SARS-CoV-2 infection during pregnancy is associated with increased risk for maternal morbidity and adverse birth outcomes.1^,2 COVID-19 vaccines are effective for preventing severe disease, including in pregnant populations.³ Although more than 100 countries recommend COVID-19 vaccination during pregnancy,⁴ COVID-19 vaccination in pregnant people has lagged behind that for age-matched, nonpregnant adults.^5,6 As of February 2022, the US Vaccine Safety Datalink estimated that 68% of pregnant individuals have completed the primary COVID-19 vaccine series.⁶ Persistent wide disparities in COVID-19 vaccination during pregnancy by race or ethnicity are likely to exacerbate longstanding disparities in maternal morbidity and mortality.⁶

Vaccine hesitancy during pregnancy was understandable when COVID-19 vaccines were first authorized,7 because pregnant people were excluded from the initial COVID-19 vaccine trials. Thus, initial data on pregnancy or birth outcomes after maternal COVID-19 vaccination were limited to inadvertent exposures among trial participants early in pregnancy. The mRNA vaccines were novel and their safety in pregnancy was presumed, but not yet proven. Over the past 14 months, a substantial body of evidence supporting the safety of the mRNA COVID-19 vaccines in pregnancy has accumulated. Observational studies from Norway, Israel, and the US have reported that the mRNA COVID-19 vaccines administered during pregnancy were not associated with increased risk for miscarriage, preterm birth, or other select obstetric and birth outcomes.^8–11

In this issue of JAMA, 2 population-based observational retrospective studies evaluating outcomes in more than 250 000 pregnancies from 3 countries together provide the strongest evidence to date regarding the safety of COVID-19 vaccines in pregnancy.12^,13

Fell and colleagues12 used data from the Ontario birth registry, linked with the provincial immunization information system, to identify 97 590 pregnancies eligible for COVID-19 vaccination and with an expected delivery date or live birth from December 14, 2020, to September 30, 2021. Of these pregnant individuals, 23% were vaccinated during pregnancy; most were vaccinated in third trimester. Compared with those vaccinated after pregnancy and, in separate analyses, compared with those who were unvaccinated during pregnancy, COVID-19 vaccination during pregnancy was not associated with increased risks for postpartum hemorrhage, chorioamnionitis, cesarean delivery, neonatal care admission, or low Apgar score.

Magnus and colleagues13 used data from the Pregnancy Register in Sweden and the Medical Birth Registry of Norway, linked with vaccine registries from both countries, to identify 157 521 singleton pregnancies from January 1, 2021, through early January 2022 and reaching 22 weeks’ gestation. In this cohort, 18% of participants received a COVID-19 vaccine during pregnancy; the majority were vaccinated in the second or third trimester of pregnancy. Compared with individuals who remained unvaccinated during pregnancy, COVID-19 vaccination during pregnancy was not associated with increased risk for preterm birth, stillbirth, small-for-gestational age, low Apgar score, or neonatal care admission.

Overall, the findings reported by Fell et al12 and Magnus et al¹³ are extremely reassuring and consistent with published data on more than 40 000 live births in the US (Vaccine Safety Datalink)⁹ and from nearly 25 000 live births in Israel (Maccabi Healthcare Services).¹¹ Strengths of these studies include the large and well-defined population-based cohorts, the availability of validated data on vaccine exposures and birth outcomes through regional and national registries, and the thoughtful approaches addressing the following common sources of bias in observational studies of maternal vaccination: healthy vaccinee bias and confounding by indication, immortal time bias, and cohort truncation.^14,15

Healthy vaccinee bias refers to differences between vaccinated and unvaccinated populations attributed to vaccination, including in their health or health-related behaviors, that can bias toward a protective effect. Confounding by indication occurs when vaccination is more common among those at increased risk for adverse outcomes after vaccination due to underlying comorbidities and can bias observational studies of vaccine safety in the opposite direction as healthy vaccinee bias. In the Ontario cohort in the study by Fell et al and in the Swedish and Norwegian cohorts in the study by Magnus et al, individuals vaccinated during pregnancy were older than those who were not vaccinated during pregnancy.12^,13 Magnus et al reported that, compared with unvaccinated individuals, those vaccinated during pregnancy had higher levels of education, whereas Fell et al observed that vaccinated individuals resided in higher-income neighborhoods and were less likely to smoke during pregnancy.^12,13 In the Vaccine Safety Datalink, compared with unvaccinated individuals, those who received a COVID-19 vaccine during pregnancy were older, less likely to have obesity, and less likely to report ever smoking.⁹

To address these potential sources of bias, Magnus et al adjusted analyses for age, parity, and select sociodemographic and clinical factors; Fell et al applied a sophisticated approach to minimize healthy vaccinee bias and confounding by indication, using all data available to calculate propensity to be vaccinated. Inverse probability weighting of the propensity to be vaccinated was then applied in adjusted analyses. When groups differ substantially in their health or health-related behaviors, or when data on key differences between groups are not available, a propensity score cannot fully minimize bias. As such, the comparison of individuals vaccinated during pregnancy vs those vaccinated after pregnancy, conducted by Fell et al, was important.12

Although these studies thoughtfully addressed these common sources of bias, both studies also have limitations. First, there were few first trimester vaccinations in these cohorts. To date, only 1 published study from Israel has described birth outcomes after first-trimester vaccination.11 Second, although the findings regarding maternal COVID-19 vaccination and low Apgar score or neonatal care admission are reassuring, future studies are needed to assess outcomes beyond the immediate perinatal period, including infant morbidity, growth, and development. Third, too few individuals received a viral vector vaccine to comment on the safety of this type of vaccine. Although many countries recommend mRNA vaccines in pregnant populations, others have financial barriers and limited supply. For example, in India, a country with one-sixth of the world’s births, the mRNA vaccines are not currently available and viral vector-based or inactivated virus vaccines are used in pregnancy.⁴

Corresponding Author: Elyse O. Kharbanda, MD, MPH, 8170 33rd Ave S, Mail stop 21112R, Minneapolis, MN 55425 (Elyse.O.Kharbanda@HealthPartners.com).

Published Online: March 24, 2022. doi:10.1001/jama.2022.2459

Conflict of Interest Disclosures: None reported.