Safety of COVID-19 Vaccines During Pregnancy: A Systematic Review and Meta-Analysis

Abstract

Background: Assessment of COVID-19 vaccine safety during pregnancy is urgently needed to inform the public, advisory committees, and policymakers.

Methods: We conducted a systematic review and meta-analysis to evaluate the safety of COVID-19 vaccines, including their components and technological platforms used in other vaccines during pregnancy. We searched literature databases from inception to September 2021 without language restriction, COVID-19 vaccine pregnancy websites, and reference lists of systematic reviews and the included studies. Pairs of reviewers independently selected studies through COVIDENCE and performed the data extraction and risk of bias assessment. Discrepancies were resolved by consensus. The study is registered in PROSPERO (CRD42021234185).

Findings: We retrieved 8,837 records from the search strategy; 71 studies (61 clinical and 10 non-clinical studies, involving 17,719,495 pregnant persons and 389 pregnant animals, respectively) were included. Most studies (94%) were conducted in high-income countries and were cohort studies (51%). Less than 15% of studies were classified as high risk of bias. We identified nine COVID-19 vaccine studies, two preclinical studies, and seven involving 309,164 pregnant persons, mostly exposed to mRNA vaccines. Among non-COVID-19 vaccines, the most frequent exposures were to the AS03 adjuvant (23 studies) and aluminum-based adjuvants (31 clinical and five preclinical studies).A meta-analysis of the studies that adjusted for potential confounders and compared exposure to maternal COVID-19 vaccines or adjuvanted non-COVID-19 vaccines with no exposure showed no association with adverse outcomes, regardless of the vaccine or the trimester of vaccination. Proportional meta-analyses of uncontrolled studies or arms assessing pregnancy and safety outcomes of COVID-19 vaccines or adjuvanted non-COVID-19 vaccines (with AS03 or aluminum) estimated the ranges for each of the following outcomes: hypertensive disorders 2·37-3·98%; antenatal bleeding 0·37-0·44%; gestational diabetes mellitus 2·63-7·74%; spontaneous abortion/miscarriage 4·97-11·98%; stillbirth 0·06-0·20%; fetal death 0·82-1·36%; fetal growth restriction 0·49-0·89%; preterm birth 5·52-5·61%; low birth weight 3·73-6·84%; small for gestational age 6·84-11·98%; congenital malformations 2·32-4·97%; neonatal infections 3·24-7·23%; neonatal encephalopathy 0·23%; newborn respiratory distress syndrome 1·23-1·82%; and neonatal death 0·07-0·43%. Medically attended adverse events (33·9%) and serious adverse events (12·31%) were only available for aluminum-based adjuvant exposure. Neither pregnancy outcomes nor reactogenicity exceeded the expected rates. The only exception was postpartum hemorrhage after COVID-19 vaccination (10·40%; 95% CI: 6·49-15·10%), reported by two studies; however, the comparison with non-exposed pregnant persons in one study found non-statistically significant differences (adjusted OR 1·09; CI 95% 0·56 to 2·12).

Interpretation: We found no safety concerns for currently administered COVID-19 vaccines during pregnancy. Further experimental and real-world evidence should expand these findings that reinforce current recommendations about vaccinating pregnant persons with approved COVID-19 vaccines. Robust safety data for non-mRNA-based COVID-19 vaccines are urgently needed.

Funding: Bill & Melinda Gates Foundation

Declaration of Interest: The authors have declared that no competing interests exist.

Keywords: COVID-19 vaccines, vaccine safety, female, humans, animals, pregnancy, SARS-CoV-2, vaccination, adjuvant, systematic review, meta-analysis