COVID-19 Vaccine Safety Surveillance in Early Pregnancy in the United States: Design Factors Affecting the Association Between Vaccine and Spontaneous Abortion.

In the Vaccine Safety Datalink (VSD), we previously reported no association between COVID-19 vaccination in early pregnancy and spontaneous abortion (SAB). The current study aims to understand how time since vaccine roll-out or other methodologic factors could affect results. Using a case-control design and generalized estimating equations, we estimated the odds ratios (OR) of COVID-19 vaccination in the 28 days before a SAB or last date of the surveillance period (index date) in ongoing pregnancies and occurrence of SAB, across cumulative 4-week periods from December 2020 through June 2021. Using data from a single site, we evaluated alternate methodologic approaches: increasing the exposure window to 42 days, modifying the index date from the last day to the midpoint of the surveillance period, and constructing a cohort design with a time-dependent exposure model. A protective effect (OR 0.78; 95% Confidence Interval (CI): 0.69-0.89), observed with 3-cumulative periods ending March 8, 2021, was attenuated when surveillance extended to June 28, 2021 (OR: 1.02; 95% CI: 0.96-1.08). We observed a lower OR for a 42-day as compared to a 28-day window. The time-dependent model showed no association. Timing of the surveillance appears to be an important factor affecting the observed vaccine-SAB association.