https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2854644?utm_campaign=articlePDF&utm_medium=articlePDFlink&utm_source=articlePDF&utm_content=jamanetworkopen.2026.37054

Metformin Exposure in Pregnancy and Childhood Developmental Outcomes

1. Hannah Gordon, MD1,2; Richard J. Hiscock, MBBS1,2; Sarah Price, PhD1,3
Alexis Shub, PhD1,2; Alexandra Roddy Mitchell, MPH1,2; Jessica Atkinson, BBiomedSc (Hons)1,2;

Susan Walker, MD1,2; Anna Forsythe, MEnv1,2; Stephen Tong, PhD1,2; Anthea Lindquist, DPhil1,2; Roxanne Hastie, PhD1,2

Key Points

Question

What is the association of metformin use during pregnancy with developmental outcomes among offspring during the first year of full-time school?
Findings In this cohort study of

177 409 singleton children born in Victoria, Australia, between 2009 and 2020,

no association was observed between metformin use during pregnancy and childhood developmental vulnerability (scoring ≤10th percentile on ≥2 of 5 assessed developmental domains using a national assessment tool) after accounting for confounding factors.

 

Meaning

These findings suggest that metformin in pregnancy is not associated with developmental vulnerability in children aged 4 to 6 years and may provide reassurance for clinicians and women considering metformin use during pregnancy.

 

 

 

Abstract
Importance

Metformin is an oral hypoglycemic agent increasingly prescribed during pregnancy. In animal models, metformin influences embryonic cortical development, and it is uncertain whether this translates to clinical implications for humans.

Objective

To examine whether metformin prescription in pregnancy is associated with a risk of developmental vulnerability among offspring at school entry.

Design, Setting, and Participants

This cohort study used population-level pregnancy and birth data from January 1, 2009, to December 31, 2020, linked with the Australian Early Development Census (AEDC), a standardized national assessment of childhood development completed every 3 years during the first year of full-time school (age 4-6 years). The data analysis was performed between March 14, 2025, and January 30, 2026.
Exposure Metformin prescription dispensation during pregnancy.

Main Outcome and Measures

The association of developmental vulnerability, defined as scoring below the 10th percentile in at least 2 of the 5 assessed domains of the AEDC (physical health and well-being, social competence, emotional maturity, school-based language and cognitive skills, and communication skills and general knowledge), was estimated using inverse probability of treatment weighting combined with regression adjustment.

Results

From 871 627 singleton births in Victoria between 2009 and 2020, 177 409 children with linked developmental outcome data were identified, of whom 1095 (0.6%) were exposed to metformin antenatally (43 [3.9%] aged ≤5 years 0 months, 860 [78.5%] aged 5 years 1 month to 6 years 0 months, and 192 [17.5%] aged ≥6 years 1 month at assessment; 557 male [50.9%]). Developmental vulnerability was observed in 199 children (18.2%) exposed to metformin compared with 24 379 children (13.9%) not exposed. After adjustment for confounders, metformin was not associated with developmental vulnerability among children exposed to metformin (adjusted relative risk, 0.97 [95% CI, 0.74-1.29]) or across any of the individual developmental domains.

Conclusions and Relevance

This cohort study found that metformin use in pregnancy was not associated with an altered risk of developmental vulnerability among children aged 4 to 6 years and may provide reassurance to clinicians and women considering metformin use during pregnancy.

 

 

From the article

Läs hela artikeln

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2854644?utm_campaign=articlePDF&utm_medium=articlePDFlink&utm_source=articlePDF&utm_content=jamanetworkopen.2026.37054

 

 

Introduction
Metformin is an oral hypoglycemic medication that is first-line treatment for type 2 diabetes.1 The use of metformin in pregnancy is increasing.2 During pregnancy, metformin crosses the placenta, with the fetus exposed to similar medication concentrations as that in the maternal blood stream,3 raising potential concerns about fetal harm. There are reassuring, short-term perinatal safety data,4,5 but long-term safety for exposed offspring remains incompletely described.6,7 Metformin may be associated with increased adiposity in childhood,8 but research in this area is conflicting9,10 and lacks follow-up into adulthood.

Considering neurodevelopmental implications, an animal study suggested that in utero exposure to metformin may cause impaired cortical development,11 but it remains unclear whether this is relevant to human offspring development. A recent systematic review of 7 studies observed no association between in utero metformin exposure and global neurodevelopmental delay in children younger than 2 years (relative risk [RR], 1.09 [95% CI, 0.54-2.17]; 3 studies; 9668 children) and aged 3 to 5 years (RR, 0.90 [95% CI, 0.56-1.45]; 2 studies; 6118 children).7 However, in this preschool age range, developmental delays may not yet be apparent. Furthermore, individual studies in this area have been limited by small sample sizes and heterogeneous study populations, with metformin prescribed for diverse indications.8,12

Larger studies focusing on outcomes for school-aged children are needed to provide evidence for women and their clinicians considering metformin use during pregnancy. Using population-level data from Victoria, Australia, we investigated whether antenatal metformin exposure during pregnancy was associated with an altered risk of developmental vulnerability on a national assessment among offspring during the first year of full-time school.

 

Discussion
This cohort study of 177 409 children in Victoria, Australia, found no association between metformin prescription in pregnancy and developmental vulnerability in the first year of full-time school. No association was observed across all assessed developmental domains from the AEDC and with restriction of the cohort to include only women with gestational diabetes or type 2 diabetes in pregnancy.
To date, there have only been 2 other observational studies that examined the association of metformin use in pregnancy with childhood development.28,29 The first included a cohort of 1681 children born to women with gestational diabetes, which observed no association between metformin exposure and teacher-assessed offspring behavioral difficulties prior to school entry.28 Our analysis supports this finding in an older group of children both after restricting the cohort to include only women with gestational diabetes or type 2 diabetes and in our primary analysis, which included children whose mothers were prescribed metformin for any indication. This finding is particularly relevant given the off-label prescription of metformin for nondiabetes indications, including treatment for polycystic ovary syndrome and obesity.30,31
The second study observed no association between metformin exposure and challenges in offspring motor-social development at various ages (2114 children exposed to metformin at age 3-5 years, 899 at age 6-8 years, and 290 at age 9-11 years) based on International Statistical Classification of Diseases, Tenth Revision codes.29 Our findings are also consistent with this study, though our study considers development across a range of domains rather than by diagnostic criteria. Children from lower socioeconomic backgrounds are less able to access and receive developmental diagnoses,32,33 and using a nationally performed assessment tool, as we have done, ensures that these children are not misclassified as developmentally on track.
The 5 randomized clinical trials in this area were small and typically used short follow-up (eg, into infancy) but, reassuringly, also demonstrated no association between metformin use and adverse offspring neurodevelopment.34-38 Overall, our study is in keeping with current research observing no association between in utero metformin exposure and adverse childhood neurodevelopment.

 

 

Läs hela artikeln open source free pdf

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2854644?utm_campaign=articlePDF&utm_medium=articlePDFlink&utm_source=articlePDF&utm_content=jamanetworkopen.2026.37054

 

 

Nyhetsinfo

www red DiabetologNytt