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

44 Pages Posted: 1 Apr 2022

See all articles by Agustin Ciapponi

Agustin Ciapponi

University of Copenhagen - Department of Immunology and Microbiology; Instituto de Efectividad Clínica y Sanitaria - Centro de Investigación en Epidemiología y Salud Pública (IECS-CIESP)

Mabel Berrueta

Independent

Ariel Bardach

Instituto de Efectividad Clínica y Sanitaria - Centro de Investigación en Epidemiología y Salud Pública (IECS-CIESP)

Agustina Mazzoni

Independent

Steven A. Anderson

U.S. Food and Drug Administration

Fernando J. Argento

Instituto de Efectividad Clínica y Sanitaria - Centro de Investigación en Epidemiología y Salud Pública (IECS-CIESP)

Jamile Ballivian

Instituto de Efectividad Clínica y Sanitaria - Centro de Investigación en Epidemiología y Salud Pública (IECS-CIESP)

Karin Bok

Government of the United States of America - National Institute of Allergy and Infectious Diseases (NIAID)

Daniel Comandé

Independent

Erin Goucher

Independent

Beate Kampmann

London School of Hygiene & Tropical Medicine - Vaccines and Immunity Theme

Edward Parker

London School of Hygiene & Tropical Medicine - Department of Clinical Research

Federico Rodriguez Cairoli

Instituto de Efectividad Clínica y Sanitaria - Centro de Investigación en Epidemiología y Salud Pública (IECS-CIESP)

María Victoria Santa María

Independent

Andy Stergachis

University of Washington - School of Public Health

Gerald Voss

Coalition for Epidemic Preparedness Innovations

Xu Xiong

Independent

Natalia Zamora

Independent

Pierre M. Buekens

Independent

Sabra Zaraa

School of Pharmacy and School of Public Health, University of Washington

More...

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

Suggested Citation

Ciapponi, Agustin and Berrueta, Mabel and Bardach, Ariel and Mazzoni, Agustina and Anderson, Steven A. and Argento, Fernando J. and Ballivian, Jamile and Bok, Karin and Comandé, Daniel and Goucher, Erin and Kampmann, Beate and Parker, Edward and Rodriguez Cairoli, Federico and Santa María, María Victoria and Stergachis, Andy and Voss, Gerald and Xiong, Xu and Zamora, Natalia and Buekens, Pierre M. and Zaraa, Sabra, Safety of COVID-19 Vaccines During Pregnancy: A Systematic Review and Meta-Analysis. Available at SSRN: https://ssrn.com/abstract=4072487 or http://dx.doi.org/10.2139/ssrn.4072487

Agustin Ciapponi (Contact Author)

University of Copenhagen - Department of Immunology and Microbiology ( email )

Copenhagen
Denmark

Instituto de Efectividad Clínica y Sanitaria - Centro de Investigación en Epidemiología y Salud Pública (IECS-CIESP) ( email )

Mabel Berrueta

Independent ( email )

Ariel Bardach

Instituto de Efectividad Clínica y Sanitaria - Centro de Investigación en Epidemiología y Salud Pública (IECS-CIESP) ( email )

Agustina Mazzoni

Independent ( email )

Steven A. Anderson

U.S. Food and Drug Administration ( email )

Silver Spring, MD
United States

Fernando J. Argento

Instituto de Efectividad Clínica y Sanitaria - Centro de Investigación en Epidemiología y Salud Pública (IECS-CIESP) ( email )

Jamile Ballivian

Instituto de Efectividad Clínica y Sanitaria - Centro de Investigación en Epidemiología y Salud Pública (IECS-CIESP) ( email )

Karin Bok

Government of the United States of America - National Institute of Allergy and Infectious Diseases (NIAID) ( email )

Bethesda, MD 20814
United States

Daniel Comandé

Independent ( email )

Erin Goucher

Independent ( email )

Beate Kampmann

London School of Hygiene & Tropical Medicine - Vaccines and Immunity Theme ( email )

Atlantic Boulevard
Banjul
Gambia

Edward Parker

London School of Hygiene & Tropical Medicine - Department of Clinical Research ( email )

London
United Kingdom

Federico Rodriguez Cairoli

Instituto de Efectividad Clínica y Sanitaria - Centro de Investigación en Epidemiología y Salud Pública (IECS-CIESP) ( email )

Andy Stergachis

University of Washington - School of Public Health ( email )

Seattle, WA
United States

Gerald Voss

Coalition for Epidemic Preparedness Innovations ( email )

United States

Xu Xiong

Independent ( email )

Natalia Zamora

Independent ( email )

Pierre M. Buekens

Independent ( email )

Sabra Zaraa

School of Pharmacy and School of Public Health, University of Washington ( email )

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