Effect of metformin on maternal and fetal outcomes in obese pregnant women (EMPOWaR): a randomised, double-blind, placebo-controlled trial

Carolyn Chiswick, Rebecca M Reynolds, Fiona Denison, Amanda J Drake, Shareen Forbes, David E Newby, Brian R Walker, Siobhan Quenby, Susan Wray, Andrew Weeks, Hany Lashen, Aryelly Rodriguez, Gordon Murray, Sonia Whyte, Jane E Norman, Carolyn Chiswick, Rebecca M Reynolds, Fiona Denison, Amanda J Drake, Shareen Forbes, David E Newby, Brian R Walker, Siobhan Quenby, Susan Wray, Andrew Weeks, Hany Lashen, Aryelly Rodriguez, Gordon Murray, Sonia Whyte, Jane E Norman

Abstract

Background: Maternal obesity is associated with increased birthweight, and obesity and premature mortality in adult offspring. The mechanism by which maternal obesity leads to these outcomes is not well understood, but maternal hyperglycaemia and insulin resistance are both implicated. We aimed to establish whether the insulin sensitising drug metformin improves maternal and fetal outcomes in obese pregnant women without diabetes.

Methods: We did this randomised, double-blind, placebo-controlled trial in antenatal clinics at 15 National Health Service hospitals in the UK. Pregnant women (aged ≥16 years) between 12 and 16 weeks' gestation who had a BMI of 30 kg/m(2) or more and normal glucose tolerance were randomly assigned (1:1), via a web-based computer-generated block randomisation procedure (block size of two to four), to receive oral metformin 500 mg (increasing to a maximum of 2500 mg) or matched placebo daily from between 12 and 16 weeks' gestation until delivery of the baby. Randomisation was stratified by study site and BMI band (30-39 vs ≥40 kg/m(2)). Participants, caregivers, and study personnel were masked to treatment assignment. The primary outcome was Z score corresponding to the gestational age, parity, and sex-standardised birthweight percentile of liveborn babies delivered at 24 weeks or more of gestation. We did analysis by modified intention to treat. This trial is registered, ISRCTN number 51279843.

Findings: Between Feb 3, 2011, and Jan 16, 2014, inclusive, we randomly assigned 449 women to either placebo (n=223) or metformin (n=226), of whom 434 (97%) were included in the final modified intention-to-treat analysis. Mean birthweight at delivery was 3463 g (SD 660) in the placebo group and 3462 g (548) in the metformin group. The estimated effect size of metformin on the primary outcome was non-significant (adjusted mean difference -0·029, 95% CI -0·217 to 0·158; p=0·7597). The difference in the number of women reporting the combined adverse outcome of miscarriage, termination of pregnancy, stillbirth, or neonatal death in the metformin group (n=7) versus the placebo group (n=2) was not significant (odds ratio 3·60, 95% CI 0·74-17·50; p=0·11).

Interpretation: Metformin has no significant effect on birthweight percentile in obese pregnant women. Further follow-up of babies born to mothers in the EMPOWaR study will identify longer-term outcomes of metformin in this population; in the meantime, metformin should not be used to improve pregnancy outcomes in obese women without diabetes.

Funding: The Efficacy and Mechanism Evaluation (EME) Programme, a Medical Research Council and National Institute for Health Research partnership.

Copyright © 2015 Chiswick et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.

Figures

Figure
Figure
Trial profile *Change in eligibility from screening of notes to recruitment visit (unable to arrange recruitment visit before 16 weeks [n=26]), recruitment stopped before screening appointment (n=14), miscarriage (n=2), moved out of area (n=1), unable to provide informed consent because of difficulties with spoken English (n=5), own doctor or midwife advised against participation (n=4), duplicate note screening number issued in error (n=4). †3 months after birth.

References

    1. O'Brien TE, Ray JG, Chan WS. Maternal body mass index and the risk of preeclampsia: a systematic overview. Epidemiology. 2003;14:368–374.
    1. Johansson S, Villamor E, Altman M, Bonamy AK, Granath F, Cnattingius S. Maternal overweight and obesity in early pregnancy and risk of infant mortality: a population based cohort study in Sweden. BMJ. 2014;349:g6572.
    1. Heslehurst N, Simpson H, Ells LJ. The impact of maternal BMI status on pregnancy outcomes with immediate short-term obstetric resource implications: a meta-analysis. Obes Rev. 2008;9:635–683.
    1. Starling AP, Brinton JT, Glueck DH. Associations of maternal BMI and gestational weight gain with neonatal adiposity in the Healthy Start study. Am J Clin Nutrit. 2015;101:302–309.
    1. Curhan GC, Willett WC, Rimm EB, Spiegelman D, Ascherio AL, Stampfer MJ. Birth weight and adult hypertension, diabetes mellitus, and obesity in US men. Circulation. 1996;94:3246–3250.
    1. Curhan GC, Chertow GM, Willett WC. Birth weight and adult hypertension and obesity in women. Circulation. 1996;94:1310–1315.
    1. Parsons TJ, Power C, Logan S, Summerbell CD. Childhood predictors of adult obesity: a systematic review. Int J Obes Relat Metab Disord. 1999;23(suppl 8):S1–107.
    1. Graversen L, Sorensen TI, Gerds TA. Prediction of adolescent and adult adiposity outcomes from early life anthropometrics. Obesity. 2015;23:162–169.
    1. Surkan PJ, Hsieh CC, Johansson AL, Dickman PW, Cnattingius S. Reasons for increasing trends in large for gestational age births. Obstet Gynecol. 2004;104:720–726.
    1. Reynolds RM, Allan KM, Raja EA. Maternal obesity during pregnancy and premature mortality from cardiovascular event in adult offspring: follow-up of 1 323 275 person years. BMJ. 2013;347:f4539.
    1. Catalano PM, Ehrenberg HM. The short- and long-term implications of maternal obesity on the mother and her offspring. BJOG. 2006;113:1126–1133.
    1. Scholl TO, Sowers M, Chen X, Lenders C. Maternal glucose concentration influences fetal growth, gestation, and pregnancy complications. Am J Epidemiol. 2001;154:514–520.
    1. Metzger BE, Lowe LP, Dyer AR. Hyperglycemia and adverse pregnancy outcomes. N Engl J Med. 2008;358:1991–2002.
    1. Eames AJ, Grivell RM, Deussen AR, Hague W, Dodd JM. Metformin for women who are obese during pregnancy for improving maternal and infant outcomes. Cochrane Database Syst Rev. 2013;6 CD010564.
    1. Chiswick CA, Reynolds RM, Denison FC. Efficacy of metformin in pregnant obese women: a randomised controlled trial. BMJ Open. 2015;5:e006854.
    1. Boney CM, Verma A, Tucker R, Vohr BR. Metabolic syndrome in childhood: association with birth weight, maternal obesity, and gestational diabetes mellitus. Pediatrics. 2005;115:e290–e296.
    1. International Association of Diabetes Pregnancy Study Groups Consensus Panel. Metzger BE, Gabbe SG, Persson B. International Association of Diabetes and Pregnancy Study Groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care. 2010;33:676–682.
    1. Stewart FM, Freeman DJ, Ramsay JE, Greer IA, Caslake M, Ferrell WR. Longitudinal assessment of maternal endothelial function and markers of inflammation and placental function throughout pregnancy in lean and obese mothers. J Clin Endocrinol Metab. 2007;92:969–975.
    1. Bonellie S, Chalmers J, Gray R, Greer I, Jarvis S, Williams C. Centile charts for birthweight for gestational age for Scottish singleton births. BMC Pregnancy Childbirth. 2008;8:5.
    1. Thangaratinam S, Rogozinska E, Jolly K. Effects of interventions in pregnancy on maternal weight and obstetric outcomes: meta-analysis of randomised evidence. BMJ. 2012;344:e2088.
    1. Dodd JM, Cramp C, Sui Z, for the Limit Randomised Trial Group The effects of antenatal dietary and lifestyle advice for women who are overweight or obese on maternal diet and physical activity: the LIMIT randomised trial. BMC Med. 2014;12:161.
    1. Poston L, Bell R, Croker H. Effect of a behavioural intervention in obese pregnant women (the UPBEAT study): a multicentre, randomised controlled trial. Lancet Diabetes Endocrinol. 2015 published online July 10.
    1. Vanky E, Stridsklev S, Heimstad R. Metformin versus placebo from first trimester to delivery in polycystic ovary syndrome: a randomized, controlled multicenter study. J Clin Endocrinol Metab. 2010;95:E448–E455.
    1. Catov JM, Bodnar LM, Ness RB, Barron SJ, Roberts JM. Inflammation and dyslipidemia related to risk of spontaneous preterm birth. Am J Epidemiol. 2007;166:1312–1319.
    1. Xu L, Lee M, Jeyabalan A, Roberts JM. The relationship of hypovitaminosis D and IL-6 in preeclampsia. Am J Obstet Gynecol. 2014;210:149. e1–7.
    1. Goldberg RB, Temprosa MG, Mather KJ, Orchard TJ, Kitabchi AE, Watson KE, Diabetes Prevention Program Research Group Lifestyle and metformin interventions have a durable effect to lower CRP and tPA levels in the diabetes prevention program except in those who develop diabetes. Diabetes Care. 2014;37:2253–2260.
    1. Xu X, Du C, Zheng Q, Peng L, Sun Y. Effect of metformin on serum interleukin-6 levels in polycystic ovary syndrome: a systematic review. BMC Womens Health. 2014;14:93.
    1. Pedersen J. Diabetes and pregnancy: blood sugar of newborn infants. Danish Science Press; Copenhagen: 1952.
    1. Catalano PM, Hauguel-De Mouzon S. Is it time to revisit the Pedersen hypothesis in the face of the obesity epidemic? Am J Obstet Gynecol. 2011;204:479–487.
    1. Salomaki H, Heinaniemi M, Vahatalo LH. Prenatal metformin exposure in a maternal high fat diet mouse model alters the transcriptome and modifies the metabolic responses of the offspring. PLoS One. 2014;9:e115778.
    1. Rowan JA, Hague WM, Gao W, Battin MR, Moore MP. Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med. 2008;358:2003–2015.

Source: PubMed

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir