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Original Investigation | Obstetrics and Gynecology
Characteristics and Outcomes of Women With COVID-19 Giving Birth

at US Academic Centers During the COVID-19 Pandemic
Justine Chinn, BS; Shaina Sedighim, MD; Katharine A. Kirby, MS; Samuel Hohmann, PhD; Afshan B. Hameed, MD; Jennifer Jolley, MD; Ninh T. Nguyen, MD
Abstract Key Points

Question What are the characteristics
IMPORTANCE Prior studies on COVID-19 and pregnancy have reported higher rates of cesarean
and outcomes associated with giving
delivery and preterm birth and increased morbidity and mortality. Additional data encompassing a
birth with COVID-19 over the first year of
longer time period are needed.
the pandemic in the US?
OBJECTIVE To examine characteristics and outcomes of a large US cohort of women who Findings This cohort study examines
underwent childbirth with vs without COVID-19. 869 079 adult women, including 18 715
women with COVID-19, who underwent
DESIGN, SETTING, AND PARTICIPANTS This cohort study compared characteristics and outcomes childbirth at 499 US medical centers
of women (age ⱖ18 years) who underwent childbirth with vs without COVID-19 between March 1, between March 1, 2020, and February
2020, and February 28, 2021, at 499 US academic medical centers or community affiliates. 28, 2021. Women with COVID-19 had
Follow-up was limited to in-hospital course and discharge destination. Childbirth was defined by increased mortality, need for intubation
clinical classification software procedural codes of 134-137. A diagnosis of COVID-19 was identified and ventilation, and intensive care unit
using International Statistical Classification of Diseases and Related Health Problems, Tenth Revision admission.
(ICD-10) diagnosis of U07.1. Data were analyzed from April 1 to April 30, 2021.
Meaning These findings suggest that
COVID-19 was associated with increased
EXPOSURES The presence of a COVID-19 diagnosis using ICD-10.
risk of morbidity and mortality for
women giving birth.
MAIN OUTCOMES AND MEASURES Analyses compared demographic characteristics, gestational
age, and comorbidities. The primary outcome was in-hospital mortality. Secondary outcomes
included hospital length of stay, intensive care unit (ICU) admission, mechanical ventilation, and Author affiliations and article information are
listed at the end of this article.
discharge status. Continuous variables were analyzed using t test, and categorical variables were
analyzed using χ2.
RESULTS Among 869 079 women, 18 715 (2.2%) had COVID-19, and 850 364 (97.8%) did not. Most
women were aged 18 to 30 years (11 550 women with COVID-19 [61.7%]; 447 534 women without
COVID-19 [52.6%]) and were White (8060 White women [43.1%] in the COVID-19 cohort; 499 501
White women (58.7%) in the non–COVID-19 cohort). There was no significant increase in cesarean
delivery among women with COVID-19 (6088 women [32.5%] vs 273 810 women [32.3%]; P = .57).
Women with COVID-19 were more likely to have preterm birth (3072 women [16.4%] vs 97 967
women [11.5%]; P < .001). Women giving birth with COVID-19, compared with women without
COVID-19, had significantly higher rates of ICU admission (977 women [5.2%] vs 7943 women
[0.9%]; odds ratio [OR], 5.84 [95% CI, 5.46-6.25]; P < .001), respiratory intubation and mechanical
ventilation (275 women [1.5%] vs 884 women [0.1%]; OR, 14.33 [95% CI, 12.50-16.42]; P < .001), and
in-hospital mortality (24 women [0.1%] vs 71 [<0.01%]; OR, 15.38 [95% CI, 9.68-24.43]; P < .001).
CONCLUSIONS AND RELEVANCE This retrospective cohort study found that women with
COVID-19 giving birth had higher rates of mortality, intubation, ICU admission, and preterm birth than
women without COVID-19.
JAMA Network Open. 2021;4(8):e2120456. doi:10.1001/jamanetworkopen.2021.20456
Open Access. This is an open access article distributed under the terms of the CC-BY License.
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JAMA Network Open | Obstetrics and Gynecology Characteristics and Outcomes of Women With COVID-19 Giving Birth at US Academic Centers
Introduction
Although there has been extensive research on COVID-19 since its initial emergence, the broad range
of perinatal COVID-19 outcomes continues to emerge.1 A study by Jering and colleagues2 reported
the largest US cohort, to date, including 6380 women with COVID-19 giving birth, and found that the
absolute death rates in women with COVID-19 were considerably higher than in women without
COVID-19. They also found higher rates of preterm birth, preeclampsia, and thrombotic events.2 Prior
studies on the effects of COVID-19 on pregnancy have reported higher rates of cesarean delivery,
preterm birth, and maternal morbidity and mortality index scores.3-5 As the COVID-19 pandemic has
progressed, mortality and outcomes in the general population have improved.6 The aim of this study
was to examine the characteristics and outcomes of a large US cohort of women who underwent
childbirth with vs without COVID-19 during the first year of the pandemic, examining a larger single
data set cohort of women with COVID-19 over a longer period than prior studies, to our knowledge.
Methods
This cohort study was determined exempt from review and informed consent by the Institutional
Review Board of the University of California, Irvine, owing to lack of patient-identifying information.
Approval for the use of the data was obtained from Vizient. This study followed the Strengthening
the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.
Using the Vizient Clinical Data Base/Resource Manager (CDB/RM), we compared characteristics
and outcomes of women (age ⱖ18 years) who underwent childbirth with vs without COVID-19
between March 1, 2020, and February 28, 2021. The CDB/RM is an administrative, clinical, and
financial database of more than 650 academic centers and their community affiliates. Data represent
clinical information submitted by 97% of academic medical centers across the US, representing a
broad range of patients across geographic zones. Childbirth was identified based on clinical
classification software procedural codes of 134 for cesarean delivery; 135 for forceps, vacuum, or
breech delivery; 136 for artificial rupture of membrane to assist delivery; and 137 for other procedures
to assist delivery. A diagnosis of COVID-19 was identified using International Statistical Classification
of Diseases and Related Health Problems, Tenth Revision (ICD-10)7 diagnosis of U07.1. Women who
received a diagnosis of COVID-19 during the same admission in which they underwent childbirth
were included. Demographic characteristics, gestational age, and comorbidities were compared
between groups. Race and ethnicity were self-reported; these data were examined because research
has found that individuals from racial and ethnic minority groups are disproportionally affected by
COVID-19 compared with White individuals. The primary outcome was in-hospital mortality.
Discharge disposition and in-hospital death were reported in all patients. Secondary outcomes
included hospital length of stay (LOS), rates of intensive care unit (ICU) admission and mechanical
ventilation, and discharge status.
Statistical Analysis
Comparisons were performed using t test for continuous variables and χ2 analysis for categorical
variables. Odds ratios (ORs) were calculated to determine the odds of mortality associated with
COVID-19 for each gestational age group. Analyses were performed using Stata statistical software
version 16 (StataCorp). P values were 2-tailed, and significance was set at P < .05. Data were analyzed
from April 1 to April 30, 2021.
Results
Among 869 079 women who gave birth at 499 US medical centers, 18 715 women (2.2%) had
COVID-19 and 850 364 women (97.8%) did not. Most women in both cohorts were aged 18 to 30
years (11 550 women with COVID-19 [61.7%]; 447 534 women without COVID-19 [52.6%]), and 8060

women (43.1%) were White in the COVID-19 cohort, compared with 499 501 women (58.7%) who
were White in the non–COVID-19 cohort (Table 1). Women with COVID-19, compared with women
giving birth without COVID-19, were more likely to be Hispanic (8132 women [43.5%] vs 189 725
women [22.3%]) and/or Black (3792 women [20.3%] vs 153 783 women [18.1%]). The most common
comorbidities for women giving birth with COVID-19 included obesity (3956 women [21.1%]), anemia
(2310 women [12.3%]), and chronic pulmonary disease (1437 women [7.7%]). There was no
significant difference in the number of cesarean deliveries performed (6088 women with COVID-19
[32.5%] vs 273 810 women without COVID-19 [32.2%]; P = .57). The median (range) LOS was 2 (1-211)
days for women with COVID-19 and 2 (1-370) days for women without COVID-19 (P < .001).
Women giving birth with COVID-19, compared with those without COVID-19, had significantly
higher rates of ICU admission (977 women [5.2%] vs 7943 women [0.9%]; OR, 5.84 [95% CI, 5.46-
6.25]; P < .001), respiratory intubation and mechanical ventilation (275 women [1.5%] vs 884
women [0.1%]; OR, 14.33 [95% CI, 12.50-16.42]; P < .001), and in-hospital mortality (24 women
[0.1%] vs 71 women [<0.01%]; OR, 15.38 [95% CI, 9.68-24.43]; P < .001) (Table 2).
Additionally, women with COVID-19, compared with women without COVID-19, were more
likely to have a preterm delivery of less than 37 weeks (3072 women [16.4%] vs 97 967 women
[11.5%]; P < .001). A total of 779 women with COVID-19 (4.2%) delivered at less than 32 weeks,
compared with 22 355 women without COVID-19 (2.6%) (Table 3).
Discussion
To our knowledge, this cohort study is the largest single-database study of women giving birth with
COVID-19, and we found that women with COVID had an overall peripartum death rate of 0.1%. The
death rates and need for ICU admission and respiratory failure requiring intubation were significantly
Table 1. Demographic and Clinical Characteristics of Hospitalized Women Undergoing Childbirth

With and Without COVID-19
Women, No. (%)

Characteristic With COVID-19 (n = 18 715) Without COVID-19 (n = 850 364) P value
Age, y
18-30 11 550 (61.7) 447 534 (52.6)
31-50 7165 (38.3) 403 657 (47.5) <.001
>50 NAa 173 (0.02)
Race
White 8060(43.1) 499 501 (58.7)
Black 3792 (20.3) 153 783 (18.1)
<.001
Asian 659 (3.5) 49 638 (5.8)
Unavailable 6208 (33.2) 147 445 (17.4)
Ethnicity
Hispanic origin 8132 (43.5) 189 725 (22.3)
<.001
Preexisting comorbidities
Obesity 3956 (21.1) 141 486 (16.7) <.001
Anemia 2310 (12.3) 86 890 (10.3) <.001
Chronic pulmonary disease 1437 (7.7) 69 394 (8.2) <.001
Drug abuse 469 (2.5) 25 388 (2.9) <.001
Hypertension 750 (4.0) 28 068 (3.3) <.001
Diabetes 426 (2.3) 13 737 (1.6) <.001
Coagulation deficiency 949 (5.1) 28 702 (3.4) <.001
Depression 972 (5.2) 56 430 (6.6) <.001
Delivery
Cesarean 6088 (32.5) 273 810 (32.2)
a
.57 Owing to privacy concerns, groups with fewer than
Vaginal 12 627(67.5) 576 554 (67.8)
10 patients are suppressed.

higher among COVID-19 women. Our findings are similar to those by Jering et al,2 who reported a
0.14% (9 of 6380 women) death rate for women giving birth with COVID-19 vs 0.005% (20 of
400 066 women) among women without COVID-19.2 These data also align with the international
living meta-analysis by Allotey et al,6 which found increased admission to ICU and increased need for
invasive ventilation for pregnant and recently pregnant women with COVID-19 compared with a
cohort of nonpregnant women of reproductive age.
Our study also found that women who had COVID-19 were more likely to be Black or Hispanic
compared with women without COVID-19. This information is critically important given the ongoing
issues surrounding health care disparities and race. When considering mortality during childbirth, it
is important to understand that racial disparities have been well established preceding the COVID-19
pandemic; however, they have likely been augmented by the pandemic.8-10 In fact, previous data
from the Centers for Disease Control and Prevention have demonstrated that Black and American
Indian or Alaskan Native mothers in the US are 2- to 3-fold more likely to die from pregnancy-related
causes. Of note, pregnancy-related mortality rate in the US has been increasing over the last 10 years
and is now approximately 0.017%. The mortality rate is approximately 0.044% for Black mothers.9
While the reasons behind this difference are complex, much research has supported the role of
health disparities, social and structural determinants of health, discrimination, health care access and
quality, and disproportionate burden of underlying comorbidities.11 Each of these factors has been
heightened during the COVID-19 pandemic, and therefore further study on the association of
COVID-19 with outcomes among mothers from these communities is necessary.
Table 2. Clinical Outcomes of Hospitalized Women Undergoing Childbirth With and Without COVID-19
No. (%)
With COVID-19 Without COVID-19 Odds ratio
(n = 18 715) (n = 850 364) (95% CI) P value
In-hospital mortality 24 (0.1) 71 (<0.01) 15.38 (9.68-24.43) <.001
Median length of hospital stay, 2 (1-211) 2 (1-370) NA <.001
median (range), d
ICU admission 977 (5.2) 7943 (0.9) 5.84 (5.46-6.25) <.001
Respiratory failure and mechanical 275 (1.5) 884 (0.1) 14.33 (12.50-16.42) <.001
ventilation
Discharge status
Home 18 477 (98.7) 845 240 (99.4) 0.47 (0.41-0.54) <.001
Skilled nursing facility or other 104 (0.6) 1752 (0.2) 2.71 (2.22-3.30) <.001
inpatient care
Left against medical advice 102 (0.6) 1930 (0.2) 2.41 (1.97-2.94) <.001
Abbreviations: ICU, intensive care unit; NA, not
Died 24 (0.1) 71 (<0.01) 15.38 (9.68-24.43) <.001
available.
Table 3. Gestational Age and Associated Mortality of Hospitalized Women Undergoing Childbirth
With and Without COVID-19
Women, No. (%)

With COVID-19 Without COVID-19 Odds ratio
Gestational age (n = 18 715) (n = 850 364) (95% CI) P value
<28 wk (extremely preterm) 380 (2.0) 12 265 (1.4) 9.22 (3.70-23.01) <.001
Mortality NAa 21 (0.2) NA NA
28-31 wk (very preterm) 399 (2.1) 10 090 (1.2) 12.64 (3.79-42.24) <.001
Mortality NAa NAa NA NA
32-36 wk (moderate to late 2293 (12.3) 75 612 (8.9) 22.83 (9.74-53.49) <.001
preterm)
Abbreviation: NA, not applicable.
Mortality NAa 13 (<0.1) NA NA
a
Owing to privacy concerns, groups with fewer than
≥37 wk 15 523 (82.9) 745 581(87.7) 0.44 (3.97-27.47) <.001
a
10 patients are suppressed.
Mortality NA 23 (≤0.1) NA NA
b
Odds ratio for mortality in unknown group could not
Unknown 120 (0.64) 6816 (2.2) NAb NA
be estimated owing to zero count.

Our subset analysis based on gestational age found that women with COVID-19 were more likely
to deliver at less than 37 weeks than women who did not have COVID-19. Our findings were
consistent with a study by Villar et al5 that found higher rates of preterm birth in a multinational
cohort study, as well as with Jering and colleagues,2 who reported that COVID-19 was associated with
higher odds of preterm birth. This is in contrast to a study by Adhikari and colleagues12 that reported
no difference in preterm birth between women with COVID-19 vs those without. Our findings
suggest that additional research is warranted to understand the physiological mechanism of
COVID-19 in preterm birth.
Limitations
There are several limitations to this study, including those inherent to retrospective administrative
database studies, including missing data, misclassification, and potential coding inaccuracy. The
CDB/RM database is limited to in-hospital mortality and does not contain follow-up data; thus,
reported mortality likely underestimates the true mortality. Other limitations include the inability to
distinguish patients with COVID-19 who were symptomatic and who were admitted for management
of their symptoms versus patients who were asymptomatic and had test results positive for SARS-
CoV-2 infection when they were admitted for their birth.
Conclusions
This cohort study found that women with COVID-19 who were giving birth had a statistically
significantly higher mortality rate of 0.13% compared with women without COVID-19. The need for
ICU admission and respiratory failure requiring intubation were statistically significantly higher
among women with COVID-19. Future research is needed to further understand the pathophysiology
of COVID-19 during pregnancy and to better characterize the long-term sequelae.
ARTICLE INFORMATION
Accepted for Publication: June 2, 2021.
Published: August 11, 2021. doi:10.1001/jamanetworkopen.2021.20456
Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Chinn J
et al. JAMA Network Open.
Corresponding Author: Ninh T. Nguyen, MD, University of California, Irvine Medical Center, 333 City Bldg W, Ste
1600, Orange, CA 92868 ([email protected]).
Author Affiliations: University of California, Irvine Medical Center, Orange (Chinn, Sedighim, Kirby, Hameed,
Jolley, Nguyen); Vizient, Centers for Advanced Analytics, Chicago, Illinois (Hohmann).
Author Contributions: Dr Nguyen had full access to all of the data in the study and takes responsibility for the
integrity of the data and the accuracy of the data analysis.
Concept and design: Chinn, Sedighim, Nguyen.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Chinn, Sedighim, Nguyen.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Sedighim, Kirby.
Administrative, technical, or material support: Chinn, Nguyen.
Supervision: Sedighim, Hameed, Jolley, Nguyen.
Conflict of Interest Disclosures: Dr Nguyen reported receiving personal fees from Olympus and Endogastric
Solutions outside the submitted work. No other disclosures were reported.
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Medical Centers. JAMA Netw Open. 2021;4(3):e210417. doi:10.1001/jamanetworkopen.2021.0417
9. Janevic T, Glazer KB, Vieira L, et al. Racial/ethnic disparities in very preterm birth and preterm birth before and
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jamanetworkopen.2020.29256

Morbidity and Mortality Weekly Report
Risk for Stillbirth Among Women With and Without COVID-19 at Delivery
Hospitalization — United States, March 2020–September 2021
Carla L. DeSisto, PhD1; Bailey Wallace, MPH1; Regina M. Simeone, PhD1; Kara Polen, MPH1; Jean Y. Ko, PhD1;
Dana Meaney-Delman, MD1; Sascha R. Ellington, PhD1
On November 19, 2021, this report was posted as an MMWR Delta variant predominance. Implementing evidence-based
Early Release on the MMWR website (https://www.cdc.gov/mmwr). COVID-19 prevention strategies, including vaccination
Pregnant women are at increased risk for severe COVID-19– before or during pregnancy, is critical to reducing the impact
related illness, and COVID-19 is associated with an increased of COVID-19 on stillbirths.
risk for adverse pregnancy outcomes and maternal and neo- Delivery hospitalizations were identified from PHD-SR
natal complications (1–3). To date, studies assessing whether using International Classification of Diseases, Tenth Revision,
COVID-19 during pregnancy is associated with increased Clinical Modification (ICD-10-CM) diagnostic and procedure
risk for stillbirth have yielded mixed results (2–4). Since the codes pertaining to obstetric delivery and diagnosis-related
B.1.617.2 (Delta) variant of SARS-CoV-2 (the virus that group delivery codes.¶ Deliveries with discharge dates dur-
causes COVID-19) became the predominant circulating ing March 2020–September 2021 were included. Stillbirths,
variant,* there have been anecdotal reports of increasing rates defined as fetal deaths at ≥20 weeks’ gestation, were identified
of stillbirths in women with COVID-19.† CDC used the using maternal ICD-10-CM diagnosis codes.** Hospitalizations
Premier Healthcare Database Special COVID-19 Release without ICD-10-CM codes indicating gestational age or with
(PHD-SR), a large hospital-based administrative database,§ to ICD-10-CM codes indicating gestational age <20 weeks were
assess whether a maternal COVID-19 diagnosis documented excluded to reduce misclassification of fetal deaths at <20 weeks’
at delivery hospitalization was associated with stillbirth during gestation as stillbirths (1.5% of the overall sample).
March 2020–September 2021 as well as before and during the Maternal demographic variables assessed included age, race/
period of Delta variant predominance in the United States ethnicity (i.e., Hispanic, non-Hispanic Black, non-Hispanic
(March 2020–June 2021 and July–September 2021, respec- White, non-Hispanic Asian, and non-Hispanic other), and
tively). Among 1,249,634 deliveries during March 2020– primary payor (i.e., Medicaid, private insurance, self-pay, and
September 2021, stillbirths were rare (8,154; 0.65%): 273 other). Assessed hospital characteristics included urban or rural
(1.26%) occurred among 21,653 deliveries to women with location and U.S. Census division. COVID-19†† and selected
COVID-19 documented at the delivery hospitalization, and underlying medical conditions (i.e., obesity, smoking,§§ any
7,881 (0.64%) occurred among 1,227,981 deliveries without diabetes,¶¶ any hypertension,*** and multiple-gestation
COVID-19. The adjusted risk for stillbirth was higher in
¶ ICD-10-CM diagnostic and procedure codes pertaining to obstetric delivery:
deliveries with COVID-19 compared with deliveries without Z37.0, Z37.1, Z37.2, Z37.3, Z37.4, Z37.50, Z37.51, Z37.52, Z37.53, Z37.54,
COVID-19 during March 2020–September 2021 (adjusted Z37.59, Z37.60, Z37.61, Z37.62, Z37.63, Z37.64, Z37.69, Z37.7, Z37.9,
relative risk [aRR] = 1.90; 95% CI = 1.69–2.15), including O75.82, O80, O82, 10D00Z0, 10D00Z1, 10D00Z2, 10D07Z3, 10D07Z4,
10D07Z5, 10D07Z6, 10D07Z7, 10D07Z8, 10E0XZZ; Diagnosis-related
during the pre-Delta (aRR = 1.47; 95% CI = 1.27–1.71) and group delivery codes: 765, 766, 767, 768, 774, 775, 783, 784, 785, 786, 787,
Delta periods (aRR = 4.04; 95% CI = 3.28–4.97). COVID-19 788, 796, 797, 798, 805, 806, 807; Excluded codes for ectopic or molar
documented at delivery was associated with increased risk for pregnancies and pregnancies with abortive outcomes: O00, O01, O02, O03,
O04, O07, O08, Z33.2, 10A0. Deliveries with the O82 code were excluded if
stillbirth, with a stronger association during the period of they did not cooccur with another delivery code. Females aged 12–55 years were
included. Multiple delivery events per woman during March 2020–September
* https://covid.cdc.gov/covid-data-tracker/#datatracker-home 2021 were included if the deliveries were >6 months apart.
† https://msdh.ms.gov/msdhsite/_static/23,23645,341.html
** ICD-10-CM maternal diagnostic codes indicating a stillbirth: Z37.1, Z37.3,
§ PHD-SR, formerly known as the PHD COVID-19 Database, is a large U.S.
Z37.4, Z37.60, Z37.61, Z37.62, Z37.63, Z37.64, Z37.69, Z37.7. In multiple-
hospital-based, service-level, all-payor database that includes inpatient and gestation pregnancies, if a woman experienced multiple stillbirths, she was
hospital-based outpatient (e.g., emergency department or clinic) health care counted once as experiencing a stillbirth. If she experienced both a live birth and
encounters from >900 geographically diverse nonprofit, nongovernmental, a stillbirth during one delivery hospitalization, she was also counted once as
community, and teaching hospitals and health systems from rural and urban experiencing a stillbirth.
areas. PHD-SR represents approximately 20% of inpatient admissions in the †† COVID-19 was identified using ICD-10-CM code U07.1 (COVID-19, virus
United States. Data for this study represent a subset of 736 hospitals with identified) during April 2020–September 2021 or B97.29 (Other coronavirus
delivery hospitalizations that contributed inpatient encounters to the PHD-SR as the cause of disease classified elsewhere) during March–April 2020.
during March 2020–September 2021. Updated PHD-SR data are released §§ Includes smoking (tobacco) complicating pregnancy, childbirth, or the puerperium.
every 2 weeks; release date November 9, 2021, access date November 12, 2021. ¶¶ Includes prepregnancy diabetes and gestational diabetes.
https://offers.premierinc.com/rs/381-NBB-525/images/PHD_COVID-19_ *** Includes chronic hypertension; gestational hypertension; chronic
White_Paper.pdf hypertension with superimposed preeclampsia; preeclampsia; hemolysis,
elevated liver enzymes, low platelet count (HELLP) syndrome; and eclampsia
1640 MMWR / November 26, 2021 / Vol. 70 / No. 47 US Department of Health and Human Services/Centers for Disease Control and Prevention
pregnancy) were included if the relevant ICD-10-CM diagnosis During March 2020–September 2021, a total of 8,154
code was documented during the delivery hospitalization stillbirths were documented, affecting 0.64% and 1.26%
(3). In addition, among deliveries with documented of deliveries without COVID-19 and with COVID-19,
COVID-19, indicators of severe illness (i.e., adverse cardiac respectively (aRR = 1.90; 95% CI = 1.69–2.15) (Figure).
event/outcome,††† placental abruption, sepsis, shock, acute During the pre-Delta period (March 2020–June 2021), 6,983
respiratory distress syndrome, mechanical ventilation, and stillbirths were documented, involving 0.98% of deliveries
intensive care unit [ICU] admission) were considered present with COVID-19 compared with 0.64% of deliveries without
if the relevant ICD-10-CM diagnosis code was documented COVID-19 (aRR = 1.47; 95% CI = 1.27–1.71). During the
during the delivery hospitalization (3). Vaccination status was Delta period (July–September 2021), 1,171 stillbirths were
unable to be assessed in this analysis. documented, involving 2.70% of deliveries with COVID-19
Poisson regression models with robust standard errors were compared with 0.63% of deliveries without COVID-19
used to calculate overall unadjusted and adjusted§§§ relative risks (aRR = 4.04; 95% CI = 3.28–4.97).†††† Effect modification
for stillbirth among deliveries with COVID-19 versus deliveries was present in the model; the risk for stillbirth was significantly
without COVID-19, accounting for within-hospital and within- higher during the period of Delta predominance than during
woman correlation. To better understand the potential biologic the pre-Delta period (p<0.001).
mechanism for stillbirth among women with COVID-19 at Among deliveries with COVID-19, chronic hypertension,
delivery, Poisson regression models with robust SEs were used multiple-gestation pregnancy, adverse cardiac event/outcome,
to calculate unadjusted and adjusted¶¶¶ prevalence ratios for placental abruption, sepsis, shock, acute respiratory distress
stillbirth for each underlying medical condition and indicator syndrome, mechanical ventilation, and ICU admission were
of severe illness among deliveries with documented COVID-19. associated with a higher prevalence of stillbirth (Table 2). The
Relative risks and prevalence ratios were calculated overall as well associations for adverse cardiac event/outcome and ICU admis-
as during the pre-Delta and Delta periods. Effect modification sion varied significantly between the periods before and during
by period was assessed using adjusted models with interaction Delta predominance (p = 0.03 and p = 0.003, respectively); for
terms. For all models, p-values <0.05 were considered statisti- each of these, the associations were stronger during the period
cally significant. All analyses were performed using SAS software of Delta predominance.
(version 9.4; SAS Institute). This activity was reviewed by CDC
Discussion
and was conducted consistent with applicable federal law and
CDC policy.**** Although stillbirth was a rare outcome overall, a COVID-19
Among 1,249,634 deliveries at 736 hospitals during diagnosis documented during the delivery hospitalization was
March 2020–September 2021, 53.7% of women were non- associated with an increased risk for stillbirth in the United
Hispanic White, and 50.6% had private insurance as the States, with a stronger association during the period of Delta vari-
primary payor (Table 1). Overall, 15.4% had obesity, 11.2% ant predominance. A previous study of pregnancies complicated
had diabetes, 17.2% had a hypertensive disorder, 1.8% by SARS-CoV-2 infection identified placental histopathologic
had a multiple-gestation pregnancy, and 4.9% had smok- abnormalities, suggesting that placental hypoperfusion and
ing (tobacco) documented on the delivery hospitalization inflammation might occur with maternal COVID-19 infec-
record. Overall, 21,653 (1.73%) delivery hospitalizations had tion (5); these findings might, in part, explain the association
COVID-19 documented. between COVID-19 and stillbirth. Among deliveries with
††† Includes acute myocardial infarction, cardiomyopathy, heart failure/arrest
COVID-19 documented during the delivery hospitalization,
during surgery or procedure, cardiac arrest/ventricular fibrillation,
certain underlying medical conditions and markers of maternal
conversion of cardiac rhythm, incident ventricular tachycardia, ischemia, morbidity, including the need for intensive care, were associated
pulmonary edema/acute heart failure, and atrial fibrillation/atrial flutter/ with stillbirth. Additional studies are warranted to investigate
supraventricular tachycardia.
§§§ Models accounted for within-facility and within-woman correlation, and the role of maternal complications from COVID-19 on the risk
were adjusted for maternal age, race/ethnicity (Hispanic, non-Hispanic for stillbirth. Further, given the differences observed before and
Black, non-Hispanic White, and non-Hispanic other), primary payor during the period of Delta variant predominance, comparisons
(Medicaid, private insurance, and other), obesity, smoking, any diabetes,
any hypertension, and multiple-gestation pregnancy. of placental findings might improve understanding of biologic
¶¶¶ Models accounted for within-facility and within-woman correlation, and
reasons for the observed differences.
were adjusted for maternal age, race/ethnicity (Hispanic, non-Hispanic
Black, non-Hispanic White, and non-Hispanic other), and primary payor †††† Sensitivity analyses were conducted to check for possible seasonality of
(Medicaid, private insurance, and other). stillbirths. In models using calendar year quarters, traditional seasons based
**** 45 C.F.R. part 46, 21 C.F.R. part 56; 42 U.S.C. Sect. 241(d); 5 U.S.C. on temperature patterns, and waves of SARS-CoV-2 variants, the results
Sect. 552a; 44 U.S.C. Sect. Sect. 3501 et seq. did not substantively change.
US Department of Health and Human Services/Centers for Disease Control and Prevention MMWR / November 26, 2021 / Vol. 70 / No. 47 1641
TABLE 1. Maternal demographic and health characteristics and hospital characteristics among delivery hospitalizations with and without a
documented COVID-19 diagnosis — Premier Healthcare Database Special COVID-19 Release, United States, March 2020–September 2021
No. (%)
Overall Pre-Delta* (Mar 2020–Jun 2021) Delta* (Jul–Sep 2021)
N = 1,249,634 n = 1,076,745 n = 172,889
Total No COVID-19 COVID-19 No COVID-19 COVID-19 No COVID-19 COVID-19
Characteristic N = 1,249,634 n = 1,227,981 n = 21,653 n = 1,058,651 n = 18,094 n = 169,330 n = 3,559
Maternal age, 29.0 (5.8) 29.0 (5.8) 28.0 (6.0) 29.0 (5.8) 28.0 (6.0) 29.0 (5.7) 28.0 (5.8)
median (SD)
Maternal race/ethnicity
White, non-Hispanic 671,392 (53.7) 663,136 (54.0) 8,256 (38.1) 574,368 (54.3) 6,660 (36.8) 88,768 (52.4) 1,596 (44.8)
Hispanic 230,836 (18.5) 223,784 (18.2) 7,052 (32.6) 188,114 (17.8) 6,164 (34.1) 35,670 (21.1) 888 (25.0)
Black, non-Hispanic 181,143 (14.5) 177,508 (14.5) 3,635 (16.8) 153,408 (14.5) 2,947 (16.3) 24,100 (14.2) 688 (19.3)
Asian 57,535 (4.6) 56,855 (4.6) 680 (3.1) 49,583 (4.7) 604 (3.3) 7,272 (4.3) 76 (2.1)
Other/Unknown, 108,728 (8.7) 106,698 (8.7) 2,030 (9.4) 93,178 (8.8) 1,719 (9.5) 13,520 (8.0) 311 (8.7)
non-Hispanic
Primary payor
Private 631,894 (50.6) 624,069 (50.8) 7,825 (36.1) 537,957 (50.8) 6,367 (35.2) 86,112 (50.9) 1,458 (41.0)
Medicaid 534,139 (42.7) 521,739 (42.5) 12,400 (57.3) 450,813 (42.6) 10,548 (58.3) 70,926 (41.9) 1,852 (52.0)
Self-pay 21,022 (1.7) 20,557 (1.7) 465 (2.1) 17,351 (1.6) 386 (2.1) 3,206 (1.9) 79 (2.2)
Other 62,579 (5.0) 61,616 (5.0) 963 (4.4) 52,530 (5.0) 793 (4.4) 9,086 (5.4) 170 (4.8)
Hospital location
Rural 159,634 (12.8) 157,006 (12.8) 2,628 (12.1) 134,615 (12.7) 2,014 (11.1) 22,391 (13.2) 614 (17.3)
Urban 1,090,000 (87.2) 1,070,975 (87.2) 19,025 (87.9) 924,036 (87.3) 16,080 (88.9) 146,939 (86.8) 2,945 (82.7)
U.S. Census division
East North Central 200,701 (16.1) 198,061 (16.1) 2,640 (12.2) 169,631 (16.0) 2,259 (12.5) 28,430 (16.8) 381 (10.7)
East South Central 94,224 (7.5) 92,902 (7.6) 1,322 (6.1) 80,335 (7.6) 1,018 (5.6) 12,567 (7.4) 304 (8.5)
Middle Atlantic 147,774 (11.8) 144,423 (11.8) 3,351 (15.5) 124,755 (11.8) 3,123 (17.3) 19,668 (11.6) 228 (6.4)
Mountain 91,554 (7.3) 90,458 (7.4) 1,096 (5.1) 77,393 (7.3) 939 (5.2) 13,065 (7.7) 157 (4.4)
New England 25,158 (2.0) 24,892 (2.0) 266 (1.2) 21,463 (2.0) 246 (1.4) 3,429 (2.0) 20 (0.6)
Pacific 126,615 (10.1) 124,277 (10.1) 2,338 (10.8) 107,760 (10.2) 1,890 (10.4) 16,517 (9.8) 448 (12.6)
South Atlantic 332,317 (26.6) 326,419 (26.6) 5,898 (27.2) 283,595 (26.8) 4,683 (25.9) 42,824 (25.3) 1,215 (34.1)
West North Central 80,263 (6.4) 78,710 (6.4) 1,553 (7.2) 66,326 (6.3) 1,310 (7.2) 12,384 (7.3) 243 (6.8)
West South Central 151,028 (12.1) 147,839 (12.0) 3,189 (14.7) 127,393 (12.0) 2,626 (14.5) 20,446 (12.1) 563 (15.8)
Obesity
No 1,057,646 (84.6) 1,039,849 (84.7) 17,797 (82.2) 897,069 (84.7) 14,881 (82.2) 142,780 (84.3) 2,916 (81.9)
Yes 191,988 (15.4) 188,132 (15.3) 3,856 (17.8) 161,582 (15.3) 3,213 (17.8) 26,550 (15.7) 643 (18.1)
Diabetes (any)†
No 1,109,053 (88.8) 1,090,087 (88.8) 18,966 (87.6) 940,575 (88.8) 15,803 (87.3) 149,512 (88.3) 3,163 (88.9)
Yes 140,581 (11.2) 137,894 (11.2) 2,687 (12.4) 118,076 (11.2) 2,291 (12.7) 19,818 (11.7) 396 (11.1)
Hypertensive disorders of pregnancy (any)§
No 1,034,519 (82.8) 1,016,918 (82.8) 17,601 (81.3) 877,063 (82.8) 14,678 (81.1) 139,855 (82.6) 2,923 (82.1)
Yes 215,115 (17.2) 211,063 (17.2) 4,052 (18.7) 181,588 (17.2) 3,416 (18.9) 29,475 (17.4) 636 (17.9)
Multiple-gestation pregnancy
No 1,226,534 (98.2) 1,205,299 (98.2) 21,235 (98.1) 1,039,095 (98.2) 17,751 (98.1) 166,204 (98.2) 3,484 (97.9)
Yes 23,100 (1.8) 22,682 (1.8) 418 (1.9) 19,556 (1.8) 343 (1.9) 3,126 (1.8) 75 (2.1)
Smoking¶
No 1,187,831 (95.1) 1,166,855 (95.0) 20,976 (96.9) 1,005,234 (95.0) 17,598 (97.3) 161,621 (95.4) 3,378 (94.9)
Yes 61,803 (4.9) 61,126 (5.0) 677 (3.1) 53,417 (5.0) 496 (2.7) 7,709 (4.6) 181 (5.1)
Stillbirth
No 1,241,480 (99.3) 1,220,100 (99.4) 21,380 (98.7) 1,051,845 (99.4) 17,917 (99.0) 168,255 (99.4) 3,463 (97.3)
Yes 8,154 (0.7) 7,881 (0.6) 273 (1.3) 6,806 (0.6) 177 (1.0) 1,075 (0.6) 96 (2.7)
Timing of stillbirth, wks (trimester)**
20–27 (2nd) 3,607 (44.2) 3,498 (44.4) 109 (39.9) 3,058 (44.9) 77 (43.5) 440 (40.9) 32 (33.3)
28–42 (3rd) 4,547 (55.8) 4,383 (55.6) 164 (60.1) 3,748 (55.1) 100 (56.5) 635 (59.1) 64 (66.7)
Gestational age at 29.0 (6.8) 29.0 (6.8) 29.0 (6.2) 29.0 (6.8) 29.0 (6.5) 30.0 (6.7) 30.0 (5.7)
stillbirth, wks,
median (SD)
Abbreviation: HELLP = hemolysis, elevated liver enzymes, low platelet count.
* Deliveries with discharge dates during March 2020–June 2021 were considered to have occurred during the pre-Delta period, whereas deliveries with discharge
dates during July–September 2021 were considered to have occurred during the period of Delta predominance.
† Includes prepregnancy diabetes and gestational diabetes.
§ Includes chronic hypertension, gestational hypertension, chronic hypertension with superimposed preeclampsia, preeclampsia, HELLP syndrome, and eclampsia.
¶ Includes smoking (tobacco) complicating pregnancy, childbirth, or the puerperium.
** Only among deliveries with a stillbirth.
FIGURE. Relative risk for stillbirth among women with COVID-19 at delivery hospitalization compared with those without COVID-19 at delivery
hospitalization — Premier Healthcare Database Special COVID-19 Release, United States, March 2020–September 2021*,†,§
h Options 10
ide = 7.5”
tats = 5.0”
ns = 4.65”
mn = 3.57”
Relative risk (log scale)
0.1
Overall Overall Pre-Delta Pre-Delta Delta Delta
unadjusted adjusted unadjusted adjusted unadjusted adjusted
Period of variant predominance
Abbreviation: RR = relative risk.
* Deliveries with discharge dates during March 2020–June 2021 were considered to have occurred during the period preceding SARS-CoV-2 B.1.617.2 (Delta) variant
predominance, whereas those with discharge dates during July–September 2021 were considered to have occurred during the period of Delta predominance.
† Overall: unadjusted RR = 1.96 (95% CI = 1.74–2.21); adjusted RR = 1.90 (95% CI = 1.69–2.15); pre-Delta: unadjusted RR = 1.52 (95% CI = 1.31–1.77); adjusted RR = 1.47
(95% CI = 1.27–1.71); Delta: unadjusted RR = 4.25 (95% CI = 3.46–5.22); adjusted RR = 4.04 (95% CI = 3.28–4.97); p-value for effect modification by period (pre-Delta
period versus period of Delta predominance): <0.001.
§ Models accounted for within-facility and within-woman correlation, and were adjusted for maternal age, race/ethnicity (Hispanic, non-Hispanic Black, non-Hispanic White,
and non-Hispanic other), primary payor (Medicaid, private insurance, and other), obesity, smoking, any diabetes, any hypertension, and multiple-gestation pregnancy.
The rates of stillbirth in women without COVID-19 at infectious and is associated with increased risk for hospitaliza-
delivery in this analysis (0.64% overall) were similar to the tion compared with previous variants (7,8); however, non-
known prepandemic stillbirth rate of 0.59% (6). However, pregnant patients are not more likely to have severe outcomes
0.98% of COVID-19–affected deliveries pre-Delta and 2.70% during hospitalization (9). In this analysis, the association
during the Delta period resulted in stillbirth. Data on the between COVID-19 and stillbirth was stronger during the
association between COVID-19 in pregnancy and stillbirth period of Delta predominance. Further studies that examine
are emerging. Two metaanalyses found an association between the effect of SARS-CoV-2 infection, including with the Delta
COVID-19 during pregnancy and stillbirth but were unable variant, on fetal well-being are warranted.
to adjust for potential confounders (2,4). In a previous analysis The findings in this report are subject to at least seven
of the PHD-SR data, comparing women with and without limitations. First, the analysis relied on administrative data
COVID-19 documented at the delivery hospitalization dur- from hospital discharge ICD-10-CM codes; thus, identifica-
ing March–September 2020, the risk for stillbirth was not tion of COVID-19 status, underlying medical conditions,
significantly increased after adjusting for confounders (3). The gestational age, and stillbirths might be misclassified. Second,
current analysis includes an additional year of data, adding to gestational age at SARS-CoV-2 infection was not available, and
the growing evidence that COVID-19 is associated with an it is unknown whether COVID-19 diagnoses documented
increased risk for stillbirth. during the delivery hospitalization represented current or
Delta became the predominant variant of SARS-CoV-2 in past infection. Third, many hospitals implemented univer-
the United States in July 2021.§§§§ The Delta variant is more sal SARS-CoV-2 testing among pregnant women assessed
§§§§ https://www.reuters.com/world/us/delta-variant-already-dominant-us-cdc-
in labor and delivery units during spring 2020 (10), which
estimates-show-2021-07-07/ would increase the detection of asymptomatic COVID-19.
Laboratory information was unavailable for most hospitals in
TABLE 2. Risk for stillbirth by maternal health characteristics and indicators of severe illness among delivery hospitalizations with a documented
COVID-19 diagnosis — Premier Healthcare Database Special COVID-19 Release, United States, March 2020–September 2021
Overall Pre-Delta* (Mar 2020–Jun 2021) Delta* (Jul–Sep 2021)
N = 21,653 n = 18,094 n = 3,559
Outcome RR Outcome RR Outcome RR
No. (%) (95% CI) No. (%) (95% CI) No. (%) (95% CI)
No No No
Characteristic stillbirth Stillbirth Unadjusted Adjusted† stillbirth Stillbirth Unadjusted Adjusted† stillbirth Stillbirth Unadjusted Adjusted† p-value§
Hypertensive 3,995 57 1.15 1.08 3,379 37 1.14 1.05 616 20 1.21 1.19 <0.001
disorders of (18.7) (20.9) (0.86–1.53) (0.81–1.44) (18.9) (20.9) (0.79–1.63) (0.73–1.50) (17.8) (20.8) (0.74–1.96) (0.74–1.92)
pregnancy
(any)¶
Chronic 515 13 2.00 1.79 418 7 1.71 1.49 97 6 2.24 2.11 0.02
hypertension (2.4) (4.8) (1.15–3.47) (1.03–3.11) (2.3) (4.0) (0.81–3.62) (0.70–3.19) (2.8) (6.3) (1.00–4.99) (0.94–4.74)
Pregnancy- 3,480 44 0.99 0.94 2,961 30 1.03 0.97 519 14 0.97 0.96 0.005
associated (16.3) (16.1) (0.72–1.36) (0.68–1.29) (16.5) (16.9) (0.70–1.52) (0.66–1.43) (15.0) (14.6) (0.66–1.43) (0.55–1.69)
hypertension**
Obesity 3,810 46 0.94 0.90 3,181 32 1.02 0.97 629 14 0.77 0.78 0.02
(17.8) (16.8) (0.68–1.28) (0.66–1.23) (17.8) (18.1) (0.70–1.50) (0.66–1.42) (18.2) (14.6) (0.44–1.36) (0.44–1.37)
Diabetes 2,659 28 0.81 0.80 2,273 18 0.78 0.78 386 10 0.93 0.88 0.005
(any)†† (12.4) (10.3) (0.55–1.19) (0.53–1.18) (12.7) (10.2) (0.48–1.27) (0.47–1.30) (11.1) (10.4) (0.49–1.77) (0.46–1.67)
Smoking§§ 663 14 1.67 1.56 488 8 1.68 1.60 175 6 1.24 1.09 0.18
(3.1) (5.1) (0.98–2.85) (0.91–2.68) (2.7) (4.5) (0.83–3.39) (0.79–3.27) (5.1) (6.3) (0.55–2.80) (0.47–2.52)
Multiple- 399 19 3.80 3.54 330 13 4.10 3.76 69 6 3.10 3.04 0.11
gestation (1.9) (7.0) (2.41–6.00) (2.24–5.59) (1.8) (7.3) (2.36–7.14) (2.16–6.57) (2.0) (6.3) (1.40–6.85) (1.35–6.82)
pregnancy
Adverse cardiac 160 10 4.81 4.44 120 4 3.35 3.09 40 6 5.09 5.18 0.03
event/ (0.7) (3.7) (2.60–8.87) (2.38–8.29) (0.7) (2.3) (1.26–8.89) (1.15–8.34) (1.2) (6.3) (2.35–11.03) (2.34–11.48)
outcome¶¶
Placental 273 36 10.49 10.12 206 22 11.12 10.63 67 14 7.33 7.53 0.07
abruption (1.3) (13.2) (7.53–14.63) (7.28–14.08) (1.1) (12.4) (7.26–17.05) (6.96–16.22) (1.9) (14.6) (4.35–12.36) (4.47–12.66)
Sepsis 306 10 2.57 2.55 211 6 2.89 2.83 95 4 1.52 1.58 0.56
(1.4) (3.7) (1.38–4.78) (1.37–4.76) (1.2) (3.4) (1.30–6.45) (1.27–6.31) (2.7) (4.2) (0.57–4.05) (0.59–4.21)
Shock 121 15 9.20 9.31 91 8 8.60 8.70 30 7 7.49 7.95 0.07
(0.6) (5.5) (5.62–15.05) (5.65–15.35) (0.5) (4.5) (4.35–17.00) (4.35–17.39) (0.9) (7.3) (3.73–15.04) (3.95–16.00)
Acute respiratory 915 25 2.22 2.16 601 12 2.07 2.01 314 13 1.55 1.53 0.09
distress (4.3) (9.2) (1.48–3.33) (1.44–3.23) (3.4) (6.8) (1.16–3.71) (1.13–3.59) (9.1) (13.5) (0.87–2.75) (0.87–2.70)
syndrome
Mechanical 379 20 4.21 4.12 257 12 4.82 4.79 122 8 2.40 2.41 0.57
ventilation (1.8) (7.3) (2.70–6.57) (2.62–6.48) (1.4) (6.8) (2.72–8.55) (2.67–8.61) (3.5) (8.3) (1.19–4.84) (1.17–4.95)
ICU admission 1,074 36 2.81 2.74 800 18 2.39 2.31 274 18 2.58 2.57 0.003
(5.0) (13.2) (1.99–3.97) (1.93–3.89) (4.5) (10.2) (1.48–3.87) (1.42–3.76) (7.9) (18.8) (1.57–4.25) (1.54–4.28)
Abbreviations: HELLP = hemolysis, elevated liver enzymes, low platelet count; ICU = intensive care unit; RR = relative risk.
* Deliveries with discharge dates during March 2020–June 2021 were considered to occur during the pre-Delta period, whereas deliveries with discharges dates
during July–September 2021 were considered to occur during the period of Delta predominance.
† Models accounted for within-facility and within-woman correlation, and were adjusted for maternal age, race/ethnicity (Hispanic, non-Hispanic Black, non-Hispanic
White, and non-Hispanic other), and primary payor (Medicaid, private insurance, and other).
§ Assessing for effect modification by period (pre-Delta versus period of Delta predominance), based on interaction term added to adjusted model.
¶ Includes chronic hypertension, gestational hypertension, chronic hypertension with superimposed preeclampsia, preeclampsia, HELLP syndrome, and eclampsia.
** Includes gestational hypertension, chronic hypertension with superimposed preeclampsia, preeclampsia, HELLP syndrome, and eclampsia.
†† Includes prepregnancy diabetes and gestational diabetes.
§§ Includes smoking (tobacco) complicating pregnancy, childbirth, or the puerperium.
¶¶ Includes acute myocardial infarction, cardiomyopathy, heart failure/arrest during surgery or procedure, cardiac arrest/ventricular fibrillation, conversion of cardiac
rhythm, incident ventricular tachycardia, ischemia, pulmonary edema/acute heart failure, and atrial fibrillation/atrial flutter/supraventricular tachycardia.
PHD-SR and therefore not used in this analysis; if participating was restricted to codes included during the delivery hospitaliza-
hospitals had different screening practices, some patients with tion and did not examine COVID-19 diagnoses or underlying
SARS-CoV-2 infection might have been missed or misclassi- medical conditions recorded before the delivery hospitalization
fied. In hospitals not conducting universal SARS-CoV-2 test- (i.e., during a prenatal visit). Fifth, whole genome sequencing
ing, women experiencing adverse outcomes during the delivery data were not available to confirm the variant of SARS-CoV-2
hospitalization, including stillbirth, might have been more for this analysis, and period was used as a proxy; however,
likely to be tested for SARS-CoV-2 infection. Fourth, because the Delta variant accounted for >90% of U.S. COVID-19
outpatient records were not universally available, and linkage cases during July–September 2021.¶¶¶¶ Sixth, it was not
across different hospital systems was not possible, the analysis ¶¶¶¶ https://covid.cdc.gov/covid-data-tracker/#variant-proportions
Acknowledgments
Summary
Tegan Boehmer, Lara Bull, Jennifer Wiltz, Data, Analytics, and
What is already known about this topic?
Visualization Task Force, CDC COVID-19 Response Team; Romeo
Pregnant women are at increased risk for severe disease from
Galang, Suzanne Gilboa, Titilope Oduyebo, Emily O’Malley Olsen,
COVID-19, and COVID-19 is associated with an increased risk for
Maria Rivera, Neha Shinde, Van Tong, Kate Woodworth, Lauren
adverse perinatal outcomes.
Zapata, Pregnancy and Infant Linked Outcomes Team, CDC
What is added by this report? COVID-19 Response Team.
Among 1,249,634 delivery hospitalizations during March Corresponding author: Carla L. DeSisto, [email protected].
2020–September 2021, U.S. women with COVID-19 were at
increased risk for stillbirth compared with women without 1CDC COVID-19 Response Team.
COVID-19 (adjusted relative risk [aRR] = 1.90;
All authors have completed and submitted the International
95% CI = 1.69–2.15). The magnitude of association was higher
during the period of SARS-CoV-2 B.1.617.2 (Delta) variant Committee of Medical Journal Editors form for disclosure of potential
predominance than during the pre-Delta period. conflicts of interest. No potential conflicts of interest were disclosed.
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identify the biologic mechanism for the observed increased risk 6. Hoyert DL, Gregory ECW. Cause-of-death data from the fetal death
file, 2015–2017. Natl Vital Stat Rep 2020;69:1–20. PMID:32510316
for stillbirth with maternal COVID-19, and assess differences 7. Allen H, Vusirikala A, Flannagan J, et al.; COVID-19 Genomics UK
in risks relative to the timing and severity of infection and the (COG-UK Consortium). Household transmission of COVID-19 cases
contribution of maternal risk factors. In addition, further inves- associated with SARS-CoV-2 delta variant (B.1.617.2): national case-
control study. Lancet Reg Health Eur 2021;100252. PMID:34729548
tigation of vaccine effectiveness during pregnancy, including https://doi.org/10.1016/j.lanepe.2021.100252
prevention of stillbirth, is warranted. Most importantly, these 8. Sheikh A, McMenamin J, Taylor B, Robertson C; Public Health Scotland
findings underscore the importance of COVID-19 prevention and the EAVE II Collaborators. SARS-CoV-2 Delta VOC in Scotland:
strategies, including vaccination before or during pregnancy. demographics, risk of hospital admission, and vaccine effectiveness.
Lancet 2021;397:2461–2. PMID:34139198 https://doi.org/10.1016/
S0140-6736(21)01358-1
***** https://covid.cdc.gov/covid-data-tracker/#vaccine-effectiveness 9. Taylor CA, Patel K, Pham H, et al.; COVID-NET Surveillance Team.
††††† https://www.cdc.gov/vaccines/imz-managers/coverage/covidvaxview/
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interactive.html COVID-19 before and during the period of SARS-CoV-2 B.1.617.2
(Delta) predominance—COVID-NET, 14 states, January–August 2021.
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https://doi.org/10.15585/mmwr.mm7043e1
10. Adhikari EH, Moreno W, Zofkie AC, et al. Pregnancy outcomes among
women with and without severe acute respiratory syndrome coronavirus 2
infection. JAMA Netw Open 2020;3:e2029256. PMID:33211113
https://doi.org/10.1001/jamanetworkopen.2020.29256
Research
JAMA Pediatrics | Original Investigation
Maternal and Neonatal Morbidity and Mortality

Among Pregnant Women With and Without COVID-19 Infection
The INTERCOVID Multinational Cohort Study
José Villar, MD; Shabina Ariff, MD; Robert B. Gunier, PhD; Ramachandran Thiruvengadam, MD; Stephen Rauch, MPH; Alexey Kholin, MD;
Paola Roggero, PhD; Federico Prefumo, PhD; Marynéa Silva do Vale, MD; Jorge Arturo Cardona-Perez, MD; Nerea Maiz, PhD; Irene Cetin, MD;
Valeria Savasi, PhD; Philippe Deruelle, PhD; Sarah Rae Easter, MD; Joanna Sichitiu, MD; Constanza P. Soto Conti, MD; Ernawati Ernawati, PhD;
Mohak Mhatre, MD; Jagjit Singh Teji, MD; Becky Liu, MBBS; Carola Capelli, MD; Manuela Oberto, MD; Laura Salazar, MD; Michael G. Gravett, MD;
Paolo Ivo Cavoretto, PhD; Vincent Bizor Nachinab, MD; Hadiza Galadanci, MSc; Daniel Oros, PhD; Adejumoke Idowu Ayede, MD; Loïc Sentilhes, PhD;
Babagana Bako, MD; Mónica Savorani, MD; Hellas Cena, PhD; Perla K. García-May, MD; Saturday Etuk, MD; Roberto Casale, MD;
Sherief Abd-Elsalam, PhD; Satoru Ikenoue, PhD; Muhammad Baffah Aminu, MD; Carmen Vecciarelli, MD; Eduardo A. Duro, MD;
Mustapha Ado Usman, MBBS; Yetunde John-Akinola, PhD; Ricardo Nieto, MD; Enrico Ferrazi, MD; Zulfiqar A. Bhutta, PhD; Ana Langer, MD;
Stephen H. Kennedy, MD; Aris T. Papageorghiou, MD
Editorial
IMPORTANCE Detailed information about the association of COVID-19 with outcomes in Supplemental content
pregnant individuals compared with not-infected pregnant individuals is much needed.
OBJECTIVE To evaluate the risks associated with COVID-19 in pregnancy on maternal and
neonatal outcomes compared with not-infected, concomitant pregnant individuals.
DESIGN, SETTING, AND PARTICIPANTS In this cohort study that took place from March to
October 2020, involving 43 institutions in 18 countries, 2 unmatched, consecutive,
not-infected women were concomitantly enrolled immediately after each infected woman
was identified, at any stage of pregnancy or delivery, and at the same level of care to minimize
bias. Women and neonates were followed up until hospital discharge.
EXPOSURES COVID-19 in pregnancy determined by laboratory confirmation of COVID-19

and/or radiological pulmonary findings or 2 or more predefined COVID-19 symptoms.
MAIN OUTCOMES AND MEASURES The primary outcome measures were indices of (maternal
and severe neonatal/perinatal) morbidity and mortality; the individual components of these
indices were secondary outcomes. Models for these outcomes were adjusted for country,
month entering study, maternal age, and history of morbidity.
RESULTS A total of 706 pregnant women with COVID-19 diagnosis and 1424 pregnant women
without COVID-19 diagnosis were enrolled, all with broadly similar demographic
characteristics (mean [SD] age, 30.2 [6.1] years). Overweight early in pregnancy occurred in
323 women (48.6%) with COVID-19 diagnosis and 554 women (40.2%) without. Women
with COVID-19 diagnosis were at higher risk for preeclampsia/eclampsia (relative risk [RR],
1.76; 95% CI, 1.27-2.43), severe infections (RR, 3.38; 95% CI, 1.63-7.01), intensive care unit
admission (RR, 5.04; 95% CI, 3.13-8.10), maternal mortality (RR, 22.3; 95% CI, 2.88-172),
preterm birth (RR, 1.59; 95% CI, 1.30-1.94), medically indicated preterm birth (RR, 1.97; 95%
CI, 1.56-2.51), severe neonatal morbidity index (RR, 2.66; 95% CI, 1.69-4.18), and severe
perinatal morbidity and mortality index (RR, 2.14; 95% CI, 1.66-2.75). Fever and shortness of
breath for any duration was associated with increased risk of severe maternal complications
(RR, 2.56; 95% CI, 1.92-3.40) and neonatal complications (RR, 4.97; 95% CI, 2.11-11.69).
Asymptomatic women with COVID-19 diagnosis remained at higher risk only for maternal
morbidity (RR, 1.24; 95% CI, 1.00-1.54) and preeclampsia (RR, 1.63; 95% CI, 1.01-2.63). Among
women who tested positive (98.1% by real-time polymerase chain reaction), 54 (13%) of their
neonates tested positive. Cesarean delivery (RR, 2.15; 95% CI, 1.18-3.91) but not breastfeeding
Author Affiliations: Author
(RR, 1.10; 95% CI, 0.66-1.85) was associated with increased risk for neonatal test positivity. affiliations are listed at the end of this
article.
CONCLUSIONS AND RELEVANCE In this multinational cohort study, COVID-19 in pregnancy was
Corresponding Author: Aris T.
associated with consistent and substantial increases in severe maternal morbidity and Papageorghiou, MD, Nuffield
mortality and neonatal complications when pregnant women with and without COVID-19 Department of Women’s &
diagnosis were compared. The findings should alert pregnant individuals and clinicians to Reproductive Health, University of
Oxford, Women’s Centre, John
implement strictly all the recommended COVID-19 preventive measures.
Radcliffe Hospital, Headington,
JAMA Pediatr. doi:10.1001/jamapediatrics.2021.1050 Oxford OX3 9DU, United Kingdom
Published online April 22, 2021. ([email protected]).
(Reprinted) E1

Research Original Investigation Maternal and Neonatal Morbidity and Mortality Among Pregnant Women With and Without COVID-19 Infection
A
t the outset of the COVID-19 pandemic, the precise ex-
tent of the risks in pregnancy was uncertain, which was Key Points
affecting pregnant individuals’ mental health.1,2 The
Question To what extent does COVID-19 in pregnancy alter the
lack of clarity arose because, in an early systematic review,3 risks of adverse maternal and neonatal outcomes compared with
only 4 studies that involved small numbers compared out- pregnant individuals without COVID-19?
comes between pregnant women w ith and w ithout
Findings In this multinational cohort study of 2130 pregnant
COVID-19.4-7 The question is relevant because of the known
women in 18 countries, women with COVID-19 diagnosis were at
deleterious effects of other coronavirus infections in preg- increased risk of a composite maternal morbidity and mortality
nancy (eg, severe acute respiratory syndrome and Middle East index. Newborns of women with COVID-19 diagnosis had
respiratory syndrome).8 Therefore, the INTERGROWTH-21st significantly higher severe neonatal morbidity index and severe
Consortium conducted a prospective, longitudinal, observa- perinatal morbidity and mortality index compared with newborns
tional study (INTERCOVID), involving 43 hospitals in 18 coun- of women without COVID-19 diagnosis.
tries, to assess the association between COVID-19 and mater- Meaning This study indicates a consistent association between
nal and neonatal outcomes in pregnant women with COVID-19 pregnant individuals with COVID-19 diagnosis and higher rates of
diagnosis, compared with concomitantly enrolled pregnant adverse outcomes, including maternal mortality, preeclampsia,
women without COVID-19 diagnosis. and preterm birth compared with pregnant individuals without
COVID-19 diagnosis.
approached until 2 women without COVID-19 diagnosis were

Methods enrolled per woman with COVID-19 diagnosis. We sought con-
Study Design firmation from a biweekly random 10% sample that the 2
The Oxford Tropical Research Ethics Committee and all local women without COVID-19 diagnosis were appropriately cho-
ethics committees approved the study, which did not inter- sen; we excluded 5 women who had a COVID-19 diagnosis and
fere with clinical management. Informed consent (oral or writ- the corresponding 10 women without a COVID-19 diagnosis,
ten) was obtained from study participants according to local without such confirmation. Live and stillborn singleton and
requirements, except when a waiver/exemption of such con- multiple pregnancies were included, including those with con-
sent was granted by a local committee. We adhered to the Dec- genital anomalies. However, in keeping with reporting require-
laration of Helsinki9 and Good Clinical Practice guidelines. The ments during the pandemic,12 we excluded women/neonates
study protocol, including the laboratory tests used, has been from the final analysis if their data were already published in
previously published.10 any comparative study with women without COVID-19
For 8 months from March 2, 2020, we enrolled women 18 diagnosis.5,13-23
years or older at any stage of pregnancy or delivery with the
diagnosis of COVID-19 during the present pregnancy based on Outcomes
laboratory confirmation of COVID-19 and/or radiologic pul- The primary outcomes24 were 3 unweighted indices: (1) ma-
monary findings suggestive of COVID-1911 or 2 or more pre- ternal morbidity and mortality index including at least 1 of the
defined COVID-19 symptoms. A range of different real-time following pregnancy-related morbidities: third-trimester vagi-
polymerase chain reaction and antibody tests were used at par- nal bleeding, pregnancy-induced hypertension, preeclampsia/
ticipating institutions (eBox in the Supplement). Two imme- eclampsia/hemolysis, elevated liver enzymes, and low plate-
diately concomitant pregnant women 18 years or older with- let count (HELLP) syndrome, preterm labor, infections
out any of those diagnostic criteria were enrolled per woman requiring antibiotics, or any other pregnancy-related condi-
with COVID-19 diagnosis to create an unbiased sample of all tions requiring treatment or referral; maternal admission to the
pregnant women without COVID-19 diagnosis in these insti- intensive care unit (ICU); referral to a higher level of care; or
tutions. Women were enrolled from 43 institutions in 18 coun- death; (2) severe neonatal morbidity index (SNMI) including
tries (Argentina, Brazil, Egypt, France, Ghana, India, Indone- at least 3 of the following severe complications: bronchopul-
sia, Italy, Japan, Mexico, Nigeria, North Macedonia, Pakistan, monary dysplasia, hypoxic-ischemic encephalopathy, sep-
Russia, Spain, Switzerland, UK, and the US). Data on race were sis, anemia requiring transfusion, patent ductus arteriosus re-
not collected. quiring treatment or surgery, intraventricular hemorrhage, and
When a woman with a COVID-19 diagnosis was identified necrotizing enterocolitis or retinopathy of prematurity diag-
antenatally, 2 women without COVID-19 diagnosis of similar nosed before hospital discharge; and (3) severe perinatal mor-
gestational age (±2 weeks) receiving standard antenatal care bidity and mortality index (SPMMI) including fetal death, at
were enrolled that day. If not possible or if those women with- least 1 of the severe neonatal conditions listed above, admis-
out COVID-19 diagnosis were lost to follow-up, we enrolled 2 sion to the neonatal ICU (NICU) for 7 days or longer, or neo-
women without COVID-19 diagnosis who delivered immedi- natal death before hospital discharge. Secondary outcomes
ately after the woman with COVID-19 diagnosis. The same se- were each individual component of the indices described above
lection strategy was used when a woman with COVID-19 di- considered as separate conditions.
agnosis was identified at hospital admission and delivery was Gestational age estimation was based on ultrasonogra-
likely during that admission. If a woman without COVID-19 di- phy measurement of fetal crown-rump length (<14 weeks’ ges-
agnosis declined participation, the next woman was tation) against the international INTERGROWTH-21st
E2 JAMA Pediatrics Published online April 22, 2021 (Reprinted) jamapediatrics.com

Maternal and Neonatal Morbidity and Mortality Among Pregnant Women With and Without COVID-19 Infection Original Investigation Research
standards25 or, if early ultrasonography dating was not car- overweight early in pregnancy compared with 40.2%
ried out, the best obstetric estimate was used based on all clini- (n = 554) of the group without COVID-19 diagnosis. Women
cal and ultrasonography data available at the time of deliv- with COVID-19 diagnosis had a higher rate of recreational
ery. Newborn weight, length, and head circumference at birth drug use but lower rate of smoking during the index preg-
were assessed against the international INTERGROWTH-21st nancy, higher rates of previous preterm birth, stillbirth, neo-
standards.26 natal death, and preexisting medical conditions (eTable 1 in
the Supplement).
Data Management and Statistical Analysis During the index pregnancy, women with a COVID-19 di-
We used a centrally coordinated data management system agnosis had higher rates of pregnancy-induced hypertension
developed for the IN TERGROWTH-21st P rojec t (RR, 1.46; 95% CI, 1.05-2.02), preeclampsia/eclampsia (RR, 1.76;
(MedSciNet).27 Associations between being diagnosed as 95% CI, 1.27-2.43), and infections requiring antibiotics
having COVID-19 and morbidity/mortality indices expressed (RR, 3.38; 95% CI, 1.63-7.01), and there was an association with
as binary outcomes were assessed using Poisson models a greater risk of admission to ICU/high-dependency unit
w ith a log link function and robust standard errors (RR, 5.04; 95% CI, 3.13-8.10) and referral to a higher level of
expressed as relative risk (RR) and 95% CI. Associations care (RR, 6.07; 95% CI, 1.23-30.01). Among all ICU admis-
with number of days in ICU were assessed using negative sions, women with COVID-19 diagnosis stayed 3.73 (95% CI,
binomial models with robust standard errors (expressed as 2.37-5.86) days longer than women without COVID-19
an incidence rate ratio and 95% CI). We set statistical signifi- diagnosis (Table 1).
cance at P < .05. Models for our primary outcomes were Eleven women (1.6%) with COVID-19 diagnosis died (ma-
adjusted for country, month entering study, maternal age, ternal mortality ratio, 159/10 000 births). Of these, 4 had se-
and history of maternal morbidity (including diabetes, thy- vere preeclampsia (1 superimposed on chronic hypertension
roid, and other endocrine disorders; cardiac disease; hyper- and 1 associated with cardiomyopathy); 3 of these 4 women
tension; chronic respiratory disease; kidney disease; had respiratory failure that required mechanical ventilation and
malaria; or tuberculosis). Models with preterm birth as an the fourth woman died of a pulmonary embolism. Five women
outcome were also adjusted for previous preterm birth. We had worsening respiratory failure antenatally, 2 of whom un-
plotted Kaplan-Meier curves with the percentage of women derwent cesarean delivery and, despite intensive respiratory
remaining pregnant by gestational age to compare the distri- support, died later. The remaining 2 women developed fever,
butions between women with and without COVID-19 diag- cough, and breathlessness within 7 days of an uneventful de-
nosis, according to symptom status. We evaluated women livery and died shortly after, despite ICU care. In the group of
with COVID-19 diagnosis for the primary and secondary out- women without COVID-19 diagnosis, there was 1 death due to
comes using the women without COVID-19 diagnosis as the preexisting liver malignant neoplasm and cirrhosis. Thus,
reference group. We further categorized women with women with COVID-19 diagnosis were 22 times more likely to
COVID-19 diagnosis as asymptomatic or symptomatic based die (RR, 22.3; 95% CI, 2.88-172), although the CIs were wide
on type and duration of symptoms, as well as according to owing to the small numbers (Table 1).
past maternal morbidity and normal weight or overweight Overall, women with COVID-19 diagnosis had a lower
to explore effect modification. We assessed the association rate of spontaneous initiation of labor but higher cesarean
of neonates testing positive for SARS-CoV-2 infection. In delivery rate, reflecting the higher rates of pregnancy com-
separate sensitivity analyses, we adjusted for additional plications in this group. They also had higher RRs for pre-
potential confounders, restricted the definition of women term birth and fetal distress of 1.59 (95% CI, 1.30-1.94) and
with COVID-19 diagnosis to mothers with a positive labora- 1.70 (95% CI, 1.06-2.75), respectively. Overall, 83% of pre-
tory test result, and excluded twins. We also performed term births (n = 130) in women with COVID-19 diagnosis
separate meta-analyses for our primary outcomes of inter- were medically indicated; hence, the increased risk in this
est using the stratified results to estimate pooled effects and group (RR, 1.97; 95% CI, 1.56-2.51) (Table 1). The leading
assess heterogeneity by country. indications for preterm delivery among women with
COVID-19 diagnosis were preeclampsia/eclampsia/HELLP
(31 [24.7%]), small for gestational age (24 [15.5%]), and fetal
distress (17 [13.2%]). The proportions of spontaneous pre-
Results term birth were similar. Women with COVID-19 diagnosis
We enrolled 706 women with COVID-19 diagnosis, of which had a higher low birth weight rate (RR, 1.58; 95% CI, 1.29-
656 (92.9%) had laboratory/radiological confirmation and 1.94). The rates of prelabor rupture of membranes were
50 (7.1%) had more than 2 symptoms without laboratory similar in both groups (Table 1). Fully adjusting models of
confirmation. Of those who tested positive, almost exclu- our primary outcomes for all planned variables reduced the
sively (640 of 652 [98.1%]) by real-time polymerase chain sample size owing to missing data, but affected the results
reaction, 287 (44.0%) were asymptomatic. We also enrolled minimally (eTable 2 in the Supplement).
1424 women without COVID-19 diagnosis (eFigure in the Women with COVID-19 diagnosis delivered earlier than those
Supplement). The groups of women with and without diag- without COVID-19 diagnosis after approximately 30 weeks’ ges-
nosis had similar demographic characteristics. However, tation, with the greatest difference less than 37 weeks’ gesta-
48.6% (n = 323) of the group with COVID-19 diagnosis had tion. The Figure illustrates the probability of remaining preg-
jamapediatrics.com (Reprinted) JAMA Pediatrics Published online April 22, 2021 E3

Table 1. Pregnancy Complications, Perinatal Events, and Neonatal Morbidities

Among Women With and Without COVID-19 Diagnosis and Their Newborns
No. (%)
Women without
Women with COVID-19 COVID-19 diagnosis
Characteristic diagnosis (n = 706) (n = 1424) Relative risk (95% CI)
Maternal morbidity and mortality indexa 225 (31.9) 296 (20.8) 1.54 (1.33 to 1.78)b
Vaginal bleeding 44 (6.2) 87 (6.1) 1.02 (0.72 to 1.46)
Pregnancy-induced hypertension 58 (8.2) 80 (5.6) 1.46 (1.05 to 2.02)
Preeclampsia/eclampsia/HELLP 59 (8.4) 63 (4.4) 1.76 (1.27 to 2.43)b
Hemoglobin level <10 g/dL at >27 wk gestation 130 (18.4) 228 (16.0) 1.15 (0.91 to 1.45)
Preterm labor 52 (7.4) 88 (6.2) 1.20 (0.86 to 1.68)
Infections requiring antibiotics 25 (3.6) 16 (1.1) 3.38 (1.63 to 7.01)
Admitted to ICU 59 (8.4) 23 (1.6) 5.04 (3.13 to 8.10)
Time in ICU, mean (SD), d 7.3 (7.8) 2.0 (1.7) 3.73 (2.37 to 5.86)c
Referred for higher dependency care 6 (0.9) 1 (0.1) 6.07 (1.23 to 30.01)
Maternal death 11 (1.6) 1 (0.1) 22.26 (2.88 to 172.11)
Fetal distress 87 (12.3) 120 (8.4) 1.70 (1.06 to 2.75)b
Spontaneous initiation of labor 333 (47.2) 793 (55.7) 0.85 (0.77 to 0.93)
Induced labor 157 (22.3) 320 (22.5) 0.99 (0.84 to 1.18)
Cesarean delivery 346 (49.0) 547 (38.4) 1.28 (1.16 to 1.40)b
Prelabor rupture of membranes 114 (16.1) 262 (18.4) 0.87 (0.71 to 1.07)
Gestational age at birth, mean (SD), wk 37.9 (3.3) 38.5 (3.1) −0.61 (−0.90 to −0.32)d
Preterm birth (<37 wk gestation) 159 (22.5) 194 (13.6) 1.59 (1.30 to 1.94)e
Spontaneous preterm birth 27 (3.8) 66 (4.6) 0.81 (0.52 to 1.27)
Medically indicated preterm birth 133 (18.8) 127 (8.9) 1.97 (1.56 to 2.51)e
Birth weight, mean (SD), kg 2.96 (0.70) 3.07 (0.68) −0.11 (−0.18 to −0.04)d
Male 353 (50.0) 749 (52.6) 0.95 (0.87 to 1.04)
Female 353 (50.0) 675 (47.6) 1.06 (0.96 to 1.16)
Low birth weight (<2500 g) 145 (20.5) 181 (12.7) 1.58 (1.29 to 1.94)b
Small for gestational age (<10th centile)f 97 (13.7) 181 (12.7) 1.03 (0.81 to 1.31)
Exclusive breastfeeding at discharge 378 (53.5) 953 (66.9) 0.80 (0.74 to 0.87)
Any breastfeeding at discharge 588 (83.3) 1290 (90.6) 0.92 (0.88 to 0.96)
SNMIg 44 (6.2) 33 (2.3) 2.66 (1.69 to 4.18)b
Severe perinatal morbidity and mortality indexh 120 (17.0) 113 (7.9) 2.14 (1.66 to 2.75)b
e
Abbreviations: HELLP, hemolysis, elevated liver enzymes, low platelet count; Models for preterm birth adjusted for history of preterm birth, country, month
ICU, intensive care unit; SNMI, severe neonatal morbidity index. entering study, maternal age, and history of maternal morbidity (including
SI conversion factors: To convert hemoglobin to grams per liter, multiply by 10. diabetes, thyroid and other endocrine disorders, cardiac disease,
a
hypertension, chronic respiratory disease, kidney disease, malaria, or
Maternal morbidity and mortality index includes at least 1 of the following
tuberculosis).
complications during pregnancy: vaginal bleeding, pregnancy-induced
f
hypertension, preeclampsia, eclampsia, HELLP, preterm labor, infections Against the international INTERGROWTH-21st Newborn Size Standards.22
g
requiring antibiotics or maternal death, admission to ICU, or referral for higher SNMI includes at least 1 of the following morbidities: bronchopulmonary
dependency care. dysplasia, hypoxic-ischemic encephalopathy, sepsis, anemia requiring
b
Models adjusted for country, month entering study, maternal age, and history transfusion, patent ductus arteriosus, intraventricular hemorrhage,
of maternal morbidity (including diabetes, thyroid and other endocrine necrotizing enterocolitis, or retinopathy of prematurity.
h
disorders, cardiac disease, hypertension, chronic respiratory disease, kidney Severe perinatal morbidity and mortality index includes any of the morbidities
disease, malaria, or tuberculosis). listed in the SNMI or intrauterine or neonatal death or neonatal ICU stay ⱖ7
c
Incidence rate ratio and 95% CI are reported. days.
d
β and 95% CI are reported.
nant after 25 weeks’ gestation for those women with COVID-19 with COVID-19 diagnosis and 0.8 weeks shorter (95% CI, −1.2 to
diagnosis, stratified into those with and without symptoms. −0.5) in symptomatic women with COVID-19 diagnosis than in
Using the log-rank test for trend of survivor curves, we ob- women without COVID-19 diagnosis.
served a significant downwards trend in the gestational age dis- The risk of the SNMI among neonates of women with
tributions that progressed from women without COVID-19 di- COVID-19 diagnosis was significantly higher (RR, 2.66; 95% CI,
agnosis, to asymptomatic women with COVID-19 diagnosis, to 1.69-4.18) than in those of women without COVID-19 diagno-
symptomatic women with COVID-19 diagnosis (P < .001 for this sis. The risk of the SPMMI was more than twice as high in the
trend) (Figure). In regression models, the gestational age at de- group of women with COVID-19 diagnosis (RR, 2.14; 95% CI,
livery was 0.6 weeks shorter (95% CI, −0.9 to −0.3) in all women 1.66-2.75) (Table 1).

Figure. Gestational Age at Delivery Among Women With COVID-19 Diagnosis,

With and Without Symptoms, and Women Without COVID-19 Diagnosis
100
Individuals remaining pregnant, %

80
There were 1420 women without
60 COVID-19 diagnosis (dark blue). In the
group of women with COVID-19
diagnosis, 417 women were
40 symptomatic (light blue) and 288
COVID-19 not diagnosed women were asymptomatic (orange).
20 COVID-19 diagnosed (asymptomatic) There was a significant trend
COVID-19 diagnosed (symptomatic) (P < .001) in shorter gestational age
at delivery going from women
0
20 25 30 35 40 45
without COVID-19 diagnosis, to
Gestational age at delivery, wk asymptomatic women with COVID-19
No. at risk diagnosis, to symptomatic women
COVID-19 not diagnosed 1391 1381 1371 1359 1318 1131 435 11 with COVID-19 diagnosis (log-rank
COVID-19 diagnosed (asymptomatic) 284 283 280 276 261 214 70 0 test for trend of survivor curves). Five
COVID-19 diagnosed (symptomatic) 407 403 399 382 355 267 92 1 women with missing data were
excluded from the figure.
A total of 416 neonates born to women with COVID-19 diag- However, for maternal outcomes, those women with COVID-19
nosis were tested for SARS-CoV-2 (57.1% [n = 729] of the total diagnosis with prepregnancy morbidities had the highest risk in
mother with COVID-19 diagnosis/neonate dyads); 220 (51.5%) the index pregnancy, suggesting that past morbidities modify
were tested in the first 24 hours after birth and 369 (84.8%) within the effect of COVID-19 exposure, especially for preeclampsia/
the first 48 hours. Of these, 54 (12.9%) tested positive. Among test- eclampsia (RR, 3.29; 95% CI, 2.03-5.33) (Table 3). Women who
positive women with test-positive neonates, the cesarean deliv- had overweight at the first antenatal visit and subsequently were
ery rate was 72.2% (n = 39) and among test-positive women with diagnosed with COVID-19 had the highest risk for the maternal
test-negative neonates was 47.9% (n = 173). The rate in women morbidity and mortality index (RR, 1.81; 95% CI, 1.48-2.21), SNMI
without COVID-19 diagnosis was 39.4% (n = 568). (RR, 4.15; 95% CI, 2.15-8.01), and SPMMI and preeclampsia/
In regression models, exploring factors associated with eclampsia (RR, 2.62; 95% CI, 1.57-4.36), suggesting that over-
neonatal SARS-CoV-2 positivity that included gestational age weight status modifies the effect of COVID-19 exposure (Table 3).
at delivery, cesarean delivery, NICU stay 7 days or longer, and We also compared the risk for severe neonatal complications
exclusive breastfeeding at discharge, only cesarean delivery in test-positive and test-negative neonates of women with and
was independently associated with the risk of a test-positive without COVID-19 diagnosis, the latter as a reference group. The
neonate (RR, 2.15; 95% CI, 1.18-3.91). Reassuringly, there was risks for the SNMI, SPMMI, and NICU stay 7 days or longer were
no association between exclusive breastfeeding and neonatal higher in the test-negative neonates of women with COVID-19 di-
test positivity (RR, 1.10; 95% CI, 0.66-1.85). agnosis. However, the test-positive neonates of women with
eTable 3 in the Supplement shows the type, number, and COVID-19 diagnosis had considerably higher risk for the SPMMI
prevalence of symptoms reported. Overall, the presence of any and, as expected, a large increased risk for a NICU stay of 7 days
symptoms increased the association with adverse outcomes com- or longer (Table 4).
pared with the group of women without COVID-19 diagnosis. Al- In separate sensitivity analyses, adjusting for additional con-
though asymptomatic women with COVID-19 diagnosis had lim- founders (marital status, overweight, smoking and drug use dur-
ited risk for most outcomes, there was still an association between ing pregnancy), restricting mothers with COVID-19 diagnosis to
the disease and preeclampsia (RR, 1.63; 95% CI, 1.01-2.63). The laboratory-confirmed positive results and excluding twins, we
presence of fever and shortness of breath, separately or in com- found that relative risks for COVID-19–associated maternal and
bination with any symptom cluster, was markedly associated with neonatal morbidities were similar to our main results (eTable 2
a risk of the 3 summary indices, as well as preterm birth (Table 2). in the Supplement). Furthermore, we treated each country (all
Having shortness of breath, chest pain, and cough with fe- hospitals in a country pooled) as if they were separate studies in
ver was associated with a substantial increase in the risk for a meta-analysis. The pooled estimated RRs (95% CI) were prac-
severe maternal and neonatal conditions and preterm birth. tically identical to the unadjusted and adjusted estimations, ex-
However, it appears that a longer exposure to symptoms is cept for the SNMI, which was increased from the unadjusted RR
needed to see an associated increase in risk for preeclampsia, of 2.69 (95% CI, 1.72-4.20) to 2.91 (95% CI, 1.76-4.74). As expected,
eg, 5 to 10 days of respiratory symptoms (RR, 2.43; 95% CI, 1.29- considering the variability of underlying populations and care sys-
4.58) (eTable 4 in the Supplement). tems, we identified some heterogeneity of RR estimates across
Among those with no prepregnancy morbidities and those countries in the meta-analysis for the maternal morbidity and
without overweight at their first antenatal visit, women with mortality index (I2 = 50.0%; P = .02) and SPMMI (I2 = 57.4%; P =
COVID-19 diagnosis were still at increased risk of these compli- .005), although there was no systematic pattern among the
cations compared with women without COVID-19 diagnosis. countries.

Table 2. Adjusted Associations for Maternal and Perinatal Outcomes

Among Women With and Without COVID-19 Diagnosis According to Symptom Statusa
RR (95% CI)
Preeclampsia/
Symptom No. (%) MMMIb SNMIc SPMMId Preterm birthe eclampsia/HELLP
No diagnosis of COVID-19 1424 (66.9) 1 [Reference] 1 [Reference] 1 [Reference] 1 [Reference] 1 [Reference]
COVID-19
Asymptomatic 288 (13.5) 1.24 (1.00-1.54) 1.42 (0.65-3.08) 1.08 (0.69-1.69) 0.99 (0.72-1.36) 1.63 (1.01-2.63)
Any symptom 418 (19.6) 1.76 (1.49-2.08) 3.45 (2.14-5.56) 3.09 (2.36-4.04) 2.10 (1.67-2.62) 2.00 (1.34-2.99)
Symptomatic
With diarrhea/vomiting 48 (2.3) 1.36 (0.85-2.19) 4.66 (1.93-11.30) 2.79 (1.57-4.95) 2.76 (1.77-4.30) 0.48 (0.07-3.81)
With fever 199 (9.3) 1.89 (1.54-2.32) 4.34 (2.53-7.43) 3.81 (2.81-5.17) 2.39 (1.82-3.13) 1.82 (1.08-3.06)
With shortness of breath 89 (4.2) 2.46 (1.96-3.08) 3.88 (1.78-8.49) 3.86 (2.62-5.67) 2.88 (2.12-3.89) 2.72 (1.59-4.64)
With fever and shortness 45 (2.1) 2.56 (1.92-3.40) 4.97 (2.11-11.69) 5.09 (3.30-7.86) 3.40 (2.38-4.86) 2.22 (1.06-4.64)
of breath
Abbreviations: HELLP, hemolysis, elevated liver enzymes, low platelet count; HELLP, preterm labor, infections requiring antibiotics or maternal death,
MMMI, maternal morbidity and mortality index; RR, relative risk; SNMI, severe admission to intensive care unit, or referral for higher dependency care.
neonatal morbidity index; SPMMI, severe perinatal morbidity and mortality c
SNMI includes at least 1 of the following morbidities: bronchopulmonary
index. dysplasia, hypoxic-ischemic encephalopathy, sepsis, anemia requiring
a
All models adjusted for country, month entering study, maternal age, and transfusion, patent ductus arteriosus, intraventricular hemorrhage,
history of maternal morbidity (including diabetes, thyroid and other endocrine necrotizing enterocolitis, or retinopathy of prematurity.
disorders, cardiac disease, hypertension, chronic respiratory disease, kidney d
SPMMI includes any of the morbidities listed in the SNMI, intrauterine or
disease, malaria, or tuberculosis). neonatal death, or neonatal intensive care unit stay ⱖ7 days.
b
MMMI includes at least 1 of the following complications during pregnancy: e
Models for preterm birth also adjusted for history of preterm birth.
vaginal bleeding, pregnancy-induced hypertension, preeclampsia, eclampsia,
Table 3. Adjusted Associations Between Preexisting Maternal Morbidity or Being Overweight Prepregnancy
and Maternal and Neonatal Outcomes According to COVID-19 Diagnosisa,b
RR (95% CI)
Maternal COVID-19 Preeclampsia/
diagnosis No. (%) MMMIc SNMId SPMMIe Preterm birthf eclampsia/HELLP
Not diagnosed
No past morbidity 1179 (55.4) 1 [Reference] 1 [Reference] 1 [Reference] 1 [Reference] 1 [Reference]
Past morbidity 245 (11.5) 1.20 (0.92-1.54) 3.04 (1.48-6.28) 1.48 (0.95-2.29) 1.73 (1.26-2.39) 1.86 (1.11-3.12)
Diagnosed
No past morbidity 547 (25.7) 1.57 (1.33-1.85) 4.02 (2.39-6.76) 2.35 (1.76-3.13) 1.76 (1.40-2.22) 1.88 (1.24-2.86)
Past morbidity 159 (7.5) 1.71 (1.33-2.20) 1.88 (0.74-4.73) 2.29 (1.50-3.51) 1.96 (1.41-2.73) 3.29 (2.03-5.33)
Not diagnosed
Normal weight 823 (40.3) 1 [Reference] 1 [Reference] 1 [Reference] 1 [Reference] 1 [Reference]
Overweight 554 (27.1) 1.01 (0.81-1.24) 1.56 (0.76-3.20) 1.14 (0.78-1.67) 0.78 (0.59-1.05) 1.37 (0.82-2.30)
Diagnosed
Normal weight 342 (16.8) 1.28 (1.03-1.58) 2.07 (0.99-4.31) 1.99 (1.38-2.88) 1.42 (1.07-1.90) 1.80 (1.06-3.07)
Overweight 323 (15.8) 1.81 (1.48-2.21) 4.15 (2.15-8.01) 2.44 (1.72-3.48) 1.43 (1.08-1.85) 2.62 (1.57-4.36)
c
Abbreviations: HELLP, Hemolysis, elevated liver enzymes, low platelet count; MMMI includes at least 1 of the following complications during pregnancy:
MMMI, maternal morbidity and mortality index; RR, relative risk; SNMI, severe vaginal bleeding, pregnancy-induced hypertension, preeclampsia, eclampsia,
neonatal morbidity index; SPMMI, severe perinatal morbidity and mortality HELLP, preterm labor, infections requiring antibiotics or maternal death,
index. admission to intensive care unit, or referral for higher dependency care.
a d
All models adjusted for country, month entering study, maternal age, and SNMI includes at least 1 of the following morbidities: bronchopulmonary
history of maternal morbidity (including diabetes, thyroid and other endocrine dysplasia, hypoxic-ischemic encephalopathy, sepsis, anemia requiring
disorders, cardiac disease, hypertension, chronic respiratory disease, kidney transfusion, patent ductus arteriosus, intraventricular hemorrhage,
disease, malaria, or tuberculosis). necrotizing enterocolitis, or retinopathy of prematurity.
b e
Prepregnancy maternal morbidities included at least 1 of the following: SPMMI includes any of the morbidities listed in the SNMI, intrauterine or
diabetes, thyroid and other endocrine disorders, cardiac disease, neonatal death, or neonatal intensive care unit stay ⱖ7 days.
hypertension, chronic respiratory disease, kidney disease, malaria, or f
Models for preterm birth also adjusted for history of preterm birth.
tuberculosis.

Table 4. Adjusted Associations Between Maternal and Neonatal COVID-19 Diagnosis With Perinatal Morbidity and Mortalitya
RR (95% CI)
Maternal and neonatal COVID-19 diagnosis No. (%) SNMIb SPMMIc NICU stay ≥7 d
Not-diagnosed mother and neonate 1462 (66.7) 1 [Reference] 1 [Reference] 1 [Reference]
Diagnosed mother but neonate not tested 313 (14.3) 1.40 (0.72-2.70) 1.68 (1.20-2.37) 1.02 (0.60-1.83)
Diagnosed mother but test-negative neonate 362 (16.5) 4.00 (2.29-6.97) 2.31 (1.69-3.17) 3.13 (2.10-4.65)
Diagnosed mother and test-positive neonate 54 (2.5) 4.13 (1.69-10.08) 3.46 (2.13-5.63) 6.03 (3.35-10.86)
b
Abbreviations: NICU, neonatal intensive care unit; RR, relative risk; SNMI, SNMI includes at least 1 of the following morbidities: bronchopulmonary
severe neonatal morbidity index; SPMMI, severe perinatal morbidity and dysplasia, hypoxic-ischemic encephalopathy, sepsis, anemia requiring
mortality index. transfusion, patent ductus arteriosus, intraventricular hemorrhage,
a
Models adjusted for country, month entering study, maternal age, and history necrotizing enterocolitis, or retinopathy of prematurity.
c
of maternal morbidity (including diabetes, thyroid and other endocrine SPMMI includes any of the morbidities listed in the SNMI, intrauterine or
disorders, cardiac disease, hypertension, chronic respiratory disease, kidney neonatal death, or NICU stay ⱖ7 days.
disease, malaria, or tuberculosis).
It is known that in nonpregnant patients, distinct sub-

Discussion types may be predictive of clinical outcomes.33 We found
the presence of any COVID-19 symptoms was associated
We conducted a large-scale, prospective, multinational study with increased morbidity and mortality. Specifically, severe
to assess the symptoms and associations between COVID-19 pregnancy and neonatal complication rates were highest in
in pregnancy and maternal and neonatal outcomes that in- women if fever and shortness of breath were present,
cluded, to our knowledge for the first time, immediately con- reflecting systemic disease; their presence for 1 to 4 days
comitant pregnant women without COVID-19 diagnosis from was associated with severe maternal and neonatal compli-
the same populations, carefully enrolled to minimize selec- cations. This observation should influence clinical care and
tion bias. referral strategies.
We demonstrated that women with COVID-19 diagnosis, The risks of severe neonatal complications, including
compared with those without COVID-19 diagnosis, were at sub- NICU stay for 7 days or longer, as well as the summary index
stantially increased risk of severe pregnancy complications, of severe neonatal morbidity and its individual compo-
including preeclampsia/eclampsia/HELLP syndrome, ICU ad- nents, were also substantially higher in the group of women
mission or referral to higher level of care, and infections re- with COVID-19 diagnosis. The increased neonatal risk
quiring antibiotics, as well as preterm birth and low birth remained after adjusting for previous preterm birth and pre-
weight. The risk of maternal mortality was 1.6%, ie, 22 times term birth in the index pregnancy; thus, a direct effect on
higher in the group of women with COVID-19 diagnosis. These the newborn from COVID-19 is likely.
deaths were concentrated in institutions from less developed Overall, our results were consistent across morbidities and
regions, implying that when comprehensive ICU services are mostly at an RR near or greater than 2 for maternal and neo-
not fully available, COVID-19 in pregnancy can be lethal. Re- natal outcomes, with narrow CIs excluding unity, and above 3
assuringly, we also found that asymptomatic women with to 4 in several estimates. Sensitivity and stratified analyses con-
COVID-19 diagnosis had similar outcomes to women without firmed the observed results. They are probably conservative
COVID-19 diagnosis, except for preeclampsia. because overall, 41% of women with COVID-19 diagnosis were
Importantly, women with COVID-19 diagnosis, already at asymptomatic, a subgroup with a low risk of complications.
high risk of preeclampsia and COVID-19 because of preexist- Hence, higher morbidity and mortality risk should be ex-
ing overweight, diabetes, hypertension, and cardiac and pected for the general pregnant population, especially in low-
chronic respiratory diseases,28 had almost 4 times greater risk to middle-income countries.
of developing preeclampsia/eclampsia, which could reflect the We found 12.1% of neonates born to test-positive women
known association with these comorbidities and/or the acute also tested positive, a higher figure than in a recent system-
kidney damage that can occur in patients with COVID-19.29 atic review.34 We speculate whether contamination at the time
Our data support reports of an association between of cesarean delivery was responsible because the rate in this
COVID-19 and higher rates of preeclampsia/eclampsia/ mother/neonate positive subgroup was 72.2%. Reassuringly,
HELLP syndrome,19,30 but it is still uncertain whether COVID-19 as SARS-CoV-2 has not been isolated from breast milk,35 breast-
manifests in pregnancy with a preeclampsialike syndrome or feeding was not associated with any increase in the rate of test-
infection with SARS-CoV-2 results in an increased risk for pre- positive neonates.
eclampsia. Uncertainty persists because the placentas of Our results mostly reflect COVID-19 diagnosed in the third
women with COVID-19, compared with controls, show vascu- trimester. Thus, women with COVID-19 diagnosis or whose
lar changes consistent with preeclampsia,31 but the state of sys- pregnancy ended earlier in pregnancy are underrepresented
temic inflammation and hypercoagulability found in nonpreg- either because our study was exclusively hospital based or ear-
nant patients with severe illness and COVID-19 is also a feature lier infection may manifest with mild symptoms, which are
of preeclampsia.32 either ignored or managed in primary care. Alternatively, most

women might have avoided the hospital until late in preg- natally), which would result in more conservative estimates by
nancy or when in labor. Clearly, the effect of COVID-19 early reducing the differences between groups. Finally, we acknowl-
in pregnancy needs urgently to be studied. edge a risk of reporting bias relating to maternal and neonatal
morbidity because women with COVID-19 diagnosis and their
Limitations newborns may have been more carefully evaluated, tested, and
Our study has expected limitations. Ideally, we would have col- have more events reported than in the sample of women with-
lected data prospectively from all pregnancies in the participat- out COVID-19 diagnosis. However, we are reassured that the re-
ing institutions, but this was impractical because of their large sults reflect a true increased risk because of our careful data
number of deliveries. There was a small risk of selection bias as- monitoring and use of severe morbidity markers.
sociated with the reference group of women without COVID-19
diagnosis, despite all efforts to ensure they represented an un-
biased sample of the general noninfected pregnant population.
The selection of cases with COVID-19 diagnosis was affected by
Conclusions
whether routine testing was conducted, awareness of COVID-19 In summary, in this study, COVID-19 infection during preg-
symptoms particularly early in the pandemic, and the availabil- nancy was associated with substantial risk of morbidity and
ity of test kits. Where universal testing in pregnancy has been mortality in postpartum parents and their infants worldwide,
introduced, real-time polymerase chain reaction positive rates compared with their not-infected pregnant counterparts, es-
are 0.5% to 14% in asymptomatic women.36,37 Hence, this group pecially if the these individuals were symptomatic or have co-
of women without COVID-19 diagnosis may have included small morbidities. There is an urgent need to follow up with these
numbers of asymptomatic infected women (a crossover effect parents and infants because of possible long-term health ef-
when women without COVID-19 diagnosis were enrolled ante- fects, including long-term COVID-19.
ARTICLE INFORMATION Hôpitaux Universitaires de Strasbourg, Strasbourg, of Obstetrics and Gynecology, Bordeaux University
Accepted for Publication: January 21, 2021. France (Deruelle); Division of Maternal-Fetal Hospital, Bordeaux, France (Sentilhes); Department
Medicine, Brigham and Women’s Hospital, Harvard of Obstetrics and Gynaecology, Faculty of Clinical
Published Online: April 22, 2021. Medical School, Boston, Massachusetts (Easter); Sciences, College of Medical Sciences, Gombe State
doi:10.1001/jamapediatrics.2021.1050 Division of Critical Care Medicine, Brigham and University, Gombe, Nigeria (Bako); Hospital de
Open Access: This is an open access article Women’s Hospital, Harvard Medical School, Boston, Moron, Moron, Provincia de Buenos Aires,
distributed under the terms of the CC-BY License. Massachusetts (Easter); Hôpital Universitaire Argentina (Savorani); Laboratory of Dietetics and
© 2021 Villar J et al. JAMA Pediatrics. Necker-Enfants Malades, AP-HP, Université de Clinical Nutrition, Department of Public Health,
Author Affiliations: Nuffield Department of Paris, Paris, France (Sichitiu); Division Neonatología, Experimental and Forensic Medicine, University of
Women’s & Reproductive Health, University of Hospital Materno Infantil Ramón Sarda, Buenos Pavia, Pavia, Italy (Cena); Clinical Nutrition and
Oxford, Oxford, United Kingdom (Villar, Kennedy, Aires Argentina (Soto Conti, Nieto); Department of Dietetics Service, Unit of Internal Medicine and
Papageorghiou); Oxford Maternal and Perinatal Obstetrics and Gynecology, Medical Faculty, Endocrinology, ICS Maugeri IRCCS, University of
Health Institute, Green Templeton College, Universitas Airlangga, Surabaya, Indonesia Pavia, Pavia, Italy (Cena); Hospital Regional Lic.
University of Oxford, Oxford, United Kingdom (Ernawati); Soetomo General Academic Hospital, Adolfo López Mateos ISSSTE, Mexico City, Mexico
(Villar, Kennedy, Papageorghiou); Department of Surabaya, Indonesia (Ernawati); Tufts Medical (García-May); University of Calabar Teaching
Paediatrics and Child Health, The Aga Khan Center, Boston, Massachusetts (Mhatre); Ann and Hospital, Calabar, Nigeria (Etuk); Maternal and Child
University Hospital, Karachi, Pakistan (Ariff); School Robert H. Lurie Children’s Hospital of Chicago, Department, Hospital Nacional Profesor Alejandro
of Public Health, University of California, Berkeley, Northwestern Feinberg School of Medicine, Posadas, Buenos Aires, Argentina (Casale); Tropical
Berkeley (Gunier, Rauch); Translational Health Chicago, Illinois (Teji); St George’s University Medicine and Infectious Diseases Department,
Science and Technology Institute, Faridabad, India Hospitals NHS Foundation Trust, London, United Tanta University, Tanta, Egypt (Abd-Elsalam);
(Thiruvengadam); National Medical Research Kingdom (Liu, Papageorghiou); Servicio de Department of Obstetrics and Gynecology, Keio
Center for Obstetrics, Gynecology and Neonatologia del Departamento Materno Infantil University School of Medicine, Tokyo, Japan
Perinatology, Moscow, Russia (Kholin); Department del Hospital Universitario Austral, Pilar, Provincia de (Ikenoue); Department of Obstetrics and
of Clinical Sciences and Community Health, Buenos Aires, Argentina (Capelli); S.C. Obstetrics Gynaecology, Abubakar Tafawa Balewa University
University of Milan, Milan, Italy (Roggero); 2U, Sant’Anna Hospital, AOU Città della Salute e Teaching Hospital, Bauchi, Nigeria (Aminu);
Department of Woman, Child and Neonate, della scienza di Torino, Turin, Italy (Oberto); Fetal Sanatorio Otamendi, Ciudad de Buenos Aires,
Fondazione IRCCS Cà Granda Ospedale Maggiore Medicine Unit, University College London Hospitals Argentina (Vecciarelli); Universidad de Buenos
Policlinico, Milan, Italy (Roggero, Ferrazi); Division NHS Foundation Trust, London, United Kingdom Aires, Buenos Aires, Argentina (Duro); Universidad
of Obstetrics and Gynecology, ASST Spedali Civili di (Salazar); Department of Obstetrics and de Moron, Moron, Argentina (Duro); Department of
Brescia, Brescia, Italy (Prefumo); Department of Gynecology, University of Washington, Seattle Obstetrics and Gynaecology, Muhammad Abdullahi
Clinical and Experimental Sciences, University of (Gravett); Department of Global Health, University Wase Teaching Hospital, Kano State, Nigeria
Brescia, Brescia, Italy (Prefumo); Universidade of Washington, Seattle (Gravett); Obstetrics and (Usman); Center for Global Child Health, Hospital
Federal do Maranhão, São Luís, Brazil (do Vale); Gynaecology Department, IRCCS San Raffaele for Sick Children, Toronto, Ontario, Canada
Instituto Nacional de Perinatología Isidro Espinosa Hospital and University, Milan, Italy (Cavoretto); Fr. (Bhutta); Women and Health Initiative, Global
de los Reyes, Mexico City, Mexico (Cardona-Perez); Thomas Alan Rooney Memorial Hospital, Health and Population Department, Harvard T.H.
Obstetrics Department, Hospital Universitari Vall Asankragwa, Ghana (Nachinab); Africa Center of Chan School of Public Health, Boston,
d’Hebron, Barcelona Hospital Campus, Barcelona, Excellence for Population Health and Policy, Bayero Massachusetts (Langer).
Spain (Maiz); Ospedale Vittore Buzzi Children’s University Kano, Kano, Nigeria (Galadanci); Aminu Author Contributions: Drs Villar and
Hospital, Department of BioMedical and Clinical Kano Teaching Hospital, Kano, Nigeria (Galadanci); Papageorghiou had full access to all of the data in
Sciences, University of Milan, Milan, Italy (Cetin); Aragon Institute of Health Research, Obstetrics the study and take responsibility for the integrity of
Ospedale Luigi Sacco University Hospital, Department, Hospital Clínico Universitario Lozano the data and the accuracy of the data analysis. Drs
Department of BioMedical and Clinical Sciences, Blesa Zaragoza, Zaragoza, Spain (Oros); College of Kennedy and Papageorghiou contributed equally.
University of Milan, Milan, Italy (Savasi); Medicine, University of Ibadan, Ibadan, Nigeria Concept and design: Villar, Thiruvengadam, Arturo
Department of Obstetrics and Gynecology, (Ayede, John-Akinola); University College Hospital, Cardona-Perez, Ayede, Bako, Duro, Langer,
Ibadan, Nigeria (Ayede, John-Akinola); Department

Kennedy, Papageorghiou. University of Oxford, Oxford, UK), study UK: national population based cohort study. BMJ.
Acquisition, analysis, or interpretation of data: Villar, coordinator, Nkawkaw, Ghana; Eric Baafi, MD (Holy 2020;369:m2107. doi:10.1136/bmj.m2107
Ariff, Gunier, Thiruvengadam, Rauch, Kholin, Family Hospital, Nkawkaw, Ghana), data collection, 6. Li N, Han L, Peng M, et al. Maternal and neonatal
Roggero, Prefumo, Silva do Vale, Maiz, Cetin, Ghana; Anne Caroline Benski, MD (Hôpitaux outcomes of pregnant women with coronavirus
Savasi, Deruelle, Easter, Sichitiu, Soto Conti, Universitaires de Genève, Département de la disease 2019 (COVID-19) pneumonia: a case-control
Ernawati, Mhatre, Singh Teji, Liu, Capelli, Oberto, Femme, de l’Enfant et de l'Adolescent, Geneva, study. Clin Infect Dis. 2020;71(16):2035-2041.
Salazar, Gravett, Cavoretto, Bizor Nachinab, Switzerland), data collection, Geneva, Switzerland; doi:10.1093/cid/ciaa352
Galadanci, Oros, Ayede, Sentilhes, Bako, Savorani, Rachel Craik, BSc (Nuffield Department of Women’s
Cena, Garcia-May, Etuk, Casale, Abd-Elsalam, & Reproductive Health, University of Oxford, 7. Liao J, He X, Gong Q, Yang L, Zhou C, Li J.
Ikenoue, Baffah Aminu, Vecchiarelli, Usman, Oxford, UK), study coordinator (overall study); Analysis of vaginal delivery outcomes among
John-Akinola, Nieto, Ferrazzi, Bhutta, Sonia Deantoni, MD (Nuffield Department of pregnant women in Wuhan, China during the
Papageorghiou. Women’s & Reproductive Health, University of COVID-19 pandemic. Int J Gynaecol Obstet. 2020;
Drafting of the manuscript: Villar, Gunier, Oxford, Oxford, UK; Oxford Maternal and Perinatal 150(1):53-57. doi:10.1002/ijgo.13188
Thiruvengadam, Rauch, Prefumo, Maiz, Singh Teji, Health Institute, Green Templeton College, 8. Alfaraj SH, Al-Tawfiq JA, Memish ZA. Middle East
Liu, Etuk, Kennedy, Papageorghiou. University of Oxford, Oxford, UK; Neonatal Care Respiratory Syndrome Coronavirus (MERS-CoV)
Critical revision of the manuscript for important Unit, Department of Public Health and Pediatrics, infection during pregnancy: report of two cases &
intellectual content: Villar, Ariff, Thiruvengadam, School of Medicine, University of Turin, Italy), data review of the literature. J Microbiol Immunol Infect.
Kholin, Roggero, Prefumo, Silva do Vale, Arturo collection, Oxford, UK, and data input (multiple 2019;52(3):501-503. doi:10.1016/j.jmii.2018.04.005
Cardona-Perez, Cetin, Savasi, Deruelle, Easter, sites); Ken Takahashi, PhD (Department of 9. World Medical Association. World Medical
Sichitiu, Soto Conti, Ernawati, Mhatre, Singh Teji, Obstetrics and Gynecology, The Jikei University Association Declaration of Helsinki: ethical
Capelli, Oberto, Salazar, Gravett, Cavoretto, Bizor School of Medicine, Tokyo, Japan), data collection, principles for medical research involving human
Nachinab, Galadanci, Oros, Ayede, Sentilhes, Bako, Jikei, Japan; Gabriela Tavchioska, MSc (Department subjects. JAMA. 2013;310(20):2191-2194. doi:10.
Savorani, Cena, Garcia-May, Casale, Abd-Elsalam, of Pediatrics, General Hospital Borka Taleski, Prilep, 1001/jama.2013.281053
Ikenoue, Baffah Aminu, Vecchiarelli, Duro, Usman, Republic of North Macedonia), data collection,
John-Akinola, Nieto, Ferrazzi, Bhutta, Langer, Prilep, Republic of North Macedonia; Jim G. 10. The Global Health Network. INTERCOVID.
Kennedy, Papageorghiou. Thornton, MD (Division of Child Health, Obstetrics Accessed April 5, 2021. https://intergrowth21.tghn.
Statistical analysis: Villar, Gunier, Rauch, and Gynaecology, University of Nottingham, org/intercovid/
Papageorghiou. Nottingham, UK), literature reviews and study 11. Shi H, Han X, Jiang N, et al. Radiological findings
Obtained funding: Villar, Papageorghiou. advisor; Albertina Rego, PhD (Departamento de from 81 patients with COVID-19 pneumonia in
Administrative, technical, or material support: Villar, Pediatria, Faculdade Universidade Federal de Minas Wuhan, China: a descriptive study. Lancet Infect Dis.
Ariff, Thiruvengadam, Silva do Vale, Arturo Gerais, Belo Horizonte, Brazil), study coordinator, 2020;20(4):425-434. doi:10.1016/S1473-3099(20)
Cardona-Perez, Savasi, Easter, Sichitiu, Ernawati, Brazil; and Adele Winsey, PhD (Nuffield 30086-4
Singh Teji, Liu, Galadanci, Oros, Ayede, Bako, Department of Women’s & Reproductive Health, 12. Bauchner H, Golub RM, Zylke J. Editorial
Savorani, Garcia-May, Etuk, Baffah Aminu, University of Oxford, Oxford, UK), study concern-possible reporting of the same patients
John-Akinola, Papageorghiou. coordinator (overall study). Dr Winsey and Ms Craik with COVID-19 in different reports. JAMA. 2020;
Supervision: Villar, Thiruvengadam, Kholin, were supported by the COVID-19 Research 323(13):1256. doi:10.1001/jama.2020.3980
Roggero, Cetin, Savasi, Ayede, Cena, Etuk, Usman, Response Fund from the University of Oxford.
Ferrazzi, Langer, Papageorghiou. Other contributors did not receive any 13. Kayem G, Lecarpentier E, Deruelle P, et al. A
compensation (eAppendix 1 in the Supplement). snapshot of the Covid-19 pandemic among
Conflict of Interest Disclosures: Dr Gunier pregnant women in France. J Gynecol Obstet Hum
reported grants from Oxford University during the We also thank all the contributing institutions and
local researchers involved in the study. eAppendix 2 Reprod. 2020;49(7):101826. doi:10.1016/j.jogoh.
conduct of the study. Dr Sentilhes reported 2020.101826
personal, lecture, and consulting fees from Ferring in the Supplement contains their details as well as
Pharmaceutical and personal and lecture fees from details of the study committees. 14. Sentilhes L, De Marcillac F, Jouffrieau C, et al.
Bayer outside the submitted work. Dr Coronavirus disease 2019 in pregnancy was
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collection, management, analysis, and postpartum: a living systematic review protocol. undergoing surgery with perioperative SARS-CoV-2
interpretation of the data; preparation, review, or BMJ Open. 2020;10(12):e041868. doi:10.1136/ infection: an international cohort study. Lancet.
approval of the manuscript; and decision to submit bmjopen-2020-041868 2020;396(10243):27-38. doi:10.1016/S0140-6736
the manuscript for publication. 4. Campbell KH, Tornatore JM, Lawrence KE, et al. (20)31182-X
Disclaimer: The views expressed herein are those Prevalence of SARS-CoV-2 among patients 18. Ochiai D, Kasuga Y, Iida M, Ikenoue S, Tanaka M.
of the authors and not necessarily those of the UK admitted for childbirth in southern Connecticut. Universal screening for SARS-CoV-2 in
National Health System, the US National Institute JAMA. 2020;323(24):2520-2522. doi:10.1001/jama. asymptomatic obstetric patients in Tokyo, Japan.
for Health Research Department of Health, or any 2020.8904 Int J Gynaecol Obstet. 2020;150(2):268-269.
of the other funders. 5. Knight M, Bunch K, Vousden N, et al; UK doi:10.1002/ijgo.13252
Additional Contributions: We are grateful to the Obstetric Surveillance System SARS-CoV-2 Infection 19. Mendoza M, Garcia-Ruiz I, Maiz N, et al.
following colleagues for their contributions to the in Pregnancy Collaborative Group. Characteristics Pre-eclampsia-like syndrome induced by severe
study: Josephine Agyeman-Duah, MSc (Nuffield and outcomes of pregnant women admitted to COVID-19: a prospective observational study. BJOG.
Department of Women’s & Reproductive Health, hospital with confirmed SARS-CoV-2 infection in 2020;127(11):1374-1380. doi:10.1111/1471-0528.16339

20. Lokken EM, Walker CL, Delaney S, et al. Clinical measurement of crown-rump length in the first 31. Shanes ED, Mithal LB, Otero S, Azad HA, Miller
characteristics of 46 pregnant women with a severe trimester of pregnancy. Ultrasound Obstet Gynecol. ES, Goldstein JA. Placental pathology in COVID-19.
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223(6):911.e1-911.e14. doi:10.1016/j.ajog.2020.05.031 International Fetal and Newborn Growth 32. Narang K, Enninga EAL, Gunaratne MDSK, et al.
21. Onwuzurike C, Diouf K, Meadows AR, Nour NM. Consortium for the 21st Century (INTERGROWTH- SARS-CoV-2 infection and COVID-19 during
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22. Goldfarb IT, Diouf K, Barth WH, et al. Universal (9946):857-868. doi:10.1016/S0140-6736(14) Symptom clusters in Covid19: a potential clinical
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pregnancy dating based on ultrasound ajogmf.2020.100107

RESEARCH
The impact of COVID-19 on pregnancy

outcomes: a systematic review and
meta-analysis
Shu Qin Wei MD PhD, Marianne Bilodeau-Bertrand MSc, Shiliang Liu MB PhD, Nathalie Auger MD MSc
n Cite as: CMAJ 2021 April 19;193:E540-8. doi: 10.1503/cmaj.202604; early-released March 19, 2021
ABSTRACT
Background: The impact of coronavirus and keywords for “severe acute respira- Compared with no SARS-CoV-2 infection
disease 2019 (COVID-19) on maternal tory syndrome coronavirus 2 OR SARS- in pregnancy, COVID-19 was associated
and newborn health is unclear. We CoV-2 OR coronavirus disease 2019 OR with preeclampsia (OR 1.33, 95% CI 1.03
aimed to evaluate the association COVID-19” AND “pregnancy.” We evalu- to 1.73), preterm birth (OR 1.82, 95% CI
between severe acute respiratory syn- ated the methodologic quality of all 1.38 to 2.39) and stillbirth (OR 2.11, 95%
drome coronavirus 2 (SARS-CoV-2) included studies using the Newcastle– CI 1.14 to 3.90). Compared with mild
infection during pregnancy and adverse Ottawa Scale. Our primary outcomes COVID-19, severe COVID-19 was strongly
pregnancy outcomes. were preeclampsia and preterm birth. associated with preeclampsia (OR 4.16,
Secondary outcomes included stillbirth, 95% CI 1.55 to 11.15), preterm birth
METHODS: We conducted a systematic gestational diabetes and other preg- (OR 4.29, 95% CI 2.41 to 7.63), gesta-
review and meta-analysis of observa- nancy outcomes. We calculated sum- tional diabetes (OR 1.99, 95% CI 1.09 to
tional studies with comparison data on mary odds ratios (ORs) or weighted 3.64) and low birth weight (OR 1.89, 95%
SARS-CoV-2 infection and severity of mean differences with 95% confidence CI 1.14 to 3.12).
COVID-19 during pregnancy. We intervals (CI) using random-effects
searched for eligible studies in MEDLINE, meta-analysis. INTERPRETATION: COVID-19 may be
Embase, ClinicalTrials.gov, medRxiv and associated with increased risks of pre-
Cochrane databases up to Jan. 29, 2021, RESULTS: We included 42 studies involv- eclampsia, preterm birth and other
using Medical Subject Headings terms ing 438 548 people who were pregnant. adverse pregnancy outcomes.
C
oronavirus disease 2019 (COVID-19) is caused by severe increased risk of SARS-CoV-2 infection or symptomatic COVID-
acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 19, but they were at risk of severe COVID-19 compared with
and was declared a global pandemic in March 2020.1 those who were not pregnant.5 However, this review included
Pregnant people and infants may be particularly susceptible to suspected COVID-19 cases in addition to confirmed cases. 5
COVID-19 because the physiologic changes of pregnancy Although some recent observational studies have suggested
involve cardiorespiratory and immune systems, which may that people with confirmed asymptomatic and symptomatic
result in an altered response to SARS-CoV-2 infection in preg- COVID-19,6–15 as well as mild and severe infections,6,8,9,15–22 may
nancy.2 Fetuses may be exposed to SARS-CoV-2 during critical be at risk of adverse pregnancy outcomes, we are unaware of
periods of fetal development.3 The nature of the association any systematic reviews that have comprehensively evaluated
between COVID-19 and pregnancy outcomes remains unclear, these data.
and meta-analyses involving patients with COVID-19 who are We performed a systematic review and meta-analysis of
pregnant are limited. Previous reviews have focused mostly on maternal, fetal and neonatal outcomes among pregnant patients
prevalence estimates from case reports or case series that are with COVID-19. We aimed to determine the association between
difficult to interpret and potentially biased.4,5 A 2020 systematic SARS-CoV-2 infection and adverse pregnancy outcomes, includ-
review suggested that people who are pregnant did not have an ing preeclampsia, preterm birth and stillbirth.
E540 CMAJ | APRIL 19, 2021 | VOLUME 193 | ISSUE 16 © 2021 CMA Joule Inc. or its licensors
Methods 93% or less on room air, or findings consistent with pneumonia.24
We defined mild COVID-19 as a positive test result for SARS-CoV-2
This systematic review was conducted according to Preferred without development of severe symptoms. We classified cases of
RESEARCH
Reporting Items for Systematic Reviews and Meta-Analyses COVID-19 as symptomatic or asymptomatic and severe or mild. For
(PRISMA) guidelines. symptomatic COVID-19, we included patients with any symptom
regardless of severity. For severe COVID-19, we included patients
Data sources, search strategy and study selection with severe and critical symptoms, whereas mild COVID-19
We performed a systematic search of MEDLINE, Embase, C linicalTrials. included asymptomatic or mild cases.6,7,19
gov, medRxiv and Cochrane databases up to Jan. 29, 2021, to identify
observational studies with comparative data for p eople with COVID-19 Outcomes
who were pregnant (Appendix 1, available at www.cmaj.ca/lookup/ We selected outcomes based on clinical importance and avail-
doi/10.1503/cmaj.202604/tab-related-content). Our search strategy ability in published studies. Our primary outcomes included pre-
followed the Peer Review of Electronic Search Strategies (PRESS) eclampsia and preterm birth. Our secondary outcomes were ges-
guidelines. We searched the databases using a combination of Medical tational diabetes, chorioamnionitis or intra-amniotic infection,
Subject Headings (MeSH) terms and keywords for “severe acute res cesarean delivery, abnormal liver function, lymphopenia,
piratory syndrome coronavirus 2 OR SARS-CoV-2 OR 2019 novel mechanical ventilation, admission to the intensive care unit
coronavirus OR COVID-19” AND “pregnancy,” with language restricted (ICU), stillbirth (fetal loss at the 20th week of pregnancy or later),
to English abstracts. We also manually searched references cited in fetal distress, birth weight, low birth weight, gestational age at
these articles to identify any additional studies. birth, admission to the neonatal ICU (NICU) and neonatal death.
Two investigators independently screened the titles and
abstracts identified by the electronic searches, compared selected Assessment of study quality
studies and resolved discrepancies by discussion. Two reviewers independently assessed the methodologic quality of
We scrutinized and selected full-length articles of studies each study using the Newcastle–Ottawa Scale.23 Cohort studies were
evaluating COVID-19 in pregnancy and maternal and infant out- evaluated for the following 3 domains: quality of selection of
comes that met the following inclusion criteria: observational cohorts (4 stars), comparability of cohorts (2 stars) and assessment
study; population included pregnant people; SARS-CoV-2 infec- of outcome (3 stars). Case–control studies were assessed for quality
tion was confirmed by a polymerase chain reaction (PCR) test or of selection of cases and controls (4 stars), comparability of cases
with codes for confirmed COVID-19 from the International Statis and controls (2 stars) and ascertainment of exposure (3 stars). We
tical Classification of Diseases and Related Health Problems, 10th considered a total of 7 out of 9 stars to be a low risk of bias, 4–6 stars
Revision (ICD-10); comparisons included patients with COVID-19 to be a moderate risk and less than 4 stars to be a high risk of bias
versus those without COVID-19, patients with symptomatic versus (Appendix 2, available at www.cmaj.ca/lookup/doi/10.1503/
those with asymptomatic COVID-19, or severe versus mild COVID- cmaj.202604/tab-related-content). In case of a disagreement,
19; outcomes included maternal, fetal or neonatal morbidity and reviewers reached consensus by discussion with a third reviewer.
mortality; comparative data needed to calculate effect sizes were
available; and methodologic quality assessment criteria in the Data extraction and analysis
Newcastle–Ottawa Scale suggested low or moderate risk of bias.23 Two authors extracted data independently and in duplicate, with
We excluded studies that met at least 1 of the following exclu- any discrepancy resolved by discussion. Data were extracted and
sion criteria: reviews, case reports or case series; studies with no statistical analysis carried out using Review Manager 5.4. We used
comparison data; and studies that included cases of infective unadjusted estimates for meta-analysis because most of the stud-
pneumonia caused by other viral agents. If more than 1 study ies reported only data for raw outcomes. We used the Mantel–
was published that involved the same cohort with identical out- Haenszel method to combine data on dichotomous outcomes, and
comes, we included the report containing the most comprehen- measures of effect are presented as odds ratios (ORs) with 95%
sive information to avoid including the same data twice. confidence intervals (CIs). For continuous data, we calculated the
sample size weighted mean difference (MD) when outcomes were
Case definition measured the same way between studies. We assessed the associa-
We defined cases of COVID-19 as confirmed SARS-CoV-2 infection in tions between COVID-19 morbidity and pregnancy outcomes
a person who was pregnant. Controls without COVID-19 included (patients with COVID-19 versus pregnant people with no SARS-
pregnant people with negative PCR tests, those who were pregnant CoV-2 infection). We also evaluated outcomes of COVID-19 severity
before the pandemic or those who were pregnant and asymptom- in pregnant patients with confirmed infection (symptomatic versus
atic early in the pandemic. We defined asymptomatic COVID-19 as asymptomatic and severe versus mild COVID-19).
a positive test result for SARS-CoV-2 in a patient who never devel- We used forest plots to show individual point estimates (95%
oped symptoms of COVID-19 and symptomatic COVID-19 as a posi- CIs) for each study, and a diamond to represent the pooled point
tive test result for SARS-CoV-2 with the development of fever, estimate (95% CI) for each outcome of interest. We evaluated het-
cough, shortness of breath, fatigue, or loss of taste or smell. We erogeneity with the I2 statistic. If the I2 value was 40% or greater, we
defined severe COVID-19 as the presence of dyspnea, respiratory considered heterogeneity to be present.25 We pooled results using
rate at 30 breaths per minute or more and oxygen saturation at random-effects models. We performed a sensitivity analysis that
CMAJ | APRIL 19, 2021 | VOLUME 193 | ISSUE 16 E541

excluded preprints and studies with moderate risk of bias and used titles and abstracts, we read 357 full-text articles. Forty-two obser-
fixed-effect models for outcomes from studies with small numbers vational studies7–15,17,19,21,22,26–54 involving 438 548 pregnant people
of patients. We used funnel plots to assess publication bias. met the inclusion criteria and were included in the systematic
RESEARCH
review and meta-analysis. Our assessment of the methodologic

Ethics approval quality of each eligible study is summarized in Appendix 2. Ninety-
Ethics approval was not sought for this systematic review five percent (40 out of 42) of the observational studies had an over-
because the data were publicly available. all low risk of bias according to the Newcastle–Ottawa Scale, and
5% (2 out of 42) of the studies had moderate risk.
Results Characteristics of the included studies are summarized in
Appendix 3, available at www.cmaj.ca/lookup/doi/10.1503/
We found 7212 potentially relevant citations using our search cmaj.202604/tab-related-content. Of the 42 studies, 16 were pro-
strategy. The PRISMA flow diagram (Figure 1) summarizes the prospective cohorts,7,9,11,18,19,21,28,30,33,34,36,37,46,49–51 21 were retrospective
cess of literature search and selection of studies. After screening cohorts 8,10,12–14,17,27,29,32,35,38–45,48,53,54 and 5 were case–control
Records identified through Additional records identified

the database search through other sources
n = 7212 n = 38
Total no. of records found

n = 7250
Excluded n = 4253
• Studies published before 2019
No. of articles available

n = 2997
Excluded n = 519
• Duplicates
No. of articles available to screen

n = 2478
Excluded n = 703
• Reviews
No. of articles screened

n = 1775
Excluded n = 1418
• Found to be unsuitable after screening of titles and abstracts
Full-text articles assessed for eligibility

n = 357
Excluded n = 315
• Descriptive studies without comparative data n = 143
• Population included people who were not pregnant n = 122
• Cases included pneumonia caused by other agents n = 31
• Inappropriate outcomes n = 19
Studies included in qualitative and

quantitative synthesis (meta-analysis)
n = 42
Figure 1: Flow chart for the selection of studies.
E542 CMAJ | APRIL 19, 2021 | VOLUME 193 | ISSUE 16

studies.22,31,47,50,52 One prospective study resulted in 2 publications, with gestational diabetes, cesarean delivery, postpartum hemor-
1 preprint study for positive versus negative SARS-CoV-2 infection34 rhage or neonatal death compared with no COVID-19 (Table 1).
and another for severe versus mild COVID-19.18 Cases of COVID-19 were Compared with asymptomatic COVID-19, symptomatic
RESEARCH
confirmed by PCR testing. There were 28 studies of confirmed versus COVID-19 in pregnancy was associated with increased risk of pre-
no SARS-CoV-2 infection in pregnancy.11–13,15,22,27–32,34,35,37,39–45,47–51,53,54 term birth (OR 2.29, 95% CI 1.49 to 3.53; I 2 = 57%; based on
Twelve studies compared symptomatic versus asymptomatic COVID- 9 studies) (Figure 3B) and cesarean delivery (OR 1.57, 95% CI 1.32
19.7–15,46,48,52 There were 13 studies of severe versus mild COVID-19 in to 1.85; I2 = 1%; 9 studies) (Appendix 4). Symptomatic COVID-19
pregnancy.8,9,15,17–19,21,22,26,33,36,38,48 was not associated with gestational diabetes (Table 1).
Compared with no infection, we found that SARS-CoV-2 infec- Compared with mild COVID-19, severe COVID-19 was strongly
tion in pregnancy was associated with preeclampsia (OR 1.33, associated with preeclampsia (OR 4.16, 95% CI 1.55 to 11.15; I2 =
95% CI 1.03 to 1.73; I2 = 31%; based on 13 studies) (Figure 2A), 0%; based on 5 studies) (Figure 2C), preterm birth (OR 4.29, 95%
preterm birth (OR 1.82, 95% CI 1.38 to 2.39; I2 = 64%; 18 studies) CI 2.41 to 7.63; I2 = 61%; 10 studies) (Figure 3C), gestational dia-
(Figure 3A), stillbirth (OR 2.11, 95% CI 1.14 to 3.90; I2 = 24%; betes (OR 1.99, 95% CI 1.09 to 3.64; I2 = 14%; 5 studies), ICU
6 studies) (Figure 4), ICU admission (OR 4.78, 95% CI 2.03 to admission (OR 15.46, 95% CI 5.79 to 41.23; I2 = 0%; 5 studies),
11.25; I2 = 76%; 5 studies), lower birth weight (grams; mean differ- mechanical ventilation (OR 19.31, 95% CI 9.38 to 39.72; I2 = 0%;
ence –68.96, 95% CI –130.22 to –7.69; I2 = 29%; 13 studies) and 5 studies), cesarean delivery (OR 2.58, 95% CI 1.64 to 4.06; I2 =
NICU admission (OR 3.69, 95% CI 1.39 to 9.82; I2 = 94%; 10 studies) 43%; 8 studies), low birth weight (OR 1.89, 95% CI 1.14 to 3.12; I2 =
(Appendix 4, available at www.cmaj.ca/lookup/doi/10.1503/ 0%; 2 studies) and NICU admission (OR 3.95, 95% CI 1.43 to 10.95;
cmaj.202604/tab-related-content). COVID-19 was not associated I2 = 79%; 5 studies) (Table 1, Appendix 4).
A COVID-19 No COVID-19
Decreased Increased
risk risk
Study or subgroup Events Total Events Total OR (95% CI)
Adhikari et al.48 26 245 359 3035 0.88 (0.58 to 1.35)
Ahlberg et al.43 12 155 26 604 1.87 (0.92 to 3.79)
Brandt et al.22 6 61 10 122 1.22 (0.42 to 3.53)
Erol et al.50 2 60 0 36 3.12 (0.15 to 66.83)
Gulersen et al.29 5 50 7 50 0.68 (0.20 to 2.32)
Jering et al.53 564 6380 27 078 400 066 1.34 (1.22 to 1.46)
Martínez-Perez et al.18 11 246 44 763 0.76 (0.39 to 1.51)
Patberg et al.41 5 77 0 56 8.57 (0.46 to 158.29)
Pirjani et al.37 6 66 4 133 3.23 (0.88 to 11.85)
Wang et al.39 10 53 59 760 2.76 (1.32 to 5.78)
Yang et al.42 1 65 83 11 013 2.06 (0.28 to 15.01)
Yazihan et al.47 3 95 0 92 7.00 (0.36 to 137.43)
Zhang et al.40 1 16 4 45 0.68 (0.07 to 6.61)
Total (95% CI) 7569 416 775 1.33 (1.03 to 1.73)

Total events 652 27 674
Heterogeneity: I2 = 31%
0.01 0.1 1 10 100
OR (95% CI)
B Severe Mild Decreased Increased

COVID-19 COVID-19 risk risk
Adhikari et al.
48
2 12 24 233 1.74 (0.36 to 8.42)
Barbero et al.26 3 42 0 49 8.77 (0.44 to 174.89)
Brandt et al.22 2 7 4 54 5.00 (0.73 to 34.46)
Mendoza et al.19 1 8 0 34 13.80 (0.51 to 372.88)
Total (95% CI) 73 448 4.16 (1.55 to 11.15)

Total events 9 31
0.005 0.1 1 10 200
OR (95% CI)
Figure 2: Forest plots of summary crude odds ratios (ORs) and 95% confidence intervals (CIs) for the association between coronavirus disease 2019
(COVID-19) and preeclampsia. (A) Association between COVID-19 and preeclampsia (patients with COVID-19 versus patients without COVID-19).
(B) Association between severe COVID-19 and preeclampsia (patients with severe versus mild COVID-19).

Decreased Increased
A COVID-19 No COVID-19 risk risk
RESEARCH
Ahlberg et al.43 14 155 45 604 1.23 (0.66 to 2.31)

Cunarro-Lopez et al.44 13 68 2 43 4.85 (1.04 to 22.66)
Diaz-Corvillon et al.15 4 37 27 549 2.34 (0.77 to 7.09)
Edlow et al.49 10 64 5 63 2.15 (0.69 to 6.69)
Flaherman et al.27 21 179 9 84 1.11 (0.48 to 2.53)
Hcini et al.51 11 137 36 370 0.81 (0.40 to 1.64)
Jering et al.53 459 6380 23 234 400 066 1.26 (1.14 to 1.38)
Li et al.31 3 16 6 121 4.42 (0.99 to 19.82)
Nayak et al.35 38 141 90 836 3.06 (1.99 to 4.71)
Pineles et al.54 5 77 90 858 0.59 (0.23 to 1.51)
Prabhu et al.11 11 70 57 605 1.79 (0.89 to 3.61)
Smithgall et al.13 10 51 4 25 1.28 (0.36 to 4.57)
Wang et al.39 9 53 66 760 2.15 (1.01 to 4.60)
Woodworth et al.46 8 16 99 594 5.00 (1.83 to 13.64)
Yang et al.42 9 65 579 11 013 2.90 (1.43 to 5.88)
Yazihan et al.47 3 95 0 92 7.00 (0.36 to 137.43)
Zhang et al.40 3 16 6 45 1.50 (0.33 to 6.87)
Total (95% CI) 7866 417 491 1.82 (1.38 to 2.39)

Total events 665 24 406
0.01 0.1 1 10 100
OR (95% CI)
Symptomatic Asymptomatic
B COVID-19 COVID-19 Decreased Increased
risk risk
Adhikari et al.48 20 147 7 98 2.05 (0.83 to 5.04)
Delahoy et al.7 31 134 25 311 3.44 (1.94 to 6.11)
Di Mascio et al.55 60 189 10 77 3.12 (1.50 to 6.48)
Jenabi et al.52 12 45 6 45 2.36 (0.80 to 6.99)
Khoury et al.9 25 139 11 102 1.81 (0.85 to 3.88)
London et al.10 9 33 0 22 17.45 (0.96 to 317.38)
Smithgall et al.13 6 25 4 26 1.74 (0.43 to 7.09)
Verma et al.14 14 89 2 60 5.41 (1.18 to 24.77)
Woodworth et al.46 297 2315 43 376 1.14 (0.81 to 1.60)
Total (95% CI) 3116 1117 2.29 (1.49 to 3.53)

Total events 474 108
0.005 0.1 1 10 200
OR (95% CI)
Severe Mild
C COVID-19 COVID-19
Decreased Increased
risk risk
Adhikari et al.48 5 12 22 233 6.85 (2.00 to 23.41)
Barbero et al.26 5 11 3 12 2.50 (0.43 to 14.61)
Brandt et al.22 4 7 3 54 22.67 (3.40 to 151.02)
Di Mascio et al.55 60 189 10 77 3.12 (1.50 to 6.48)
Kayem et al.17 37 58 13 123 14.91 (6.80 to 32.70)
Khoury et al.9 18 73 18 166 2.69 (1.31 to 5.54)
Maraschini et al.33 15 47 13 99 3.10 (1.33 to 7.23)
Panagiotakopoulos et al.36 5 32 9 61 1.07 (0.33 to 3.51)
Savasi et al.21 4 11 8 46 2.71 (0.64 to 11.52)
Total (95% CI) 444 949 4.29 (2.41 to 7.63)

0.005 0.1 1 10 200
OR (95% CI)
Figure 3: Forest plots of summary crude odds ratios (ORs) and 95% confidence intervals (CIs) for the association between coronavirus disease 2019 (COVID-19)
and preterm birth. (A) Association between COVID-19 and preterm birth (patients with COVID-19 versus no COVID-19). (B) Association between symptomatic
COVID-19 and preterm birth (patients with symptomatic versus asymptomatic COVID-19). (C) Association between severe COVID-19 and preterm birth (patients
with severe versus mild COVID-19).

Decreased Increased
COVID-19 No COVID-19
risk risk
RESEARCH
Adhikari et al.48 0 245 18 3035 0.33 (0.02 to 5.53)

Ahlberg et al.43 1 155 4 604 0.97 (0.11 to 8.78)
Hcini et al.51
7 137 4 370 4.93 (1.42 to 17.11)
Jering et al.53 34 6380 1289 400 066 1.66 (1.18 to 2.33)
Knight et al.30 3 427 2 694 2.45 (0.41 to 14.71)
Total (95% CI) 7590 405 532 2.11 (1.14 to 3.90)

0.01 0.1 1 10 100
OR (95% CI)
Figure 4: Forest plots of summary crude odds ratios (ORs) and 95% confidence intervals (CIs) for the association between coronavirus disease 2019
(COVID-19) and stillbirth.
Sensitivity analyses produced similar results (Appendices 5 and with COVID-19 who were not pregnant.5 Our meta-analysis of recent
6, available at www.cmaj.ca/lookup/doi/10.1503/cmaj.202604/ good-quality cohort studies with comparative data does not align
tab-related-content). Funnel plots for preeclampsia and preterm with these previous reviews, and provides clear evidence that symp-
birth did not suggest that the conclusions were affected by publi- tomatic or severe COVID-19 is associated with a considerable risk of
cation bias (Appendix 7, available at www.cmaj.ca/lookup/ preeclampsia, preterm birth and low birth weight.
doi/10.1503/cmaj.202604/tab-related-content). The mechanisms underlying the association between COVID-19
and preeclampsia are unclear, but investigators have shown that
Interpretation SARS-CoV-2 may lead to renin–angiotensin system dysfunction and
vasoconstriction by binding to angiotensin-converting enzyme 2
We found that COVID-19 in pregnancy is associated with preeclamp- receptors.57 The hallmark of preeclampsia is a systematic endothel
sia, stillbirth and preterm birth compared with no COVID-19. Symp- ial dysfunction, which may share a common pathway with COVID-
tomatic COVID-19 was associated with an increased risk of cesarean 19 illness as the vascular effects of SARS-CoV-2 infection are
delivery and preterm birth compared with asymptomatic COVID-19. increasingly recognized. One study found that people with severe
Compared with mild COVID-19, severe COVID-19 was strongly asso- COVID-19 who were pregnant acquired clinical manifestations simi-
ciated with preeclampsia, gestational diabetes, preterm birth and lar to preeclampsia and were distinguishable by biomarker levels,
low birth weight. This meta-analysis of observational studies is including serum-soluble fms-like tyrosine kinase and placental
unique in providing comparative data on COVID-19 morbidity during growth factor.19 Some studies have shown that SARS-CoV-2 infec-
pregnancy. Our findings suggest that COVID-19 in pregnancy is asso- tion may create a proinflammatory state that is followed by sys-
ciated with preeclampsia and preterm birth, and that severe COVID- temic endothelial dysfunction and preeclampsia.58,59 Our finding is
19 can lead to considerable maternal and neonatal morbidity. consistent with a 2020 study in Sweden that reported that pregnant
We selected studies with low-to-moderate risk of bias using strict people with COVID-19 had a higher prevalence of preeclampsia.43
quality assessment criteria.23 Although the number of publications Our meta-analysis also suggests that SARS-CoV-2 infection was
on COVID-19 in pregnant people continues to increase, previous sys- associated with preterm birth, stillbirth and lower birth weight but
tematic reviews on COVID-19 in pregnancy have included mainly not with cesarean delivery, compared with the absence of SARS-
case reports and case series,4,5 or reviewed case reports for other CoV-2 infection. We also found that severe COVID-19 was strongly
types of coronavirus,55 describing the proportion of patients with associated with preterm birth and other adverse perinatal out-
clinical manifestations or pregnancy complications. These reviews comes. Some of these excess risks could relate to preeclampsia,
recognized the lack of good-quality data in the early stage of the although SARS-CoV-2 infection may also cause exaggerated systemic
pandemic that are needed to draw unbiased conclusions. One of the inflammatory responses involved in the pathogenesis of preterm
earliest systematic reviews reported that there was no difference in birth or a suboptimal environment for fetal growth and develop-
the clinical characteristics of patients with COVID-19 who were preg- ment. Placental fetal vascular malperfusion has been found in pla-
nant compared with patients who were not pregnant.56 A living sys- cental histopathologic findings in patients with COVID-19 at deliv-
tematic review that included mainly case reports and case series,5 ery,41 which may contribute to fetal growth, stillbirth and preterm
many of which used control groups of people who were not preg- birth. A recent national quasi-experimental study in the Netherlands
nant, or did not have a comparison group, reported that pregnant found that COVID-19 mitigation measures were associated with a
patients were less likely to have COVID-19 symptoms than those reduced incidence of preterm birth.60

Table 1: Summary of pooled results using random-effects models
RESEARCH
No. of Mean difference OR

Outcome No. of studies participants No. of events (95% CI) (95% CI) Heterogeneity, %
Patients with COVID-19 versus those without COVID-19

Preeclampsia 13 424 344 28 326 1.33 (1.03 to 1.73) 31
Gestational diabetes 13 425 890 40 567 1.03 (0.76 to 1.39) 54
Fetal distress 3 874 47 1.50 (0.64 to 3.53) 8
Stillbirth 6 413 122 1366 2.11 (1.14 to 3.90) 24
Chorioamnionitis or 5 4368 433 0.85 (0.57 to 1.26) 0
intra-amniotic infection
Admission to the ICU 5 409 737 2012 4.78 (2.03 to 11.25) 76
Cesarean delivery 22 429 366 121 650 1.00 (0.82 to 1.23) 78
Postpartum hemorrhage 5 2981 355 0.89 (0.52 to 1.53) 55
Preterm birth 18 425 357 25 071 1.82 (1.38 to 2.39) 64
Neonatal sex, male 5 11 985 6369 0.97 (0.71 to 1.33) 9
Gestational age at birth, wk 13 4197 –0.24 61
(–0.49 to 0.00)
Birth weight, g 13 2973 –68.96 29
(–130.22 to –7.69)
Low birth weight 2 1054 678 2.32 (0.26 to 21.07) 85
Admission to the NICU 10 5675 785 3.69 (1.39 to 9.82) 94
Neonatal death 5 2838 1.10 (0.41 to 2.95) 0
Patients with symptomatic versus asymptomatic COVID-19
Gestational hypertension 8 4122 333 1.20 (0.92 to 1.56) 1
or preeclampsia
Gestational diabetes 5 3767 256 1.12 (0.82 to 1.55) 0
Mechanical ventilation 3 1023 62 16.29 (3.88 to 68.47) 0
Admission to the ICU 4 1178 97 7.40 (0.48 to 114.24) 76
Cesarean delivery 9 4232 1406 1.57 (1.32 to 1.85) 1
Preterm birth 9 4233 582 2.29 (1.49 to 3.53) 57
Neonatal death 4 938 11 3.67 (0.88 to 15.29) 0
Patients with severe versus mild COVID-19
Preeclampsia 5 521 40 4.16 (1.55 to 11.15) 0
Gestational diabetes 5 1140 105 1.99 (1.09 to 3.64) 14
Abnormal liver function 4 350 116 6.47 (2.60 to 16.09) 50
Lymphopenia 4 561 221 3.04 (1.93 to 4.79) 0
Admission to the ICU 5 757 70 15.46 (5.79 to 41.23) 0
Mechanical ventilation 5 962 97 19.31 (9.38 to 39.72) 0
Cesarean delivery 8 1138 452 2.58 (1.64 to 4.06) 43
Preterm birth 10 1393 277 4.29 (2.41 to 7.63) 61
Gestational age at birth, wk 8 709 –3.50 91
(–5.96 to –1.03)
Low birth weight 2 400 74 1.89 (1.14 to 3.12) 0
Neonatal death 3 827 12 33.71 (5.18 to 219.44) 0
Note: CI = confidence interval, COVID-19 = coronavirus disease 2019, ICU = intensive care unit, NICU = neonatal intensive care unit, OR = odds ratio.

7. Delahoy MJ, Whitaker M, O’Halloran A, et al. Characteristics and maternal and
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RESEARCH
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Competing interests: None declared. Funding: This work was supported by a grant from the Canadian
Institutes of Health Research (no. PJT-162300). Nathalie Auger has
This article has been peer reviewed.
received a career award from the Fonds de recherche du Québec-
Affiliations: Department of Obstetrics and Gynecology (Wei), Centre Santé (no. 34695).
hospitalier universitaire Sainte-Justine; Centre de recherche du Centre
Content licence: This is an Open Access article distributed in accordance
hospitalier de l’Université de Montréal, Department of Social and
with the terms of the Creative Commons Attribution (CC BY-NC-ND 4.0)
Preventive Medicine (Auger), School of Public Health, Université de
licence, which permits use, distribution and reproduction in any medium,
Montréal; Bureau d’information et d’études en santé des populations
provided that the original publication is properly cited, the use is non-
(Wei, Bilodeau-Bertrand, Auger), Institut national de santé publique du
commercial (i.e., research or educational use), and no modifications or
Québec, Montréal, Que.; Centre for Surveillance and Applied Research
adaptations are made. See: https://creativecommons.org/licenses/
(Liu), Public Health Agency of Canada, Ottawa, Ont.
by-nc-nd/4.0/
Contributors: Shu Qin Wei and Nathalie Auger contributed to the concep-
Data sharing: All relevant data are provided in the article and the
tion and design of the study. Shu Qin Wei and Marianne Bilodeau-
appendices, and are available for use.
Bertrand screened the articles and assessed the quality of the studies.
Shu Qin Wei and Shiliang Liu performed the data extraction and analysis. Accepted: Mar. 2, 2021
Shu Qin Wei drafted the manuscript, and Nathalie Auger, Marianne
Correspondence to: Nathalie Auger, [email protected]
Bilodeau-Bertrand and Shiliang Liu revised the manuscript critically for
important intellectual content. All of the authors contributed to the inter-
pretation of the data, gave final approval of the version to be published
and agreed to be accountable for all aspects of the work.

Original Research
Association of Gestational Age at

Coronavirus Disease 2019 (COVID-19)
Downloaded from http://journals.lww.com/greenjournal by /nOPLdiPzMaERaNiPuX2xWkULsSKyb/DLmyw+K9kp9umZNWGRKLRsB1723CYAqXmtHgeO1Wfu/fN3ZwtuKEa/T6AxNSU7/VnsAywhuSpSeDVtnGLbKPaFvLPTkJ0fE71NUXoVAJBCUNmayHBCIjtFOWaPRFkyXFjxR2krcjakIA= on 01/11/2022
Vaccination, History of Severe Acute

Respiratory Syndrome Coronavirus 2
(SARS-CoV-2) Infection, and a Vaccine
Booster Dose With Maternal and Umbilical
Cord Antibody Levels at Delivery
Yawei J. Yang, MD, PhD, Elisabeth A. Murphy, PhD, Sunidhi Singh, BA, Ashley C. Sukhu, BS,
Isabel Wolfe, BS, Sanjana Adurty, BA, Dorothy Eng, BA, BS, Jim Yee, BS, Iman Mohammed, BA,
Zhen Zhao, PhD, Laura E. Riley, MD, and Malavika Prabhu, MD
OBJECTIVE: To describe maternal and umbilical cord were analyzed for semi-quantitative anti-spike IgG. We
blood anti-spike immunoglobulin (Ig)G levels at delivery examined the association between timing of maternal
with coronavirus disease 2019 (COVID-19) vaccination vaccination and maternal and umbilical cord anti-spike
before and during pregnancy and to assess the associa- levels using a rank sum test. The relationships between a
tion of prior severe acute respiratory syndrome corona- prior history of SARS-CoV-2 infection and maternal and
virus 2 (SARS-CoV-2) infection and a vaccine booster umbilical cord anti-spike IgG levels, and between a
dose with anti-spike maternal and umbilical cord IgG booster dose and maternal and umbilical cord anti-
levels. spike levels, were also evaluated using a rank sum test.
METHODS: We conducted a retrospective cohort study RESULTS: We included data from 1,359 vaccinated
of women with self-reported COVID-19 vaccination pregnant women, including 20 women who received a
(Pfizer-BioNTech, Moderna, or Johnson & Johnson/Jans- booster dose, and 1,362 umbilical cord samples. Mater-
sen), including a booster dose, during or before preg- nal anti-spike IgG levels were detectable at delivery
nancy, who delivered at 34 weeks of gestation or more. regardless of timing of vaccination throughout pregnancy
Maternal and umbilical cord blood samples at delivery among fully vaccinated women; however, early third-
trimester vaccination was associated with the highest
anti-spike IgG levels in maternal and umbilical cord
From the Department of Pathology and the Department of Obstetrics and
Gynecology, Weill Cornell Medicine, and NewYork-Presbyterian/Weill Cornell blood. Among women with a history of SARS-CoV-2
Medical Center, New York, New York. infection, maternal and cord blood antibody response
Supported by the Weill Cornell Medicine COVID-19 Research Grant and The achieved with vaccination in early pregnancy was com-
Bender Foundation, Inc. parable with third-trimester vaccination in pregnant
Each author has confirmed compliance with the journal’s requirements for women without a history of SARS-CoV-2 infection. A
authorship. booster dose in the third trimester was associated with
Corresponding author: Malavika Prabhu, MD, Department of Obstetrics and maternal anti-spike IgG levels greater than third-
Gynecology, Weill Cornell Medicine, New York, NY; email: malavika.prabhu@ trimester vaccination in women with or without a history
gmail.com.
of SARS-CoV-2 infection.
Financial Disclosure
The authors did not report any potential conflicts of interest. DISCUSSION: Vaccination against COVID-19 before
© 2021 by the American College of Obstetricians and Gynecologists. Published
and throughout pregnancy was associated with detect-
by Wolters Kluwer Health, Inc. All rights reserved. able maternal anti-spike IgG levels at delivery. A com-
ISSN: 0029-7844/21 plete vaccination course, prior history of SARS-CoV-2
VOL. 00, NO. 00, MONTH 2021 OBSTETRICS & GYNECOLOGY 1
© 2021 by the American College of Obstetricians

and Gynecologists. Published by Wolters Kluwer Health, Inc.
Unauthorized reproduction of this article is prohibited.
infection, and a third-trimester booster dose were liveborn neonate at 34 weeks of gestation or more at
associated with the highest maternal and umbilical cord a single academic medical center between March 6
antibody levels. and October 28, 2021. At the time of admission for
(Obstet Gynecol 2021;00:1–8) delivery, all women were tested for SARS-CoV-2
DOI: 10.1097/AOG.0000000000004693 infection using reverse transcription polymerase chain
reaction (RT-PCR), and admission blood samples
C oronavirus disease 2019 (COVID-19) vaccina-

tion is recommended for pregnant individuals
at any gestational age to decrease the risk of
were collected for routine clinical studies. At the time
of delivery, umbilical cord blood was collected for
routine neonatal clinical studies. Among patients
COVID-19 in pregnancy, because pregnancy meeting inclusion criteria, leftover maternal blood
increases the risk of severe disease.1 However, gesta- samples and corresponding leftover umbilical cord
tional age at vaccination may influence umbilical cord blood samples were de-identified and analyzed for
antibody levels at delivery. Therefore, although semi-quantitative IgG against anti-spike using a rela-
maternal protection is the priority for vaccination, tive index value.7 The relative index value is defined as
determining the immune protection provided to neo- the instrument readout of the test sample antibody
nates will help inform future infant-immunization value divided by the instrument cutoff value (mean
strategies. Data drawn from severe acute respiratory readout of noninfected and nonvaccinated control
syndrome coronavirus 2 (SARS-CoV-2) infection samples+6 SDs). We included data only if we were
across various gestational ages in pregnancy have able to obtain at least the maternal blood sample from
demonstrated that transplacental transfer of anti- a dyad.
bodies varies by gestational age of infection.5 In Clinical data and vaccination data were
women vaccinated against COVID-19, transplacental abstracted from the electronic medical record. Data
immunoglobulin (Ig)G transfer occurs 4–6 weeks after on race and ethnicity were included to describe the
maternal vaccine dose 1; some data have demon- population of women vaccinated against COVID-19
strated that maternal and umbilical cord anti-spike who were included in this study. The Pfizer and
antibody levels are positively correlated, whereas Moderna vaccinations follow a two-dose vaccination
other data have demonstrated that neonatal anti- course; women who received the Pfizer or Moderna
spike levels at birth are unrelated to timing of mater- vaccines were categorized at delivery as having
nal vaccination.2,3 received one dose of the vaccine, two doses of vaccine
Previous exposure to an antibody-inducing event, (but less than 14 days after dose 2), or fully vaccinated
such as prior infection or vaccination, may lead to (14 days or more after dose 2). The J&J/Janssen vac-
differential antibody response, but the effects in cination follows a one-dose vaccination course;
pregnant women are not well understood. In non- women who received the J&J/Janssen vaccine were
pregnant individuals, vaccination after previous categorized at the time of delivery as having received
SARS-CoV-2 infection leads to a more rapid and one dose of the vaccine (less than 14 days after the
sustained antibody response.6 single dose) or fully vaccinated (14 days or more after
We sought to describe the association of COVID- the single dose). Women were also categorized as hav-
19 vaccination before and during pregnancy with ing a prior SARS-CoV-2 infection if they had a his-
maternal and umbilical cord anti-spike IgG levels at tory of positive RT-PCR or serology test results or
the time of delivery, as well as the association of prior positive anti-nucleocapsid antibodies (which are pro-
SARS-CoV-2 infection and a booster dose during duced only in the setting of infection). Women who
pregnancy with anti-spike maternal and umbilical received an additional dose of an mRNA COVID-19
cord IgG levels. vaccine after completing the initial course of vaccina-
tion as above were categorized as having received a
METHODS booster dose (initial course Pfizer or Moderna,
We conducted a retrospective cohort study of preg- received three total vaccine doses; initial course J&J/
nant women with a self-report in the medical record of Janssen, received two total vaccine doses). No woman
receipt of at least one dose of an mRNA-based who received a booster dose had a history of being
COVID-19 vaccine (Pfizer-BioNTech BNT162b2 immunocompromised. Clinical data were de-
[Pfizer] or Moderna mRNA-1273 [Moderna]) or one identified and linked with the de-identified samples
dose of a viral vector–based COVID-19 vaccine for analyses.
(Johnson & Johnson/Janssen JNJ-78436735 [J&J/Jans- We evaluated the relationship between maternal
sen]) before or in pregnancy, and who delivered a anti-spike IgG levels at delivery and time of initiation
2 Yang et al COVID-19 Vaccination and Antibody Levels OBSTETRICS & GYNECOLOGY

of vaccination before or throughout pregnancy among Maternal anti-spike IgG levels at delivery were
women not receiving a booster dose, using a Wilcox- lowest after first-trimester mRNA vaccination and
on rank sum test. We conducted a similar analysis for highest after third-trimester mRNA vaccination for
umbilical cord anti-spike IgG levels compared with all women and for fully vaccinated women (Table 2
time of maternal vaccination. Among dyads with both and Fig. 2A). Among women who received the J&J/
a maternal and umbilical cord blood sample, we Janssen vaccine, there was no statistically significant
calculated the placental transfer ratio (umbilical cord difference in anti-spike IgG levels by trimester of vac-
IgG/maternal IgG). We also compared the maternal cination (Table 2).
and umbilical cord anti-spike IgG levels by timing of Among women without a prior history of SARS-
maternal vaccination initiation, stratified by prior CoV-2 infection (Fig. 2A, left), fully vaccinated
history of SARS-CoV-2 infection, using a Wilcoxon women demonstrated the lowest levels of anti-spike
rank sum test. Finally, we studied the maternal and IgG at delivery with prepregnancy or first-trimester
umbilical cord anti-spike IgG levels of women who initiation of vaccination, with statistically significantly
received a booster dose by trimester of maternal higher levels with second-trimester initiation of vacci-
vaccination initiation, using a Wilcoxon rank sum nation and statistically significantly even higher anti-
test. All analyses were performed using the geometric body levels at delivery if fully vaccinated in the third
means of anti-spike IgG levels. trimester. A similar statistically significant response
Statistical analysis was performed using R 3.6.3, was noted in umbilical cord anti-spike IgG levels by
RStudio 1.1.463. The study was approved by the trimester of maternal vaccination (Fig. 2B, left). Being
Weill Cornell Medicine Institutional Review Board. fully vaccinated in the first trimester was associated
This work was supported in part by the Weill Cornell with statistically significantly higher maternal and
Medicine COVID-19 Research Grant and The umbilical cord IgG levels than receiving only one
Bender Foundation, Inc. dose of vaccine in the third trimester (Fig. 2A and
B, left). In contrast, among women with a prior history
RESULTS of SARS-CoV-2 infection, the maternal and umbilical
We included 1,359 women who delivered 1,374 cord blood antibody response achieved among
neonates (15 sets of twins) in this study (Table 1). women both fully vaccinated and not fully vaccinated
From this cohort, we captured samples from 1,359 in pregnancy was not statistically significantly differ-
pregnant women and 1,362 neonates. All women ent and was comparable with third-trimester vaccina-
had negative RT-PCR test results for SARS-CoV-2 tion in women without a prior history of SARS-CoV-2
during the delivery admission. Women received vac- infection, with the exception of statistically higher
cine dose 1 between December 16, 2020, and Septem- maternal anti-spike IgG levels after third-trimester
ber 1, 2021, vaccine dose 2 between January 5, 2021, vaccination in women with a prior history of SARS-
and September 22, 2021, and a vaccine booster dose CoV-2 infection (Fig. 2A and B, middle).
between August 27, 2021, and October 14, 2021. Finally, women receiving a booster dose demon-
Women were vaccinated between 6 weeks before strated maternal anti-spike IgG levels that were
pregnancy and 41 weeks of gestation (Table 1). statistically significantly greater than third-trimester
Maternal anti-spike IgG levels were detectable at vaccination among fully vaccinated women in women
delivery regardless of gestational age at vaccination both with and without a history of SARS-CoV-2
among fully vaccinated women. Levels of maternal infection (Fig. 2A, right). Umbilical cord anti-spike
anti-spike IgG at delivery increased with greater IgG levels after receipt of a booster dose were not
gestational age at vaccination until vaccine initiation statistically significantly different from levels gener-
at 34 weeks of gestation, at which point anti-spike IgG ated in vaccinated women with a history of SARS-
levels were lower (these women were often not fully CoV-2 infection but were statistically significantly
vaccinated before delivery, Fig. 1A). We noted a sim- higher than levels elicited among those without a his-
ilar trend in umbilical cord anti-spike IgG levels based tory of SARS-CoV-2 infection who were fully vacci-
on timing of maternal vaccination, with lower anti- nated in the third trimester (Fig. 2B, right).
spike IgG levels at delivery noted with maternal vac-
cine initiation after 32 weeks of gestation (Fig. 1B). DISCUSSION
The median placental transfer ratio ranged between Maternal immunization against COVID-19 is para-
1 and 2 for much of the time period of maternal vac- mount to minimizing the risks of COVID-19 in
cination initiation but dropped below 1 with vaccina- pregnancy; thus, vaccination is recommended irre-
tion initiation after 32 weeks of gestation (Fig. 1C). spective of gestational age.1,8,9 In this large cohort, we
VOL. 00, NO. 00, MONTH 2021 Yang et al COVID-19 Vaccination and Antibody Levels 3

Table 1. Demographic, Clinical, and Vaccine Characteristics of the Cohort
Timing of 1st Vaccine Dose

Entire Cohort Prepregnancy 1st Trimester 2nd Trimester 3rd Trimester
Characteristic (N51,359) (n538) (n5193) (n5699) (n5429) P
Demographic characteristics
Maternal age (y) 35.363.8 34.463.9 34.863.6 35.463.7 35.463.9 .079
Race .062
Asian 201 (14.8) 8 (21) 24 (12.4) 98 (14.0) 71 (16.6)
Black 27 (2.0) 2 (5) 4 (2.1) 14 (2.0) 7 (1.6)
Mixed 79 (5.8) 1 (3) 8 (4.1) 30 (4.3) 40 (9.3)
Native American 3 (0.2) 0 (0) 1 (0.5) 1 (0.1) 1 (0.2)
White 856 (63.0) 23 (61) 133 (68.9) 451 (64.5) 249 (58.0)
None of the above or 193 (14.2) 4 (11) 23 (11.9) 105 (15.0) 61 (14.2)
declined
Ethnicity .147
Hispanic 97 (7.1) 5 (13) 10 (5.2) 51 (7.3) 31 (7.2)
Non-Hispanic 1,055 (77.6) 30 (79) 160 (82.9) 545 (78.0) 320 (74.6)
Unknown 207 (15.2) 3 (8) 23 (11.9) 103 (14.7) 78 (18.2)
Insurance type .703
Public 7 (0.5) 0 (0) 1 (0.5) 5 (0.7) 1 (0.2)
Private 1,352 (99.5) 38 (100) 192 (99.5) 694 (99.3) 428 (99.8)
Clinical characteristics
Gravidity 2 (1–4) 2 (1–3) 2 (0–4) 2 (0–4) 2 (1–3) .749
Parity 0 (0–1) 0 (0–1) 0 (0–1) 0 (0–1) 0 (0–1) .479
Gestational age at delivery 39.3 38.8 39.1 39.3 39.4 ,.001
(wk) (37.9–40.7) (37.0–40.6) (37.6–40.7) (38.0–40.6) (38.3–40.6)
History of SARS-CoV-2 174 (12.8) 4 (2) 11 (6.3) 97 (55.7) 62 (35.6) .014
infection*
Vaccine characteristics
Pfizer n51,025 n533 n5135 n5523 n5334 NA
1 dose received 45 (4.4) 0 (0) 2 (1.5) 5 (1.0) 38 (11.4)
2 doses received 45 (4.4) 0 (0) 0 (0) 0 (0) 45 (13.5) NA
Fully vaccinated† 917 (89.5) 20 (61) 129 (95.6) 517 (98.9) 251 (75.1)
Fully vaccinated and 18 (1.8) 13 (39) 4 (3.0) 1 (0.2) 0 (0)
received a booster
dose‡
Moderna n5301 n55 n551 n5162 n583
1 dose received 17 (5.6) 0 (0) 2 (3.9) 0 (0) 15 (18.1)
2 doses received 15 (5.0) 0 (0) 0 (0) 0 (0) 15 (18.1)
Fully vaccinated† 267 (88.7) 5 (100) 47 (92.2) 162 (100) 53 (63.9)
Fully vaccinated and 2 (0.7) 0 (0) 2 (3.9) 0 (0) 0 (0)
received a booster
dose‡
J&J/Janssen n533 n50 n57 n514 n512
1 dose received 2 (6.1) 0 0 (0) 0 (0) 2 (16.7)
Fully vaccinated† 31 (93.9) 0 7 (100) 14 (100) 10 (83.3)
Fully vaccinated and 0 (0) 0 0 (0) 0 (0) 0 (0)
received a booster
dose‡
SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; Pfizer, Pfizer-BioNTech BNT162b2; NA, not applicable; Moderna, Moderna
mRNA-1273; J&J/Janssen, Johnson & Johnson/Janssen JNJ-78436735.
Data are mean6SD, n (%), or median (interquartile range) unless otherwise specified.
* Prior positive reverse transcription polymerase chain reaction or serology test result or positive anti-nucleocapsid antibodies.
†
Fourteen days or more after the final dose of vaccine.
‡
One additional dose of Pfizer or Moderna vaccine.
demonstrate that immunization at any point in preg- Although the highest maternal, and consequently
nancy, or before pregnancy, is associated with detect- umbilical cord blood, antibody levels occur with early
able maternal anti-spike antibody levels at delivery. third-trimester vaccination, our data should not be

Fig. 1. Maternal and umbilical
cord blood anti-spike immuno-
globulin (Ig)G levels at delivery in
response to coronavirus disease
2019 (COVID-19) vaccination. A.
All vaccinated women at delivery.
Maternal anti-spike IgG levels at
time of delivery binned by gesta-
tional age or prepregnancy weeks
at dose 1 of vaccination. Blue
circles depict women fully vacci-
nated by delivery; red circles
indicate women not fully vacci-
nated by delivery. Moderna vac-
cine (n5299), Pfizer-BioNTech
(Pfizer) vaccine (n51,007), and
Johnson & Johnson/Janssen (J&J/
Janssen) vaccine (n533). B. Neo-
nates born to all vaccinated
women. Umbilical cord anti-spike
IgG levels categorized by mater-
nal gestational age or prepreg-
nancy weeks at dose 1 of
vaccination. Blue circles depict cord
blood samples from neonates of
women fully vaccinated by delivery;
red circles indicate cord blood
samples from neonates of women
not fully vaccinated by delivery.
Moderna vaccine (n5301), Pfizer
vaccine (n51,008), and J&J/Janssen
(n534). C. Vaccinated dyads. Pla-
cental transfer ratio (umbilical cord
anti-spike IgG/maternal anti-spike
IgG levels). Blue circles depict dyads
with fully vaccinated women, and
red circles depict dyads with not
fully vaccinated women. Moderna
vaccine (n5295), Pfizer vaccine
(n5994), and J&J/Janssen vaccine
(n530). Women at least 14 days
postvaccination course are de-
noted as fully vaccinated. All
positive serology cutoffs were 1
(horizontal dashed line). Vertical
dashed lines indicate separation
of pregnancy trimesters. Women
who received a booster dose are
not included.
Yang. COVID-19 Vaccination and Antibody Levels. Obstet Gynecol 2022.
interpreted to suggest that women should defer vacci- we demonstrate that neonates born to fully vaccinated
nation until the third trimester. Rather, our data sup- women, even those vaccinated early in the first trimes-
port the importance of early completion of a full ter, had similar or higher umbilical cord anti-spike IgG
vaccination series. First, women cannot predict levels than neonates born to women who initiated vac-
whether they may deliver prematurely, and these data cination in the third trimester but were not fully vacci-
reflect findings only from deliveries after 34 weeks of nated before delivery. Thus, the risks of waiting until
gestation. Second, maternal protection throughout the third trimester to initiate vaccination in the hopes of
pregnancy through vaccination is best for the fetus, optimizing neonatal antibody level at delivery do not
by minimizing risks of severe COVID-19. Moreover, benefit either the pregnant woman or the fetus.

Table 2. Maternal Anti-Spike Immunoglobulin G Levels at Delivery by Trimester of Vaccine Initiation and
Vaccine Type, Excluding Women Who Received a Booster Dose
Entire Cohort Prepregnancy 1st Trimester 2nd Trimester 3rd Trimester P*
All women
Pfizer n51,007 n520 n5131 n5522 n5334
Anti-spike IgG 5.1 (2.7–7.5) 3.7 (1.3–6.1) 3.9 (2.4–5.4) 4.8 (3.0–6.6) 6.2 (4.4–8.0) ,.001
(relative index value†)
Moderna n5299 n55 n549 n5162 n583
Anti-spike IgG 5.7 (3.8–7.6) 4.8 (3.8–5.8) 4.8 (3.1–6.5) 5.7 (4.2–7.2) 6.6 (4.8–8.4) ,.001
J&J/Janssen n533 n50 n57 n514 n512
Anti-spike IgG 3.1 (0.7–5.5) 3.6 (1.7–5.5) 3.0 (1.2–4.8) 2.5 (0–7.4) .791
Fully vaccinated women‡
Pfizer n5917 n520 n5129 n5517 n5251
Anti-spike IgG 5.1 (2.7–7.5) 3.7 (1.3–6.1) 3.9 (2.4–5.4) 4.8 (3.1–6.5) 6.4 (4.9–7.9) ,.001
Moderna n5267 n55 n547 n5162 n553
Anti-spike IgG 5.8 (4.0–7.6)) 4.8 (3.8–5.8) 4.8 (3.3–6.3) 5.7 (4.2–7.2) 7.1 (5.8–8.4) ,.001
J&J/Janssen n531 n57 n514 n510
Anti-spike IgG 3.1 (0.9–5.3) 3.6 (1.7–5.5) 3.0 (1.2–4.8) 2.5 (0–6.4) .765
Pfizer, Pfizer-BioNTech BNT162b2; IgG, immunoglobulin G; Moderna, Moderna mRNA-1273; J&J/Janssen, Johnson & Johnson/Janssen JNJ-
78436735.
Data are median (interquartile range) unless otherwise specified.
* Statistical testing done with a Kruskal Wallis test.
†
The relative index value is instrument readout of the test sample antibody value divided by instrument cutoff value (mean readout of
noninfected and nonvaccinated control samples+6 SDs).
‡
Fully vaccinated: 14 days or more after the final dose of vaccine.
We also observed an association between a prior We note some limitations to our study. First, the
history of SARS-CoV-2 infection and a higher and cohort of women included in this study does not reflect
more sustained immune response among women after every vaccinated woman who delivered at 34 weeks of
vaccination in pregnancy. Although the data regard- gestation or more during the study period. Some
ing a booster dose are limited in this study, women women were not included owing to either lack of
without a history of SARS-CoV-2 infection who leftover clinical sample or lack of documentation in
received a booster dose in the third trimester but the medical record regarding vaccination status. How-
were vaccinated before pregnancy or in the first ever, we do not believe this omission introduces bias
trimester demonstrate the highest anti-spike IgG into the study, because this loss of patients is random. In
levels in maternal and umbilical cord blood. Whether addition, we are unable to comment on the associations
the response to a booster dose is associated with a between maternal antibody levels and clinical charac-
sustained immune response is unknown at this time. teristics such as immunosuppressing conditions or
However, it is possible that the sustained response medication use or other comorbidities. It is also possible
noted with vaccination after SARS-CoV-2 infection that women may have had a distant history of SARS-
may illustrate what we can expect with receipt of a CoV-2 infection with both lack of documentation and
booster dose across trimesters in pregnancy. If this is waning levels of anti-nucleocapsid antibodies below the
the case, the discussion on optimal timing of COVID- limit of detection. These women would thus have been
19 vaccination may be moot, because primary vacci- miscategorized as not having a prior history of SARS-
nation series followed by a booster dose when eligible CoV-2 infection. Finally, our findings on the effect of a
is associated with the highest anti-spike IgG antibody booster dose are limited by the small sample size and
levels in both pregnant women and neonates. This is reflect a booster dose only in the third trimester. How-
the currently recommended strategy for protection ever, we were able to confirm that all women who
against COVID-19 but may evolve as more data received a booster dose were not immunosuppressed
define immune correlates of protection for adults and or using immunosuppressing medications; thus, none
neonates. received an additional mRNA vaccine as a “third dose.”

Fig. 2. Maternal and umbilical cord blood anti-spike immunoglobulin (Ig)G levels in response to coronavirus disease 2019
(COVID-19) vaccination, stratified by previous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, maternal
vaccination status, prepregnancy or trimester of vaccination, and receipt of booster dose. A. All women at delivery, including
women who received a booster dose. Maternal anti-spike IgG levels stratified by prior history of SARS-CoV-2 infection (blue
represents no prior history, and yellow represents prior history) and vaccination status at delivery (dark grey represents fully vac-
cinated, and red represents not fully vaccinated). Anti-spike IgG levels were grouped by timing of vaccine initiation: prepregnancy
or first, second, or third trimester. Women who received a booster dose are represented in green. B. Neonates born to all vaccinated
women, including women who received a booster dose. Umbilical cord anti-spike IgG levels are stratified similarly to part A, based
on maternal history of SARS-CoV-2 infection, maternal vaccination status, timing of maternal vaccination, and maternal booster
dose status. Women at least 14 days postvaccination course are denoted as fully vaccinated. *P,.05; †P,.005; NS, not significant.
Yang. COVID-19 Vaccination and Antibody Levels. Obstet Gynecol 2022.

Other categories of maternal and corresponding umbil- 4. Gray KJ, Bordt EA, Atyeo C, Deriso E, Akinwunmi B, Young N,
et al. Coronavirus disease 2019 vaccine response in pregnant and
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throughout pregnancy is associated with detectable load, transplacental antibody transfer, and placental pathology in
pregnancies during the COVID-19 pandemic. JAMA Netw
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initiation, transmit higher levels of antibodies to 6. Racine-Brzostek SE, Yee JK, Sukhu A, Qiu Y, Rand S, Barone
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Original Investigation | Obstetrics and Gynecology

Characteristics and Outcomes of Women With COVID-19 Giving Birth

Abstract Key Points

JAMA Network Open. 2021;4(8):e2120456. doi:10.1001/jamanetworkopen.2021.20456

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Table 1. Demographic and Clinical Characteristics of Hospitalized Women Undergoing Childbirth

Women, No. (%)

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Women, No. (%)

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JAMA Pediatrics | Original Investigation

Maternal and Neonatal Morbidity and Mortality

EXPOSURES COVID-19 in pregnancy determined by laboratory confirmation of COVID-19

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approached until 2 women without COVID-19 diagnosis were

E2 JAMA Pediatrics Published online April 22, 2021 (Reprinted) jamapediatrics.com

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jamapediatrics.com (Reprinted) JAMA Pediatrics Published online April 22, 2021 E3

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Table 1. Pregnancy Complications, Perinatal Events, and Neonatal Morbidities

E4 JAMA Pediatrics Published online April 22, 2021 (Reprinted) jamapediatrics.com

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Figure. Gestational Age at Delivery Among Women With COVID-19 Diagnosis,

Individuals remaining pregnant, %

jamapediatrics.com (Reprinted) JAMA Pediatrics Published online April 22, 2021 E5

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Table 2. Adjusted Associations for Maternal and Perinatal Outcomes

E6 JAMA Pediatrics Published online April 22, 2021 (Reprinted) jamapediatrics.com

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It is known that in nonpregnant patients, distinct sub-

jamapediatrics.com (Reprinted) JAMA Pediatrics Published online April 22, 2021 E7

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E8 JAMA Pediatrics Published online April 22, 2021 (Reprinted) jamapediatrics.com

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jamapediatrics.com (Reprinted) JAMA Pediatrics Published online April 22, 2021 E9

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The impact of COVID-19 on pregnancy

CMAJ | APRIL 19, 2021 | VOLUME 193 | ISSUE 16 E541

review and meta-analysis. Our assessment of the methodologic

Records identified through Additional records identified

Total no. of records found

No. of articles available

No. of articles available to screen

No. of articles screened

Full-text articles assessed for eligibility

Studies included in qualitative and

Figure 1: Flow chart for the selection of studies.

E542 CMAJ | APRIL 19, 2021 | VOLUME 193 | ISSUE 16

Total (95% CI) 7569 416 775 1.33 (1.03 to 1.73)

B Severe Mild Decreased Increased

Total (95% CI) 73 448 4.16 (1.55 to 11.15)

CMAJ | APRIL 19, 2021 | VOLUME 193 | ISSUE 16 E543

Ahlberg et al.43 14 155 45 604 1.23 (0.66 to 2.31)

Total (95% CI) 7866 417 491 1.82 (1.38 to 2.39)

Total (95% CI) 3116 1117 2.29 (1.49 to 3.53)

Total (95% CI) 444 949 4.29 (2.41 to 7.63)