Observed-to-Expected Fetal Losses Following mRNA COVID-19 Vaccination in Early Pregnancy

BackgroundThe clinical trials used to approve COVID-19 vaccines excluded pregnant women, and existing safety assessments of COVID-19 vaccination, particularly during early stages of pregnancy, are limited to observational studies prone to various types of potential bias, including healthy vaccinee bias. MethodsThe study includes pregnancies in Israel with last menstruation period (LMP) between March 1, 2016 and February 28, 2022. The main analysis presents observed-to-expected comparisons of the number of eventual fetal losses among pregnant women exposed to mRNA COVID-19 vaccination (almost all Pfizer) during gestational weeks 8-13 and 14-27, respectively. Women vaccinated for influenza during gestational weeks 8-27, as well as women vaccinated prior to pregnancy for COVID-19 or influenza, were used as comparative controls. Cohort-specific expected number of fetal losses are established based on estimates from a regression model trained on historical data from 2016-2018 that incorporates individual-level risk factors and gestational week of each pregnant woman included in the cohort. ResultsAnalysis of 226,395 singleton pregnancies in Israel from 2016 to 2022 indicates that COVID-19 vaccination with dose 1 during weeks 8-13 was associated with higher-than-expected observed number of fetal losses of approximately 13 versus 9 expected for every 100 exposed pregnancies, i.e., nearly 3.9 (95% CI: [2.55-5.14]) additional fetal losses above expected per 100 pregnancies Most of the excess fetal losses occurred after gestational week 20 and nearly half occurred after gestational week 25. Similarly, women vaccinated with dose 3 during weeks 8-13 exhibited a higher-than-expected number of fetal losses with nearly 1.9 (95% CI: 0.39-3.42]) additional fetal losses above expected per 100 pregnancies. In contrast, pregnant women vaccinated for influenza during weeks 8-27 exhibited a consistently lower-than-expected observed number of fetal losses, likely the result of healthy vaccinee bias. Women vaccinated for COVID-19 or influenza prior to pregnancy exhibited according-to-expected or lower-than-expected numbers of fetal losses. ConclusionThe results provide evidence for a substantially higher-than-expected number of eventual fetal losses associated with COVID-19 vaccination during gestational weeks 8-13.