Study on Maternal RSV Vaccine Flags Possible Risk, Calls for More Research

Vaccinating against respiratory syncytial virus (RSV) during pregnancy was not associated with an increased risk of preterm birth, or a host of other adverse outcomes, but may be linked to an increased risk of pregnancy-associated hypertensive disorders, according to a cohort study with a sequential surveillance design.

Risk of preterm birth among pregnant women who received the bivalent RSV prefusion F subunit-based vaccine (RSVpreF; Abrysvo) was not elevated compared with a concurrent comparator group who received other vaccines (adjusted relative risk [aRR] 0.79, 95% CI 0.65-0.98) or a historical comparator group vaccinated before the RSV vaccine was available (aRR 0.87, 95% CI 0.78-0.96).

However, increased risks were observed for pregnancy-associated hypertensive disorders in those who received the RSV vaccine compared with the concurrent (aRR 1.14, 95% CI 1.02-1.27) and historical (aRR 1.29, 95% CI 1.24-1.34) comparator groups, reported Ashley Michnick, PharmD, PhD, of Harvard Medical School and Harvard Pilgrim Health Care Institute in Boston, and colleagues, in JAMA Network Open.

There was also an observed increased risk for premature rupture of membranes (PROM) compared with both comparator groups and preterm PROM compared with the historical comparator.

The researchers cautioned that the study is just one analysis in a multiphase approach to safety monitoring for the RSV vaccine.

“This early monitoring did what it was designed to do: It ruled out some concerns and raised other possible safety questions quickly,” Michnick told MedPage Today. “The purpose of early rapid-cycle analyses like those described in this paper is to guide more robust studies, not necessarily to draw firm conclusions about risk.”

The FDA approved the vaccine in August 2023 for use at 32-36 weeks’ gestation to confer protection to infants, but the vaccine’s prescribing information includes a warning to inform pregnant women about a numerical imbalance in preterm births observed in the phase III MATISSE study — 5.7% for those who got the vaccine versus 4.7% for those who got placebo. Trials also found some numerical imbalances in pregnancy-associated hypertensive disorders.

An interim analysis of the current study published earlier this year found no statistically significant differences in preterm birth, pregnancy-associated hypertensive disorders, PROM, or preterm PROM in two matched cohorts of vaccinated and unvaccinated women.

“RSVpreF and monoclonal antibodies are changing the epidemiology of RSV, and the findings … provide additional evidence for the safety of RSVpreF during pregnancy,” noted Gabriela Vazquez-Benitez, PhD, of HealthPartners Institute in Bloomington, Minnesota, and colleagues in an accompanying editorial.

A potential association between maternal RSV vaccination and pregnancy-associated hypertensive disorders “warrants particular attention,” they wrote, given the “inconsistent findings” in safety evaluations.

Hypertensive disorders of pregnancy comprise a spectrum of diseases, Vazquez-Benitez and team explained, and a composite outcome “may contribute to the lack of consistent findings.” Accurate assessment also could be hampered by factors such as onset of the disorder, which may precede vaccination, and links between inadequate prenatal care and delayed or undiagnosed disorders.

“Further examination of the accuracy of HDP [hypertensive disorders of pregnancy] diagnoses, whether onset of HDP predated vaccine exposure, and biologic plausibility of HDP development following vaccination are needed,” they concluded.

Michnick and colleagues analyzed health plan data from five research partners across five sequential surveillance periods from April 2024 to April 2025 on pregnancies that culminated in a live birth or stillbirth and reached 32 gestational weeks.

They included three cohorts: pregnancies exposed to RSV vaccination (September 2023 to August 2024); comparator pregnancies receiving influenza, COVID-19, and/or Tdap (tetanus, diphtheria, and acellular pertussis) vaccines but not the RSV vaccine concurrently; and historical comparator pregnancies (vaccinated from September 2018 through January 2023).

Across the three groups, the mean age at delivery was 32-33, and 51.4% of the RSV group was white versus 45.2% of the concurrent comparator group; in the historical comparator group, race was unknown for 85%. The percentage of women with conditions that have a high risk for preterm birth was greater in the RSV group than the other groups (58.2% vs 55.9% and 52.4%, respectively).

The outcome of pregnancy-associated hypertensive disorders was a composite of gestational hypertension; preeclampsia; eclampsia; hemolysis, elevated liver enzymes, and low platelet syndrome; or preexisting hypertension superimposed with preeclampsia or eclampsia.

No increased risks were observed for the secondary outcomes of preterm labor without preterm delivery, maternal Guillain- Barré syndrome, stillbirth, large for gestational age, small for gestational age, and low birth weight.

Study limitations included the greater likelihood of assisted reproduction among those receiving the RSV vaccine, which is an independent risk factor for hypertensive disorders in pregnancy. Small sample sizes in the early period after vaccine approval may have allowed imbalances in patient characteristics to affect the study’s findings. Differences in health plans’ documentation and coding may lead to misclassification of outcomes.