COVID-19 vaccination around the time of conception and risk of placenta-mediated adverse pregnancy outcomes

Abstract

Introduction: Although numerous studies have documented no association between COVID-19 vaccination during pregnancy and maternal and fetal health outcomes, fewer studies have evaluated fetal health effects after COVID-19 vaccination around the time of conception and early pregnancy, a time when maternal exposures may affect early placentation and the subsequent risk of placenta-mediated adverse pregnancy outcomes.

Material and methods: We used province-wide databases in Ontario to conduct a population-based cohort study including all live and stillbirths ≥20 weeks' gestation with a last menstrual period (LMP) between April 1 and December 31, 2021. We deterministically linked birth registry data to the vaccine registry for all 80 253 eligible pregnancies; 31 209 (38.9%) received ≥1 dose of the COVID-19 vaccine around the time of conception or first trimester. Using Cox regression, we estimated propensity score weighted hazard ratios (aHR) and 95% confidence intervals (CI) for associations between ≥1 dose of mRNA COVID-19 vaccine during the periconceptional/first trimester exposure window (28 days before the LMP to the end of first trimester) and study outcomes: hypertensive disorders (gestational hypertension, preeclampsia, eclampsia), placental abruption, preterm birth (<37 weeks), small-for-gestational-age (SGA) birth (<10th percentile), and stillbirth.

Results: COVID-19 vaccination around the time of conception or first trimester was associated with a small increased risk of hypertensive disorders in pregnancy in exposed versus unexposed individuals (7.4% vs. 6.1%; aHR: 1.10, 95% CI: 1.03-1.17), mostly attributed to gestational hypertension (5.0% vs. 4.1%; aHR 1.13, 95% CI: 1.05-1.22). There was no increased risk of preeclampsia (1.8% vs. 1.5%; aHR 1.08, 95% CI: 0.95-1.22), eclampsia (0.1% vs. 0.1%; aHR: 1.12, 95% CI 0.65-1.95), placental abruption (0.8% vs. 1.0%; aHR: 0.77, 95%CI: 0.65-0.91), preterm birth (8.0% vs. 8.9%; aHR: 0.92, 95%CI: 0.87-0.97), SGA birth (8.9% vs. 9.3%; aHR: 1.00, 95%CI: 0.95-1.06), or stillbirth (0.4% vs. 0.6%; aHR: 0.66, 95%CI: 0.52-0.82).

Conclusions: This population-based Canadian study provides additional evidence evaluating COVID-19 vaccine administration around the start of pregnancy. While we identified no association with most placenta-mediated outcomes, we report a slight increase in the rate of gestational hypertension. This could be a true association or attributed to residual confounding. Further research is needed to verify.

Keywords: COVID‐19 vaccines; first; placenta; pregnancy; pregnancy trimester.

FIGURE 1

Exposure window for measuring periconceptional and first trimester COVID‐19 vaccination.

FIGURE 2

Frequency of timing of first second, and/or first booster dose of COVID‐19 vaccine, relative to pregnancy. *The ‘Exposed’ group in the figure refers to those who received a first, second and/or first booster dose of COVID‐19 vaccine during the periconceptional period/first trimester (i.e., the exposure window). **The wash out period refers to a 30‐day timeframe before the start of the exposure window.

FIGURE 3

Flow diagram for selection of participants into analytic sample. The periconceptional period occurs from 28 days prior to the LMP date up to 13 days after LMP date. The first trimester occurs from 14 days after the LMP date to 97 days of gestation.