eMethods. Statistical Analysis.
eResults 1. Comparing Individuals Who Tested Negative With Individuals Who Were Not Tested
eResults 2. Need for Respiratory Support Among Hospitalizations in Individuals With and Without SARS-CoV-2
eTable 1. ICD-10 Diagnostic Codes
eTable 2. Crude and Adjusted Hazard Ratio or Relative Risk of Perinatal Complications Stratified by Intervals of Gestational Age in Association With SARS-Cov-2 Test Status During Pregnancy Among Individuals Who Delivered Between March 2020 and March 2021
eTable 3. Frequency of Outcomes by Prepregnancy BMI Missing Status
eTable 4. Characteristics of Individuals Who Delivered Between March 2020 and March 2021 by Testing Status for SARS-Cov-2 During Pregnancy
eTable 5. Distribution of Conditions Included in the Severe Maternal Morbidity by SARS-Cov-2 During Pregnancy
eTable 6. List Of Severe Maternal Morbidity Diagnoses Among Those With SARS-Cov-2 and 2 or More Severe Maternal Morbidity Diagnoses on the Same Day
eTable 7. Crude and Adjusted Hazard Ratio or Relative Risk Of Perinatal Complications in Association With SARS-Cov-2 Occurring at Less Than 21 Weeks’ Gestation or at 21 Weeks’ or More Gestation Among Individuals Who Delivered Between March 2020 and March 2021
eTable 8. Crude and Adjusted Hazard Ratio or Relative Risk of Perinatal Complications in Association With SARS-Cov-2 Detected in Inpatient or Outpatient Settings During Pregnancy Among Individuals Who Delivered Between March 2020 and March 2021
eTable 9. Adjusted Hazard Ratios for Perinatal Complications Severe Maternal Morbidity In Association With SARS-CoV-2 Among Individuals With and Without Comorbidities
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Ferrara A, Hedderson MM, Zhu Y, et al. Perinatal Complications in Individuals in California With or Without SARS-CoV-2 Infection During Pregnancy. JAMA Intern Med. 2022;182(5):503–512. doi:10.1001/jamainternmed.2022.0330
What is the risk of perinatal complications associated with SARS-CoV-2 infection during pregnancy and what factors are associated with hospitalizations?
In this cohort study of 43 886 pregnant individuals, SARS-CoV-2 infection during pregnancy was associated with an increased risk of severe maternal morbidity, preterm birth, and venous thromboembolism. Pregestational diabetes and Asian or Pacific Islander and Black race and ethnicity were associated with an increased risk of hospitalization.
This study found that SARS-CoV-2 infection may be associated with an increased risk of perinatal complications; this information can help inform treatment of the infection during pregnancy, aid patients in understanding the risks of these complications, and support the recommendation for vaccination of pregnant individuals and those planning conception.
Additional research from population-based studies is needed to inform the treatment of SARS-CoV-2 infection during pregnancy and to provide health risk information to pregnant individuals.
To assess the risk of perinatal complications associated with SARS-CoV-2 infection and to describe factors associated with hospitalizations.
Design, Setting, and Participants
This population-based cohort study included 43 886 pregnant individuals with longitudinal electronic health record data from preconception to delivery who delivered at Kaiser Permanente Northern California between March 1, 2020, and March 16, 2021. Individuals with diagnostic codes for COVID-19 that did not have a confirmatory polymerase chain reaction test for SARS-CoV-2 were excluded.
SARS-CoV-2 infection detected by polymerase chain reaction test (from 30 days before conception to 7 days after delivery) as a time varying exposure.
Main Outcomes and Measures
Severe maternal morbidity including 21 conditions (eg, acute myocardial infarction, acute renal failure, acute respiratory distress syndrome, and sepsis) that occurred at any time during pregnancy or delivery; preterm birth; pregnancy hypertensive disorders; gestational diabetes; venous thromboembolism (VTE); stillbirth; cesarean delivery; and newborn birth weight and respiratory conditions. Standardized mean differences between individuals with and without SARS-CoV-2 were calculated. Cox proportional hazards regression was used to estimate the hazard ratios (HRs) and 95% CIs for the association between SARS-CoV-2 infection and perinatal complications and hospitalization and to consider the timing of SARS-CoV-2 infection relative to outcomes.
In this study of 43 886 pregnant individuals (mean [SD] age, 30.7 [5.2] years), individuals with a SARS-CoV-2 infection (1332 [3.0%]) were more likely to be younger, Hispanic, multiparous individuals with a higher neighborhood deprivation index and obesity or chronic hypertension. After adjusting for demographic characteristics, comorbidities, and smoking status, individuals with SARS-CoV-2 infection had higher risk for severe maternal morbidity (HR, 2.45; 95% CI, 1.91-3.13), preterm birth (<37 weeks; HR, 2.08; 95% CI, 1.75-2.47), and VTE (HR, 3.08; 95% CI, 1.09-8.74) than individuals without SARS-CoV-2. SARS-CoV-2 infection was also associated with increased risk of medically indicated preterm birth (HR, 2.56; 95% CI, 2.06-3.19); spontaneous preterm birth (HR, 1.61; 95% CI, 1.22-2.13); and early (HR, 2.52; 95% CI, 1.49-4.24), moderate (HR, 2.18; 95% CI, 1.25-3.80), and late (HR, 1.95; 95% CI, 1.61-2.37) preterm birth. Among individuals with SARS-CoV-2 infection, 76 (5.7%) had a hospitalization; pregestational diabetes (HR, 7.03; 95% CI, 2.22-22.2) and Asian or Pacific Islander (HR, 2.33; 95% CI, 1.06-5.11) and Black (HR, 3.14; 95% CI, 1.24-7.93) race and ethnicity were associated with an increased risk of hospitalization.
Conclusions and Relevance
In this cohort study, SARS-CoV-2 infection was associated with increased risk of severe maternal morbidity, preterm birth, and VTE. The study findings inform clinicians and patients about the risk of perinatal complications associated with SARS-CoV-2 infection in pregnancy and support vaccination of pregnant individuals and those planning conception.
Since the COVID-19 pandemic began, physicians have had concerns about SARS-CoV-2 infection during pregnancy and its potential association with perinatal complications, how to inform pregnant individuals about possible risks of infection, and more recently, the use of vaccines. Most reports on COVID-19 infection during pregnancy are based on case series, making it difficult to inform medical guidelines.1,2
Few large longitudinal, population-based studies exist that evaluate perinatal health outcomes among pregnant individuals with and without a SARS-CoV-2 infection status detected during pregnancy. A Swedish study reported increases in the risk of preterm birth and neonatal respiratory conditions associated with SARS-CoV-2 infection.3 A US study4 and a systematic review5 reported increased risk of preterm birth and mortality in individuals with a COVID-19 diagnosis vs those without such a diagnosis at the time of hospitalization for delivery.
To better inform treatment of SARS-CoV-2 infection during pregnancy and provide health risk information to pregnant individuals, we aimed to assess the risk of perinatal complications associated with SARS-CoV-2 infection confirmed by polymerase chain reaction (PCR) testing in a population-based sample of 43 886 pregnant individuals with longitudinal clinical data from preconception to delivery. We also examined factors associated with hospitalizations in individuals with SARS-CoV-2.
This population-based cohort study was conducted at Kaiser Permanente Northern California (KPNC), an integrated health care delivery system, using longitudinal data obtained from electronic health records (EHRs), allowing quantification of factors and outcomes across the continuum of pregnancy. Kaiser Permanente Northern California serves 4.5 million patients (including approximately 60 000 pregnant individuals) annually, which accounts for approximately 30% of the population residing in the served geographical areas.6-8 The study was conducted between March 1, 2020, and March 16, 2021. Using the EHR data, we identified all pregnant individuals who had a live birth or stillbirth, perinatal complications, and medical conditions of interest. The EHR was searched for all encounters with associated diagnoses and procedures (according to International Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ICD-10] codes; eTable 1 in the Supplement), inpatient flowsheets, laboratory tests and results, and medications from 2 years before pregnancy through the pregnancy delivery date. This data-only project was approved by the KPNC Institutional Review Board, which waived the requirement for informed consent from study individuals given the use of only electronic data and the large sample size, which made it not possible to obtain authorization from each individual included in the study. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.9
The following data were obtained from the EHRs: age; self-reported race and ethnicity (captured in the outpatient setting or hospital admission or at the time of enrollment in the health plan); neighborhood deprivation index (a composite index in which higher values indicate more socioeconomically disadvantaged neighborhood characteristics)10; parity; and smoking status. All patients who self-identified as having Hispanic ethnicity, regardless of race, were categorized as Hispanic individuals.
At KPNC, testing for SARS-CoV-2 infection started on March 13, 2020, and was limited to suspected infections. On April 2, 2020, testing was expanded to asymptomatic surgical patients on April 2, 2020, and was further expanded to asymptomatic individuals on April 21, 2020, prioritizing health care workers, first responders, close contacts, essential workers, those with high-risk medical conditions, and congregate setting residents and employees. On December 1, 2020, all individuals who were admitted for delivery underwent testing for SARS-CoV-2. We identified all PCR tests performed from 30 days before the last menstrual period to 7 days after delivery and captured all diagnoses for COVID-19 infection according to ICD-10 codes. We classified individuals as having a SARS-CoV-2 infection if they had a positive PCR test result, whereas individuals were classified as without SARS-CoV-2 infection if they (1) had a negative PCR test result or (2) were not tested for SARS-CoV-2 and did not have an ICD-10 code for COVID-19.
We used the Centers for Disease Control and Prevention criteria11,12 described by Callaghan et al13 to define the presence of severe maternal morbidity, which included 21 conditions occurring at any time during pregnancy or delivery.12 To define preterm birth, we used previously validated14 obstetric estimate–based gestational age at delivery at less than 37 weeks. We further classified preterm birth as spontaneous (based on hospital discharge codes for early spontaneous onset of delivery or premature rupture of membranes) or indicated (if individuals had no indication of spontaneous birth and a hospital discharge diagnosis of induced or cesarean delivery). In addition, preterm birth was classified as early (22-31 weeks), moderate (32-33 weeks), and late (34-36 weeks).
Individuals with gestational hypertension were identified using ICD-10 codes, information on prescriptions for antihypertensive medications, or at least 2 blood pressure readings of 140/90 mm Hg or higher on 2 occasions at least 4 hours apart after 20 weeks’ gestation with no diagnosis of chronic hypertension.15 We classified individuals as having preeclampsia and eclampsia by using ICD-10 codes or having both of the following after 20 weeks’ gestation: (1) at least 2 blood pressure readings higher than 140/90 mm Hg on 2 occasions at least 4 hours apart or at least 2 readings higher than 160/110 mm Hg on 2 occasions within 1 hour16,17; and (2) new onset of proteinuria, thrombocytopenia, or pulmonary edema.15 We identified individuals as having gestational diabetes on the basis of their inclusion in the KPNC gestational diabetes registry18,19 according to the criteria described by Carpenter and Coustan.20 We used ICD-10 codes to define venous thromboembolism (VTE), stillbirth, and cesarean delivery.
We used ICD-10 codes to identify neonates with transient tachypnea and searched EHRs to obtain data on 5-minute Apgar scores, neonatal intensive care unit admission, and surfactant administration; use of respiratory support was identified through the inpatient flowsheet. Small for gestational age and large for gestational age were defined according to a gestation age- and sex-specific birth weight of less than 10th percentile and greater than 90th percentile, respectively.21
We searched EHRs to identify all hospitalizations in the cohort and classified a hospitalization as related to delivery if the discharge date occurred on or after the delivery date and the admission date was within 2 days of the delivery date. Among women with SARS-CoV-2 infection, we searched the EHRs to identify the first hospitalization during which a positive SARS-CoV-2 test result occurred or the first hospitalization within 3 weeks after a positive test result. We used respiratory care flowsheets from the EHR in which the respiratory therapists documented the mode of respiratory support and any changes to assess respiratory support, such as supplemental oxygen via nasal cannula, face mask, or nonrebreather face mask; high-flow oxygen; noninvasive ventilation (continuous positive airway pressure or bilevel positive airway pressure); and invasive mechanical ventilation.
In addition to the comorbidities mentioned previously (ie, chronic hypertension and pregestational diabetes), we assessed body mass index (BMI, calculated as weight in kilograms divided by height in meters squared) as a risk factor and categorized it according to the World Health Organization’s racial- and ethnic-specific cutoffs.22 We defined a history of asthma, autoimmune diseases, and allergies using ICD-10 codes.
Standardized mean differences between individuals with and without SARS-CoV-2 were calculated. We used Cox proportional hazards regression to estimate hazard ratios (HR) and 95% CIs for any associations of SARS-CoV-2 infection with preterm birth, severe maternal morbidity, VTE, gestational hypertension, preeclampsia and eclampsia, gestational diabetes, and hospitalizations to consider the timing of SARS-CoV-2 infection relative to outcomes. The SARS-CoV-2 infection status was treated as a time varying exposure (ie, a person was considered unexposed until a SARS-CoV-2 positive test result, after which the person was considered exposed). The reference group was composed of individuals without SARS-CoV-2 infection. Follow-up began on the date of the last menstrual period and ended when an individual had an event of interest except for gestational hypertension (follow-up started at 20 weeks of gestation according to its definition) or had a live birth or stillbirth.
We used modified Poisson regression23 with robust variance estimation to calculate relative risks and 95% CIs for the associations of SARS-CoV-2 infection with stillbirth, cesarean section, and infant perinatal complications. For 632 multiple births, analyses on complications included only the firstborn infant.
We conducted a priori stratified analyses by prepregnancy obesity, chronic hypertension, and pregestational diabetes. To assess for potential effect modification by these conditions in the association between SARS-CoV-2 and outcomes, we added a multiplicative interaction term in regression models and used α = .05 for assessing statistical significance with the Wald test. Heterogeneity in the associations between SARS-CoV-2 and preterm birth by whether the delivery was spontaneous or medically induced was assessed using a joint Cox proportional hazards regression model method proposed for analyzing competing risk events.24
We assessed departures from the proportional hazards assumption in the Cox proportional hazards regression analyses of outcomes of interest by testing the significance of time (log gestational age) by SARS-CoV-2 exposure interaction terms in regression models. There was evidence of heterogeneity in strength of association by gestational age for severe maternal morbidity (P for interaction <.001), preterm birth (P = .003), and VTE (P < .001) (all supporting data are reported in eTable 2 in the Supplement). Therefore, for these outcomes we also present HRs stratified by intervals of gestational age (eTable 2 in the Supplement). We note that the small number of VTE events among the exposed precludes stable estimation of HRs for specific intervals of gestational age. Similarly, estimation of severe maternal morbidity HRs stratified by gestational age was unstable given that most of these diagnoses occurred at the end of pregnancy.
We used multiple imputation25,26 for variables with missing data, such as pregestational BMI, smoking status (Table 1), 7-minute Apgar score (which had 0.3% of data missing), and neonatal intensive care unit admission (which had 0.3% of data missing) (eMethods and eTable 3 in the Supplement). Analyses were conducted using SAS, version 9.4 (SAS Institute), and a 2-tailed P < .05 was considered to be statistically significant.
Between March 1, 2020, and March 16, 2021, 44 318 individuals who delivered at KPNC had a live birth or stillbirth. We excluded from the analyses 432 individuals with diagnostic codes for COVID-19 who did not have a confirmatory PCR test for SARS-CoV-2 infection. The remaining 43 886 individuals had a mean (SD) age of 30.7 (5.2) years and self-reported being of American Indian or Alaska Native (151 [0.3%]), Asian or Pacific Islander (11 368 [25.9%]), Black (2874 [6.5%]), Hispanic (12 457 [28.4%]), White (14829 [33.8%]), and multiracial or had an unknown race and ethnicity (2207 [5.0%]) (Table 1). Among these 43 886 individuals, 22 676 PCR tests for SARS-CoV-2 were performed, with at least 1 test in 16 070 (36.6%) individuals. A total of 1332 (3.0%) had at least 1 test result positive for SARS-CoV-2. The first positive test result was observed in 2 (0.2%) individuals within 30 days before their last menstrual period, 104 (7.8%) at less than 14 weeks of gestation, 324 (24.3%) at 14 to 27 weeks’ gestation, 400 (30.0%) at 28 to 33 weeks’ gestation, 238 (17.9%) at 34 to 36 weeks’ gestation, 246 (18.5%) at 37 or more weeks’ gestation, and 18 (1.4%) within 1 week after delivery.
Table 1 shows the characteristics of the 1332 individuals with SARS-CoV-2 infection and the 42 554 without SARS-CoV-2, which included 14 763 with a negative PCR test result and 27 791 who were not tested (eResults 1 and 2 and eTable 4 in the Supplement). Compared with those without SARS-CoV-2 infection, individuals with SARS-CoV-2 infection were more likely to be younger, Hispanic, and multiparous, be in the highest quartile of the neighborhood deprivation index, and have obesity.
Table 2 shows the association between SARS-CoV-2 infection and perinatal complications. After adjusting for age, neighborhood deprivation index, race and ethnicity, parity, prepregnancy BMI, pregestational diabetes, and chronic hypertension, individuals with SARS-CoV-2 infection had a higher risk for severe maternal morbidity than those without infection (HR, 2.45; 95% CI, 1.91-3.13). Among the severe maternal morbidity conditions, individuals with SARS-CoV-2 infection were more likely to have acute respiratory distress syndrome or sepsis than individuals without the infection (eTables 5 and 6 in the Supplement). Individuals with SARS-CoV-2 infection also had a higher risk for preterm birth (HR, 2.08; 95% CI, 1.75-2.47) and VTE (HR, 3.08; 95% CI, 1.09-8.74) than those without infection. The risk for preterm birth associated with SARS-CoV-2 infection was higher for medically indicated than for spontaneous preterm birth (HR, 2.56; 95% CI, 2.06-3.19 vs HR, 1.61; 95% CI, 1.22-2.13; P = .003). The risk for preterm birth associated with SARS-CoV-2 infection was higher for early preterm birth (HR, 2.52; 95% CI, 1.49-4.24), intermediate for moderate preterm birth (HR, 2.18; 95% CI, 1.25-3.80), and lower for late preterm birth (HR, 1.95; 95% CI, 1.61-2.37) (P = .003 for time heterogeneity). SARS-CoV-2 infection was associated with an increased risk of preeclampsia or eclampsia (HR, 1.62; 95% CI, 1.03-2.56) only in an unadjusted model. No other significant associations were observed between SARS-CoV-2 infection and maternal and neonatal outcomes (Table 2).
Given the large overlap of the 95% CIs around the point estimates, the association between SARS-CoV-2 infection and perinatal complications was similar for individuals who had an infection at less than 21 or at 21 or more weeks’ gestation and for individuals who had an infection detected in inpatient or outpatient settings (eTables 7 and 8 in the Supplement).
In analyses in which individuals were stratified by prepregnancy obesity, chronic hypertension, and pregestational diabetes, we did not observe any statistically significant effect modification by these conditions (eTable 9 in the Supplement).
The proportion of pregnant individuals with SARS-CoV-2 infection increased from 1.3% (435 of 33 637) to 8.0% (897 of 11 249) on or after December 1, 2020, when testing was expanded to all individuals admitted for delivery. We stratified individuals according to the delivery date before and on or after December 1, 2020, and observed similar associations between SARS-CoV-2 infection and severe maternal morbidity, preterm birth, and VTE in both cohorts (Table 3). For example, for severe maternal morbidity, the HRs (95% CI) associated with SARS-CoV-2 infection were 2.80 (1.91-4.11) among individuals who delivered before December 1, 2020, and 2.30 (1.64-3.23) among individuals who delivered on or after December 1, 2020. Similarly, for preterm birth, the HRs (95% CI) were 2.07 (1.54-2.78) and 2.06 (1.66-2.57), respectively.
Among the 1332 individuals with SARS-CoV-2 infection, 307 (23.0%) had a hospitalization during which they had a positive PCR test result or had a hospitalization within 3 weeks after a positive PCR test result. Among these 307 individuals, 76 (24.8%) (or 5.7% of the 1332 individuals with SARS-CoV-2) required respiratory support; specifically, 72 (94.7%) received supplemental oxygen via nasal cannula, face mask, or high-flow nasal cannula; 3 (4.0%) had continuous positive airway pressure or bilevel positive airway pressure; and 1 (1.3%) needed mechanical ventilation. Compared with the 231 individuals who were hospitalized but did not need respiratory support, hospitalizations among individuals who needed respiratory support occurred less frequently around the time of delivery (26 of 76 [34.2%] vs 199 of 231 [86.1%]; P < .001). In addition, more of these individuals had a COVID-19 hospital discharge diagnosis compared with those who did not require respiratory support (73 of 76 [96.1%] vs 190 of 231 [82.3%]; P = .003). One individual who required respiratory support died. Compared with individuals with SARS-CoV-2 infection who were not hospitalized, the 76 who were hospitalized and needed respiratory support were more likely to be Asian or Pacific Islander (HR, 2.33; 95% CI, 1.06-5.11) or Black (HR, 3.14; 95% CI, 1.24-7.93) than White and to have pregestational diabetes (HR, 7.03; 95% CI, 2.22-22.2) (Table 4).
In this population-based cohort study including 43 886 individuals who had a live birth or stillbirth during the first year of the COVID-19 pandemic, a time when the general population of California was not yet vaccinated, we found that 1332 (3.0%) had SARS-CoV-2 infection detected by PCR testing. SARS-CoV-2 infection during pregnancy was associated with an increased risk of severe maternal morbidity, preterm birth, and VTE as well as medically indicated or spontaneous preterm birth and early, moderate, or late preterm birth. Among individuals with SARS-CoV-2 infection, 5.7% were hospitalized and required respiratory support.
The observed association between SARS-CoV-2 infection and an increased risk of severe maternal morbidity is consistent with increased risks associated with some severe morbidities in individuals with COVID-19 infection during childbirth that were reported by Ko et al.27 Because severe maternal morbidity has been associated with several adverse short-term and long-term health sequelae,11 the findings of the present study highlight the importance of monitoring individuals with SARS-CoV-2 infection during pregnancy. Conversely, interpretation of the findings requires consideration that the occurrence of severe maternal morbidity was predominated by diagnoses of acute respiratory distress syndrome and sepsis, which may be directly associated with the SARS-CoV-2 infection itself.
The association between SARS-CoV-2 infection and preterm birth is consistent with findings reported in previous studies,3,4,28 including a study of pregnant individuals with SARS-CoV-2 infection that found that those with severe to critical SARS-CoV-2 infection had a higher risk of preterm birth compared with those who were asymptomatic.29 The association between SARS-CoV-2 infection and preterm birth is physiologically plausible given previous evidence of other infections and various inflammatory cytokines associated with preterm birth. The present study further showed that the risk of preterm birth associated with SARS-CoV-2 infection was higher for early or moderate preterm birth than for late preterm birth and for medically indicated than for spontaneous preterm birth, suggesting that SARS-CoV-2 infection may exacerbate underlying medical conditions, leading to a medical indication to deliver preterm. These findings raise concerns because children who are born preterm, especially early preterm, have an increased risk for short-term and long-term health sequelae, including impaired neurodevelopment and cardiometabolic complications.30,31 At present, the possible long-term health implications of in utero exposure to SARS-CoV-2 infection for children’s growth and development are not known. Therefore, children with in utero exposure to SARS-CoV-2 infection should be followed up to assess their health during childhood and beyond.
Recent studies have reported that COVID-19 is associated with abnormal coagulation profiles.32,33 This is a serious concern for pregnant patients because pregnancy is associated with a hypercoagulable state, which might be exacerbated by SARS-CoV-2 infection. As previously reported in pregnant4 and nonpregnant individuals,34 we found that SARS-CoV-2 infection was associated with an increased risk of VTE.
In the present study, SARS-CoV-2 infection was associated with increased risk of preeclampsia and eclampsia in an unadjusted model; however, the association was attenuated after adjusting for confounders. This result contrasts with the results from a multinational study of 706 pregnant individuals with a COVID-19 diagnosis and 1424 matched control participants, which found an association between COVID-19 infection and preeclampsia and eclampsia.28 Differences in the study designs or the ability to adjust for possible confounders may explain the disparate results.
In contrast with a recent study based on 1 249 634 births,35 we did not find an association between SARS-CoV-2 infection and stillbirth, possibly because of the smaller sample size.
The present study did not find an association between SARS-CoV-2 infection and newborn complications. Although a Swedish study reported increases in the risk of neonatal respiratory conditions associated with SARS-CoV-2 infection, it also found that these associations were largely mediated by infant prematurity.3
This study has strengths. First, the study had a population-based design that included a large cohort and represented the racial, ethnic and sociodemographic diversity of the region. Second, use of robust longitudinal clinical data allowed analysis of perinatal outcomes. Third, use of PCR test results to confirm SARS-CoV-2 infection throughout pregnancy facilitated assessment of time to exposure to SARS-CoV-2 in relation to perinatal complications. Fourth, we were able to perform longitudinal analyses and control for prepregnancy conditions.
This study also has limitations. First, there was potential exposure misclassification. Individuals who were not tested and classified as without SARS-CoV-2 infection may have included a small number of asymptomatic persons, possibly leading to an underestimated risk of perinatal complications associated with SARS-CoV-2 infection. Second, we were not able to rule out the possibility of detection bias owing to increased testing in patients at risk of perinatal complications. However, in the analysis with individuals stratified by delivery date occurring before and after universal screening for SARS-CoV-2 infection was implemented, similar results were obtained in the 2 groups, suggesting that detection bias was unlikely. Third, we could not exclude the possibility that the association between SARS-CoV-2 and preterm birth was partially attributable to medical intervention, such as purposeful earlier delivery in individuals with SARS-CoV-2 infection. This possibility appears less likely, however, given the finding that there was no association between SARS-CoV-2 infection and cesarean delivery. Fourth, we were unable to assess disease severity or symptoms related to SARS-CoV-2 infection. Fifth, there were differences in the distributions of covariates that may be associated with perinatal complications between individuals with and without SARS-CoV-2 infection. However, given the large sample size, statistical adjustment for confounding in the regression models should have adequately controlled for these differences.
In this cohort study, SARS-CoV-2 infection during pregnancy was associated with severe maternal morbidity; preterm birth, especially medically indicated, early, and moderate preterm birth; and VTE. These findings are important in the context of recent SARS-CoV-2 variants, which may be associated with a higher risk of infections and perinatal complications than the previous variants,35-38 and the number of young adults and pregnant individuals who remain unvaccinated. The findings support recommendations on vaccination for pregnant individuals and those planning conception.39
Accepted for Publication: January 28, 2022.
Published Online: March 21, 2022. doi:10.1001/jamainternmed.2022.0330
Corresponding Author: Assiamira Ferrara, MD, PhD, Division of Research, Kaiser Permanente Northern California, 2000 Broadway, Oakland, CA 94612 (email@example.com).
Author Contributions: Dr Ferrara had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Ferrara, Hedderson, Avalos, Gunderson, Greenberg.
Acquisition, analysis, or interpretation of data: Ferrara, Hedderson, Zhu, Avalos, Kuzniewicz, Myers, Ngo, Ritchie, Quesenberry, Greenberg.
Drafting of the manuscript: Ferrara, Hedderson, Greenberg.
Critical revision of the manuscript for important intellectual content: Ferrara, Zhu, Avalos, Kuzniewicz, Myers, Ngo, Gunderson, Ritchie, Quesenberry, Greenberg.
Statistical analysis: Ferrara, Ngo, Quesenberry.
Obtained funding: Ferrara, Hedderson, Avalos, Greenberg.
Administrative, technical, or material support: Ferrara, Zhu, Kuzniewicz, Ritchie.
Supervision: Ferrara, Hedderson.
Other - defining critical variables: Myers.
Conflict of Interest Disclosures: Drs Ferrara, Hedderson, Zhu, Avalos, Kuzniewicz, Myers, Gunderson, Quesenberry, and Greenberg reported receiving grants from the National Institutes of Health during the conduct of the study. No other disclosures were reported.
Funding/Support: This study was funded by the Delivery Science Grants Program, The Permanente Medical Group, Inc, which provided comments on an initial draft.
Role of the Funder/Sponsor: The Permanente Medical Group had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.