Safety of BNT162b2 COVID-19 Vaccine in Pregnancy: A Systematic Review

Since COVID-19 vaccine introduction in December 2020, > 13 billion doses have been distributed globally, including > 5 billion Pfizer-BioNTech (BNT162b2) doses. Real-world evidence in pregnancy remains heterogenous in design and outcome definitions, with limited analysis by dose timing or variant period. Most reviews evaluated COVID-19 vaccines as a class without focus on individual products, limiting product-specific interpretation. Given expanding evidence and public concern around safety of vaccines during pregnancy, an updated, pregnancy-focused systematic review of BNT162b2 safety is warranted. This study aimed to review and synthesize evidence on the safety of Pfizer-BioNTech COVID-19 vaccine in pregnant women, including pregnancy-related outcomes.

A systematic literature review (PROSPERO registered) was conducted in accordance with Cochrane methodology and reported following PRISMA guidelines. Medline and Embase were searched from December 2020 to June 2025, supplemented by regulatory reports and conference searches. Eligible randomized and observational studies reporting obstetric or neonatal outcomes after ≥ 1 dose of BNT162b2 were included. Quality appraisal was conducted using NICE checklists. Results were narratively synthesized and reported following SWiM guidance.

Across 25 studies, comprising > 450,000 BNT162b2-vaccinated pregnant women, no increased risk was observed for miscarriage, congenital anomalies, preterm birth, hypertensive disorders, small for gestational age, low birth weight, or neonatal death, with effect estimates broadly consistent and centered around the null across available trimester-stratified analyses, dose numbers, and study design. However, trimester-specific data, particularly for first-trimester exposure, were limited.

The cumulative evidence demonstrates a reassuring safety profile for Pfizer-BioNTech (BNT162b2) COVID-19 vaccination with no indication of increased pregnancy-related or neonatal risk. The evidence is mainly observational and heterogeneous, with limited precision for rare outcomes, but the results align with findings from international registry, surveillance, and population-based evidence and support BNT162b2 vaccination in pregnancy as an effective and safe means to reduce preventable maternal morbidity, although evidence remains limited for first-trimester-specific exposure.

The review protocol was prospectively registered with PROSPERO [CRD420251080193] [1].