Update on Perinatal Viral Infections - Placental Pathology Perspective
Edwina J. Popek
Baylor College of Medicine
There are two basic modes of intrauterine infection, ascending and hematogenous. In addition
organisms harbored within the birth canal may infect an infant during the birthing process, often
resulting in features similar to an ascending infection, but with "late-onset" of symptoms. Rarely
infection may reach the fetus through invasive procedures such as amniocentesis. Infection of the
maternal endometrium or fallopian tube can also directly infect the chorion and amnion. Some infectious
agents have a preferred mode of infection, while others may be acquired by multiple modes (See below)
Excellent in-depth discussions of placental pathology in intrauterine infections are found in current
placental pathology texts
. The integrity of the fetal-placental-maternal unit is key to the
prevention of intrauterine infection. Infectious agents must traverse placental barriers to reach the
fetus. In most instances, intrauterine infection leaves "foot-prints" in the placenta either as direct
evidence of infection (organisms) or indirect evidence of infection (inflammation or tissue injury). The
placenta acts as a successful barrier to fetal infection. In most cases, despite placental infection,
the fetus remains uninfected; although, not necessary unaffected by the infection. Other factors that
affect the severity of intrauterine infection include the pathogen load, the virulence of the organism,
immunocompetence of both mother and fetus and gestational age at time of infection.
The placenta demonstrates two relatively distinct patterns of inflammation in response to either an
ascending (chorioamnionitis) or hematogenous (villitis) infection. Therefore, examination of the
placenta may be very helpful in determining the mode of infection, the specific infectious agent and even
the potential for fetal/neonatal infection. In general the severity of placental inflammation is
reflected in fetal/neonatal disease, although as in all medicine, there are exceptions.
Modes of Perinatal Infection, Selected Agents and Fetal/Placental Pathology
| ||Bacteria||Viruses ||Other ||Placenta||Fetal|
|Hematogenous ||Listeria, syphilis, E. coli ||CMV, HSV, VZV, HIV, parvovirus B19, rubella, enterovirus, dengue, HHV-8, West Nile ||Toxoplasma Chagas ||acute or chronic villitis, chronic vasculitis, necrotizing funisitis ||sepsis, viremia, disseminated infection, tissue necrosis (liver, lung)|
|Ascending ||Group B |
Strep., E. coli, Listeria
|CMV, HSV, HIV ||Mycoplasma, Ureaplasma, Candida ||acute chorio-amnionitisacute funisitis, vasculitis, necrotizing funisitis ||cutaneous, pneumonia, gastroenteritis, sepsis, meningitis|
|Intrapartum ||Group B |
Strep., Listeria, E. coli
|CMV, HSV, HIV, HBV, HPV ||Candida ||chorio-amnionitis ||cutaneous, eye, rarely systemic, meningitis|
|Postnatal ||Group B |
|CMV, HSV, HIV, HHV-8enterovirus, dengue || ||normal ||misc., agent specific|
Most cases of ascending infection are bacterial in origin. Organisms colonizing the cervix, vagina or
perineum may infect the maternal endometrium or fetal membranes at the cervical os. While it is true
that ruptured membranes carry an increased risk for infection of the amniotic cavity, most cases of
premature rupture of membranes are secondary to the membranes being already weakened by infection.
Bacteria can cross intact membranes . The structure of the fetal membranes is complex. Amnion and
chorion completely surround the gestational sac. The chorion of the free membranes is in direct contact
with the maternal decidualized endometrium and the attached chorion is exposed to the maternal blood flow
within the subchorionic intervillous space. The chorion has 3 layers and is thicker than the amnion
which has 5 thinner layers but greater tensile strength .
Most infants born with a clinical or histologic diagnosis of chorioamnionitis are not septic, but may
have localized infection in the lungs or within the gastrointestinal tract from aspirated or swallowed
contaminated amniotic fluid. The more severe the inflammation within the membranes, the more likely the
infant will be septic. Even more predictive for fetal sepsis is the presence of a fetal inflammatory
reaction within the umbilical cord (funisitis) or chorionic plate vessels (vasculitis)
Necrotizing chorioamnionitis and three-vessel inflammation of the umbilical cord are associated with an
increased incidence of preterm birth and perinatal death
. Only 20-33% of women with histologically
important inflammation of the membranes are symptomatic
. While many infants are not infected they
are affected by the fetal inflammatory response syndrome, which may be independently responsible for
morbidity and/or mortality 
Benirschke & Kaufmann feel that chorioamnionitis (which they use as synonymous with acute
chorioamnionitis) is always (their bold) caused by infection
. Other forms
of injury to the placenta, such as infarction will also illicit an acute inflammatory reaction, but will
be localized to the area of injury. Chorioamnionitis is much more common in preterm placentas; and is
responsible for at least 50% of all preterm deliveries
. At term, acute chorioamnionitis is only
present in 4-10% of placentas
The gross appearance of the membranes is a very poor judge of inflammation. The membranes are usually
macroscopically normal. Infection may result in slight clouding (loss of translucency) of the membranes,
granularity or a dull appearance which may be obscured by formalin fixation. Only severe inflammation
will result in grossly, thickened cloudy membranes that may be yellow or green due to the pyocyanin
within the white blood cells, obscuring the fetal vessels on the chorionic plate. Infection is
frequently associated with membrane edema.
The intensity or grade of inflammation used to define chorioamnionitis differs from publication to
. It has been described very generally as dense, or as specifically as one focus of
at least five neutrophils or ten or greater neutrophils in ten nonadjacent fields at 400x magnification
within free or attached membranes
Defined criteria for examination of membranes in premature
preterm rupture of membranes have been reported . A recent publication from the Perinatal Section of
the Society for Pediatric Pathology suggests a definition for both grade and stage of acute inflammation
Stage or progression of inflammation is also inconsistent. Naeye uses three histologic stages of
chorioamnionitis (I, II, III) to indicate subchorionic inflammation, chorionic inflammation and full
thickness inflammation of both chorion and amnion, respectively . Redline also uses 3 stages, but
they are slightly different . Early infection may be confined to the maternal decidua near the
cervical os, exemplified by a diffuse sprinkling of maternal neutrophils that is often associated with
some decidual necrosis. Membrane rupture occurs overlying the cervical os, probably due to unequal
stretch or unequal wall tension or possibly due to a loss of decidual blood supply in that area .
Some acute decidual inflammation is seen in 85% of term deliveries, especially near the zone of membrane
rupture . Inflammation marginated at the junction of the cellular and fibroblastic chorion indicates
migration towards the amniotic cavity and is a feature of intra amniotic fluid infection. Maternal
neutrophils marginate within the subchorionic fibrinoid, prior to migrating in the chorion and amnion on
their way towards the amniotic fluid cavity. Chellam suggests that this is equivalent to margination of
inflammatory cells within a vascular space and therefore may represent the earliest maternal response to
infection within the amniotic cavity . The inflammatory infiltrate progresses through the chorion
(chorionitis) and amnion (chorioamnionitis), and eventually into the amniotic fluid. Since inflammation
is chemotactically attracted to stimulus within the amniotic fluid, thickening of the membranes either by
squamous metaplasia or placement of the chorionic plate vessels, will focally interrupt this process.
Romero et al, have proposed a four stage, clinical progression of ascending infection . Stage I
is an overgrowth of organisms in the vagina and/or cervix. Stage II is localized inflammation of the
intrauterine cavity localized to the decidua. Stage III is intra amniotic infection. Stage IV is
infection of the fetus, through breathing or swallowing the contaminated amniotic fluid, or through
cutaneous infection, including conjunctiva. It would be appropriate to add a stage V to this to scheme
to indicate systemic fetal infection (sepsis or meningitis).
Location and appearance of the inflammation has lead to assumptions about duration of infection. In
general the inflammatory response is neutrophilic, regardless of the duration of infection; hampering our
ability to determine duration of infection. Intact neutrophils have led some to estimate infection of
<24 hours , as the average life span of neutrophils outside the vascular space is 24 hours .
The problem with this correlation is that the neutrophils that migrate into the avascular tissues of the
amnion may not disintegrate as quickly as in ischemia tissues which have been studies in acute myocardial
infarction. Naeye reports that maternal inflammation is subchorial intervillositis in the first 48 hours
of an infection and that only in the next few subsequent days do the neutrophils migrate into the
chorionic plate . The maternal inflammatory cells continue their progress towards the amniotic
fluid cavity. The time necessary for complete progress from the maternal space to the intra amniotic
fluid space has been estimated at 5-7 days, but may occur more quickly with highly virulent organisms
. Fox says that it would be imprudent to try to date a chorioamnionitis with any degree of precision
Cultures of the placenta are of limited value, in part due to antibiotic use during labor and
especially due to contamination through a vaginal delivery. There is no correlation between organisms
isolated from the cervical canal or from the placenta and fetal infection . Microorganisms were not
isolated significantly more often from placentas in cases with chorioamnionitis than those without .
There was a correlation between increased severity of membrane inflammation and fetal vascular
inflammation with increasing incidence of positive cultures . In preterm labor, bacteria can be
isolated from amniotic fluid of intact membranes or from placental cultures with variable success .
Approximately 70% of placental cultures are positive when there is histologic chorioamnionitis . Any
cultures should be sent directly from labor delivery. There is a decreased recovery of organisms with
refrigeration and prolonged interval between delivery and cultures. It has been proposed that cultures
are most reliable when obtained from the space between the amnion and chorion, thus eliminating surface
contamination. Cultures for aerobes, anaerobes, Mycoplasma and Ureaplasma will increase the yield.
Recently Ohyama et al, described subacute chorioamnionitis as a specific entity that is associated
with prematurity, development of chronic lung disease . In his study 54% of placentas with
chorioamnionitis had this form of inflammation, while in my experience it is present in <20%.
Subacute chorioamnionitis was defined as a mixed degenerative neutrophil and mononuclear cell infiltrate.
Amnion necrosis was present in 40%. Subacute chorioamnionitis was felt to be an indicator of persistent
intrauterine inflammation, possibly caused by organisms with low virulence. Rarely an antibiotic treated
acute chorioamnionitis may have mixed acute and chronic inflammation.
Chronic chorioamnionitis is often associated with chronic inflammatory lesions elsewhere within the
placental or decidual tissues, but can occur as an isolated phenomena. It has rarely been described in
conjunction with viral infections; HSV  , rubella , and toxoplasmosis . Chronic
chorioamnionitis tends to be most often associated with villitis of undetermined etiology . It is
usually focal and rarely involves the amnion connective tissue and does not result in necrosis of the
amnion epithelium .
Fetal Vasculitis and Funisitis
Fetal inflammatory response of the umbilical cord and chorionic plate vessels occurs after the
maternal response and usually suggests a more well established infection. It may be attenuated of absent
in midgestation, although I have seen a significant funisitis as early as 18 weeks gestation and rare
neutrophils even earlier.
Funisitis can rarely be grossly identified. The umbilical cord may be quite edematous. Within the
extra fluid within the cord substance, large accumulations of neutrophils may be visible as white rings
incompletely around the fetal vessels. The fetal response to infection within the amniotic fluid is
towards the amnion surface (amniotropic), similar to an Ochterlony-type reaction. Concentric
inflammation may be the result of cord injury. Funisitis may be segmental due to positioning of the cord
within the uterus , thus the recommendation for examination of two sections of umbilical cord from
An acute fetal inflammatory response is most often a response to ascending bacterial infection.
Chronic vasculitis or funisitis is less common, but may occur in cases of hematogenous acquired viral
infection . In severely macerated fetuses, caution should be used in diagnosing funisitis, as
degeneration of the vascular smooth muscle may falsely give the impression of inflammation.
Acute inflammation of the chorionic plate vessels, may precede inflammation of the umbilical vessels.
Gross examination rarely demonstrates an amniotropic intravascular density. Inflammation of the
chorionic plate vessels is usually obscured by the associated chorioamnionitis. Inflammation within the
amniotic fluid is mixed maternal and fetal. Most of the fetal cells come from the chorionic plate
vessels . Chronic fetal vasculitis is most often a nonspecific response, associated with villitis of
undetermined etiology. Inflammation of the chorionic plate, may therefore be a combination of maternal
and fetal inflammation. The fetal inflammatory response frequently includes eosinophils as an acute
reaction, not only in the preterm , but in the term baby as well. This may be due to the small pool
of neutrophils and the presence of large amounts of eosinophilic extramedullary hematopoiesis within the
liver. The most severe consequence of inflammation of the chorionic plate vessels is thrombosis.
As with chorioamnionitis, no uniform definition has been accepted but van Hoeven defined funisitis are
presence of neutrophils within the vessel wall, with or without extension into the substance of Wharton's
jelly, simple margination of neutrophils was excluded from their definition . Redline has also
proposed 3 stages and 2 grades, but combines the chorionic plate and umbilical vessels. The umbilical
vein becomes inflamed first, then the arteries . Inflammation begins as margination of neutrophils
at the endothelium with progressive movement through the muscle wall into the cord substance.
Necrotizing or sclerosing funisitis is evidence of a prolonged fetal inflammatory response. Fetal
neutrophils that have migrated out of the umbilical vessels towards to amnion surface undergo
degeneration, necrosis, and finally calcification. Lack of lymphatic drainage of the umbilical cord
results in accumulation of debris. The etiology has been attributed to a number of organisms, which have
in common, the ability to result in prolonged infection without spontaneous uterine contractions. In
many cases no infectious cause is identified. The most common etiology is syphilis , but it has also
been reported in HSV , and cultures have been positive with common organisms such as group B Streptococcus and Gardnerella, many with a history of
prolonged rupture of membranes . There was no statistically significant correlation between the
degree of necrotizing funisitis and fetal outcome; however poorer fetal outcome is suggested with severe
necrotizing funisitis, including a high rate of intrauterine growth restriction, stillbirth and
necrotizing enterocolitis and chronic lung disease
Other Causes of Inflammation of the Umbilical Cord
While acute chorioamnionitis is thought to be exclusively due to infection, funisitis may be due to
other things. In the case of cord compression, inflammation may be secondary to tissue injury.
Theoretically, the inflammation cells should be evenly distributed around the injured vessel, not in the
usual amniotropic pattern. Meconium laden macrophages have been identified within Wharton's jelly and
are associated with smooth muscle injury and inflammation of the umbilical cord vessels (39). Meconium
associated inflammation is usually more severe in the cord than the membranes. This may be due to direct
injury of the cord vessels by meconium. It has been postulated that the muscle injury is secondary
injury due to vasoconstriction. The presence of meconium within the fetal lung may also set up an
inflammatory response which is then manifest within the cord vessels (40).
Intrauterine Acquired Maternal Hematogenous Infection
Infectious agents within the maternal blood may infect the placental villi from the intervillous
space. In order for this to happen, there must be maternal bacteremia, viremia or parasitemia. Rarely
villitis may be seen as a late complication associated with chorioamnionitis as the result of fetal
sepsis and reinfection of the placental villi. Most cases of villitis are idiopathic, referred to as
villitis of undetermined etiology (VUE)
. Infectious etiologies are most often viral. Infection may
stay confined to the placental tissues are enter the fetal blood stream through the villous capillaries.
There are several proposed mechanisms for how the infectious agents gain entrance to the fetal system.
The two most commonly accepted theories include either the direct transport of infected maternal cells or
free pathogen into the fetal circulation, or contiguous infection of a placental cell with subsequent
infection of fetal cell. Placental factors that control this include physical barriers (villus
trophoblast epithelium), immune mechanisms (probably related to both maternal and fetal immune
competence) especially the phagocytic and killing capabilities of the Hofbauer cell.
The gross appearance of a placenta with villitis is usually normal. There may rarely be a granular,
hydropic or pale appearance of the parenchyma. Increased thickness of the basal plate has been noted
, and is most commonly seen in basal villitis. In cases of abscess formation, white nodules may be
visible on the basal plate or cut surface. Pallor or friability of the villi may be due to widespread
necrosis, atrophy and fibrin deposition, but is nonspecific and may be due to prolonged retention after
fetal demise, or immaturity of the placenta
. Villitis is usually considered a microscopic
diagnosis. Examination of four blocks of placenta is sufficient for detection of the majority of cases
of villitis .
Various classifications of villitis have been proposed. Altshuler has described villitis based on
tissue response as proliferative, necrotizing, reparative and stromal fibrosis. It was proposed that
these may be progressive stages of villitis with necrosis as the initial acute stage and fibrosis the end
point of the various forms . Villitis can be described by the type of inflammation; acute
(neutrophilic), chronic (lymphocytic, histiocytic, lymphohistiocytic, plasmacytic, mixed), or
granulomatous (including Langhans type giant cells). Categorizing the villitis on the type of
inflammation is more useful in determining the etiology. The villous inflammation is a combination of
maternal and fetal inflammatory cells . The number of inflammatory cells within the villus necessary
to diagnose villitis has not been specified.
Most cases of villitis are thought to be an immune reaction against fetal/placental antigens and are
referred to as nonspecific villitis or VUE. The lymphocytes within the stroma are predominantly
helper/inducer CD3+ or CD4+, T-cells, with few suppressor, CD8+ T-cells, CD45/LCA positive and CD68
and no B-cells or plasma cells. The placenta has a limited ability to respond
specifically to various antigenic stimuli. The histology of villitis is sufficiently varied to suggest
that the entity designated as VUE may well be a response to more than one antigen/organism. Anchoring
villi at the placental base are intimately associated with maternal tissues and do not have a protective
syncytiotrophoblast layer. In this way the anchoring villi may be more susceptible to maternal immune
stimulus and do contain more inflammatory cells compared to non-basal villi in normal placentas .
Involvement of the stem villi occurs in about 10% of cases. This is usually associated with a higher
grade of villous inflammation. Intercellular adhesion molecule 1 (ICAM-1) is not normally present on
villous trophoblast, but becomes so in the inflamed villi. ICAM is involved in lymphocyte-endothelial
VUE has been reported in 5%-18%
of placentas. The lower incidence is from random placentas and
the higher incidence is from placentas that were selected for examination, based on abnormal maternal or
fetal features. The only consistent finding in infants is IUGR . There is some correlation between
severity of villitis and severity of IUGR . Fetal/neonatal IgM has not been found to be elevated,
as you would expect for an in utero exposure .
Villitis attributable to specific infectious agents are the exception, probably accounting for only 5%
of all villitides . Acute villitis is seen in maternal sepsis with organisms such as E. coli, group B Streptococcus and Listeria monocytogenes. The inflammatory infiltrates in VUE and known infectious
etiologies are similar  and has provided "circumstantial evidence that VUE is the result of chronic
infection" . Most investigators are less convinced of an underlying pathogen in most cases of VUE.
The most significant difference in VUE and the specific villitides appears to be the presence of
significant numbers of plasma cells which should be a warning to rule out infectious agents, particularly
CMV, syphilis EBV and HSV. Infectious etiologies of villitis are often associated with a significant
increase in the number of nucleated red blood cells within the villous vessels. Granulomatous villitis,
may be seen in infection with organisms that cause granulomatous inflammation elsewhere; as in
mycobacterium, toxoplasmosis, HSV and varicella.
Special Stains and Molecular Techniques in the Diagnosis of Infectious Agents.
There have been considerable advances in the use of molecular techniques to rapid detection of
pathogens, especially those that are fastidious or non-culturable. Some of the rewards of diagnostic
molecular techniques include rapid turnaround time, increased specificity, enhanced sensitivity, ability
to identify esoteric microorganisms, quantitation, genotyping, and monitoring of drug resistance.
Qualitative assays determine presence or absence of a nucleic acid consistent with the presence of an
infectious agent. Polymerase chain reaction (PCR) replaces the conventional process of biologic
amplification (growth in culture) with enzymatic amplification, allowing identification of as few as 100
copies of a particular DNA sequence . Reverse transcription PCR may be useful in detection of RNA
virus infections including hepatitis C virus, HIV and enteroviruses
. Because of the sensitivity,
contamination is a constant threat and specimen integrity is very important. These techniques are labor
intensive and expensive. Most of the newer techniques allow for extraction of DNA from fixed tissues, it
is still preferable in some cases to have fresh or frozen samples. It must be remembered that a positive
PCR does not mean the same thing as a positive culture (viability), or a rise in antibody titer (response
to recent infection). Quantitative assays are useful for correlating the number of nuclei acid molecules
with clinical disease and monitoring responses to therapy. Sequence analysis can be used to subtype or
detect drug resistance .
More readily accessible to most laboratories is immunohistochemistry (IHC) to identify specific
antigens (CMV, parvovirus, toxoplasmosis, syphilis, GBS) within formalin-fixed, paraffin-embedded tissue
. I have found CMV and parvovirus IHC to be the most useful, especially identifying
positive cells in autolyzed tissues.
Less sophisticated methods may also be useful in identifying infectious agents. Many are readily
identifiable on routine hematoxylin and eosin (H&E) stain. Tissue gram stains such as Brown and Bren
(B&B) are useful for Gram-positive organisms but Brown & Hopps (B&H) or the Gram-Twort method
is preferable for Gram-negative organisms. Silver impregnation methods (Steiner & Steiner,
Warthin-Starry) will stain virtually all bacteria and most fungi; and are therefore not specific but
sensitive methods for identifying small numbers of bacteria. The advantage of silver is that very thin
organisms are coated with the metal, making them visible with light microscopy, making is particularly
applicable to Fusobacterium and syphilis. Treponema spirochetes are identified within the necrotic debris of the necrotizing
funisitis of the umbilical cord, but organisms have also been identified within cord which is free of
inflammation . If the patient has been treated within a few hours of delivery, no organisms will be
seen. Histologic examination alone may be as specific and nearly as sensitive as the PCR performed on
formalin-fixed, paraffin-embedded tissues. Steiner & Steiner stain and Warthin-Starry stains are
difficult to perform and yield fewer positive results compared to PCR (61).
Specific Perinatal Viral Infections
CMV is the most common viral infection acquired in utero. CMV may also be acquired during the birth
or with injection of breast milk. The placenta is grossly unremarkable or may be hydropic and pale.
Meconium staining of the fetal membranes is frequently seen
. The villi may have appropriate
maturation or reflect immaturity. The villitis is usually distinctively lymphoplasmacytic but may also
be absent or granulomatous
. CMV has an affinity for endothelium that will result in vascular
injury and hemosiderin deposition within the villous stromal or Hofbauer cells. Syncytiotrophoblast
necrosis may result in increased perivillous fibrin deposition . Calcification of sclerotic blood
vessels, stroma or decidua may be seen . The severity of the fetal infection is usually reflected in
the severity of the placental changes
Characteristic viral inclusions, are present in 43-75% of the cases
, and are identifiable
within Hofbauer cells or villous endothelium and rarely syncytiotrophoblast or cytotrophoblast on routine
H&E stain. Virus may be detected in cells without characteristic Cowdry inclusions by
in situ hybridization , polymerase chain reaction  or
immunofluorescence . In situ hybridization is less specific as it detects unencapsulated,
intranuclear viral DNA where as immunohistochemistry detects DNA contained within complete CMV
nucleocapsid of replicating virus. Nuclear and cytoplasmic staining is seen
. CMV probably
accounts for only 1-6% of all villitides . Endometrial and cervical cells are frequently culture
positive in seropositive women. Infection of the placenta may occur directly from the infected
Seropositivity varies from 59-80% and reactivation occurs in 1-15%. Maternal risk for infection
during gestation is approximately 2%. Risk for transmission to the fetus is greatest with primary
infection [35%], equal during all trimesters, worse with earlier infection. Fetal infection during
reactivation is rare (1-3%), there is also consideration for reinfection with a different strain. 0.5-3%
of newborns are infected (many postnatally through breast milk) with CMV; 93% are asymptomatic. Those
asymptomatic during the neonatal period have 10-15% incidence of long term sequelae, including
neurosensory deafness (progressive, uni or bilateral), chorioretinitis, neurologic abnormalities, and
learning disabilities. Symptomatic infants may be stillborn, neonatal death, premature, low birth
weight, have thrombocytopenia, purpura, jaundice, hematomegaly, anemia and intracranial calcifications
(ependyma is especially vulnerable). Outcome for symptomatic infants is poor with 60% hearing loss, 45%
mental retardation, 35% cerebral palsy and 15% chorioretinitis. Neuroimaging may show multifocal lesions
in the deep parietal white matter, with or without cysts, ventricular dilatation and gyral abnormalities.
Co-Infection of CMV and HIV
There has not be an increase in CMV infection during pregnancy in our cohort of HIV positive women and
this is supported by others
. Caselli, et al reported an infant co-infected with CMV and HIV who
was asymptomatic at birth . We have had two cases of congenital CMV associated with intrauterine
fetal demise in HIV infected women with advanced disease. Both had serologic confirmation of prior CMV
infection and thus are recurrent cases with severe consequences to the fetus. HIV status of the fetuses
was not determined.
Human Immunodeficiency virus (HIV)
There are no specific features of the placenta in HIV infected women
. There is a higher rate
of acute chorioamnionitis in HIV infected women, particularly those who have AIDS-defining
characteristics . Increased transmission of HIV to the infant has also been associated with
The chorioamnionitis and funisitis appears to be secondary to usual ascending bacterial infection.
Rarely acute or chronic villitis has been reported . Viral load within the placenta is very low and
routine IHC techniques for demonstration of p24 antigen and gp41 antigen consistently are negative. In
situ hybridization and in situ PCR have been more successful in demonstrating virus within placental
tissues . The placenta acts as a good barrier to infection and demonstration of viral antigens in
placental tissues does not predict fetal infection  cells found to contain HIV include
syncytiotrophoblast, cytotrophoblast, Hofbauer cells and endothelial cells
Herpes Simplex Virus (HSV)
Perinatal infection may occur with either HSV-1 or HSV-2. Herpes is the only virus that has been well
documented to cause in utero and ascending types of infection. Most infants are infected during primary
genital infection, via an ascending route or at the time of delivery; infection rate is 50-75%. The risk
for ascending infection is increased with prolonged rupture of membranes. In utero infection occurs
rarely during the viremic phase of a primary HSV-2 infection . Recurrent genital infection carries a
very low risk for fetal infection (5%)
The gross placenta is usually normal, or in the case of primary in utero infection, may be hydropic.
Necrotizing funisitis containing neutrophils and nuclear debris admixed with eosinophils, lymphocytes
and plasma cells has been reported . When two rings were present the inner contained neutrophils and
eosinophils and the outer ring nuclear debris, lymphocytes and plasma cells . Acute necrotizing
chorioamnionitis, with necrosis of the amniotic epithelium may also be seen . Focal
lymphoplasmacytic infiltrates in the decidua basalis with multiple foci of bland decidual necrosis both
basalis and capsularis. Multifocal coagulative necrosis of villi with minimal or absent inflammation is
I have seen one placenta and fetus with confirmed transplacental infection. Necrotizing
endovasculitis with rare cells with characteristic intranuclear inclusions were seen in the umbilical
cord or large stem vessels. Large numbers of "smudged"were noted in the Wharton's jelly, just beneath
the amnion epithelium. Both of these cell types were positive by IHC. Such transplacental infection may
result in diffuse skin lesions and severe hepatic necrosis. In the case of ascending infection, a few
multinucleated giant cells were found within the connective tissue of the membranes. Similar findings
have been reported by others
. Acute or plasmacytic chorioamnionitis has been also reported .
HSV is easily cultured and grows very quickly in many different cells lines. Direct
immunofluorescence performed on scrapings from lesions is sensitive and specific. Immunohistochemistry
is widely available and useful . In situ hybridization is sensitive for cells in tissue sections and
lesion scrapings, but not widely available. PCR is highly sensitive and specific, especially for
detection of viral DNA within small brain biopsies or CSF. None of these techniques has been applied to
the placenta in large numbers
Babies with congenital HSV infection are usually asymptomatic at delivery. Onset of fever and
seizures occurs within the first few days of life. Persistent fever in the presence of antibiotics
should suggest HSV. Skin, eye or mucosal lesions may be present, and are most commonly seen in the area
of the presenting part (scalp), often mistaken as lesion from fetal scalp electrode. Disseminated
disease affects the fetal liver primarily, but necrotic lesions will also be present in lungs and adrenal
glands. Seizures are usually secondary to hepatic encephalopathy. Pregnancy is infrequently associated
with an increased risk for disseminated disease and maternal death due to fulminant hepatic failure.
Human Herpes Virus 8 (HHV-8)
Selected populations with a high prevalence of HHV-8 have been studied to determine whether vertical
transmission occurs. 15% of seropositive women had HHV-8 DNA detectable within their peripheral blood
mononuclear cells (PBMC). 0-16% of baby samples drawn at birth showed HHV-8 DNA within PBMC, suggesting
infrequent perinatal transmission . Acquisition of antibody to HHV-8 occurs in older children,
implying a horizonal route as the more common form of transmission
. A high incidence of
co-infection of HHV-8 and HIV suggests sexual transmission.
Epstein-Barr Virus (EBV)
EBV infection is relatively common among women of child-bearing age. Congenital EBV has been
described resulting from maternal infection in the first trimester and less commonly in the third
trimester . The placenta from first trimester infection, has been reported to show slight to
moderate chronic chorionitis, lymphohistiocytic and plasmacytic with large atypical vacuolated cells
probably Hofbauer cells . Inflammation of the fetal vessels has been described as endovasculitis,
perivasculitis with occasional vascular obliteration . We have had one case of IUGR with PCR
positive amniotic fluid for EBV. The placenta showed chronic intervillositis with a rare intervillous
macrophage positive with in situ hybridization for EBER.
Hepatitis B virus (HBV)
Hepatitis B virus usually infects infants perinatally either through transfusion during labor or as a
result of exposure to vaginal secretions during delivery . Rare cases of intrauterine transmission
can occur . Lucifora et al showed strong reactivity of the Hofbauer cells and villous endothelium,
with IHC but no pathologic changes were noted . A jaundiced patient with HBV showed a deep
yellow-green staining of the villous Hofbauer cells, trophoblast and membranes .
Hepatitis C virus (HCV)
The prevalence of HCV in the general population is 0.2%, but is 1.5% in HIV positive individuals
. Vertical transmission of HCV occurs only in the presence of positive HCV-RNA and is higher in
HIV-positive mothers than HIV-negative mothers. There is also a higher rate of HIV transmission in the
presence of HCV infection. Rarely infants will clear viremia, while most will remain viremic. Liver
dysfunction has been noted as early a 1 year of age. Breast milk is not known as a vehicle for HCV
Varicella- Zoster Virus (VZV)
Placentas from three women who had onset of symptoms of varicella from 27 weeks before delivery to one
day postpartum, were examined by Qureshi and Jacques. One placenta showed extensive basal chronic
villitis with a lymphohistiocytic infiltrate and occasional multinucleated giant cells . Garcia
examined three macerated stillborns that showed tiny, yellow, scattered lesions on the placental surface
that were large areas of granulomatous villitis. Homogeneous intranuclear inclusions were found in the
decidual cells . First trimester varicella infection with subsequent fetal demise demonstrates,
acute, chronic or granulomatous villitis with eosinophilic "glassy" appearing nuclei, confirmed by IHC
. PCR has been utilized for prenatal diagnosis using chorionic villus sampling .
In utero infection is associated with skin scarring, disseminated foci of necrosis, hypoplasia or
flexion contractures of limbs and fetal demise . Mothers who develop a varicella rash 5 days before
to 2 days after delivery and this carries a great risk to the neonate. Up to 20% of these infants will
develop neonatal varicella which carries a 20-30% mortality rate. This is associated with stillbirth and
preterm delivery, hemorrhagic pneumonia, and neonatal mortality but no structural defects. Higher rate
of maternal pneumonia and mortality are also noted during pregnancy. VZIG can prevent up to 50% of
infections and reduces severity in remainder.
Most of the placental findings of congenital rubella are those associated with early spontaneous or
elective terminations. Focal damage of the syncytiotrophoblast, cytotrophoblast and endothelium with
eosinophilic inclusions in trophoblast, decidua and Hofbauer cells have been reported . Acute and
chronic villitis may be present
placental lesions do not correlate completely with fetal
infection . Identification of rubella viral RNA is sensitive in early pregnancy, but may disappear
from the placenta in a term pregnancy, infected earlier .
Garcia et al, described sparse focal areas of hyalinization and lymphocytic infiltrate in umbilical
vessels and stem vessels . Rubella viral intracytoplasmic or intranuclear eosinophilic round
inclusions were seen in cytotrophoblast and decidual cells. Focal, basal, necrotizing villitis, was
seen. Indirect immunofluorescence done on formalin-fixed, paraffin-embedded tissues and was positive in
most cases within the amnion epithelium, chorionic vessels, and subchorionic fibrin . A review of
all cases submitted with a diagnosis of congenital rubella were examined at Texas Children's Hospital and
the AFIP and no viral inclusions were identified within placental tissues on routine H&E stains.
There are an estimated 100,000 cases of congenital rubella worldwide, primarily in developing
countries with low immunization rates. Congenital rubella syndrome is characteristically IUGR, failure
to thrive, mental retardation, cardiac defects (PDA, ASD, VSD), hepatosplenomegaly, thrombocytopenia,
microcephaly, encephalitis, mental retardation and cataracts. The most significant sequelae are
blindness and deafness. Risk for fetal infection is greatest during the first month of gestation (50%)
and essentially 0% after 20 weeks gestation. Pathology is that of widespread chronic inflammation and
scarring, with vasculitis and calcifications noted only in the brain.
Chandwani, et al. showed two placenta with focal chronic villitis and intervillositis.
Multinucleated giant cells containing intranuclear inclusions were confirmed as paramyxovirus on electron
Parvovirus B19 is a known cause of fetal anemia, nonimmune hydrops fetalis and intrauterine fetal
demise. It has been predicted that up to 20-30% of hydrops may be due to parvovirus  The virus
binds to an antigen of the P-system blood group known as P antigen or globoside, which is present on
erythrocytes, erythroblasts, megakaryocytes, endothelial cells, placental trophoblasts and fetal liver
and heart cells 
The placenta grossly is enlarged, thickened and pale, relatively nonspecific features of hydrops
. The severity of the anemia in fatal cases, is so severe as to render the placenta nearly
Microscopically the villi are massively edematous. The capillaries are usually packed with nucleated
cells, often so immature as to not have hemoglobinized cytoplasm and are nearly indistinguishable from
myeloblasts. The most characteristic cell is a nucleated red blood cell with well hemoglobinized
cytoplasm. The retained nucleus contains a characteristic eosinophilic inclusion with a band of dense
chromatic at the periphery. Early nuclear inclusions are basophilic. While theoretically possible for
infection of multiple cell type, the erythroblast is the only cell microscopically infected
Giant pronormoblasts may be an example of the toxic effects of the virus in a cell that is not fully
permissive for viral replication .
Immunohistochemistry for parvovirus is very useful in suspicious cases, as all phases of nuclear
inclusions are positive and degenerative changes can be ruled out
. Most sensitive methods such
as PCR, rarely identifies a case not already characterized by the intranuclear inclusions
Congenital parvovirus was once thought to be an all or none phenomena; but in utero infection can
occur without adverse consequences. The classic presentation is hydrops fetalis with marked fetal
anemia. The bone marrow is hypocellular and there may be increased extramedullary hematopoiesis.
Intranuclear inclusions are seen in immature red blood cells throughout all organs. Ascitic fluid may be
bile stained. Rare infants who are symptomatic at birth have shown a neonatal hepatitis-like picture.
Infected, asymptomatic infants do not show any long term sequelae.
Enteroviruses including coxsackie virus, echovirus, enterovirus, and poliovirus may cause
intrauterine infection which may result in abortion, neonatal illness or possibly congenital
anomalies, but most babies are asymptomatic
. The possibility of long term neurologic sequelae
has yet to be confirmed
. Diagnosis relies on suspicion and a positive cell culture, however
molecular techniques are becoming more available, such as RT-PCR, and RT in-situ PCR, for detection of
Garcia et al, have review the only large series of placentas from enteroviral infections
Microscopically there was mild acute and chronic chorionitis. Fetal vasculitis was present in all cases,
sometimes associated with myocytolysis, edema, perivascular infiltrate and neutrophils marginated within
the vessel wall. Villitis involving single or multiple villi could be acute or chronic and have massive
areas of necrosis associate with intervillositis. IHC detected positivity in the cytoplasm of the
cytotrophoblast, but by electron microscopy virus was found in the syncytiotrophoblast .
Human papilloma virus
HPV has been identified in syncytiotrophoblast of first trimester spontaneous abortions, but not in
third trimester placental tissue, by PCR . Perinatal infection occurs during the delivery process
with the upper respiratory tract most severely affected. Recurrent laryngeal papillomas necessitating
multiple resections and rarely transformation to squamous cell carcinoma has occurred.
West Nile Virus (WNV)
WNV is a single-stranded RNA flavivirus and spread by the mosquito. Infection during pregnancy is
associated rarely with spontaneous abortion or neonatal illness. Chorioretinitis and cystic lesions of
the brain have been reported .
Dengue is a also a flavivirus and is spread by a mosquito vector. Vertical transmission of dengue has
been documented with primary and secondary infection resulting in neonatal fever, thrombocytopenia and
elevated liver enzymes
. All cases have been associated with maternal febrile illness at the
time of delivery.
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