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

Wenneke van Weelden, Vincent Wekker, Leon de Wit, Jacqueline Limpens, Hilkka Ijäs, Aleid G van Wassenaer-Leemhuis, Tessa J Roseboom, Bas B van Rijn, J Hans DeVries, Rebecca C Painter

Research output: Contribution to journalReview articlepeer-review

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: Plain language summary available for this article.

Original languageEnglish
Pages (from-to)1811-1829
Number of pages19
JournalDiabetes therapy : research, treatment and education of diabetes and related disorders
Volume9
Issue number5
Early online date30 Aug 2018
DOIs
Publication statusPublished - Oct 2018

Keywords

  • Journal Article
  • Review
  • Systematic review
  • Polycystic ovary
  • Insulin
  • Prenatal exposure
  • Syndrome
  • Pregnancy
  • Child development
  • Cardiometabolic health
  • Oral antidiabetic drugs
  • Gestational diabetes
  • Metformin

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