Major malformations risk following early pregnancy exposure to metformin: a systematic review and meta-analysis

Nazanin Abolhassani, Ursula Winterfeld, Yusuf C Kaplan, Cécile Jaques, Beatrice Minder Wyssmann, Cinzia Del Giovane, Alice Panchaud, Nazanin Abolhassani, Ursula Winterfeld, Yusuf C Kaplan, Cécile Jaques, Beatrice Minder Wyssmann, Cinzia Del Giovane, Alice Panchaud

Abstract

Metformin is considered as first-line treatment for type 2 diabetes and an effective treatment for polycystic ovary syndrome (PCOS). However, evidence regarding its safety in pregnancy is limited. We conducted a systematic review and meta-analysis of major congenital malformations (MCMs) risk after first-trimester exposure to metformin in women with PCOS and pregestational diabetes mellitus (PGDM). Randomized controlled trials (RCTs) and observational cohort studies with a control group investigating risk of MCM after first-trimester pregnancy exposure to metformin were searched until December 2021. ORs and 95% CIs were calculated separately according to indications and study type using Mantel-Haenszel method; outcome data were combined using random-effects model. Eleven studies (two RCTs; nine observational cohorts) met the inclusion criteria: four included pregnant women with PCOS, four included those with PGDM and three evaluated both indications separately and were considered in both indication groups. In PCOS group, there were two RCTs (57 exposed, 52 control infants) and five observational studies (472 exposed, 1892 control infants); point estimates for MCM rates in RCTs and observational studies were OR 0.93 (95% CI 0.09 to 9.21) (I2=0%; Q test=0.31; p value=0.58) and OR 1.35 (95% CI 0.37 to 4.90) (I2=65%; Q test=9.43; p value=0.05), respectively. In PGDM group, all seven studies were observational (1122 exposed, 1851 control infants); the point estimate for MCM rates was OR 1.05 (95% CI 0.50 to 2.18) (I2=59%; Q test=16.34; p value=0.01). Metformin use in first-trimester pregnancy in women with PCOS or PGDM do not meaningfully increase the MCM risk overall. However, further studies are needed to characterize residual safety concerns.

Keywords: Metformin; Polycystic Ovary Syndrome; Pregnancy; Type 2 Diabetes.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
Meta-analysis of overall major congenital malformation (MCM) rates in metformin-exposed women with polycystic ovary syndrome (PCOS).
Figure 2
Figure 2
Meta-analysis of overall major congenital malformation (MCM) rates in metformin-exposed women with pregestational diabetes mellitus (PGDM).

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