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This study assesses the safety of the bivalent prefusion F subunit-based respiratory syncytial virus (RSVpreF) vaccine during pregnancy, revealing no increased risk for preterm birth, stillbirth, or small-for-gestational-age (SGA) birth weight but a modestly higher risk of hypertensive disorders of pregnancy (HDP).
The analysis employed a target trial emulation using a large, multi-state Vaccine Safety Datalink (VSD) cohort, matching vaccinated pregnant patients to unvaccinated controls by gestational age and propensity to vaccinate, providing robust comparative safety data.
Background
Respiratory syncytial virus (RSV) remains a significant cause of respiratory illness in infants worldwide, with considerable morbidity in early infancy. Maternal vaccination during pregnancy represents a promising preventive strategy, potentially conferring passive immunity to neonates during the critical first months of life. However, the safety profile of RSV vaccines in pregnancy requires thorough evaluation to ensure no deleterious obstetric or neonatal outcomes, particularly during the initial roll-out season of the novel bivalent prefusion F subunit-based RSV vaccine (RSVpreF).
Study Design
This investigation was a target trial emulation study conducted across eight health systems representing diverse US states in the Vaccine Safety Datalink (VSD) network. Eligible participants were pregnant patients aged 16 to 49 years enrolled between September 22, 2023, and February 29, 2024. The exposure of interest was RSVpreF vaccination administered between 32 and less than 37 weeks of gestation.
Vaccinated individuals were matched 1:1 to unvaccinated pregnant controls by gestational week of vaccination, propensity scores, and VSD site. Controls were assigned a matching index date for comparison. Cases where unvaccinated controls subsequently received vaccination were censored. Outcomes included preterm birth (PTB), stillbirth (confirmed by chart review), small-for-gestational-age (SGA) birth weight, and hypertensive disorders of pregnancy (HDP), all derived from electronic health records.
Key Findings
The cohort comprised 13,966 pregnant patients vaccinated with RSVpreF. Notably, vaccinated patients had a higher proportion of nulliparity (46.4%) compared with unvaccinated counterparts (38.7%).
| Outcome | Vaccinated (%) | Unvaccinated (%) | Adjusted Risk Ratio (95% CI) |
|---|---|---|---|
| Preterm Birth (PTB) | 4.0 | 4.5 | 0.90 (0.80-1.00) |
| Stillbirth (per 1,000 births) | 0.79 | 0.72 | 0.99 (0.41-2.36) |
| Small-for-Gestational-Age (SGA) | 6.8 | 6.5 | 1.02 (0.92-1.12) |
| Hypertensive Disorders of Pregnancy (HDP) | 17.3 | 15.0 | 1.13 (1.07-1.19) |
The results demonstrate no statistically significant difference in PTB, stillbirth, or SGA rates between RSVpreF vaccinated and unvaccinated pregnant patients. However, there was a statistically significant 13% increase in the risk of hypertensive disorders of pregnancy among vaccinated individuals.
Expert Commentary
This initial large-scale safety surveillance provides reassuring evidence supporting the currently favorable safety profile of RSVpreF vaccine administered in late pregnancy. The absence of elevated preterm birth or stillbirth aligns with findings from similar maternal immunization programs against influenza and pertussis, where benefits have outweighed risks.
The modest increase in hypertensive disorders of pregnancy warrants further investigation to elucidate biological mechanisms and potential confounders. It remains critical to contextualize this finding considering the absolute risk difference and benefits of neonatal RSV protection. Current data do not establish causality, and ongoing active surveillance will be essential to monitor for rare or delayed adverse events.
Potential limitations include residual confounding by indication, with higher nulliparity among vaccinated patients possibly influencing HDP risk, and the relatively short observation window given the recent vaccine introduction. Replication across disparate populations and longitudinal outcome tracking should be prioritized.
Conclusion
This comprehensive evaluation of RSVpreF vaccination in pregnancy during its first active season indicates no increased risks for preterm birth, stillbirth, or small-for-gestational-age birth weight. The identified slight increase in hypertensive disorders after vaccination is statistically significant but requires further scrutiny through extended monitoring and mechanistic studies.
Overall, these findings support the incorporation of RSVpreF vaccination into prenatal care protocols to reduce RSV burden in infants while emphasizing the need for vigilant safety monitoring. This balance is crucial for public health strategies aimed at protecting vulnerable neonates from RSV-associated morbidity and mortality.
Funding and Registration
The study was supported by the Vaccine Safety Datalink project under the Centers for Disease Control and Prevention. No clinical trial registration number is reported.
References
- DeSilva M et al. Association of Respiratory Syncytial Virus Vaccination During Pregnancy With Adverse Obstetric and Neonatal Outcomes. Obstet Gynecol. 2026 Jun 18. PMID: 42314184.
- Madhi SA, Polack FP, Piedra PA, et al. Respiratory syncytial virus vaccination during pregnancy and effects in infants. N Engl J Med. 2020;383(5):426-439.
- Munoz FM. Respiratory syncytial virus in infants: is maternal vaccination the answer? J Infect Dis. 2019;219(Supplement_1):S87-S90.