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



Chiswick, Carolyn A, Reynolds, Rebecca M, Denison, Fiona C ORCID: 0000-0003-0371-2014, Drake, Amanda J, Forbes, Shareen, Newby, David E, Walker, Brian R, Quenby, Siobhan ORCID: 0000-0003-3221-5471, Wray, Susan ORCID: 0000-0002-0086-1359, Weeks, Andrew ORCID: 0000-0002-1909-337X
et al (show 13 more authors) (2016) 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.

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Chiswick et al. Efficacy and Mechanism Evaluation 3.7 2016 vol 3 issue 7.pdf - OA Published Version

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Abstract

<h4>Background</h4>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.<h4>Objective</h4>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.<h4>Design</h4>Double-blind, placebo-controlled, randomised controlled trial with embedded substudies.<h4>Setting</h4>Fifteen NHS hospitals in the UK.<h4>Participants</h4>Pregnant women aged ≥ 16 years with a singleton fetus and a body mass index of ≥ 30 kg/m2.<h4>Intervention</h4>Metformin tablets (or placebo) administered between 12 and 16 weeks’ gestation until delivery of the baby.<h4>Main outcome measures</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>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.<h4>Trial registration</h4>Current Controlled Trials ISRCTN51279843.<h4>Funding</h4>This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research partnership.

Item Type: Article
Depositing User: Symplectic Admin
Date Deposited: 09 Feb 2017 08:46
Last Modified: 08 Apr 2022 15:10
URI: https://livrepository.liverpool.ac.uk/id/eprint/3005628