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380 Non-neoplastic Lesions of the Placenta, Pathology of the Placenta
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• Age
FMH has not been associated with a particular
maternal or gestational age, though the impact
of FMH may vary depending on the latter.
The fetoplacental blood volume is estimated
to be 30 mL at 20 weeks gestational age. At
term, studies have found that the volume varies
by fetal weight from 80 to 125 mL per kg
(Wylie and D’Alton 2010).
• Sex
Small vessel rupture is not associated with a
particular fetal sex.
• Site
Chorionic villi and intervillous space.
• Treatment
FMH can be detected by the Kleihauer Betke
test or by flow cytometry and treated with Rh
Non-neoplastic Lesions of the Placenta, Pathology of
the Placenta, Fig. 36 Low power view of an intervillous
thrombus, characterized by layers of fibrin and blood
splaying apart the chorionic villi
immune globulin to prevent maternal immune
response in future pregnancies (Redline 2015;
Lewis et al. 2017).
• Outcome
Even small amounts of FMH can result in Rh
alloimmunization. Large FMH may result in
fetal anemia and hypovolemia, and their
sequelae, including fetal hydrops (hydrops
fetalis), hypovolemic shock, neurologic injury,
and fetal/neonatal death. However, it is notable
that high volume FMH occurring over longer
periods of time may have different consequences compared to rapid hemorrhage
(Carles et al. 2014; Lewis et al. 2017; Wylie
and D’Alton 2010).
Macroscopy
FMH can presen t as intervillous thrombi (IVT),
Non-neoplastic Lesions of the Placenta, Pathology of
the Placenta, Fig. 37 Periphery of an intervillous throm-
bus showing no entrapment or necrosis of the surrounding
villi
which can be identified grossly as red, gelatinous
to tan, fibrinous lesions within the placental parenchyma. Examination of the fetus in the context of
fetal death will usually show striking generalized
pallor and liver weight below what is expected for
no entrapped villi, and minimal villous necrosis
(Fig. 37). If FMH is chronic and/or severe, nucleated red blood cells may also be seen in the fetal
circulation and within IVT (Redline 2015).
gestational age. If anemia and hypovolemia were
chronic and/or severe, findings of fetal hydrops
(e.g., anasarca, effusions) may also be observed
(Carles et al. 2014).
Immunophenotype
Immunohistochemistry is not routinely used
for the diagnosis of small vessel rupture/IVT.
However, immunostains for hemoglobin F have
Microscopy
Histologically, IVT appears as layers of fibrin and
blood splaying apart the villi (Fig. 36), with few to
been used to confirm that a subset of erythro-
cytes within IVT is fetal in origin (Kaplan
et al. 1982).
Non-neoplastic Lesions of the Placenta, Pathology of the Placenta 381
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Molecular Features
Genetic testing is not routinely used in the diagnosis of small vessel rupture.
Differential Diagnosis
IVT should be differentiated from placental
infarction, particularly infarction hematomas.
While the central hemorrhage and hematoma of
infarction hematomas may resem ble IVT, they
can be differentiated by their prominent rim of
infarcted villi.
Villous Edema
Synonyms
Placental hydrops (hydrops placentalis); Villous
hydrops.
Definition
A spectrum of lesions ranging from focal/patchy
villous edema to placen tal hydrops, with various
etiologies, most of which affect the hydrostatic
equilibrium of fetal circulation.
Clinical Features
twin-twin transfusion, and tumors of the fetus
and placenta. Hydrops is most often secondary
to fetal anemia. Patchy villous edema is seen in
the setting of fetal hypoxia and acidemia,
though it may be seen on a spectrum with
more diffuse villous edema in the clinical scenarios listed above, depending on the severity
(Redline 2015; Bellini et al. 2015).
• Age
Villous edema is not associated with a particular maternal or gestational age.
• Sex
Villous edema is not associated with a particular fetal sex.
• Site
Chorionic villi.
• Treatment
Treatment and management depend on the
underlying etiology.
• Outcome
Villous edema has been associated with perinatal mortality (Stanek 2018). Hydrops has a
particularly poor prognosis, with survival of
approximately 50%, though this varies markedly depending on the underlying etiology
(Nassr et al. 2018).
N
• Incidence
Placental hydrops usually accompanies fetal
hydrops (hydrops fetalis), the etiologies of
which can be divided into immune and nonimmune. Rh incompatibility is the classic
example of immune hydrops, though this is
now rarely seen thanks to prenatal screening
and administration of Rh immune globulin;
ABO incompatibility is now more common.
Non-immune hydrops (NIH) is seen most frequently (greater than 85% of cases) and has a
number of different causes. The most common
causes of NIH are cardiovascular (e.g., structural malformations, arrhythmias), hematologic (e.g., thalassemia, fetomaternal
hemorrhage), congenital lym phatic dysplasia,
infections, and chromosomal abnormalities.
A significant number of cases are
idiopathic. Other rarer causes include inborn
errors of metabolism, gastrointestinal tract
malformation, urinary tract malformation,
Macroscopy
Cases with diffuse villous edema or hydrops will
have placentomegaly with boggy, pale paren-
chyma. The umbilical cord may also be
enlarged/edematous.
Microscopy
In placental hydrops, the majority of the villi will
be enlarged with pale, edematous stroma, confer-
ring an immature appearance (Fig. 38). In non-
hydropic placentas with villous edema, the villi
may have variable sizes and varying amounts of
pale, edematous to lacey or reticulated stroma.
Immunophenotype
Immunohistochemistry is not routinely used to
diagnose villous edema.
Molecular Features
Specific molecular features are not associated
with villous edema in general, though underlying
382 Non-neoplastic Lesions of the Placenta, Pathology of the Placenta
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This section discusses inflammatory placental
pathologies and is divided into categories by infectious and idiopathic/immune-mediated etiologies.
Infectious Inflammatory Lesions
Definition
Cellular inflammatory responses to infection,
which are typically divided into maternal and
fetal acute inflammatory responses to ascending
amniotic fluid infection (a.k.a. acute chorioamnionitis) and chronic respon ses to hematogenous
infection (Redline 2015; Khong et al. 2016).
Non-neoplastic Lesions of the Placenta, Pathology of
the Placenta, Fig. 38 An example of villous edema in a
case of Hemoglobin Barts (hydrops fetalis)
Acute
Maternal Inflammatory Response: Chorioam-
etiologies with genetic abnormalities, such as
nionitis, Subchorionitis
thalassemia and aneuploidy (e.g., trisomy 21, trisomy 18, 45, X0) are associated with this finding
(Bellini et al. 2015).
Synonyms
Acute chorioamnionitis; Acute chorionitis; Acute
Differential Diagnosis
subchorionitis; Necrotizing chorioamnionitis.
Severe villous edema and hydrops can result in
markedly enlarged villi with cistern formation and
should be differentiated from other etiologies of
villous enlargement and villous cisterns, such as
gestational trophoblastic disease and placental
mesenchymal dysplasia.
Definition
The maternal response to amniotic fluid infection,
which can be staged and graded based on the
location and extent of acute inflammation in the
subchorion, chorion, and amnion of the chorionic
plate and free membranes:
Placental Inflammatory-Immune
Processes
“The placenta resides at 2 impo rtant interfaces: with
the outside environment (cervicovaginal canal) and
between antigenically distinct organisms (mother
and fetus). An incompletely resolved tension exists
between the need to promote local immune
responses to protect against exogenous microorganisms and to suppress them to prevent fetal rejection.
This results in increased susceptibility to infection,
occasional breakdown in tolerance leading to
immune mediated allograft-type responses, and
helps explain why cellular inflammation is the
major nonvascular abnormality is observed in the
placenta.”–Raymond W. Redline, MD, “Classifi-
cations of placental lesions. ”
• Stage 1 (early) – Acute subchorionitis or
chorionitis.
• Stage 2 (intermediate) – Acute
chorioamnionitis.
• Stage 3 (advanced) – Necrotizing
chorioamnionitis.
• Grade 1 (mi ld, moderate) – Defined as not
severe.
• Grade 2 (severe) – Confluent neutrophils with
subchorionic microabscesses (Khong et al.
2016; Redline et al. 2003; Redline 2015).
Clinical Features
• Incidence
Clinical chorioamnionitis is estimated to affect
5–12% of term gestations and up to 20% of
Non-neoplastic Lesions of the Placenta, Pathology of the Placenta 383
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preterm gestations (Oh et al. 2017). Studies
have identified histologic chorioamnionitis in
approximately 5%of examined placentas overall, but it is seen more frequently in the placentas delivered after spontaneous labor
(11.6%) and from preterm births (Kim et al.
2015c).
• Age
The prevalence of chorioamnionitis increases
as gestational age at delivery decreases, affecting up to 94% of placentas delivered at
21–24 weeks of gestation (Kim et al. 2015c).
Chorioamnionitis has not been associated with
a specific maternal age.
• Sex
Chorioamnionitis has not been associated with
a particular fetal sex.
• Site
Subchorion, chorion, and/or amnion
depending on stage.
• Treatment
Antibiotics (may reduce the risk of maternal
and fetal sepsis), delivery, and fetal support
(when necessary) (Oh et al. 2017).
• Outcome
Mothers with chorioamnionitis have an
increased rate of adverse outcomes, including
endometritis, postoperative wound infection,
sepsis, disseminated intravascular coagulation, septic pelvic thrombophl ebitis, postpartum hemorrhage, and pelvic abscess.
Neonatal adverse outcomes include congenital sepsis, localized infections (e.g., pneumonia, dermatitis, otitis media), and cerebral
palsy. Other complications include preterm
labor and fetal demise (Redline et al. 2003;
Oh et al. 2017).
subchorionitis is considered less specific for
infection.
• Stage 2 (Intermediate) – Acute chorioam-
nionitis: neutrophils extend into fibrous cho-
rion and/or amnion.
• Stage 3 (Advanced) – Necrotizing chorioam-
nionitis: neutrophilic karyorrhexis, amniocyte
necrosis, and/or amnion basement membrane
thickening/hypereosinophilia.
• Grade 1 (Mild-Moderate): Individual or small
clusters of neutrophils.
• Grade 2 (Severe): Three or more chorionic
microabscesses (confluent neutrophils of at
least 10 20 cells in extent; Fig. 39
) between
chorion and decidua in the membranes and/or
under the chorionic plate or a continuous band
of confluent neutrophils (>10 cells in width;
Fig. 40) involving more than half of the subchorionic fibrin or one revolution of the membrane role (Khong et al. 2016; Redline et al.
2003; Redline 2015; Redline et al. 2021).
Immunophenotype
Immunohistochemistry and special stains for
microorganisms may be employed.
Molecular Features
Polymerase chain reaction (PCR) may be used
for diagnosis or speciation of certain microorganisms, though 24% of clinical chorioamnionitis
N
Macroscopy
Chorioamnionitis may result in dull gray, cloudiness of the amnionic membrane and even yellowgreen, opaque discoloration (Redline et al. 2021).
Microscopy
• Stage 1 (Early) – Acute subchorionitis or
chorionitis: neutrophils in subchorionic fibrin
and/or membrane trophoblast; of note, isolated
Non-neoplastic Lesions of the Placenta, Pathology of
the Placenta, Fig. 39 A chorionic microabscess in the
setting of acute candidal infection (fungal forms can be
seen on the surface of the chorionic plate)
384 Non-neoplastic Lesions of the Placenta, Pathology of the Placenta
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Decidual leukocytoclastic necrosis is associated
with preeclampsia and preterm birth (Goldenberg
et al. 2007).
Fetal Inflammatory Response: Chorionic/
Umbilical Vasculitis
Synonyms
Chorionic vasculitis; Necrotizing funisitis;
Umbilical vasculitis.
Definition
Fetal response to amniotic fluid infection charac-
Non-neoplastic Lesions of the Placenta, Pathology of
the Placenta, Fig. 40 Severe (Grade 2) acute chorioam-
nionitis (Stage 2) – a continuous band of confluent neutrophils extending into the chorion and amnion
terized by an elevation in the fetal plasma concentration of interleukin-6 and associated with the
impending onset of preterm labor, a higher rate
of neonatal morbidity (after adjustment for gesta-
in preterm gestations have no evidence of
either culture-proven intra-amniotic infection
(molecular microbiology) or intra-amniotic
inflammation (Oh et al. 2017).
tional age), and multiorgan fetal involvement; can
be staged and graded on the basis of the location
and extent of neutrophils in the umbilical cord and
chorionic vessels:
Additionally, a recent study hasshown molecular
evidence supporting the role of the inflammasome
in the pathologic inflammation implicated in spontaneous preterm labor with acute histologic
chorioamnionitis (Gomez-Lopez et al. 2017).
• Stage 1 (Early) – Chorionic plate vasculitis or
umbilical vein phlebitis.
• Stage 2 (Intermediate) – Inflammation of one
or both umbilical arteries inflammation of
the vein.
Differential Diagnosis
Acute chorioamnionitis should be differentiated
from chronic placental inflammatory lesions
(discussed below), such as chronic chorioamnionitis, which is characterized predominantly by
lymphocytic inflammatory infiltrates (Redline
et al. 2021).
Meconium exposure can also result in neutrophilic inflammation in the placental membranes,
but lacks subchorionitis, which is typical of a
maternal inflammatory respon se (Redline
et al. 2021).
The differential diagnosis also includes decid-
• Stage 3 (Advanced) –
with neutrophils and associated debris around
one or more umbilical vessels.
• Grade 1 (Mild-moderate) – Defined as not
severe; individual or small clusters of
neutrophils.
• Grade 2 (Severe) – Near-confluent intramural
neutrophilic infiltrate involving the chorionic
and/or umbilical vessels with attenuation/
degeneration of vascular smooth muscle cells
(Redline et al. 2003, 2021; Katzman and
Metlay 2010; Redline 2015; Khong et al.
2016).
Necrotizing funisitis
ual leukocytoclastic necrosis, a lesion characterized by laminar necrosis of the decidual stromal
Clinical Features
cells of the membrane with karyorrhectic debris
and neutrophilic infiltrate. It can be difficult to
differentiate from chorioamnionitis. The most
helpful distinguishing feature of the latter would
be acute inflammation at other characteristic sites.
• Incidence
Studies in the literature have found funisitis in
13–25% of examined placentas and cord vasculitis in ~20% (Katzman and Metlay 2010).
Non-neoplastic Lesions of the Placenta, Pathology of the Placenta 385
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• Age
Umbilical arteritis is associated with preterm
delivery (Katzman and Metlay 2010). Fetal
inflammatory response is not associated with
a particular maternal age.
• Sex
Fetal inflammatory response is not associated
with a particular fetal sex.
• Site
Umbilical cord (vessels and Wharton’s jelly)
and chorionic vessels.
• Treatment
Antibiotics (may reduce the risk of maternal
and fetal sepsis), delivery, and fetal support
(when necessary) (Oh et al. 2017).
• Outcome
Non-neoplastic Lesions of the Placenta, Pathology of
the Placenta, Fig. 41 Mild to moderate (Grade 1) cho-
rionic plate vasculitis (Stage 1) with mural fibrin thrombus
formation
Mothers with chorioamnionitis have an
increased rate of adverse outcomes, including
endometritis, postoperative wound infection,
sepsis, disseminated intravascular coagulation,
septic pelvic thrombophlebitis, postpartum
hemorrhage, and pelvic abscess. Neonatal
adverse outcomes include congenital sepsis,
localized infections (e.g., pneumonia, dermatitis, otitis media), and cerebral palsy. Other
complications include preterm labor and fetal
demise (Redline et al. 2003; Oh et al. 2017).
N
Macroscopy
Chorionic vessels may appear hazy and the umbilical cord can demonstrate gray-white or alternating red and white striations (“barber pole”
appearance) around the vessels due to necrotic/
calcified debris. Candida funisitis may grossly
demonstrate yellow-white lesions on the surface
of the umbilical cord (Redline et al. 2021).
Microscopy
• Stage 1 (Early) – Intramural neutrophils
involving the chorionic vessels (Fig. 41)
and/or umbilical vein (Fig. 42).
• Stage 2 (Intermediate) – Intramural neutrophils
involving one or both umbilical arteries the
vein.
• Stage 3 (Advanced) – Neutrophils and associated debris in concentric bands/rings/halos
around one or more umbilical vessels.
Non-neoplastic Lesions of the Placenta, Pathology of
the Placenta, Fig. 42 Mild to moderate (Grade 1) umbil-
ical vein phlebitis (Stage 1)
• Grade 1 (Mild-moderate) – Individual or small
clusters of neutrophils.
• Grade 2 (Severe) – Near-confluent intramural
neutrophilic infiltrate involving the chorionic
and/or umbilical vessels with attenuation/
degeneration of vascular smooth muscle cells
(Redline et al. 2003, 2021; Redline
2015;
Khong et al. 2016).
Immunophenotype
Immunohistochemistry and special stains for
microorganisms are often employed.
386 Non-neoplastic Lesions of the Placenta, Pathology of the Placenta
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Molecular Features
Polymerase chain reaction (PCR) may be
used for diagnosis or speciation of certain
microorganisms.
Differential Diagnosis
Fetal inflammatory response should be differentiated from eosinophilic/T-cell vasculitis, which is
characterized by a mixed eosinophilic and lymphocytic infiltrate in the wall of chorionic and
stem villous vessels (described below) (Redline
et al. 2021).
Acute Villitis
Synonyms
Acute placental villitis.
Definition
Neutrophilic inflammation of the chorionic villi.
Clinical Features
• Incidence
Acute villitis is extremely rare and is thought to
reflect fetal sepsis, most often secondary to
E. coli or group B streptococcus. It can also
be seen in infections caused by Listeria mono-
cytogenes. Rare causative infections include
Campylobacter, coccidiomycosis, psittacosis,
tularemia, brucellosis, and mycobacterium
(Redline et al. 2003; Bae et al. 2016;
Abramowsky et al. 2012).
• Age
Acute villitis is not associated with a specific
maternal or gestational age.
• Sex
Acute villitis is not associated with a particular
fetal sex.
• Site
Chorionic villi.
• Treatment
Antimicrobial therapy is needed in the setting
of congenital infection.
• Outcome
Congenital infection can lead to fetal/neonatal
sepsis and death.
Non-neoplastic Lesions of the Placenta, Pathology of
the Placenta, Fig. 43 Acute villitis with neutrophils
collecting beneath the villous trophoblast and infiltrating
the villous stroma
Macroscopy
Acute villitis usually does not confer gross abnormalities unless accompanied by acute chorioamnionitis (described above) or intervillositis
(described below). Microabscesses are a classic
finding of Listeria monocytogenes infection.
Microscopy
Neutrophils are seen within the villous stroma or
between the trophoblast and villous stroma
(Fig. 43). This may be accompanied by intervillous
inflammation, which is seen most often inthe setting
of Listeria monocytogenes infection. Acute
chorioamnionitis can also be seen to varying
degrees in the se tting of these infections. Mycobacterial infections may have necrotizing granulomatous inflammation (Redline et al. 2003; Bae et al.
2016; Abramowsky et al. 2012).
Immunophenotype
Immunohistochemistry and special stains for
microorganisms are often employed.
Molecular Features
Polymerase chain reaction (PCR) may be used for
diagnosis or speciation of certain microorganisms.
Differential Diagnosis
Acute villitis should be differentiated from
chronic villitis (described below).
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Chronic
Villitis
Definition
Chronic inflammation of the chorionic villi resulting
from placental infections (particularly the TORCH
organisms: toxoplasmosis, other (hepatitis B),
rubella, cytomegalovirus, and herpes simplex
virus) that if missed may have serious consequences
for the neonate. A few of these are discussed below.
While chronic villous inflammation is a common
histopathologic feature in the discussed infections,
certain unique histopathologic features may be seen
and point to a speci fic organism. V i llitis of unknown
etiology (VUE) is discussed later as a specificentity
where chronic villous inflammation is observed but
no infectious etiology is found.
Cytomegalovirus
Synonyms
CMV; CMV placentitis; Congenital CMV infection; Human cytomegalovirus.
Definition
Placental or neonatal infection caused by the Cytomegalovirus (CMV). CMV is a member of the
herpesvirus family and contains a double-stranded
DNA genome packaged into an icosahedral capsid.
It is a ubiquitous human pathogen that may cause
asymptomatic infections in healthy individuals. In
immunocompromised populations,CMV can cause
a severe and potentially life-threatening infection.
Neonates, with their immatureimmune systems, are
especially at risk of developing a serious CMV
infection with severe lifelong consequences.
Clinical Features
• Incidence
CMV is the cause of the most common congenital viral infection worldwide and is the leading
cause of non-genetic sensorineural hearing loss
in children in the developed countries (Liu et al.
2017). Seropositivity for this ubiquitous virus
varies considerably throughout the world, with
resource-poor countries having a higher seroprevalence levels (84–100% IgG-positivity)
(Emery and Lazzarotto 2017). In developed
countries, CMV seropositivity in women of
childbearing age ranges from less than 45% to
85% (Liu et al. 2017). The prevalence of congenital CMV infection is 0.2–2% in newborns,
with 10–15% of infected neonates having
symptomatic CMV infection (Uenaka et al.
2019). It merits mentioning that CMV DNA
and proteins are detected in the placental and
decidual tissue samples in greater than 50% of
uneventful term births underlining the ubiquitous nature of this virus (Kim and Kim 2019).
Pregnant women who are seronegative and
become infected with CMV (particularly in the
first trimester) are especially at risk of transmitting the virus to the fetus (primary infection). In this circumstance, fetal transmission
occurs in 30–35% of cases, with 10–15% of
infected newborns developing congenital
CMV disease (Emery and Lazzarotto 2017).
In non-primary infection , CMV reactivation
or reinfection can be found in women with
preexisting immunity to CMV. However, the
in utero transmission rate in non-primary infection is much lower (less than 2%) than in
primary infection (Liu et al. 2017).
• Age
Pregnant women of any age are at risk of
acquiring the infection.
• Sex
A particular fetal sex has not been associated
with increased risk of CMV infection.
• Site
The placenta plays an important role in vertical
transmission of CMV infection to the fetus.
CMV replication occurs in the decidua, extravillous cytotrophoblast, and villous
cytotrophoblast. The virus appears to utilize
syncytiotrophoblast transcytosis of IgG to gain
entry via immune complex formation
(Heerema-McKenney 2018). Recent research
suggests that CMV enters trophoblasts utilizing
a CD46-dependent pathway (Stein et al. 2019).
Additionally, it has been shown that CMV particularly infects amniotic membranes as well as
interferes with lymphangiogenesis and vascular
N
388 Non-neoplastic Lesions of the Placenta, Pathology of the Placenta
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remodeling of the placenta, impairing the earliest stages in the growth of new villi. This, in
turn, results in fetal hypoxia and growth restriction (Tabata et al. 2012; Tabata et al. 2015).
• Treatment
Valganciclovir administration for 6 months is
currently recommended for congenitally
infected neonates with moderate to severe
CMV disease. The treatment regimen should
be started within the first month of life (Emery
and Lazzarotto 2017).
• Outcome
Approximately 4% of infected fetuses will die
in utero or shortly after birth. Of the infected
Non-neoplastic Lesions of the Placenta, Pathology of
the Placenta, Fig. 44 Medium-power view of a chori-
onic villus with lymphoplasmacytic inflammation andviral
inclusions (Photomicrograph courtesy of Halit Pinar, MD
[Women and Infants Hospital of Rhode Island])
newborns who survive, 60% will have profound cognitive defects, progressive sensorineural hearing loss, and neurological
impairment (Emery and Lazzarotto 2017).
Macroscopy
There are no specific gross features observed in
the CMV-infected placentas. Dystrophic calcifi-
cations and thrombosis of chorionic vessels may
sometimes be seen (Kim and Kim 2019). One
study has also reported increased placental thickness (and therefore presumed increased placental
weight, though this was not measured) in pregnantwomenwithprimaryCMVinfectioncompared to CMV-seropositive controls (La Torre
et al. 2006).
Microscopy
Non-neoplastic Lesions of the Placenta, Pathology of
the Placenta, Fig. 45 High-power view of a chorionic
villus infected by CMV with classic viral “owl’s eye”
intranuclear inclusions
Chorionic villi show lymphoplasmacytic
inflammation, and a subset of cases may demonstrate the characteristic “owl-eye” viral inclusions; however, histopathologic findings may
become more subtle later in infection, and inclusions may be more difficult to find (Costa et al.
2020). These pathognomonic viral inclusions
are typically identifi ed in the nuclei and cytoplasm of villous endothelial and stromal cells
(Figs. 44 and 45). Chorionic vessels may show
and Kim 2019). Avascular and fibrotic villi may
be observed. It has been reported that chronic
villitis and other villous changes are observed
more frequently in placentas from mothers with
symptomatic congenital CMV infections than
from t hose with asymptomatic infections.
Moreover, the number of CMV-infected cells
is inversely correlated with the gestational age
(Uenaka et al. 2019).
thrombosis and calcification while the surrounding villous stroma may display hemosiderin deposits. The presence of plasma cells and
hemosiderin deposits is a histological clue for
CMV infection, even in cases where the pathognomonic viral inclusions are not found (Kim
Immunophenotype
Immunohistochemistry (Fig. 46), in situ hybridi-
zation, and PCR of paraffin-em bedded tissues are
available for confirmation of CMV infection (Kim
and Kim 2019). PCR of paraffin-embedded
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Clinical Features
• Incidence
Infection with parvovirus B19 is one of the
most significant causes of miscarriage in the
second trimester. Fetal loss in the first trimester
and fetal demise in the third trimester have also
been reported in association with parvovirus
B19. Fetal infection occurs in 25–33% of pregnant women who become infected with the
virus during pregnancy (Kim and Kim 2019).
• Age
Non-neoplastic Lesions of the Placenta, Pathology of
the Placenta, Fig. 46 Medium-power view of a positive
(brown) immunohistochemical stain for CMV
(Photomicrograph courtesy of Halit Pinar, MD [Women
and Infants Hospital of Rhode Island])
If infection occurs before 20 weeks of gestation, parvovirus B19 can be transmitted to the
fetus in 25–50% of cases, with fetal death
occurring in 5–10% of those. The most critical
period for parvovirus B19 infection is from
13 to 16 weeks of gestation, as this is when
placental tissue may be a more sensitive method
for detection of CMV infection than immunohistochemical analysis (Liu et al. 2017).
there is intense hepatic extramedullary hematopoiesis in the fetus (Costa et al. 2020).
• Sex
A particular fetal sex has not been associated
Molecular Features
HumanCMVvariantsmayvaryinvirulence,
tropism, and pathogenic potential. Identification
of highly pathogenic variants could provide
clinically useful data (Emery and Lazzarotto
2017).
with increased risk of parvovirus B19
infection.
• Site
Infection depends on the presence of mitotically active cells that replicate, such as the
erythroid precursors. Complete replication of
the B19 virus can only occur in the highly
Differential Diagnosis
CMV infection should be differentiated from
other infectious and noninfectious/idiopathic
causes of chronic villitis.
undifferentiated, rapidly dividing erythroid
progenitor cells. Globoside is the cellular
receptor necessary for binding of B19 to the
erythroid cells. Globoside is also expressed on
certain non-erythroid cells, such as megakar-
Parvovirus B19
yocytes, endothelium, fetal cardiac myocytes,
villous syncytiotrophoblast, and extravillous
Synonyms
B19; Human parvovirus B19; Parvovirus B19
placentitis.
and villous cytotrophoblast cells (Wegner and
Jordan 2004
).
• Treatment
No specific treatment is available; however,
Definition
Placental infection with parvovirus B19. The
virus is transmitted by droplets. In children, B19
is the cause of the so-called fifth disease or erythema infectiosum (the “slapped cheek” disease).
Two-thirds of the adult population are fortunately
immune to parvovirus B19 by age 40 (Costa
et al. 2020).
intrauterine transfusion may be attempted to
treat fetal anemia caused by the parvovirus
B19 infection (De Jong et al. 2012).
• Outcome
Parvovirus B19 is capable of crossing placenta
to cause fetal anemia and hydrops. B19
induces cell-cycle arrest in the red blood cells
at the G
phase resulting in acute anemia. One
2
N
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