SARS-CoV-2 infection in pregnancy is associated with an increased risk of adverse birth outcomes such as preterm birth, stillbirth, and maternal and infant complications.¹ Previous research using administrative datasets or national surveillance data suggest an increased risk of severe COVID-19 illness in pregnant people.^2,3 The delta variant (B.1.617.2) represented the majority of US cases during July to December 2021 and was characterized by higher rates of hospitalization, intensive care unit admission, and death among the unvaccinated, likely due to a higher propensity for infection and greater replication in the lower respiratory tract.^4,5 Reports of pregnant people with COVID-19 during delta showed higher frequency of maternal morbidity and mortality and stillbirth.^6,7 A previous study conducted on SARS-CoV-2 infections before the emergence of the delta variant found differential risks of adverse pregnancy outcomes, with a higher proportion of preterm births when infection occurred in the third trimester than in the first and second trimesters.⁸ However, studies of adverse perinatal outcomes associated with the delta variant did not report on timing of infection during pregnancy, and a few studies report on COVID-19 vaccination status.

Vaccination during pregnancy is highly effective in reducing severe disease, provides protection to the infant, and therefore is recommended for pregnant people.^9–11 The Centers for Disease Control and Prevention (CDC) strengthened communications recommending vaccines to pregnant persons in August, 2021 in response to the growing body of evidence associating COVID-19 with adverse outcomes and with indication of increased deaths and stillbirths among pregnant people with COVID-19 during the delta variant period.¹² Although vaccine uptake among pregnant persons increased in late 2021, vaccine hesitancy persisted, and only approximately 31% of pregnant people were considered fully vaccinated (ie, received 2 mRNA doses or 1 Janssen dose) by September 2021.^13,14

Few studies have reported on birth outcomes, timing of infection, and vaccination status during the delta variant predominance period in the United States. This study aimed to describe characteristics of pregnant people with SARS-CoV-2 infection, including vaccination status at the time of infection, and frequency of adverse birth and infant outcomes prior to and during the delta predominance period. We also explored the associations, by trimester, of infection during the delta period, because previous studies using this cohort reported differences in frequency of adverse outcomes by trimester.⁸

This analysis utilized data from the following 6 US jurisdictional health departments reporting to the Surveillance for Emerging Threats to Pregnant People and Infants Network by September 15, 2023: Massachusetts, Missouri, New Jersey, Pennsylvania (excluding Philadelphia), City of Philadelphia, and Tennessee. The jurisdictions were included based on reported cases during the delta period and ability to link data to birth certificates, fetal death records, and immunization registries to obtain outcomes and COVID-19 vaccination status. We included pregnant people with known birth outcomes and SARS-CoV-2 infection during pregnancy between March 3, 2020 and December 25, 2021. Infection was confirmed using the first SARS-CoV-2-positive polymerase chain reaction (PCR) result during pregnancy, and gestational age was calculated based on estimated date of delivery. For this analysis, we restricted to only the first infection during a pregnancy. Reinfections, defined as a positive PCR result >90 days from the first positive, accounted for 3.1% of the population, and did not impact the main findings when they were excluded.

Because sequencing of every infection is impossible, we utilized a methodology that used time periods as a proxy for variant predominance.^15,16 The delta predominance period was defined as the time when the delta variant accounted for 50% or more of sequenced isolates in each US Department of Health and Human Services region. The pre-delta (March 3, 2020–June 26, 2021) and delta (June 27, 2021–December 25, 2021) time periods approximately correspond to variant predominance in the United States and differed by 1 to 3 weeks by region.¹⁷

Pregnancy outcomes included live births, spontaneous abortion (<20 weeks of gestation) and stillbirth (≥20 weeks of gestation). Preterm birth (<37 weeks of gestation) was analyzed among live births with infection at <37 weeks to capture the population at risk. Small for gestational age was calculated among all infants based on INTERGROWTH-21st standards,¹⁸ and neonatal intensive care unit (NICU) admission was reported among term, liveborn infants. Associations between trimester of infection and pregnancy outcomes were also assessed among infections occurring during the delta period.

Unadjusted and adjusted prevalence ratios (PRs and aPRs) of outcome measures were estimated using Poisson regression. Estimates were adjusted for continuous maternal age, race and ethnicity, and insurance status at delivery. Analyses were performed using R version 4.2.2 (R Foundation), and statistical significance was defined as a P value of <.05. This activity was reviewed by the CDC and was conducted consistent with applicable federal law and policy.¹⁹

A total of 56,856 pregnant persons infected with SARS-CoV-2 were included, with 38,828 (68.3%) infected during the pre-delta period and 18,028 (31.7%) during the delta period (Table 1). The median maternal age was 29.5 years with 59.5% aged 25 to 34 years, which did not differ by time period. In the pre-delta period, 51.2% were White non-Hispanic and 23.7% were Hispanic/Latino compared to 64.4% White non-Hispanic and 12.7% Hispanic/Latino in the delta period. Medicaid was the most common insurance at delivery among pregnant people with infection during the pre-delta period (47.3%), whereas private insurance was most common during delta (43.1%). The trimester of infection was similar across variant periods with the third trimester being most frequent (40.4%), followed by second trimester (33.8%), then first trimester (25.9%). Underlying health conditions were similar across variant periods with 36.6% having at least 1 condition and 28.5% with pre-pregnancy obesity. Gestational diabetes and pregnancy-induced hypertension were reported among 9.3% and 9.1% of pregnant persons and were similar across variant periods. In the pre-delta period, 99.4% of pregnant persons infected with SARS-CoV-2 were unvaccinated compared to 78.4% in the delta period. Of those vaccinated, median time since last vaccination dose to infection during pregnancy was 32 days in pre-delta compared to 183 days in the delta period. There were 29 maternal deaths reported overall with 16 during the pre-delta period (0.41/1000 pregnant persons) and 13 during the delta period (0.72/1000 pregnant persons).

During the pre-delta period, 99.4% of birth outcomes resulted in live births, 0.4% stillbirths, and 0.1% spontaneous abortions compared to 99.1% live births, 0.7% stillbirths, and 0.1% spontaneous abortions in the delta period (Table 2). The delta period was associated with a higher frequency of stillbirths than pre-delta (aPR, 1.55; 95% confidence interval [CI], 1.14–2.09). When restricting to infections at <37 weeks of gestation, 11.9% of births in pre-delta were preterm compared to 12.8% in delta (aPR, 1.14; 95% CI, 1.07–1.20). The proportion of indicated preterm births were similar across time periods, although there were substantial proportions with unknown indication (>50%). NICU admission among term, liveborn infants was 5.1% in the pre-delta period compared to 4.2% in delta period (aPR, 0.74; 95% CI, 0.67–0.82), with a greater proportion of missing for pre-delta than delta (8.1%, 2.2%). Small for gestational age was similar across pre-delta (5.4%) and delta (5.7%) periods (aPR, 1.07; 95% CI, 0.98–1.16).

Among pregnant people who experienced a stillbirth, median time from infection to stillbirth outcome in the pre-delta period was 29 days compared to 13 days in delta, with shorter days from infection to delivery among those with later trimester infection (Table 3). Across variant periods, most pregnant people who experienced a stillbirth were infected in the second trimester (43.9%), followed by third trimester (31.3%), then first trimester (24.8%).

During the delta period, infection during the third trimester was associated with a higher frequency of preterm birth than infection during the first and second trimesters combined (aPR, 1.41; 95% CI, 1.28–1.56) (Table 4). There was also a higher frequency of NICU admission (aPR, 1.21; 95% CI, 1.01–1.45) among term infants infected during the third trimester. Frequency of stillbirth and small for gestational age during the delta period was not statistically different by trimester of infection.

Our study confirmed previous findings of increased frequency of preterm birth and stillbirth during the delta variant predominance period compared to pre-delta period, even after adjusting for age, race and ethnicity, and health insurance. The delta variant has been shown to have more propensity for infection and higher viral loads,²¹ which may lead to more severe maternal illness and death and inducing abnormalities in the placenta leading to adverse fetal and/or infant outcomes.^22,23 During the delta variant period, third trimester infection was associated with an increase in preterm birth and NICU admission compared to first or second trimester infection; however, we did not find an association between timing of infection and stillbirth, although the frequency of stillbirth was higher during the delta period overall.

We found a lower frequency of NICU admission among term infants in the delta period although previous studies have reported either higher risk or no difference between the pre-delta and delta predominance periods.^24,25 This may be due to differential missingness in the pre-delta period compared to the delta predominance period. Future analyses can assess the impacts of disease severity and whether vaccination status modifies the association.

Frequency of stillbirth and preterm birth following SARS-CoV-2 infection in pregnancy were higher during the delta variant predominance period than during the pre-delta period. These findings highlight the impact of COVID-19 in pregnancy on adverse fetal and infant outcomes, specifically in the presence of a variant with more severe presentation, and support recommendations for pregnant people and those who may become pregnant to stay up to date with COVID-19 vaccines.