mRNA COVID-19 vaccination in the first trimester of pregnancy isn't tied to an elevated risk of 75 major congenital malformations (MCMs) affecting 13 organ systems, supporting the safety of the vaccines in early pregnancy, French researchers write today in JAMA Network Open.
The nationwide, population-based study was conducted using the comprehensive Mother-Child EPI-MERES Register, which included all live-born infants in France from pregnancies beginning in April 2021 to January 2022, with follow-up to December 2024.
Of 527,564 infants, 24.7% were exposed to an mRNA COVID-19 vaccine during the first trimester of pregnancy. Exposure was considered receipt of one or more doses of mRNA vaccine early in pregnancy.
"When women are infected during pregnancy, the risks of complications increase significantly, particularly for preterm birth and both maternal and infant morbidity and mortality," the researchers wrote. "To prevent these adverse outcomes, messenger RNA (mRNA)–based COVID-19 vaccines have widely been recommended during pregnancy, initially only in high-income countries and subsequently worldwide."
No increased risk by age, deprivation, or folic acid intake
MCM prevalence was 176.6 per 10,000 (2,302 infants) among exposed infants and 179.4 per 10,000 (7,128) in unexposed controls. No increased risk of MCMs was observed overall (weighted odds ratio [OR], 0.98), by organ system (range of weighted ORs, 0.84 for digestive system malformations to 1.20 for abdominal-wall abnormalities), or for any of the 75 individual MCMs.
For example, weighted ORs were 1.00 each for the heart abnormalities ventricular septal defect and atrial septal defect and 0.91 for hydronephrosis (kidney fluid retention). Slight declines in risk were noted in lobulated or ectopic kidney (weighted OR, 0.59) and situs inversus (weighted OR, 0.25). Situs inversus is a condition in which the organs in the chest and abdomen are positioned opposite of where they normally would be found.
Four weighted ORs—three cardiovascular system MCMs and one urinary system MCM—were four times higher but weren't statistically significant. No cases of five MCMs were reported in the exposed or control groups, precluding risk estimation.
Of the 64 remaining estimations, 17 were higher than 1.10, and 22 were less than 0.90, but none were statistically significant. When stratifying by age, social deprivation, and folic acid consumption, no underlying increased risk of any of the 13 organ system groups was found.
Stillbirth rates same in both groups
Sensitivity and stratified analyses confirmed the results. When comparing the main exposure group with the three control subgroups (infants of mothers who received at least one vaccine dose in the second or third trimester, those whose mothers received one or more doses before conception, and those whose mothers were unvaccinated until the end of pregnancy), no increased risk of any MCMs grouped by organ system was observed.
Our study confirms the fetal safety of mRNA COVID-19 vaccines during pregnancy, showing no increased risk of MCMs and reassuring the millions of women worldwide who received these vaccines early in pregnancy.
The stillbirth-rate analysis found that 556 stillbirths (0.4%) occurred after exposure to an mRNA COVID-19 vaccine during the first trimester of pregnancy, the same rate as in the control group (1,773 stillbirths [0.4%]). The risk ratio was 0.96, which shows it was not statistically significant.
"Our study confirms the fetal safety of mRNA COVID-19 vaccines during pregnancy, showing no increased risk of MCMs and reassuring the millions of women worldwide who received these vaccines early in pregnancy," the authors wrote.
"Policymakers and health care practitioners should update vaccination guidelines to ensure that pregnant women are adequately informed about the safety of these vaccines," they concluded. "These findings also provide valuable insight into the fetal safety of mRNA-based vaccines, which could inform future considerations for their use in pregnant women."
