Placental pathology in SARS-CoV-2 infected pregnancies: A single-institution retrospective cohort analysis

Abstract

BACKGROUND:

Our objectives were to determine 1) the prevalence and description of placental pathologic lesions in pregnancies complicated by SARS-CoV-2 infection compared to healthy controls and 2) whether the prevalence and/ or pattern of placental pathologic lesions differed in the few neonates who tested positive for SARS-CoV-2 in the first 48 hours of life at a busy urban county hospital.

METHODS:

This study included all pregnant mothers who tested positive for SARS-CoV-2 and delivered at our institution from March 2020 to June 2021, while control placentas were collected from term pregnancies without complications.

RESULTS:

Approximately 90% (n = 380/425) of placentas from pregnancies complicated by SARS-CoV-2 infections had placental pathologic lesions, compared to 32% (n = 16/50) of controls. The predominant lesions were acute histologic chorioamnionitis with or without fetal response (n = 209/380, 55%), maternal vascular malperfusion (n = 180/380, 47%), and other inflammatory lesions (n = 148/380, 39%). Only 14 (2.5%) infants tested positive for SARS-CoV-2 within the first 48 hours of life. There were no significant differences in placental histopathology between infants who tested positive vs. those that were negative for SARS-CoV-2. Placental lesions in mothers who tested positive for SARS-CoV-2 during the first vs. second vs. third pregnancy trimesters, were significantly different in the incidence of inflammatory placental pathologic lesions (n = 9/19, 53% vs. n = 37/98, 49% vs. n = 102/439, 31%, respectively; p < 0.01).

CONCLUSION:

A significant proportion of women with SARS-CoV-2 infection during pregnancy at a single county hospital have inflammatory and vascular placental lesions at birth, raising questions regarding their downstream effects and clinical consequences.

Keywords

Chorioamnionitis chronic deciduitis COVID-19 intervillositis placental pathology SARS-CoV-2

1 Introduction

The coronavirus disease 2019 (COVID-19) pandemic, caused by the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), remains a prominent public health issue. At the end of 2021, a total of 159,682 pregnant women in the U.S. had been diagnosed with SARS-CoV-2 and 261 pregnant women had died of the disease [1]. Pregnancy related SARS-CoV-2 infection has been reported as an independent risk factor for severe adverse health outcomes in pregnant women and their neonates [2 –6]. Despite this, the mechanism and full extent to which this infection impacts maternal and neonatal outcomes has not yet been fully elucidated.

The placenta is located at the fetal-maternal interface and is the single most reliable source of precise information about the intrauterine environment, as well as maternal and fetal health. SARS-CoV-2 can directly infect the placenta [7, 8], but may also cause placental injury by indirect effects due to the associated cytokine storm and/ or maternal cardio-respiratory complications. Thus, postpartum pathologic examination of the placenta provides a unique opportunity to evaluate the effects of SARS-CoV-2 infection during pregnancy. While the incidence of maternal-fetal vertical transmission appears rare, with only a limited number of studies reporting such cases, SARS-CoV-2 has been reported to potentially affect the placenta [7 , 9–12]. Several small studies have suggested an increased risk of placental pathologic lesions secondary to SARS-CoV-2 infection, reporting a disproportionate number of maternal and fetal vascular lesions [10 , 12–25]. Although informative, these studies are limited by a small sample size, lack of healthy controls for comparison, and inconsistencies in placental sampling and lesion definitions due to nonadherence to the Amsterdam Placental Workshop Group Consensus Statement recommendations for placental pathologic examination [26].

The objectives of this large retrospective cohort study were to determine the prevalence and description of placental pathologic lesions in pregnancies complicated by SARS-CoV-2 infection compared to healthy controls using the Amsterdam Placental Workshop Group Consensus Statement recommendations; and, secondary, to determine whether the prevalence and/ or pattern of placental pathologic lesions differed in the few neonates who tested positive for SARS-CoV-2 in the first 48 hours of life.

2 Materials and methods

2.1 Study design

The study was approved by the Institutional Review Board at University of Texas Southwestern Medical Center. This cohort study included all pregnant women who tested SARS-CoV-2 positive during pregnancy and delivered at our institution from March 1, 2020, to June 30, 2021. Women were included if they were tested for SARS-CoV-2 during pregnancy and delivered at Parkland Health and Hospital System, which serves the medically indigent community of Dallas County. Testing was performed for outpatient areas and, before May 14, 2020, for inpatient areas on the basis of symptoms (fever, cough, dyspnea, myalgia, loss of smell or taste, vomiting, diarrhea, or sore throat) or specific risk criteria. These included contact with a confirmed or suspected case, incarceration or group home setting, homelessness, outside hospital transfers, or unknown results from COVID-19 testing ordered from an outside clinic or facility. A universal SARS-Cov-2 testing protocol was implemented in the labor and delivery unit on May 14, 2020. Testing was on-site or via drive-through at 10 community-based prenatal clinics, and on-site in emergency department (ED) and inpatient units. Diagnosis was by reverse transcriptase–polymerase chain reaction (PCR) detection of SARS-CoV-2 nucleic acid using either nasal or nasopharyngeal specimens. Women presenting for care with external positive testing results were included without repeat testing. If previous results were negative or greater than 10 days in the past, repeat PCR testing was performed on admission to the labor and delivery unit.

Control placentas were collected as part of a prospective study, with inclusion criteria of gestational age of at least 37 weeks, uncomplicated singleton pregnancy, no evidence of fetal anomalies or fetal growth restriction, and absence of perinatal asphyxia or clinical chorioamnionitis (27). They were randomly chosen, uncomplicated, term pregnant women admitted to the ‘Low Risk’ Delivery Service at Parkland Hospital between June 2015- January 2016. Hence these women were not exposed to unknown sub-clinical SARS-CoV-2 (if not tested) or any other tangible variable that could have potentially contributed to the placental histopathologic lesions.

The medical charts were reviewed, and the following maternal data were recorded: maternal demographics; pregnancy complications; timing of SARs-CoV-2 infection with respect to delivery; associated SARS-CoV-2 complications and management. Neonatal data included: gestational age at birth, birth weight, length, birth frontal-occipital circumference (FOC) and sex; delivery room data including Apgar scores at 1 & 5 minutes of life, delivery room resuscitation (i.e., need for oxygen, CPAP, PPV or intubation); neonatal characteristics including the presence and type of neonatal intensive care unit (ICU) respiratory support, if required. All neonates were tested for neonatal SARS-CoV-2 by nasopharyngeal swab and polymerase chain reaction (PCR) at 24 and 48 hours of life, if they were born to a mother with a confirmed or suspected SARS-CoV-2 infection during the pregnancy and/or within 10 days of the time of delivery. Presence and type of placental pathology was also noted.

2.2 Placental pathology

All available placentas from pregnancies complicated by SARS-CoV-2 infection were sent for gross and histologic examination by placental pathologists. Placentas associated with specific maternal-fetal complications are routinely collected at delivery at our institution for examination by a pediatric pathologist according to a standardized protocol [28, 29]. Initial gross examination includes placental weight obtained following removal of the umbilical cord, fetal membranes, and nonadherent blood clots [30].

The placental disc is then serially sectioned at 1- to 2-cm intervals and examined for intraparenchymal lesions. Representative sections of the umbilical cord, fetal membranes, normal placental parenchyma, and any abnormalities seen on gross exam are submitted for histological examination using the standardized classification and diagnostic terminology for major placental findings and lesions [26, 31]. Based on the Amsterdam criteria, the histopathologic abnormalities assessed were divided into the following subcategories [26].

Acute histologic chorioamnionitis, further categorized as maternal inflammatory response (MIR) and fetal inflammatory response (FIR) and classified by stages and grades.

Villitis of unknown etiology (VUE), further classified into low grade, high grade, and villitis with avascular villi.

Maternal vascular malperfusion (MVM) including maternal vascular lesions; infarcts, hemorrhage or hematoma, thrombi (involving > 5% of parenchyma); villous changes, and placental hypoplasia.

Fetal vascular malperfusion (FVM).

Other lesions including inflammatory lesions characterized by chronic deciduitis with plasma cells, massive chronic intervillositis, perivillous fibrin, and histiocytic intervillositis, delayed villous maturation, and villous edema.

Abnormalities in size of placentas were reported as either small for gestation (<10th percentile, SGA) or large for gestation (>90th percentile, LGA).

2.3 Statistical analysis

Descriptive statistical analysis used percentages, means, medians, and measures of variability to describe demographic data. Primary analysis of the data used a χ² analysis or Fisher exact test for categorical data, and Mann-Whitney rank sum test for continuous data. The significance level was P < .05. A Bonferroni correction was applied for pair-wise comparison when needed to adjust for multiple comparisons. An a priori power analysis was conducted to test the difference between two independent group means using a two-tailed test, a medium effect size (d = 0.50), and an alpha of.05. SPSS (version 25) was used to perform the statistical analysis.

3 Results

3.1 Study subjects

Between March 2020 and June 2021, a total of 556 women, who were SARS-CoV-2 positive, were admitted for delivery at our institution. Of these, 131 (23%) did not have placenta sent for pathology and were excluded from the analysis, resulting in 425 (77%) placentas included in the analysis. As Controls were collected as part of a prospective study, placental pathology was available in all 50 Control subjects. Of the 425 placentas from SAR-CoV-2 infected pregnancies, 17 (0.04%) were from women with SARS-CoV-2 infection during 1st trimester, 76 (17.9%) from those infected during their 2nd trimester, and 332 (82.1%) with infection during their 3rd trimester. Among the neonates delivered to women with history of SARS-CoV-2 infection during pregnancy, 14 (2.5%) neonates tested SARS-CoV-2 positive within the first 48 hours of life (Fig. 1).

Fig. 1

Flow diagram of the study population.

Maternal characteristics were similar between SARS-CoV-2 positive mothers and controls. Neonates born to SARS-CoV-2 positive mothers had lower Apgar scores at 1 min and were more likely to be female (Table 1). Neonates who tested positive for SAR-CoV-2 within 48 hrs of delivery were delivered from mothers with documented SARS-CoV-2 infection closer to the time of delivery compared to neonates who tested negative (Table 2). Other neonatal characteristics including gestational age at birth, birth weight, Apgar scores, and respiratory outcomes were similar between SARS-CoV-2 positive and negative neonates (Table 2).

Table 1

Comparison of maternal and infant characteristics of pregnancies complicated by SARS-CoV-2 infection vs. controls

	SARS-CoV-2 positive (N = 556)	Controls (N = 50)	P-value^*
Age (yr)	27 (23, 33)	29 (24, 31)	0.64
Gravidity	3 (2, 4)	3 (1, 4)	0.31
Parity	2 (1, 4)	3 (1, 3)	0.50
Race/Ethnicity, n (%)	0.71
White Non-Hispanic	11 (2)	2 (4)
Black Non-Hispanic	40 (7)	3 (6)
Hispanic	492 (90)	45 (90)
Other	5 (1)	0 (0)
C-section, n (%)	162 (30)	20 (40)	0.13
GA category, n (%)
<32 weeks	8 (1)	0 (0)	0.14
32–36 + 6 weeks	45 (8)	0 (0)
37–41 weeks	451 (81)	46 (92)
>41 weeks	52 (9)	4 (8)
APGAR 1 min	8 (8, 8)	8 (8, 9)	0.01
APGAR 5 min	9 (9, 9)	9 (9, 9)	0.29
Birth weight (g)	3340 (2976, 3630)	3465 (3131, 3695)	0.11
Female, n (%)	303 (55)	19 (38)	0.03

^*n (%) compared with Chi-square or Fisher exact test; Median (25th, 75th) compared with Mann-Whitney U-test.

Table 2

Comparison of complications in SARS-CoV-2 infected pregnancies between SARS-CoV-2 positive vs. negative newborns

	Infant COVID negative (N = 534)	Infant COVID Positive (N = 14)	P-value^*
Maternal Age (yr)	27 (23, 33)	31 (21, 36)	0.31
Gravidity	3 (2, 4)	3 (2, 4)	0.31
Parity	2 (1, 4)	3 (2, 4)	0.29
COVID (+) days before birth	12 (1, 78)	0.5 (0, 1)	0.01
Race/Ethnicity, n (%)
White Non-Hispanic	^*9 (2)	2 (14)	0.01
Black Non-Hispanic	39 (7)	1 (7)
Hispanic	481 (90)	11 (79)
Other	5 (1)	0 (0)
Diabetes	43 (8)	2 (14)	0.32
Pregnancy induced hypertension	54 (10)	1 (7)	1.00
Preeclampsia	51 (10)	2 (14)	0.64
Oligohydramnios	63 (12)	2 (14)	0.68
Polyhydramnios	4 (1)	0 (0)	1.00
COVID symptomatic	63 (12)	4 (29)	0.08
Non-invasive management	4 (1)	0 (0)	1.00
Intubation	2 (<1)	0 (0)	1.00
Clinical Chorioamnionitis	71 (13)	4 (29)	0.11
C-section, n (%)	159 (30)	3 (21)	0.77
Meconium, n (%)	90 (17)	2 (14)	1.00
Duration of PROM	3.0 (0.0, 8.0)	2.8 (0.4, 11.0)	0.70
Duration of PROM > 18 HR, n (%)	35/520 (7)	2 /14 (14)	0.25
Delivery room CPAP, n (%)	14 (3)	0 (0)	1.00
Delivery room PPV, n (%)	13 (2)	0 (0)	1.00
Delivery room NC, n (%)	22 (4)	0 (0)	1.00
GA category, n (%)
<32 weeks	8 (2)	0 (0)	0.81
32-36 + 6 weeks	43 (8)	2 (14)
37-41 weeks	440 (81)	11 (79)
>41 weeks	51 (9)	1 (7)
APGAR 1 min	8 (8, 8)	8 (8, 8)	0.38
APGAR 5 min	9 (9, 9)	9 (9, 9)	0.26
Birth weight (g)	3340 (2979, 3631)	3305 (2928, 3560)	0.74
Birth length (cm)	51 (49, 52)	49 (48, 51)	0.28
Birth FOC (cm)	34.0 (33.5, 35.0)	34.0 (33.0, 35.1)	0.51
Female, n (%)	294 (54)	9 (64)	0.46
NICU respiratory support	20 (4)	1 (7)	0.42
	N=20	N=1
Intubated	2 (10)	0 (0)	1.00
CPAP	12 (60)	0 (0)	0.43
NC	16 (80)	1 (100)	1.00

^*n (%) compared with Chi-square or Fisher exact test; Median (25th, 75th) compared with Mann-Whitney U-test.

3.2 Placental pathology

In pregnancies complicated by SARS-CoV-2 infection, 89.4% placentas demonstrated at least one placental pathologic lesion compared to 32% in our control group (p = 0.02). The predominant lesions were acute histologic chorioamnionitis, namely MIR with or without FIR (n = 209/425, 49%) and MVM (n = 180/425, 42%). There was also an increased prevalence of other inflammatory lesions (n = 148/425, 35%), VUE (n = 113/425, 27%) and FVM (n = 73/425, 17%). We noted a high incidence (35%) of the ‘other inflammatory placental lesions’ (including chronic deciduitis, massive chronic intervillositis, leukocytoclastic decidual necrosis, massive perivillous fibrin deposition, and histiocytic intervillositis) in pregnancies complicated by SARS-CoV-2 infections (Table 3). When compared to controls, placentas from SARS-CoV-2 positive women had a significantly higher prevalence of all placental pathologic lesions (both inflammatory and vascular) compared to controls (89.4% vs. 32.0%; P < 0.01) (Table 3). The relative abundance of placental pathologic lesions remained high in the subset of cases that delivered after 37 completed weeks of gestational age (n = 503) when compared to a historical cohort of term-born healthy controls (n = 50). Overall, the frequency of chronic lesions was high and only found in SARS-CoV-2 group [MVM (42.4% vs. 0.0%; P < 0.01) and FVM (17.2% vs. 0.0%; P < 0.01)]. When controlling for severe pre-eclampsia (SPE) and pregnancy induced hypertension (PIH), there was no difference in rates of MVM (51% vs. 41%; P = 0.10) and FVM (13% vs. 18%; P = 0.24) between SARS-CoV-2 positive mothers with SPE and/or PIH compared to those without. Moreover, 229 (54%) of placentas from SARS-CoV-2 positive group had multiple placental pathologic lesions, i.e.>1 placental histopathologic lesions (54% vs. 0.0% in controls; P < 0.01) (Table 3). The predominant combination in multiple placental pathologies was MIR with MVM, followed by a combination with other inflammatory lesions and MIR.

Table 3
Comparison of placental pathologic lesions in pregnancies complicated by SARS-CoV-2 vs. controls

Mom COVID positive (N = 556) Control (N = 50) P-value^*

Pathology report 425 (76) 50 (100) <0.01

N=425 N=50

SGA placenta 63 (15) 0 (0) <0.01

LGA placenta 59 (14) 0 (0) <0.01

Acute Inflammation 209 (49) 16 (32) 0.02

Maternal Inflammatory Response (MIR) 186 (44) 16 (32) 0.11

N=186 N=16

Stage MIR

1 65 (35) 3 (19) 0.32

2 117 (63) 13 (81)

3 4 (2) 0 (0)

Grade MIR 0.60

1 174 (94) 16 (100)

2 12 (7) 0 (0)

N=425 N=50

Fetal Inflammatory Response (FIR) 141 (33) 9 (18) 0.03

N=141 N=9

Stage FIR

1 95 (67) 8 (89) 0.40

2 44 (31) 1 (11)

3 2 (1) 0 (0)

Grade FIR

1 134 (95) 9 (100) 1.00

2 7 (5) 0 (0)

N=425 N=50

Villitis of Unknown Etiology (VUE) 113 (27) 0 (0)

N=113 N=0

Low grade 86 (76) 0 (0) N/A

High grade 22 (20) 0 (0) N/A

With avascular villitis 16 (14) 0 (0) N/A

N=425 N=50

Maternal Vascular Malperfusion (MVM) 180 (42) 0 (0) <0.01

N=180 N=0

Maternal vascular lesions 52 (29) 0 (0) N/A

Infarct 32 (18) 0 (0) N/A

Hemorrhage/hematoma 28 (16) 0 (0) N/A

Thrombi 39 (22) 0 (0) N/A

Villous changes 18 (10) 0 (0) N/A

Placental hypoplasia 52 (29) 0 (0) N/A

N=425 N=50

Fetal Vascular Malperfusion (FVM) 73 (17) 0 (0) <0.01

Other Lesions

Other Inflammatory lesions 148 (35) 0 (0) <0.01

Delayed Villous maturation 10 (2) 0 (0) 0.61

Villous edema 26 (6) 0 (0) 0.10

Multiple Placental Pathologic Lesions 229 (54) 0 (0) <0.01

Chronic (at least one) 316 (74) 0 (0) <0.01

Multiple chronic lesions 63 (15) 0 (0) <0.01

Multiple chronic and acute 166 (39) 0 (0) <0.01

	Mom COVID positive (N = 556)	Control (N = 50)	P-value^*
Pathology report	425 (76)	50 (100)	<0.01
	N=425	N=50
SGA placenta	63 (15)	0 (0)	<0.01
LGA placenta	59 (14)	0 (0)	<0.01
Acute Inflammation	209 (49)	16 (32)	0.02
Maternal Inflammatory Response (MIR)	186 (44)	16 (32)	0.11
	N=186	N=16
Stage MIR
1	65 (35)	3 (19)	0.32
2	117 (63)	13 (81)
3	4 (2)	0 (0)
Grade MIR	0.60
1	174 (94)	16 (100)
2	12 (7)	0 (0)
	N=425	N=50
Fetal Inflammatory Response (FIR)	141 (33)	9 (18)	0.03
	N=141	N=9
Stage FIR
1	95 (67)	8 (89)	0.40
2	44 (31)	1 (11)
3	2 (1)	0 (0)
Grade FIR
1	134 (95)	9 (100)	1.00
2	7 (5)	0 (0)
	N=425	N=50
Villitis of Unknown Etiology (VUE)	113 (27)	0 (0)
	N=113	N=0
Low grade	86 (76)	0 (0)	N/A
High grade	22 (20)	0 (0)	N/A
With avascular villitis	16 (14)	0 (0)	N/A
	N=425	N=50
Maternal Vascular Malperfusion (MVM)	180 (42)	0 (0)	<0.01
	N=180	N=0
Maternal vascular lesions	52 (29)	0 (0)	N/A
Infarct	32 (18)	0 (0)	N/A
Hemorrhage/hematoma	28 (16)	0 (0)	N/A
Thrombi	39 (22)	0 (0)	N/A
Villous changes	18 (10)	0 (0)	N/A
Placental hypoplasia	52 (29)	0 (0)	N/A
	N=425	N=50
Fetal Vascular Malperfusion (FVM)	73 (17)	0 (0)	<0.01
Other Lesions
Other Inflammatory lesions	148 (35)	0 (0)	<0.01
Delayed Villous maturation	10 (2)	0 (0)	0.61
Villous edema	26 (6)	0 (0)	0.10
Multiple Placental Pathologic Lesions	229 (54)	0 (0)	<0.01
Chronic (at least one)	316 (74)	0 (0)	<0.01
Multiple chronic lesions	63 (15)	0 (0)	<0.01
Multiple chronic and acute	166 (39)	0 (0)	<0.01

^*n (%) compared with Chi-square or Fisher exact test; Median (25th, 75th) compared with Mann-Whitney U-test.

3.3 Association with neonatal infection

2.5% (14/556) of neonates born to mothers with SARS-CoV-2 infection during pregnancy and/or at the time of delivery were positive for SARS-CoV-2 by RT-PCR within the first 48 hours of life. Of the 14 neonates that tested positive for SARS-CoV-2 within the first 48 hours of life, 7 (50%) neonates had placentas available for evaluation. We found no significant difference in frequency of any placental pathologic lesion between neonates that tested positive for SARS-CoV-2 and those that tested negative (90.6 % vs. 89.6%; P = 0.39). Among discrete placental pathologies there were no differences between the cohorts for MIR (44.0% vs. 28.6%; p = 0.48), FIR (33.5% vs. 14.3%; p = 0.43), MIR or FIR (49.3% vs. 42.9%; p = 1.00), VUE (26.6% vs. 28.6%; p = 1.00), MVM (42.1% vs. 57.1%; p = 0.46), FVM (17.5% vs. 0.0%; p = 0.61), or other lesions (34.9% vs. 28.6%; p = 1.00). The incidence of ‘SARS-CoV-2 placentitis’(32, 33) (i.e., chronic intervillositis and massive perivillous fibrin deposition) was not different between SARS-CoV-2 positive vs. SARS-CoV-2 negative neonates. Furthermore, placentas from SARS-CoV-2 positive infants demonstrated no significant difference in frequency of SGA placentas (15.1% vs. 0.0%; p = 0.60) or LGA placentas (13.4% vs. 42.9%; p = 0.06) (Table 4). Of note, in this cohort, there was a case of perinatal or congenital SARS-CoV-2 transmission. This preterm infant’s placenta showed chronic inflammation within placental villi with histiocytic infiltration within the intervillous space and showed virus like particles with the syncytiotrophoblasts on routine placental histopathologic examination.

Table 4
Comparison of Placental Pathologic Lesions in SARS-CoV-2 infected pregnancies between SARS-CoV-2 positive vs. negative newborns

Infant COVID negative (N = 542) Infant COVID Positive (N = 14) P-value^*

Pathology report 418 (77) 7 (50) 0.03

N=418 N=7

SGA placenta 63 (15) 0 (0) 0.60

LGA placenta 56 (13) 3 (43) 0.06

Acute Inflammation 206 (49) 3 (43) 1.00

MIR 184 (44) 2 (29) 0.48

N=184 N=2

Stage MIR 0.89

1 64 (35) 1 (50)

2 116 (63) 1 (50)

3 4 (2) 0 (0)

Grade MIR 1.00

1 172 (94) 2 (100)

2 12 (7) 0 (0)

N=418 N=7

FIR 140 (34) 1 (14) 0.43

N=140 N=1

Stage FIR 0.78

1 94 (67) 1 (100)

2 44 (31) 0 (0)

3 2 (1) 0 (0)

Grade FIR 1.00

1 133 (95) 1 (100)

2 7 (5) 0 (0)

N=418 N=7

Villitis of Unknown Etiology (VUE) 111 (27) 2 (29) 1.00

N=111 N=2

Low grade 84 (76) 2 (100) 1.00

High grade 22 (20) 0 (0) 1.00

With avascular villitis 15 (14) 1 (50) 0.26

N=418 N=7

Maternal Vascular Malperfusion (MVM) 176 (42) 4 (57) 0.46

N=176 N=4

Maternal vascular lesions 51 (29) 1 (25) 1.00

Infarct 30 (17) 2 (50) 0.15

Hemorrhage/hematoma 27 (15) 1 (25) 0.50

Thrombi 39 (22) 0 (0) 0.58

Villous changes 18 (10) 0 (0) 1.00

Placental hypoplasia 52 (30) 0 (0) 0.33

N=418 N=7

Fetal Vascular Malperfusion 73 (18) 0 (0) 0.61

Other Lesions

Other Inflammatory Lesions 146 (35) 2 (29) 1.00

Delayed Villous maturation 10 (2) 0 (0) 1.00

Villous edema 26 (6) 0 (0) 1.00

Multiple Placental Patholpogic Lesions 227 (54) 2 (29) 0.39

Multiple chronic lesions 63 (15) 0 (0) 0.60

Multiple chronic and acute 164 (39) 2 (29) 0.71

	Infant COVID negative (N = 542)	Infant COVID Positive (N = 14)	P-value^*
Pathology report	418 (77)	7 (50)	0.03
	N=418	N=7
SGA placenta	63 (15)	0 (0)	0.60
LGA placenta	56 (13)	3 (43)	0.06
Acute Inflammation	206 (49)	3 (43)	1.00
MIR	184 (44)	2 (29)	0.48
	N=184	N=2
Stage MIR	0.89
1	64 (35)	1 (50)
2	116 (63)	1 (50)
3	4 (2)	0 (0)
Grade MIR			1.00
1	172 (94)	2 (100)
2	12 (7)	0 (0)
	N=418	N=7
FIR	140 (34)	1 (14)	0.43
	N=140	N=1
Stage FIR			0.78
1	94 (67)	1 (100)
2	44 (31)	0 (0)
3	2 (1)	0 (0)
Grade FIR			1.00
1	133 (95)	1 (100)
2	7 (5)	0 (0)
	N=418	N=7
Villitis of Unknown Etiology (VUE)	111 (27)	2 (29)	1.00
	N=111	N=2
Low grade	84 (76)	2 (100)	1.00
High grade	22 (20)	0 (0)	1.00
With avascular villitis	15 (14)	1 (50)	0.26
	N=418	N=7
Maternal Vascular Malperfusion (MVM)	176 (42)	4 (57)	0.46
	N=176	N=4
Maternal vascular lesions	51 (29)	1 (25)	1.00
Infarct	30 (17)	2 (50)	0.15
Hemorrhage/hematoma	27 (15)	1 (25)	0.50
Thrombi	39 (22)	0 (0)	0.58
Villous changes	18 (10)	0 (0)	1.00
Placental hypoplasia	52 (30)	0 (0)	0.33
	N=418	N=7
Fetal Vascular Malperfusion	73 (18)	0 (0)	0.61
Other Lesions
Other Inflammatory Lesions	146 (35)	2 (29)	1.00
Delayed Villous maturation	10 (2)	0 (0)	1.00
Villous edema	26 (6)	0 (0)	1.00
Multiple Placental Patholpogic Lesions	227 (54)	2 (29)	0.39
Multiple chronic lesions	63 (15)	0 (0)	0.60
Multiple chronic and acute	164 (39)	2 (29)	0.71

^*n (%) compared with Chi-square or Fisher exact test; Median (25th, 75th) compared with Mann-Whitney U-test.

3.4 Association with Timing of SARS-CoV-2 Infection

We also compared the placental pathologic lesions between women who tested SARS-CoV-2 positive during their first vs. second vs. third trimester of pregnancy. Analysis of placental lesions across trimesters showed a significant difference in frequency of MIR (16.9% vs. 55.3% vs. 39.5%; p < 0.01) and MIR and/or FIR (16.9% vs. 59.2% vs. 45.5%; p < 0.01). There was no significant difference in frequency of FIR (41.2% vs. 42.1% vs 30.7%; p = 0.13), VUE (35.3% vs. 31.6% vs. 25.0%; p = 0.36), MVM (52.9% vs. 31.6% vs. 44.3%; p = 0.09), or FVM (17.6% vs. 15.8% vs. 17.5%; p = 0.94). The frequency of other inflammatory lesions (52.9% vs. 48.7% vs. 30.7%; p < 0.01), acute lesions (76.5% vs. 61.8% vs. 50.0%; p = 0.03), and multiple (acute+chronic) placental lesions (64.7% vs. 47.4% vs. 35.8%; p = 0.02) were statistically significant across trimesters. No significant difference was seen for SGA placentas (29.4% vs. 11.8% vs. 14.8%; p = 0.18) or LGA placentas (0.6% vs. 10.5% vs. 15.1%; p = 0.37) (Table 5).

Table 5
Comparison of placental pathologic lesions in pregnant women infected by SARS-CoV-2 during different trimesters

1st Trimester (N = 19) 2nd trimester (N = 98) 3rd trimester (N = 439) P-value^*

Pathology report 17 (90) 76 (78) 332 (76) 0.36

N=17 N=76 N=332

SGA placenta 5 (29) 9 (12) 49 (15) 0.18

LGA placenta 1 (6) 8 (11) 50 (15) 0.37

Acute Inflammation 13 (77)^a 45 (59)^a,b 151 (46)^b <0.01

Maternal Inflammatory Response (MIR) 13 (77)^a 42 (55)^a 131 (40)^b <0.01

N=13 N=42 N=131

Stage MIR 0.78

1 5 (39) 15 (36) 45 (34)

2 8 (62) 27 (64) 82 (63)

3 0 (0) 0 (0) 4 (3)

Grade MIR 0.87

1 12 (92) 40 (95) 122 (93)

2 1 (8) 2 (5) 9 (7)

N=17 N=76 N=332

Fetal Inflammatory Response 7 (41) 32 (41) 102 (31) 0.13

N=7 N=32 N=102

Stage FIR 0.10

1 6 (86) 16 (50) 73 (72)

2 1 (14) 16 (50) 27 (27)

3 0 (0) 0 (0) 2 (2)

Grade FIR 0.79

1 7 (100) 30 (94) 97 (95)

2 0 (0) 2 (6) 5 (5)

N=17 N=76 N=332

Villitis of Unknown Etiology (VUE) 6 (35) 24 (32) 83 (25) 0.36

N=6 N=24 N=83

Low grade 3 (50) 19 (79) 64 (77) 0.30

High grade 3 (50) 5 (21) 14 (17) 0.14

With avascular villitis 2 (33) 1 (4) 13 (16) 0.14

N=17 N=76 N=332

Maternal Vascular Malperfusion (MVM) 9 (53) 24 (32) 147 (44) 0.09

N=9 N=76 N=147

Vascular lesions maternal 3 (33) 10 (42) 39 (27) 0.30

Infarct 0 (0) 4 (17) 28 (19) 0.35

Hemorrhage/hematoma 2 (22) 5 (21) 21 (14) 0.61

Thrombi 2 (22) 6 (25) 31 (21) 0.91

Villous changes 0 (0) 1 (4) 17 (12) 0.32

Placental hypoplasia 4 (44) 8 (33) 40 (27) 0.47

N=17 N=76 N=332

Fetal Vacular Malperfusion (FVM) 3 (18) 12 (16) 58 (18) 0.94

Other Lesions

Other inflammatory lesions 9 (53)^a,b 37 (49)^b 102 (31)^a <0.01

Delayed Villous maturation 0 (0) 1 (1) 9 (3) 0.62

Villous edema 0 (0) 6 (8) 20 (6) 0.47

Multiple Placental Pathologic Lesions 12 (71) 46 (61) 171 (52) 0.29

Multiple chronic Lesions 1 (6) 10 (13) 52 (16) 0.49

Multiple chronic and acute 11 (65)^a 36 (47)^a,b 119 (36)^b 0.02

	1st Trimester (N = 19)	2nd trimester (N = 98)	3rd trimester (N = 439)	P-value^*
Pathology report	17 (90)	76 (78)	332 (76)	0.36
	N=17	N=76	N=332
SGA placenta	5 (29)	9 (12)	49 (15)	0.18
LGA placenta	1 (6)	8 (11)	50 (15)	0.37
Acute Inflammation	13 (77)^a	45 (59)^a,b	151 (46)^b	<0.01
Maternal Inflammatory Response (MIR)	13 (77)^a	42 (55)^a	131 (40)^b	<0.01
	N=13	N=42	N=131
Stage MIR				0.78
1	5 (39)	15 (36)	45 (34)
2	8 (62)	27 (64)	82 (63)
3	0 (0)	0 (0)	4 (3)
Grade MIR				0.87
1	12 (92)	40 (95)	122 (93)
2	1 (8)	2 (5)	9 (7)
	N=17	N=76	N=332
Fetal Inflammatory Response	7 (41)	32 (41)	102 (31)	0.13
	N=7	N=32	N=102
Stage FIR				0.10
1	6 (86)	16 (50)	73 (72)
2	1 (14)	16 (50)	27 (27)
3	0 (0)	0 (0)	2 (2)
Grade FIR				0.79
1	7 (100)	30 (94)	97 (95)
2	0 (0)	2 (6)	5 (5)
	N=17	N=76	N=332
Villitis of Unknown Etiology (VUE)	6 (35)	24 (32)	83 (25)	0.36
	N=6	N=24	N=83
Low grade	3 (50)	19 (79)	64 (77)	0.30
High grade	3 (50)	5 (21)	14 (17)	0.14
With avascular villitis	2 (33)	1 (4)	13 (16)	0.14
	N=17	N=76	N=332
Maternal Vascular Malperfusion (MVM)	9 (53)	24 (32)	147 (44)	0.09
	N=9	N=76	N=147
Vascular lesions maternal	3 (33)	10 (42)	39 (27)	0.30
Infarct	0 (0)	4 (17)	28 (19)	0.35
Hemorrhage/hematoma	2 (22)	5 (21)	21 (14)	0.61
Thrombi	2 (22)	6 (25)	31 (21)	0.91
Villous changes	0 (0)	1 (4)	17 (12)	0.32
Placental hypoplasia	4 (44)	8 (33)	40 (27)	0.47
	N=17	N=76	N=332
Fetal Vacular Malperfusion (FVM)	3 (18)	12 (16)	58 (18)	0.94
Other Lesions
Other inflammatory lesions	9 (53)^a,b	37 (49)^b	102 (31)^a	<0.01
Delayed Villous maturation	0 (0)	1 (1)	9 (3)	0.62
Villous edema	0 (0)	6 (8)	20 (6)	0.47
Multiple Placental Pathologic Lesions	12 (71)	46 (61)	171 (52)	0.29
Multiple chronic Lesions	1 (6)	10 (13)	52 (16)	0.49
Multiple chronic and acute	11 (65)^a	36 (47)^a,b	119 (36)^b	0.02

^*n (%) compared with Chi-square or Fisher exact test; Median (25th, 75th) compared with Mann-Whitney U-test. Each superscript letter denotes a subset of three group comparison whose column proportions do not differ significantly from each other adjusted for Bonferroni correction.

3.5 Association with maternal symptomatology

A total of 68 women in the study had symptomatic SARS-CoV-2 infection at the time of delivery. Placental pathology was available for 54 (79%) women with symptomatic SARS-CoV-2 infection at delivery and 371 (76%) women with asymptomatic SARS-COV-2 infection upon hospital admission for delivery. No significant differences were demonstrated in placental lesions between mothers with documented symptomatic SARS-CoV-2 infection at time of delivery versus those with asymptomatic infection (Table 6).

Table 6
Comparison of placental pathology in pregnant women who are symptomatic vs. asymptomatic due to SARS-CoV-2 infection at the time of delivery

COVID asymptomatic at delivery (N = 488) COVID symptomatic at delivery (N = 68^) P-value^

Pathology report 371 (76) 54 (79) 0.54

N=371 N=54

SGA placenta 56 (15) 7 (13) 0.68

LGA placenta 47 (13) 12 (22) 0.06

Acute Inflammation 186 (50) 23 (43) 0.30

MIR 168 (45) 18 (33) 0.10

N=168 N=18

Stage MIR 0.01

1 53 (32) 12 (67)

2 111 (66) 6 (33)

3 4 (2) 0 (0)

Grade MIR 0.33

1 158 (94) 16 (89)

2 10 (6) 2 (11)

N=371 N=54

FIR 125 (34) 16 (30) 0.55

N=125 N=16

Stage FIR 0.19

1 81 (65) 14 (88)

2 42 (34) 2 (13)

3 2 (2) 0 (0)

Grade FIR 0.18

1 120 (96) 14 (88)

2 5 (4) 2 (13)

N=371 N=54

VUE 101 (27) 12 (22) 0.44

N=101 N=12

Low grade 74 (73) 12 (100) 0.07

High grade 22 (22) 0 (0) 0.12

With avascular villitis 15 (15) 1 (8) 1.00

N=371 N=54

MVM 154 (42) 26 (48) 0.36

N=154 N=26

Vascular lesions maternal 41 (27) 11 (42) 0.10

Infarct 31 (20) 1 (4) 0.05

Hemorrhage/hematoma 23 (15) 5 (19) 0.56

Thrombi 34 (22) 5 (19) 0.74

Villous changes 14 (9) 4 (15) 0.30

Placental hypoplasia 47 (31) 5 (19) 0.24

N=371 N=54

FVM 64 (17) 9 (17) 0.92

Other Lesions

Other Inflammatory lesions 134 (36) 14 (26) 0.14

Delayed Villous maturation 10 (3) 0 (0) 0.62

Villous edema 22 (6) 4 (7) 0.76

Multiple Placental Pathologic Lesions 203 (55) 26 (48) 0.31

Multiple chronic only 55 (15) 8 (15) 1.00

Multiple chronic and acute 148 (40) 18 (33) 0.36

	COVID asymptomatic at delivery (N = 488)	COVID symptomatic at delivery (N = 68^*)	P-value^*
Pathology report	371 (76)	54 (79)	0.54
	N=371	N=54
SGA placenta	56 (15)	7 (13)	0.68
LGA placenta	47 (13)	12 (22)	0.06
Acute Inflammation	186 (50)	23 (43)	0.30
MIR	168 (45)	18 (33)	0.10
	N=168	N=18
Stage MIR			0.01
1	53 (32)	12 (67)
2	111 (66)	6 (33)
3	4 (2)	0 (0)
Grade MIR			0.33
1	158 (94)	16 (89)
2	10 (6)	2 (11)
	N=371	N=54
FIR	125 (34)	16 (30)	0.55
	N=125	N=16
Stage FIR			0.19
1	81 (65)	14 (88)
2	42 (34)	2 (13)
3	2 (2)	0 (0)
Grade FIR			0.18
1	120 (96)	14 (88)
2	5 (4)	2 (13)
	N=371	N=54
VUE	101 (27)	12 (22)	0.44
	N=101	N=12
Low grade	74 (73)	12 (100)	0.07
High grade	22 (22)	0 (0)	0.12
With avascular villitis	15 (15)	1 (8)	1.00
	N=371	N=54
MVM	154 (42)	26 (48)	0.36
	N=154	N=26
Vascular lesions maternal	41 (27)	11 (42)	0.10
Infarct	31 (20)	1 (4)	0.05
Hemorrhage/hematoma	23 (15)	5 (19)	0.56
Thrombi	34 (22)	5 (19)	0.74
Villous changes	14 (9)	4 (15)	0.30
Placental hypoplasia	47 (31)	5 (19)	0.24
	N=371	N=54
FVM	64 (17)	9 (17)	0.92
Other Lesions
Other Inflammatory lesions	134 (36)	14 (26)	0.14
Delayed Villous maturation	10 (3)	0 (0)	0.62
Villous edema	22 (6)	4 (7)	0.76
Multiple Placental Pathologic Lesions	203 (55)	26 (48)	0.31
Multiple chronic only	55 (15)	8 (15)	1.00
Multiple chronic and acute	148 (40)	18 (33)	0.36

^*n (%) compared with Chi-square or Fisher exact test; Median (25th, 75th) compared with Mann-Whitney U-test.

4 Discussion

In this retrospective cohort study, we found a remarkably high rate of abnormal placental histopathology in women with confirmed SARS-CoV-2 infection during pregnancy, totaling ∼90% of our cohort. Of note, prominent placental pathologies included acute and chronic inflammatory lesions as well as vascular placental lesions. Together, these data suggest that maternal SARS-CoV-2 infection during pregnancy damages placental microstructure, but the mechanism and clinical consequences of this effect remain unclear. Maternal SARS-CoV-2 infection in the 1st and 2nd trimester was associated with a higher incidence of inflammatory placental lesions compared to those infected later in pregnancy, but presence of maternal infectious symptoms at delivery was not predictive of placental histopathologic lesions when compared to those with asymptomatic infection at delivery. Interestingly, the presence of placental histopathologic lesions was not associated with higher prevalence of neonatal SARS-CoV-2 infection confirmed by postnatal PCR testing at two timepoints, and overall, only 2.5% of neonates in our cohort tested positive for SARS-COV-2. Importantly, maternal SARS-CoV-2 infection was not associated with adverse short term neonatal outcomes including preterm birth, low birthweight, or decreased Apgar scores.

Previous studies have yet to identify a discrete histopathologic placental finding associated with maternal SARS-CoV-2 infection. There has been disagreement about whether FVM or MVM is the predominant lesion [12, 24], but few studies have commented on inflammatory placental lesions. These studies however likely have lacked power as they have included relatively few placentas for analysis. Among the inflammatory placental lesions, the incidence of acute chorioamnionitis was very high in our cohort of SARS-CoV-2 infected pregnancies. Maternal hypoxia and systemic inflammation may possibly be factors that make the placental-amniotic fluid barrier more vulnerable for bacterial amniotic fluid infection during COVID-19 disease. Our report is the largest single center study looking at placental pathologic lesions in pregnancies complicated by SARS-CoV-2 to date using the Amsterdam Placental Workshop Group Consensus Statement placental pathology recommendations. The most recent systematic review examining the placental histopathologic effects of SARS-CoV-2 only found an increased incidence of FVM in women infected by SARS-CoV-2 during pregnancy [15] compared to our results indicating a more variable pattern of placental lesions associated with SARS-CoV-2. Other small studies noted no difference in the incidence of placental pathologic lesions [25], high incidence of villitis of unknown origin (34) and increased incidence of maternal vascular malperfusion [8 , 36]. However, the sample size of these individual studies was very small compared to our cohort.

While some prior studies have commented on overall incidence of lesions in placentas of SARS-CoV-2 infected mothers [34], very few studies have commented on the effect of timing of maternal SARS-CoV-2 infection. Our results indicate that there is a marked difference in incidence of acute and chronic placental pathologic lesions across pregnancy trimesters, yet transmission by any method to the neonate remains uncommon even with maternal symptomatic SARS-CoV-2 infection at the time of delivery. This low transmission rate is likely attributable in part to our institution’s initial practice during the pandemic of separating mothers with active infection from their neonates; however, this was not investigated and is outside the scope of our study.

Importantly, the placentas of SARS-CoV-2 positive neonates did not differ significantly in type and/or number of lesions when compared to neonates who tested negative, suggesting that placental damage by SARS-CoV-2 infection is variable and does not predict risk of infection to the neonate. Additionally, these findings may lend further credence to the role of the placenta as a protective barrier between mother and neonate. As seen in previous studies, while vertical transmission of SARS-CoV-2 may occur, it appears to do so very rarely [9 , 38]. This is consistent with our findings which found no widespread evidence of vertical transmission of virus across the placenta. Out of 556 SARS-CoV-2 positive mothers, only 14 neonates tested positive. The majority of these neonates were born to mothers with an acute infection having tested positive on average less than one day prior to delivery. Only one neonate’s placenta showed evidence of virions in the syncytiotrophoblasts [7]. Given these findings, it is likely these neonates became infected either during or after birth. Clinically, this is an important distinction to make about SARS-CoV-2 infection. Unlike many other viral and bacterial infections (e.g. rubella, mumps, poliomyelitis, smallpox, rubeola, syphilis, malaria, toxoplasmosis, V fetus, L monocytogenes, cytomegalovirus, and herpes simplex virus), which have the ability to cross the placenta and cause direct harm to the developing fetus, damage from SARS-CoV-2 seems limited to the placenta and potential injury to the fetus is indirect through placental dysfunction. Furthermore, it is notable that despite the placental pathologic lesions, short term outcomes of neonates born to mothers with SARS-CoV-2 infection at any time during pregnancy were most commonly normal; specifically, there was no marked increase in preterm birth in our maternal SARS-CoV-2 group, no difference in birthweight, head circumference or length of neonates born to women infected during pregnancy; and we found no significant difference in Apgar scores, birth weight and respiratory complications after delivery. Collectively our findings suggest that the placenta acts as a protective interface serving to prevent vertical transmission of maternal SARS-CoV-2 infection from mother to neonate. In doing so, resultant placental damage may contribute to fetal and neonatal complications, which will require further studies with longer term outcome measures to define.

The mechanism of SARS-CoV-2 injury in the placenta remains an important area for further investigation. SARS-CoV-2 infection enters host cells via interaction with the angiotensin-converting enzyme 2 receptor (ACE2) in concert with proteases like transmembrane serine protease 2 (TMPRSS2) [39]. ACE 2 is highly expressed in the placenta mainly in the syncytiotrophoblasts, cytotrophoblasts, endothelium and vascular smooth muscle of primary and secondary villi [40]. Thus, it is possible for SARS-CoV-2 to cause direct damage through binding of ACE 2 with subsequent downregulation of the renin-angiotensin system (RAS) throughout the placenta resulting in vasoconstriction and impaired blood flow and indirect damage through the upregulation of proinflammatory modulators resulting in an excessive inflammatory response resulting in placental damage [39]. It is likely that both, in addition to other factors not yet defined, play a role in the placental pathogenesis of SARS-CoV-2 resulting in the observed increased incidence of inflammatory and vascular lesions.

Our findings of high rates of MVM and FVM are consistent with current knowledge regarding SARS-CoV-2 and its association with a hypercoagulable state [41]. Likely, the same micro- and macrovascular thromboembolic complications frequently observed in the vasculature of the lungs, kidney, heart, brain, and periphery are also present in the placenta [22, 42]. Such complications in the placenta would first manifest as vascular damage at the maternal interface as MVM and progress to encompass the fetal side as FVM. As MVM and FVM lesions are independently associated with comorbidities of pregnancy, specifically severe preeclampsia (SPE) and pregnancy-induced hypertension (PIH), we conducted a separate analysis controlling for these factors. This analysis demonstrated persistently high rates of both MVM and FVM in women with SARS-CoV-2 infection during pregnancy. These lesions are suggestive of placental hypoperfusion and inflammation, which may be attributed to the effects of SARS-CoV-2 on the vasculature architecture of the placenta. This is further supported by our findings suggesting an increased frequency in SGA placentas among women with SARS-CoV-2 infection since hypoperfusion is linked with poor placental growth [26]. Together, these findings point to a potential pregnancy-specific sequalae of SARS-CoV-2 on the placenta mediated through a heightened inflammatory state and vascular endothelial damage, which may be connected to the higher risk of adverse outcomes from SARS-CoV-2 in pregnant women. However, additional studies are needed to confirm this potential mechanism of placental damage during maternal SARS-CoV-2 infection.

To our knowledge, this the largest cohort of placentas from pregnancies complicated by maternal SARS-CoV-2 infection studied to date. We were able to capture 76.4% of SARS-CoV-2 affected placentas during our study period, resulting in a cohort of 425 placentas that underwent a rigorous and thorough pathologic examination, as detailed in the Amsterdam Placental Workshop Group Consensus Statement recommendations [26]. In addition to our large sample size, we also had a control group comprised of 50 placentas from complication-free pregnancies from our institution to use as a comparison group for statistical analysis, which provides the essential framework for interpreting our data. Despite these strengths, there are key limitations of our research that leave unanswered questions in this area. Specifically, this study is limited by all of the inherent biases of a retrospective analysis including missing, incomplete, or inaccurate data. Despite inclusion of 425 placentas, we were limited to placenta pathology reports available to us. Furthermore, our placentas were analyzed by multiple different pathologists, none of whom were blinded to maternal infection status, which is a potential source of bias. Among the SARS-CoV-2 positive neonates, only 50% of placentas were available for analysis is another limitation of our study. As with any study involving placental pathology, histologic sampling evaluates only a portion of the placenta through representative sampling. This may lead to biases in the frequency and type of lesions identified. Additionally, placentas were not stained with immunohistochemistry for SARS-CoV-2 given institutional protocol, but this should be done in future studies to better investigate maternal-fetal vertical transmission of SARS-CoV-2. Nevertheless, in our cohort we found a very high prevalence of placental abnormalities associated with maternal SARS-CoV-2 infection during pregnancy.

5 Conclusion

In our retrospective cohort, a significant proportion of women with SARS-CoV-2 infection during pregnancy have identifiable histopathologic placental abnormalities at birth. These abnormalities, most specifically MVM and FVM, which are suggestive of placental hypoperfusion and inflammation, raise questions regarding their downstream effects and clinical consequences. Further large multicenter prospective studies with routine and blinded histopathologic placental examination are needed. Longitudinal follow up of neonates of born to mothers who tested positive for SARS-CoV-2 infection during pregnancy is needed to determine if any potential long term neurodevelopmental and/or behavioral problems result from the exposure.

Footnotes

Acknowledgments

This study was supported by the Children’s Health Clinical Research Advisory Council awarded to Imran N. Mir.

Disclosure statement

The authors report no conflict of interest.

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