Villitis of Unknown Etiology in the Placenta of a Pregnancy Complicated by COVID-19
Erdener OZER1, Erkan CAGLIYAN2, Resmiye Irmak YUZUGULDU1, Mustafa Cüneyt CEVIZCI1, Nuray DUMAN3
1Department of Pathology, Dokuz Eylul University Hospital, IZMIR, TURKEY
2Department of Obstetrics & Gynecology Dokuz Eylul University Hospital, IZMIR, TURKEY
3Department of Neonatology, Dokuz Eylul University Hospital, IZMIR, TURKEY
Keywords: COVID-19, Placenta, SARS-CoV-2, Villitis of unknown etiology
Villitis of unknown etiology (VUE) is noninfectious chronic villitis thought to be associated with fetal growth restriction and stillbirth. COVID-19
and the pandemic SARS-CoV-2 infection can cause an increased risk in pregnant women for potential maternal and fetal complications from
an immunological mechanism. We report a 39-week-gestational-age infant delivered to a 37-year-old mother diagnosed with SARS-CoV-2
infection at 37 weeks gestation. The placental examination showed the morphological features of VUE. We showed immunohistochemically that
macrophages and CD4-positive T cells predominated in the villous tissue, although elevated numbers of CD8-positive cells were also present.
We hypothesize that VUE may represent a maternal anti-viral immune response, in this case to SARS-CoV-2.
The emergence of the pandemic severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2) infection and
coronavirus disease (COVID-19) has created a serious
public health problem. Covid-19 can affect pregnant
women because they become an extremely sensitive group
during any pandemic of viral infections due to altered
immune functions and susceptibility to infection. Although
Hosier et al. 1
has demonstrated SARS-CoV-2 to be
localized to syncytiotrophoblast cells at the maternal-fetal
interface of the placenta, there is no reliable evidence for
vertical transmission of the virus in pregnant women with
COVID-19; however, an increased prevalence of perinatal
problems has been reported 2,3
. It is also unexplained yet
by which mechanism SARS-CoV-2 virus infection can be
effective on the pregnancy outcome because there is little
data on adverse pregnancy outcomes in pregnant women
with COVID-19 4
Placental pathology can provide significant knowledge of
SARS-CoV-2 virus infection in pregnancy regarding the
wellbeing of both mother and fetus, thus regarding perinatal
outcome. In a few recent cohort studies, the placentas of
pregnant women infected with SARS-CoV-2 have shown
higher rates of maternal or fetal vascular malperfusion
features associated with adverse outcomes 5,6. We
report herein a case of chronic villitis in the placenta of a pregnancy complicated by COVID-19. We hypothesize that
chronic inflammatory or immune pathological lesions of
the placenta may be also effective on the perinatal outcome
in SARS-CoV-2 virus infection, and result from an antiviral
The patient was a 39-week-gestational-age infant delivered
to a 37-year-old G2, P1 mother with no significant prior
obstetric history. Three days prior to presentation, the
mother developed fever, flu-like symptoms, mild sore throat,
and a non-productive cough. The molecular detection test
by reverse transcription–polymerase chain reaction (RTPCR)
for SARS-CoV-2 RNA in a nasopharyngeal swab
obtained from the patient on admission was positive. She
had no history of social contact with a COVID-19 positive
individual. Neither her husband nor her older child had a
positive test result for SARS-CoV-2. No further details were
available to us.
The mother was admitted for labor and birth. Fetal
ultrasound revealed a healthy fetus with an estimated
fetal weight within expected range and normal amniotic
fluid volume. Laboratory studies revealed normal liver
transaminases, as well as normal partial thromboplastin
time, fibrinogen, and D-dimer level. Blood smear revealed
normal blood count with unremarkable morphology. She underwent cesarean section. The boy infant had a birth
weight of 3360 grams and a good Apgar score. His RT-PCR
test for SARS-CoV-2 was negative. Both mother and infant
were discharged in good health.
Macroscopic and microscopic examinations of the placenta
were performed according to the standard protocol. The
placental disc measured 18x17x2.5 cm and weighed 564
g without the fetal membranes or umbilical cord (75th
percentile). The umbilical cord showed three vessels and no
thrombosis, was 14 cm in length, was inserted eccentrically,
and measured 1.2 cm in diameter. Placental membranes
were translucent, complete, and morphologically normal.
The fetal surface showed subchorionic fibrin and both
surfaces appeared otherwise normal. On cut section, there
was no grossly visible villous lesion.
On histological examination, the villi showed focally an
inflammatory infiltrate composed of macrophages and
plasma cells as well as many lymphocytes (Figure 1). In
addition, mononuclear cells in the decidua and avascular
villi adjacent to a subchorionic thrombohematoma were
present (Figure 2, 3). The maternal vessels did not show
any features of decidual vasculopathy. Neither histological
chorioamnionitis nor funusitis were seen. The inflammatory
infiltrate in the villi and decidua predominantly consisted
of macrophages and CD4-positive T lymphocytes, as
demonstrated by immunohistochemistry for CD4, CD8
and CD163 (Figure 4A-D). The pathological diagnosis
was made as low-grade chronic villitis graded according to
the Amsterdam criteria 7. However, we were not able to
demonstrate the presence of SARS-CoV-2 in the placental
tissue with histological signs of chronic villitis, and therefore
we classified the morphology as villitis of unknown etiology
Click Here to Zoom
|Figure 1: Low-grade chronic villitis characterized by a
mononuclear cell infiltrate (<10 inflamed villi per focus) (H&E;
Click Here to Zoom
|Figure 2: Chronic deciduitis: Predominantly lymphocytic
infiltration in the decidua (H&E; x200).
Click Here to Zoom
|Figure 3: Avascular chorionic villi compatible with fetal vascular
malperfusion (H&E; x40).
Click Here to Zoom
|Figure 4: Immunohistochemical findings. A) CD163-positive macrophages in the villi (IHC; x200). B) CD8-positive T lymphocytes
in the villi (IHC; x200). C) CD4-positive T lymphocytes in the villi (IHC; x200). D) CD4-positive T lymphocytes in the decidua (IHC;
The physiologic and immunologic changes that occur
as a normal component of pregnancy can have systemic
effects that increase the risk for complications from viral
infections. We reported here a case of VUE in the placenta
of a successful pregnancy complicated with SARS-CoV-2
The etiology of chronic villitis is not fully addressed yet.
A large proportion of cases of chronic villitis is VUE
and may reflect a noninfectious immune response 8,9.
However, 41% of lesions originally classified as VUE have
been reported in a study to have a viral infectious etiology
demonstrated by electron microscopy 10. We did not plan
to demonstrate the presence of SARS-CoV-2 because RTPCR
tests for SARS-CoV-2 RNA in the nasopharyngeal
swab obtained from the infant were negative.
To the best of our knowledge, there is only one case
reporting localization of SARS-CoV-2 in the placenta 1.
However vertical transmission of the virus is still unproven.
We do not know whether the clinical condition of the
infected mother may be associated with the risk of viral
transmission and the virus might also have been cleared
from placental tissue depending on the time between viral
infection and labor. We think that the chronic villitis in our
case may be unrelated to viral transmission because the
mother developed milder symptoms of COVID-19 and the
symptoms appeared at the 39th week of pregnancy, only
three days prior to presentation.
Recent data regarding VUE in live birth have shown that
villous lesions are composed of mainly fetal macrophages
and maternal CD4- or CD8-positive T lymphocytes 11.
We showed immunohistochemically that macrophages
and CD4-positive T cells predominated, although
elevated numbers of CD8-positive cells were also present.
This composition that we observed, with CD4 positive
lymphocytes outnumbering CD8 positive lymphocytes,
is in accordance with the study of Labarrere et al. 12
and supports the hypothesis that the anti-viral immune
response in VUE is of the Th1-type including anti-fetal cellmediated
There is an immunologic paradox in normal pregnancy,
which is the shift from Th1- to Th2-type responses.
Suppression of anti-fetal cell-mediated responses and a
functional predominance of antibody-mediated immunity
provide an advantage in the maintenance of a successful
pregnancy. The cytokine profile in Th2-type responses includes mainly IL-4, IL-10, and TGF-β, whereas the antiinflammatory
cytokines IL-2, IL-6, and IL-12 predominate
in Th1-type responses 13,14.
SARS-CoV-2-specific CD4+ T cell and antibody responses
in lung lesions were observed in all COVID-19 cases,
whereas CD8+ T cell responses were observed in not all but
most patients in a study 15. In addition, the immunological
reaction triggered by SARS-CoV- 2 infection has been
shown to be effective in mobilizing numerous cytokines
such as IL-1, IL-6, IL-12, IFN-γ, and TNF-α, preferentially
targeting lung tissue 16. Therefore, we think that there may
be a strong similarity in the characteristics of inflammatory
cell distribution and cytokine production among the lung
lesions and placental VUE lesions of COVID-19 patients.
In accordance with our suggestion, increased levels of IL-2
and IL-12 have been shown in VUE lesions 11. This likely
indicates that there may be an inappropriate shift toward
the Th2-type immune response in pregnant women with
VUE lesions, which may explain the higher risk of stillbirth.
Therefore, the presence of VUE may carry a risk of adverse
perinatal outcome for COVID-19 infected pregnant
In a recent cohort study, maternal Covid-19 infection was
found to be significantly associated with fetal vascular
thrombosis 5. Besides, VUE sometimes progresses to
obliterative fetal vasculopathy. The presence of cytotoxic
CD8-positive T cells is responsible for the development
of the fetal placental vasculopathy often observed in VUE
and also the increased apoptosis of intravillous cells 9,17.
These may explain why we did not find any features of fetal
vascular malperfusion in our case because CD8-positive
lymphocytes were relatively low in the lesions. In addition,
obliterative fetal vasculopathy occurs in response to chronic
inflammation in VUE when there is multifocal involvement
9. This may also explain the absence of fetal vascular
malperfusion because chronic villitis in our case was of
low grade (<10 inflamed villi per focus). Furthermore,
there was no gross umbilical cord abnormality or maternal
hypercoagulability known to be associated with fetal
We conclude that SARS-CoV-2 infection may be related to
VUE resulting from an anti-viral response. As SARS-CoV-2
is a virus, it is likely to induce inflammation. This is a Th1-type
response including several types of T cells, predominantly
CD4-positive lymphocytes resulting from a disturbance
of normal pregnancy tolerance. The immunogenic
activity of these cells is influenced by cytokines that are
increased in SARS-CoV-2 infection as well. We therefore
hypothesize that the burst of inflammatory cytokines accompanying SARS-CoV-2 infection may produce lesions
of VUE. Further studies are needed to prove this hypothesis
regarding whether VUE is related to an antiviral immune
response in COVID-19.
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