Viral Infections and Pregnancy

Background
Viral infections in pregnancy are major causes of maternal and fetal morbidity
and mortality. Infections can develop in the neonate transplacentally,
perinatally (from vaginal secretions or blood), or postnatally (from breast milk
or other sources). The clinical manifestations of neonatal infections vary
depending on the viral agent and gestational age at exposure. The risk of
infection is usually inversely related to gestational age at acquisition, some
resulting in a congenital malformation syndrome.
Infections known to produce congenital defects have been described with the
acronym TORCH (Toxoplasma,
others, rubella, cytomegalovirus [CMV], herpes). The "others" category has
rapidly expanded to include several viruses known to cause neonatal disease.
Traditionally, the only viral infections of concern during pregnancy were those
caused by rubella virus, CMV, and herpes simplex virus (HSV). Other viruses
now known to cause congenital infections include parvovirus
B19 (B19V), varicella-zoster virus (VZV), West Nile virus, measles
virus, enteroviruses, adenovirus, human immunodeficiency virus (HIV),
and Zika virus.
Also of importance is hepatitis E virus because of the high mortality rate
associated with infection in pregnant women. Recently, lymphocytic
choriomeningitis virus(LCMV) has been implicated as a teratogenic rodent-
borne arenavirus.
Worldwide, congenital HIV infection is now a major cause of infant and
childhood morbidity and mortality, responsible for an estimated 4 million
deaths since the start of the HIV pandemic. The breadth and depth of this
problem is beyond the scope of this article.
With emerging concerns for an influenza pandemic, attention has also now
been directed to the effects of influenza on pregnant women. Pregnant
women are more likely to develop severe disease, perhaps related to
physiological changes in pregnancy, such as decreased lung capacity,
increased oxygen needs, and increased heart rate. Currently, inactivated
influenza vaccine is recommended in all trimesters of pregnancy. [1] One study
found that influenza vaccination of high-risk pregnant patients also provides
some protective immunity for newborns and reduces subsequent
hospitalizations in the infants. [2] Influenza has historically been shown to
produce significant morbidity and mortality in this population
(see Influenza and H1N1 Influenza [Swine Flu]).
With the recent Ebola-related deaths in the United States, there is some
suggestion that pregnant women may be more susceptible to severe disease
and death from Ebola.
Cytomegalovirus
Cytomegalovirus (CMV) infection is the most common perinatal viral infection
in the United States. CMV is a double-stranded DNA herpes virus and
represents the most common congenital viral infection. The CMV
seropositivity rate increases with age. Geographic location, socioeconomic
class, and work exposure are other factors that influence the risk of infection.
CMV infection requires intimate contact through saliva, urine, and/or other
body fluids. Possible routes of transmission include sexual contact, organ
transplantation, transplacental transmission, transmission via breast milk, and
blood transfusion (rare).
Primary, reactivation, or recurrent CMV infection can occur in pregnancy and
can lead to congenital CMV infection. Transplacental infection can result
in intrauterine growth restriction, sensorineural hearing loss, intracranial
calcifications, microcephaly, hydrocephalus, hepatosplenomegaly, delayed
psychomotor development, and/or optic atrophy.
Vertical transmission of CMV can occur at any stage of pregnancy; however,
severe sequelae are more common with infection in the first trimester, while
the overall risk of infection is greatest in the third trimester. The risk of
transmission to the fetus in primary infection is 30%-40%. Most (90%) CMV
infections cause no symptoms, but 10% result in signs and symptoms such as
microcephaly, thrombocytopenia, hepatosplenomegaly, intrauterine growth
restriction, or a combination thereof.
Thirty percent of infants with severe CMV infection die; among survivors, more
than half eventually develop neurological sequelae, including microcephaly,
mental retardation, and/or sensorineural hearing loss. Seven percent of
asymptomatic neonates develop sensorineural hearing loss or developmental
delays during the first 2 years of life. [3, 4, 5, 6, 7] Five percent eventually develop
microcephaly and neuromuscular defects, and 2% develop chorioretinitis.
Congenital hearing loss is the most common sequela of recurrent CMV
infection.
Herpes simplex virus
Thirty to 60% of women receiving obstetric care have serologic evidence of
past HSV infection. Although both HSV-1 and HSV-2 may cause neonatal
herpes, HSV-2 is responsible for 70% of cases. Neonatal herpetic infection is
defined as infection within 28 days of birth. Ninety percent of infections are
perinatally transmitted in the birth canal. HSV infection acquired in this
manner carries a 70% risk of dissemination and is associated with 3 distinct
syndromes, each with its own typical outcome. The first and most common
(45%) is localized skin, eye, or mouth disease. Approximately 30% of cases
manifest as central nervous system (CNS) disease, including meningitis or
encephalitis, with evidence of HSV DNA in the cerebrospinal fluid (CSF).
Finally, 25% of neonatal herpetic infections manifest as disseminated disease
that involves multiple organs. Initial symptoms of this disease usually present
during the first 4 weeks of life.
Approximately 10% of infections are congenital, usually a consequence of the
mother acquiring primary HSV infection during pregnancy and the fetus
acquiring the infection transplacentally or via an ascending infection from the
cervix. Intrauterine infection is associated with intrauterine growth restriction,
preterm labor, and miscarriage. [8, 9] The risk of neonatal herpes and death is
highest in infants born to mothers who have not seroconverted by the time of
delivery.

Viral infections and

pregnancy. Transmission electron micrograph of herpes simplex virus. Some
nucleocapsids are empty, as shown by penetration of electron-dense stain.
Image and caption from US Centers for Disease Control and Prevention
Public Health Image Library, available at: http://phil.cdc.gov/Phil/search.asp.
Use Image ID 281.
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 Viral infections and
pregnancy. Blisters on the vulva due to a recurring herpes II (HSV-2) virus
infection. Image and caption from US Centers for Disease Control and
Prevention Public Health Image Library, available at:
http://phil.cdc.gov/Phil/search.asp. Use Image ID 2319.
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Rubella
Rubella is one of the more teratogenic viruses. Congenital rubella syndrome
(CRS) is characterized by intrauterine growth restriction, intracranial
calcifications, microcephaly, cataracts, cardiac defects (most commonly
patent ductus arteriosus or pulmonary arterial hypoplasia), neurologic disease
(with a broad range of presentations, from behavior disorders to
meningoencephalitis), osteitis, and hepatosplenomegaly.

Viral infections and

pregnancy. Transmission electron micrograph of rubella virus. Image and
caption from US Centers for Disease Control and Prevention Public Health
Image Library, available at: http://phil.cdc.gov/Phil/search.asp. Use Image ID
269.
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Neonates with rubella may have a "blueberry muffin" appearance caused by
purpuric skin lesions that result from extramedullary hematopoiesis. Heart
defects in these infants include ventricular septal defects, patent ductus
arteriosus, pulmonary stenosis, and coarctation of the aorta. The presentation
of rubella at birth varies greatly. Most of these complications develop in infants
born to mothers who acquire rubella infection during the first 16 weeks of
pregnancy. Ninety percent of infants present with some finding of congenital
rubella if infection occurs within the first 12 weeks, and 20% present with
congenital disease if the infection occurs between weeks 12 and
16. [10] Cataracts results when infection occurs between the third and eighth
week of gestation, deafness between the 3rd and 18th week, and heart
abnormalities between the 3rd and 10th week. [11]

Viral infections and

pregnancy. Infant with congenital rubella and blueberry muffin skin lesions.
Lesions are sites of extramedullary hematopoiesis and can be associated with
several different congenital viral infections and hematologic diseases. Image
and caption from US Centers for Disease Control and Prevention Public
Health Image Library, available at: http://phil.cdc.gov/Phil/search.asp. Use
Image ID 713.
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Parvovirus B19
B19V causes erythema infectiosum (fifth disease). Although most adults with
B19V infection are asymptomatic, the effects of this virus on the fetus are
much greater and include miscarriage, fetal anemia, hydrops fetalis,
myocarditis, and/or intrauterine fetal death. Infection occurs most frequently in
the winter and spring. B19V infection accounts for 15%-20% of cases of
nonimmune hydrops fetalis. Thirty to 40% of pregnant women are
seronegative for B19V and are thus susceptible to infection.
Various studies have estimated that 3%-14% of intrauterine fetal deaths occur
in the setting of B19V infection. Second-trimester infections have been studied
most frequently because infection in this trimester carries a 1%-3% risk of
hydrops; however, infection in any trimester may result in intrauterine fetal
loss. The critical period for the development of fetal hydrops is when maternal
B19V infection is acquired between the 13th and 16th week of gestation,
possibly because of the relative immaturity of the fetal immune response, as
well as the shortened life span of the red blood cells at this gestational age.
Varicella-zoster virus
VZV is a common virus that carries risks for both the mother and fetus during
pregnancy. Morbidity and mortality rates associated with VZV infection are
much higher in adults than in children. Primary varicella infection during
pregnancy is considered a medical emergency. Pneumonitis due to VZV
infection is 25 times more common in adults than in children; in the third
trimester, the risk for life-threatening ventilatory compromise is significant, with
a mortality rate of 14%. Prior to the development of antiretrovirals,
pneumonitis in pregnant women carried a mortality rate of 45%. Other risk
factors for the development of pneumonitis include smoking and a large lesion
burden (>100 lesions). [12]
Congenital varicella syndrome (CVS) results in spontaneous abortion,
chorioretinitis, cataracts, limb atrophy, cerebral cortical atrophy, and/or
neurological disability. Spontaneous abortion has been reported in 3%-8% of
first-trimester VZV infections, and CVS has been reported in
12%. [13] Acquisition of infection by the mother in the perinatal period,
specifically 5 days prior to delivery or 2 days afterward, poses a risk of severe
neonatal varicella, which carries a mortality rate of 30%. Infection at this time
prevents development of maternal antibodies that avert transplacental transfer
of immunoglobulin G (IgG) antibodies, which confer passive immunity to the
fetus.
Enterovirus
Enterovirus infections are not believed to cross the placenta and cause fetal
disease. [14] However, some studies have linked coxsackievirus and echovirus
to miscarriage, neurodevelopmental delay, myocarditis, and cortical
necrosis. [15, 16]One study linked the presence of coxsackievirus in the third
trimester with respiratory failure and global cognitive defects. [17]
Measles virus
Measles virus infection (rubeola) during pregnancy, as with VZV infection,
tends to be severe, with pneumonitis predominating. Although it is not known
to be teratogenic, rubeola has been associated with spontaneous abortion,
premature labor, and low birth weight. Neonates born to mothers with active
measles virus infection are at risk of developing neonatal measles, but no
congenital syndrome has been described. [18]
Lymphocytic choriomeningitis virus
LCMV has been associated with sporadic cases of congenital infection
worldwide. Affected infants demonstrate chorioretinitis, hydrocephalus, mental
retardation, and/or visual impairment; in addition, intrauterine death is
possible. Unlike congenital CMV and rubella infections, hearing deficits and
hepatosplenomegaly are rarely seen in congenital LCMV.

Pathophysiology
Human CMV is the largest of the beta herpes viruses and can cause lytic and
productive infection. Like other herpes viruses, it can be latent and reactivate.
CMV infection in pregnancy can be primary (initial acquisition in pregnancy) or
recurrent. Vertical transmission can occur transplacentally; in addition, the
virus can be transmitted via cervicovaginal secretions at the time of delivery or
by ingestion of breast milk postpartum. Transplacental transmission is
associated with congenital CMV infection. Maternal shedding at time of
delivery is associated with a 50% risk of infection. [23] CMV infection acquired
through exposure to infected cervical secretions or breast milk is usually
asymptomatic and is not associated with neonatal sequelae.
Herpes may be transmitted to the fetus in the peripartum period (as the
neonate passes through the birth canal [85%]), via intrauterine transmission
(either from ascending infection through the cervical canal or transplacentally
[5%]), or via postnatal transmission (10%). Both HSV and VZV have tropisms
for neural tissue. Peripartum transmission leads to disseminated disease in
70% of infants and is characterized by skin lesions, encephalitis, and
neurological disability. The risk of neonatal herpetic infection is much higher in
women with primary infection (ACOG Practice Bulletin). Primary infection
carries a transmission rate of 25%-50%, while recurrent maternal herpes
infection carries a transmission rate of less than 1%. [24]The difference in
transmission rates may be due to the presence of antibodies and lower viral
loads with recurrent infection.
In addition to miscarriage, B19V can cause fetal anemia due to effects on fetal
red blood cell precursors, which can lead to hydrops. B19V has a tropism for
the fetal bone marrow and liver, causing apoptosis of erythroid precursors and
thus inhibiting erythropoiesis. Fetal liver erythroblasts exhibit viral DNA and
pathognomonic changes of B19V infection. The myocardium has also been
affected, causing myocarditis and resultant heart failure.
VZV is a DNA herpes virus. Following primary VZV infection, it can remain
latent in the dorsal root ganglia. Primary varicella usually confers lifelong
immunity. VZV is most often transmitted to the fetus transplacentally;
however, ascending infection from lesions in the birth canal has been
reported. [25] The mechanism of in utero VZV infection is unknown. Infection of
developing nerve bundles may explain limb atrophy and chorioretinitis in CVS.
Rubella is an RNA virus found to infect only humans. It is spread by airborne
respiratory secretions and is most common in late winter and early spring. The
virus travels from the upper respiratory tract to the cervical lymph nodes and
is then disseminated throughout the body. The incubation period is 2-3 weeks.
Antibodies against rubella do not appear in the serum until after the rash has
developed. Fetal infection results from transplacental vertical transmission.
Ebola is a zoonotic infection, and the natural reservoir is thought to be fruit
bats. This virus is transmitted person-to-person via direct skin contact or
mucous membranes with blood or bloody fluids of infected patients. The
incubation period can range from 2-21 days.
Zika virus is an arthropod-borne flavivirus that is similar to other flaviviruses
such as dengue fever, yellow fever, and West Nile virus. The virus spreads to
humans through infected Aedes species of mosquitoes, sexual contact, and
perinatal transmission to fetus in pregnancy. Both male-to-female and female-
to-male sexual transmissions have been reported. It remains unclear whether
pregnant women are more susceptible to infection.
Frequency
CMV is the most common virus known to be transmitted in utero, affecting
approximately 0.5%-1.5% of births. [7] Approximately 40% of maternal CMV
infections during pregnancy result in congenital infection. [26]
Depending on the demographic population, neonatal herpes infection affects 1
per 1700 to 1 per 12,500 live births. [24] The rate of HSV-2 seroconversion
during pregnancy is estimated to be 0.2%-4%.
The estimated incidence of primary B19V infection in pregnancy ranges from
1%-5%.
Varicella occurs in approximately 1-7 per 10,000 pregnancies. [13]
In 1999, the incidence of rubella was 0.1 per 100,000. The incidence of
congenital rubella syndrome has decreased dramatically in the United States
because of rubella vaccination; currently, fewer than 50 cases occur each
year. [27]
LCMV infection occurs in the Americas and Europe in areas where people are
exposed to the host species of hamsters, Mus domesticus and Mus
musculus.Infections tend to occur in focal geographic areas in autumn.
Morbidity and mortality
The risk of primary maternal CMV infection leading to congenital CMV
infection is approximately 40%. Of neonates with congenital CMV infection,
85%-90% are asymptomatic at birth, yet 10%-15% eventually present with
developmental, visual, hearing, or dental abnormalities in the first years of life.
Of those who are symptomatic at birth, about half will present with some
isolated findings, while the other half will present with cytomegalic inclusion
disease. CMV disease in this group carries a mortality rate of around 30%; up
to 80% of affected infants develop late complications, including
developmental, visual, or hearing delay.
Morbidity and mortality rates are higher in patients infected with HSV-2 than in
those with HSV-1. Neonatal disseminated HSV infection acquired perinatally
carries a 65% mortality rate if untreated and a 25% mortality rate if treated.
Congenital varicella syndrome (CVS) carries a 30% mortality
rate. [13] Acquisition of varicella infection by the mother in the immediate
perinatal period, specifically 5 days prior to or 2 days following delivery, poses
the greatest risk for severe neonatal varicella infection, as maternal antibodies
have not yet developed to confer passive immunity to the fetus. Reactivation
of the virus results in zoster infection, commonly known as shingles. No
evidence has shown that herpes zoster infection causes a more severe
infection in pregnancy or results in congenital malformations.
Fifty to 80% of infants exposed to rubella virus within 12 weeks of conception
show signs of congenital infection. [27] The rate of congenital infection drops
dramatically with advancing gestational age, such that the risk of congenital
infection is very small if infection occurs after 18 weeks of gestation.
LCMV infection is rarely fatal in the adult host, but fetal acquisition may lead to
intrauterine death.
Up to 20% of pregnant women who acquire hepatitis E develop fulminant
hepatic failure.
Historic data from previous pandemics suggest a mortality rate of up to 50%
among pregnant women. During the 2009 H1N1 pandemic, pregnant women
were more likely to be hospitalized and accounted for 5% of all influenza
mortality. [28]
Congenital Zika virus infection can be associated with neurological
abnormalities, positional abnormalities, hearing loss, and multiple ocular
abnormalities, including, but not limited to, retinal dysplasia, glaucoma, optic
nerve abnormalities, and nystagmus. These cannot be detected antenatally.
Clinical Presentation
The hallmark of diagnosis of congenital disease is maternal history and history
of any recent exposures to ill individuals, workplace or daycare exposures,
and/or travel; physical findings in the newborn; and appropriate laboratory
testing. The maternal immunization history is also extremely important.
History
Cytomegalovirus
Maternal CMV infection is most likely due to reactivation of latent virus and
thus causes no symptoms or manifests as low-grade fever, malaise, and
myalgias. Primary CMV infection is usually asymptomatic but may manifest as
a mononucleosislike picture, with fever, fatigue, and lymphadenopathy.
Women who are in close contact with toddlers or preschool-aged children,
daycare workers, or health care workers are at a higher risk for CMV infection.
Herpes simplex virus
Asking about previous HSV lesions is important; however, approximately 70%
of women who have been exposed to HSV do not know they are infected. The
3 stages of HSV infection include primary, nonprimary first episode, and
recurrent infection, categorized based on clinical presentation and serological
findings. Primary infection demonstrates a more severe symptomatic picture.
One third of patients with primary infection report multiple painful vesicular
eruptions on the vulva and perineum. In rare cases, a systemic flulike illness
develops. Rare forms of disseminated disease are associated with hepatitis,
pneumonia, or encephalitis. [29]Nonprimary infections and recurrent infections
due to reactivation of latent virus are associated with fewer systemic
manifestations, fewer lesions, less pain, and a shorter duration of viral
shedding than primary infection.
Parvovirus B19
Adults with parvovirus infection may present with fever, arthralgias, and flulike
symptoms; however, 20%-30% are asymptomatic. A faint macular rash
associated with arthralgias may be a clue to B19V infection in the mother. The
clinician should ask about exposure to an infected child with the classic facial
rash that manifests as erythema of the cheeks (slapped-cheek appearance).
Varicella
The incubation period of chickenpox is 10-21 days. Primary infection is
associated with a maculopapular and vesicular rash accompanied by
constitutional symptoms that last 3-5 days. Varicella pneumonia manifests as
nonproductive cough, dyspnea, fever, and pleuritic chest pain.
Rubella
A history of typical rubella rash starting on the face or neck, along with
suboccipital lymphadenopathy, arthralgias, fever, and cough, suggests
rubella. Obtaining an immunization history and rubella titers (usually obtained
at the outset of pregnancy) are important. Immigrants from developing
countries are often inadequately immunized; thus, the alert clinician inquires
about rash acquired during early pregnancy in this population. Of note, 20%-
50% of infected patients are asymptomatic.
Measles
Measles virus infection is also associated with inadequate immunization and
is characterized by cough, coryza, and conjunctivitis. Koplik spots are
pathognomonic for measles and appear as bluish-gray spots on a red base in
the buccal mucosa.[18] The rash begins several days prior to fever and spreads
from the head downward to cover most of the body.
LCMV
This infection may also present as nonspecific flulike symptoms, including
fever, malaise, myalgias, and headache. It may progress to aseptic meningitis
in adults but is usually self-limited in nonpregnant adults, with resolution within
2-3 weeks.
Influenza
Pregnant women with influenza present with symptoms that are similar to
those in the general population, including fever, cough, rhinorrhea, headache,
sore throat, myalgia, and shortness of breath.
Zika virus
Zika virus causes clinical manifestations in 20% of infected patients. Patients
who report residence or travel to an area where mosquito-borne Zika virus
transmission has been reported, who have had sexual contact with a Zika-
infected person, who reside in or have traveled to an area where mosquito-
borne transmission of Zika virus infection has been reported, or who report a
mosquito bite after residency or travel to such an area are at risk of infection.
Patients with Zika virus infection may present with rash, arthralgia,
conjunctivitis, and fever.
Physical
CMV
Most infants with congenital CMV infection are asymptomatic at birth but may
develop sequelae later in life. Symptomatic infants may have splenomegaly,
petechiae, or jaundice. Congenital CMV infection, occurring in 5%-10% of
infants, is characterized by jaundice, hepatosplenomegaly, petechial rash,
respiratory distress, and neurological involvement, which may include
microcephaly, motor delay, cerebral calcifications, lethargy, and seizures.
HSV
Most infants exposed to HSV during gestation appear healthy at birth.
Findings in those who develop clinical disease may include fever or
temperature instability, respiratory distress, lethargy, and poor feeding. HSV
infection can also rapidly lead to sepsis and septic shock. The classic skin
findings of vesicular lesions may be absent or may appear late.
B19V
The mother may present with a photosensitive erythematous rash on the face
that spares the periorbital and nasal area. She may develop painful, swollen,
stiff joints, especially of the wrist, hand, knees and ankle that may persist up
to 1-3 weeks. [30]This infection may lead to hydrops fetalis, which is
characterized by 2 or more fluid filled-cavities in the fetus (pleural effusion,
ascites, skin edema, hydropic placenta, pericardial effusion, cardiomegaly, or
heart failure). These findings are usually identified with ultrasonography. In
some cases, the infection resolves spontaneously, leaving the fetus or infant
unaffected. Although a congenital parvovirus infection syndrome has been
described in premature infants, most intrauterine parvovirus infections do not
have a teratogenic effect. [31]
Varicella
Mothers with VZV infection may experience fever, malaise, and myalgia prior
to the onset of rash, which is vesicular and may affect the face, trunk,
oropharynx, and scalp. Adults are more prone to complications, including
bacterial superinfection of the vesicles, pneumonitis, and CNS abnormalities
such as Guillain-Barré syndrome. Manifestations of CVS in infants may
include multiple reddish pigmented areas or dermatoma scarring, hypoplastic
limbs or other limb abnormalities, chorioretinitis, optic nerve atrophy, and
failure to thrive. Most of these cases occur if the mother was infected between
8 and 20 weeks’ gestation. [32] Neonatal VZV infection that occurs when the
mother has been infected within two weeks of delivery may manifest as fever
and a vesicular eruption. Some cases of herpes zoster have also been
described in infants born to mothers who had varicella in pregnancy. [33]
Rubella
In adults, rubella may manifest as fever and maculopapular rash on the face
that spreads cephalad to the feet. While infected patients may present with
suboccipital lymphadenopathy, arthralgias, conjunctivitis, and cough, 20%-
50% are asymptomatic. Congenital rubella syndrome (CRS) is associated with
4 common anomalies: deafness (60%-70% of fetuses), central nervous
system abnormalities (10%-25%), eye defects such as cataracts (10%-30%),
and cardiac malformations (10%-20%). At birth, many infants with congenital
rubella show evidence of growth restriction and bone disease.
Hepatosplenomegaly may also be present. Extramedullary hematopoiesis
results in a "blueberry muffin" appearance in many infected infants. Physical
examination may also reveal findings of cataracts or evidence of congenital
heart disease. Other associated abnormalities include mental retardation,
microcephaly, and blood abnormalities such as anemia and
thrombocytopenia.
Influenza
Like the general population, pregnant women with influenza may exhibit fever,
runny nose, cough, sore throat, and myalgias. It remains unclear whether
influenza has any effect on the fetus and whether there is a risk of congenital
abnormalities, although transplacental transmission of influenza appears to be
rare. Hyperthermia associated with influenza, particularly in the first trimester,
may increase the risk of certain birth defects. [34]
Ebola
Ebola infection should be suspected in patients with recent travel to West
Africa. Illness is characterized by sudden onset of fever, chills, myalgia,
weakness, fatigue, and gastrointestinal disturbances.
Zika virus
Symptoms of Zika virus infection appear 3-14 days after exposure and include
acute onset of low-grade fever, conjunctivitis, arthralgia, and maculopapular
rash.
Workup
Laboratory studies
Careful interpretation of serologic markers for most of these infections is
important. Immunoglobulin M (IgM) can persist for up to a year, leading to
difficulty in determining fetal exposure during pregnancy. Furthermore, the
specificity and positive predictive value of some of these tests may vary
depending on the method used, requiring that positive findings be confirmed
by a specialized laboratory.
Serology for CMV can be difficult to interpret. Although 50-80% of women may
have serological findings of a past infection, this is not completely protective
against reinfection. A 4-fold or greater rise in the CMV-IgG titer within 2 weeks
is consistent with a recent infection. Assessing for avidity of the IgG antibody
has also been useful to differentiate primary and recurrent CMV infection.
Low-to-moderate avidity IgG antibody is more likely to represent an acute
infection. CMV infection is also diagnosed with urine culture or polymerase
chain reaction (PCR) using urine or serum. Rapid virus isolation in cell
cultures (shell vial) is also highly sensitive and specific. To summarize,
primary CMV infection is suspected in a pregnant woman if she has IgG
seroconversion or positive CMV IgM, IgG, and low IgG avidity.
Type-specific antibodies to HSV-1 and HSV-2 are used to confirm past
exposure and current infection in the mother; however, because of the high
prevalence of HSV infection, results may be difficult to interpret in terms of
diagnosing neonatal disease. The most sensitive test for detecting HSV is cell
culture, which is used to isolate the virus in tissue. PCR can be used to
diagnose lesions found during pregnancy. Papanicolaou tests and Tzanck
tests are poor HSV-screening tests. When a neonate has been exposed to
HSV lesions, some groups advocate swabbing the skin and mucous
membranes at 5- to 10-day intervals to screen for development of infection.
HSV PCR of amniotic fluid is sensitive but may not correlate with neonatal
HSV infection. [35] In newborns with suspected disease, cultures of the skin
lesions, mouth, eyes, urine, blood, stool, rectum, and CSF should be
obtained. PCR can be used to detect HSV in the spinal fluid.
Traditionally, B19V infection has been confirmed with serological testing with
IgM and IgG reactivity against virus capsid proteins. IgM may be present 10-
12 days after exposure and can persist for up to 6 months, while IgG
antibodies are formed by 3 weeks and may persist for years, potentially
conferring lifelong immunity. In women with negative serology, repeat IgM and
IgG 2-3 weeks later is recommended. Other laboratory abnormalities in
women with parvovirus infection may include anemia, leukopenia,
transaminitis, and elevated lactate dehydrogenase (LDH) levels. To test the
fetus, PCR has been shown to be a more sensitive diagnostic study and can
be used with amniotic fluid, cord blood, maternal serum, or placental
tissue. [36]Cordocentesis, which is recommended in fetuses with signs of
anemia, may also reveal fetal thrombocytopenia.
Serology can be used to confirm VZV infection or previous exposure in the
mother. A known lack of exposure should prompt further testing of the
antibody response.[13] Primary varicella confers lifelong immunity. However,
the diagnosis is usually made clinically. IgM can appear as soon as 3 days
after the onset of symptoms. Viral culture can be performed using skin
lesions, or PCR for VZV DNA can be performed using specimens obtained
from unroofed skin lesions. [37] Prenatal diagnosis is possible by detecting VZV
antibodies via percutaneous blood sampling or DNA in fetal blood or amniotic
fluid. Unfortunately, although serological identification is possible, there is
poor correlation with fetal sequelae from VZV infection.
Diagnosis of VZV infection in the infant is difficult because only 27% have an
IgM response. Serology for VZV IgG can be performed after the sixth month
of life. Viral culture in infants has not been found to be helpful. PCR of skin
tissue may be useful. [13]
Rubella virus infection in the mother is confirmed with IgM and IgG
serology. [10]Serum IgM levels peak 7-10 days after the onset of clinical illness
and can persist for 6 weeks before declining. IgG can be detected within 2-3
weeks of infection. IgG antibodies persist throughout life. PCR and viral
culture of amniotic fluid has been used for prenatal diagnosis in difficult cases.
Chorionic villi sampling and cordocentesis can also be used to test for rubella
antigen with PCR. However, cordocentesis is difficult before 20 weeks’
gestation, and fetal immunoglobulins usually go undetected before 22 weeks’
gestation. Although these tests can reveal rubella virus in the fetus, they do
not indicate the degree of fetal injury. Infection in infants can be diagnosed
with acute and convalescent serology, especially using rubella IgM or viral
cultures of the throat, nasal secretions, urine, or CSF.
Coxsackievirus infection can be confirmed by serology in the mother. In situ
hybridization or reverse-transcriptase PCR of tissue can be performed on the
newborn. [17]
Measles virus infection can be confirmed by IgM serology. [18]
LCMV infection can be diagnosed based on an IgM enzyme-linked
immunosorbent assay (ELISA) of CSF or serum. CSF pressure is generally
increased, with protein levels of 50-300 mg/dL and lymphocytes. Patients may
also exhibit leukopenia or thrombocytopenia.
Diagnosis of influenza in pregnancy should be based on clinical symptoms
without waiting for diagnostic tests due to the high morbidity and mortality
during pregnancy. Rapid influenza diagnostic tests may not be sensitive
enough to rule out infection, but more sensitive tests are more time
consuming. [38]
Zika virus testing is recommended in all pregnant women with possible Zika
virus exposure, even if they are asymptomatic. The challenge of laboratory
testing for Zika virus is that the window of time for Zika virus identification in
blood or urine via PCR is within the first two weeks of infection. In addition,
testing can be difficult, particularly for patients who have resided in dengue-
endemic areas, as there is cross-reactivity between Zika virus and other
flaviviruses, especially dengue viruses. ACOG recommends combined Zika
virus real-time reverse-transcription PCR (rRT-PCR) and IgM and plaque
reduction neutralization test (PRNT) testing. [39]Zika testing may also yield both
false-positive and false-negative results, so exclusion of the infection is not
always possible.
Imaging
Fetal ultrasonography can be used to diagnose growth restriction and may
reveal specific findings associated with perinatal viral infections but cannot be
used to diagnose fetal infection.
In a large cohort of 600 women with primary CMV infection, almost 15% of
fetuses had an ultrasound abnormality, yielding a positive predictive value of
35%. [40]Ultrasonographic findings associated with CMV infection include
intracranial calcifications, microcephaly, echogenic bowel, and fetal growth
restriction. However, normal ultrasonographic findings do not guarantee
normal neurodevelopment outcome.
If a mother tests positive for B19V IgM and negative for IgG, suggesting a new
infection, she should undergo serial ultrasonography to monitor for
development of fetal anemia for 10-12 weeks after exposure. Fetal demise is
most likely if infection occurs before 20 weeks' gestation, approaching
10%. [30] Doppler flow of the fetal middle cerebral artery (peak systolic velocity)
is the most sensitive noninvasive test for fetal anemia. The anemic fetus tries
to preserve oxygen delivery to the brain by increasing flow of low-viscosity
blood. As such, Doppler assessment shows elevated middle cerebral artery
peak systolic velocity (MCA-PSV) in cases of fetal anemia. [41] Elevated MCA-
PSV values warrant fetal blood sampling (cordocentesis) to assess the degree
of anemia and intrauterine transfusion, if necessary.
Chest radiography should be performed in any pregnant patient with a recent
VZV infection and respiratory symptoms to rule out pneumonia. Pneumonia
demonstrates classic viral signs, with diffuse peribronchial nodular infiltrates
and interstitial pneumonitis.
Prenatal diagnosis of varicella infection is possible with examination at 5 or
more weeks following the initial time of suspected VZV infection in the first
trimester. Ultrasonographic findings include limb abnormalities such as
hypoplasia, stippling of the epiphyseal plates, and club-foot deformities.
Ventriculomegaly may also be present. Fetal echocardiography should be
performed to assess for fetal cardiac abnormalities, with a follow-up
postnatally in infants with CRS to evaluate for cardiac defects, including
patent ductus arteriosus.
Detailed fetal ultrasonography may also be used to identify fetal injury
associated with congenital rubella syndrome and include intracranial
calcifications, hydrocephalus, microcephaly and cardiac defects. Fetal growth
evaluations may also show intrauterine growth restriction (IUGR). Fetal
echocardiogram is recommended to diagnose cardiac abnormalities, followed
by postnatal echocardiogram evaluation. The most common neonatal cardiac
abnormality is patent ductus arteriosus.
Ultrasonography can be used to assess fetal anatomy and growth when
congenital Zika virus infection is suspected. The Centers for Disease Control
and Prevention (CDC) and ACOG suggest fetal ultrasonographic examination
in pregnant women with recent Zika virus infection, recent flavivirus infection,
and/or presumed recent Zika virus infection. The intracranial anatomy is most
important, and ultrasonographic findings may include microcephaly,
ventriculomegaly, and intracranial calcifications. Other brain abnormalities
may include abnormalities of the corpus callosum and cerebellum.
Abnormalities of limbs, such as clubbed feet and arthrogryposis, have been
reported. Negative ultrasonography findings may not reflect late-appearing
abnormalities or growth restriction; as such, serial ultrasonography every 4
weeks should be considered. If imaging findings suggest congenital Zika virus
infection, amniocentesis is recommended.
Diagnostic procedures
Amniocentesis or chorionic villous sampling can assist in confirming infections
with rubella virus, CMV, B19V, Zika virus, varicella, and, possibly, HSV.
Amniocentesis for CMV PCR can be performed after 21 weeks’ gestation and
at more than 6 weeks from maternal infection. Before this point, the fetus does
not mount an immunological response. Testing fetal serum for IgM antibodies
is highly sensitive for congenital infection; however, it must be performed after
21 weeks’ gestation, it carries a significant risk to the pregnancy (fetal loss
related to cordocentesis), and it is technically very difficult. [7, 42, 43] As such,
identification of CMV DNA in the amniotic fluid via PCR can allow for
diagnosis. When amniocentesis is performed after 21 weeks' gestation and
greater than 6 weeks from primary maternal infection, a negative PCR for
CMV has a specificity of 97%-100%. [40] It is unclear whether the amount of
detected viral load is associated with severity of infection; as such, severity of
disease cannot be determined with amniocentesis.
Positive Zika virus rRT-PCR in amniotic fluid is diagnostic of fetal viral
exposure. As with CMV, positive results are not predictive of outcome. The
interval between maternal infection and transmission to the fetus is unknown
Treatment & Management
Medical care
The treatment of these infections had been limited in the past. However, many
studies of antivirals have shown that treatment may yield benefit in some
selected cases. Among these newly described treatments, the most studied
include ganciclovir in congenital CMV infection and acyclovir in maternal
varicella infections (see Medication).
Other treatment options that have shown to be lifesaving in small case reports
include intrauterine blood transfusions to treat hydrops fetalis due to B19V
infection. The procedure is performed with continuous ultrasound guidance,
and the umbilical vein is preferred. Cordocentesis has been associated with a
1.2-4.9% fetal loss rate. Nonetheless, most studies have shown that this
procedure may confer survival and outcome advantages in patients with
hydrops fetalis. [44]
There is currently no specific treatment for Ebola infection. Treatment consists
of supportive care, including hydration and correction of electrolytic
disturbance and coagulopathy. Prompt isolation and infection control
measures are critical. [45]
There is no treatment for maternal Zika virus infection. Supportive measures
include acetaminophen for fever and prevention of dehydration. Breastfeeding
is not contraindicated, as no cases of transmission via breast milk have been
reported. Zika virus rRT-PCR positivity in amniotic fluid is diagnostic of fetal
viral exposure but is not predictive of outcome.
Surgical care
If primary or recurrent HSV genital infection occurs late in pregnancy, elective
caesarian delivery is performed to prevent neonatal infection, although
neonatal infection is still possible via transplacental passage of HSV prior to
birth.
Consultations
The treatment of all of these infections should involve a team of well-
experienced high-risk obstetricians, as well as infectious disease specialists
and neonatologists
Follow-up
Further inpatient care
Some pregnant patients with varicella may require admission for treatment if
pneumonitis is suspected.
Further outpatient care
Infants with confirmed congenital CMV infection, even if asymptomatic at birth,
should undergo frequent audiometric evaluations through at least age 6
years. [7]
Infants who survive intrauterine B19V infection generally have an excellent
long-term prognosis. Isolated reports have described neurological deficits in
children who have received several intrauterine transfusions; as such, these
children should undergo follow-up to monitor psychomotor development. [27]
Infants with congenital rubella syndrome have a guarded prognosis and
require close follow-up for psychomotor development and audiometric
evaluation. Half of these children eventually need to attend schools for the
hearing impaired. [46]
Deterrence and prevention
Hand washing is the most important measure for reducing the spread of CMV.
Among women with children in daycare, women who care for young children,
and healthcare workers, the CDC recommends hand washing after contact
with saliva, nasal secretions, or urine. Women should avoid placing objects in
their mouths that children have had in their mouths. Most women have a
difficult time being told not to kiss their young children on the mouth. [47]
Animal studies of CMV immunization have shown promising results in the
prevention of congenital CMV infection and its complications. [48, 49] CMV
vaccines currently in various stages of preclinical and clinical testing include
protein subunit vaccines, DNA vaccines, vectored vaccines using viral
vectors, peptide vaccines, and live attenuated vaccines. [50]
Congenital CMV infection is an important cause of hearing, cognitive, and
motor impairments in newborns. A phase II, placebo-controlled, randomized,
double blind trial by Pass et al evaluated a recombinant CMV vaccine
(enveloped glycoprotein B with MF59 adjuvant). Three doses of the CMV
vaccine or placebo were administered at 0, 1, and 6 months to 464 CMV-
seronegative women within 1 year after they had given birth. After a minimum
of 1-year follow-up, 49 confirmed infections were noted, 18 in the vaccine
group and 31 in the placebo group. One congenital infection among infants of
the study subjects occurred in the vaccine group, and 3 infections occurred in
the placebo group. Ongoing research continues to evaluate the potential for a
CMV vaccine to decrease maternal and congenital CMV infection. [51]
Pregnant women who are seronegative for HSV can prevent infection by
abstaining from sex. An alternative would be the use of condoms and
abstinence from oral-genital sex. As mentioned above, the results of several
trials suggest that the use of acyclovir or famciclovir near term decreases the
expression of genital herpes and, thus, the need for a cesarean delivery.
VZV immunization in unexposed women or teenage girls helps prevent CVS,
but varicella vaccine (live attenuated virus) is not administered during
pregnancy. Inadvertent vaccination of a pregnant woman is not an indication
for pregnancy termination. The Varicella Vaccination in Pregnancy Registry, a
prospective outcome monitoring system, has not shown any adverse risk
related to the varicella vaccine in pregnancy.
Varicella-zoster immunoglobulin (VZIG) therapy after known exposure to
varicella has been the mainstay of disease prevention in pregnant women.
However, VZIG can be obtained only from the manufacturer. VariZIG, a
similar product, is available under expanded access for use in pregnant
women at a high risk of developing varicella. If this is not an option, IVIG can
also be administered. VZIG should be administered within 96 hours of
exposure; however, according to the CDC, when VZIG is not given within the
ideal window, it may still be administered up to 10 days after exposure. VZIG
administration may decrease the severity of neonatal disease in infants born
to mothers with active varicella at delivery. Again, the use of this medication
may be limited by availability, and VariZIG can be used under expanded
access protocol. A clinical history of varicella infection is very sensitive;
however, serology for varicella antibody can be obtained, and, when positive,
it reflects life-long immunity. In pregnant women who are not immune, the first
dose of varicella vaccine can be given in the immediate postpartum period
and the second dose 4-8 weeks after the first dose.
The measles-mumps-rubella (MMR) vaccine was introduced in 1988, and
worldwide universal vaccination has become a priority. MMR vaccination is
administered to all children in a series of 3 vaccinations and is offered to all
women of child-bearing age who immigrate to the United States. Patients
should undergo testing for rubella immunity at their first prenatal visit. If they
are susceptible to infection, they should be counseled to avoid exposure to
patients with viral exanthema and to report any exposure to their provider.
Additionally, seronegative women should be immunized immediately after
delivery prior to discharge from the hospital.
As it is a live attenuated strain, MMR vaccination is contraindicated within one
month of pregnancy or during pregnancy; however, no cases of CRS have
been reported after inadvertent immunization during pregnancy. Counseling
the patient about the very low risk of CRS is warranted, and termination of
pregnancy, although optional, is not recommended. Adverse effects of the
vaccine are minimal, and 95% of vaccinated patients seroconvert.
Avoidance of rodents, including mice and hamsters, may help prevent LCMV
infection.
The CDC and American College of Obstetrics and Gynecology (ACOG)
recommend vaccination of all pregnant women through the influenza season
(October through May). Vaccination early in the season and at any gestational
age is recommended. Pregnant women receive the inactivated influenza
vaccine, and the nasal mist is not recommended in pregnancy, as it is a live-
attenuated vaccine. Although thimerosal, a mercury-containing preservative,
has not been shown to be associated with short- or long-term adverse effects
(other than possibly site irritation), due to growing concerns, a thimerosal-free,
trivalent vaccine is available. As infants younger than 6 months are unable to
be vaccinated for influenza, vaccination of pregnant women allows for passive
immunization of the fetus. [52]
Women who are pregnant or trying to conceive should avoid travel to areas
where Zika outbreaks are ongoing. When women or their partners must travel
to these areas, they should follow precautions, including avoiding skin
exposure, using EPA-approved insect repellant with DEET, and avoiding
sexual contact with possibly exposed persons. Condoms or abstinence is
recommended to decrease sexual transmission. Men with confirmed Zika
virus infection should use condoms for 6 months from onset of infection.
Women with Zika virus infection should avoid pregnancy for at least 8 weeks.
Both the CDC and ACOG recommend the use of DEET in pregnancy.
Topically applied DEET has not been shown to be teratogenic, regardless of
gestational age of exposure.
Prognosis
Prognosis depends on the viral syndrome and the severity of the initial
infection.
Patient education
It is important to educate women of child-bearing age about the importance of
vaccination against some of these diseases, as many of these congenital
infections are preventable. Most of this education should be targeted toward
teenaged girls, as many young women will not seek medical care outside their
pediatrician until they are already pregnant.
CMV screening has not been recommended, and awareness of CMV remains
low. Women with small children in daycare need education regarding contact
with urine and saliva. Hand washing remains the primary method of
prevention. Routine serological screening for parvovirus is not recommended
by the ACOG.
Educating the pregnant patient to avoid contact with persons with varicella
infections and frequent hand washing when handling children can prevent
infection. If exposure does occur, the patient should seek immediate
assistance for postexposure prophylaxis with varicella immunoglobulin.
Varicella vaccine is available to anyone aged 12 months or older as a two-
dose regimen. Because this is a live-attenuated virus, it is recommended that
pregnancy be delayed for 3 months after administration. [53]
Pregnant women should be counseled regarding travel to active areas of Zika
transmission. Women and their partners who want to conceive should also be
counseled regarding prevention and time lag prior to attempting pregnancy if
one partner is infected.
Medications
Antenatal maternal treatment with ganciclovir or valacyclovir is not
recommended, as their effect has not been proven. Several studies have
shown that ganciclovir at 12 mg/kg/day for 6 weeks stops the progression of
hearing loss in affected infants and can even reverse it. [54, 55] It is not yet clear
if ganciclovir therapy can improve growth or other developmental outcomes.
Adverse effects, including pancytopenia, are common in infants treated with
ganciclovir and may limit its use. [55]
Recent data have emerged suggesting the potential benefits of
administering intravenous hyperimmunoglobulin (HIG) therapy to pregnant
women for the treatment and prophylaxis of congenital CMV infection. [56]
Nigro et al divided women into a therapy group if they had an amniocentesis-
positive diagnosis of CMV infection and a prevention group with no
amniocentesis diagnosis. The women in the therapy group were treated with
200 U/kg IVIG, and the prevention group was given 100 U/kg monthly until
delivery. In the women who opted for treatment in the therapy group, 1 in 31
infants was born with symptomatic CMV disease, compared with 7 of 14 who
opted for no treatment. In the prevention group, 6 in 37 who opted for IVIG
had infants with symptomatic CMV disease at birth, versus 19 of 47 who
opted for no treatment. They concluded a decreased risk of 50% to 3%.
However, gestational age at time of diagnosis was significantly higher in the
treatment group, and later gestation is associated with increased risk of
transmission. A case control study recently showed that children of mothers
receiving CMV immunoglobulin during pregnancy for primary CMV infection
had decreased severity of disabilities at age 3 years. [57] As no randomized
controlled trials have been conducted, the impact of this treatment on
transmission remains unclear. Currently, the use of HIG is reserved for
research protocols. [58]
Although promising, 2 large trials (NIH and European trial) are currently
underway that way provide better guidelines and recommendations for
treatment with IVIG. A 2014 randomized trial of hyperimmune globulin to
prevent congenital CMV infection did not modify the course of primary CMV
infection in pregnancy. A total of 123 women were randomized to
hyperimmune globulin or placebo every 4 weeks between 4 weeks’ and 36
weeks’ gestation, and treatment did not change the outcome of congenital
infection at birth. [59]
Acyclovir, a nucleoside analogue that selectively inhibits viral replication, has
been shown to prevent recurrences of HSV lesions during pregnancy and is
indicated for the treatment of neonatal HSV. [60] Although categorized a class
C drug in the Acyclovir in Pregnancy Registry, in which more than 1200
women had documented exposures to acyclovir, even in the first trimester, no
adverse effects were directly attributed to this drug.
Suppressive therapy is used to decrease the risk of recurrent infections and to
reduce transmission rates. Antivirals are used after 36 weeks’ gestation to
decrease the risk of herpetic lesion recurrence near term that would
necessitate cesarean delivery (ACOG). Newer antivirals such
as valacyclovir and famciclovir are class B drugs and have greater
bioavailability, allowing for less-frequent dosing but are more expensive.
Acyclovir is also indicated for the treatment of varicella pneumonia during
pregnancy; however, acyclovir therapy for uncomplicated chickenpox in
immunocompetent pregnant women has not been studied. Pregnant women
with no evidence of immunity who are at high risk for severe disease and have
been exposed to varicella may receive varicella-zoster immune
globulin (VariZIG) within 96 hours of exposure. Acyclovir may be helpful in
neonates born with CVS in order to stop the progression of eye disease. No
studies have been performed to determine if treatment of varicella during
pregnancy prevents CVS. [13] Infants with neonatal disease should also be
treated with acyclovir.
The treatment of parvovirus infection is limited to symptomatic relief of
mothers with acetaminophen and to the treatment of fetal anemia, as no
vaccine or treatment is currently available to infected mothers.
The CDC recommends treatment of influenza in pregnant and postpartum
women (up to 2 wk after birth) with a neuroaminidase inhibitor such
as oseltamivir and zanamivir (Seasonal Influenza (Flu)). [61] Early treatment
within 2 days of onset of symptoms is associated with lower morbidity.
Treatment of fever is also recommended with antipyretics, with
acetaminophen being the best option, as nonsteroidal anti-inflammatory drugs
are not recommended in pregnancy. These latter drugs are associated with
potential adverse fetal effects, including decreased fetal renal function,
oligohydramnios, and premature closure of the ductus arteriosus.
Early initiation of treatment (< 2 days) is recommended for pregnant women,
although some evidence shows that later treatment may still provide benefit.
Treatment should be initiated regardless of time of symptoms in severely ill
pregnant women. Antiviral prophylaxis for significant exposure to influenza
virus, as well as treatment once clinical signs appear, is available. Oseltamivir
and zanamivir are category C drugs in pregnancy. Oseltamivir is preferred
because of its systemic absorption, as zanamivir is inhaled and may
exacerbate respiratory symptoms. The usual dose of oseltamivir is 75 mg
twice daily for 5 days. Zanamivir may be preferable for prophylaxis because
its systemic absorption is less. Although the numbers remain small, there
does not appear to be an increased fetal risk following prenatal exposure to
influenza antiviral medication. [62]