Does metformin reduce excess birthweight in offspring of obese pregnant women? A randomised controlled trial of efficacy, exploration of mechanisms and evaluation of other pregnancy complications: Metformin taken by obese pregnant women did not reduce their baby's birthweight.

Carolyn Chiswick, Rebecca Reynolds, Fiona Denison, Amanda Drake, Shareen Forbes, David Newby, Brian Walker, Siobhan Quenby, Susan Wray, Andrew Weeks, Hany Lashen, Gordon Murray, Sonia Whyte, Ruth Andrew, Natalie Homer, Scott Semple, Calum Gray, Marian Aldhous, Karen Noble, Sarah Cunningham-BurleyJane Norman

Research output: Contribution to journalArticle (Academic Journal)peer-review

113 Downloads (Pure)

Abstract

Background
Maternal obesity is associated with high birthweight, obesity and premature mortality in adult offspring, probably as a result of maternal hyperglycaemia and insulin resistance. We present the results of a trial designed to test the hypothesis that metformin will improve insulin sensitivity in obese pregnant women, thereby reducing the incidence of high-birthweight babies.

Objective
To determine the efficacy of metformin (up to 2500 mg daily) given to obese pregnant women in reducing the gestational age-, parity- and sex-adjusted birthweight centile of the baby.

Design
Double-blind, placebo-controlled, randomised controlled trial with embedded substudies.

Setting
Fifteen NHS hospitals in the UK.

Participants
Pregnant women aged ≥ 16 years with a singleton fetus and a body mass index of ≥ 30 kg/m2.

Intervention
Metformin tablets (or placebo) administered between 12 and 16 weeks’ gestation until delivery of the baby.

Main outcome measures
The primary outcome measure was z-score corresponding to the gestational age-, parity- and sex-adjusted birthweight centile of live-born babies delivered at ≥ 24 weeks’ gestation. The main secondary outcome was maternal insulin resistance at 36 weeks’ gestation. Embedded substudies were included to assess the effect of metformin on insulin sensitivity using the hyperinsulinaemic–euglycaemic clamp; endothelial function; maternal and fetal fat distribution using magnetic resonance imaging; placental expression of 11β-hydroxysteroid dehydrogenase types 1 and 2 and glucocorticoid receptor; and myometrial contractility and glycogen storage.

Results
We randomised 449 women to either placebo (n = 223) or metformin (n = 226), of whom 434 were included in the final intention-to-treat analysis. Mean birthweight at delivery was 3463 g [standard deviation (SD) 660 g] in the placebo group and 3462 g (SD 548 g) in the metformin group. The estimated effect size of metformin on the primary outcome was non-significant [adjusted mean difference in z-score –0.029, 95% confidence interval (CI) –0.217 to 0.158; p = 0.7597]. There was no evidence of a reduction in the main secondary outcome of homeostatic model assessment – insulin resistance (HOMA-IR) at 36 weeks’ gestation (mean HOMA-IR 5.98 and 6.30 molar units in the placebo and metformin groups, respectively; adjusted mean ratio 0.974, 95% CI 0.865 to 1.097). Metformin had no effect on the combined adverse outcome of miscarriage, termination of pregnancy, stillbirth or neonatal death. Subjects taking metformin demonstrated increased insulin sensitivity [glucose disposal per unit plasma insulin difference between means during high-dose insulin 0.02 mg/kg, 95% CI 0.001 to 0.03 mg/kg (fat-free mass)/minute/µIU/l; p = 0.04] compared with those taking placebo and enhanced endogenous glucose production [difference between means 0.54 mg/kg, 95% CI 0.08 to 1.00 mg/kg (fat-free mass)/minute; p = 0.02]. There were no differences in endothelial function, maternal or fetal body fat distribution, placental expression of 11β-hydroxysteroid dehydrogenase types 1 and 2 and glucocorticoid receptor, or myometrial contractility and glycogen storage.

Conclusions
Metformin has no clinically significant effect on birthweight centile in obese pregnant women. Follow-up studies of the children born to participants in the trial are required to determine whether or not there are any longer-term benefits or harms of maternal metformin for offspring weight, fat mass or metabolism.
Original languageEnglish
Number of pages802
JournalEfficacy and Mechanism Evaluation
Volume3
Issue number7
DOIs
Publication statusPublished - 31 Aug 2016

Bibliographical note

RIS file

Fingerprint

Dive into the research topics of 'Does metformin reduce excess birthweight in offspring of obese pregnant women? A randomised controlled trial of efficacy, exploration of mechanisms and evaluation of other pregnancy complications: Metformin taken by obese pregnant women did not reduce their baby's birthweight.'. Together they form a unique fingerprint.

Cite this