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Medical Journal of Obstetrics and Gynecology Investigating Placental Pathologies in Pregnant Women with and Without SARS-Cov-2: A Systematic Review

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Medical Journal of Obstetrics and Gynecology
Cite this article: Oltean I, Mavedatnia D, Tran J, Kaur M, Hayawi L, et al. (2022) Investigating Placental Pathologies in Pregnant Women with and Without
SARS-Cov-2: A Systematic Review. Med J Obstet Gynecol 10(1): 1155.
*Corresponding author
Dina El Demellawy, Pediatric Pathologist, Department of
Pathology, Children’s Hospital of Eastern Ontario, Ottawa,
ON, K1H 8L1, Canada, Tel: 613-737-7600 ext. 3846, Email:
deldemellawy@cheo.on.ca
Submitted: 18 January 2022
Accepted: 07 February 2022
Published: 10 February 2022
ISSN: 2333-6439
Copyright
© 2022 Oltean I, et al.
OPEN ACCESS
Research Article
Investigating Placental
Pathologies in Pregnant Women
with and Without SARS-Cov-2: A
Systematic Review
Irina Oltean1, Dorsa Mavedatnia2, Jason Tran2, Manvinder Kaur1,
Lamia Hayawi1, Nicholas Mitsakakis1, and Dina El Demellawy1-3*
1Childrens Hospital of Eastern Ontario Research Institute, Canada.
2Department of Medicine, University of Ottawa, Canada
3Department of Pathology, Childrens Hospital of Eastern Ontario, Canada
Keywords
•Placenta
•Infant, Newborn
•Female
•Pregnancy
•SARS-CoV-2
INTRODUCTION
The maternal-placental-fetal interface (MPFI) is critical for
communication between the placenta, uterine mucosa, and fetal
chorioamniotic membranes [1]. In particular, the placenta is
a crucial organ of fetal origin, providing oxygen and nutrients,
enabling the fetus to develop and function during pregnancy [1].
Immune tolerance is important throughout pregnancy, and is a
mechanism enabling embryo implantation [2].
Pregnant women are vulnerable to viral infections, resulting
from altered adaptive immune response, which can affect self-
tolerance and may dysregulate circulating cytokines [3-5]. As
such, viral infections may have detrimental consequences for
mother and baby, like tissue damage, fetal demise, and infection-
induced fetal tolerance disruptions [6].
At present, obstetrical and neonatal outcomes are linked to
the severity of COVID-19 and maternal disease. Maternal diseases,
include pulmonary problems, hypertensive disorders, obesity,
inflammation and clotting activity, and diabetes predispose
pregnant women with SARS-CoV-2 to severe adverse outcomes,
such as needing advanced oxygen support, ICU admission, and
maternal death [7-10]. In fact, a greater percentage of pregnant
women who tested positive for SARS-CoV-2 with severe maternal
diseases underwent a caesarean section, delivered preterm, and
gave birth to newborns requiring admission into the neonatal
intensive care unit (NICU) [7,11]. Overall, adverse perinatal
outcomes are more prevalent in pregnant women exhibiting
severe COVID-19 symptoms versus mild-moderate COVID-19
or pregnant women who are asymptomatic [11,12]. Moreover,
rates of stillbirth/neonatal deaths appear higher in SARS-CoV-2
infected pregnant women than controls [13-15]. Preterm birth
(i.e., <37 weeks’ gestation) is also a prevalent, detrimental
outcome of pregnancy [16], occurring in 41.1% of SARS-CoV-2
positive cases [17].
One systematic review determined that the pooled proportion
of perinatal death was 7% (2/41, 95% CI, 1.4–16.3), 43% of
fetuses (12/30, 95% CI, 15.3–73.4) with fetal distress, and 8.7% of
newborns (1/10, 95% CI, 0.01–31.4) were admitted to the NICU.
Though one study reported no signs of vertical transmission
among any newborn during the follow-up period [17], recent
literature suggests the possibility of vertical transmission in
3-6% of third-trimester pregnancies [18,19].
With respect to pregnancy outcomes, another systematic
review and meta-analysis determined that SARS-CoV-2 is
Abstract
An investigation into placental pathologies, with respect to SARS-CoV-2 in pregnant women and their neonates or infants, requires critical attention. The aim of this systematic
review is to assess the rate of placental pathologies among pregnant women who test positive for SARS-CoV-2, in comparison to pregnant women without SARS-CoV-2.
Records were sourced from MEDLINE, Embase, Cochrane Covid-19 study register, and the WHO Covid-19 Collection. Studies followed the PRISMA guidelines. Primary outcomes
included the presence of any placental pathologies as dened by the Amsterdam Consensus. Using a random effects model, proportions of study endpoints were pooled.
Sixteen observational studies were included, in which 593 pregnant women were tested positive for SARS-CoV-2 on RT-PCR testing and 21 716 were controls. Results loosely
suggest that the percentage of maternal vascular malperfusion (MVM), fetal vascular malperfusion (FVM), chronic inammation, and acute chorioamnionitis appeared slightly higher
in cases than controls, although the majority of pathologies were similar in proportion.
There is an increase rate of MVM and FVM diagnosis, and chronic inammation in positive pregnant women in SARS-CoV-2 positive versus negative pregnant women, although
the reason remains unclear. Future studies of robust sample sizes with adequate blinding and control procedures are needed.
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correlated with preeclampsia (OR 1.33, 95% CI 1.03 to 1.73) [20].
Compared with mild COVID-19, severe COVID-19 had higher risk
of preeclampsia (OR 4.16, 95% CI 1.55 to 11.15), gestational
diabetes (OR 1.99, 95% CI 1.09 to 3.64), and low birth weight
(OR 1.89, 95% CI 1.14 to 3.12) [20]. Pooled proportion analysis
demonstrated that pregnant women with SARS-CoV-2 experience
premature rupture of membranes [18.8% (5 of 31, 95% CI, 0.8–
33.5)], caesarean delivery [91% (38 of 41, 95% CI, 81.0–97.6)]
[17], and are more frequently admitted to the intensive care unit
and hospitalized in comparison to SARS-CoV-2 negative women
[21,22].
A systematic investigation of placental pathology in
SARS-CoV-2 pregnancies is still limited, and studies differ by
ascertainment, evaluation methods, and whether results are
adjusted for known confounders. A 2022 systematic review
supports that there is no evidence of a COVID-19 placental
        
non-COVID-19 pregnancies [23]. Furthermore , certain evidence
suggests that vertical transmission is rare [24-28], with a couple
of reports having demonstrated direct placental infection [29,30].
In contrast, other studies documented increased frequencies
maternal vascular malperfusion (MVM) features, intervillous
thrombi [31], fetal vascular malperfusion (FVM) or fetal vascular
thrombosis [32,33]     
and intervillositis, in placentas at third trimester, versus controls
[34]. This evidence is further supported by Patberg et al. In
         
deposition [32.5% (25/77) vs. 3.6% (2/56), p<0.0001], and villitis
of unknown etiology (VUE) [20.8% (16/77) vs. 7.1% (4/56)],
p=0.030] than controls. Their multivariable models (controlling
for maternal age, ethnicity, mode of delivery, oligohydramnios,
preeclampsia, and fetal growth restriction) demonstrated higher
odds of FVM [OR 12.63 (2.40, 66.40)] and VUE [OR 2.11 (0.50,
8.97) among cases [35].
        
gross or microscopic pathological attributes [36]. Furthermore,
Gulersen et al found that decidual vasculopathy was not detected
in any third trimester placentas with severe SARS-CoV-2
infection, and there was no statistical difference in placental
histopathological characteristics between cases and controls
[37].
The impact of placental pathologies in SARS-CoV-2 pregnant
women, and their neonates, is of keen interest to pathologists
and obstetricians worldwide. Thus, the aim of this systematic
review is to determine the prevalence of placental pathologies
among pregnant women who test positive for SARS-CoV-2 versus
pregnant women without SARS-CoV-2.
MATERIALS AND METHODS
This review followed the Cochrane Methodology to identify
and select the studies [38] and the Preferred Reporting Items for
Systematic Reviews and Meta-Analyses (PRISMA) [39].
Search Strategy and Selection Criteria
A systematic search for relevant studies was performed
between January 1st 2020 to November 17th 2020 using these
databases: MEDLINE including Epub Ahead of Print, In-Process &
Other Non-Indexed Citations, and Embase. Our review thus only

the pandemic mainly from the USA and Italy, followed by Brazil
and Switzerland. All studies were captured before COVID-19
vaccination was made available internationally. Two specialized
COVID-19 resources were also searched on November 18,
2020; Cochrane Covid-19 study register, and the WHO Covid-19
Collection, as well as MedRxiv, OSF Preprints, and database for
Disaster Medicine and Public Health (Supplemental Material 1).
A librarian experienced in systematic reviews developed
and conducted the searches [40]. The study protocol has been
registered in Open Science Framework (10.31219/osf.io/
e5tns). Duplicates were deleted online, and studies collected by
the electronic search were imported into a systematic review
software InsightScope [(www.insightscope.ca)] for title, abstract,
and full text review. Three reviewers (IO, DM, JT) screened at title/
abstract level and full text review stages. Studies were omitted if
at least two reviewers agreed to exclude. Any discrepancies were
resolved by the corresponding author (DD).
Inclusion Criteria
Case series, case-control and cohort studies written in
English or French of asymptomatic and symptomatic pregnant
women, who tested positive for SARS-CoV-2 on admission, as
       
using real-time reverse-transcriptase-polymerase chain reaction
(rRT-PCR) were considered. Control groups were differentiated
into: controls recruited before the pandemic (historical prior to
January 2020), controls recruited during the pandemic period
who screened negative after rRT-PCR testing, or negative based
on a clinical diagnosis (absence of presenting symptoms during
initial screening).
Exclusion Criteria
Studies were excluded if non-pregnant women or non-human
trials were examined, could not be accessed online, and written in
a language other than English or French. We excluded conference
abstracts, literature and systematic reviews, and editorials or
commentaries.
Data extraction and Outcomes
Three authors (DM, JT, and IO) extracted frequencies and
percentages using a pre-constructed and piloted data abstraction
sheet in REDCap (Research Electronic Data Capture), a secure,
third-party web server [41,42]. The extracted information
included: title; year of publication; study location and design;
publishing journal; maternal age; gestational age; maternal
chronic or gestational hypertension; chronic or gestational
diabetes; preeclampsia; trimester of pregnancy (1st- conception
to 12 weeks, 2nd- week 13 to 27, and 3rd- week 28 to birth); mode
of delivery (vaginal, elective caesarean, emergency caesarean);
th percentile,
appropriate 10-90th percentile, or large >90th percentile for that
gestational age). To approximate placental weight categories in
case series studies, the reference weights for trimmed singleton
placentas were used with corresponding gestational age (weeks)
[43].
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The primary endpoints were frequency or percent of any
placental pathology syndromes (i.e., any individual feature)
in cases vs controls, as outlined in the Amsterdam placental
workshop group consensus statement (Supplemental Table 2)
[44]. If the authors of the included studies did not provide any
individual feature, the study team followed the Amsterdam
criteria and advice from an experienced pathologist (DD), to
determine a diagnosis of MVM and FVM, respectively. A diagnosis
of MVM was made if accelerated villous maturation (AVM), and/
or decidual arteriopathy (DA), was present, regardless if other
features were present. The presence of fetal thrombosis or
avascular villi without chronic villitis was indicative of FVM. If the
study did not report chronic deciduitis and villitis separately, but
  
was collected. Acute chorioamnionitis included stages 1 and 2 of
chorioamionitis.
        
endpoints referred to frequency or percent of preterm birth (34
weeks or less gestation), small-for-gestational age (SGA) (birth
weight < 10th percentile), large-for-gestational age (LGA) (birth
weight > 10th percentile), abortions (< 24 weeks of pregnancy),
and stillbirths (mortality after 24 completed weeks of pregnancy).
Assessment of Risk of Bias (ROB) within studies
DM and JT independently assessed risk of bias using the
Ottawa-Newcastle Scale to evaluate the quality of nonrandomized
studies in meta-analyses [45,46]. To score the quality of the
included studies, three factors were assessed: (1) selection, such
as representativeness of the exposed cohort, selection of the
non-exposed cohort, exposure ascertainment, and evidence that
the outcome of interest was not present at study initiation; (2)
comparability in the study design and analysis, including methods
of controlling important confounding variables (hypertensive
diseases like preeclampsia, chronic and gestational hypertension,
and diabetes); and (3) outcome, including the follow-up
period, cohort retention, and possibility of independent blind
assessment. We rated the quality of the studies (good, fair and
poor) by awarding points in each domain following the guidelines
of the Ottawa-Newcastle Scale. A “good” quality score implied 3
or 4 points in selection, 1 or 2 points in comparability, and 2 or
3 points in outcomes. A “fair” quality score referred to 2 points
in selection, 1 or 2 points in comparability, and 2 or 3 points
          
in selection, or 0 points in comparability, or 0 or 1 point(s) in
outcomes        
the appropriate study design and in the context of placental
pathology, where placentas are typically dissected immediately
after birth. Under the outcomes section, length and adequacy of
follow-up may not have been applicable; as such, certain studies
were not penalized for this.
Statistical analysis
The R statistical programming language Version 4.0.3 was
used for all statistical analysis [47]. Frequencies and percentages
represented the categorical variables. Using a random effects
        
study endpoints were pooled for each study design and for
positive pregnant women and negative women separately.
RESULTS AND DISCUSSION
Study Selection
Figure 1 depicts the results of the search strategy, which
yielded 627 studies. After level I screening, 440 studies were
excluded because they did not meet the inclusion criteria. Overall,
16 studies were included in the systematic review (Figure 1).
Study characteristics and individual results
Seven studies (44%) were case controls, 5 (31%) case
series, and 4 (25%) were cohort studies, and 12/16 (75%),
were conducted in the United States of America (Table 1). Five
hundred and ninety-three pregnant women tested positive for
SARS-CoV-2 on RT-PCR testing and 21 716 controls (including
historical, RT-PCR negative, and abnormal controls).
Risk of bias across studies
A detailed quality appraisal of case-control, cohort, and case
series studies is summarized in the Supplemental Table 3. After
formally assessing risk of bias for all studies based on limitations

and one study [35] as “good”. Due to poor study quality, a meta-
analysis of the association between positive test for SARS-CoV-2
and outcomes of interest was not performed. One case-control
study did not describe how the non-exposed cohort was derived
[48], in addition to two case series studies [32,49]. There was no
description of statistical adjustment for known confounders of
placental pathology like preeclampsia, chronic and gestational
hypertension and diabetes or non-hypertensive factors such as
maternal age in fourteen studies [31,32,53-56,33,36,37,48-52],
apart from Patberg et al., 2020 [35]. The authors were able to
produce multivariable logistic regression models adjusting
for variables that could be on the causative pathway of MVM
and villitis of unknown etiology (preeclampsia, fetal growth
restriction etc.), despite their inability to examine pre-existing and
[35]. Twelve
studies did not provide a description as to whether pathologists
were independently blinded to SARS-CoV-2 exposure before
evaluating placental specimens [31,32,56,57,33,36,37,50,52-
55], excluding Facchetti et al., 2020 [51], and Richtmann et al.,
2020 [49]. Follow-up periods were not applicable to the majority
of study designs as the assessment of placental histopathology
occurs immediately after delivery, without prospective follow-
up. Such studies were not penalized.
Demographic characteristics
Table 2 summarizes the demographic characteristics
by study design of SARS-CoV-2 positive versus women who
tested negative, where appropriate. Results were divided
by study design to enable direct comparisons between the
studies consistently. Maternal age for positive and negative
women ranged from 29.1 to 32.4 years. Prevalent hypertensive
diseases for both study groups included chronic hypertension,
diabetes, and preeclampsia. However, the percentage of chronic
hypertension in case control studies was elevated in SARS-CoV-2
positive pregnant women vs SARS-CoV-2 negative women [7.1%
(1.0%, 16.3%) vs 5.9% (1.3%, 12.7%)], respectively. In cohort
studies, the percentage of chronic hypertension [10.5% (0.1%,
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Figure 1 2021 PRISMA Flowchart.
Table 1: Study Characteristics.
Author, year Study design Location
SARS-CoV-2 positive
pregnant women with
placental pathology
assessed (cases, N)a
SARS-CoV-2 negative pregnant
women with placental pathology
assessed (controls, N)
Baergen & Heller, 2020[32] Case series USA 20 N/Ab
Shanes et al., 2020[31] Case Control USA 15 Historical controls: 17,479
Melanoma: 215
Prabhu et al., 2020[50] Prospective Cohort USA 29 106
Cribiu et al., 2020[53] Case series Italy 9 N/A
Richtmann et al., 2020[49] Case series Brazil 5 N/A
Facchetti et al., 2020[51] Case control Italy 15 PCR controls: 34
‘Not determinate’: 52
[52] Case control USA 74 290
Gulersen et al., 2020[37] Cohort USA 50 50
Menter et al., 2020[48] Case series Switzerland 5 N/A
He et al., 2020[36] Case control USA 21 20
Patberg et al., 2020[35] Retrospective Cohort USA 77 56
Adhikari et al., 2020[83] Cohort USA 187 Not clear how many controls underwent
placental pathological examination
Schwartz et al.,2020[56] Case series USA 11 N/A
Hecht et al., 2020[54] Case control USA 19
COVID-19 mothers before pandemic or
with negative tests: 10
Historical: 122
“Abnormal” with HIEc: 130
Smithgall et al., 2020[55] Case control USA 51 25
Mulvey et al., 2020[33] Case control USA 5 5

bNot applicable based on study design.
cHypoxic ischemic encephalopathy (HIE).
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Table 2: Demographic Characteristics.
Characteristic # of studies for
positive womena
SARS-CoV-2 positive pregnant
women (Percentage, 95% CI)
# of studies for
negative women
SARS-CoV-2 negative pregnant
women (Percentage, 95% CI)
Case control studies
Maternal age (years), mean 6 31.0 (28.3,33.6) 4 29.1 (26.3,31.9)
Gestational age (weeks), mean 5 38.1 (37.1,39.0) 3 36.5 (35.6,37.4)
Hypertensive diseases
Chronic hypertension 3 7.1 (1.0, 16.3) 2 5.9 (1.3, 12.7)
Gestational hypertension 5 5.8 (0.8, 13.5) 2 5.3 (0.1, 15.2)
Diabetes 6 5.1 (1.5, 10.1) 3 6.9 (4.2, 10.1)
Preeclampsia 6 3.1 (0.3, 7.4) 3 12.0 (6.5, 18.7)
Trimester of pregnancy
First trimesterb5 0.0 (0.0, 2.4) 2 0.0 (0.0, 0.9)
Second trimesterc6 5.6 (0.1, 16.0) 3 3.9 (0.0, 13.3)
Third trimesterd 6 94.4 (84.0, 99.9) 3 96.1 (86.7, 100.0)
Mode of delivery
Vaginal 5 55.3 (37.9, 72.1) 2 52.5 (33.0, 71.6)
Elective caesarean 0 N/A 0 N/A
Emergency caesarean 0 N/A 0 N/A
Cohort studies
Maternal age (years), mean 4 29.1 (26.3,31.9) 4 31.0 (26.6,35.4)
Gestational age (weeks), mean 3 39.1 (38.6,39.7) 3 39.2 (38.8,39.6)
Hypertensive diseases
Chronic hypertension 2 10.5 (0.1, 30.8) 2 3.9 (1.7, 6.9)
Gestational hypertension 1 6.0 (0.8, 14.7) 1 2.0 (0.0, 8.4)
Diabetes 4 6.0 (3.6, 8.9) 4 7.3 (2.8, 13.5)
Preeclampsia 3 9.7 (6.5, 13.3) 3 6.9 (0.6, 18.4)
Trimester of pregnancy
First trimesterb2 0.0 (0.0, 0.6) 2 0.0 (0.0, 0.0)
Second trimesterc2 1.7 (0.0, 6.8) 2 1.9 (0.0, 7.1)
Third trimesterd2 98.3 (93.2, 100.0) 2 98.1 (92.7, 100.0)
Mode of delivery
Vaginal 4 71.2 (64.8, 77.1) 4 54.5 (38.9, 69.7)
Elective caesarean 0 N/A 0 N/A
Emergency caesarean 0 N/A 0 N/A
Case series studies
Maternal age (years), mean 5 32.4 (31.1,33.7)
Gestational age (weeks), mean 5 36.9 (32.3,41.5)
Hypertensive diseases
Chronic hypertension 1 5.0 (0.0, 20.2)
Gestational hypertension 1 0.0 (0.0 , 0.4)
Diabetes 3 16.6 (0.4, 43.4)
Preeclampsia 3 9.9 (1.0, 23.6)
Trimester of pregnancy
First trimesterb5 0.0 (0.0, 3.4)
Second trimesterc5 4.6 (0.0, 21.0)
Third trimesterd5 95.4 (79.0, 100.0)
Mode of delivery
Vaginal 4 69.2 (52.8, 83.8)
Elective caesarean 0
Emergency caesarean 2 23.9 (4.4, 49.8)
aNumber of studies that captured a particular variable
bConception to 12 weeks
cWeek 13 to 27
dWeek 28 to birth
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30.8%) vs 3.9% (1.7%, 6.9%)], gestational hypertension [6.0%
(0.8%, 14.7%) vs 2.0% (0.0%, 8.4%)] and preeclampsia [9.7%
(6.5%, 13.3%) vs 6.9% (0.6%, 18.4%)] was also increased,
relative to the SARS-CoV-2 negative cohorts. The overwhelming

delivered vaginally (Table 2).
Overall, the percentage of symptomatic cases on admission
ranged from 13% to 81.8%, similar to the percent range of
asymptomatic cases (9.1% to 80%), indicating that mothers may
have been asymptomatic initially and then tested positive during
pregnancy or presented with common, documented COVID-19
      
pain) upon admission. For data available in SARS-CoV-2 positive
women (N=593), there were 52 (8.8%) ICU admissions in women
with severe COVID-19 or obstetric complications (preeclampsia,
diabetes, preterm labour), 22 had pneumonia (3.7%), 5 women
had hypoxia (0.8%), and there were 25 cases of severe or critical
COVID-19 illness (4.2%). No maternal deaths were reported.
Primary endpoints: Placental Pathology Syndromes
Table 3 provides a detailed overview of the distribution of

across all study designs included any feature of MVM or FVM,
      
among SARS-CoV-2 positive and negative pregnant women. In
case controls, prevalence of retroplacental hematoma, MVM
and FVM diagnosis, and placental villous edema was higher in
positive pregnant women than controls. Apart from edema,
         
there is no indication that placental weight was lower (<10th
Percentile) or higher (>90th Percentile) in SARS-CoV-2 positive
women compared to negative (Table 3).
Secondary endpoints: Perinatal outcomes
Table 4 succinctly demonstrates the clinical endpoints of
interest. Overall, SARS-CoV-2 positive pregnant women gave
birth to more SGA babies than negative pregnant women in case
control and cohort studies. Interestingly, the percent of LGA
babies was higher among SARS-CoV-2 negative controls than
cases. Percentages of prematurity, abortion, and stillbirth were
relatively similar in case control and cohort studies. Despite this,
a high percent of stillbirth was documented in case series studies
with SARS-CoV-2 [76.9% (95% CI (13.1%, 100.0%)] but was not
evident in cohort and case control studies (Table 4).
The aim of this systematic review was to identify and quantify
any differences in placental pathologies and clinical endpoints
in pregnant women who test positive for SARS-CoV-2 versus
pregnant women without SARS-CoV-2. Along with the structured
review by Sharps et al 2020 [58]       
current reviews of its kind to comprehensively quantify placental
pathologies, including any individual feature of MVM and FVM,
via the structured and detailed assessment of the Amsterdam
Consensus. Previous systematic reviews have either investigated
pathologies from SARS-CoV-2 positive biopsies from other parts
of the body, including the lungs, liver, and skin [59,60], or provide
only a general overview of the placental abnormalities examined
[61]        
Sharps et al 2020, where 35.5% of cases had evidence of FVM,
        
between 5.3% to 8.7% of cases, in their study [58].
Interestingly, only one of our included studies documented
the rare association of diffuse synctiotrophoblast necrosis with
histiocytic intervillositis in 5 stillborn, and liveborn infants,
who acquired SARS-CoV-2 infection before delivery [62]. These
       [62],
which are echoed in case reports [63-66], or recently published
communications [67,68]. However, the true prevalence of
trophoblast necrosis with histiocytic intervillositis may be
underreported, since we excluded case reports in our review
and more literature has been generated since the end date of our
capture period.
A systematic review conducted by Peiris et al determined that
11/19 (57.9%) of SARS-CoV-2 placentas showed microthrombi
    [59]. Further, AbdelMassih et
al showed evidence of placental infarction and vascular villi
compromise in 64% of SARS-CoV-2 positive placentas [61].
Thrombotic tendency in villous apparatus was evident, as well as
multiple organizing intervillous hemorrhage/thrombi/avascular
 [61]. Lastly, Polak et al. [60]  
[24], while three other women had no
placental abnormalities [26].
Interestingly, our review shows that the percentage of
MVM is similar between cases and controls. We do know that
maternal hypertensive diseases of pregnancy can predispose
pregnant women to severe COVID-19 [7,10,11]. Since the
percentage of chronic hypertension, gestational hypertension,
and preeclampsia was higher relative to SARS-CoV-2 negative
cohorts, MVM placental changes may not be driven by COVID-19
itself. Rather, maternal risk factors might elevate the risk of
developing severe COVID-19. MVM features are usually seen
in women with hypertensive diseases of pregnancy [69,70], or
coincident infarctions [71,72]. Therefore, the presence of MVM
in SARS-CoV-2 cases could be driven by maternal risk factors or
thrombi deposition in response to the virus [73–75]. Baud et al
 
of MVM in SARS-CoV-2 pregnant women [24], but other authors
         
demise [54], or features of a coagulopathic process [25], rather
than SARS-CoV-2.
Our review noted greater percentage of FVM in SARS-CoV-2
   
is distinctly different in its distribution between the two groups.
        
heart, and kidney of COVID-19 patients [35,76-78]. As such, SARS-
CoV-2 may induce FVM pathology due to changes in coagulopathy
leading to microthrombi and/or avascular villi in the fetal
vessels. In COVID-19 placentas, most FVM lesions showed global
distribution, which could suggest partial obstruction in umbilical
[35]. Hence, endothelial damage in COVID-19 placental
[35].
      
      [31,52,54]. Chronic

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Table 3: Placental pathologies in SARS-CoV-2 positive versus SARS-CoV-2 negative pregnant women.
Pathologies
Number of
studies for
positive
womena
SARS-CoV-2
positive
pregnant women
(Percentage, 95%
CI)
Number
of studies
for
negative
women
SARS-CoV-2
negative pregnant
women (Percentage,
95% CI)
Case control studies
Placental weight
Small placental weight (<10th percentile) 4 30.5 (7.9, 59.0) 0
Appropriate placental weight (10-90th percentile) 4 39.2 (14.6, 66.7) 0
Large placental weight (>90th percentile) 4 5.6 (0.2, 15.1) 0
Placental pathologies
Retroplacental hematoma or placental abruption 3 5.4 (0.9, 12.4) 5 2.2 (0.9, 4.0)
Maternal vascular malperfusion (MVM)b5 43.3 (22.7, 65.0) 9 33.2 (21.0, 46.6)
Diagnosis of MVMc5 15.9 (5.6, 29.3) 5 9.3 (1.5, 21.4)
Fetal vascular malperfusion (FVM)b7 41.5 (18.5, 66.4) 11 19.6 (5.5, 38.6)
Diagnosis of FVMc6 15.9 (2.1, 36.5) 6 2.7 (0.2, 6.9)
Chronic plasma cell deciduitis 4 12.3 (4.9, 21.7) 4 12.4 (4.2, 23.4)
Chronic villitis 6 9.0 (2.8, 17.6) 7 9.9 (5.5, 15.3)
d4 13.7 (6.0, 23.5) 7 21.9 (12.4, 33.1)
Acute chorioamnionitise 3 14.2 (2.0, 32.4) 2 14.2 (2.0, 32.4)
Chronic chorioamnionitis 0 0
Undifferentiated chorioamnionitis 1 64.9 (53.6, 75.4) 1 65.9 (60.3, 71.2)
Placental villous edema 3 13.8 (5.3, 24.9) 2 7.5 (7.1, 7.9)
Normal pathology 1 6.7 (0.0, 26.4) 0
Cohort studies
Placental weight
Small placental weight (<10th percentile) 2 10.8 (5.8, 17.0) 2 16.1 (9.5, 24.0)
Appropriate placental weight (10-90th percentile) 2 85.6 (75.0, 93.8) 2 76.5 (67.8, 84.2)
Large placental weight (>90th percentile) 2 3.0 (0.0, 9.1) 2 7.5 (3.0, 13.5)
Placental pathologies
Retroplacental hematoma or placental abruption 3 6.5 (0.0, 31.2) 3 3.7 (0.0, 16.5)
Maternal vascular malperfusion (MVM)b3 27.0 (11.8, 45.4) 2 25.2 (13.8, 38.7)
Diagnosis of MVMc2 8.4 (0.0, 50.8) 2 13.6 (0.0, 51.5)
Fetal vascular malperfusion (FVM)b3 31.2 (17.2, 47.2) 2 7.6 (1.9, 16.5)
Diagnosis of FVMc3 25.5 (7.6, 48.9) 3 7.8 (2.2, 15.9)
Chronic plasma cell deciduitis 2 10.4 (0.0, 34.7) 0
Chronic villitis 4 12.5 (1.3, 31.4) 3 3.6 (0.0, 14.0)
d2 37.9 (12.4, 67.7) 1 7.5 (1.9, 15.9)
Acute chorioamnionitise 2 23.6 (16.5, 31.5) 2 17.9 (11.0, 25.9)
Chronic chorioamnionitis 2 1.1 (0.0, 5.0) 0
Undifferentiated chorioamnionitis 1 6.9 (0.1, 19.7) 1 6.6 (2.5, 12.2)
Placental villous edema 1 5.9 (2.9, 9.8) 0
Normal pathology 3 32.2 (1.3, 77.5) 2 72.1 (26.0, 99.7)
Case series studies
Placental weight
Small placental weight (<10th percentile) 2 14.7 (0.0, 57.8)
Appropriate placental weight (10-90th percentile) 2 64.7 (36.1, 89.3)
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Large placental weight (>90th percentile) 2 13.6 (0.0, 39.3)
Placental pathologies
Retroplacental hematoma or placental abruption 2 0.0 (0.0, 5.9)
Maternal vascular malperfusion (MVM)b4 35.1 (4.7, 73.2)
Diagnosis of MVMc4 21.4 (7.5, 38.8)
Fetal vascular malperfusion (FVM)b4 34.8 (13.3, 59.4)
Diagnosis of FVMc4 17.8 (6.1, 32.8)
Chronic plasma cell deciduitis 2 40.0 (9.7, 74.1)
Chronic villitis 3 25.0 (9.3, 43.9)
d3 47.8 (10.0, 86.8)
Acute chorioamnionitise 2 51.5 (0.0, 100.0)
Chronic chorioamnionitis 0
Undifferentiated chorioamnionitis 1 20.0 (0.0, 67.5)
Placental villous edema 1 0.0 (0.0, 31.7)
Normal pathology 1 0.0 (0.0, 15.1)
aNumber of studies that captured a particular variable
bAny individual feature
cUsing Amsterdam Consensus guidelines or advice from co-investigator and pediatric pathologist (DD)
d
reported together
eIncludes stage 1 and 2 of chorionitis (mild acute chorioamnionitis)
Table 4: Adverse perinatal outcomes.
Perinatal outcome Number of studies
positive womena
SARS-CoV-2 positive
pregnant women
(Percentage, 95% CI)
Number of studies
negative women
SARS-CoV-2 negative pregnant
women (Percentage, 95% CI)
Case control studies
Small-for-gestational age
(SGA)b2 50.9 (19.6, 81.8) 2 32.4 (18.7, 47.8)
Large-for-gestational age
(LGA)c2 1.5 (0.0, 12.5) 2 7.3 (6.9, 7.7)
Pretermd 4 15.1 (8.2, 23.4) 3 12.7 (0.8, 32.9)
Abortione1 0.0 (0.0, 3.3) 1 0.0 (0.0, 6.8)
Stillbirthf3 0.2 (0.0, 4.1) 3 1.6 (0.0, 5.8)
Cohort studies
Small-for-gestational age
(SGA)b1 16.6 (11.6, 22.3) 1 10.0 (9.0, 11.1)
Large-for-gestational age
(LGA)c1 16.0 (11.1, 21.7) 0
Pretermd 4 3.0 (0.0, 10.5) 2 3.3 (0.0, 18.0)
Abortione1 3.2 (1.1, 6.3) 1 3.0 (2.4, 3.6)
Stillbirthf1 0.0 (0.0, 0.4) 2 0.4 (0.2, 0.7)
Case series studies
Small-for-gestational age
(SGA)b3 11.3 (0.9, 27.7)
Large-for-gestational age
(LGA)c2 6.6 (0.0, 36.0)
Pretermd 2 2.2 (0.0, 15.1)
Abortione0
Stillbirthf2 76.9 (13.1, 100.0)
aNumber of studies that captured a particular variable
bth percentile
cth percentile
d
eAbortion occurring at 24 weeks or less of pregnancy
f
Central
Oltean I, et al. (2022)
Med J Obstet Gynecol 10(1): 1155 (2022) 9/12
acid (RNA) viruses [54,79]. Regression results indicate that
the risk of chronic villitis of unknown etiology (VUE) varies
seasonally; in fact the risk of VUE is 16% to 17% higher in the fall
and winter versus summer (fall relative risk [RR]: 1.17, 95% CI
(1.06, 1.29); winter RR: 1.16, 95% CI (1.05, 1.29)] [80]. Although
    
virus, seasonality might also contribute to causing infection or
loss of organism tolerance [31]
may be similar between cases and controls, partly due to seasonal
variations, not only because of SARS-CoV-2. Case reports have
   
intervillositis [25,29,30]. Two cases had massive intervillous
       
  [49]. Chronic
villitis has been described in placentitis due to STORCH (Syphilis,
Toxoplasmosis, Other Agents, Rubella, Cytomegalovirus, and
Herpes Simplex), and other viral infections, indicating heightened
maternal immune response [31,32]. The presence of VUE in
healthy patients without SARS-CoV-2 might be explained by its
development as sequelae after harboring the virus, in healthy
patients with normal placental weights in the third trimester
[35]. Authors suspect that the presence of chronic villitis might
be a direct or indirect effect of viral infection, from a heightened
systemic immune response (i.e., cytokine storm) characteristic of
other respiratory viral infections [81].
Results from this review demonstrate that having an SGA baby
is more prevalent in SARS-CoV-2 positive pregnant women than
negative pregnant women. Percentages of prematurity, abortion,
and stillbirth remained unchanged between SARS-CoV-2 positive

with a previous systematic review, showing higher preterm birth
rate in pregnant women with COVID-19 (15.9%), than uninfected
women (6.1%) [82]. However, caution should be exercised when
        
review were small, included only case series, and preprints were
not peer reviewed [83]. Although we did not explicitly measure
intrauterine fetal demise (<23 weeks), previous literature of
   
negative bacteria, without showing mildly increased perivillous
[84,85].
Overall, many of the studies included in this review differed
by ascertainment of placental changes, sample size, and whether
results were adjusted for known confounders. There is a potential

authors did not explicitly differentiate acute versus chronic. There
is also possible overlap of cases, since three studies included
data from New York Presbyterian Hospital [32,50,52], and two
collected data from the University of Brescia, Italy during similar
periods [51,56]       
observed. There is also wide variability in the number of and
minimal individual features needed for a diagnosis of MVM [51],

the Amsterdam Criteria consistently. Further exacerbating this

Certain studies did not have comparable control groups [31,54],
       
controls who test negative for SARS-CoV-2 during the pandemic
period, historical controls, or pregnant women with underlying
issues such as melanoma and hypoxic ischemic encephalopathy.
We did not exclusively examine the relationship between
COVID-19 severity to pregnancy outcomes, yet we did collect
adverse maternal outcomes like ICU admission, pneumonia,
and mortality, when COVID-19 severity (severe or critical)
was reported. A statistical investigation into the percentage
of pregnant women with hypertensive diseases of pregnancy
          
performed. However, we did capture important differences in
       
between SARS-CoV-2 positive and negative women, to describe
this relationship narratively.
CONCLUSIONS
Results from the sixteen studies included in our review
suggest that there are differences in placental pathologies
between SARS-CoV-2 positive versus negative pregnant women
         
we were unable to test for statistical differences to validate this
claim. Notably, percent of any individual feature of MVM, FVM,

controls. Presence of SARS-CoV-2 RNA in placentas is rare [48].
     
were reported after the diagnosis of SARS-CoV-2 in women
        
matched historical control group [37].
In the future, there is a need for high caliber evidence (with
robust sample sizes, adequate blinding, statistical adjustment
for known confounders, and identical control populations) to
determine if any conclusive link exists between SARS-CoV-2
and the development of placental pathologies in pregnant
women. Future studies can explore placental pathologies during
different phases of the pandemic, including among vaccinated vs.
unvaccinated pregnant women, to consider the potential role of
the delta or omicron variants on placental pathology. Moreover,
future studies can investigate changes in placental pathologies
         
of possible transmission, or the possible impact of maternal
stress precipitating adverse, perinatal outcomes. Acute vs.
chronic placental phenotypic pathologies in relation to SARS-
 
correlations to different SARS-CoV-2 variants and placental

AUTHOR CONTRIBUTIONS
All Authors accept responsibility for the entirety of this
manuscript and approve its submission.
ACKNOWLEDGEMENTS
We thank Katie O’Hearn, MSc, (Children’s Hospital of Eastern
Ontario Research Institute) for assistance with methodology,
and Margaret Sampson, MLIS, PhD, AHIP (Children’s Hospital of
Eastern Ontario) for developing the electronic search strategies.
FUNDING ACKNOWLEDGEMENT
        

Central
Oltean I, et al. (2022)
Med J Obstet Gynecol 10(1): 1155 (2022) 10/12
REFERENCES
1. Zaga-Clavellina V, Diaz L, Olmos-Ortiz A, Godínez-Rubí M, Rojas-
Mayorquín AE, Ortuño-Sahagún D. Central role of the placenta
during viral infection: Immuno-competences and miRNA defensive
responses. Biochim Biophys Acta - Mol Basis Dis. 2021; 1867.
2. Moffett A, Chazara O, Colucci F. Maternal allo-recognition of the fetus.
Fertil Steril. 2017; 107: 1269-1272.
3. Goodnight WH, Soper DE. Pneumonia in pregnancy. Crit Care Med.
2005; 33.
4. Stone S, Nelson-Piercy C. Respiratory disease in pregnancy. Obstet
Gynaecol Reprod Med. 2010; 20: 14-21.
5. van Well GTJ, Daalderop LA, Wolfs T, Kramer BW. Human perinatal
immunity in physiological conditions and during infection. Mol Cell
Pediatr. 2017; 4: 1-11.
6. Yockey LJ, Lucas C, Iwasaki A. Contributions of maternal and fetal
antiviral immunity in congenital disease. Science (80- ) 2020; 368:
608-612.
7. Vouga M, Favre G, Martinez-Perez O, Pomar L, Acebal LF, Abascal-Saiz
A, et al. Maternal outcomes and risk factors for COVID-19 severity
among pregnant women. Sci Rep. 2021; 11: 13898.
8. Loza A, Farias R, Banton J, Borgida A, Feldman D. Impact of COVID-19
infection during pregnancy on maternal and neonatal outcomes. Am J
Obstet Gynecol. 2022; 226: S371–372.
9. Macias DA, Schell RC, Garner WH, Eribo T, McIntire DD, Adhikari EH.
Is maternal diabetes associated with COVID-19 disease progression in
pregnancy? Am J Obstet Gynecol. 2022; 226: S655.
10. Altendahl M, Jang C, Mok T, Quach A, Afshar Y. Severe COVID-19 in
        
outcomes. Am J Obstet Gynecol. 2022; 226: S603-604.
11. Metz TD, Clifton RG, Hughes BL, Sandoval G, Saade GR, Grobman WA,
et al. Disease Severity and Perinatal Outcomes of Pregnant Patients
With Coronavirus Disease 2019 (COVID-19). Obstet Gynecol. 2021;
137: 571-580.
12. Brandt JS, Hill J, Reddy A, Schuster M, Patrick HS, Rosen T, et al.
Epidemiology of coronavirus disease 2019 in pregnancy: risk factors
and associations with adverse maternal and neonatal outcomes. Am J
Obstet Gynecol. 2021; 224: 389.e1-389.e9.
13. Mullins E, Evans D, Viner RM, O’Brien P, Morris E. Coronavirus in
pregnancy and delivery: rapid review. Ultrasound Obstet Gynecol.
2020.
14. Elsaddig M, Khalil A. Effects of the COVID pandemic on pregnancy
outcomes. Best Pract Res Clin Obstet Gynaecol. 2021; 73: 125-136.
15. DeSisto CL, Wallace B, Simeone RM, Polen K, Ko JY, Meaney-Delman
D, et al. Risk for Stillbirth Among Women With and Without COVID-19
at Delivery Hospitalization — United States, March 2020–September
2021. MMWR Morb Mortal Wkly Rep. 2021; 70: 1640-1645.
16. Chi J, Gong W, Gao Q. Clinical characteristics and outcomes of pregnant
women with COVID-19 and the risk of vertical transmission: a
systematic review. Arch Gynecol Obstet. 2021; 303: 337-345.
17. Di Mascio D, Khalil A, Saccone G, Rizzo G, Buca D, Liberati M, et al.
Outcome of Coronavirus spectrum infections (SARS, MERS, COVID 1
-19) during pregnancy: a systematic review and meta-analysis. Am J
Obstet Gynecol MFM. 2020: 100107.
18. Bwire GM, Njiro BJ, Mwakawanga DL, Sabas D, Sunguya BF. Possible
vertical transmission and antibodies against SARS-CoV-2 among
infants born to mothers with COVID-19: A living systematic review. J
Med Virol. 2021; 93: 1361-1369.
19. Kotlyar AM, Grechukhina O, Chen A, Popkhadze S, Grimshaw A, Tal O,
et al. Vertical transmission of coronavirus disease 2019: a systematic
review and meta-analysis. Am J Obstet Gynecol. 2021; 224: 35-53.e3.
20. Wei SQ, Bilodeau-Bertrand M, Liu S, Auger N. The impact of COVID-19
on pregnancy outcomes: A systematic review and meta-analysis.
Cmaj. 2021; 193: E540-548.
21. Ko JY, DeSisto CL, Simeone RM, Ellington S, Galang RR, Oduyebo T,
et al. Adverse pregnancy outcomes, maternal complications, and
severe illness among U.S. delivery hospitalizations with and without
a COVID-19 diagnosis. Clin Infect Dis. 2021; 2019.
22. Jelliffe-pawlowski LL, Oltman SP, Rand L, Scott KA, Kuppermann M,
Baer R, et al. Examining the Impact of the 2019 Novel Coronavirus
and Pandemic-Related Hardship on Adverse Pregnancy and Infant
Outcomes: Design and Launch of the HOPE COVID-19 Study. Reprod
Med. 2020: 91-107.
23. Suhren JT, Meinardus A, Hussein K, Schaumann N. Meta-analysis on

pattern. Placenta. 2022; 117: 72-77.
24. Baud D, Greub G, Favre G, Gengler C, Jaton K, Dubruc E, et al. Second
trimester miscarriage in a pregnant woman with SARS-CoV-2
infection. N Engl J Med. 2020; 323: 2198-2199.
25. Kirtsman M, Diambomba Y, Poutanen SM, Malinowski AK,
Vlachodimitropoulou E, Parks WT, et al. Probable congenital sars-
cov-2 infection in a neonate born to a woman with active sars-cov-2
infection. Cmaj. 2020; 192: E647-650.
26. Chen S, Huang B, Luo DJ, Li X, Yang F, Zhao Y, et al. Pregnant women
with new coronavirus infection: a clinical characteristics and placental
pathological analysis of three cases. Zhonghua Bing Li Xue Za Zhi =
Chinese J Pathol. 2020; 49: E005.
27. Liu Y, Chen H, Tang K, Guo Y. Clinical manifestations and outcome of
SARS-CoV-2 infection during pregnancy. J Infect. 2020.
28. Zhu H, Wang L, Fang C, Peng S, Zhang L, Chang G, et al. Clinical analysis
of 10 neonates born to mothers with 2019-nCoV pneumonia. Transl
Pediatr. 2020; 1: 51-60.
29. Hosier H, Farhadian SF, Morotti RA, Deshmukh U, Lu-Culligan A,
Campbell KH, et al. SARS-CoV-2 infection of the placenta. J Clin Invest.
2020; 130: 4947-4953.
30. Patanè L, Morotti D, Giunta MR, Sigismondi C, Piccoli MG, Frigerio
L, et al. Vertical transmission of coronavirus disease 2019: severe
acute respiratory syndrome coronavirus 2 RNA on the fetal side of
the placenta in pregnancies with coronavirus disease 2019-positive
mothers and neonates at birth. Am J Obstet Gynecol. MFM 2020; 2:
100145.
31. Shanes ED, Mithal LB, Otero S, Azad HA, Miller ES, Goldstein JA.
Placental Pathology in COVID-19. Am J Clin Pathol. 2020; 154: 23-32.
32. Baergen RN, Heller DS. Placental Pathology in Covid-19 Positive
Mothers: Preliminary Findings. Pediatr Dev Pathol. 2020; 23: 177-
180.
33. Mulvey JJ, Magro CM, Ma LX, Nuovo GJ, Baergen RN. Analysis of
complement deposition and viral RNA in placentas of COVID-19
patients. Ann Diagn Pathol. 2020; 46: 151530.
34. Mongula JE, Frenken MWE, van Lijnschoten G, Arents NLA, de Wit-
Zuurendonk LD, Schimmel-de Kok APA, et al. COVID-19 during
pregnancy: non-reassuring fetal heart rate, placental pathology and
coagulopathy. Ultrasound Obstet Gynecol. 2020; 56: 773-776.
35. Patberg E, Adams T, Rekawek P, Vahanian S, Akerman M. Coronavirus
disease infection and placental histopathology in women delivering at
term. Am J Obstet Gynecol. 2020: n1-36.
Central
Oltean I, et al. (2022)
Med J Obstet Gynecol 10(1): 1155 (2022) 11/12
36. He M, Skaria P, Kreutz K, Chen L, Hagemann IS, Carter EB, et al.
Histopathology of Third Trimester Placenta from SARS-CoV-2-
Positive Women. Fetal Pediatr Pathol. 2020; 12: 1-10.
37. Gulersen M, Prasannan L, Tam Tam H, Metz CN, Rochelson B, Meirowitz
N, et al. Histopathologic evaluation of placentas after diagnosis of
maternal severe acute respiratory syndrome coronavirus 2 infection.
Am J Obstet Gynecol MFM. 2020; 2: 100211.
38. Higgins J, Thomas J, Chandler J, Cumpston M, Li T, Page M, et al.
Cochrane Handbook for Systematic Reviews of Interventions version
6.2 (updated February 2021). 2019.
39. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow
CD, et al. The PRISMA 2020 statement: an updated guideline for
reporting systematic reviews. Syst Rev. 2021; 10: 1-10.
40. Bramer WM, de Jonge GB, Rethlefsen ML, Mast F, Kleijnen J. A
 
to develop literature searches. J Med Libr Assoc. 2018; 106: 531-541.
41. Harris PA, Taylor R, Minor BL, Elliott V, Fernandez M, O’Neal L, et al.
The REDCap consortium: Building an international community of
software platform partners. J Biomed Inform. 2019; 95: 103208.
42. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research
electronic data capture (REDCap)-A metadata-driven methodology

support. J Biomed Inform. 2009; 42: 377-381.
43. Pinar H, Sung CJ, Oyer CE, Singer DB. Reference values for singleton
and twin placental weights. Pediatr Pathol Lab Med. 1996; 16: 901-
907.
44. Khong TY, Mooney EE, Ariel I, Balmus NCM, Boyd TK, Brundler MA, et

workshop group consensus statement. Arch Pathol Lab Med. 2016;
140: 698-713.
45. Wells G, Shea B, O’Connell D, Peterson J. The Newcastle-Ottawa Scale
(NOS) for assessing the quality of nonrandomised studies in meta-
analyses. Ottawa, Ottawa Hosp Res Inst. 2000: 2020.
46. Stang A. Critical evaluation of the Newcastle-Ottawa scale for the
assessment of the quality of nonrandomized studies in meta-analyses.
Eur J Epidemiol 2010; 25: 603-605.
47. R Core Team. A language and environment for statistical computing.
2018.
48. Menter T, Mertz KD, Jiang S, Chen H, Monod C, Tzankov A, et al.
Placental Pathology Findings during and after SARS-CoV-2 Infection:
Features of Villitis and Malperfusion. Pathobiology. 2020: 1-9.
49. Richtmann R, Torloni MR, Oyamada Otani AR, Levi JE, Crema Tobara
M, de Almeida Silva C, et al. Fetal deaths in pregnancies with SARS-
CoV-2 infection in Brazil: A case series. Case Reports Women’s Heal.
2020; 27: 2-6.
50. Prabhu M, Cagino K, Matthews KC, Friedlander RL, Glynn SM, Kubiak
JM, et al. Pregnancy and postpartum outcomes in a universally tested
population for SARS-CoV-2 in New York City: a prospective cohort
study. BJOG An Int J Obstet Gynaecol. 2020; 127: 1548-1556.
51. Facchetti F, Bugatti M, Drera E, Tripodo C, Sartori E, Cancila V, et
al. SARS-CoV2 vertical transmission with adverse effects on the
newborn revealed through integrated immunohistochemical, electron
microscopy and molecular analyses of Placenta. EBioMedicine. 2020;
59: 102951.
52.            
Detection of severe acute respiratory syndrome coronavirus 2 in
placentas with pathology and vertical transmission. Am J Obstet
Gynecol MFM. 2020; 2: 100197.
53. Cribiù FM, Croci GA, Del Gobbo A, Rizzuti T, Iurlaro E, Tondo M, et
al. Histological characterization of placenta in COVID19 pregnant
women. Eur J Obstet Gynecol Reprod Biol. 2020; 252: 619-621.
54. Hecht JL, Quade B, Deshpande V, Mino-Kenudson M, Ting DT, Desai
N, et al. SARS-CoV-2 can infect the placenta and is not associated
    
COVID-19-positive mothers. Mod Pathol. 2020: 2092-2103.
55. Smithgall MC, Liu-Jarin X, Hamele-Bena D, Cimic A, Mourad M,
Debelenko L, et al. Third-trimester placentas of severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2)-positive women:
histomorphology, including viral immunohistochemistry and in-situ
hybridization. Histopathology. 2020; 77: 994-999.
56. Schwartz D, Baldewijns M, Benachi A, Bugatti M, Collins R, De Luca
D, et al. Chronic Histiocytic Intervillositis with Trophoblast Necrosis
are Risk Factors Associated with Placental Infection from Coronavirus
Disease 2019 (COVID-19) and Intrauterine Maternal-Fetal Severe
Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Transm.
Arch Pathol Lab Med. 2021; 145: 517-528.
57. Zhou P, Yang X, Wang X, Hu B, Zhang L, Zhang W, et al. Discovery of a
novel coronavirus associated with the recent pneumonia outbreak in
2 humans and its potential bat origin. Nature 2020; 579.
58. Sharps MC, Hayes DJL, Lee S, Zou Z, Brady CA, Almoghrabi Y, et al.
A structured review of placental morphology and histopathological
lesions associated with SARS-CoV-2 infection. Placenta. 2020; 101:
13-29.
59. Peiris S, Mesa H, Aysola A, Manivel J, Toledo J, Borges-Sa M, et al.

A systematic review. PLoS One. 2021; 16: 1-18.
60. Polak SB, Van Gool IC, Cohen D, von der Thüsen JH, van Paassen
         
pathophysiological timeline and possible mechanisms of disease
progression. Mod Pathol. 2020; 33: 2128-2138.
61. AbdelMassih A, Fouda R, Essam R, Negm A, Khalil D, Habib D, et al.
COVID-19 during pregnancy should we really worry from vertical

A systematic review. Egypt Pediatr Assoc Gaz. 2021; 69.
62. Schwartz D, Baldewijns M, Benachi A, Bugatti M, Collins R. Chronic
Histiocytic Intervillositis with Trophoblast Necrosis are Risk Factors
Associated with Placental Infection from Coronavirus Disease 2019
(COVID-19) and Intrauterine Maternal-Fetal Severe Acute Respiratory
Syndrome Coronavirus 2 (SARS-CoV-2) Transm. Arch Pathol Lab Med.
2021: 0-36.
63. Schwartz DA, Bugatti M, Santoro A, Facchetti F. Molecular pathology
demonstration of sars-cov-2 in cytotrophoblast from placental tissue
with chronic histiocytic intervillositis, trophoblast necrosis and
covid-19. J Dev Biol. 2021; 9.
64. Lesieur E, Torrents J, Fina F, Zandotti C, Blanc J, Collardeau-Frachon S.
Congenital infection of SARS-CoV-2 with intrauterine foetal death: a
clinicopathological study with molecular analysis. Infect Dis (Auckl).
2021.
65. Libbrecht S, Van Cleemput J, Vandekerckhove L, Colman S, Padalko
E, Verhasselt B, et al. A rare but devastating cause of twin loss in a
near-term pregnancy highlighting the features of severe SARS-CoV-2
placentitis. Histopathology. 2021; 79: 674-676.
66. Roberts J, Cheng JD, Moore E, Ransom C, Ma M, Rogers BB. Extensive
Perivillous Fibrin and Intervillous Histiocytosis in a SARS-CoV-2
Infected Placenta From an Uninfected Newborn: A Case Report
   
2-5.
Central
Oltean I, et al. (2022)
Med J Obstet Gynecol 10(1): 1155 (2022) 12/12
67. Schwartz DA, Morotti D. Placental pathology of covid-19 with and
without fetal and neonatal infection: Trophoblast necrosis and
chronic histiocytic intervillositis as risk factors for transplacental
transmission of sars-cov-2. Viruses. 2020; 12.
68. Bouachba A, Allias F, Nadaud B, Massardier J, Mekki Y, Bouscambert
Duchamp M, et al. Placental lesions and SARS-Cov-2 infection: Diffuse
placenta damage associated to poor fetal outcome. Placenta. 2021;
112: 97-104.
69. Bustamante Helfrich B, Chilukuri N, He H, Cerda SR, Hong X, Wang G,
et al. Maternal vascular malperfusion of the placental bed associated
with hypertensive disorders in the Boston Birth Cohort. Placenta.
2017; 52: 106-13.
70. Weiner E, Feldstein O, Tamayev L, Grinstein E, Barber E, Bar J, et
al. Placental histopathological lesions in correlation with neonatal
outcome in preeclampsia with and without severe features. Pregnancy
Hypertens. 2018; 12: 6-10.
71. Pathak S, Sebire NJ, Hook L, Hackett G, Murdoch E, Jessop F, et al.

in an unselected population near term. Virchows Arch. 2011; 459: 11-
20.
72. Becroft DMO, Thompson J, Mitchell EA. Placental Infarcts, Intervillous
Fibrin Plaques, and Intervillous Thrombi: Incidences, Cooccurrences,
and Epidemiological Associations. Pediatr Dev Pathol. 2004; 7: 26-34.
73. Klok FA, Kruip MJHA, van der Meer NJM, Arbous MS, Gommers DAMPJ,
Kant KM, et al. Incidence of thrombotic complications in critically ill
ICU patients with COVID-19. Thromb Res. 2020; 191: 145-147.
74. Helms J, Tacquard C, Severac F, Leonard-Lorant I, Ohana M,
Delabranche X, et al. High risk of thrombosis in patients with severe
SARS-CoV-2 infection: a multicenter prospective cohort study.
Intensive Care Med. 2020; 46: 1089-1098.
75. Cui S, Chen S, Li X, Liu S, Wang F. Prevalence of venous thromboembolism
in patients with severe novel coronavirus pneumonia. J Thromb
Haemost. 2020; 18: 1421-1424.
76. Labò N, Ohnuki H, Tosato G. Vasculopathy and Coagulopathy
Associated with SARS-CoV-2 Infection. Cells. 2020; 9: 1-30.
77. Zhang J, Tecson KM, McCullough PA. Endothelial dysfunction
     
coagulopathy. Rev Cardiovasc Med. 2020; 21: 315-319.
78. Gómez-Mesa JE, Galindo-Coral S, Montes MC, Muñoz Martin AJ.
Thrombosis and Coagulopathy in COVID-19. Curr Probl Cardiol. 2021;
46.
79. Garcia A, Fonesca E, Marques R. Placental morphology in
cytomegalovirus infection. Placenta. 1989; 10: 1-18.
80. Freedman AA, Goldstein JA, Miller GE, Borders A, Keenan-Devlin L,
Ernst LM. Seasonal Variation of Chronic Villitis of Unknown Etiology.
Pediatr Dev Pathol. 2020; 23: 253-259.
81. Meijer WJ, Wensing AMJ, Bruinse HW, Nikkels PGJ. High rate of chronic
     
infection. Infect Dis Obstet Gynecol. 2014; 2014.
82. Allotey J, Stallings E, Bonet M, Yap M, Chatterjee S, Kew T, et al. Clinical
manifestations, risk factors, and maternal and perinatal outcomes of
coronavirus disease 2019 in pregnancy: Living systematic review and
meta-analysis. BMJ. 2020; 370.
83. 
RRJ, et al. Pregnancy Outcomes Among Women With and Without
Severe Acute Respiratory Syndrome Coronavirus 2 Infection. JAMA
Netw Open. 2020; 3: e2029256.
84.            
C. Correlation between placental bacterial culture results and
histological chorioamnionitis: A prospective study on 376 placentas.
J Clin Pathol. 2013; 66: 243-248.
85. Romero R, Kusanovic JP, Chaiworapongsa T, Hassan SS. Placental bed
disorders in preterm labor, preterm PROM, spontaneous abortion and
abruptio placentae. Best Pract Res Clin Obstet Gynaecol. 2011; 25:
313-327.
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A subset of placentas from pregnant women having the SARS-CoV-2 infection have been found to be infected with the coronavirus using molecular pathology methods including immunohistochemistry and RNA in situ hybridization. These infected placentas can demonstrate several unusual findings which occur together—chronic histiocytic intervillositis, trophoblast necrosis and positive staining of the syncytiotrophoblast for SARS-CoV-2. They frequently also have increased fibrin deposition, which can be massive in some cases. Syncytiotrophoblast is the most frequent fetal-derived cell type to be positive for SARS-CoV-2. It has recently been shown that in a small number of infected placentas, villous stromal macrophages, termed Hofbauer cells, and villous capillary endothelial cells can also stain positive for SARS-CoV-2. This report describes a placenta from a pregnant woman with SARS-CoV-2 that had chronic histiocytic intervillositis, trophoblast necrosis, increased fibrin deposition and positive staining of the syncytiotrophoblast for SARS-CoV-2. In addition, molecular pathology testing including RNAscope and immunohistochemistry for SARS-CoV-2 and double-staining immunohistochemistry using antibodies to E-cadherin and GATA3 revealed that cytotrophoblast cells stained intensely for SARS-CoV-2. All of the cytotrophoblast cells that demonstrated positive staining for SARS-CoV-2 were in direct physical contact with overlying syncytiotrophoblast that also stained positive for the virus. The pattern of cytotrophoblast staining for SARS-CoV-2 was patchy, and there were chorionic villi having diffuse positive staining of the syncytiotrophoblast for SARS-CoV-2, but without staining of cytotrophoblast. This first detailed description of cytotrophoblast involvement by SARS-CoV-2 adds another fetal cell type from infected placentas that demonstrate viral staining.
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Pregnancy is a unique immunological condition in which an “immune-diplomatic” dialogue between trophoblasts and maternal immune cells is established to protect the fetus from rejection, to create a privileged environment in the uterus and to simultaneously be alert to any infectious challenge. The maternal-placental-fetal interface (MPFI) performs an essential role in this immunological defense. In this review, we will address the MPFI as an active immuno-mechanical barrier that protects against viral infections. We will describe the main viral infections affecting the placenta and trophoblasts and present their structure, mechanisms of immunocompetence and defensive responses to viral infections in pregnancy. In particular, we will analyze infection routes in the placenta and trophoblasts and the maternal-fetal outcomes in both. Finally, we will focus on the cellular targets of the antiviral microRNAs from the C19MC cluster, and their effects at both the intra- and extracellular level.
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Coronavirus disease 2019 (COVID-19) pneumonia rarely occur in pregnant women. Case reports indicate that fibrin and lymphohistiocytic lesions in placentas may be typical. However, a meta-analysis to clarify whether there is a COVID-19-associated pattern of placental lesions has not yet been conducted. Systematic literature search with meta-analysis of publications on 10 or more cases of pregnancy with SARS-CoV-2 infection and placenta examination (30 publications from 2019-2021; 1452 placenta cases). The meta-analysis did not reveal any COVID-19-specific placenta changes. The incidence of both vascular and inflammatory lesions was mainly comparable to that of non-COVID-19 pregnancies. Transplacental viral transmission is very rare and there are no typical placental changes. The most important prognostic factor seems to be maternal-fetal hypoxia in the context of pneumonia.
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Introduction Pregnant women with covid-19 are more likely to experience preterm birth. The virus seems to be associated with a wide range of placental lesions, none of them specific. Method We collected cases of Covid-19 maternal infection during pregnancy associated with poor pregnancy outcomes, for which we received the placenta. We studied clinical data and described pathological findings of placenta and post-mortem examination of fetuses. We performed an immunohistochemical study and RT-PCR of SARS-Cov-2 on placenta samples. Results We report 5 cases of poor fetal outcome, 3 fetal deaths and 2 extreme premature neonates, one with growth restriction, without clinical and biological sign of SARS-Cov-2 infection. All placenta presented massive perivillous fibrin deposition and large intervillous thrombi associated with strong SARS-Cov-2 expression in trophoblast and SARS-CoV-2 PCR positivity in amniotic fluid or on placenta samples. Chronic histiocytic intervillositis was present in 4/5 cases. Placental ultrasound was abnormal and the sFLT1-PIGF ratio was increased in one case. Timing between mothers’ infection and the poor fetal outcome was ≤10 days in 4 cases. The massive placental damage are directly induced by the virus whose receptors are expressed on trophoblast, leading to trophoblast necrosis and massive inflammation in villous chamber, in a similar way it occurs in diffuse alveolar damage in adults infected by SARS-Cov-2. Discussion SARS-Cov-2 can be associated to a rare set of placental lesions which can lead to fetal demise, preterm birth, or growth restriction. Stronger surveillance of mothers infected by SARS-Cov-2 is required.