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

Am J Epidemiol. 2023 Aug 4;192(8):1386-1395. doi: 10.1093/aje/kwad059.


In the Vaccine Safety Datalink (VSD), we previously reported no association between coronavirus disease 2019 (COVID-19) vaccination in early pregnancy and spontaneous abortion (SAB). The present study aims to understand how time since vaccine rollout or other methodological factors could affect results. Using a case-control design and generalized estimating equations, we estimated the odds ratios (ORs) 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 alternative methodological 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: 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% confidence interval: 0.96, 1.08). We observed a lower OR for a 42-day window compared with 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.

Keywords: COVID-19 vaccines; case-control; pregnancy; safety; spontaneous abortion; study design; surveillance.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Abortion, Spontaneous* / chemically induced
  • Abortion, Spontaneous* / epidemiology
  • COVID-19 / epidemiology
  • COVID-19 / prevention & control
  • COVID-19 Vaccines* / adverse effects
  • Female
  • Humans
  • Pregnancy
  • United States / epidemiology
  • Vaccination / adverse effects


  • COVID-19 Vaccines