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Diabetes Ther. 2018 Oct;9(5):1811-1829. doi: 10.1007/s13300-018-0479-0. Epub 2018 Aug 30.

Long-Term Effects of Oral Antidiabetic Drugs During Pregnancy on Offspring: A Systematic Review and Meta-analysis of Follow-up Studies of RCTs.

Author information

1
Department of Obstetrics and Gynaecology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
2
Department of Obstetrics and Gynaecology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands. v.wekker@amc.nl.
3
Amsterdam Reproduction and Development Research Institute, Amsterdam UMC, Amsterdam, The Netherlands. v.wekker@amc.nl.
4
Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands. v.wekker@amc.nl.
5
Amsterdam Public Health Research Institute, Amsterdam UMC, Amsterdam, The Netherlands. v.wekker@amc.nl.
6
Department of Gynaecology and Obstetrics, Wilhelmina Children's Hospital Birth Centre, University Medical Centre Utrecht, Utrecht, The Netherlands.
7
Medical Library, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
8
Department of Obstetrics and Gynaecology, Oulu University Hospital, Oulu, Finland.
9
Amsterdam Reproduction and Development Research Institute, Amsterdam UMC, Amsterdam, The Netherlands.
10
Department of Neonatology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
11
Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
12
Amsterdam Public Health Research Institute, Amsterdam UMC, Amsterdam, The Netherlands.
13
Department of Endocrinology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Abstract

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 available for this article.

KEYWORDS:

Cardiometabolic health; Child development; Gestational diabetes; Insulin; Metformin; Oral antidiabetic drugs; Polycystic ovary; Pregnancy; Prenatal exposure; Syndrome; Systematic review

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