key: cord-0895805-5rpd8d0t
authors: Regan, Annette K; Arah, Onyebuchi; Fell, Deshayne B; Sullivan, Sheena G
title: SARS-CoV-2 infection during pregnancy and associated perinatal health outcomes: a national US cohort study
date: 2021-12-27
journal: J Infect Dis
DOI: 10.1093/infdis/jiab626
sha: cec5061ff446811e149dd07e2db3116ec5a6f7b1
doc_id: 895805
cord_uid: 5rpd8d0t

BACKGROUND: SARS-CoV-2 infection has been associated with increased risk of adverse perinatal health outcomes. However, few large-scale, community-based epidemiological studies have been conducted. METHODS: We conducted a national cohort study using de-identified administrative claims data for 78,283 pregnancies with estimated conception before 30 April 2020 and pregnancy end after 11 March 2020. We identified maternal infections using diagnostic and laboratory testing data. We compared the risk of pregnancy outcomes using Cox proportional hazard models treating COVID-19 as a time-varying exposure and adjusting for baseline covariates. RESULTS: 2,655 (3.4%) pregnancies had a documented SARS-CoV-2 infection; 3.4% required admission to intensive care, invasive mechanical ventilation or ECMO treatment. COVID-19 during pregnancy was not associated with risk of miscarriage, antepartum hemorrhage, or stillbirth, but was associated with 2-3 fold higher risk of induced abortion (adjusted hazard ratio [aHR] 2.60, 95% CI 1.17-5.78), c-section (aHR 1.99, 95% CI 1.71-2.31), clinician-initiated preterm birth (2.88; 95% CI 1.93, 4.30), spontaneous preterm birth (aHR 1.79, 95% CI 1.37-2.34), fetal growth restriction (aHR 2.04, 95% CI 1.72-2.43), and postpartum hemorrhage (aHR 2.03, 95% CI 1.6-2.63). CONCLUSIONS: Prenatal SARS-CoV-2 infection was associated with increased risk of adverse pregnancy outcomes. Prevention could have fetal health benefits.

A c c e p t e d M a n u s c r i p t 3 Background COVID-19, the disease caused by the SARS-CoV-2 virus, can result in serious, potentially lifethreatening respiratory disease. Several conditions place certain adults at higher risk of severe COVID-19, including immunocompromising conditions, diabetes, heart disease, liver disease, and other. More recently, the Centers for Disease Control and Prevention (CDC) listed pregnancy as a medical condition placing adults at higher risk of severe infection. Emerging surveillance data have shown that pregnant individuals may be at increased risk of a severe outcome following maternal SARS-CoV-2 infection [1, 2] . Early data from Wuhan, China suggested no increased risk of severe outcomes for pregnant individuals [3] ; however, more recent and robust evidence from a living systematic review and large case series from the US has shown that pregnant individuals are at higher risk of hospitalization, intensive care unit (ICU) admission and death from COVID-19 compared to non-pregnant adults of reproductive age [4, 5] .

A living systematic review of 192 studies last updated on March 2021 [6] concluded that compared to their uninfected counterparts, pregnant individuals infected with SARS-CoV-2 have higher mortality and a higher risk of ICU admission [4] . Moreover, their pregnancies are more likely to be preterm and end in stillbirth [4] . These risks have also been reported in a large claimsbased study of over 400,000 pregnancies in the US [5] and a pooled Nordic study of over 300,000 pregnancies [7] . Other factors that have been variously reported to increase the risks of severe outcomes or occur more frequently in pregnant individuals infected with SARS-CoV-2, include myocardial infarction, eclampsia, pre-eclampsia, and gestational diabetes [5] . Evidence of vertical transmission of SARS-CoV-2 has been reported [8] , but neonatal infection has more commonly been associated with post-delivery infection [8, 9] .

Despite the large number of studies, there remain major gaps in our knowledge of how SARS-CoV-2 impacts pregnancy health. First, although a large number of studies have been published since the beginning of the COVID-19 pandemic, these have been mostly small, regional, hospital-based studies [4] . Second, the majority of studies to date have focused on hospitalized patients, often identified at A c c e p t e d M a n u s c r i p t 4 the time of delivery, which will over-represent more severe SARS-CoV-2 infections and may be driven by routine testing at admission for delivery. Second, all observational studies which have examined pregnancy outcomes among all pregnancies presenting run the risk of right truncation bias or live-birth bias, if not properly addressed [10, 11] . As a result, these studies might under-or overestimate the risks of pregnancy outcomes. Finally, many studies have included as risk factors conditions which may be mediating factors for severe disease, which can also lead to spurious estimates.

Here, we report on outcomes associated with both hospitalized and community COVID-19 diagnoses anytime during pregnancy using large administrative claims and electronic health record data from the OptumLabs ® Data Warehouse (OLDW). We included only pregnancies conceived prior to 30 April 2020 to allow sufficient time for full follow up, thereby averting right truncation.

We conducted a claims-based cohort study using de-identified administrative claims and electronic health record (EHR) data from the OLDW [12] . The database includes longitudinal health information for enrollees across the United States. Claims data in OLDW include medical and pharmacy claims, laboratory results and enrolment records for commercial enrollees. Pregnancies were identified from facility and physician claims data using a previously validated algorithm (eTable 1) [13] . The cohort included individuals with an estimated date of conception before 30 April 2020 (i.e., allowing ≥43 weeks of follow up to prevent cohort truncation bias) [10] and pregnancy end date after 11 March 2020 (i.e., declaration of COVID-19 pandemic status). We excluded molar and ectopic pregnancies from our analysis. We extracted physician, facility and laboratory claims records in addition to EHR data for one year preceding and 30 days following the date the pregnancy ended. Pregnancies were included in the final analysis if they were continuously enrolled in the health insurance plan for one year preceding the date of delivery and 30 days after the date of delivery. To evaluate early pregnancy outcomes, including miscarriage and induced abortion, we extracted a sub-cohort with a date of A c c e p t e d M a n u s c r i p t 5 conception between 1 January and 30 April 2020, which restricted the cohort to pregnancies where exposure to SARS-CoV-2 during first trimester was possible.

We identified SARS-CoV-2 cases based on the presence of a COVID-19 diagnosis in a facility or physician claim, their EHR, or a positive laboratory test result for a SARS-CoV-2 laboratory test (eTable 2). We classified COVID-19 as "severe" if they had a medical record indicating diagnosis of acute respiratory distress syndrome or use of invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) treatment (eTable 2). Participants without severe symptoms and with no record of hospital diagnosis coinciding with the COVID-19 admission were classed as having "mild" COVID-19 symptoms.

Information on maternal age, race/ethnicity, residence, educational attainment, and household income were derived from enrollment data and linked data supplied by an external vendor. Socioeconomic variables were obtained from a third-party vendor. In brief, the third-party vendor applies imputation procedures to derive race/ethnicity, education level and household income based on a variety of publicly and privately available data sources. Race/ethnicity is imputed based on a model using an individual's full name and geographic location. Education level is derived from the US Census Bureau's American Community Survey. Educational attainment is assigned to the individual based on the median level of education achieved among all residents 25 years and older within a census block group. Household income is imputed based on a model using public and private consumer data (e.g., loan amounts and loan payments, credit card statements). We identified pre-existing health conditions and pregnancy complications using medical claims records (eTable 3). Medical claims information was also used to identify pregnancy complications and outcomes (eTable 1). Early pregnancy outcomes included miscarriage and induced abortion. Pregnancy complications (including hyperemesis, antepartum hemorrhage, pre-eclampsia, gestational diabetes, pre-labor rupture of membranes, and placental abruption) and birth outcomes (cesarean section, induction of labor, clinician-induced preterm birth, spontaneous preterm birth, fetal growth restriction, and stillbirth) were evaluated for pregnancies with gestational length ≥20 weeks.

A c c e p t e d M a n u s c r i p t 6

We measured the incidence of SARS-CoV-2 infection among pregnant individuals and estimated proportionate severity of prenatal SARS-CoV-2 infection as the proportion of COVID-19 cases classed as "severe." We compared incidence rates by sociodemographic and chronic health factors using Poisson regression with robust standard errors to account for limited number of available predictors. We adjusted for the timing of pregnancy by including the week of pregnancy conception as a B-spline (a cubic spline with three knots) in the model. Missing covariate information was imputed using expectation-maximization with bootstrapping procedures in the amelia() package in R. [14] To estimate the risks of adverse pregnancy outcomes among SARS-CoV-2 infected pregnancies compared to uninfected pregnancies, we used Cox proportional hazard models with gestational age (in weeks) as the underlying time variable. Models treated COVID-19 as a time-varying exposure.

Adjusted models accounted for maternal age, race/ethnicity, household income, presence of a preexisting medical condition (yes/no), and week of pregnancy conception (cubic spline). We performed separate models by the trimester of SARS-CoV-2 infection (first, second or third) to estimate the risk of adverse pregnancy outcomes by gestational age at infection.

We performed additional analyses comparing the risks of adverse pregnancy outcomes for severe COVID-19 to mild COVID-19. To evaluate the sensitivity of our findings to potential variation in COVID-19 diagnoses, we performed several sensitivity analyses. First, we restricted to individuals with a positive or negative test result for COVID-19 during pregnancy. Second, since testing may occur routinely at admission for delivery, we stratified our analyses by proximity of the SARS-CoV-2 infection to delivery (within 3 days of delivery or ≥3 days). We did not perform any modelling where there were <11 exposed pregnancies with a pregnancy outcome (consistent with OLDW criteria for reporting results) [12] .

Because this study involved analysis of pre-existing, de-identified data, it was considered exempt from Institutional Review Board approval. M a n u s c r i p t The incidence of SARS-CoV-2 infection declined as maternal age increased ( April 2020. In this sub-cohort, the risk of miscarriage (aHR 1.27, 95% CI 0.86-1.87) was similar for SARS-CoV-2-infected pregnancies compared to uninfected. Induced abortion was 2.6 times higher (95% CI 1.17-5.78) among pregnancies infected with SARS-CoV-2 compared to uninfected A c c e p t e d M a n u s c r i p t 9 pregnancies. Effect estimates were similar for SARS-CoV-2 infections whether they were identified in first, second, or third trimester ( Table 3) . We observed indications of a dose-response relationship between severity of SARS-CoV-2 infection and risk of adverse pregnancy outcomes, with a trend toward higher risk associated with infections classed as "severe." However, we identified a small number of "severe" infections (n=91) and this resulted in low precision in our effect estimates ( Figure   2 ).

When we evaluated pregnancy outcomes for those who were tested for SARS-CoV-2 during pregnancy (n=5,644), we observed similar results to our primary analysis (eTable 4). We observed no associations for prenatal SARS-CoV-2 infections occurring near delivery. following SARS-CoV-2 infection occurring more than 3 days prior to delivery (eTable 5).

Based on clinical health information from a large cohort of pregnancies during the COVID-19 pandemic in the US, results suggest that 3% of pregnant individuals who delivered between March and January 2021 experienced a SARS-CoV-2 infection, and infection was associated with increased risks of poor pregnancy outcomes. These findings suggest prevention of SARS-CoV-2 infection during pregnancy may confer maternal and fetal health benefits. In addition to handwashing and social distancing measures, with the availability of highly efficacious vaccines [15] [16] [17] , guidelines encouraging vaccination of pregnant individuals [18] , and early results suggesting mRNA vaccine safety in pregnancy [19] , effective prevention of maternal SARS-CoV-2 infection is possible.

Our findings corroborate those of the living systematic review [4] and a recent review of systematic reviews [20] , indicating that preterm birth rates, especially those medically indicated, are higher among pregnancies with SARS-CoV-2 infection. The recent review of systematic reviews by Papapanou et al (2021) identified similar findings based on their summary of evidence from smaller, A c c e p t e d M a n u s c r i p t 10 regional studies [20] . Although the relationship between preterm birth and the COVID-19 pandemic has been debated [21] , our findings from a large US cohort support increased risk of preterm birth associated with SARS-CoV-2 infection during pregnancy. We additionally identified increased risks of fetal growth restriction and prelabor rupture of membranes -pregnancy outcomes which could implicate the role of ischemic placental pathology. Several studies have observed evidence of placental injury and vascular malperfusion in SARS-CoV-2 infected pregnancies, even when infection was asymptomatic. [22] [23] [24] [25] While our data offer additional support for this potential mechanism, further evidence elucidating biological mechanisms through which SARS-CoV-2 infection may impact pregnancy health would be useful.

In addition to aligning with pooled analyses of multiple smaller studies [4] , our results contribute several additional important points of knowledge. First, few previous studies have been powered to independently evaluate the risk of stillbirth. Higher rates of stillbirth have been reported in Israel during their first wave of the pandemic [26] , and prospective cohort studies have identified higher rates of stillbirth and neonatal mortality, potentially associated with decreases in quality of clinical care [27] . A large systematic review estimated the pooled risk of stillbirth from 5,794 participants in nine studies to be 2.84 (95% CI 1.25, 6.45). However, recent surveillance data from the UK suggested there was no increase in stillbirths during their first COVID-19 epidemic (prior to June 30, 2020) [28] .

To our knowledge, our study is the largest single comparative epidemiological study to date to evaluate the risk of stillbirth associated with SARS-CoV-2 infection [4] . We observed no association between the risk of stillbirth with SARS-CoV-2 infection. However, since we identified only 401 stillbirths, further large-scale evaluation remains important.

Second, few studies have been able to assess early pregnancy outcomes [4] . Examination of fetal tissues from patients infected in early pregnancy has shown that congenital SARS-CoV-2 infection is possible during first trimester, with documented damage to the placenta and fetal organs following hyperinflammatory processes [25] . However, epidemiological evidence has not supported an association with miscarriage. A recent Danish cohort study of pregnant individuals diagnosed with COVID-19 during the first trimester of pregnancy found no difference in nuchal translucency A c c e p t e d M a n u s c r i p t 11 thickness for those who tested positive compared to those who tested negative for SARS-CoV-2 and there was no increased risk of pregnancy loss [29] . However, these data were based on a small number of SARS-CoV-2 infections (n=18) with only one event identified among SARS-CoV-2 positive pregnancies. Our cohort, drawing from a larger number of infected pregnancies (n=2,655) corroborate those of the Danish study, suggesting no association between COVID-19 infection and risk of miscarriage.

Finally, due to the large sample of cases, we were able to evaluate pregnancy outcomes by trimester of exposure to COVID-19. Risk of preterm birth was elevated regardless of trimester of infection and more commonly among pregnancies where infection occurred weeks prior to delivery. Previous studies of SARS-CoV-2 infected pregnancies have suggesting a mechanistic role of placenta [30] , outlining a biologically plausible pathway from infection with SARS-CoV-2 virus to preterm birth, fetal growth restriction and other adverse outcomes [24, 25, 31] . However, further research into mechanisms involved in exposure to SARS-CoV-2 early in pregnancy is needed.

Despite the novel contributions to the literature, our study is not without limitations. First, we relied on diagnostic coding and laboratory testing records to identify a large sample of pregnant individuals with a record of SARS-CoV-2 infection. While this allowed us the opportunity to draw from a large sample using medical data, it is possible that we included asymptomatic cases. The inclusion of asymptomatic cases in the epidemiological evaluation of COVID-19 and perinatal health has been debated [32] . We attempted to address this limitation by evaluating severe cases of COVID-19, which would have been exhibiting severe symptoms of infection. Second, although the maternal mortality rate identified in our cohort was higher than the national average in 2019 (32 per 100,000 live births in our cohort vs. 20 per 100,000 in 2019 in the US [33] ), the small number of deaths precluded us from more detailed analyses. Several studies have identified higher rates of maternal mortality associated with SARS-CoV-2 infection during pregnancy [34, 35] , and this remains an important maternal health outcome for consideration in future studies. Second, our analysis drew from a large data repository of longitudinal clinical health information, but data were restricted to commercially insured pregnant individuals. As a result, these results may not be generalizable to the entire Relative risk calculated using Poisson regression with robust standard errors (using sandwich estimator) and adjusting for week of pregnancy conception (cubic spline).

A c c e p t e d M a n u s c r i p t 22 

Characteristics of Women of Reproductive Age with Laboratory-Confirmed SARS-CoV-2 Infection by Pregnancy Status -United States

Update: Characteristics of Symptomatic Women of Reproductive Age with Laboratory-Confirmed SARS-CoV-2 Infection by Pregnancy Status -United States

Clinical Characteristics of Pregnant Women with Covid-19 in Wuhan, China

Clinical manifestations, risk factors, and maternal and perinatal outcomes of coronavirus disease 2019 in pregnancy: living systematic review and metaanalysis

Clinical Characteristics and Outcomes of Hospitalized Women Giving Birth With and Without COVID-19

Update to living systematic review on covid-19 in pregnancy

COVID-19 in pregnancy -characteristics and outcomes of pregnant women admitted to hospital because of SARS-CoV-2 infection in the Nordic countries

Pregnancy Outcomes Among Women With and Without Severe Acute Respiratory Syndrome Coronavirus 2 Infection

Characteristics and outcomes of pregnant women admitted to hospital with confirmed SARS-CoV-2 infection in UK: national population based cohort study

Educational note: addressing special cases of bias that frequently occur in perinatal epidemiology

OptumLabs and OptumLabs Data Warehouse (OLDW) Descriptions and Citation

Using insurance claims data to identify and estimate critical periods in pregnancy: An application to antidepressants

Efficacy and Safety of the mRNA-1273 SARS-CoV-2

Safety and Efficacy of the BNT162b2 mRNA Covid-19

Safety and Immunogenicity of Two RNA-Based Covid-19 Vaccine Candidates

COVID-19 Vaccination in Pregnant and Lactating Women

Preliminary Findings of mRNA Covid-19 Vaccine Safety in Pregnant Persons

Maternal and Neonatal Characteristics and Outcomes of COVID-19 in Pregnancy: An Overview of Systematic Reviews

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Placental deficiency during maternal SARS-CoV-2 infection

Acute SARS-CoV-2 alpha variant infection leading to placental insufficiency and fetal distress

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Fetal and placental infection with SARS-CoV-2 in early pregnancy

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Effect of the COVID-19 pandemic response on intrapartum care, stillbirth, and neonatal mortality outcomes in Nepal: a prospective observational study

Stillbirths During the COVID-19 Pandemic in England

SARS-CoV-2 in first trimester pregnancy: a cohort study

Pregnancy and postpartum outcomes in a universally tested population for SARS-CoV-2 in New York City: a prospective cohort study

Persistence of SARS-CoV-2 in the first trimester placenta leading to transplacental transmission and fetal demise from an asymptomatic mother

Implications of asymptomatic carriers for infectious disease transmission and control

Maternal mortality rates in the United States

Mortality in pregnancy and the postpartum period in women with severe acute respiratory distress syndrome related to COVID-19 in Brazil

Abbreviations: RR, relative risk

Adjusted models controlled for maternal age, race/ethnicity, annual household income, presence of a pre-existing medical condition (yes/no), and week of pregnancy conception (cubic spline)

Cox proportional hazard model comparing risk of outcome among COVID-19 infected pregnancies vs. uninfected pregnancies, treating COVID-19 infection as a time-varying exposure. Adjusted models controlled for maternal age, race/ethnicity, household income, presence of a pre-existing medical condition

A c c e p t e d M a n u s c r i p t 25 A c c e p t e d M a n u s c r i p t 27 Figure 2