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Intrauterine metformin exposure and adiposity outcomes in children: a systematic review and meta-analysis
Jennifer Fu1, Najla Tabbara2, George Tomlinson1,3
1Department of Medicine, University of Toronto Faculty of Medicine, Toronto, Ontario, Canada.
Insights
Intrauterine metformin exposure did not significantly alter offspring adiposity in later childhood. This systematic review supports the long-term safety of metformin use during pregnancy for children.
Area of Science:
- Reproductive Medicine
- Pediatric Endocrinology
- Clinical Pharmacology
Background:
- Metformin is frequently used in pregnancy for insulin-resistant conditions.
- Long-term effects of in utero metformin exposure on offspring adiposity are not fully understood.
Purpose of the Study:
- To systematically review and meta-analyze the effect of intrauterine metformin exposure on childhood adiposity measures.
Main Methods:
- Systematic review and meta-analysis of 18 studies including over 7975 exposed and 1 million unexposed children.
- Searched Medline, Embase, and Cochrane Central up to October 2024.
- Assessed risk of bias and certainty of evidence using GRADE methodology.
Main Results:
- No significant difference in body mass index (BMI) was observed in metformin-exposed children at the oldest follow-up age (mean 4.4 years).
- Slightly higher BMI was noted between 1-3 years, but differences resolved by 3-11 years.
- No differences in overweight, obesity, or waist circumference were found; however, a subgroup analysis for polycystic ovary syndrome (PCOS) showed increased BMI in exposed children.
Conclusions:
- Children exposed to metformin in utero do not exhibit altered adiposity measures in later childhood.
- Findings support the established safety profile of metformin use during pregnancy.
Objective:
The study aims to assess the effect of intrauterine metformin exposure on offspring adiposity measures in childhood.
Design:
Systematic review and meta-analysis.
Data Sources:
Medline, Embase and Cochrane Central were searched from inception to 4 October 2024.
Eligibility Criteria For Selecting Studies:
Follow-up studies of randomised-controlled trials and observational studies involving metformin use in pregnancy for any insulin-resistant maternal condition were included.
Data Extraction And Synthesis:
Two reviewers independently extracted data and completed risk-of-bias assessments using either Cochrane Risk-Of-Bias tool V.2 or Risk of Bias in Non-Randomised Studies of Exposure depending on study design. Meta-analyses were conducted using the generic inversed variance method in a random-effects model. Grading of Recommendations Assessment, Development and Evaluation methodology was used to assess certainty of evidence.
Results:
18 studies reporting on 7975 children with metformin exposure in utero and over 1 million children without metformin exposure were included. At the oldest age of follow-up reported (weighted mean age of 4.4 years), children with metformin exposure for any maternal indication had comparable body mass index (BMI) with their non-exposed peers (standardised mean difference (SMD) -0.02; 95% CI: -0.11, 0.07; low certainty). When stratified by age at follow-up, while metformin-exposed children had slightly higher BMI at 1-3 years of age (SMD 0.15; 95% CI: 0.04, 0.27; low certainty), no difference remained between the two groups by ages 3-6 and 6-11 years. When stratified by maternal diagnosis, no difference in BMI was found in the diabetes and obesity subgroups, while in the polycystic ovary syndrome subgroup metformin-exposed children were heavier than non-exposed peers (SMD 0.31; 95% CI: 0, 0.62; low certainty). No difference was seen in overweight, obesity or waist circumference.
Conclusions:
Metformin-exposed children did not differ in adiposity measures compared with their non-exposed peers in later childhood. This adds to the growing body of evidence supporting the long-term safety of metformin use in pregnancy.
Prospero Registration Number:
CRD42023394464.
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