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Cited by 143Pregnancy and Medication ImpactPharmacological Effects and Toxicity StudiesGestational Diabetes Research and Management

First-trimester exposure to metformin and risk of birth defects: a systematic review and meta-analysis

Cassina, Matteo, Donà, Marta, Di Gianantonio, Elena, Litta, Pietro, Clementi, Maurizio·2014·Human Reproduction Update
DOI 10.1093/humupd/dmu022
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Abstract

BACKGROUND: Metformin is generally considered a non-teratogenic drug; however, only a few studies specifically designed to assess the rate of congenital anomalies after metformin use have been published in the literature. The objects of the present study were to review all of the prospective and retrospective studies reporting on women treated with metformin at least during the first trimester of their pregnancy and to estimate the overall rate of major birth defects. METHODS: Databases were searched for English language articles until December 2013. Inclusion criteria for the meta-analysis were: a case group of women with PCOS or pre-pregnancy type 2 diabetes and first-trimester exposure to metformin; a disease-matched control group which was not exposed to metformin or other oral anti-diabetic agents; and a list of the major anomalies in both the study and the control groups. A random effects model was used for the meta-analysis of data, using odds ratios. Studies not fulfilling the inclusion criteria for the meta-analysis but reporting relevant data on major malformations in women diagnosed with PCOS were then used to estimate the overall birth defects rate. RESULTS: Meta-analysis of nine controlled studies with women affected by PCOS detected that the rate of major birth defects in the metformin-exposed group was not statistically increased compared with the disease-matched control group and that there was no significant heterogeneity among the studies. The metformin-exposed sample was composed of 351 pregnancies and the OR of major birth defects was 0.86 (95% confidence interval: 0.18-4.08; Pheterogeneity = 0.71). By evaluating all of the non-overlapping PCOS studies reported in the literature, even those without an appropriate control group, the overall rate of major anomalies was 0.6% in the sample of 517 women who discontinued the therapy upon conception or confirmation of pregnancy and 0.5% in the sample of 634 women who were treated with metformin throughout the first trimester of their pregnancy. Regarding type 2 diabetic women, we did not identify a sufficient number of studies with metformin exposure during the first trimester to proceed with the meta-analysis. CONCLUSIONS: There is currently no evidence that metformin is associated with an increased risk of major birth defects in women affected by PCOS and treated during the first trimester. However larger ad hoc studies are warranted in order to definitely confirm the safety and efficacy of this drug in pregnancy.

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Crossref · 10.1093/humupd/dmu022

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Authors
Cassina, M., Donà, M., Di Gianantonio, E., Litta, P., & Clementi, M.
Affiliations
University of Padua (IT)
Corresponding author
Clementi, Maurizio
ORCID
Venue
Human Reproduction Update
Publisher
Oxford University Press (OUP)
Published
2014-05-25
Volume
20
Issue
5
Pages
656-669
ISSN
  • 1355-4786 (ISSN-L)
  • 1460-2369
DOI
10.1093/humupd/dmu022
OpenAlex
W2131158789
Cited by
143
References
117
Citations by year
2026: 6 · 2025: 6 · 2024: 9 · 2023: 12 · 2022: 8 · 2021: 12 · 2020: 11 · 2019: 14 · 2018: 25 · 2017: 16 · 2016: 8 · 2015: 16
FWCI
2.08
Type
journal article
Language
en
Open access
closed
Locations
  • Human Reproduction Update (publishedVersion)
  • PubMed (publishedVersion)
  • HighWire Press Open Archive (submittedVersion)
  • Padua Research Archive (University of Padova) (submittedVersion)
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Pregnancy and Medication Impact
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmacological Effects and Toxicity Studies
  • Health Sciences › Medicine › Obstetrics and Gynecology › Gestational Diabetes Research and Management
Keywords
metformin, first trimester drug exposure, congenital malformations, polycystic ovary syndrome, type 2 diabetes, drug safety in pregnancy, teratogenicity
MeSH terms
Abnormalities, Drug-Induced, Female, Humans, Hypoglycemic Agents, Infant, Newborn, Maternal-Fetal Exchange, Metformin, Polycystic Ovary Syndrome, Pregnancy, Pregnancy Complications, Pregnancy in Diabetics, Pregnancy Trimester, First, Prenatal Exposure Delayed Effects, Prospective Studies, Retrospective Studies

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