Elisheva D Shanes1, Emily S Miller2, Sebastian Otero3, Rebecca Ebbott4, Raveena Aggarwal4, Antonia S Willnow3, Egon A Ozer5, Leena B Mithal3, Jeffery A Goldstein1. 1. Department of Pathology, 12244Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. 2. Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, 12244Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. 3. Department of Pediatrics, 12244Northwestern University Feinberg School of Medicine and Department of Infectious Diseases, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA. 4. 12244Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. 5. Department of Internal Medicine, Section of Infectious Disease, 12244Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Abstract
Objectives.The goal of this study is to describe placental pathology after infection with SARS-CoV-2 before the predominance of variants of concern (pre-VOC) and during eras of predominant transmission of the Alpha & Gamma (co-circulating), Delta, and Omicron variants. Methods. We used county-level variant data to establish population-level variant proportions, SARS-CoV-2 PCR to identify cases, and IgG serology to exclude latent infections from controls and histopathologic examination to identify placental pathology. Results. We report findings in 870 placentas from pregnancies complicated by SARS-CoV-2 including 90 with infection in the Alpha/Gamma era, 60 from the Delta era and 56 from the Omicron era. Features of maternal vascular malperfusion (MVM), including decidual arteriopathy, were significantly more frequent after SARS-CoV-2 infection. The risk of these findings varied over time, with the highest rates in the Delta era. Increased COVID-19 severity and the presence of comorbidities strengthened these associations. Conclusion. MVM is a feature of SARS-CoV-2 infection in pregnancy. Lesion frequency changed with the predominant circulating virus and should be considered with new variants.
Objectives.The goal of this study is to describe placental pathology after infection with SARS-CoV-2 before the predominance of variants of concern (pre-VOC) and during eras of predominant transmission of the Alpha & Gamma (co-circulating), Delta, and Omicron variants. Methods. We used county-level variant data to establish population-level variant proportions, SARS-CoV-2 PCR to identify cases, and IgG serology to exclude latent infections from controls and histopathologic examination to identify placental pathology. Results. We report findings in 870 placentas from pregnancies complicated by SARS-CoV-2 including 90 with infection in the Alpha/Gamma era, 60 from the Delta era and 56 from the Omicron era. Features of maternal vascular malperfusion (MVM), including decidual arteriopathy, were significantly more frequent after SARS-CoV-2 infection. The risk of these findings varied over time, with the highest rates in the Delta era. Increased COVID-19 severity and the presence of comorbidities strengthened these associations. Conclusion. MVM is a feature of SARS-CoV-2 infection in pregnancy. Lesion frequency changed with the predominant circulating virus and should be considered with new variants.
Pregnant patients with SARS-CoV-2 infection have a higher risk of hospitalization,
severe disease, and death compared to similarly-aged non-pregnant women with
SARS-CoV-2.[1] SARS-CoV-2 infection is also associated with adverse pregnancy
outcomes, including a possible increased risk of preterm birth and, rarely, vertical
transmission or stillbirth.[2-8] In utero exposures to infection
may have life-long consequences. Rates of adverse outcomes, including stillbirth,
have increased with variants of concern (variants), including the Delta
variant.[8]The placenta is the physiologic interface between maternal and fetal circulation and
is responsible for providing a fetus with resources needed for growth and
development. As such, it is also in many ways the “black box “of pregnancy –
maternal and fetal conditions that impact growth and maturation often leave marks on
the placenta which can be diagnosed on pathologic examination after birth. For
example, maternal hypertensive disorders, including preeclampsia, are associated
with the pathologic finding of maternal vascular malperfusion (MVM) in the
placenta.Pathologic examination of placentas from women with SARS-CoV-2 infection during
pregnancy may provide insight into the intrauterine stresses experienced by their
fetuses. The first studies of placentas from women infected with SARS-CoV-2
suggested an increased incidence of fetal vascular malperfusion (FVM), sequelae of
perturbations of fetal circulation through the placenta, or decidual arteriopathy,
damage to maternal decidual vessels.[9,10] Subsequent studies have
varied from case reports or small case series to larger studies of around 100
placentas.[11] While some studies re-demonstrated FVM[12] or
MVM,[11] others have not demonstrated any significant placental findings
in women with SARS-CoV-2 infection.[13] A meta-analysis conducted in
the summer of 2021 reported findings suggestive of placental hypoperfusion and
inflammation in pregnancies complicated by SARS-CoV-2 infection,[14] while a more
recent meta-analysis suggested that there are no typical placental
findings.[15] However, the majority of these studies have looked at broad
categories of placental pathology, ie MVM or FVM, rather than at a more granular
level, eg components of MVM such as decidual arteriopathy or accelerated villous
maturation independently, and most of these studies do not include control groups of
placentas without SARS-CoV-2 infection. Additionally, published studies generally do
not relate diagnosis frequency to strain or timing within the pandemic.
Heterogeneity across viral strains, when analyzed collectively as opposed to
sequentially, may mask clinically relevant findings.We have now collected placentas from SARS-CoV-2 positive pregnant women for nearly
two years, including during the waves of the Alpha/Gamma, Delta, and Omicron
variants. Given the heterogeneity in prior results that may be informed by sample
selection and variant prevalence, our objective was to provide a large,
comprehensive, and well controlled study of the impact of SARS-CoV-2 infection in
pregnancy on the placenta and to examine the impact of COVID-19 disease severity and
presence of comorbidities.
Methods
Patients were included if they delivered between March 18, 2020 and February 14,
2022. Prior to April 30, 2021, we collected specimens on all patients with
SARS-CoV-2 delivering at our institution, an academic medical center in a large
urban area. Afterward, we transitioned to purposeful recruitment of patients with
first or second trimester infection, moderate to critical COVID-19, or infection
during a period with high prevalence of variants. Routine testing for SARS-CoV-2 was
performed for all admissions to Labor & Delivery during the entire study
period.Placental examination was performed using the Amsterdam Criteria.[16] Individual
features of MVM and FVM are reported, as is the frequency of identifying any MFM
feature or any FVM features. Accelerated and delayed villous maturation were
diagnosed clinically on the basis of villous maturation different from that expected
by gestational age in the areas of villous diameter, abundance of syncytial knots,
stromal cellularity, stromal density, and position of capillaries. For statistical
purposes, we grouped cases where the diagnosis was qualified as “mild”, “patchy”,
“regional” or otherwise into the parent diagnosis. Decidual arteriopathy is a parent
category diagnosed when mural hypertrophy of membrane arterioles, persistent
muscularization of basal plate arterioles (which we consider equivalent to
incomplete remodeling of spiral arterioles), atherosis or fibrinoid necrosis are
present. Formal diagnoses of MVM or FVM are reported separately. Individual practice
varies, but members of our section generally render a formal diagnosis when multiple
features of MVM or FVM are present; for example, MVM is diagnosed when accelerated
villous maturation, decidual arteriopathy, and infarct are all present. Less often,
a formal diagnosis is made or suggested when a single feature is extremely
prominent, such as a macroscopic focus of avascular villi for FVM.Histologic slides were imaged on a Leica GT450 scanner at 40 × objective
magnification.Clinical information was abstracted from the electronic health record and stored in a
REDCap database.[17] Comorbidity data were abstracted from the electronic health
record using the following ICD9/10 codes. Obesity: 278, E66, O99.21*; Diabetes: 250,
648.0*, E08, E10, E11, O24; Hypertension: 642, 401, I10, O10-15; where * includes
any sub-codes. Pre-pregnancy body mass index was not available for most patients;
therefore we were reliant on formal diagnosis of obesity.The trimester of SARS-CoV-2 infection was determined using the gestational age of
diagnosis of COVID-19. COVID-19 disease severity was determined using CDC
criteria.[18]Controls were patients without history of vaccination, no history of SARS-CoV-2
infection in pregnancy, and negative SARS-CoV-2 PCRs during routine admission
testing. To rule out prior asymptomatic infection we tested for anti-SARS-CoV-2
spike protein IgG and IgM levels similar to that previously described.[19] Positive
immunity, defined as signal/cutoff > 1.0 AU/ml, was identified in 21 of 206
patients tested (10.3%). Those patients were excluded as infection could have been
during or prior to the current pregnancy, complicating interpretation of their
biospecimen.To characterize proportions of SARS-CoV-2 clades circulating in our patient catchment
area, lineage data was downloaded from the GISAID public sequence database for all
isolates collected between Jan 1, 2021 and April 1, 2022 and identified as having
been isolated from either [our city] or [our county]. Isolates were identified as
Alpha if they belonged to pango lineage B.1.1.7 or any Q sublineages (ie Q.1, etc),
Gamma if they belonged to lineage P.1 or any sublineages (ie P.1.1, etc), Delta if
they belonged to lineage B.1.647.2 or any sublineages (ie AY.1, etc) and Omicron if
they belonged to lineage B.1.1.529 or any sublineages (ie BA.1, etc). Of note, our
institution is the major contributor to GISAID for our geographic locale, so these
data should represent our patient population. The Pre-VOC, Alpha/Gamma, Delta, and
Omicron eras were delineated based on the most frequent variant and shifted to the
nearest week. Era boundaries were set by an investigator that was unaware of the
placental diagnoses. Of note, some SARS-CoV-2 diagnoses in our population were
self-reported without a specific date, therefore not all cases can be definitively
assigned to an era. They are excluded from era-specific analyses.For descriptive values, quantitative values are reported as mean + /- standard
deviation. Categorical variables are reported as counts and percentages. Bivariable
analyses utilized Student's t-test for continuous variables or Fisher exact test
comparing SARS-CoV-2 or subgroups against the controls only. We used Benjamini and
Hochberg's method to control for multiple comparisons, with corrected P-value based
on the number of placental lesions tested for each population with a false discovery
rate of 0.05. The study was approved by the institutional review board as
STU00212232. Multivariable analyses were performed controlling for birthing person
characteristics that significantly differed in bivariable analyses
(p < 0.05).
Results
Defining Population Level Variant of Concern Eras
The Alpha and Gamma variants of SARS-CoV-2 were first identified in our
population in the second week of February 2021. These variants rose together in
frequency through the week of June 6, 2021 (Figure 1). Delta first appeared the week
of April 25 but became dominant in the week of June 27, 2021. Omicron became
predominant in the week of December 19, 2021. Based on these estimates, we
categorized patients based on the date of their first positive swab as: Pre-VOC:
3/2020–2/2021, Alpha/Gamma: 3/2021–6/2021, Delta: 7/2021–12/18/2021, Omicron:
12/19/2021 – present.
Figure 1.
SARS-CoV-2 variant frequency over time. Alpha and Gamma variants emerge
together and become dominant March 2021 – June 2021. Delta appears in
April but represents almost all infections by the week of June 27, 2021.
Omicron becomes dominant December 19, 2021. Numbers above the graph
indicate the number of patients sampled that week.
SARS-CoV-2 variant frequency over time. Alpha and Gamma variants emerge
together and become dominant March 2021 – June 2021. Delta appears in
April but represents almost all infections by the week of June 27, 2021.
Omicron becomes dominant December 19, 2021. Numbers above the graph
indicate the number of patients sampled that week.
Patient Demographics and Infection Details
There were 185 controls and 883 patients with SARS-CoV-2 infection. Of those with
SARS-CoV-2 infection, 673 were in the pre-variant of concern era, 90 in the
Alpha/Gamma era, 60 in the Delta era, and 56 in the Omicron era. Characteristics
of the sample are depicted in Table 1. Patients with SARS-CoV-2
infection were, on average, slightly younger than controls and less likely to be
multiparous. The utilization of public insurance differed strikingly between
populations:more individuals with SARS-CoV-2 infection utilized public insurance
compared to controls. Comorbidity rates were broadly similar, however patients
in the Omicron era were more likely to be diagnosed as obese. Individuals with
SARS-CoV-2 delivered at earlier gestational ages and were more likely to deliver
preterm compared to controls. The incidence of cesarean section was similar
between groups. SARS-CoV-2 disease severity was similar between different eras,
though Omicron cases were more likely to be symptomatic. Omicron era patients
had a preponderance of third trimester infection, possibly reflecting study
timing.
SARS-CoV-2 Infection is Associated with Maternal Vascular Malperfusion and
Decidual Arteriopathy
We tested the association of SARS-CoV-2 infection with different placental
lesions and categories of lesions. The strongest association was with the
presence of any feature of maternal vascular malperfusion (MVM), which was
identified in 87 of 185 controls (47%), as compared to 555 of 883 patients with
SARS-CoV-2 infection (63%, OR 1.9, p < .001, Figure 2, Table 2, Supplementary Table 1). MVM describes a constellation of
findings associated with hypertensive disorders of pregnancy, fetal growth
restriction, preterm delivery, and stillbirth. Among the major findings in MVM,
decidual arteriopathy (DA) was identified in 23 of 185 controls (12%) as
compared to 227 of 883 patients with SARS-CoV-2 (26%, OR 2.4, p < .001).
Decidual arteriopathy includes a group of lesions associated with failure of
uterine blood vessels to adapt to pregnancy and resulting injury to those
vessels. Among the decidual arteriopathies, the signal is driven by incomplete
remodeling of basal plate arterioles (OR 3.8, p < .001). We previously
reported an association between infection and atherosis with fibrinoid necrosis,
a particularly severe lesion, however the association is not statistically
significant in this cohort (p = 0.23). Other features of MVM, such as
accelerated villous maturation were also elevated, as was a formal “topline”
diagnosis of MVM (Table 2, Supplementary Table 1).
Figure 2.
Histology. Representative H&E images of placental diagnoses. Mural
hypertrophy of membrane arterioles (A). Persistent muscularization of
basal plate arterioles (B). Accelerated villous maturation at 37 weeks
gestation, characterized by lower villous diameter, increased stromal
density and syncytial knots (C). versus Delayed villous maturation at 39
weeks gestation characterized by larger villous diameter, looser stroma,
increased vascularity, and fewer syncytial knots (D). Objective
magnification 10x, scale bar 300 µm.
Table 2.
Lesions Associated with SARS-CoV-2 and Variant Infection.
Controls (n = 185)
SARS-CoV-2 (n = 883)
Pre-VOC (n = 673)
Alpha / Gamma (n = 90)
Delta (n = 56)
Omicron (n = 40)
MVM
Accelerated villous maturation
10(5.4)
106(12)**
80(12)**
11(12)
10(17)*
4(7.1)
Decidual arteriopathy
23(12)
227(26)***
175(26)***
14(16)
18(30)**
18(32)**
Atherosis and fibrinoid necrosis
1(0.5)
19(2)
14(2)
1(0.5)
2(3.4)
2(5)
Mural hypertrophy of membrane arterioles
17(9)
168(17)**
114(17)**
9(10)
10(17)
17(27)**
Persistent muscularization of basal plate arterioles
5(2.7)
84(9.5)**
71(11)***
8(9)*
3(5)
2(3.6)
Formal diagnosis of MVM
3(1.6)
55(6)*
37(5.5)*
5(5.6)
6(10)**
6(11)**
Any MVM feature
87(47)
555(63)***
413(61)***
59(65)**
49(82)***
31(55)
FVM
Clustered avascular villi
33(18)
155(18)
127(19)
11(12)
11(18)
5(8.9)
Villous stromal vascular karyorrhexis
12(6.5)
77(8.7)
57(8.5)
10(11)
4(6.7)
5(8.9)
Fetal vascular thrombosis or intramural fibrin
deposition
21(11)
128(14)
88(13)
13(14)
13(22)
14(25)*
Stem villous obliteration
14(7.6)
40(7.6)
34(5)
2(2.2)
2(3.3)
2(3.5)
Delayed villous maturation
38(21)
129(15)
109(16)
10(11)
5(8.3)*
4(7.1)*
Abnormal umbilical cord (hypercoiled etc)
23(12)
168(19)*
124(18)
14(16)
11(18)
18(32)*
Formal diagnosis of FVM
12(6.5)
52(5.9)
33(4.9)
6(6.7)
6(10)
6(11)
Any FVM feature
80(43)
455(52)
346(51)
43(48)
32(53)
31(55)
Values are frequency(%). FVM: Fetal vascular malperfusion; MVM:
Maternal vascular malperfusion. *: uncorrected p < 0.05, **:
p < 0.01; ***: p < 0.001.
Histology. Representative H&E images of placental diagnoses. Mural
hypertrophy of membrane arterioles (A). Persistent muscularization of
basal plate arterioles (B). Accelerated villous maturation at 37 weeks
gestation, characterized by lower villous diameter, increased stromal
density and syncytial knots (C). versus Delayed villous maturation at 39
weeks gestation characterized by larger villous diameter, looser stroma,
increased vascularity, and fewer syncytial knots (D). Objective
magnification 10x, scale bar 300 µm.Lesions Associated with SARS-CoV-2 and Variant Infection.Values are frequency(%). FVM: Fetal vascular malperfusion; MVM:
Maternal vascular malperfusion. *: uncorrected p < 0.05, **:
p < 0.01; ***: p < 0.001.Results from multivariable analyses using logistic regression and controlling for
gestational age, insurance type, gravidity, and parity were similar to the
bivariable analyses (Supplementary Table 1).
Associations with Variants of Concern
SARS-CoV-2 infection in the Alpha / Gamma and Delta eras was associated with MVM
features (Figure 2,
Table 2,
Supplementary Table 1). MVM feature were seen in 87 of 185
controls (47%), as opposed to 59/90 patients in the Alpha / Gamma era (65%,
p < .001). Infection in the Delta era had an even higher risk with MVM
features seen in 49/56 (82%, p < .001), though Omicron showed a weaker
signal, with MVM features in only 31/40 (55%, p = ns). Delta (18/56, 30%, OR
3.0, p < 0.01) and Omicron (18/40, 32%, OR 3.9, p < 0.01) era infections
were associated with decidual arteriopathy. Delta era infection was associated
with accelerated villous maturation, seen in 10/60 (17%, OR 3.5, p < 0.05).
Finally, Delta and Omicron era infections were associated with a formal
diagnoses of MVM (10% and 11%, OR 6.7 and 7.3, p < 0.01 and <0.01,
respectively). Associations of Delta and Omicron era infection with decidual
arteriopathy and formal diagnosis of MVM and between Delta era infection and MVM
features and accelerated maturation survived correction for multiple comparison
testing (Supplementary Table 2). Placental weights were slightly lower in
the Delta era.FVM and features of FVM have frequently been reported in association with
SARS-CoV-2. Among FVM features, delayed villous maturation was observed in 38
controls (21%), as compared to 129 SARS-CoV-2 cases (15%, p = ns) and 109
pre-VOC cases (18%, p = ns). Delayed villous maturation was less frequent in the
Delta era with 5 cases (8.3%, OR = 0.35, p < 0.05) and the Omicron era with 4
cases (7.1%, OR 0.29, p < 0.05). Other FVM features did not significantly
differ with infection (Table 2). A formal diagnosis of FVM was made in 12 controls (6.5%)
as opposed to 52 SARS-CoV-2 cases (5.9%, p = ns), 33 pre-VOC cases (4.9%,
p = ns), 6 Alpha / Gamma era cases (6.7%, p = ns), 6 Delta cases (10%, p = ns)
and 6 Omicron cases (11%, p = ns). Any feature of FVM was identified in 80
controls (43%), 455 SARS-CoV-2 cases (52%), 346 pre-VOC cases (51%), 43 Alpha /
Gamma era cases (48%), 32 Delta cases (53%), and 31 Omicron cases (55%).
Association with Severity
We tested the association of COVID-19 severity with placental lesions (Figure 3, Supplementary Table 1). Any MVM feature was present in 87/185
controls (47%) as compared to 142/245 patients with asymptomatic SARS-CoV-2
(58%, OR 1.6, p < 0.05), 290/449 of those with mild COVID-19 (65%, OR 2.1,
p < 0.001) and 60/92 of those with moderate to severe disease (65%,
p < 0.01). A similar trend was seen for decidual arteriopathy, with decidual
arteriopathy in 23/185 controls (12%), as compared with 72/245 with asymptomatic
SARS-CoV-2 (29%, OR 2.9, p < 0.001), 100/449 with mild COVID-19 (22%, OR 2.0,
p < 0.01), and 33/92 with moderate to severe COVID-19 (36%, OR 3.9,
p < 0.001). Similar trends were seen for the component decidual
arteriopathies and formal diagnosis of MVM. Interestingly, accelerated villous
maturation was sharply and significantly elevated in moderate to severe
COVID-19, seen in 26/92 cases (28%) as compared to 10/185 in controls (5.4%, OR
6.9, p < 0.001)
Figure 3.
SARS-CoV-2 infection is associated with increased risk of MVM findings,
particularly decidual arteriopathy. SARS-CoV-2 infection, or variant of
concern other than Omicron, was associated with the presence of at least
1 MVM feature (A). Accelerated villous maturation was increased in
SARS-CoV-2 and delta. (B). Decidual arteriopathy was associated with
SARS-CoV-2 infection in the pre-VOC era, but the association weakened in
the Alpha / Gamma era. It was stronger in the Delta and Omicron (C).
Delayed villous maturation was decreased (D). after SARS-CoV-2
infection, significantly so in the Delta and Omicron eras. ***:
uncorrected p < 0.001, **: p < 0.01, *:p < 0.05. MVM: maternal
vascular malperfusion; pre-VOC: era prior to any predominant variant of
concern.
SARS-CoV-2 infection is associated with increased risk of MVM findings,
particularly decidual arteriopathy. SARS-CoV-2 infection, or variant of
concern other than Omicron, was associated with the presence of at least
1 MVM feature (A). Accelerated villous maturation was increased in
SARS-CoV-2 and delta. (B). Decidual arteriopathy was associated with
SARS-CoV-2 infection in the pre-VOC era, but the association weakened in
the Alpha / Gamma era. It was stronger in the Delta and Omicron (C).
Delayed villous maturation was decreased (D). after SARS-CoV-2
infection, significantly so in the Delta and Omicron eras. ***:
uncorrected p < 0.001, **: p < 0.01, *:p < 0.05. MVM: maternal
vascular malperfusion; pre-VOC: era prior to any predominant variant of
concern.
Association with Comorbidities
We tested the association of SARS-CoV-2 infection in the presence or absence of
comorbidities, defined here as any diagnosis of hypertension in pregnancy,
diabetes in pregnancy, or diagnosed obesity (Figure 4). Overall, MVM features were
more pronounced with either comorbidities or SARS-CoV-2, and were most
pronounced when both were present, however the relatively small number of
control patients with comorbidities (34) hampered comparisons. Specifically, any
feature of MVM was seen in 69/151 non-comorbid controls and 18/34 comorbid
controls (46% vs. 53%, p = ns), as compared to 414/673 patients with SARS-CoV-2
without comorbidities (62%, OR 1.9, p < 0.01 vs. non-comorbid controls) and
141/210 (67%, OR 2.4, p < 0.001 vs. non-comorbid controls). Accelerated
villous maturation was seen in 6/151 non-comorbid controls (4.0%) as opposed to
4/34 comorbid controls (12%, p = ns), 64/673 non-comorbid SARS-CoV-2 patients
(9.5%, OR 2.5, p < 0.04 vs. non-comorbid controls) and 42/210 comorbid
SARS-CoV-2 patients (20%, OR 6.0 p < 0.001 vs. non-comorbid controls and OR
2.4, p < 0.001 vs. non-comorbid SARS-CoV-2 patients). Decidual arteriopathy
was seen in 15/151 non-comorbid controls (10%) versus 8/34 comorbid controls
(24%, OR 2.8, p = 0.04), 156/673 non-comorbid SARS-CoV-2 patients (23%, OR 2.7,
p < 0.001 vs. non-comorbid controls) and 71/210 comorbid controls (34%, OR
4.6, p < 0.001 vs. non-comorbid controls and OR 1.7 p < 0.01 vs.
non-comorbid SARS-CoV-2). Delayed villous maturation was seen in 34 of 151
non-comorbid controls versus 4/34 comorbid controls (22% vs. 11%, p = ns), 111
of 673 non-comorbid SARS-CoV-2 patients (16.4%, p = ns) and 18/210 comorbid
SARS-CoV-2 patients (8.6%, OR 0.47, p < 0.01).
Figure 4.
Increasing severity of COVID-19 is associated with increased risk of MVM
findings. Asymptomatic SARS-CoV-2 infection was associated with the
presence of at least 1 MVM feature, with increasing risk in mild or
moderate to severe COVID-19 (A). Accelerated villous maturation was
markedly increased after moderate to severe COVID-19 (B). Decidual
arteriopathy was associated with SARS-CoV-2 infection at all severities,
but particularly moderate to severe disease (C). Delayed villous
maturation was non-significantly decreased in all severities of COVID
1-9 (D). ***: uncorrected p < 0.001, **: p < 0.01, *:p < 0.05.
MVM: maternal vascular malperfusion.
Increasing severity of COVID-19 is associated with increased risk of MVM
findings. Asymptomatic SARS-CoV-2 infection was associated with the
presence of at least 1 MVM feature, with increasing risk in mild or
moderate to severe COVID-19 (A). Accelerated villous maturation was
markedly increased after moderate to severe COVID-19 (B). Decidual
arteriopathy was associated with SARS-CoV-2 infection at all severities,
but particularly moderate to severe disease (C). Delayed villous
maturation was non-significantly decreased in all severities of COVID
1-9 (D). ***: uncorrected p < 0.001, **: p < 0.01, *:p < 0.05.
MVM: maternal vascular malperfusion.
Changing Lesion Frequency Over the Course of the Pandemic
We determined the frequency of each lesion among patients diagnosed with
SARS-CoV-2 in a particular month between March 2020 and February 2022 (Figures 5 and 6Supplementary Table 2). MVM features waned slightly toward the
end of the pre-VOC era, before increasing with Alpha / Gamma and markedly
increasing with Delta. Decidual arteriopathy was very frequent in April 2020 but
became steadily less common in patients with SARS-CoV-2 over time, before
increasing again in the Delta and Omicron eras.
Figure 5.
Impact of comorbidities on MVM in the context of SARS-CoV-2 infection. In
a stepwise fashion comorbidities, SARS-CoV-2, and SARS-CoV-2 with
comorbidities are associated with increased risk of any feature of MVM
(A). particularly, accelerated villous maturation (B) and decidual
arteriopathy (C). The risk of abnormally delayed villous maturation is
decreased (D). Groups are compared using chi-squared and post-hoc Fisher
exact tests. a: significantly different from non-comorbid controls; c:
significantly different from non-comorbid SARS-CoV-2. MVM: maternal
vascular malperfusion.
Figure 6.
Frequency of selected diagnoses throughout the pandemic. Features of MVM
(black line) were identified in 60% of patients with symptomatic
SARS-CoV-2 diagnosed in April 2020, but only 29% of patients diagnosed
with SARS-CoV-2 in October 2020. Decidual arteriopathy (blue line) rates
mirrored those of MVM overall. Note there are only 2 patients in
February 2022.
Impact of comorbidities on MVM in the context of SARS-CoV-2 infection. In
a stepwise fashion comorbidities, SARS-CoV-2, and SARS-CoV-2 with
comorbidities are associated with increased risk of any feature of MVM
(A). particularly, accelerated villous maturation (B) and decidual
arteriopathy (C). The risk of abnormally delayed villous maturation is
decreased (D). Groups are compared using chi-squared and post-hoc Fisher
exact tests. a: significantly different from non-comorbid controls; c:
significantly different from non-comorbid SARS-CoV-2. MVM: maternal
vascular malperfusion.Frequency of selected diagnoses throughout the pandemic. Features of MVM
(black line) were identified in 60% of patients with symptomatic
SARS-CoV-2 diagnosed in April 2020, but only 29% of patients diagnosed
with SARS-CoV-2 in October 2020. Decidual arteriopathy (blue line) rates
mirrored those of MVM overall. Note there are only 2 patients in
February 2022.
Discussion
SARS-CoV-2 infection in pregnancy is strongly associated with features of maternal
vascular malperfusion, specifically decidual arteriopathy. This association is more
pronounced in eras of high-circulation of Alpha/Gamma,, Delta, and Omicron variants.
MVM and decidual arteriopathy frequency were also increased with more severe
COVID-19.While the present study includes 50-fold more patients with SARS-CoV-2 than the
earliest studies, it upholds similar conclusions.[10] Decidual arteriopathy was
reported in 7 of 15 patients (47%), representative of the point estimates seen in
our study in April 2020 (see Figure 3). Over the course of the pandemic, the frequency of decidual
arteriopathy has decreased. Our current findings do not support an association of
atherosis and fibrinoid necrosis with SARS-CoV-2 infection.The same effect of random sampling which caused us early studies to over-estimate the
association between SARS-CoV-2 infection and placenta pathologic findings may have
impacted other small studies which failed to identify an association of SARS-CoV-2
with MVM features or DA. Some larger studies may have low baseline rates of MVM
features or DA, making it more difficult for them to detect changes.[20] Interobserver
variability may also drive some disagreement, as agreement for MVM features is
low.[21] Studies using pandemic-era controls have not generally
performed SARS-CoV-2 serology to exclude possible silent infection in pregnancy. Our
findings (see Methods) suggest 10% of such controls could be latent
cases, decreasing study power.MVM represents a constellation of findings that are associated with hypertensive
disorders in pregnancy, including preeclampsia. Decidual arteriopathy represents a
collection of lesions involving failed adaptation of uterine vessels during
pregnancy and is considered causative of preeclampsia. The interaction of SARS-CoV-2
infection, COVID-19 severity, and comorbidities, including hypertension in
pregnancy, diabetes in pregnancy, and pre-pregnancy obesity is complex. More severe
COVID-19 in pregnancy has been associated with comorbidities.[22,23] Conversely,
SARS-CoV-2 infection in pregnancy has been reliably associated with the subsequent
development of pre-eclampsia.[24](p) Our data are
agnostic as to causation, but support that 1) in patients without co-morbidities,
SARS-CoV-2 infection is associated with the presence of MVM features including
decidual arteriopathy and accelerated villous maturation and 2) among patients with
SARS-CoV-2 infection, the presence of comorbidities is associated with increased
rates of decidual arteriopathy and accelerated villous maturation.The changes in lesion frequency over time indicate that placental pathology in
response to SARS-CoV-2 is not fixed, but varies by the demographics of the pandemic,
treatment, and viral strain. SARS-CoV-2 strains also show regional differences in
prevalence over time. Our contemporaneous data allow us to impute the probable viral
strain of a larger dataset, suggesting another possible explanation for the
discordance between our findings and other, geographically disparate studies.
Limitations
This study is subject to several limitations. It is a single center study.
Pathology data are largely from clinical examination, where pathologists were
generally aware of the patient's SARS-CoV-2 infection status. SARS-CoV-2
variants were imputed based on population prevalence, rather than testing of the
actual patient specimens. This is likely to manifest as imperfect boundaries –
for example, patients with infection in July 2021 are extreme outliers in terms
of MVM prevalence, possibly representing a mélange of different variants.
Conclusion
Examination of placental pathology from patients with SARS-CoV-2 infection in
pregnancy showed elevated risk of MVM and DA, particularly with infection in the
eras of the Delta or Omicron variants.Click here for additional data file.Supplemental material, sj-docx-1-ijs-10.1177_10668969221102534 for Placental
Pathology After SARS-CoV-2 Infection in the Pre-Variant of Concern, Alpha /
Gamma, Delta, or Omicron Eras by Elisheva D. Shanes, Emily S. Miller, Sebastian
Otero, Rebecca Ebbott, Raveena Aggarwal, Antonia S. Willnow, Egon A. Ozer, Leena
B. Mithal and Jeffery A. Goldstein in International Journal of Surgical
PathologyClick here for additional data file.Supplemental material, sj-docx-2-ijs-10.1177_10668969221102534 for Placental
Pathology After SARS-CoV-2 Infection in the Pre-Variant of Concern, Alpha /
Gamma, Delta, or Omicron Eras by Elisheva D. Shanes, Emily S. Miller, Sebastian
Otero, Rebecca Ebbott, Raveena Aggarwal, Antonia S. Willnow, Egon A. Ozer, Leena
B. Mithal and Jeffery A. Goldstein in International Journal of Surgical
Pathology
Authors: David A Schwartz; Marcella Baldewijns; Alexandra Benachi; Mattia Bugatti; Rebecca R J Collins; Danièle De Luca; Fabio Facchetti; Rebecca L Linn; Lukas Marcelis; Denise Morotti; Raffaella Morotti; W Tony Parks; Luisa Patanè; Sophie Prevot; Bianca Pulinx; Veena Rajaram; David Strybol; Kristen Thomas; Alexandre J Vivanti Journal: Arch Pathol Lab Med Date: 2021-05-01 Impact factor: 5.534
Authors: Karola S Jering; Brian L Claggett; Jonathan W Cunningham; Ning Rosenthal; Orly Vardeny; Michael F Greene; Scott D Solomon Journal: JAMA Intern Med Date: 2021-05-01 Impact factor: 21.873
Authors: Elisheva D Shanes; Leena B Mithal; Sebastian Otero; Hooman A Azad; Emily S Miller; Jeffery A Goldstein Journal: Am J Clin Pathol Date: 2020-06-08 Impact factor: 2.493
Authors: E Mullins; M L Hudak; J Banerjee; T Getzlaff; J Townson; K Barnette; R Playle; A Perry; T Bourne; C C Lees Journal: Ultrasound Obstet Gynecol Date: 2021-04 Impact factor: 7.299
Authors: Kate R Woodworth; Emily O'Malley Olsen; Varsha Neelam; Elizabeth L Lewis; Romeo R Galang; Titilope Oduyebo; Kathryn Aveni; Mahsa M Yazdy; Elizabeth Harvey; Nicole D Longcore; Jerusha Barton; Chris Fussman; Samantha Siebman; Mamie Lush; Paul H Patrick; Umme-Aiman Halai; Miguel Valencia-Prado; Lauren Orkis; Similoluwa Sowunmi; Levi Schlosser; Salma Khuwaja; Jennifer S Read; Aron J Hall; Dana Meaney-Delman; Sascha R Ellington; Suzanne M Gilboa; Van T Tong Journal: MMWR Morb Mortal Wkly Rep Date: 2020-11-06 Impact factor: 17.586
Authors: Laura D Zambrano; Sascha Ellington; Penelope Strid; Romeo R Galang; Titilope Oduyebo; Van T Tong; Kate R Woodworth; John F Nahabedian; Eduardo Azziz-Baumgartner; Suzanne M Gilboa; Dana Meaney-Delman Journal: MMWR Morb Mortal Wkly Rep Date: 2020-11-06 Impact factor: 17.586
Figure 1.
Figure 2.
Figure 3.
Figure 4.
Figure 5.
Figure 6.