University of Oulu

van Weelden, W., Wekker, V., de Wit, L. et al. Diabetes Ther (2018) 9: 1811.

Long-term effects of oral antidiabetic drugs during pregnancy on offspring : a systematic review and meta-analysis of follow-up studies of RCTs

Saved in:
Author: van Weelden, Wenneke1; Wekker, Vincent1,2,3,4; de Wit, Leon5;
Organizations: 1Department of Obstetrics and Gynaecology, Amsterdam UMC, University of Amsterdam
2Amsterdam Reproduction and Development Research Institute, Amsterdam UMC
3Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam UMC, University of Amsterdam
4Amsterdam Public Health Research Institute, Amsterdam UMC
5Department of Gynaecology and Obstetrics, Wilhelmina Children’s Hospital Birth Centre, University Medical Centre Utrecht
6Medical Library, Amsterdam UMC, University of Amsterdam
7Department of Obstetrics and Gynaecology, Oulu University Hospital
8Department of Neonatology, Emma Children’s Hospital, Amsterdam UMC, University of Amsterdam
9Department of Endocrinology, Amsterdam UMC, University of Amsterdam
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.1 MB)
Persistent link:
Language: English
Published: Springer Nature, 2018
Publish Date: 2018-11-12


Introduction: Antidiabetic drugs (OADs) are increasingly prescribed to treat hyperglycaemia during pregnancy in women with gestational diabetes mellitus (GDM) or polycystic ovary syndrome (PCOS), even though long-term effects on offspring are unknown. This systematic review summarises the evidence of follow-up studies of randomised controlled trials (RCTs) reporting on long-term effects of prenatal exposure to OADs on offspring.

Methods: The MEDLINE, EMBASE and CENTRAL databases were searched from inception to April 2018 for the concepts antidiabetic agents and prenatal exposure (or pregnancy and offspring/child) in combination with an RCT search filter. RCTs evaluating post-neonatal health effects in offspring and comparing maternal treatment with an OAD with no treatment, placebo, an alternative OAD or insulin during pregnancy were eligible for inclusion. Two independent researchers selected, extracted and assessed the data. Meta-analyses were performed using a random effects model and the Cochrane Collaboration’s risk of bias tool was used for quality assessment.

Results: Ten studies were included, with a maximal follow-up duration of 9 years, comprising 778 children of mothers with GDM or PCOS who were randomised to either metformin or insulin/placebo during pregnancy. Meta-analysis showed that children prenatally exposed to metformin were heavier compared to controls (standardised mean difference (SMD) 0.26 [95% CI 0.11–0.41]), but not taller (SMD 0.10 [95% CI −0.14–0.33]). Additionally, offspring body mass index (BMI) z scores did not differ according to metformin exposure (mean difference 0.30 [95% CI −0.01–0.61]). Individual small studies reported that prenatal exposure to metformin was associated with greater mid-upper arm, head and waist circumferences, biceps skinfolds, waist-to-height ratio, more arm fat, higher fasting glucose, ferritin and lower LDL cholesterol in offspring.

Conclusion: Prenatal exposure to metformin is associated with increased offspring weight, but not with height or BMI. Larger follow-up studies are needed to confirm and look into the implications of these findings.

Plain language summary: Plain language summary available for this article.

see all

Series: Diabetes therapy
ISSN: 1869-6953
ISSN-E: 1869-6961
ISSN-L: 1869-6953
Volume: 9
Issue: 5
Pages: 1811 - 1829
DOI: 10.1007/s13300-018-0479-0
Type of Publication: A2 Review article in a scientific journal
Field of Science: 3121 General medicine, internal medicine and other clinical medicine
3123 Gynaecology and paediatrics
317 Pharmacy
Funding: V. Wekker is funded by the Dutch Heart Foundation grant: 2013T085. The funder had no part in the initiation of the study, nor in the analyses and interpretation. All authors had full access to all of the data in this study and take complete responsibility for the integrity of the data and accuracy of the data analysis. Article processing charges were funded by the authors.
Dataset Reference: Supplementary material:
Copyright information: © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (, which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.