This is a master research protocol published by the World Health Organization (WHO) in 2025.
Its primary purpose is to provide a standardized, ready-to-use blueprint for countries—particularly low- and middle-income countries (LMICs)—to conduct studies that establish baseline (background) rates for four critical neonatal outcomes:
- Preterm Birth (birth before 37 weeks of gestation)
- Stillbirth
- Neonatal Death (death within the first 28 days of life)
- Low Birthweight (birthweight <2500g)
These outcomes are classified as Adverse Events of Special Interest (AESIs) in the context of maternal immunization (vaccination during pregnancy).
Why is this crucial?
Before introducing a new vaccine for pregnant women (like a maternal RSV vaccine), scientists and regulators need to know how often these serious events naturally occur in the population. This “background rate” serves as a critical reference point. After vaccine introduction, if the observed rate of an event increases significantly compared to this baseline, it can trigger a safety investigation to determine if the vaccine might be a contributing factor. Without this baseline data, it is impossible to distinguish a potential vaccine safety signal from normal, expected occurrences.
Key Drivers & Rationale (The “Why Now?”)
The protocol addresses several urgent global health needs:
- Introduction of New Maternal Vaccines: With vaccines like the maternal RSV vaccine being approved and rolled out, LMICs need the capacity to monitor their safety independently.
- Equity in Pharmacovigilance: High-income countries often use existing electronic health records to calculate these rates. LMICs frequently lack such robust data systems, creating a “data gap” that can delay or hinder vaccine introduction and safety monitoring. This protocol is designed for settings with limited digital infrastructure.
- Combatting Vaccine Hesitancy: Robust, local safety monitoring builds public trust by demonstrating that authorities are proactively watching for any potential risks.
- Standardization: The protocol uses internationally agreed GAIA (Global Alignment of Immunization Safety Assessment in Pregnancy) case definitions. This ensures data from different countries is comparable and of high quality.
Study Methodology & Design (The “How”)
- Design: Multisite prospective cohort study. This means it follows a group of pregnant women (a cohort) forward in time (prospectively) from delivery through their infant’s first 28 days, across multiple health facilities in different countries.
- Setting: Conducted in selected sentinel health facilities in LMICs that have at least 1000 deliveries per year and adequate diagnostic capabilities.
- Participants: All pregnant women registered to deliver at the participating facilities during the study period and their newborns (live and stillborn).
- Consent: Uses opt-out consent or oral consent processes to ensure practicality and high participation rates, while adhering to strict ethical standards. This is especially important in busy maternity wards.
- Data Collection: Trained study staff will collect data using standardized case report forms (provided in the annexes) for each of the four AESIs. Data sources include medical records, interviews with mothers, and follow-up calls/visits for infants discharged before 28 days.
- Key Challenge Addressed: The study acknowledges it will only capture deliveries that occur in health facilities, which may introduce a selection bias in regions where many births happen at home. This limitation must be considered when interpreting the results.
Statistical Plan & Analysis
The protocol provides a clear plan for calculating the background rates:
- Sample Size: Includes calculations and tables to determine how many births are needed at a site to estimate each AESI rate with a desired level of statistical precision (e.g., a narrow confidence interval).
- Rate Calculations:
- Preterm Birth Rate:
(Number of preterm births / Total live births) x 1000 - Stillbirth Rate:
(Number of stillbirths / Total births (live+still)) x 1000 - Neonatal Mortality Rate:
(Number of neonatal deaths / Total live births) x 1000 - Low Birthweight Proportion:
(Number of low birthweight infants / Total live births) x 100%
- Preterm Birth Rate:
- Analysis: Rates will be calculated annually and, if possible, monthly to assess seasonality. Results will be stratified by country, site, and maternal characteristics.
Governance, Ethics, and Data Management
The protocol outlines a robust framework to ensure the study is conducted ethically and data is handled securely:
- Structure: Involves a Scientific Advisory Committee, the WHO Pharmacovigilance Team, National Focal Points, and local Site Teams.
- Ethics: Requires approval from both the WHO Research Ethics Review Committee and all relevant local/national ethics committees. It emphasizes participant autonomy, confidentiality, and the right to withdraw.
- Data: Stresses anonymization, secure storage, and compliance with standards like the GDPR. Data ownership remains with the local institution, with sharing for public health purposes.
Dissemination & Long-Term Goals
The goal is not just to produce numbers, but to:
- Build Sustainable Capacity: Strengthen local pharmacovigilance systems in LMICs.
- Inform Policy: Provide evidence for national immunization programs and regulatory decisions.
- Communicate Transparently: Share results with participating communities, healthcare professionals, and the global scientific community through publications, reports, and community-appropriate channels.
Annexes (The “Toolkit”)
The protocol is exceptionally practical, providing all necessary tools for implementation:
- Annex 1: Health facility screening questionnaire to select study sites.
- Annex 2: Detailed GAIA case definitions with levels of diagnostic certainty for each AESI.
- Annex 3-7: Ready-to-use Case Report Forms (CRFs) for collecting data on baseline info, preterm birth, stillbirth, neonatal death, and low birthweight.
- Annex 8 & 9: Templates for oral informed consent and assent information sheets.
Summary
This WHO master protocol is a comprehensive, ethical, and operational “playbook” designed to empower LMICs to generate their own high-quality, baseline safety data for maternal immunization programs. By standardizing methods globally, it aims to close the pharmacovigilance equity gap, ensure safer vaccine introductions, and ultimately protect the health of mothers and newborns worldwide. It represents a proactive, capacity-building approach to global vaccine safety.
