Increased risk for hypertensive disorders was present, but modest, in a new surveillance analysis of a bivalent respiratory syncytial virus (RSV) prefusion F subunit-based (RSVpreF) vaccine for pregnant women, based on data from more than 13,000 individuals.

The vaccine (RSVpreF) was approved by the FDA in 2023 for use in pregnant women at 32 through 36 weeks’ gestational age for the prevention of lower respiratory tract disease and severe lower respiratory tract disease in infants from birth to age 6 months. The vaccine contains prefusion forms of RSV-A and RSV-B subtypes.

In an early postapproval surveillance study published in JAMA Network Open, the researchers assessed whether the use of the RSVpreF vaccine during pregnancy was associated with increased risks for key safety outcomes, “with the understanding that these early analyses would be followed by larger and more methodologically robust studies as additional data accrued,” said lead author Ashley I. Michnick, PharmD, PhD, a research associate at the Department of Population Medicine, Harvard Pilgrim Health Care Institute, Harvard Medical School in Boston.

The current study is the first of multiple components required by the FDA to identify 10 prespecified safety outcomes after the vaccine’s first season of use in the US. The primary outcomes were preterm birth and a composite of pregnancy-associated hypertensive disorders (gestational hypertension, preeclampsia, eclampsia, hemolysis, elevated liver enzymes, and low platelet syndrome; or preexisting hypertension superimposed with preeclampsia or eclampsia). Secondary outcomes included premature rupture of membranes (PROMs), preterm PROM, preterm labor without preterm delivery, maternal Guillain-Barré syndrome, and stillbirth. For each outcome, the researchers identified crude incidence proportions (IPs) and adjusted relative risks (ARRs).

The study population included 13,619 RSVpreF-exposed pregnancies in individuals aged 15-54 years (mean age, 33.3 years) that resulted in live birth or stillbirth after 32 weeks’ gestation. The researchers reviewed health insurance data from five sequential surveillance periods from April 25, 2024, to April 10, 2025.

Pregnancy-associated hypertensive disorders and PROMs were the most common safety outcomes (IP, 17.3%; 95% CI, 16.6%-17.9% and IP, 14.1%; 95% CI, 13.5%-14.7%, respectively).

Overall, no significant associations appeared between RSVpreF exposure and risk for preterm birth was noted for current or historical comparators (ARR, 0.79; 95% CI, 0.65-0.98 and ARR, 0.87; 95% CI, 0.78-0.96, respectively). However, elevated risk appeared for pregnancy-associated hypertensive disorders (ARR, 1.14; 95% CI, 1.02-1.27 and ARR 1.29; 95% CI, 1.24-1.34 for concurrent and historical comparators, respectively). The researchers also identified elevated risks for PROM (ARR, 1.09; 95% CI, 0.97-1.22 and ARR, 1.14; 95% CI, 10.9-1.19 for concurrent and historical comparators, respectively) and preterm PROM (ARR, 1.18; 95% CI, 1.08-1.29 for historical comparator).

The researchers also assessed infant outcomes of large for gestational age, small for gestational age, and low birth weight, but no significantly increased risks for these outcomes were associated with RSVpreF exposure.

Results Reassuring

“Preapproval trials demonstrated that the vaccine prevented RSV disease in infants, but they also identified small and uncertain signs suggesting a possible increase in risks of preterm birth or high blood pressure in pregnancy,” said Michnick. “Given that context, we were reassured to identify more than 13,000 RSVpreF-vaccinated pregnancies during the first respiratory season after approval and to find no evidence of increased risk for preterm birth or eight other assessed outcomes,” she said.

Although the study showed a modest elevated risk in hypertensive disorders during pregnancy, the findings were consistent with preapproval studies, and some postapproval studies, and may be affected by confounding given the observational design, Michnick noted.

“Importantly, our first follow-up study, conducted after this analysis and published separately in JAMA, allowed for more robust control of potential confounders and did not confirm this potential increased risk, and we are continuing to monitor this and other safety outcomes as vaccine uptake expands,” she said.

The current early safety analysis served its intended purpose by ruling out several priority safety concerns and identifying others that warrant closer evaluation and more complete studies to determine whether observed patterns reflected real risks, Michnick said.

“The analyses described in this study represent only the first step in the ongoing monitoring of the RSVpreF vaccine,” said Michnick. “We will continue to study pregnancy, maternal, and infant safety outcomes in larger and more diverse populations as additional data becomes available, and we remain committed to keeping the clinicians, regulators, and the public informed as evidence evolves,” she added. Further data analyses are expected to be published in 2029.

Follow-up studies that were conducted after the current analysis was run (including the first large cohort analysis now published in JAMA which controlled for even more confounding/biasing factors) and have not confirmed increased risks for high blood pressure or waters breaking before the start of labor contractions, suggested in these early analyses, Michnick noted. “Taken together, this early study and our follow-up studies demonstrate that our vaccine safety surveillance system is functioning as intended: it is transparent, cautious, and guided by evolving evidence, which is an encouraging message for clinicians and patients navigating vaccine decisions during pregnancy,” she said.

More Information for Informed Decisions

Post-market studies such as the current observational study are important to identify any potential elevated risks that may not have been fully realized during the initial safety studies that supported the drug’s approval, said Aleksandr M. Fuks, MD, professor and chair in the Department of Ob/Gyn at the Quillen College of Medicine, East Tennessee State University in Johnson City, Tennessee. 

The results of the current study were not necessarily surprising, but rather somewhat concerning, as the study demonstrated increased risk for pregnancy-associated hypertensive disorders, PROM, and preterm PROM in patients who underwent RSVpreF vaccination during third trimester of pregnancy, said Fuks, who was not involved in the study. “While increased risk of PROM and preterm PROM were observed in other, smaller studies, the findings of increased risk of pregnancy-associated hypertensive disorders was unique to the current study and not previously observed,” he noted.

The findings are important with respect to appropriate patient counseling regarding risks, benefits, and alternatives of RSVpreF vaccination, said Fuks. “While the limitations of this large study need to be acknowledged during counseling (pregnancies receiving RSVpreF vaccination were more likely to be conceived via assisted reproductive technology), the findings of increased risk of pregnancy-associated hypertensive disorders, PROM, and preterm PROM need to be communicated to patients. Vaccinated patients need to be closely monitored for those pregnancy complications as well,” he said.

Additional research should include a full epidemiologic study that accounts for risk factors of pregnancy-associated hypertensive disorders and PROM as well as other comorbidities (including those of immunologic etiology) to quantify the exact impact of RSVpreF vaccination on these outcomes, Fuks added.

The study was funded by Pfizer. Several coauthors disclosed support from Pfizer, and some disclosed additional funding from other companies and agencies unrelated to the current study. Lead author disclosed receiving grants to Harvard Pilgrim Health Care Institute from Pfizer during the study and grants from the FDA unrelated to the current study. Fuks disclosed having no financial conflicts of interest.