This U.S. surveillance review of the safety of mRNA Covid-19 vaccines during pregnancy and the periconception period indicates that some pregnant persons in the United States are choosing to be vaccinated against Covid-19 in all trimesters of pregnancy. Solicited local and systemic reactions that were reported to the v-safe surveillance system were similar among persons who identified as pregnant and nonpregnant women. Although not directly comparable, the proportions of adverse pregnancy and neonatal outcomes (i.e., preterm birth, small size for gestational age, congenital anomalies, and neonatal death) among participants with completed pregnancies from the v-safe pregnancy registry appear to be similar to the published incidences in pregnant populations studied before the Covid-19 pandemic.15-26 Many participants in the v-safe pregnancy registry were included in the phase 1a (highest) priority group for Covid-19 vaccination owing to their work as health care personnel.27 V-safe participation is voluntary, and registration information is not uniformly available at all vaccination locations, although information about the surveillance system is included on the EUA fact sheets for health care providers and patients. Thus, comparisons of the proportions of vaccinated women with these outcomes to previously published estimates are limited by likely differences between these populations in age, ethnic group, and other social, demographic, and clinical characteristics that are known to be associated with pregnancy and neonatal outcomes. However, such comparisons are helpful to provide a crude sense of whether there are any unexpected safety signals in these early data. At the time of this analysis, just 14.7% of persons who identified as pregnant in the v-safe surveillance system had been contacted to offer enrollment in the pregnancy registry.

Other limitations should also be noted. As with all participant-reported surveillance systems, mistakes in completion of v-safe health surveys can result in misclassification of participants as pregnant; as a result, data for local and systemic reactions that participants reported to the v-safe platform may include some reports from nonpregnant persons. Participants are not required to complete surveys at the same time every day, and our ability to assess onset or duration of adverse events, such as fever, is limited. The registry data are preliminary, are from a small sample, and describe mostly neonatal outcomes from third-trimester vaccination; the findings may change as additional pregnancy outcomes are reported and the sample size increases, which may facilitate detection of rare outcomes. We were unable to evaluate adverse outcomes that might occur in association with exposures earlier in pregnancy, such as congenital anomalies, because no pregnant persons who were vaccinated early in pregnancy have had live births captured in the v-safe pregnancy registry to date; follow-up is ongoing. In addition, the proportion of pregnant persons who reported spontaneous abortion may not reflect true postvaccination proportions because participants might have been vaccinated after the period of greatest risk in the first trimester, and very early pregnancy losses might not be recognized. Whereas some pregnancies with vaccination in the first and early second trimester have been completed, the majority are ongoing, and a direct comparison of outcomes on the basis of timing of vaccination is needed to define the proportion of spontaneous abortions in this cohort. Because of sample-size constraints, both pregnancy and neonatal outcomes were calculated as a proportion instead of a rate.

Our preliminary analysis uses participant-reported data and has limited information on other potential risk factors for adverse pregnancy and neonatal outcomes. The VAERS is subject to the limitations of passive surveillance.12 Despite EUA mandatory reporting requirements and CDC guidance on VAERS reporting, there is probably substantial underreporting of pregnancy- and neonatal-specific adverse events. We also do not know the total number of Covid-19 vaccine doses administered to pregnant persons, which further limits our ability to estimate rates of reported adverse events from VAERS data. Among pregnancy-specific conditions reported to the VAERS after Covid-19 vaccination, miscarriage was the most common. This is similar to what was observed during the influenza A (H1N1) pandemic in 2009 after the introduction of the 2009 H1N1 inactivated influenza vaccine, where miscarriage was the most common adverse event reported by pregnant persons who received that vaccine.28

In addition to vaccination protecting women against Covid-19 and its complications during pregnancy, emerging evidence has shown transplacental transfer of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies after maternal Covid-19 vaccination during the third trimester, which suggests that maternal vaccination might provide some level of protection to the neonate.29-32 However, we do not have data on antibody transfer and level of protection relative to the timing of vaccination. The CDC and the FDA are continuing to monitor and disseminate information about the safety of mRNA and additional types of Covid-19 vaccines in pregnant persons.

Early data from the v-safe surveillance system, the v-safe pregnancy registry, and the VAERS do not indicate any obvious safety signals with respect to pregnancy or neonatal outcomes associated with Covid-19 vaccination in the third trimester of pregnancy. Continued monitoring is needed to further assess maternal, pregnancy, neonatal, and childhood outcomes associated with maternal Covid-19 vaccination, including in earlier stages of pregnancy and during the preconception period. Meanwhile, the present data can help inform decision making about vaccination by pregnant persons and their health care providers.