The research question is: What is the risk of adverse pregnancy outcomes, including preterm birth, hypertensive disorders, and other maternal and neonatal/infant outcomes, following exposure to RSV vaccine between 32 weeks, 0 days and 36 weeks, 6 days of gestation in the CorEvitas Respiratory Syncytial Virus Vaccine Pregnancy Registry (RSV-PR)? The primary study objective is to estimate the risk of (1) preterm birth and (2) hypertensive disorders following exposure to RSV vaccine between 32 weeks, 0 days and 36 weeks, 6 days of gestation.

The secondary study objective is to estimate the risk of other safety outcomes of interest following exposure to RSV vaccine between 32 weeks, 0 days and 36 weeks, 6 days of gestation, including:

• Pregnancy-related outcomes: stillbirth, premature labor, premature rupture of membranes, preterm premature rupture of membranes, cesarean delivery, prolonged maternal duration of hospital stay
• Maternal outcomes: thrombocytopenia, Guillain-Barré syndrome, other immune-mediated demyelinating conditions, polyneuropathies, atrial fibrillation, maternal death
• Neonatal/infant outcomes: small for gestational age, large for gestational age, low birth weight, admission to a neonatal intensive care unit (NICU), NICU duration of stay, mechanical ventilation in neonatal period, neonatal death, postnatal growth at 1 year of age The exploratory study objective is to describe the most frequently reported maternal adverse events following exposure to RSV vaccine between 32 weeks, 0 days and 36 weeks, 6 days of gestation.

Rationale and background: Respiratory syncytial virus (RSV) vaccine is approved for use in pregnant individuals during late pregnancy (32 weeks, 0 days through 36 weeks, 6 days of gestation) to prevent RSV-related severe lower respiratory tract disease in infants from birth through 6 months of age.

Research question and objectives: This work is intended to answer the question regarding what is the risk of adverse pregnancy outcomes, including preterm birth, hypertensive disorders, and other maternal and neonatal/infant outcomes, following exposure to RSV vaccine between 32 weeks, 0 days and 36 weeks, 6 days of gestation? The primary study objective is to estimate the risk of (1) preterm birth and (2) hypertensive disorders of pregnancy following exposure to RSV vaccine between 32 weeks, 0 days and 36 weeks, 6 days of gestation.

The secondary study objective is to estimate the risk of other safety outcomes of interest following exposure to RSV vaccine between 32 weeks, 0 days and 36 weeks, 6 days of gestation, including:

• Pregnancy-related outcomes: stillbirth, premature labor, premature rupture of membranes (PROM), preterm premature rupture of membranes (PPROM), cesarean delivery, prolonged maternal duration of hospital stay
• Maternal outcomes: thrombocytopenia, Guillain-Barré syndrome (GBS), other immune-mediated demyelinating conditions, polyneuropathies, atrial fibrillation, maternal death
• Neonatal/infant outcomes: small for gestational age (SGA), large for gestational age, low birth weight (LBW), admission to a neonatal intensive care unit (NICU), NICU duration of stay, mechanical ventilation in neonatal period, neonatal death, postnatal growth deficiency at 1 year of age The exploratory study objective is to describe the most frequently reported maternal adverse events (AEs) occurring within 42 days of RSV vaccine administration between 32 weeks, 0 days and 36 weeks, 6 days of gestation.

Outcomes occurring before 32 weeks, 0 days of gestation, including but not limited to spontaneous abortion and major congenital malformations, will not be evaluated.

Study design: This US-based observational cohort study is designed to evaluate RSV vaccine exposure during weeks 32 through 36 of pregnancy (i.e., 32 weeks, 0 days through 36 weeks, 6 days) and the risk of subsequent pregnancy, maternal, and neonatal/infant outcomes. For this study, the index date will be the date of RSV vaccine administration for the exposed cohort and the date of enrollment for the unexposed cohort. The risks of pregnancy-related outcomes, maternal outcomes, and neonatal/infant outcomes for participants exposed and unexposed to RSV vaccine during pregnancy will be estimated.

Population: The study population will include 2 cohorts of individuals enrolled in the Respiratory Syncytial Virus Vaccine Pregnancy Registry (RSV-PR): (1) those exposed to RSV vaccine between 32 weeks, 0 days and 36 weeks, 6 days and (2) those unexposed to RSV vaccine during pregnancy.

Variables: Exposure to RSV vaccine will be defined as receipt of RSV vaccine at any time between 32 weeks, 0 days and 36 weeks, 6 days of gestation. The primary outcomes are preterm birth and hypertensive disorders of pregnancy. Secondary pregnancy outcomes of interest include stillbirth, premature labor, PROM, PPROM, cesarean delivery, and prolonged maternal duration of hospital stay. Maternal outcomes of interest include thrombocytopenia, GBS, other immune-mediated demyelinating conditions, polyneuropathies, atrial fibrillation, and maternal death. The neonatal/infant outcomes of interest are SGA, large for gestational age, LBW, admission to a NICU, prolonged infant duration of hospital stay, mechanical ventilation in neonatal period, neonatal death, and postnatal growth deficiency at 1 year of age. Maternal AEs occurring within 42 days of RSV vaccine administration will be captured for the cohort of RSV vaccine-exposed pregnant individuals.

Information on covariates (including demographics, risk factors for the study outcomes, comorbidities, concomitant medications, and predictors of RSV vaccine use) will be incorporated into the analyses.

Data source: This study will collect data from participants and the healthcare providers (HCPs) involved in their care or the care of their infants via concise data collection forms at pre-defined timepoints during pregnancy, at pregnancy outcome, and up to 1 year of infant age.

Study Size: The study will aim to include 2,062total participants (1,031 per cohort) to detect a minimum risk ratio of 1.5 or greater for the primary outcome of preterm birth (fewer participants are required to detect hypertensive disorders of pregnancy), assuming equal accrual (1:1) of RSV vaccine-exposed and -unexposed participants, and accounting for exclusions from the analysis population and loss of effective sample size due to inverse probability of treatment weighting.

Data analysis: Participant characteristics will be summarized with descriptive statistics for each cohort. Comparative analyses will be conducted for each outcome if sample size permits. Supplementary analyses will be conducted that include pregnant individuals who were excluded from the analysis population (i.e., those lacking HCP confirmation of RSV vaccine exposure, pregnancy, or outcomes of interest). If sample size permits, subgroup and sensitivity analyses will be performed to examine the extent to which changes in certain methods or assumptions affect the results.

Milestones: Start of data collection is planned for 30 September 2024, and the end of data collection is planned for 30 September 2030. The final study report and analysis is projected for 30 September 2031.

Inclusion Criteria:

• Individuals must meet the following inclusion criteria to be eligible for inclusion in the study:

  1. A resident of the US at enrollment
  2. 18 to 50 years of age at enrollment
  3. Gestational age of ≥32 weeks, 0 days at enrollment
  4. If exposed to RSV vaccine, receipt of any RSV vaccine between 32 weeks, 0 days and 36 weeks, 6 days of gestation
  5. Evidence of a personally signed and dated informed consent document or, upon waiver of written consent by the relevant IRB/independent ethics committee, verbal consent indicating that the individual (or a legally acceptable representative) has been informed of all pertinent aspects of the study
  6. Authorization obtained for the relevant HCP(s) to provide data to the registry
  7. Contact information available (for participant and HCPs)

Exclusion Criteria:

• Individuals meeting any of the following criteria will not be included in the study:

  1. Receipt of an RSV vaccine during pregnancy before 32 weeks, 0 days gestation
  2. Multi-fetal pregnancy
  3. Enrolled in the RSV-PR with a previous pregnancy

Pregnant individuals across the US who learn of the study via a nationwide advertising campaign or via their health care providers or maternal care sites