. Lansoprazole
C. Omeprazole
D. Pantoprazole
E. Rabeprazole
Pharmacology & Statistics Question 5
The P450 cytochrome system in the liver is an important enzyme system for the metabolism of
many drugs.
Which one of the following medications can induce the P450 cytochrome system?
A. Erythromycin
B. Indomethacin
C. Omeprazole
D. Phenobarbital
E. Ranitidine
Pharmacology & Statistics Question 6
You have decided to study a drug for the prevention of chronic lung disease. You would like to
confirm the effectiveness of the drug, document side effects, compare its effectiveness with other
treatments, and track its safety in a large patient cohort.
What type of clinical trial are you initiating?
A. Phase I
B. Phase II
C. Phase III
D. Phase IV
Pharmacology & Statistics Question 7
There has been increasing concern that exposure to Bisphenol A (BPA) can lead to adverse health
effects. In order to investigate this further, you would like to initiate a study comparing infants who
were fed with BPA-containing bottles versus infants who were fed with BPA-free bottles. You would
like to follow these infants until adolescence and assess if there is a significant difference in the
incidence of adverse health outcomes between the two groups.
What type of study are you performing?
A.Case-control study
B.Clinical trial
C.Cohort study
D.Cross-sectional study
Pharmacology & Statistics Question 8
You are initiating a study to compare hospital readmission rates for infants born between 34 to 42
weeks’ gestation. You would like to group the infants into late preterm infants (34 0/7 – 36 6/7
weeks), early term infants (37 0/7 – 38 6/7 weeks), and term infants (39 0/7 – 42 6/7 weeks).
What type of data are you creating?
A.Continuous
B.Discrete
C.Nominal
D.Ordinal
E.Ranked
Pharmacology & Statistics Question 9
In a hypothetical study of 10,000 newborns, the mean platelet count is 179,000/µL.
Approximately how many infants were born with platelet counts within one standard deviation
from the mean in this study population?
A.5,000
B.6,000
C.7,000
D.8,000
E.9,000
Pharmacology & Statistics Question 10
The cumulative incidence will approximate the incidence rate in all of the following situations
EXCEPT when the:
A.Duration of disease is the same among the exposed and non-exposed
B.Incidence rate remains constant
C.Period of observation is extremely short
D.Prevalence of disease is low
Pharmacology & Statistics Answers 1-10
Pharmacology & Statistics Answer 1
E. Reduce selection bias in the allocation of treatment
Well-designed randomized control trials (RCTs) are currently the gold standard for measuring an
intervention’s impact across many diverse fields of human inquiry, such as education, welfare and
employment, medicine, and psychology. This is based on persuasive evidence that: (i) RCTs are
superior to other methods in estimating an intervention’s true effect; and (ii) the most common study
designs – including “pre-post” studies and “comparison-group” (or “quasi-experimental”) studies
without careful matching – often produce erroneous conclusions.
RCTs are studies that measure an intervention’s effect by randomly assigning individuals (or
groups of individuals) to an intervention or control group. This random assignment allows
researchers to assess whether the intervention itself, as opposed to other factors, causes the observed
outcomes. Specifically, the process of randomly assigning a large number of individuals into either an
intervention or control group ensures, to a high degree of confidence, that there are no systematic
differences between the groups in any characteristics (observed and unobserved) except one – the
intervention group participates in the intervention, and the control group does not. Therefore,
assuming the RCT is undertaken appropriately, the resulting difference in outcomes between the two
groups can confidently be attributed to the intervention and not to other factors.
References:
Arizona Department of Education. www.ade.az.gov (Subscription required). Accessed September
30, 2011
Hermansen M. Biostatistics: Some Basic Concepts. Patterson, NJ: Caduceus Medical Publishers, Inc;
1990
Norman GR, Streiner DL. Biostatistics: The Bare Essentials. 3rd ed. St. Louis: Mosby; 2008
Pagano M, Gauvreau K. Principles of Biostatistics. 2nd ed. Belmont: Duxbury Press; 2000
Pharmacology & Statistics Answer 2
2a=C (80%); 2b=D (89%); 2c=A (44%); 2d=E (97%).
The validity of a test is defined as its ability to distinguish between someone who has a disease
and someone who does not. Validity has 2 components: sensitivity and specificity. The sensitivity
represents the probability of a test being positive when true disease is present; this number
demonstrates the percentage of correctly identified patients who HAVE the disease (in this case,
80/100=80%).

The specificity represents the probability of a test being negative when true disease is absent; this
represents the percentage of the population who are correctly identified as NOT having the disease
(in this case, 800/900=89%).

The positive predictive value describes the probability of having true disease when the test is
positive. In this vignette, this calculation is 80/180 =44%
The negative predictive value describes the probability of NOT having true disease when the test is
negative. In this vignette, this calculation is 800/820 =97%

These calculations are summarized in the Tables below.

Evaluation of a Test
Screening Results True Characteristics of the Population
Disease No Disease Total
Positive True positive False positive Total test positive
Negative False negative True negative Total test negative
Total Total with Disease Total without Disease Population
Vignette Specifics
Screening Results True Characteristics of the Population
Disease No Disease Total
Positive 80 100 180
Negative 20 800 820
Total 100 900 1000
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Hermansen M. Biostatistics: Some Basic Concepts. Patterson, NJ: Caduceus Medical Publishers, Inc;
1990
Norman GR, Streiner DL. Biostatistics: The Bare Essentials. 3rd ed. St. Louis: Mosby; 2008
Pagano M, Gauvreau K. Principles of Biostatistics. 2nd ed. Belmont: Duxbury Press; 2000
Pharmacology & Statistics Answer 3
A. Case-control
This study describes a case-control study whereby study groups are defined by their disease status
and there is a comparison of risks between individuals with and without the disease of interest. This
type of study is rapid, inexpensive and ideal for rare diseases or diseases with a long latency period.
There are several weaknesses of this type of study including: recall bias, reporting bias, selection
bias, inefficient for rare exposures, and temporal relationship may be difficult to establish.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Hermansen M. Biostatistics: Some Basic Concepts. Patterson, NJ: Caduceus Medical Publishers, Inc;
1990
Norman GR, Streiner DL. Biostatistics: The Bare Essentials. 3rd ed. St. Louis: Mosby; 2008
Pagano M, Gauvreau K. Principles of Biostatistics. 2nd ed. Belmont: Duxbury Press; 2000
Pharmacology & Statistics Answer 4
D. Pantoprazole
 At present, many proton pump inhibitors are available for administration, including esomeprazole,
lansoprazole, omeprazole, rabeprazole, and pantoprazole. These medications have been found to be
inhibitors of the P450 cytochrome system. Research suggests that pantoprazole has the least
interaction with the cytotochrome P450 system, thus limiting potential drug-drug interactions.
References:
Arnold R. Safety of proton pump inhibitors-an overview. Aliment Pharmacol Ther. 1994;1:65-70
Blume H, Donath F, Warnke A, et al. Pharmacokinetic drug interaction profiles of proton pump
inhibitors. Drug Saf. 2006;29:769-784
Pharmacology & Statistics Answer 5
D. Phenobarbital
After drug administration, drug modification can occur by oxidation, reduction, hydrolysis, or
demethylation; these modifications are known as Phase I reactions and are responsible for 75% of
drug alterations. The P450 cytochrome system in the liver is the most important enzyme system
involved in Phase I reactions. Potential inducers and inhibitors of the P450 cytochrome system are
shown in the Table below. Alternatively, drugs can be modified by Phase II reactions, which involve
conjugation with endogenous compounds, such as glycine, sulfate or glutathione.
Inducers of the P450 Cytochrome System Inhibitors of the P450 Cytochrome System
Dexamethasone Chloramphenicol
Phenobarbital Cimetidine
Phenytoin Erythromycin
Rifampin Fluconazole
Indomethacin
Methadone
Omeprazole
Ranitidine
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Goshamn L, Fish J, Roller K. Pharmacotherapy perspectives: Clinically significant cytochrome
P450 drug interactions. J Pharm Soc Wisconsin. May, 1999; 23-38
Pharmacology & Statistics Answer 6
C. Phase III
There are four types of clinical trials summarized below:
Phase I – intervention tested on a small cohort to: (1) evaluate safety; (2) establish a safe range
for dosing; and (3) document side effects
Phase II – intervention tested on a larger cohort to: (1) determine effectiveness and (2) evaluate
safety
Phase III – intervention in an even larger cohort to: (1) confirm effectiveness; (2) document
side effects; (3) compare effectiveness against other treatment modalities for the same
condition; and (4) continued safety profiling
Phase IV – tests the intervention after it has been released to the public (“post-marketing”) to
continue to establish and document: (1) benefits and effectiveness; (2) risks and side effects;
and (3) appropriate use and indications
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
ClinicalTrials.gov. US National Institute of Health. Available at: www.clinicaltrials.gov
Pharmacology & Statistics Answer 7
C. Cohort study
The proposed study described in this vignette is an example of a cohort study. There are two types
of cohort studies. In a prospective cohort study, the groups of interest are characterized by exposure
status to a specific risk factor (in this case, Bisphenol A). The groups are then followed for a period
of time to assess the development of a specified outcome or disease.
In a retrospective cohort study, the exposure and outcome have already occurred when the study is
initiated and the cohort is identified based on risk status followed by disease/outcome determination.
In a case-control study, the study groups are defined by disease states, and the risk factors for the
group with the disease are compared with those of the group without the disease.
Clinical trials are intervention studies that can establish direct evidence between exposure or
treatment and an outcome of interest. This type of trial requires randomization, which allocates all
variables/risk factors or potential confounders equally to the exposed and unexposed groups. Thus,
the only difference between the two groups should be the exposure or treatment of interest.
Cross-sectional studies are descriptive studies that measure exposure and disease status at one
point in time. These students can provide information about disease prevalence but temporal
relationships between exposure and outcome cannot be established.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Dawson B, Trapp RG. Basic & Clinical Biostatistics. 4th ed. New York: Lange Medical
Books/McGraw-Hill; 2004
Rothman KJ, Greenland S, Lash T. Modern Epidemiology. 3rd ed. Philadelphia: Lippincott-Raven
Publishers; 2008
Pharmacology & Statistics Answer 8
C. Nominal
Nominal or categorical data arbitrarily assigns numbers, labels or codes to a particular study
group. In this study, infants between 34 0/7 – 36 6/7 weeks’ gestation are labeled late preterm,
infants between 37 0/7 – 38 6/7 weeks’ gestation are labeled early term, etc. Other examples include
gender and race categories.
Continuous data represents measurable quantities. For example, in this vignette, the study could
have been performed using weeks of gestation. Other examples include body weight and measured
serum concentrations of a medication.
Discrete data are integer or counts where the order and magnitude are important. Examples
include number of accidents, number of children, and number of hospital readmissions. Fractional or
intermediate values cannot be used.
In ordinal data, the order among the categories is important while the difference between the two
ordered groups is not the same for another two. Examples include Apgar scoring, retinopathy of
prematurity staging, and intraventricular hemorrhage grading.
Ranked data is ordered by magnitude and then assigned a number rank. Once the number rank is
assigned, the actual magnitude between the items is disregarded. Examples include the ranked list of
leading causes of death and the list of leading causes for pediatric hospital admissions.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Dawson B, Trapp RG. Basic & Clinical Biostatistics. 4th ed. New York: Lange Medical
Books/McGraw-Hill; 2004
Rothman KJ, Greenland S, Lash T. Modern Epidemiology. 3rd ed. Philadelphia: Lippincott-Raven;
2008
Pharmacology & Statistics Answer 9
C. 7,000
Standard deviation (SD) is defined as the amount of variability or spread that observations or
values have about the mean of the sample.
One SD from the mean (µ) = 68.2% (34.1% x 2) of the total sample or population
Two SD from the mean = 95.4% [(34.1% + 13.6%) X 2]
Three SD from the mean = 99.8% [(34.1% + 13.6% + 2.2%) X 2]
This is depicted in the Figure below.

In this vignette, the number of infants with the mean platelet count within one SD would be 68.2%
of 10,000, which is 6,820 or approximately 7,000 infants.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Dawson B, Trapp RG. Basic & Clinical Biostatistics. 4th ed. New York: Lange Medical
Books/McGraw-Hill; 2004
Pharmacology & Statistics Answer 10
B. Incidence rate remains constant
The cumulative incidence can be calculated by the following formula:

The cumulative incidence provides an estimate of the probability that an individual will develop a
disease during a specified period of time.
The incidence rate can be calculated by the following formula:

The incidence rate, unlike the cumulative incidence, takes into account the varying time periods of
risk exposure. The denominator in this equation is the sum of each individual’s time at risk or the
sum of time that each person remained under observation and free from disease.
Cumulative incidence will approximate incidence rate when the period of observation is short, the
disease prevalence is low, or when the duration of disease is the same among exposed and non-
exposed groups. The constancy of the incidence rate does not affect its relationship to the cumulative
incidence.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Glanz SA. Primer of Biostatistics. 4th ed. New York: McGraw-Hill; 1997
Pharmacology & Statistics Questions 11-20
Pharmacology & Statistics Question 21
A 1-hour old large for gestational age infant has just been admitted to your NICU. The infant’s
admission serum glucose is 33 mg/dL. You initiate enteral feedings.
How will glucose be transported from this infant’s gastrointestinal system?
A.Active transport
B.Facilitated diffusion
C.Pinocytosis
D.Simple diffusion
Pharmacology & Statistics Question 12
You are caring for a 5-day old female infant born at 32 weeks’ gestation who has intractable
seizures. She is being treated with phenytoin, which is a drug that is highly protein-bound.
Which of the following statements is TRUE about this infant’s handling of this drug?
A.This infant has an equal volume of distribution for this drug than a full-term infant
B.This infant has a greater volume of distribution for this drug than a full-term infant
C.This infant has a smaller volume of distribution for this drug than a full-term infant
Pharmacology & Statistics Question 13
You are caring for a 5-day old full-term female infant who is being treated with Phenobarbital to
manage her seizures. The nurse informs you that this infant is having blood-tinged and coffee-ground
colored gastric aspirates. You are concerned about the possibility of gastritis or a gastric ulcer and
initiate therapy with Ranitidine.
Which of the following statements about drug metabolism is correct?
A.Phenobarbital will induce the metabolism of Ranitidine
B.Phenobarbital will inhibit the metabolism of Ranitidine
C.Ranitidine will induce the metabolism of Phenobarbital
D.Ranitidine will inhibit the metabolism of Phenobarbital
Pharmacology & Statistics Question 14
Which of the following statements is FALSE about first-order kinetics of drug elimination?
A.A constant amount of drug per unit time is excreted regardless of the serum drug concentration
B.The fraction of drug that is eliminated is constant
C.The half-life is independent of drug dosage
D.The rate of drug elimination is directly proportional to the serum drug concentration
Pharmacology & Statistics Question 15
You are caring for a 20-day old female infant born at 28 weeks’ gestation who is receiving
parenteral nutrition through a central line. She develops lethargy, temperature instability, and severe
respiratory distress, prompting you to initiate an evaluation for sepsis. You empirically start
Vancomycin and Gentamicin while awaiting culture results.
Shown below is a plot of log drug concentration versus time.
 Which of the following drugs administered to this infant demonstrates the elimination pattern
represented in this plot?
A.Gentamicin
B.Vancomycin
C.Both Gentamicin and Vancomycin
Pharmacology & Statistics Question 16
A hypothetical drug has an elimination rate constant of 2.5 hour-1. Assume that a female patient
weighs 2 kg and the total amount of drug in her body is 100 mg. Her plasma concentration of the drug
is 25 mg/L.
What is the clearance of the drug?
A.2 L/hr/kg
B.3 L/hr/kg
C.4 L/hr/kg
D.5 L/hr/kg
E.6 L/hr/kg
Pharmacology & Statistics Question 17
You are treating a 4-day old full-term infant with Gentamicin for presumed sepsis. You are
monitoring the serum concentrations of Gentamicin in this infant.
Which of the following statements about drug monitoring in this patient is FALSE?
A.If the infusion of the drug is lengthened, the peak concentration will be lower
B.If the peak concentration is too high, the dose of the drug should be decreased
C.If the trough concentration is too high, the dosing interval should be increased
D.Trough concentrations are most valuable in assessing therapeutic success
Pharmacology & Statistics Question 18
All of the following approaches can improve the statistical power of a trial, EXCEPT:
A. Decreasing the standard deviation of outcome measurement
B. Increasing the effect size
C. Increasing the heterogeneity of the sample
D. Increasing the sample size
E. Increasing the Type I error rate
Pharmacology & Statistics Question 19
The hierarchy of evidence for medical studies from least to most reliable and informative is:
A.Case series, case-control, cohort, randomized controlled trial (RCT), systematic review
B.Cohort, case-control, case series, RCT, systematic review
C.RCT, systematic review, case series, case-control, cohort
D.Systematic review, case-control, case series, cohort study, RCT
E.Systematic review, case series, case-control, cohort, RCT
Pharmacology & Statistics Question 20
In order to claim that an exposure (e.g., X) causes an outcome (e.g., Y), a study must satisfy all of
the following, EXCEPT:
A.The effect of X on Y has been studied in a randomized trial
B.There are no other plausible explanations for Y other than X
C.X and Y are statistically associated
D.X occurs before Y
Pharmacology & Statistics Answers 11-20
Pharmacology & Statistics Answer 11
B. Facilitated diffusion
Absorption is the process by which a substrate moves from the site of administration, in this case,
the gastrointestinal system, to the circulation. There are four primary modes of transport of substrate
across cell membranes. Simple or passive diffusion is the transport methods for most compounds. In
this case, transport is directly related to the concentration gradient with the compound moving from an
area of high concentration to an area of low concentration. This mode of transport is dependent on
the compound’s lipid solubility, ionization, and molecular weight. Facilitated diffusion is transport
mediated by a carrier that moves the compound along the concentration gradient. Energy is not
required for this type of transport. Glucose is mediated by this mode of transport. Active transport is
mediated by a carrier that moves the compound against the concentration gradient. It requires energy
and is dependent on carrier availability, specificity, and energy availability. Pinocytosis is the
transport method of a minority of drugs. Compounds are engulfed and packaged by the cell and
energy is required.
References:
Beers MH, Porter RS, Jones TV (eds): The Merck Manual of Diagnosis and Therapy. 18th edition.
New Jersey: Merck Research Laboratories; 2006
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Pharmacology & Statistics Answer 12
B. This infant has a greater volume of distribution for this drug than a full-term infant
The volume of distribution is calculated by the formula below:

A large volume of distribution suggests that the drug is distributed into many tissues. In general,
medications that are highly protein-bound have a lower volume of distribution. Premature neonates
have a lower protein-binding ability compared to full-term infants as a result of decreased total
protein, albumin, and glycoprotein concentrations, and thus have a greater volume of distribution for a
given drug.
References:
Beers MH, Porter RS, Jones TV (eds): The Merck Manual of Diagnosis and Therapy. 18th edition.
New Jersey: Merck Research Laboratories; 2006
Bhat R. Neonatology Pharmacology I. Specialty Review in Neonatology/Perinatology. National
Center for Advanced Medical Education. Chicago, 1995
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Hatzopoulos FK. Neonatology Pharmacology II. Specialty Review in Neonatology/Perinatology.
National Center for Advanced Medical Education. Chicago, 1995
Pharmacology & Statistics Answer 13
D. Ranitidine will inhibit the metabolism of Phenobarbital
Drug metabolism occurs via Phase I and II reactions. In Phase I reactions, drugs are modified by
oxidation, reduction, hydrolysis or demethylation. The most important enzyme system in this phase is
cytochrome P450 metabolism, which transfers electrons from NADPH to cytochrome P450. These
enzymes lack substrate specificity and thus a few enzymes can metabolize many drugs. This system is
important in the metabolism of 75% of all drugs, including Phenobarbital. Some drugs, such as
Rifampin, can induce the cytochrome system while others, such as Ranitidine, can inhibit the system.
In this vignette, the initiation of Ranitidine would inhibit the metabolism of Phenobarbital.
References:
Beers MH, Porter RS, Jones TV (eds): The Merck Manual of Diagnosis and Therapy. 18th edition.
New Jersey: Merck Research Laboratories; 2006
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Pharmacology & Statistics Answer 14
A. A constant amount of drug per unit time is excreted regardless of the serum drug concentration
First-order kinetics of drug elimination is characterized by the excretion of a certain percentage of
drug per unit time so that the rate of drug elimination is directly proportional to the serum drug
concentration. In first-order kinetics there is an exponential decrease of serum drug concentration
over time and the half-life is independent of drug dosage. The fraction of drug that is eliminated
(elimination rate constant) is constant.
Zero-order kinetics is characterized by the excretion of a constant amount of drug per unit time
regardless of the serum drug concentration. For zero-order kinetics, the half-life is dependent on drug
dosage with larger dosages being cleared more slowly and the fraction of the drug that is eliminated
is not constant.
References:
Beers MH, Porter RS, Jones TV (eds): The Merck Manual of Diagnosis and Therapy. 18th edition.
New Jersey: Merck Research Laboratories; 2006
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Pharmacology & Statistics Answer 15
A. Gentamicin
Gentamicin demonstrates the one-compartment model of drug distribution and equilibration, which
assumes that a drug distributes equally to all areas of the body and that the drug rapidly equilibrates
with peripheral tissues. It assumes first-order kinetics, where the elimination rate of the drug is
constant over time.
In contrast, Vancomycin assumes the two-compartment model of equilibration where a drug initially
rapidly equilibrates with a central compartment and then more slowly equilibrates with a peripheral
compartment. The plot of drug distribution and elimination would appear as follows:

References:
Beers MH, Porter RS, Jones TV (eds): The Merck Manual of Diagnosis and Therapy. 18th edition.
New Jersey: Merck Research Laboratories; 2006
Bhat R. Neonatology Pharmacology I. Specialty Review in Neonatology/Perinatology. National
Center for Advanced Medical Education. Chicago, 1995
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Hatzopoulos FK. Neonatology Pharmacology II. Specialty Review in Neonatology/Perinatology.
National Center for Advanced Medical Education. Chicago, 1995
Pharmacology & Statistics Answer 16
D. 5 L/hr/kg
The clearance of a drug is determined by the following equation:

Volume of distribution (Vd) is calculated by the following equation:

A medication with a large Vd is usually distributed into many tissues and typically has a long half-
life. A medication with a small Vd usually binds well to proteins. Thus, substituting the equation for
the volume of distribution into the equation for the clearance of a drug,
Clearance of our hypothetical drug = 2.5 hour -1 x [100mg / (25mg/L x 2kg)] = 2.5 x 2 = 5
L/hour/kg
References:
Beers MH, Porter RS, Jones TV (eds): The Merck Manual of Diagnosis and Therapy. 18th edition.
New Jersey: Merck Research Laboratories; 2006
Bhat R. Neonatology Pharmacology I. Specialty Review in Neonatology/Perinatology. National
Center for Advanced Medical Education. Chicago, 1995
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Hatzopoulos FK. Neonatology Pharmacology II. Specialty Review in Neonatology/Perinatology.
National Center for Advanced Medical Education. Chicago, 1995
Pharmacology & Statistics Answer 17
D. Trough concentrations are most valuable in assessing therapeutic success
The peak concentrations of drugs are dependent on the infusion rate and dosage of drug. The longer
the infusion rate, the lower the peak concentration. If the peak concentration is too high, the dose of
the drug should be decreased. Trough concentrations of drugs are dependent on the interval of drug
administration. Thus, if the trough is too high, the interval of administration should be increased. For
Gentamicin, trough concentrations are most valuable in assessing toxicity risk, not therapeutic risk.
For antibiotics that display time-dependent killing such as Vancomycin, the trough levels are helpful
in assessing therapeutic effectiveness.
References:
Beers MH, Porter RS, Jones TV (eds): The Merck Manual of Diagnosis and Therapy. 18th edition.
New Jersey: Merck Research Laboratories; 2006
Bhat R. Neonatology Pharmacology I. Specialty Review in Neonatology/Perinatology. National
Center for Advanced Medical Education. Chicago, 1995
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Hatzopoulos FK. Neonatology Pharmacology II. Specialty Review in Neonatology/Perinatology.
National Center for Advanced Medical Education. Chicago, 1995
Pharmacology & Statistics Answer 18
C. Increasing the heterogeneity of the sample
Statistical power is defined mathematically as 1 - β, which is also know as the Type II error rate.
Beta can be interpreted as the chance of accepting the null hypothesis if it were false. In turn, this
means that power is considered the probability of rejecting the null hypothesis when it is indeed
false.
There are several ways to increase the statistical power when designing a study. The first
approach is to increase the sample size. Doing so does not change the actual point estimate of the
outcome measure, but it does make that estimate more precise. Second, you can choose an outcome
with a large effect size, as it is more likely to see a difference between groups if the effect of your
intervention is large. Third, you can increase power by increasing the Type I error rate for your
analysis. This is called α and it presents the probability of rejecting the null hypothesis when it is in
fact true. This is traditionally set at 5% (p=0.05), but by increasing this Type I error rate, statistical
power will correspondingly increase. Fourth, decreasing the standard deviation of the outcome will
increase statistical power because, for a given statistical test, power is inversely related to standard
deviation.
Option D is incorrect because increasing the heterogeneity of respondents typically increases the
standard deviation of outcome responses, leading to a decrease in power.
Reference:
Murnane RJ, Willett JB. Methods Matter. New York, New York: Oxford University Press, 2011
Pharmacology & Statistics Answer 19
A. Case series, case-control, cohort, randomized controlled trial (RCT), systematic review
The idea that there is a hierarchy of evidence, from least to most reliable and informative, has
been established for several decades. Observational studies, such as case series or case reports,
provide limited quality of evidence. Case-control and then cohort studies provide a greater quality of
evidence. Randomized controlled trials (RCT) were once considered the gold standard, but recent
thinking has replaced RCT with systematic reviews and meta-analyses at the top of the hierarchy.
This is because of added power in meta-analyses, mainly as a result of a larger sample size.
Reference:
Evans D. Hierarchy of evidence: a framework for ranking evidence evaluating healthcare
interventions. J Clin Nurs. 2003;12:77–84
Pharmacology & Statistics Answer 20
A. The effect of X on Y has been studied in a randomized trial
Though this might appear to be a simple question at first glance, few studies achieve the three
stipulations for making causal claims:
1.The exposure (e.g., X) and outcome (e.g., Y) must be shown to be associated;
2.The exposure (Y) must occur before the effect (X), and
3.No other plausible explanation exists.
The most robust way of meeting these stipulations is through a randomized controlled trial. However,
trials are time-consuming and costly and not all exposures can be randomized for practical and/or
ethical reasons.
Reference:
Murnane RJ, Willett JB. Methods Matter. New York, New York: Oxford University Press, 2011
Pharmacology & Statistics Questions 21-30
Pharmacology & Statistics Question 21
What is the primary purpose of including covariates in the analysis of a randomized controlled
trial?
A.Because publishers typically expect to see analyses that include controls for race, sex, and age
B.To control for post-randomization events
C.To control for residual pre-randomization confounding
D.To increase statistical power
E.To increase the likelihood of finding a significant result
Pharmacology & Statistics Question 22
All of the following are methods used to increase the ability to infer causality from observational
data, EXCEPT:
A.Instrumental variable estimation
B.Propensity score matching
C.Regression discontinuity design
D.Sensitivity analysis
E.Stratification
Pharmacology & Statistics Question 23
You are interested in learning whether a new nutrition regimen recently introduced into your NICU
has had an impact on infant weight gain. Wanting to obtain the most definitive answer to this
question, you consider conducting a randomized controlled trial (RCT).
23a. A RCT is considered the best way to establish causation between an exposure and an
outcome because:
A.Blinding is part of all RCTs to ensure that study participants never know which group to
which they have been randomized
B.Each individual randomized to the intervention group will be matched with a similar
individual in the control group
C.Randomization creates two groups equal in expectation of the outcome
D.Randomization reduces bias introduced by the Hawthorne Effect
E.The researcher has control over the exposure status of all individuals in the study
23b. Participants in a RCT are expected to remain in the treatment group to which they have been
assigned. This does not always happen as some individuals cross over between treatment and
control groups.
The analytic strategy employed to reduce bias introduced by such crossover is called:
A.Bonferroni correction
B.Intent-to-treat
C.Multiple regression
D.Stratification
E.Treatment-on-treated
23c. One common criticism of randomized controlled trials is that they lack external validity. This
means that:
A.The researchers have not used validated measures in obtaining data
B.The results are only applicable to the patient population in which the intervention was
tested
C.The results are susceptible to selection bias
 D.The results are vulnerable to confounding from external sources
E.Trial protocols require validation from outside experts in order to be externally valid
23d. Due to logistical constraints, you decide that a RCT is not feasible. What type of study might
you perform to answer the research question: How quickly do infants exposed to the new
nutrition regimen regain birthweight?
A.Case-control study
B.Case series
C.Cross-sectional natural experiment
D.Cross-sectional pre-post study
E.Longitudinal cohort study
23e. After analyzing your data, you find that there is no statistical difference in the amount of time
for infants to regain birthweight between the old and new nutrition regimens. A colleague asks
you whether you had enough statistical power to observe a difference between groups, if one
indeed exists.
Statistical power depends on all of the following, EXCEPT:
A.Pretest probability of the outcome
B.The magnitude of the effect size
C.The sample size
D.The Type I error rate
E.The Type II error rate
Pharmacology & Statistics Question 24
You are interested in studying the efficacy of a new pharmaceutical agent to prevent preterm birth.
You randomize 100 pregnant women to receive the study drug and 100 pregnant women to receive a
placebo. The outcome of interest is delivery prior to 37 weeks’ gestation. Of those in the treatment
arm, 30 women delivered prior to 37 weeks’ gestation. In the placebo arm, 65 women delivered
prior to 37 weeks’ gestation.
24a. What is the risk ratio associated with drug exposure?
A.0.02
B.0.5
C.0.8
D.1.0
E.1.2
24b. What is the odds ratio of having a preterm delivery in women exposed to the new drug
compared to those women who were not exposed?
A.0.2
B.0.8
C.1.9
D.2.5
E.3.4
24c. What is the absolute risk reduction between the drug and placebo groups?
A.10%
B.20%
C.35%
D.45%
E.70%
 24d. Under what circumstances does the odds ratio closely approximate the risk ratio?
A.The outcome is common
B.The outcome is rare
C.The sample size is large
D.The treatment groups have equal numbers of participants
E.The odds ratio and risk ratio are never closely approximated
24e. For this randomized controlled trial, which of the following statistical tests might you use to
test the hypothesis that randomization to treatment drug reduces the likelihood of preterm
delivery compared to being randomized to placebo?
A.Chi square test
B.Mann-Whitney test
C.Pearson correlation
D.T-test
E.Wilcoxon rank-sum test
Pharmacology & Statistics Question 25
Of the following, the mechanism of caffeine in decreasing apnea of prematurity includes all of the
following, EXCEPT:
A.Adenosine antagonism
B.Decreased hypoxic ventilatory depression
C.Enhanced diaphragmatic contractility
D.Increased laryngeal reflex
E.Increased minute ventilation
Pharmacology & Statistics Question 26
You are covering on a weekend in the NICU. During sign-out, you learn that a male infant born at
26 weeks’ gestation with a postmenstrual age of 40 weeks’ gestation is scheduled to go home
tomorrow. His current medications are vitamin D and iron. He has been in room air for over 2 weeks
and has been gaining weight will all feedings by mouth for the last 3 days.
His initial course had been notable for frequent apneic events associated with bradycardia that
required treatment with caffeine. The frequency of these episodes has decreased over the last 2
weeks. He has had no such episode for the last 10 days and has been off caffeine for the last 2 days.
The policy in your NICU states that an infant has to be free of episodes of apnea and bradycardia
at rest for 5 days prior to discharge. Assuming that the baby does not have any spells overnight, his
parents ask you if it is safe to take him home tomorrow.
Which of the following is an appropriate response to the question posed by the parents in this
vignette?
A.He can be safely discharged home because he has been event free for 2 days off caffeine
B.He can be safely discharged tomorrow as he has been without cardiorespiratory episodes for
greater than 5 days, which is the NICU policy
C.He cannot be discharged home because he needs a home monitor since preterm infants can have
cardiorespiratory events up to 44 weeks’ postmenstrual age
D.He cannot be discharged home tomorrow as he has to be event-free off caffeine for longer than 3
to 4 days
E.He may be discharged home tomorrow if he remains without any events for the next 24 hours
Pharmacology & Statistics Question 27
A term infant with meconium aspiration syndrome is diagnosed with pulmonary hypertension by
echocardiography. The baby requires ventilatory support and is treated with inhaled nitric oxide
(iNO).
Of the following, the compound that requires serum level monitoring when infants are receiving
iNO is:
A.Arginine
B.Methemoglobin
C.Nitric dioxide
D.Nitric oxide
E.Phosphodiesterase 5
Pharmacology & Statistics Question 28
A randomized controlled trial was performed and outcomes were measured in the control and
intervention group. The researcher then analyzes the data to determine the effect of the intervention.
If the number-needed-to treat is calculated to be 6, which of the following is an accurate
interpretation of this data?
A.6 people will have to be treated to see the desired effect in one person
B.For every 6 people who are not treated, one will have the desired outcome
C.For every 6 people who have the desired outcome, one will not have the desired outcome
D.The difference in the incidence of disease in the treated and the control group is 6
E.The relative risk of the disease in the treated and control group is 6
Pharmacology & Statistics Question 29
A randomized controlled trial was performed and the findings need to be analyzed. In this study, a
randomly selected group of patients with a disease were given an intervention and an outcome was
measured. The findings in this group were compared to the outcome of a group of control patients
with the same disease who did not receive the intervention. The desired outcome was documented in
both groups and is shown below in the Table.
Outcome Present Outcome Absent Total
Intervention 142 459 601
Control 301 300 601
Calculate the absolute risk reduction (ARR) and number needed to treat (NNT) for this
intervention.
A.ARR = 0.26 and NNT = 4
B.ARR = 0.31 and NNT = 3
C.ARR = 0.48 and NNT = 2
D.ARR = 0.52 and NNT = 2
E.Cannot be calculated with the information given
Pharmacology & Statistics Question 30
An infant born at 29 weeks’ gestation is admitted to the NICU with severe respiratory distress and
requires endotracheal intubation and mechanical ventilation. The infant is started on Ampicillin and
Gentamicin.
Of the following, the rationale that best explains the need for monitoring Gentamicin trough levels
in neonates is:
A.Because Gentamicin has a broad therapeutic window
B.Because Gentamicin has a low volume of distribution
C.Because Gentamicin is very efficient at penetrating the blood-brain barrier
D.To ensure therapeutic efficacy
E.To monitor toxicity
Pharmacology & Statistics Answers 21-30
Pharmacology & Statistics Answer 21
D. To increase statistical power
If a randomized controlled trial (RCT) is performed diligently and reliably, the randomization will
control for measured and unmeasured confounders. Thus, the results can be presented using a simple
analysis, such as a t-test or a chi square test. It is inaccurate to add covariates based on
characteristics or post-randomization events; this is because anything that happens after the groups are
randomized might effect the treatment and control groups differently, introducing bias into the estimate
of the outcome and undoing the very purpose of randomization. While it is true that publishers like to
see results controlled for common confounders and modifiers, it is not strictly necessary for a
randomized trial. Adding variables to the analysis model does not increase the chances of finding a
significant result if the trial was well-designed and randomization was done correctly.
The addition of covariates increases the statistical power of the trial. To understand why this is
so, consider the following general regression equation:

In this equation, Y represents the outcome of interest, β0 is the intercept, β1 is the effect estimate of
the exposure X, and e is the residual variance in Y not explained by X. If you were to add a
covariate, say C, this would explain some of the residual variance in Y and make e smaller. The
standard error of β1 decreases, as well, which increases the statistical power of the association
between X and Y.
Reference:
Moore KL, Neugebauer R, Valappil T, Laan MJ. Robust extraction of covariate information to
improve estimation efficiency in randomized trials. Stat Med. 2011 Aug 30;30(19):2389-408
Pharmacology & Statistics Answer 22
D. Sensitivity analysis
It is difficult to claim causal relationships from observational data because of several threats to
validity with the most common being endogeneity in treatment or exposure status. Many methods
have been developed to address these threats to validity. Instrumental variable estimation is the use
of an exposure variable that is exogenously related to both the exposure and outcome of interest.
There are three ways to conduct such an analysis with the simplest explanation using the two stage
least squares. This involves predicting values of the exposure of interest using the instrument and
then using those predicted values in a regression model for the outcome.
Regression discontinuity design takes advantage of a naturally occurring change in an exposure that
results from a natural event or policy change. A model is then constructed that views outcomes
immediately before and after the event or change.
Another strategy is to include covariates in the analysis or stratifying results by given values of
important covariates, such as age or sex. A more sophisticated method uses propensity scores to
match participants based on likeness of a number of given variables. This only works when there is
data on many characteristics. Even still, there may be confounding by unmeasured variables that
cannot be included in the analysis.
Sensitivity analysis assists to observe differences in outcome based on entering different values of
exposure variables into the statistical model. It will not aid in the determination of causation.
Reference:
Murnane RJ, Willett JB. Methods Matter. New York, New York: Oxford University Press, 2011
Pharmacology & Statistics Answer 23
23a. C. Randomization creates two groups equal in expectation of the outcome
Randomized controlled trials involve randomization that creates two groups of individuals that are
equal in expectation of the outcome of interest. That is, both exposure and control groups have the
same probability of having the outcome prior to the start of the study. In this way, the groups only
differ in their exposure to the intervention or treatment being studied. Matching is not a component of
RCT.
Blinding is intended to hide study group assignment from participants. Although blinding is a
component of RCTs, some interventions cannot be blinded, such as surgical interventions or drug
therapies with significant side effects.
The Hawthorne Effect is the improvement in outcomes simply as a result of being involved in a
study. This can occur equally in the treatment and control groups.
Once randomized to a study group, the researchers have little control over adherence to the
intervention or treatment. Some individuals will be compliant, others will not be compliant, and still
others will select themselves into the alternate study arm.
23b. B. Intent-to-treat
Randomization reduces bias by creating two groups of individuals that have equal likelihood of
having the outcome of interest. Once participants self-select into treatment groups, the benefits of
randomization are lost and bias is re-introduced into the study. Therefore, the outcomes must be
analyzed according to the original treatment group assignments. This is called intent-to-treat.
Bonferroni correction is an approach to handling multiple testing. Multivariable regression is an
analysis with multiple predictor variables. Stratification is a way of looking at study data in different
subgroups or populations. A treatment-on-treated analysis examines the results of an intervention on
those individuals randomized to the treatment arm of an RCT who actually received the intervention.
23c. B. The results are only applicable to the patient population in which the intervention was tested
External validity means that the results of a study apply, or are valid, to a wide range of
populations. This generalizability is missing in RCTs, in which the study population and setting are
highly specialized.
Using non-validated measures may impact the results of any study, but has nothing to do with external
validity. Selection bias and confounding are examples of threats to internal validity. Outside
validation of study protocols is not required of any study.
23d. C. Cross-sectional natural experiment
A natural experiment takes advantage of a factor external to the study subjects in assigning
treatment groups. In this case, the implementation of a new nutrition regimen in the NICU creates two
groups of infants – those admitted before and those admitted after the new nutrition regimen.
Case-control studies are observational and useful for studying outcomes of rare diseases. A case
series is a description of clinical cases of rare diseases. A pre-post study uses each individual as his
or her own control by measuring outcomes before and after treatment. Longitudinal cohort studies are
also observational and are helpful in understanding the outcomes of a group of individuals with a
particular characteristic or illness.
23e. A. Pretest probability of the outcome
Statistical power is the probability of rejecting the null hypothesis when the alternative hypothesis
is true. It is defined as follows:
Statistical power = 1 – Type II error rate
The Type II error rate is the probability of accepting the null hypothesis when the alternative
hypothesis is true. The Type I error rate is the probability of rejecting the null hypothesis when it is
true. As Type I error decreases, the required power increases. A greater amount of power is
necessary for detecting smaller effect sizes. Sample size determines the sampling error in a test
result. Generally, the larger the sample size, the smaller the sampling error and the greater the
power. Pretest probability has no relation to power.
Reference:
Shadish WR, Cook TD, Campbell DT. Experimental and Quasi-Experimental Designs for
Generalized Causal Inference. Belmont, CA: Wadsworth, Cengage Learning, 2002
Pharmacology & Statistics Answer 24
24a. B. 0.5
When thinking about the effect measures of a given intervention or exposure, it can be helpful to
construct a 2 x 2 Table of the general form, as shown below:
Outcome + Outcome -
Exposure + a b
Exposure - c d
Or, for this specific example:
Preterm delivery Term delivery Total
Drug 30 70 100
Placebo 65 35 100
Total 95 105 200
The risk ratio, or relative risk, is the probability of having an outcome among exposed individuals
compared to the probability of having that outcome among unexposed individuals. It can be
represented as:
RR = a(a+b)/c(c+d) = 30(30+70)/65(65+35) = 0.46
24b. A. 0.2
The odds ratio is the odds of having an outcome given an exposure is present compared to the odds
of having that outcome in the absence of exposure. It can be represented as:
OR = (a/c)/(b/d) = (a x d)/(b x c)
Thus, for this vignette, the odds ratio = (30 x 35)/(70 x 65) = 0.23
24c. C. 35%
The absolute risk reduction is the difference in the event rate between exposed and unexposed
groups. This can be represented as:
ARR = [a x (a+b)] – [c x (c+d)]
In this vignette, the absolute risk reduction = (30/100) – (65/100) = 35%
24d. B. The outcome is rare
The odds ratio and risk ratio are both effect measures used to describe the extent to which an
exposure or treatment impacts the rate of disease or health. A risk ratio is a comparison of
probabilities and is measured on an absolute scale. Odds ratios compare odds and are measured on a
relative scale. When an outcome is rare, the risk and odds of its occurrence will almost be the same.
However, as the outcome becomes more likely, the odds increase relative to the risk.
24e. A. Chi square test
The Chi square test is a statistical test that assesses the goodness of fit between observed findings
and the data that are expected. The Mann-Whitney test is another name for the Wilcoxon rank-sum
test. The Wilcoxon rank-sum test is used to compare means when the parameter of interest is not
normally distributed. A Pearson correlation is not a test, per se, but a measure of the linear
relationship between two variables. The T-test compares the mean values between two groups in
which the parameter of interest is normally distributed.
Reference:
Rosner B. Fundamentals of Biostatistics. 7th Edition. Boston, MA: Brooks/Cole, Cengage Learning,
2011
Pharmacology & Statistics Answer 25
D. Increased laryngeal reflex
Methylxanthines include caffeine, theophylline, and the intravenous form of theophylline –
aminophylline. These are competitive antagonists of adenosine, which is thought to play a major role
in preventing apnea of prematurity. As a central and peripheral inhibitory neurotransmitter, adenosine
is involved in inhibiting breathing. The exact mechanisms of adenosine are still being elucidated. All
3 forms of methylxanthines have been shown to be effective in preventing apnea of prematurity
although caffeine is often used because of its wider therapeutic index, minimizing the need for
monitoring blood levels.
Other receptor level actions attributed to caffeine include phosphdiesterase inhibition, stimulation
of calcium release from intracellular stores, and inhibition of GABA receptors (Rierio et al).
Clinical effects of methylxanthines include all of the options listed except laryngeal reflex. Mediated
via the superior laryngeal nerve in response to laryngeal mucosal irritation, the laryngeal reflex is
prominent in preterm infants and can result in an exaggerated inhibition of respiration. Therefore, an
increase in this reflex would result in increased apneic events.
References:
Baird TM, Martin RJ, Abu-Shaweesh JM. Clinical associations, treatment, and outcome of apnea of
prematurity. NeoReviews. 2002;3:e66-e70
Ribeiro JA, Sebastião AM. Caffeine and adenosine. J Alzheimers Dis. 2010;20 Suppl 1:S3-15
Murnane RJ, Willett JB. Methods Matter. New York, New York: Oxford University Press, 2011
Pharmacology & Statistics Answer 26
D. He cannot be discharged home tomorrow as he has to be event-free off caffeine for longer than 3
to 4 days.
The half-life of a drug is defined as the time required by the body to eliminate half of the dose of
an administered drug. The steady state is defined as the time taken for the body to reach an
equilibrium such that the amount of intake matches the amount eliminated and the concentration of the
drug in the body is relatively stable. Approximately 5 half-lives is the time needed to reach steady
state. Conversely, if a drug is in a steady state, 5 half-lives are needed to eliminate it from the body
after intake has stopped.
Caffeine is a methylxanthine that has a long half-life – close to 50 hours in a preterm infant.
Therefore, the time to eliminate caffeine from the body will be close to 7 days. In preterm infants
born prior to 28 weeks’ gestation, apnea of prematurity can often last beyond 40 weeks’
postmenstrual age. Prior to discharging a preterm infant who had been treated with caffeine, the
clinician must make sure that apnea does not recur after cessation of caffeine therapy. This would be
possible only after observing this infant for at least 7 days after cessation of caffeine therapy. To
facilitate discharge, the decision to discharge some infants with persistent apneic events to home with
monitoring may be an option if the events are low in severity. Although the infant in this vignette is
not having any such episodes, he needs to be observed until the caffeine has been eliminated from his
body. If he remains free from apneic events, he will not require home monitoring.
Reference:
Baird TM, Martin RJ, Abu-Shaweesh JM. Clinical associations,treatment, and outcome of apnea of
prematurity. NeoReviews 2002;3:e66-e70
Pharmacology & Statistics Answer 27
B. Methemoglobin
The effect of iNO is specific to the pulmonary system because of its rapid inactivation by
hemoglobin after it binds with heme moieties after entering the bloodstream. This prevents the
activated form from reaching the systemic circulation. Interaction of NO with the iron (Fe) in
hemoglobin leads to its oxidization from the ferrous (Fe2+) to the ferric (Fe3+) state, giving rise to
methemoglobin (MetHb). The oxygen dissociation curve of MetHb causes a leftward shift, which can
result in tissue hypoxia because of its strong affinity for oxygen and its failure to release it at the level
of the tissues. Normally serum MetHb levels are about 1%. Conversion of MetHb back to Hb occurs
by the hexose-monophosphate shunt pathway and the nicotinamide adenine dinucleotide (NADH)
diaphorase I and NAD phosphate (NADPH) diaphorase II pathways, the latter being utilized
therapeutically during methylene blue administration. When iNO is used for a long duration, in high
doses (usually above 40 parts per million), or in conjunction with other MetHb-promoting agents,
MetHb can accumulate and lead to methemoglobinemia. Therefore, blood levels of MetHb are
monitored during iNO therapy in infants.
Nitric dioxide (NO2) is generated in the metabolism of iNO and is a pulmonary irritant. Its levels
are monitored in-line at the inspiratory circuit in the iNO delivery device (not in the patient’s
blood). Although firm guidelines have not been established, the typical goal is to aim for a NO2
concentration of <5 parts per million.
Phosphodiesterase 5 is one of the main inactivators of cGMP, the second messenger required for
nitric oxide’s vasodilatory action. Arginine is the substrate required to produce endogenous NO.
Neither of these compounds is measured in the patient directly.
References:
DiBlasi RM, Myers TR, Hess DR. Evidence-based clinical practice guideline: inhaled nitric oxide
for neonates with acute hypoxic respiratory failure. Respir Care. 2010;55:1717-1745
Edwards AD. The pharmacology of inhaled nitric oxide. Arch Dis Child Fetal Neonatal Ed.
1995;72:F127-F130
van de Vijver M, Parish E, Aladangady N. Thinking outside of the blue box: A case presentation of
neonatal methemoglobinemia. J Perinatol. 2013;33:903-904
Pharmacology & Statistics Answer 28
A. 6 people will have to be treated to see the desired effect in one person
Most interventions are not 100% effective and the response to an intervention varies by patient.
For example, oral hypoglycemic agents are not effective in all diabetic patients. However, if the
intervention is effective in some patients and there is no way of predicting who those patients are, the
clinician needs to decide if treating patients with a drug that may or may not work is worth it. The
number-needed-to-treat (NNT) provides clinicians with a sense of how many patients need to receive
the treatment in order to benefit one patient. The decision of whether a NNT is low enough to mandate
the intervention depends on many aspects such as gravity of the disease, alternative interventions, and
cost of therapy.
The NNT is calculated as a reciprocal of the absolute risk reduction, which is the difference in the
incidence of the outcome in the treated and control group (Option D). The relative risk is the
incidence of the outcome in the intervention group relative to that in the control group calculated as:
Incidence in intervention / Incidence in control (Option E). As the absolute difference in incidence in
the 2 groups increases, the number of patients to observe an effect in one person becomes lower (i.e.,
a lower NNT).
Reference:
Furukawa T, Jaeschke R, Cook D, et al. Measuring patient’s experience. In: Guyatt G, Rennie D,
Meade MO, Cook D (eds).JAMA Evidence: User’s Guide to the Medical Literature. 2nd edition.
McGraw-Hill. 2008:264-5
Pharmacology & Statistics Answer 29
A. ARR = 0.26 and NNT = 4
Outcome Present Outcome Absent Total
Intervention 142 = a 459 = b 601 = a + b
Control 301 = c 300 = d 601 = c + d
Calculating basic forms of comparisons is possible from a 2 x 2 Table using the following
formulas:
Control event rate (CER) = c / (c+d)=301/601=0.5
Experimental event rate (EER) = a / (a+b)=142/601= 0.24
Relative risk (RR) = EER/CER=47.2/45.8=0.48
Relative risk reduction (RRR) = 1-RR = (CER-EER) / CER= 0.52
Absolute risk reduction (ARR) = |EER – CER| = 0.26
Odds ratio (OR) = (a x d) / (b x c) =0.31
Number-needed-to-treat (NNT) = 1/ARR = 1/0.26 = 4
References:
Norman GR, Streiner DL. Biostatistics: The Bare Essentials. 3rd edition. St Louis: Mosby; 2008
Zupancic J. Statistics. Core curriculum lecture, Harvard Neonatal-Perinatal Medicine Fellowship
Program. 2013
Pharmacology & Statistics Answer 30
E. To monitor toxicity
Gentamicin is one of the most frequently used antibiotics in neonatology. It is an antibiotic that
kills bacteria by achieving a high concentration at the binding site, therefore it is a concentration-
dependent antibiotic. Optimal dosing regimens achieve a peak concentration that is at least 10 times
higher than the Minimal Inhibitory Concentration. Other classes of antibiotics, like the beta-lactam
antibiotics exert their effect if bacteria are exposed to a concentration above the Minimal Inhibitory
Concentration for a prolonged period of time.
In order to achieve therapeutic effects, Gentamicin needs to be dosed to reach an adequate peak
level. However, sustained elevated peak (>12mg/L) or trough (>2 mg/L) levels can cause
nephrotoxicity and ototoxicity. In order to maximize concentration-dependent killing and minimize
toxicity, Gentamicin is ordered with an extended interval dosing protocol (every 24 hours) in
neonates. Studies have shown that a dose of 3 to 4 mg/kg will reach adequate peak levels in most
neonates, however the trough levels can be variable. Therefore, trough levels should be monitored if
the drug is given for longer than 3 days.
Newborns have a larger total body water volume and thus, Gentamicin has a higher volume of
distribution in newborns. Gentamicin is excreted by the kidneys with a clearance that is very similar
to that of endogenous creatinine. Gentamicin diffuses poorly into the subarachnoidal space and
concentrations in the cerebrospinal fluid are very low.
References:
Begg EJ, Barclay ML, Kirkpatrick CMJ. The therapeutic monitoring of antimicrobial agents. Br J
Clin Pharmacol. 2001:52;35S-43S
Hoff D S, Wilcox RA, Tollefson LM, et al. Pharmacokinetic outcomes of a simplified, weight-based,
extended-interval Gentamicin dosing protocol in critically ill neonates. Pharmacotherapy.
2009;29:1297-1305
NeoFax Online. Available from Micromedex. Accessed on November 12, 2013. Available at
www.neofax.org
Pharmacology & Statistics Questions 31-40
Pharmacology & Statistics Question 31
31.A meta-analysis of therapeutic hypothermia (TH) for hypoxic-ischemic encephalopathy (HIE)
examined the combined outcomes of death and severe disability at age 18 months. Within the 381
infants treated with TH, 178 were found to have a combined outcome event. Of the 386 patients not
treated with TH, 223 had a combined outcome event.
Based on this analysis, how many patients need to be treated with TH to prevent one child having
death or severe disability at 18 months due to HIE?
A. 2
B. 5
C. 9
D. 10
E. 90
Pharmacology & Statistics Question 32
A study published 3 years ago determined that the use of a specialized bed can reduce the rate of
all positional plagiocephaly. In the control group, there were a total of 950 infants enrolled of whom
455 had positional plagiocephaly at the time of discharge from the NICU. With use of the specialized
bed, 368 of 1120 babies had positional plagiocephaly. The difference in the risk of plagiocephaly
was reduced by 15% with a p-value of 0.01. Of the 800 control patients seen at 18 month follow-up,
200 had plagiocephaly. From the intervention group, 225 of the 900 babies seen at follow-up had
plagiocephaly.
In light of these new results, how would you describe the results of the first study?
A.Clinically significant and statistically significant
B.Clinically significant but not statistically significant
C.Insufficient data to assess
D.Neither clinically nor statistically significant
E.Statistically significant but not clinically significant
Pharmacology & Statistics Question 33
A 20-year old woman is admitted to the Labor and Delivery floor at 23 6/7 weeks’ gestation
because of preterm labor and rupture of membranes. A fetal ultrasound demonstrates good activity
and an estimated fetal weight of 400g. Her pregnancy has otherwise been uncomplicated, with a
normal fetal survey at 20 weeks’ gestation. There have been some fetal heart rate decelerations that
are not associated with contractions and the woman’s cervix is now 6 cm dilated. Her obstetrician
requests a Neonatology consult to discuss the possible neonatal outcomes if delivery occurred today.
When discussing the likelihood that her infant would survive delivery but not survive to 7 days of
life, what type of mortality rate includes patients who die in the first week of life?
A.Infant mortality rate
B.Neonatal mortality rate
C.Perinatal mortality rate
D.A and B
E.A, B and C
Pharmacology & Statistics Question 34
The Institutional Review Board (IRB) for your institution is reviewing a possible study for the
NICU. The investigators plan to test a new device that provides transillumination to aid in
venipuncture. In the application, the researchers specify that they are hoping to improve the success
rate of IV placement on the first attempt from 40% to 60%, with a p-value of 0.05. They are planning
to enroll 100 patients in the initial study. The IRB wants to be sure that the study is powered properly
to detect a difference.
Of the following, the study change that would most likely increase the power of the study is to
A.Change the goal success rate to 50%
B.Change the statistical significance value to 0.001
C.Change the statistical significance value to 0.01
D.Enroll 200 patients
E.Start with an initial success rate of 50%
Pharmacology & Statistics Question 35
A research group is hoping to establish whether lead exposure during pregnancy impacts the rate
of jaundice in newborns.
What type of study would best determine the attributable risk of lead exposure on jaundice?
A.Both prospective and retrospective cohort studies
B.Case-control study
C.Case study
D.Prospective cohort study only
E.Retrospective cohort study only
Pharmacology & Statistics Question 36
A female infant born at 24 weeks’ gestation is now 3 days old. Her birth weight was 800g. She
has been having spells associated with 15-20 seconds of apnea that require stimulation. During these
episodes, her heart rate decreases to the 50s, and her oxygen saturation decreases to the 60s. The
neonatal team initiates caffeine at 20 mg/kg/day in a single intravenous dose. The volume of
distribution for caffeine in neonates is 0.8 L/kg and the salt factor is 0.92.
What is the peak concentration of caffeine for this infant?
A.9 mg/L
B.12 mg/L
C.18 mg/L
D.23 mg/L
E.29 mg/L
Pharmacology & Statistics Question 37
A new study is enrolling two cohorts of patients: infants born to mothers who used tobacco
vaporizers, and those infants who had no in utero tobacco exposure. The research team is looking to
identify any differences in cognition, motor development and pulmonary health between these 2
groups. Follow-up neurodevelopmental and pulmonary testing is planned every 6 months for the first
5 years of life. 300 patients are enrolled in each cohort.
All of the following is a potential disadvantage of this study design, EXCEPT for:
A.Bias due to differences in pulmonary testing equipment between centers
B.Confounding due to tobacco exposure after birth
C.Lack of a control population
D.Large cost of multiple visits
E.Potential to introduce bias with low follow-up rates
Pharmacology & Statistics Question 38
A pediatric neurologist is interested in examining the correlation between brain MRI findings and
neurodevelopmental outcomes in patients with hypoxic-ischemic encephalopathy (HIE). His study
aims to enroll all patients admitted with a diagnosis of HIE, obtain brain MRIs at 24 to 48 hours of
life and 10 days of life, and follow the patients in neurodevelopmental clinic. Primary outcomes will
be cognitive and motor achievement at 12, 24, 36 and 60 months.
What type of study is this?
A.Case-control
B.Cross-sectional
C.Longitudinal
D.Randomized control
E.Retrospective
Pharmacology & Statistics Question 39
A recent study analyzing Total Infant Mortality Rate (IMR) in the US found that there has not been
any significant decrease in IMR over the study period 1983-2005.
Which population of infants has been the most significant contributor to the LACK OF
DECREASE in IMR in the US?
A.Infants born at 36 weeks’ gestation
B.Infants born at >42 weeks’ gestation
C.Infants with a birth weight < 500 g
D.Infants with a birth weight 750-999 g
E.Infants with a birth weight >3500 g
Pharmacology & Statistics Question 40
Many drug products have the potential to adversely affect the fetus if used during pregnancy. The
US Food and Drug Administration has strict regulations about labeling and risk categorization for
drug products used in pregnancy.
Which of the following statements about these regulations is MOST ACCURATE?
A.A drug product labeled category A indicates that it has not been shown to have any risk to the
fetus during pregnancy following adequate and controlled human studies.
B.A drug product labeled category B indicates that it has not been shown to have any risk to the
fetus during pregnancy following adequate and controlled human studies, but animal studies
have shown an adverse effect.
C.A drug product labeled category C indicates that it has not been shown to have any risk to the
fetus during pregnancy following animal studies, but has no human studies.
D.A drug product labeled category D indicates that it is contraindicated in pregnancy.
E.The alphabetical risk categories A, B, C, D and X should not be displayed on drug product
labeling.
Pharmacology & Statistics Answers 31-40
Pharmacology & Statistics Answer 31
D. 10
The number of individuals need to prevent an outcome is the inverse of the absolute risk reduction
for the studied intervention.
For this analysis, the risk of the combined outcome with TH treatment is 178/381 = 0.47. The risk
of combined outcome without TH is 223/386 = 0.58. Therefore the absolute risk reduction is 0.58-
0.47 = 0.11. The number needed to treat (NNT) for this analysis is therefore the inverse of this
absolute risk reduction (1 divided by 0.11 = 9.1), which rounds up to 10 as there cannot be fractions
of patients.
Reference:
Edwards AD, Brocklehurst P, Gunn AJ et al. Neurological outcomes at 18 months of age after
moderate hypothermia for perinatal hypoxic ischaemic encephalopathy: synthesis and meta-
analysis of trial data. BMJ = 2010;340:c363
Pharmacology & Statistics Answer 32
E. Statistically significant but not clinically significant
The initial study demonstrated a reduction in the rate of positional plagiocephaly at the time of
NICU discharge that had statistical significance, as the p-value was 0.01. This indicates that the
difference in rates of plagiocephaly between the control and intervention groups were unlikely to
have occurred by chance. Therefore, the result of the first study is statistically significant.
Clinical significance implies that the change due to an intervention makes a difference in patient
outcome. Though a reduction had been seen in the rate of positional plagiocephaly, the outcome of
the first study was short-term and therefore the significance of reducing plagiocephaly by 15% at the
time of NICU discharge is not clear. The second study with longer term follow-up helps to provide
the context for clinical significance of the first study’s results. At follow-up, the rates of positional
plagiocephaly were 25% in both groups. Therefore the intervention did not cause a clinically
significant result at a later date, despite a difference in observed rates of plagiocephaly at NICU
discharge.
One reason for this lack of clinical significance could be the lack of differentiation based on
severity of plagiocephaly. It could be that the rate of severe plagiocephaly was similar between the
control and intervention groups at the time of discharge, despite the overall rate being different. If
severe plagiocephaly was more likely to persist at age 18 months, the rate of plagiocephaly measured
in the first study was not a meaningful reflection of clinical status. Therefore, for a study to be
clinically significant, the outcomes measured need to reflect relevant endpoints.
Reference:
Jüni P, Altman DG, Egger M. Assessing the quality of controlled clinical trials. BMJ. 2001;323:42-
46
Pharmacology & Statistics Answer 33
E. A, B and C
Perinatal mortality rate refers to deaths that occur between 22 weeks’ gestation and 7 days of
postnatal life. Neonatal mortality refers to deaths in the first 28 days of life. Infant mortality refers to
deaths that occur in the first year of life. Therefore a death occurring in the first seven days of life
would be included in all three rate calculations.
A recent study found that infants born weighing < 500g account for 20% of the Total Infant
Mortality Rate (IMR). In the past two decades (1983-2005) there has been no significant change in
the overall IMR due to an increase in the rate of preterm deliveries (9% to 12%) and an increase in
low birth weight infant births. For example, the birthrate of infants weighing <500g increased 50%
(0.12% to 0.18%) during this time period. When the mortality of infants with a birth weight < 500g is
removed from the overall IMR calculation, there is a significant decrease in IMR.
Reference:
Lau C, Ambalavanan N, Chakrabory H, et al. Extremely low birth weight and infant mortality rates in
the United States. Pediatrics. 2013;131: 855-860
Pharmacology & Statistics Answer 34
D. Enroll 200 patients
The power of a study is the probability that the null hypothesis will be correctly rejected. As the
power increases, the chance of a false-negative (Type II) error decreases. Statistical power can be
increased by changing parameters that make it more likely to detect a true change. The power of a
study can increase by: increasing the significance criteria, increasing the magnitude of effect, or
increasing the sample size. For this vignette, enrolling more patients would increase the power of the
study. Small sample sizes increase sampling error, and effects are therefore harder to detect with
smaller sample sizes.
The significance criterion, often reported as a p-value, is the rate at which there will be a positive
result when the null hypothesis should have been rejected. A larger p-value reduces the risk of Type
II error (false-negative) while increasing the risk of a Type I error (false-positive). Decreasing the
statistical significance value would decrease the power of the study.
Magnitude of effect is the size of the expected observed change. A larger expected change would
reduce the risk of a Type II error (false-negative). Decreasing the magnitude of the expected change
by either increasing the initial success rate or decreasing the goal success rate would decrease the
power of the study.
Reference:
Ellis PD. The Essential Guide to Effect Sizes: An Introduction to Statistical Power, Meta-Analysis
and the Interpretation of Research Results. United Kingdom: Cambridge University Press, 2010
Pharmacology & Statistics Answer 35
A. Both prospective and retrospective cohort studies
Attributable risk is the difference in the rate of a condition between individuals with and without a
specific exposure. The best way to study this is a cohort study: compare a group of infants with in
utero lead exposure to a group without exposure. The incidence of jaundice in each group can be
calculated, and the difference is the attributable risk. A prospective cohort study starts with the
exposure and follows the groups to record outcomes. A retrospective cohort study starts after the
disease has been diagnosed, but still identifies groups based on the initial exposure and therefore can
calculate an odds ratio and a relative risk.
A case-control study can identify risk factors but only calculates an odds ratio because the
researcher sets the prevalence within the study. The relative risk cannot be calculated from a case-
control study. A case study provides a description of cases but does not offer statistical
comparisons.
Reference:
Woodward M. Epidemiology: Study Design and Data Analysis. CRC Press, 2014
Pharmacology & Statistics Answer 36
D. 23 mg/L
The loading dose of a drug relates to the pharmacokinetic factors of peak concentration, volume of
distribution (Vd), bioavailability (F), and salt factor (S). The formula to calculate the loading dose
is:

Reference:
Dobson NR, Hunt, CE. Pharmacology review: Caffeine use in neonates. NeoReviews. 2013;14:e540-
e550
Pharmacology & Statistics Answer 37
C. Lack of a control population
The goal of this longitudinal study is to establish whether exposure to the vaporized tobacco
during pregnancy is associated with worse neurodevelopmental or pulmonary outcomes by 5 years of
life. Therefore, the unexposed population serves as a control, and is an optimal part of this study
design.
A longitudinal study offers the ability to identify specific risk factors. However, the length of the
study can introduce potential disadvantages. Testing at multiple centers can introduce bias if there
are systematic differences in the evaluation. Postnatal exposure to tobacco and other substances can
be independent risk factors for the measured outcomes, thereby confounding the results. The large
number of visits in this study leads to large costs, and the potential for missing data if patients are
unable to complete all visits.
Reference:
Rydell M, Cnattingius S, Granath F, et al. Prenatal exposure to tobacco and future nicotine
dependence: Population-based cohort study. Brit J Psych. 2012;200:202-209
Pharmacology & Statistics Answer 38
C. Longitudinal
This study is a prospective longitudinal study. This study will aim to examine correlations
between MRI findings and neurodevelopmental outcomes by making repeated observations of the
same outcomes over time. A study population is identified and data is collected prospectively.
Longitudinal studies can also be done retrospectively.
A case-control study would identify a study population and an appropriate control population for
comparison. Case-control studies are useful for identifying risk factors. Case-control studies can be
done retrospectively or prospectively. A retrospective study asks identified study participants to
report on past behaviors, whereas a prospective study, as in this vignette, examines future outcomes
in a population.
A cross-sectional study collects data at one particular point in time, rather than identifying subjects
now and measuring outcomes in the future. Cross-sectional studies can identify prevalence in
addition to odds. By contrast, a randomized-control study would be useful to test an intervention. In
this vignette, there is no intervention to study. However, if the investigators had planned on
comparing two different therapeutic hypothermia protocols, then the study could be a randomized-
control trial.
Reference:
Perlman M, Shah PS. Hypoxic-ischemic encephalopathy: challenges in outcome and prediction. J
Pediatr. 2011;158:e51-e54
Pharmacology & Statistics Answer 39
C. Infants with a birth weight < 500 g
A recent study found that infants born weighing < 500g account for 20% of the Total Infant
Mortality Rate (IMR). In the past two decades (1983-2005) there has been no significant change in
the overall IMR due to an increase in the rate of preterm deliveries (9% to 12%) and an increase in
low birth weight infant births. For example, the birthrate of infants weighing <500g increased 50%
(0.12% to 0.18%) during this time period. When the mortality of infants with a birth weight < 500g is
removed from the overall IMR calculation, there is a significant decrease in IMR.
Infants born >42 weeks’ gestation or with a birth weight >3500g decreased in number and
constituted a decreased proportion of infant mortality over the study period. The number of infants
born at 36 weeks’ gestation did not change during this study period, thus contributing a constant
proportion of IMR. Mortality rates have been declining significantly among infants with a birth
weight 750-999 g. This decline has been significant enough that infants born with a birth weight 750-
999g now contribute less to IMR than at the beginning of the study period despite being a larger
proportion of the birth population.
Reference:
Lau C, Ambalavanan N, Chakrabory H, et al. Extremely low birth weight and infant mortality rates in
the United States. Pediatrics. 2013;131: 855-860
Pharmacology & Statistics Answer 40
E. The alphabetical risk categories A, B, C, D and X should not be displayed on drug product
labeling.
Effective June 30, 2015, the US Food and Drug Administration’s “Content and Format of Labeling
for Human Prescription Drug and Biological Products; Requirements for Pregnancy and Lactation
Labeling”, referred to as the “Pregnancy and Lactation Labeling Rule” came into effect. This requires
labeling to provide a summary description of the risks of a product during pregnancy and lactation,
the evidence supporting this description, and additional relevant information for clinicians to counsel
their patients. It also provides information on registries, if they exist. Furthermore, the Pregnancy and
Lactation Labeling Rule requires the removal of the previously used alphabetical pregnancy
categories A, B, C, D and X from the labeling. These categories were removed as it was determined
that they lead to confusion and over simplified the issues, without significant benefit.
Reference:
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Labeling/ucm09330
Pharmacology & Statistics Questions 41-50
Pharmacology & Statistics Question 41
Numerous medications can pose a risk to the fetus.
Which of the following associations between medication and adverse effect on the fetus is
INACCURATE?
A.Angiotensin-converting enzyme inhibitor and oligohydramnios
B.Carbamazepine and neural tube defects
C.Doxycycline and discoloration of teeth
D.Methimazole and choanal atresia
E.Propranolol and macrosomia
Pharmacology & Statistics Question 42
A woman with an uncomplicated pregnancy course presents in labor at 40 weeks’ gestation. She
had a brief introduction to pain management techniques and options during her prenatal birthing
class. Although initially interested in a natural birth, she now wants to further discuss her options,
along with corresponding maternal-fetal risks.
Which of the following modes of drug administration is likely to have the LEAST effect on
maternal blood levels of analgesia?
A.Epidural
B.Intramuscular
C.Intravenous
D.Paracervical
E.Spinal
Pharmacology & Statistics Question 43
A 19-year old Gravida 3 Para 2 pregnant woman presents to a community hospital Emergency
Department in labor and delivers precipitously at 38 weeks’ gestation. She has a history of IV drug
abuse and has been in a methadone treatment program for 15 months. Her urine toxicology screens
during pregnancy had been negative except for methadone. The infant remains apneic following
tactile stimulation, and positive-pressure ventilation (PPV) is initiated. Following 2 minutes of PPV,
Naloxone 0.1mg/kg is administered IM.
In this clinical vignette, what would be considered a contraindication to Naloxone use during
neonatal resuscitation?
A.Chronic opiate exposure
B.Corrective ventilation steps have not been completed
C.Informed consent not obtained
D.Intravenous access required
E.Lack of a secure airway
Pharmacology & Statistics Question 44
A term infant is born via vacuum-assisted vaginal delivery. On physical examination, he has
extended superficial scalp markings, a significant caput succedaneum and appears to be in pain. The
fellow proposes to start acetaminophen treatment.
Which of the following statements about the use of acetaminophen to manage pain in newborns
FALSE?
A.Acetaminophen does not reduce the pain associated with assisted vaginal deliveries.
B.Acetaminophen given to newborns after assisted vaginal delivery might result in a heightened
response to later painful stimuli.
 C.Acetaminophen is more effective than sucrose at reducing pain following heel lance.
D.Acetaminophen is not effective in reducing pain following heel lance.
E.If given after major surgeries, acetaminophen might reduce the dose of morphine needed for
adequate pain control.
Pharmacology & Statistics Question 45
What are potential side effects of repeated or high dose epinephrine during neonatal resuscitation?
A.Decreased renal perfusion
B.Decreased threshold for convulsions
C.Prolonged hypertension
D.Prolonged tachycardia and increased myocardial oxygen demand
E.All of the above
Pharmacology & Statistics Question 46
A neonate with severe indirect hyperbilirubinemia caused by Rh alloimmunization is receiving
maximal phototherapy.
All of the following medications should be avoided in this infant because of their potential to
affect the binding of bilirubin to albumin, EXCEPT:
A. Ceftriaxone
B. Chloral hydrate
C. Ibuprofen
D. Phenobarbital
Pharmacology & Statistics Question 47
Which is the most common mechanism of transplacental drug transfer?
A. Active, carrier-mediated transport
B. Endocytosis
C. Facilitated diffusion
D. Pinocytosis
E. Simple diffusion
E. Sulfa drugs
Pharmacology & Statistics Question 48
The Bell’s Criteria help to describe the stages of necrotizing enterocolitis (NEC).
Of the following, the type of variable that best describes the stages of NEC is:
A. Interval
B. Mean
C. Nominal
D. Ordinal
E. Ratio
Pharmacology & Statistics Question 49
The following are gestational ages for the last 5 NICU admissions, rounded up to the whole week:
32, 24, 23, 34, 34.
What is the mode of the sample listed ABOVE?
A. 23
B. 24
C. 29
D. 32
E. 34
Pharmacology & Statistics Question 50
Neonatal resuscitation is an intervention that targets infants with birth asphyxia and depressed
apneic infants that require intervention for survival. Globally, apneic infants that do not receive
resuscitation are often misclassified as stillbirths, rather than neonatal deaths.
For a research study to capture a potential change in stillbirth misclassification as a consequence
of increased delivery room resuscitation, which of the following indicators should be used?
A.Early neonatal mortality
B.Infant mortality
C.Neonatal mortality
D.Perinatal mortality
E.Postneonatal mortality
Pharmacology & Statistics Answers 41-50
Pharmacology & Statistics Answer 41
E. Propranolol and macrosomia
A selection of medications and their potential adverse effects on the fetus is provided in the Table
below.
Medication Potential Adverse Effect on the Fetus
Angiotensin-converting enzyme inhibitor Oligohydramnios
Renal failure
Lung hypoplasia
Skull ossification defects
Βeta-blockers (Propranolol) Fetal bradycardia
Hypoglycemia
Possibly fetal growth restriction (not
macrosomia)
Carbamazepine Neural tube defects
Craniofacial defects
Hemorrhagic disease of the newborn
Developmental delay
Methimazole Choanal atresia
Esophageal atresia
Hypothyroidism, goiter
Cutis aplasia
Tetracyclines (Doxycycline, Minocycline, and Slowed bone growth
Tetracycline) Enamel hypoplasia
Permanent yellowing of the teeth
Reference:
Martin RJ, Fanaroff AA, Walsh MC. Fanaroff and Martin's Neonatal-Perinatal Medicine: Diseases of
the Fetus and Infant, 10th ed. Elsevier, 2015
Pharmacology & Statistics Answer 42
E. Spinal
There are multiple factors to consider when evaluating maternal analgesic administration. The
dose and mode of administration have an impact on the amount of medication that enters the maternal
circulation for eventual fetal distribution. All blocks and injections distribute some level of the drug
into the maternal circulation, with notable differences between modes. The ranking of drug
administration modes from greatest to least effect on maternal blood levels is as follows:
Intravenous > Paracervical > Intramuscular > Epidural > Spinal
Reference:
Martin RJ, Fanaroff AA, Walsh MC. Fanaroff & Martin’s Neonatal-Perinatal Medicine Diseases of
the Fetus and Newborn. 9th edition. St. Louis: Elsevier; 2011
Pharmacology & Statistics Answer 43
A. Chronic opiate exposure
Medications administered to a pregnant woman during labor can impact the fetus. The most
common complication of intrapartum medication exposure is perinatal respiratory depression
following opiate exposure, via a direct effect of the drug transferred across the placenta.
 Naloxone is an opiate receptor antagonist, and can be administered intramuscularly, intravenously
or endotracheally at 0.1mg/kg/dose. Importantly, this medication should only be considered in
situations of acute exposure to opiates. If the pregnant woman received opiate analgesia during labor
and the newborn does not develop spontaneous respirations after adequate resuscitation, Naloxone
may be considered. However, this should never be interpreted as a required intervention during
neonatal resuscitation, as the corresponding respiratory depression can be adequately treated with
assisted ventilation.
Newborns with chronic exposure to opiates throughout pregnancy should not receive Naloxone, as
this could precipitate a sudden withdrawal syndrome, including seizures.
Reference:
Gleason CA, Devaskar SU. Avery’s Diseases of the Newborn. 9th Edition. Philadelphia:
Elsevier;2012
Pharmacology & Statistics Answer 44
C. Acetaminophen is more effective than sucrose at reducing pain following heel lance.
Several trials have evaluated the effectiveness of acetaminophen to control pain in the newborn
period. Whereas acetaminophen can reduce the dose of morphine needed for pain control after major
surgeries, it proved to be ineffective in controlling pain associated with heel lance or eye
examinations. When given to infants after assisted vaginal delivery, acetaminophen did not reduce
pain scores. In one study, administration of acetaminophen resulted in longer crying times and higher
pain scores when infants underwent heel lance 2 to 3 days after birth.
Reference:
Ohlsson A, Shah PS. Paracetamol (acetaminophen) for prevention or treatment of pain in newborns.
Cochrane Database Syst Rev. 2015 Jun 25;6:CD011219
Pharmacology & Statistics Answer 45
E. All of the above
Epinephrine is used during neonatal resuscitation to help restore spontaneous circulation.
However, repeated doses and thus higher cumulative doses might have side effects that could have
important clinical consequences after resuscitation. Higher doses could lead to prolonged
hypertension and tachycardia, increasing the myocardial oxygen demand in an already compromised
heart. Wide fluctuations in blood pressure might place premature infants at higher risk for
intraventricular bleeding. Furthermore, the prolonged peripheral vasoconstriction might compromise
renal perfusion and result in decreased urine output. Epinephrine might also interfere with
neurotransmitter balance in the brain and decrease the threshold for convulsions. Despite these
potential side effects, epinephrine is the only vasopressor recommended for use during neonatal
resuscitation.
References:
Iacovidou N, Vasileiou PV, Papalois A, et al. Drugs in newborn resuscitation: The more we learn the
least we use. Curr Med Chem. 2012;19:4606-4616
Vishal S. Kapadia, Myra H. Wyckoff. Drugs during delivery room resuscitation - What, when and
why? Semin Fet Neonatal Med. 2013;18:357-361
Pharmacology & Statistics Answer 46
C. Phenobarbital
Protein binding is one of the factors that can affect drug distribution in the neonate. Protein binding
is lower in the neonate because of numerous factors including the poorer binding capacity of fetal
albumin. Protein binding of drugs can also be reduced by acidosis and indirect bilirubin. Drugs and
bilirubin compete with each other for binding sites. Bilirubin is displaced from albumin by
Sulfonamides, Ceftriaxone, Chloral hydrate and Ibuprofen. These drugs should be given cautiously in
infants with indirect hyperbilirubinemia as the displaced indirect bilirubin can cross the blood-brain
barrier.
In contrast, bilirubin can also displace medications. Drugs that may be displaced from albumin by
bilirubin include Ampicillin, Penicillin, Phenobarbital, and Phenytoin. As a result, if an infant has
high levels of indirect bilirubin, this can lead to higher free drug concentrations of these medications.
Reference:
Blackburn ST (ed).Maternal, Fetal & Neonatal Physiology. 4th edition. St. Louis: Elsevier Health
Sciences; 2012
Pharmacology & Statistics Answer 47
E. Simple diffusion
Several principles modulate transplacental drug transfer. These concepts help to explain how
maternal medications can affect the fetus. The most common mechanism of transplacental transfer is
simple diffusion. This is a passive process that relies on a concentration gradient from maternal to
fetal plasma. Substances move from high to low concentration. Examples of compounds that cross the
placenta by simple diffusion include oxygen, carbon dioxide, sodium, potassium, fat-soluble vitamins,
and most medications. Active, carrier-mediated transport is a less common mechanism. It requires
energy and is important for the transfer of many nutrients (e.g., amino acids, calcium, magnesium,
iron, water-soluble vitamins) but rarely transports medications. Pinocytosis allows for the transfer of
immunoglobulin G antibodies across the placenta.
Reference:
Benitz WE, Druzin ML. Pharmacology review: drugs that affect neonatal resuscitation. NeoReviews.
2005;6:e189-e195
Pharmacology & Statistics Answer 48
D. Ordinal
Any characteristic that can be measured, observed, or categorized is called a variable. There are
several different types of variables. Categorical variables, of which nominal and ordinal are two
types, cannot be quantified. Nominal variables are named categories (e.g., blood groups). Ordinal
variables are also named. However, they have an order or superiority. The stages of NEC are an
example of ordinal variables. In contrast to categorical variables, continuous variables can have an
infinite number of possible values. One type of continuous variable is the interval variable. In this
case, there are equal intervals between the values but no meaningful zero (e.g., temperature). The
ratio type of continuous variables also has equal intervals but has a meaningful zero (e.g., gastric
aspirates). The type of variable determines the statistical test to be used.
Reference:
Manja V, Lakshminrusimha S. Principles of use of biostatistics in research. NeoReviews.
2014;15:e133-e150
Pharmacology & Statistics Answer 49
E. 34
Once data is collected, its distribution can be studied. One of the ways to measure distribution of
data is to look at its central tendency. There are three methods to do this: the mean, median, and
mode. The mean is the sum of all observations divided by the number of observations. In this vignette,
the mean is 29.4 (32+24+23+34+34=147; 147/5=29.4). The median is the value such that half of the
data points fall above it and half below it when they are sequentially ordered. In this vignette
example, the median it is 32. The mode is the most frequently occurring number. The mode is 34 in
this vignette example.
Reference:
Manja V, Lakshminrusimha S. Principles of use of biostatistics in research. NeoReviews.
2014;15:e133-e150
Pharmacology & Statistics Answer 50
D. Perinatal mortality
For a research study to capture a potential change in stillbirth misclassification, stillbirth needs to
be included in the metric. Of the many vital statistic indicators for maternal-child health, only the
perinatal mortality rate includes stillbirths in the calculation.
The formula for perinatal mortality rate is:
Total number of stillbirths plus deaths (day 0-7), per 1,000 births.
The early neonatal (day 0-7), neonatal (day 0-28), infant (day 0-364) and postneonatal (day 29-
364) mortality rates all use a similar formula:
Total number of deaths in liveborn infants (within the given time period), per 1,000 live births.
References:
Barfield WD. Standard terminology for fetal, infant, and perinatal deaths. Pediatrics. 2011;128:177-
181
Bracken MB. Perinatal Epidemiology. New York: Oxford University Press;1984
Pharmacology & Statistics Questions 51-60
Pharmacology & Statistics Question 51
While reading a research paper, there are clues to illustrate the distribution of the data.
Which of the following statements confer that the data has a normal distribution?
A.The mean and the median are equal.
B.The mean and the mode are equal.
C.The mean is larger than the median.
D.The mean is smaller than the median.
E.The median and the mode are equal.
Pharmacology & Statistics Question 52
A NICU fellow would like to implement a delayed cord clamping policy for her QI project. She
intends to track Apgar scores at 1-minute and 5-minutes as balancing measures following
implementation.
What is the appropriate measure of central tendency for this indicator?
A.Geometric mean
B.Mean
C.Median
D.Mode
E.Weighted average
Pharmacology & Statistics Question 53
The Director of the NICU is reviewing summary statistics from the previous year. He is interested
in the distribution of birth weights, and asks for assistance interpreting the data. The mean and
median birth weights are 1700g.
Which of the following statements about the standard deviation in this vignette is TRUE?
A.The data is right-skewed.
B.The interquartile range equals the standard deviation.
C.There is a bimodal distribution.
D.The standard deviation is not valid on this scale of measurement.
E.95% of observations lie between the mean +/- 2 standard deviations.
Pharmacology & Statistics Question 54
Your NICU enrolled patients in a multi-center randomized controlled trial to evaluate the risk
factor of prophylactic indomethacin treatment on the development of severe intraventricular
hemorrhage (IVH) among VLBW infants, between 2012 and 2014. During this time, 400 neonates
were enrolled. 200 were randomized to treatment, and 200 were randomized to placebo. Among the
neonates treated with indomethacin, 15 developed severe IVH. Among the neonates treated with
placebo, 20 developed severe IVH.
Based on the data provided in this vignette, what is the relative risk for the development of IVH
based on exposure to indomethacin?
A.0.5
B.0.75
C.1
D.1.25
E.1.5
Pharmacology & Statistics Question 55
There is equipoise surrounding the topic of enteral nutrition during blood transfusions. For that
reason, your unit has designed a randomized controlled trial to assess the impact of NPO status during
transfusions on the development of NEC within 7-days of the transfusion. Among the 10 infants
randomized to NPO, 2 subsequently develop NEC during the following 7 days. Among the 10 infants
randomized to continue full feedings, 6 develop NEC during the following 7 days.
In this study, what was the absolute risk reduction for NPO status during red blood cell transfusion
on the development of NEC within 7 days of the transfusion?
A.20%
B.30%
C.40%
D.50%
E.66%
Pharmacology & Statistics Question 56
Which of the following statements correctly describes a type I error?
A.Concluding that the alternative hypothesis is true when it is really true.
B.Failing to reject the null hypothesis when it is false.
C.Probability of rejecting the null hypothesis when it is indeed false.
D.Rejecting the null hypothesis when the confidence interval crosses 1.
E.Rejecting the null hypothesis when it is really true.
Pharmacology & Statistics Question 57
Which of the following statements correctly describes a type II error?
A.Concluding that the alternative hypothesis is true when it is really true.
B.Failing to reject the null hypothesis when it is false.
C.Probability of rejecting the null hypothesis when it is indeed false.
D.Rejecting the null hypothesis when the confidence interval crosses 1.
E.Rejecting the null hypothesis when it is really true.
Pharmacology & Statistics Question 58
A new serum diagnostic method is being evaluated for acute bilirubin-associated neurologic
injury, including reversible stage 1 encephalopathy. Currently, there is not a timely and effective gold
standard of diagnosis. Kernicterus may be confirmed on autopsy, if the family agrees. However,
there is concern that milder cases may be missed clinically.
How does the lack of a “gold standard” impact the interpretation of results from the new
diagnostic method described in this vignette?
A.Confirmation of classification must be delayed until autopsy.
B.Mild cases will likely be categorized as true-negatives.
C.Mild reversible cases may not be confirmed on autopsy, and likely counted as false-positives.
D.Milder cases will not be picked up with the new diagnostic test.
E.The true-positive cases are those known to have the disease based on histopathologic evidence.
Pharmacology & Statistics Question 59
A new diagnostic urine test to screen for in utero exposure to drugs of abuse has been tested in an
urban hospital NICU A with 80% prevalence of neonatal abstinence syndrome. The test was found to
have a sensitivity of 75%, a specificity of 50%, a positive-predictive value (PPV) of 86% and a
negative-predictive value (NPV) of 66%. This diagnostic test will also be trialed in a suburban
hospital NICU B with 20% prevalence of neonatal abstinence syndrome.
Based on the data provided in this vignette, what results are expected at the suburban hospital
NICU B compared to the urban hospital NICU A?
 A.All results will be the same.
B.The NPV will be higher.
C.The PPV will be lower.
D.The sensitivity will be lower.
E.The specificity will be lower.
Pharmacology & Statistics Question 60
You are taking care of an infant born at 28 weeks’ gestation. Parents are Jehovah’s witnesses and
they are discussing with you the potential need for a blood transfusion and possible treatment with
erythropoietin.
Which of the following statements about early (within the first week of life) treatment with
erythropoietin in the preterm infant is FALSE?
A.Early administration reduces the need for red blood cell transfusions in preterm infants.
B.Erythropoietin administration before 8 days of age does not change mortality rates.
C.Erythropoietin does not change the rates of intraventricular hemorrhage or necrotizing
enterocolitis.
D.The reductions in red blood cell transfusions are large, therefore the use of erythropoietin is
strongly recommended to prevent anemia in preterm infants.
Pharmacology & Statistics Answers 51-60
Pharmacology & Statistics Answer 51
A. The mean and the median are equal.
The three measures of central tendency are mean, median and mode. The mean is the arithmetic
average of the observations. The median is the middle observation. The mode is the value that
occurs most frequently.
A symmetric, or normal, distribution has the same shape on both sides of the mean. To illustrate
symmetry, the mean and median are compared. The mode, although a measure of central tendency, is
not used to categorize the symmetry of the data. If the mean and median are equal, the distribution of
observations is symmetric. If the mean is larger than the median, the distribution is skewed to the
right. If the mean is smaller than the median, the distribution is skewed to the left.
Reference:
Dawson B, Trapp RG. Basic and Clinical Biostatistics.4th Edition. New York: McGraw-Hill; 2004
Pharmacology & Statistics Answer 52
C. Median
Apgar scores utilize an ordinal scale, with an inherent order among the categories. Although order
exists among categories in ordinal scales, the difference between two adjacent categories is not the
same throughout the scale (e.g., the difference between 8 and 9 does not have the same clinical
implications as the difference between 0 and 1).
When choosing the measure of central tendency to employ, two factors are important: the scale of
measurement (ordinal or numerical) and the shape of the distribution of data.
The mean is used for numerical data and for symmetric distributions. The median is used for
ordinal data, or numerical data with skewed distributions. The mode is used primarily for bimodal
distributions. The geometric mean is used for observations measured on a logarithmic scale.
The weighted average is a tool that can be used in the setting of missing observations, to estimate
the mean using the number of observations and data values that are available.
Reference:
Dawson B, Trapp RG. Basic and Clinical Biostatistics. 4th Edition. New York: McGraw-Hill;2004
Pharmacology & Statistics Answer 53
E. 95% of observations lie between the mean +/- 2 standard deviations.
If the mean and median are equal (as in this vignette), the distribution of observations is
symmetric. This is also called a normal distribution, or described as a bell-shaped curve. In a
normal distribution of numerical data, the mean is used as the measure of central tendency, and the
standard deviation (SD) as the measure of spread.
In this normal distribution, 67% of observations lie between the mean and +/- 1 SD. 95% of
observations lie between the mean and +/- 2 SD. 99.7% of observations lie between the mean and
+/- 3 SD.
The standard deviation does not inform the reader of the mode. The interquartile range represents
the difference between the 25th and 75th percentiles. This contains the central 50% of observations,
centering around the median, and differs from the SD.
Reference:
Dawson B, Trapp RG. Basic and Clinical Biostatistics. 4th Edition. New York: McGraw-Hill;2004
Pharmacology & Statistics Answer 54
B. 0.75
The relative risk, or risk ratio (RR), is the ratio of the incidence in those exposed to the risk
factors to the incidence in those unexposed to the risk factor.
For the example provided in this vignette:

Reference:
Dawson B, Trapp RG. Basic and Clinical Biostatistics. 4th Edition. New York: McGraw-Hill;2004
Pharmacology & Statistics Answer 55
C. 40%
The absolute risk reduction (ARR) is the absolute difference between the experimental event rate
and the control event rate.
ARR = 20% - 60% = 40%
The relative risk reduction (RRR) is the absolute risk reduction divided by the control event rate.
RRR= 40%/60% = 66%
Many clinicians feel that the ARR is a valuable index as it is reciprocal with the number needed to
treat. Therefore, both calculations can easily be completed if the appropriate rates are available.
Reference:
Dawson B, Trapp RG. Basic and Clinical Biostatistics. 4th Edition. New York: McGraw-Hill;2004
Pharmacology & Statistics Answer 56
E. Rejecting the null hypothesis when it is really true.
α is the probability of making a type I error. A Type I error is considered when setting the
significance level α for the test. This error results in our concluding that there is a difference when
none exists.
Reference:
Dawson B, Trapp RG. Basic and Clinical Biostatistics. 4th Edition. New York: McGraw-Hill;2004
Pharmacology & Statistics Answer 57
B. Failing to reject the null hypothesis when it is false.
β is the probability of making a type II error. Type II error would be considered when setting the
significance level β for the test. This error results in our concluding that a difference when none
exists.
Reference:
Dawson B, Trapp RG. Basic and Clinical Biostatistics. 4th Edition. New York: McGraw-Hill;2004
Pharmacology & Statistics Answer 58
C. Mild reversible cases may not be confirmed on autopsy, and likely counted as false positives.
The sensitivity and specificity of diagnostic tests are often determined by administering tests to
individuals known to have the disease, as well as those known to not have the disease. The
sensitivity is then calculated as the percentage of patients known to have the disease, who
subsequently test positive. Specificity is calculated as the number known to be free of the disease
that subsequently test negative. From those initial tests, the proportion of true-positive, true-negative,
false-positive and false-negative is calculated. Of note, a “true-positive” is known to have the
disease, and has positive testing.
When a “gold standard” is lacking, it is recognized that the above calculations may not be 100%
accurate. Specifically, if diagnostic testing is compared to histopathologic specimens from autopsy,
there is a significant time delay for “true cases” to be diagnosed. In addition, a serum test may, in
fact, diagnose someone before clinical symptoms appear. In the unique case of early acute bilirubin-
associated encephalopathy with nonspecific findings, but potentially reversible symptoms, these
cases may never be confirmed with pathologic specimens.
In the event that “true” mild cases are detected with a serum test, but unable to be diagnosed on
pathologic specimen, these would be seen as false-positive cases. Historically, kernicterus was often
diagnosed clinically. Not all cases require confirmation of classification until autopsy.
Reference:
Dawson B, Trapp RG. Basic and Clinical Biostatistics. 4th Edition. New York: McGraw-Hill; 2004
Pharmacology & Statistics Answer 59
C. The PPV will be lower.
The sensitivity and specificity are characteristics of the test, and will remain unchanged.
However, the prevalence can significantly change the predictive values.
Example:
Urban NICU A: prevalence 80%
Disease (+) Disease (-)
Test (+) 60 10
Test (-) 20 10
Sensitivity (60/80)=75%; Specificity (10/20)=50%; PPV (60/70)=86%; NPV (20/30)=66%
Suburban NICU B: prevalence 20%
Disease (+) Disease (-)
Test (+) 15 40
Test (-) 5 40
Sensitivity (15/20)=75%; Specificity (40/80)=50%; PPV (15/55)=27%; NPV (5/45) =11%
Reference:
Dawson B, Trapp RG. Basic and Clinical Biostatistics. 4th Edition. New York: McGraw-Hill;2004
Pharmacology & Statistics Answer 60
D. The reductions in red blood cell transfusions are large, therefore the use of erythropoietin is
strongly recommended to prevent anemia in preterm infants.
Several studies have examined the effect of early (before 8 days of age) erythropoietin treatment
for preterm and low birth weight infants to prevent or treat anemia. Although the early use of
erythropoietin reduced the need for red blood cell transfusions and the volume of red blood cell
transfused (mean difference 7 ml/kg), the differences were minimal and of questionable clinical
importance. Mortality rates and the rates of intraventricular hemorrhage and necrotizing enterocolitis
were not different between the erythropoietin treated and control groups.
Reference:
Ohlsson A, Aher SM. Early erythropoietin for preventing red blood cell transfusion in preterm and/or
low birth weight infants. Cochrane Database Syst Rev. 2014 Apr 26;4:CD004863
XIII. ETHICS & PRINCIPLES OF TEACHING
Ethics & Principles of Teaching Questions 1-10
Ethics & Principles of Teaching Question 1
While performing an initial assessment on a newborn in the Newborn Nursery, a neonatologist
realizes that the infant has not received Vitamin K prophylaxis because of parental wishes.
Of the following, the next best step for this neonatologist to do is to:
A.Administer an intramuscular dose of Vitamin K to the infant regardless of parental wishes
B. Describe the effects of hemorrhagic disease of the newborn and explain that, without
prophylaxis, the infant will likely die of the disease
C. Discuss the risks and benefits of prophylaxis with the parents, eliciting their perspectives and
reasons for declining Vitamin K
D.Offer oral Vitamin K as an option
E.Petition for legal rights to administer Vitamin K prophylaxis without parental consent
Ethics & Principles of Teaching Question 2
A 29 year-old G1P0 married woman has been closely monitored since 18 weeks’ gestation
because of progressively worsening polyhydramnios. Her physician recommends serial
amnioreductions for the benefit of both mother and fetus. After a conversation about the risks and
benefits of the procedure, the woman declines.
The next best course of action for her physician is to:
A.Call the woman’s husband and ask him to convince her to consent
B.Consult the institutional Ethics team without the woman’s knowledge
C.Discuss the case with the hospital judicial review board in order to compel the woman legally
D.Do nothing; it is the woman’s right to decline interventions that affect her health
E.Schedule a meeting with the woman, her family, and other members of the healthcare team to
further discuss the situation
Ethics & Principles of Teaching Question 3
A neonatologist is asked to attend the delivery of a female infant of uncertain gestational age with
an estimated fetal weight of 350 grams. As the baby is born and placed on the radiant warmer, the
neonatologist observes that the infant is small with fused eyelids, translucent skin, and is
intermittently gasping for breath.
Based on the Born-Alive Infants Protection Act, the neonatologist must:
A.Ask the parents about their wishes regarding resuscitation of their infant
B.Assess this infant, as one must for every live-born infant, in order to determine the most
appropriate course of action, including the decision to not resuscitate
C.Do nothing, as the infant is clearly not of viable gestational age
D.Immediately begin to resuscitate the infant based on Neonatal Resuscitation Program guidelines
E.Provide comfort measures for the infant but not medical interventions, as she is not of viable
gestational age and unlikely to live if resuscitation were attempted
Ethics & Principles of Teaching Question 4
Informed consent for participation in a research study includes all of the following, EXCEPT:
A.Description about how the data will be used
B.Description of procedures in place to protect participants’ confidentiality
C.Explanation of potential benefits to the participant
D.Explanation of what will happen to the study participant
E.Explanation that participation is voluntary but participants must complete the study once
enrolled
Ethics & Principles of Teaching Question 5
At the end of a service month, the neonatology fellow needs to provide feedback to the pediatric
resident. Prior to the feedback session, the fellow reviews the characteristics required to provide
effective feedback.
Of the following, essential characteristics of feedback include:
A. Descriptive, timely, focused on changeable behaviors
B. General, timely, based on first-hand data
C. General, timely, focused on changeable behaviors
D. Judgmental, timely, based on first-hand data
E. Objective, timely, address all concerns
Ethics & Principles of Teaching Question 6
Bloom’s taxonomy provides an approach to classify thinking behaviors during learning. This
classification provides six categories of learning, ranging from simple to complex levels.
Which of the following examples requires the most complex level of thinking?
A. Describe the physiology during fetal transition from intrauterine to extrauterine life
B. Differentiate respiratory distress caused by pulmonary hypertension vs pneumonia
C. Evaluate whether an infant is a candidate for extracorporeal membrane oxygenation
D. Explain the concept of right-to-left intracardiac shunting
E. Select the inotrope that would be most beneficial based on the infant’s clinical data
Ethics & Principles of Teaching Question 7
Because residency and fellowship training occurs during adulthood, programs must include
characteristics of adult learning when developing and teaching curricula.
Which of the following is NOT representative of adult learners?
A.Contextual
B.Goal-oriented
C.Passive
D.Practical
E.Reflective
Ethics & Principles of Teaching Question 8
As the attending neonatologist on service, you gather your group of pediatric interns and
neonatology fellow to practice delivery room resuscitation. During the simulation exercise, the
neonatology fellow asks for .01 mL of epinephrine to administer intravenously to a bradycardia full-
term infant.
The best approach to address this error is to:
A.Discuss this error with the neonatology fellow in private
B.Discuss this error with the entire group during the debriefing session
C.Ignore the error because you suspect that the fellow knows the correct dose
D.Notify the fellowship director about the fellow’s significant error
Ethics & Principles of Teaching Question 9
Before creating a curriculum, it is important to define the learning goal and learning objectives.
Which of the following descriptions is consistent with a learning objective?
A. Describes the learning process
B. Focuses on the instructor
C. Explains specific behaviors expected of the learners
D. Provides the educational aim of the curriculum
Ethics & Principles of Teaching Question 10
There are two types of feedback: formative and summative feedback.
Which of the following characteristics is specific for summative feedback?
A.Can be used for academic promotion
B.Focused on improving the learner’s performance
C.Occurs immediately after the observation
D.Provided regularly (i.e., daily, weekly, monthly)
Ethics & Principles of Teaching Answers 1-10
Ethics & Principles of Teaching Answer 1
C. Discuss the risks and benefits of prophylaxis with the parents, eliciting their perceptions an
reasons for declining Vitamin K
Prophylaxis with a single dose of intramuscular Vitamin K is effective in preventing classic
hemorrhagic disease of the newborn. The American Academy of Pediatrics currently recommends
administration of intramuscular Vitamin K to all infants after birth. Because of routine prophylaxis
with Vitamin K, hemorrhagic disease of the newborn is a rare occurrence in the United States. For
this reason, most parents are unaware of the consequences of Vitamin K deficiency. The currently
advised course of action is to discuss the risks and benefits of prophylaxis with the parents, eliciting
their perspectives and reasons for declining Vitamin K. It is not appropriate to administer the drug
without parental consent or knowledge. Oral Vitamin K is used in some countries, though the
effectiveness has not been proven.
Reference:
American Academy of Pediatrics Committee on Fetus and Newborn. Controversies concerning
Vitamin K and the newborn. Pediatrics. 2003;112:191-192
Ethics & Principles of Teaching Answer 2
E. Schedule a meeting with the woman, her family, and other members of the healthcare team to
further discuss the situation
This case highlights the conflict between maternal and fetal rights. It has been shown that most
women consent to fetal interventions if they are of proven efficacy and modest risk. A previous
statement from the American Academy of Pediatrics, Committee on Bioethics (published 1999,
retired 2006) stated that physicians should respect a pregnant woman’s choice if the fetal therapy is
of unproven benefit. However, physicians may intervene if all of the following criteria are met:
1.Reasonable certainty that the fetus is at risk of substantial harm without the intervention
2.The intervention has been shown to be effective
3.The risk to the health of the pregnant woman is negligible
The American Congress of Obstetricians and Gynecologists (ACOG) suggests that physicians
should first try to resolve any conflict by having discussions with the woman, her family, and the rest
of the healthcare team. If this is unsuccessful, ACOG recommends an institutional Ethics committee
review. The last course of action should be legal because ACOG imparts that legal proceedings
alienate women by disregarding their rights to autonomous decision-making; unfairly scrutinize the
most vulnerable; discourage participation in prenatal care; and criminalize maternal choices.
References:
American Academy of Pediatrics. Committee on Bioethics: Fetal therapy-ethical considerations.
Pediatrics. 1999;103:1061-1063 (retired in 2006)
ACOG Committee on Ethics. Committee Opinion: Maternal decision making, ethics, and the law.
Obstet Gynecol. 2005:106:1127-1137
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Ethics & Principles of Teaching Answer 3
B. Assess this infant, as one must for every live-born infant, in order to determine the most
appropriate course of action, including the decision to not resuscitate
The Born-Alive Infants Protection Act of 2002 affirms the legal rights of all infants born alive,
regardless of gestational age at the time of delivery or the circumstances of the birth. As a result, the
medical condition of every infant must be assessed at birth in order to determine the most appropriate
plan of care. This has been interpreted in the setting of infants born at the edge of viability to allow
for the physician’s discretion in making decisions regarding resuscitation and prolongation of life.
The American Academy of Pediatrics Neonatal Resuscitation Program Steering Committee has
ensured that the law does not mandate the provision of care to those infants born at the limits of
viability.
References:
Born-Alive Infants Protection Act. Public Law 107–207, 107th Congress; August 5, 2002
Boyle D, Carlo W, Goldsmith J, et al. Born-Alive Infants Protection Act of 2001, Public Law No.
107-207. Pediatrics. 111(3): 680-681
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Ethics & Principles of Teaching Answer 4
E. Explanation that participation is voluntary but participants must complete the study once enrolled
According to the US Department of Health and Human Services, informed consent for
participation in medical research is a process that must include thorough descriptions of:
•The overall research process
•Potential benefits of participation
•Reasonable alternatives to participation
•Assurance of the protection of confidential personal information
•Potential risks and mechanisms for compensation should they occur
•How participants’ legal rights will be protected
•Identification of a contact person available to answer questions throughout the entire study
timeline
•The voluntary nature of participation, including the right of participants to withdraw consent at
any time
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
US Department of Health and Human Services, Office for Human Research Protections. Policies and
Guidance: Informed Consent, Tips on Informed Consent;
http://www.hhs.gov/ohrp/policy/ictips.html
Ethics & Principles of Teaching Answer 5
A. Descriptive, timely, focused on changeable behaviors
The characteristics of effective feedback is summarized in the Table below.
Quality* Explanation
Descriptive, not judgmental Describes the observed behavior without attributing
value to it
Specific, not general Identifies and highlights the precise behavior and
avoids generalizations
Focus on issues that the learner can Provides specific tips on how to improve
control and change
Emphasis on the consequences Highlights the benefit(s) of change
Timely Ensures good recall
Enables learner to modify his/her behavior as early
as possible
Based on first-hand data Ensures accurate feedback
 *Also need to provide objective and realistic feedback; offer feedback with the intent of helping; be open, honest but tactful; avoid
overloading the learner with too much feedback’; Modified from Alguire PC, DeWitt DE, Pinsky LE, et al. In: Teaching in
Your Office. Philadelphia: American College of Physicians; 2001:77, Printed with permission from: Brodsky D, Martin C.
Neonatology Review. 2nd edition. Lulu. 2010
Feedback is an extremely powerful teaching tool, which provides learners with an objective
description of their specific performance to help guide future skills. However, in order for feedback
to be effective, several criteria are required.
References:
Brodsky D, Doherty EG. Educational Perspectives: Providing effective feedback. NeoReviews.
2010;11(3):e117-122
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Ethics & Principles of Teaching Answer 6
C. Evaluate whether an infant is a candidate for extracorporeal membrane oxygenation
Of the examples provided, evaluating an infant for possible extracorporeal membrane oxygenation
requires the most complex thinking. The Table below summarizes all 6 of Bloom’s classifications of
learning.
Categories of Action Words Examples
Learning
Simple Knowledge List, define, describe, Describe the physiology during transition
TO Memorization identify, show, label, of the fetus from intra- to extrauterine
Complex and recall; examine life
gathering facts
Comprehension Classify, describe, Explain what is meant by right-to-left
Analyze and discuss, explain, shunting
interpret indicate, locate,
information; organize, recognize,
understanding review, summarize
Application Apply, choose, Based on the infant’s perfusion, blood
Use the illustrate, interpret, pressure results, and echocardiographic
knowledge to =modify, practice, findings, choose the inotropic
solve solve medication that would be most
problems and beneficial for this infant
handle new
situations
Analysis Analyze, calculate, How do you distinguish respiratory
See patterns categorize, compare, distress caused by pulmonary
Identify contrast, hypertension vs congenital heart disease
components differentiate,
distinguish, examine
Synthesis Arrange, develop, Determine the infant’s most likely
Use old formulate, integrate, diagnosis by integrating the infant’s
concepts to organize, plan, clinical exam, prenatal history,
develop new predict, prepare, laboratory data, and radiographic
ideas propose findings
 Relate
knowledge
from several
areas
Evaluation Assess, choose, Decide whether the infant is a candidate
Make judgments compare, conclude, for extracorporeal membrane
Compare ideas decide, estimate, oxygenation
Make choices predict, prioritize,
evaluate
Printed with permission from: Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010; Modified from: Bloom B
(ed). Taxonomy of Educational Objectives. Handbook I: Cognitive Domain. David McKay Company, Inc: New York;
1956
References:
Bloom B (ed). Taxonomy of Educational Objectives. Handbook I: Cognitive Domain. David McKay
Company, Inc: New York; 1956
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Ethics & Principles of Teaching Answer 7
C. Passive
Adult learners like to be engaged and actively participate in their learning. Thus, educators should
use questions to engage learners, use clinical cases to encourage problem-solving and discussion, and
use interactive techniques during didactic sessions. In addition to being active learners, adults are
also contextual, goal-oriented, practical and reflective.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Knowles M, Holton EF III, Swanson RA, eds. The Adult Learner. 6th ed. Amsterdam, Netherlands:
Elsevier Inc, 2005
Ethics & Principles of Teaching Answer 8
B. Discuss this error with the entire group during the debriefing session
When an error occurs and other learners are present, it is extremely important to openly discuss
the mistake with the entire group. If the error is not discussed with the group, it is possible that
learners may incorrectly presume that the statement is correct, particularly if it was expressed by a
senior trainee.
Ethics & Principles of Teaching Answer 9
C. Explains specific behaviors expected of the learners
While a learning goal is a general educational aim or expected outcome, the learning objective
provides specifics about how that goal will be attained. Objectives need to follow the acronym
SMART: Specific, Measurable, Attainable, Relevant and Targeted to the learner. Learning
objectives explain the specific behaviors expected of the learners, such as what the learner will
“Know”, “Show” and/or “Do” after the curriculum. Learning objectives need to be learner-based.
Neither goals nor objectives describe the learning process.
References:
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Brodsky D, Newman L. Educational Perspectives: A systematic approach to curriculum
development. NeoReviews. 2011; 12:e2-7
Ethics & Principles of Teaching Answer 10
A. Can be used for academic promotion
Summative feedback provides learners with information about patterns or trends in their
performance. It is meant to verify a learner’s achievement(s), motivate the learner to improve or
maintain their performance, and certify a trainee’s performance to others, either for academic
promotion, job hire, or grading. In contrast, formative feedback provides learners with regular
feedback about their ongoing performance. It is meant to “inform” the learner so that he/she can
improve. Ideally, it should occur soon after the observation and in regular intervals.
References:
Brodsky D, Doherty EG. Educational Perspectives: Providing effective feedback. NeoReviews.
2010;11(3):e117-122
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Ethics & Principles of Teaching Questions 11-14
Ethics & Principles of Teaching Question 11
The type of teaching method used by a teacher is based on the educational objectives. Regardless
of these objectives, however, active learning strategies for adult learners are preferred over passive
learning approaches.
Which of the following teaching tools mostly utilizes passive learning?
A. Bedside teaching
B. Reading material
C. Simulation
D. Small-group discussion
Ethics & Principles of Teaching Question 12
A 15-year old girl has just delivered a male infant at 24 weeks’ gestation with an omphalocele.
There is an ongoing study in your NICU that is enrolling patients with an omphalocele. The baby’s
mother has given permission to be approached for the study.
Given the age of the mother in this vignette, what type of approval is the mother going to give if
she agrees for her son to be enrolled in the study?
A.Acknowledgement
B.Agreement
C.Assent
D.Consent
E.Permission
Ethics & Principles of Teaching Question 13
Near-infrared spectroscopy (NIRS) is a noninvasive technique that provides a real-time measure
of tissue perfusion and oxygenation. Investigators are applying for Institutional Review Board
approval for a new clinical study to enroll infants in your unit. The goal of their study is to measure
brain perfusion and oxygenation in neonates born less than 26 weeks’ gestation.
Which aspect of the study protocol would most likely VIOLATE the minimal risk principle?
A.Blood sample of 4 mL obtained at a time of the infant’s first scheduled lab draw
B.Continuous measurement of NIRS for 2 hours
C.Non-invasive probe placement on the infant’s scalp by a trained technician
D.Recording of oxygenation and blood pressure during the NIRS measurements
E.Salivary cortisol measurement from oral sample from the infant
Ethics & Principles of Teaching Question 14
There is a study that is planning on examining the use of a new monoclonal antibody for treatment
of neonatal lupus. The medication is very expensive and not otherwise available. An eligible infant
is being care for in the NICU, and the principal investigator for the study is currently the attending on
service. The attending has discussed the “miracle” treatment with the family, and how much more
attention research subjects receive compared to other patients. He mentioned that the family should
consider transfer to another NICU if they do not want to enroll, so that other patients can have the
opportunity to be enrolled.
Can the attending in this vignette obtain consent from this family to enroll their child in the study?
A.No, consent is not needed
B.No, it would be coercive
C.Yes, as long as the attending is on the study protocol
D.Yes, the attending is most knowledge about the study medication and its potential side effects
E.Yes, the attending is the best advocate for this study
Ethics & Principles of Teaching Answers 11-14
Ethics & Principles of Teaching Answer 11
B. Reading material
By using reading material from journal articles, on line resources, or textbooks, learners can
enhance their knowledge base at a low cost. However, learners need to be self-motivated to
complete assignments and learning occurs passively. While didactic sessions are also usually
passive, lectures can inspire active learning, particularly if the lecturer incorporates questions,
problem-based discussions, and small group breakout sessions into the talk. Bedside teaching,
simulation and small-group discussions all use active learning.
References:
Brodsky D. Teaching methods. American Academy of Pediatrics. NeoReviewsPlus. 2010, June;7:Q9
Brodsky D, Martin C. Neonatology Review. 2nd edition. Lulu. 2010
Kern DE, Thomas PA, Howard DM, Bass EB. Educational strategies. In: Curriculum Development
for Medical Education. 1st edition. Baltimore: Johns Hopkins University Press; 1998: 38-58
Ethics & Principles of Teaching Answer 12
E. Permission
Even though the mother of the infant in this vignette is a minor, she is viewed as an adult and can
make medical decisions on behalf of her infant. Permission to be in a study can be provided by a
guardian of a study subject. Permission applies to situations when the study subject is unable to
provide consent, commonly because the subject is a minor (<18 years old in most states).
Consent can only be provided by study subjects. Usually a person <18 years old is considered a
minor, and cannot provide legal consent. There are cases of emancipated minors who are able to
provide legal consent, and that includes minors who are parents. Therefore, this mother could
provide legal consent for a study if she was the subject. Because this study involves the infant,
consent is not the appropriate type of approval that is required.
Assent is an agreement to participate in a study; it is not a legal consent. For example, when
teenagers are involved in a study, they can provide assent to involvement, but the teenagers’ parents
must still provide legal consent. Assent is required when study subjects are able to provide assent.
Maturity, age, and medical condition all affect the ability of a minor to assent to a study.
Acknowledgement and agreement are not legal terms for study participation.
Reference:
Rossi WC, Reynolds W, Nelson RM. Child assent and parental permission in pediatric research.
Theor Med Bioeth. 2003;24:131-148
Ethics & Principles of Teaching Answer 13
A. Blood sample of 4 mL obtained at a time of the infant’s first scheduled lab draw
For studies involving patients, ethical principles dictate that patients should not be subjected to
more than a minor increment over minimal risk (i.e., the minimal risk principle). There are no
quantitative definitions of minor increment or minimal risk, so Institutional Review Boards serve to
evaluate each proposed protocol with respect to these principles.
With extremely preterm neonates, even small amounts of blood collected for a study can impact
hemodynamic stability and increase the likelihood of needing a blood transfusion. A 4 mL volume
from a patient of this gestational age would expose the infant to both of these risks. The study
protocol should be altered to use a smaller volume, take alternative approaches to testing such as
using salivary or urine samples, or avoid certain studies.
A 2-hour non-invasive measurement is not likely to cause stress to an extremely preterm neonate,
nor is the placement of the probe on the scalp. Saliva is routinely obtained and offers a less risky
alternative to blood collection. Recording measurements of oxygen saturation and blood pressure that
are taken during routine care does not incur any risk.
Reference:
Freedman B, Fuks A, Weijer C. In loco parentis: minimal risk as an ethical threshold for research
upon children. Hastings Center Report. 1993;23:13-19
Ethics & Principles of Teaching Answer 14
B. No, it would be coercive
Coercion in clinical research can take many forms, but is generally present when undue pressure
for enrollment is applied to a family. If a family perceives that there are clinical or social
repercussions for not being enrolled in a study, this is an example of inappropriate coercion. In this
vignette, the family has been told that enrolling in the study will result in more attention for their
infant, and that they would be transferred if they do not enroll. This is undue pressure and coercive.
Individuals who obtain consent for a study do need to be listed on the study protocol, but the
discussion this investigator had with the family would make approaching the family for enrollment
inappropriate. All individuals who approach families for consent should be knowledgeable about
any study medications and potential side effects. This information should also be provided on the
consent form for the study. Though principal investigators generally can obtain consent for trials, they
should not do so for subjects for whom they are currently acting as care providers.
Reference:
Emanuel EJ, Xolani EC, Herman H. Undue inducement in clinical research in developing countries:
is it a worry? Lancet. 2005;366: 336-340