CHORIOAMNIONITIS
Introduction
Chorioamnionitis is an infection that can occur before labor, during labor, or after
delivery. It can be acute, subacute, or chronic. Subacute chorioamnionitis is associated
with chronic lung disease in the infant. Chronic chorioamnionitis is associated with
retinopathy of prematurity, very low birth weight, and impaired brain development in the
premature infant. Chronic chorioamnionitis is common. This terminology refers to
histologic chorioamnionitis. Histologic chorioamnionitis at term is rarely infectious.
In general, the clinical presentation of chorioamnionitis is defined as acute
chorioamnionitis. The Greek etymology of the words chorion and amnion mean fetal
membrane and itis means inflammation. Further description denotes
chorioamnionitis includes the amniotic fluid. Chorioamnionitis may be identified
postdelivery or postmortem on a pathologic review of the placenta and cord. In
histologic chorioamnionitis, symptoms may be absent, and the placenta or cultures may
not show evidence of chorioamnionitis.
Most commonly, chorioamnionitis is associated with preterm labor, prolonged rupture of
membranes, prolonged labor, tobacco use, nulliparous pregnancy, meconium stained
fluid, multiple vaginal exams post rupture of membranes, and in women with known
bacterial or viral infections. However, it can occur at term and in women without prior
infections. Left untreated, chorioamnionitis can lead to morbidity and mortality for the
mother and neonate. Neonatal morbidity and mortality increase in severity and
occurrence with earlier gestations. Antibiotic therapy has been shown to reduce the
incidence and severity of the infection in both the mother and neonate. However,
antibiotics do not eradicate the infection in all cases.
Despite advances in obstetric and neonatal care, the prevalence of children with adverse
neurodevelopmental outcomes has increased, and the etiology of adverse neurodevelopmental
outcomes remains poorly understood. Evidence shows that neonatal factors, including premature
birth, very low birth weight, necrotizing enterocolitis (NEC), meningitis, birth asphyxia,
bronchopulmonary dysplasia (BPD), and periventricular-intraventricular hemorrhage (PV-IVH),
contribute to adverse neurodevelopmental outcomes. In addition, some prenatal factors, including
maternal age, education, obesity, race, and hypertension, contribute to adverse
neurodevelopmental outcomes.
Maternal chorioamnionitis is categorized as histologic, microbiologic, and clinical. Maternal
histologic chorioamnionitis is defined as pathologic findings on placental histology, including
neutrophil infiltration of placental membranes, funisitis (inflammation of the umbilical cord), or fetal
vasculitis. Wu et al. characterized maternal microbiological chorioamnionitis as retrieval of microbial
organisms in amniotic fluid or placental cultures. Maternal clinical chorioamnionitis is characterized
by maternal fever, malodorous amniotic fluid, uterine tenderness, maternal or fetal tachycardia, and
maternal leukocytosis. Several studies have shown evidence of an association between maternal
infection/chorioamnionitis and neurodevelopmental outcomes.
Maternal chorioamnionitis might affect the neurodevelopment of infants through multiple
pathways. Human data studies show that chorioamnionitis contributes to CP, NEC, premature birth,
low 5-minute Apgar scores, and BPD, and all these conditions contribute to adverse
neurodevelopmental outcomes. Berger et al. showed that infants with positive maternal amniotic
cavity cultures had a significantly higher risk of an adverse PDI score. Maternal chorioamnionitis may
result in infection-mediated fetal brain injury and epigenetic changes, thus altering
neurodevelopment outcomes later in life. Proinflammatory cytokines produced by inflammatory
cells can cause neurotoxicity, oligodendrocyte maturation arrest or injury, disruption of myelination
and demyelination, and microglia activation. These brain cell dysfunctions may result in impaired
neurodevelopmental outcomes. Chorioamnionitis is closely related to fetal white matter injury, thus
resulting in neurodevelopmental complications, including autism, cognitive impairments and CP.
This may explain the effects of maternal chorioamnionitis on mental development. Maternal
chorioamnionitis may contribute to maladaptive programming of the fetal brain.
Previously, we, and others, demonstrated an association between chorioamnionitis and wheezing/
asthma, decreased lung function, and other respiratory morbidities. Indeed, it has been shown that
cord blood levels of interleukin (IL) 1β and IL-6 increase in neonates with chorioamnionitis. IL-6
exposure may then alter T-cell development to promote development of T-helper-cell 17 (TH17)
effector responses and may also repress regulatory T-cell (Treg) development. Te “master regulator”
of T17 cells is retinoic acid-related orphan receptor gamma (RORγt), which directs the development
of T17 cells. These cells have been found to mediate inflammation, autoimmune disease, and may
also protect from extracellular pathogens.
Tus, the changes in cytokine expression in neonates with chorioamnionitis may eventually promote
immune dysregulation, airway remodeling via mucous cell metaplasia, smooth muscle
proliferation/migration, and further TH17 activation. Furthermore, animal models of
chorioamnionitis demonstrate an increased lung and splenic TH17-toTreg ratio, which establishes a
proinflammatory state.
Definition
The placenta is composed of three major structures: the placental disc, the chorioamniotic
membranes, and the umbilical cord (Figure 1). Acute inflammatory lesions of the placenta are
characterized by the infiltration of neutrophils in each of these structures.9 Specifically, when the
inflammatory process affects the chorion and amnion, this is termed acute chorioamnionitis9; if it
affects the villous tree, this represents acute villitis9. If the inflammatory process involves the
umbilical cord (umbilical vein, umbilical artery, and the Wharton's jelly), this is referred to as
funisitis, the histological counterpart of the fetal inflammatory response syndrome
Etiology
The literature defines chorioamnionitis as an inflammatory and infectious process.
Inflammation in utero is linked to preterm birth, brain abnormalities, and
retinopathy. Infection can be due to a bacterial, fungal, or viral agent. Bacterial agents in
chorioamnionitis can vary depending on the geographic location and population.
Common bacterial agents found in chorioamnionitis include group B streptococcus,
Mycoplasma pneumoniae, Ureaplasma, Gardnerella vaginalis, Escherichia coli, and
Bacteroides. Candida species are identified as risk factors for chorioamnionitis, leading
to preterm birth and adverse fetal outcomes. In adolescents with sexually transmitted
infections, studies show that trichomoniasis is a risk factor for the development of
chorioamnionitis. Although chorioamnionitis is a risk factor for vertical transmission in
pregnancy, the incidence of chorioamnionitis in HIV-positive versus HIV-negative
women is not significantly different during labor. In one study of 298 women with similar
risk factors and demographics, both groups of women had a high incidence of
chorioamnionitis. The higher incidence for each group was strongly associated with the
number of vaginal exams during labor.
Epidemiology
Chorioamnionitis occurs in about 4% of deliveries at term but occurs more frequently in
preterm deliveries and premature rupture of membranes. In evaluating women with
symptoms of chorioamnionitis, studies show a strong correlation between histologic
chorioamnionitis and the key clinical symptoms of fever, uterine tenderness, meconium
aspiration syndrome, and foul-smelling vaginal discharge. Histologic chorioamnionitis
with vasculitis is associated with a higher incidence of premature rupture of membranes
and preterm delivery.
In deliveries between 21 and 24 weeks gestation, chorioamnionitis can be found in more
than 94% of the placentas on evaluation. Term deliveries of mothers with
chorioamnionitis are associated with failure to progress. Chorioamnionitis in preterm
labor is likely to end in preterm delivery. Studies show that inflammation of the placenta
or chorioamnionitis can be found in approximately 8% to 50% of preterm deliveries. In
the term pregnancy, chorioamnionitis is most likely associated with labor and a history of
prolonged ruptured membranes.
Pathophysiology
Chorioamnionitis is an ascending infection, originating in the lower genitourinary tract
and migrating to the amniotic cavity. The infection usually originates from the cervical
and vaginal area. Vertical transmission has been documented in bacterial and viral
infections transmitted to the fetus.
The placenta can be considered as the apposition or fusion of the fetal
membranes/placental disc to the uterine mucosa (decidua) for physiologic exchange35.
The decidua is of maternal origin, while the chorioamniotic membranes and villous tree
are of fetal origin.Thus, the precise origin of the inflammatory process (maternal vs.
fetal) can be determined by whether infiltrating neutrophils are of maternal or fetal origin.
Neutrophils are not normally present in the chorioamniotic membranes, and are thought
to migrate from the decidua into the membranes in cases of acute
chorioamnionitis36, 37 (Figure 3). On the other hand, neutrophils in the maternal
circulation are normally present in the intervillous space (Figure 1). When there is a
chemotactic gradient attracting neutrophils toward the amniotic cavity, neutrophils in the
intervillous space migrate into the chorionic plate of the placenta, which is also normally
devoid of these cells. Thus, inflammation of the chorionic plate is also a maternal
inflammatory response.
Neutrophils in acute chorioamnionitis are of maternal origin. Fluorescence in
situ hybridization (FISH) with probes for X and Y chromosomes performed in cytospin
slides of placentas from male fetuses showed that approximately 90% of neutrophils
derived from the membranes were of maternal origin36. Subsequently, FISH combined
with immunohistochemistry for CD45 (to identify leukocytes) demonstrated that cells
staining for CD45 in the chorioamniotic membranes were of maternal origin37. In
contrast, inflammation of the umbilical cord and the chorionic vessels on the chorionic
plate of the placenta is of fetal origin38. This conclusion is largely based on the
understanding of the anatomy of these tissues, as neutrophils invading the walls of the
umbilical vein and arteries must migrate from the fetal circulation to enter the walls of
these vessels (Figure 4). Insofar as the origin of white blood cells in the amniotic fluid in
cases of intra-amniotic inflammation, the only study reported to date in cases of clinical
chorioamnionitis with intact membranes suggested that 99% of neutrophils are of fetal
origin 39.
Inflammation of the umbilical vessels begins in the vein (phlebitis) and is followed by
involvement of the arteries (arteritis), then infiltration of neutrophils into the Wharton's
jelly 40. The molecular pathogenesis of funisitis has been studied using microarray
analysis followed by quantitative real-time PCR of RNA obtained from micro-dissected
umbilical arteries and veins. The expression of IL-8 mRNA (the prototypic neutrophil
chemokine) is higher in the umbilical vein than in the umbilical artery 40. Moreover, there
are substantial differences in the genes expressed by the walls of the umbilical artery
and vein. The pattern of gene expression suggests that the wall of the umbilical vein is
more prone to a pro-inflammatory response than the umbilical arteries 40. This explains
why the umbilical vein is the first vessel to show inflammatory changes, and the
presence of arteritis is evidence of a more advanced fetal inflammatory process 40.
Indeed, the umbilical cord plasma concentrations of IL-6 (a cytokine used to define
systemic inflammation) and the frequency of neonatal complications are higher in cases
with umbilical cord arteritis than in those with phlebitis only 41.
Systematic studies of the umbilical cord suggest that acute funisitis begins as multiple,
discrete foci, along the umbilical cord, which then merge with the progression of the
inflammatory process 40. Figure 4illustrates the topography of the inflammatory process
in several umbilical cords serially sectioned at 1 mm intervals. The chemotactic gradient
attracting neutrophils from the lumen of the umbilical vessels into the Wharton's jelly is
thought to be dependent on elevated concentrations of chemokines in the amniotic fluid.
The severity of funisitis correlates with fetal plasma IL-6 concentrations (an indicator of
the severity of the systemic fetal inflammatory response) and amniotic fluid IL-6 – the
latter reflects the intensity of the intra-amniotic inflammatory response
Histopathology
Chorioamnionitis is an inflammatory process that ranges from mild to severe.
Histopathologic findings consistent with inflammation also can be present in placentas
of women with normal pregnancy.
In chorioamnionitis, the membranes may appear normal or show evidence of infection.
Fluid can be clear or cloudy. On histologic examination, there is neutrophilic infiltration
into the decidua, and in more severe cases, microabscesses are present on the
decidua. A recent study suggests that neutrophils in the amniotic cavity are mostly of
fetal origin. In extreme prematurity, both maternal and fetal neutrophils are more likely to
be present in the amniotic cavity with chorioamnionitis.
Redline et al. classified acute inflammatory lesions of the placenta into two categories:
“maternal inflammatory response” and “fetal inflammatory response” 9. The term “stage”
refers to the progression of disease based on the anatomical regions infiltrated by
neutrophils, while the term “grade” refers to the intensity of the acute inflammatory
process at a particular site 9. In the context of a maternal inflammatory response, a
stage 1 lesion is characterized by the presence of neutrophils in the chorion or
subchorionic space; stage 2 refers to neutrophilic infiltration of the chorionic connective
tissue and/or amnion, or the chorionic plate; and stage 3 is necrotizing chorioamnionitis
with degenerating neutrophils (karyorrhexis) 9.
Grade 1 (mild to moderate) refers to individual or small clusters of maternal neutrophils,
diffusely infiltrating the chorion laeve, chorionic plate, subchorionic fibrin or amnion.
Grade 2 (severe) consists of the presence of three or more chorionic microabscesses,
which are defined as confluence of neutrophils measuring at least 10×20 cells 9.
Microabscesses are typically located between the chorion and decidua, and/or under
the chorionic plate 9. Grade 2 is also applied in the presence of a continuous band of
confluent neutrophils in the chorion of more than 10 cells in width, occupying more than
half of the subchorionic fibrin, or one revolution of the membrane roll. Other staging and
grading systems have been used and subsequently modified 18, 19, 42-47.
Staging and grading are also applicable to the fetal inflammatory response 9. Staging
(which refers to the location of neutrophil infiltration) is more important and reproducible
than grading in the assessment of the severity of the inflammatory process 48. For
example, involvement of the amnion (amnionitis) is associated with more intense fetal
and intra-amniotic inflammation, measured by the concentration of cytokines, than
involvement of the chorion alone 49. The rates of funisitis and positive amniotic fluid
culture for microorganisms, as well as the median umbilical cord plasma C-reactive
protein, median amniotic fluid Matrix metalloproteinase (MMP)-8 concentration and
amniotic fluid white blood cell count are higher when the inflammatory process of the
membranes involves amnion and chorion than when neutrophil infiltration is restricted to
the chorion/decidua 49. (Figure 5 stage and grade of acute chorioamnionitis, Figure
6 acute funisitis). Moreover, amniotic fluid MMP-8 concentration is correlated with the
severity of acute histologic chorioamnionitis (grading).
6. Pathways of microbial invasion of the amniotic cavity
Under normal conditions, the amniotic cavity is sterile for microorganisms using
cultivation 51 and molecular microbiologic techniques, based on the detection of the 16S
rRNA gene (present in all bacteria, but not in mammalian cells). Four pathways have
been proposed whereby microorganisms reach the amniotic cavity 52-56: 1) ascending
from the lower genital tract 1, 7, 57, 58; 2) hematogenous 59-61; 3) accidental introduction at
the time of amniocentesis, percutaneous umbilical cord blood sampling, fetoscopy, or
another invasive procedure 62-68; and 4) retrograde seeding from the peritoneal cavity
from the fallopian tubes 57 . However, there is limited evidence in support of the latter
pathway.
Ascending microbial invasion from the lower genital tract appears to be the most
frequent pathway for intra-amniotic infection (Figure 7 and Figure 8) 53. While all
pregnant women have microorganisms in the lower genital tract, most do not have intra-
amniotic infection. The mucus plug represents an anatomical and functional barrier to
ascending infection during pregnancy 69-75. In the non-pregnant state, the endometrial
cavity is not sterile 76-78, but the decidua is thought to be sterile during pregnancy.
A hematogenous pathway can operate during the course of blood-born maternal infections 59-61.
Microorganisms such as Listeria monocytogenes 79-81, Treponema pallidum, Yersinia pestis,
Cytomegalovirus, Plasmodium species, and others can gain access through the maternal
circulation to the intervillous space, from where they invade the villi and the fetal circulation 53.
Bacteria involved in periodontal disease may use this pathway to reach the amniotic cavity 82-88.
Intra-amniotic infection has been documented in patients with preterm labor with intact
membranes 11, 89-114, prelabor rupture of membranes 13, 115-130, cervical insufficiency 131-135, an
asymptomatic short cervix 14, 136-138, idiopathic vaginal bleeding 139, placenta previa 140, and clinical
chorioamnionitis at term 15. Rupture of membranes is not necessary for bacteria to reach the
amniotic cavity – indeed, there is experimental evidence that bacteria can cross intact
membranes 141. Most of these infections are subclinical in nature, and therefore, they occur in the
absence of clinical chorioamnionitis 90, 142, 143. Hence, most of these infections are undetected
unless the amniotic fluid is analyzed. The most frequent microorganisms found in the amniotic
cavity are genital mycoplasmas 93, 103, 122, 142, 144-147, and in particular, Ureaplasma species 135, 148-
, Gardnerella vaginalis 15, 90, 127, 156-158, Fusobacteria species, etc. 11, 110, 127. Fungi can also be found
155
– women who became pregnant with intrauterine contraceptive devices are at high risk for intra-
amniotic infection with Candida albicans 159-168. Polymicrobial invasion of the amniotic cavity is
present in approximately 30% of cases 11, 13, 93, 110, 127, 169. Table 2 describes the frequency of
microbial invasion of the amniotic cavity in different obstetrical syndromes. Table 3demonstrates
the microorganisms detected in amniotic cavity in patients with preterm labor with intact
membranes 110 and clinical chorioamnionitis at term
Microorganisms gaining access to the uterine cavity from the lower genital tract are first localized in
the decidua of the supracervical region. Subsequent propagation and chorioamniotic passage of the
microorganisms can lead to the establishment of microbial invasion of the amniotic cavity 170, 171.
Although some investigators believe that there is a stage in which the bacteria are diffusely located
in the choriodecidual layer, our studies, using FISH with a bacterial 16S rRNA probe, indicate that
there is not extensive involvement of the chorion-decidua in cases with microbial invasion of the
amniotic cavity 172. Indeed, bacteria are primarily found in the amnion in cases of intra-amniotic
infection, indicating that microbial invasion of the amniotic cavity is a prerequisite for substantial
invasion of the amnion and chorion 172. Specifically, bacteria are more frequently detected in the
amniotic fluid than in the chorioamniotic membranes of patients with positive amniotic fluid
culture.
Acute inflammatory lesions of the placenta have been traditionally considered as reflective of
amniotic fluid infection1-10, 149, 320-322. In 1987, Dong et al reported that acute histologic
chorioamnionitis was present in 97% (32/33) of patients with intra-amniotic infection, defined as
the presence of microorganisms using cultivation techniques323. However, amniotic fluid samples
for microbiologic studies in that study were obtained by transcervical collection323. Indeed, acute
chorioamnionitis was found in 37% (18/49) of patients with negative amniotic fluid cultures,
suggesting that contamination of samples retrieved by a transcervical route is difficult, if not
impossible323.
The most rigorous evidence that intra-amniotic infection is associated with acute
chorioamnionitis is derived from studies in which a trans-abdominal amniocentesis was
performed in patients with preterm labor and intact membranes, and the placenta was examined
within 48 hours of the procedure7. Placentas with acute chorioamnionitis and acute funisitis were
from mothers who had intra-amniotic infection proven by culture in 71.1% and 78.7% of cases
respectively7. The prevalence of microbial invasion of the amniotic cavity was 38%. The
negative predictive values of acute chorioamnionitis and funisitis for intra-amniotic infection
were 87% and 82%, respectively7.
Recently, we reported a new type of intra-amniotic inflammation termed “sterile inflammation”,
which is more frequent than intra-amniotic infection (microbial-associated intra-amniotic
inflammation) in patients with preterm labor with intact membranes12, preterm PROM13 and an
asymptomatic short cervix14. Interestingly, sterile intra-amniotic inflammation is associated with
acute histologic chorioamnionitis (40-60% of cases)11-15. Moreover, acute inflammatory lesions of
the placenta are present in a small subset of patients without intraamniotic inflammation in the
context of preterm labor11, 13, preterm PROM13, short cervix14, and clinical chorioamnionitis15.
Potential explanations are: 1) inflammation of chorioamniotic membranes is a non-specific
mechanism of host defense against “danger signals” of non-microbial origin; 2) extra-amniotic
infection, which is probably rare; 3) non-viable microorganisms which may release chemotactic
factors leading to inflammation7. These organisms may have invaded the amniotic cavity and
been cleared by the immune system.
The observation that acute histologic chorioamnionitis is present without demonstrable intra-
amniotic infection is now well-established11-15, 324. Roberts et al reported, using both cultivation
and molecular microbiologic techniques, that only 4% of patients with acute histologic
chorioamnionitis at term have microorganisms in the placenta324. Therefore, acute histologic
chorioamnionitis should not be considered synonymous with amniotic fluid infection. The
characterization of any biological fluid as “sterile” is dependent on the sensitivity of the assays
used to detect microorganisms. Cultivation can be very sensitive, and even one microorganism
can grow into a colony under optimal conditions; however, such conditions are rarely provided
in clinical laboratories. Molecular microbiologic techniques are considered more sensitive; yet,
sufficient microbial DNA must be present for this methodology to provide a positive result. PCR
assays with specific primers for a microorganism are considered superior to broad range PCR
assays based on conserved regions of the bacterial genome (e.g. 16S gene). The use of deep
sequencing can change what is known about the microbiologic landscape of biological fluids.
Extreme caution must be used when interpreting the results of sequencing studies, as
contamination during metagenomics can occur.
The Fetal Inflammatory Response Syndrome (FIRS)
Microbial invasion of the amniotic cavity can progress to fetal invasion. The ports of entry for
bacteria into the fetus include the respiratory tract (fetal breathing), gastrointestinal tract
(swallowing), skin, and ear. Amniotic fluid fills the external auditory canal and bacteria can
invade the tympanic membrane and middle ear. Similarly, depending upon the gestational age,
microorganisms may gain access to the conjunctiva.
Once microorganisms gain access to the fetal mucosa, they are recognized by pattern recognition
receptors such as Toll-like receptors (TLRs), and ligation of such receptors can induce the
production of transcription factors such as NFκB and elicit a localized (and subsequently
systemic) inflammatory response 326. For example, fetuses exposed to bacteria can develop severe
dermatitis or pneumonitis. Subsequently, microorganisms reaching the fetal circulation could
lead to a systemic inflammatory response.
The frequency with which microorganisms invade the human fetus is difficult to ascertain;
however, studies in which amniocentesis and cordocentesis have been performed in patients with
preterm PROM indicate that 30% of patients with microbial invasion of the amniotic cavity have
positive fetal blood cultures for microorganisms (i.e. bacteremia) 327, 328. Similar findings have
been reported when cultures for genital mycoplasmas have been performed in umbilical cord
blood at the time of birth 144, 329. Therefore, the frequency of congenital microbial invasion of the
fetus is likely to be higher than that reported in the pediatric literature – the reasons for this are
multiple (e.g. bacteremia may not be continuous in the neonatal period; the inoculum size may
be small, leading to a high rate of negative blood cultures; and the lack of detection of the most
common microorganisms, genital mycoplasmas, may reflect that cultures for these organisms
require special media, and such cultures are not routinely performed in neonatal intensive care
units) 330-332.
We have defined a fetal systemic inflammatory response syndrome (FIRS) using the fetal plasma
concentrations of IL-6 16, 327, 333-343. This cytokine is a major mediator of the acute phase response,
and its concentration can be readily determined using immunoassays. It is noteworthy that the
systemic inflammatory response syndrome (SIRS, in adults) was originally defined using clinical
criteria such as fever, tachycardia, respiratory rate, and white blood cell count 344-346. However,
this definition cannot be used in the human fetus, because the vital signs (with the exception of
heart rate) cannot readily be determined before birth or during the intrapartum period 347. Our
definition of FIRS was based on the concentration of fetal plasma IL-6 associated with adverse
outcome (in samples obtained by cordocentesis) 327, and was introduced in 1997 348.
Subsequently, in 2001, the American College of Chest Physicians and the Society of Critical
Care Medicine noted that an elevated plasma concentration of IL-6 was associated with the
likelihood of SIRS, and proposed that the concentrations of this cytokine may be useful in its
diagnosis 349.
Despite the similarities between FIRS and SIRS, the unique circumstances of the patient 330 and
its environment (uterus) pose challenges which are sui generis for the diagnosis, management,
and treatment of FIRS 56, 143, 350, 351. Importantly, FIRS and SIRS share an important feature – both
can be caused by non-microbial-related insults. Although the consequences of microbial
invasion/proliferation in adult and neonatal medicine are well-known, and the evolution of
FIRS/SIRS to sepsis, septic shock and death has been well-characterized, SIRS can occur in
cases of sterile inflammation (e.g. pancreatitis or burns) 346,352. Since our original report of FIRS,
we identified that some cases of this syndrome are observed without demonstrable microbial
invasion of the amniotic cavity, and have proposed that such cases represent the response to
danger signals which cause cellular stress in the amniotic cavity and fetus 11-13. The precise nature
of the danger signals in sterile intra-amniotic inflammation and corresponding cases of FIRS has
not been elucidated; yet, we have proposed that this may result from insults that trigger cell death
(necrosis, pyroptosis, etc.) 308, 310, 311, 314, 316, 318.
The presence of FIRS was originally described in fetuses presenting with preterm labor and
preterm PROM 327, and was associated with three major consequences: 1) a shorter interval-to-
delivery 327; 2) higher neonatal morbidity after adjustment for gestational age at birth 327; and 3)
multi- organ involvement 351, including hematopoietic system 336, 338, 339, 353, immune system 336, 353-
356
thymus 357-361, heart 362, adrenal glands (e.g. alteration in cortisol) 363, skin 335, lung 188, 333,
brain 195, 294, 364-366, kidney 367 and gut 46, 368, 369 (Figure 12). Although these observations were
originally made in humans, subsequent experimental studies in non-human primates as well as
sheep have demonstrated the involvement of multiple organ systems when the fetus is exposed to
inflammatory stimuli
History and Physical
The initial history should include maternal age, gestational age, parity, highlights of the
pregnancy including any complications, whether membranes are ruptured or intact, the
presence of meconium, presence of or history of sexually transmitted infections, urinary
tract infections, and recent illness. The physical exam must be thorough and include
vitals and a complete physical evaluation including the abdomen, vagina, and uterus.
Chorioamnionitis presents as a febrile illness associated with an elevated white blood
cell (WBC) count, uterine tenderness, abdominal pain, foul-smelling vaginal discharge,
and fetal and maternal tachycardia. Diagnosing clinical chorioamnionitis includes a fever
of at least 38 C (100.4 F) and one of the clinical symptoms or between 38 C (100.4 F)
and 39 C (102.2 F) within 30 minutes. The majority of women presenting with
chorioamnionitis are in labor or have ruptured membranes when it presents.
Evaluation
Initial evaluation for chorioamnionitis includes a thorough clinical assessment of the
mother and fetus. Although the maternal WBC count is a routine test done when there is
suspicion of an infection, recent studies show that the WBC count does not identify the
presence of microbial invasion or inflammation in the amniotic cavity for women with
premature rupture of membranes on admission. The WBC count also has low sensitivity
and specificity. Bacterial cultures taken from the cervix are not indicated and do not
correlate with infection secondary to chorioamnionitis.
Treatment / Management
The primary management of chorioamnionitis is antibiotic therapy. The most common
antibiotics used are ampicillin and gentamicin. Alternative antibiotics include
clindamycin, cefazolin, and vancomycin in women allergic to penicillin. After delivery, the
current recommendation is to administer one additional dose with a cesarean section
but no additional antibiotics for vaginal deliveries. Additional broad-spectrum antibiotics
may be required, depending on the clinical status.
Differential Diagnosis
Abdominal pain and uterine tenderness associated with fever are nonspecific signs.
Women with fever, pain, and tenderness during labor must be evaluated for other
common infections such as appendicitis, urinary tract infection, pyelonephritis, and
pneumonia. Additional ancillary testing and examination must be thoroughly reviewed
before making a final diagnosis.
Prognosis
Chorioamnionitis is a risk factor for both maternal and neonatal sequelae. Endometritis
can occur in up to one-third of women treated for chorioamnionitis who undergo a
cesarean section. The rate of endometritis is the same in vaginal deliveries and
cesarean deliveries following chorioamnionitis. Recent studies show that management
with postpartum antibiotics does not decrease the risk of endometritis following
chorioamnionitis.
The majority of women with chorioamnionitis will recover and not require further
antibiotics after delivery.
Complications
Neonatal complications of chorioamnionitis include premature birth, cerebral palsy,
retinopathy of prematurity, neurologic abnormalities, respiratory distress syndrome,
bronchopulmonary dysplasia in premature infants, neonatal sepsis, and neonatal death.
Neonatal sepsis is suspected as a complication of chorioamnionitis; however, in more
than 99% of cases, cultures are negative. Perinatal listeriosis is associated with high
morbidity. Current antibiotic regimens may not cover listeriosis in chorioamnionitis.
Maternal complications of chorioamnionitis include severe pelvic infections,
subcutaneous wound infections, preterm delivery, postpartum hemorrhage, operative
delivery, and maternal sepsis.
Chorioamnionitis is associated with vertical transmission of HIV in pregnancy.
Deterrence and Patient Education
Patients who are pregnant should receive routine counseling at each prenatal visit.
Education should include reporting rupture of membranes, vaginal discharge, fever, and
abdominal pain to their obstetrical provider. Every woman should receive information on
risk factors and signs and symptoms of infection during the prenatal period.
Enhancing Healthcare Team Outcomes
Women presenting with abdominal pain, uterine tenderness, and fever during labor must
be evaluated for other causes. In women with premature rupture of membranes, the
team must consider the risk of multiple examinations and avoid multiple digital exams.
Nursing and physician communication is important to assure the initial examination is
done with a sterile speculum. Clear communication also is required between team
members to make sure the physician is alerted to any changes in pain, fever, or clinical
status.
When choosing antibiotics, medical records should be reviewed thoroughly giving
special attention to the history of allergies and any previous reactions to penicillin or any
other antibiotics. This information must be reported to the pharmacy when ordering
medication and reviewed by the team.
If the patient requires a cesarean section, these items must be reviewed again during
the time out in the operating room.
