By Ahizechukwu C. Eke, MD, PhD, MPH
Synopsis: The follow-up MATISSE study explored the safety of the respiratory syncytial virus prefusion F (RSVpreF) vaccine in pregnant women and demonstrated no significant increase in preterm birth rates compared to the placebo, although it highlighted geographical and socioeconomic disparities in outcomes.
Source: Madhi SA, Kampmann B, Simões EAF, et al. Preterm birth frequency and associated outcomes from the MATISSE (Maternal Immunization Study for Safety and Efficacy) maternal trial of the bivalent respiratory syncytial virus prefusion F protein vaccine. Obstet Gynecol. 2025;145(2):147-156.
Respiratory syncytial virus (RSV) is a widespread respiratory pathogen affecting individuals across all age groups, with a disproportionately severe effect on vulnerable populations, including pregnant women and young children.1 In the United States, RSV leads to approximately 500,000 emergency department visits annually among children younger than 5 years of age, making it the most common cause of hospitalization in infants younger than 1 year of age.1,2
Although the public health focus traditionally has been on RSV in children and infants because of its significant effect, there is increasing concern about the implications of RSV infection during pregnancy.3 This concern is particularly acute for those in their second and third trimesters, who are at heightened risk of severe respiratory infections. Furthermore, maternal RSV infection is associated with serious adverse outcomes, such as preterm birth, low birth weight, neonatal respiratory distress, and increased maternal and fetal morbidity and mortality.3
The MATISSE trial, a pivotal randomized controlled trial investigating the efficacy and safety of maternal RSV vaccination, has provided crucial insights into the vaccine’s potential effect on preterm birth.4 The trial’s findings demonstrated a nonsignificant increase in the rate of preterm births among those administered the RSV vaccine compared to the control group (5.7% vs. 4.7%).4 Sixty percent of the preterm births occurred more than 30 days following vaccination, and 90% of these births were late preterm, occurring between 34 and 37 weeks of gestation. However, despite these promising results, there remain concerns regarding the comprehensive understanding of the vaccine’s safety profile, particularly with respect to preterm birth and its long-term effects on neonatal health and developmental outcomes.
In response to the trial findings, there has been a recommendation for the RSV vaccine to be administered between 32 and 36 weeks of gestation, but the investigators highlighted the need for further studies to define precise timing in vaccine administration during pregnancy to optimize maternal and fetal immunity without compromising gestational milestones. Ongoing post-trial surveillance and further longitudinal studies are essential to monitor the vaccine’s effects on a larger scale and to definitively ascertain its association with preterm birth. Therefore, Madhi and colleagues sought to determine the preterm birth frequency and newborn and infant outcomes overall and among preterm children in the MATISSE cohort.5
The MATISSE trial was a Phase III, double-blind, randomized, placebo-controlled efficacy study conducted in 18 countries and involved more than 7,000 participants across four RSV seasons.5 Enrollment criteria included pregnant individuals aged 49 years of age or younger at 24 to 36 weeks of gestation, with uncomplicated, singleton pregnancies and no significant risk of pregnancy complications.
The primary efficacy endpoint was the prevention of RSV-associated illness in newborns and infants. The main safety endpoints for the maternal participants included monitoring for adverse events, such as preterm delivery (before 37 weeks of gestation) and positive SARS-CoV-2 test results, noting that active COVID-19 surveillance was not conducted. For newborns and infants, the adverse events of interest comprised preterm birth, low birth weight (less than 2,500 g), developmental delays, and positive SARS-CoV-2 tests. These outcomes were collected through six months after delivery (pregnant patients) and from birth through age 12 or 24 months (pediatric participants). Individuals with known hypersensitivity to any component of the investigational vaccine, immune-suppressing conditions, recent receipt of immune globulins or blood products, and participation in another clinical study involving an RSV vaccine within the previous month were excluded.
Preterm delivery rates were analyzed against various demographic characteristics and maternal medical history factors, including the number of previous pregnancies, smoking or alcohol use, anemia, genitourinary infections, diabetes, hypertension, and vaccination status. Outcomes were categorized by World Bank income classifications — high-income and non-high-income countries (including low-income, lower-middle-income, and upper-middle-income countries). The relative risk (RR) of preterm birth, along with 95% confidence intervals (CIs), was calculated using normal approximations to the log RR across the overall maternal population, stratified by gestational age at vaccination, by country, and by other subgroups.
From June 17, 2020, to Oct. 22, 2022, a total of 7,386 pregnant participants were administered either respiratory syncytial virus prefusion F (RSVpreF) (n = 3,698) or a placebo (n = 3,688), resulting in the inclusion of 7,305 newborns and infants in the analysis. The majority of children from both groups were born at full term (RSVpreF 93.6%, placebo 94.3%). Preterm birth rates were 5.7% in newborns whose mothers received RSVpreF and 4.7% in those whose mothers received placebo (RR, 1.20; 95% CI, 0.98-1.46), with the majority of preterm births occurring between 34w0d and 37w0d gestational age (RSVpreF 89.3%, placebo 93.0%). Outcomes for newborns and infants, including rates of low birth weight and neonatal hospitalization, were similar across both groups (RSVpreF 6.9% [253/3,659], placebo 6.4% [232/3,646]). During the study, there were 22 deaths among newborns and infants (eight in the RSVpreF group and 14 in the placebo group). Stratifying by income region revealed consistent preterm birth rates of 5.0% in both the RSVpreF and placebo groups in high-income countries (RR, 1.00; 95% CI, 0.79-1.28). In non-high-income countries, the rates were 7.0% for RSVpreF and 4.0% for placebo recipients (RR, 1.73; 95% CI, 1.22-2.47). No safety concerns were reported.
Commentary
Preventing RSV infection in pregnant women and newborns is a critical public health goal. In the MATISSE randomized controlled trial, more than 93% of newborns in both the treatment and control groups were born full-term, demonstrating comparable health outcomes across both groups. The study observed a nonsignificant trend toward higher rates of preterm birth among infants whose mothers received the RSVpreF vaccine, especially during the late preterm stage. Key outcomes, such as low birth weight and neonatal hospitalization rates, were similar between the vaccine and placebo groups. Analysis stratified by income showed consistent preterm birth rates in high-income countries, whereas in non-high-income countries, higher but nonsignificant rates were noted in the RSVpreF group. The trial documented 22 infant deaths without attributing any safety concerns to the vaccine. These findings suggest that while RSVpreF is generally safe, geographical and socio-economic factors might influence the rates of preterm births.
The administration of the RSVpreF vaccine in pregnant women, as investigated in the MATISSE trial, provides important insights into the relationship between maternal RSV immunization and preterm birth outcomes. While the MATISSE trial revealed a slight, non-statistically significant increase in preterm births among recipients of the RSVpreF vaccine, especially during the late preterm period, this finding aligns with the mixed results observed in other studies examining maternal vaccinations and preterm birth rates. For instance, a Cochrane systematic review and meta-analysis by Phijffer et al demonstrated that maternal immunization generally does not increase the risk of preterm birth, although the authors advise caution in interpreting these findings.6 Contrarily, other systematic reviews and meta-analytic studies have indicated potential increases in preterm birth subcategories, which necessitates further exploration to clarify these relationships.7 The ongoing pharmacovigilance of vaccine safety profiles, particularly for newly introduced vaccines like RSVpreF, is critical to understanding these nuanced outcomes and ensuring maternal and neonatal safety.8
Geographical and socio-economic factors play a crucial role in the incidence of preterm births, as evidenced by the stratified analysis in the MATISSE trial, which found higher preterm birth rates in non-high-income countries among the RSVpreF group compared to high-income counterparts. This discrepancy highlights broader issues related to disparities in healthcare access, nutritional status, and environmental stressors that disproportionately affect low-income regions.9 Research, such as the work by Copper et al, underscores how low socio-economic status is linked to increased stress levels, poorer general health, and lower access to prenatal care, all of which contribute to higher preterm birth rates.10 Furthermore, studies like those conducted by Liang et al emphasize how significant disparities persist, especially in low socioeconomic index regions.11 Addressing these disparities requires targeted public health interventions and policies that not only focus on improving prenatal care but also on social determinants of health that influence maternal and neonatal outcomes on a global scale.
Based on the follow-up study of the MATISSE randomized trial examining RSVpreF and placebo effects on preterm birth outcomes, the current guidelines by the American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine, which recommend administering a single dose of RSVpreF to all pregnant women between 32 and 36 weeks of gestation, are unlikely going to change. These guidelines endorse RSVpreF as a safe and effective measure to prevent RSV infection in neonates and infants, based on the trial’s findings.12,13 Patients should be aware that according to ACOG recommendations, if pregnant women choose to decline the RSV vaccine and opt for nirsevimab instead, their infants should receive nirsevimab at birth to prevent RSV infection and other related lower respiratory tract infections. It is important for healthcare providers to counsel these patients on the non-significant risk of preterm birth associated with RSVpreF and inform them of the limited data regarding its impact on breastfeeding.
Ahizechukwu C. Eke, MD, PhD, MPH, is Associate Professor in Maternal Fetal Medicine, Division of Maternal Fetal Medicine, Department of Gynecology & Obstetrics, Johns Hopkins University School of Medicine, Baltimore.
References
1. Daniels D. A review of respiratory syncytial virus epidemiology among children: Linking effective prevention to vulnerable populations. J Pediatric Infect Dis Soc. 2024;13(Supplement_2):S131-s136.
2. Leader S, Kohlhase K. Recent trends in severe respiratory syncytial virus (RSV) among US infants, 1997 to 2000. J Pediatr. 2003;143(5 Suppl):S127-S132.
3. Gonik B. The burden of respiratory syncytial virus infection in adults and reproductive-aged women. Glob Health Sci Pract. 2019;7(4):515-520.
4. Kampmann B, Madhi SA, Munjal I, et al. Bivalent prefusion F vaccine in pregnancy to prevent RSV illness in infants. N Engl J Med. 2023;388(16):1451-1464.
5. Madhi SA, Kampmann B, Simões EAF, et al. Preterm birth frequency and associated outcomes from the MATISSE (Maternal Immunization Study for Safety and Efficacy) maternal trial of the bivalent respiratory syncytial virus prefusion F protein vaccine. Obstet Gynecol. 2025;145(2):147-156.
6. Phijffer EW, de Bruin O, Ahmadizar F, et al. Respiratory syncytial virus vaccination during pregnancy for improving infant outcomes. Cochrane Database Syst Rev. 2024;5(5):CD015134.
7. Kuitunen I, Haapanen M. Respiratory syncytial virus vaccination is associated with increased odds of preterm birth. Acta Paediatr. 2025; Jan 20. doi:10.1111/apa.17595. [Online ahead of print].
8. Hong-Nguyen YK, Toerner J, Lee L, et al. Regulatory review of benefits and risks of preventing infant RSV disease through maternal immunization. NPJ Vaccines. 2024;9(1):210.
9. Jones AJ, Eke UA, Eke AC. Prediction and prevention of preterm birth in pregnant women living with HIV on antiretroviral therapy. Expert Rev Anti Infect Ther. 2022;20(6):837-848.
10. Copper RL, Goldenberg RL, Das A, et al. The preterm prediction study: Maternal stress is associated with spontaneous preterm birth at less than thirty-five weeks’ gestation. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Am J Obstet Gynecol. 1996;175(5):1286-1292.
11. Liang X, Lyu Y, Li J, et al. Global, regional, and national burden of preterm birth, 1990-2021: A systematic analysis from the global burden of disease study 2021. EClinicalMedicine. 2024;76:102840.
12. The American College of Obstetricians and Gynecologists. ACOG, SMFM, and AAP statement on nirsevimab shortage. Published Oct. 25, 2023. https://www.acog.org/news/news-releases/2023/10/acog-smfm-aap-statement-on-nirsevimab-shortage
13. Society for Maternal-Fetal Medicine. RSV vaccination in pregnancy. Published Sept. 25, 2023. https://s3.amazonaws.com/cdn.smfm.org/media/4196/SMFM_Statement_RSV_September_2023.pdf
The follow-up MATISSE study explored the safety of the respiratory syncytial virus prefusion F (RSVpreF) vaccine in pregnant women and demonstrated no significant increase in preterm birth rates compared to the placebo, although it highlighted geographical and socioeconomic disparities in outcomes.
You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
- Award-winning Medical Content
- Latest Advances & Development in Medicine
- Unbiased Content