Does metformin reduce excess birthweight in offspring of obese pregnant women?

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Scientific Abstract|AIM: The aim of this study is to determine if metformin, administered to obese women during pregnancy, reduces the future life risk of obesity and metabolic syndrome in their babies. We will use high birthweight centile as a surrogate marker for future life events as its validity has been shown in large epidemiological studies [1-3]. Secondly, we will use metformin administration as a tool to explore the mechanism by which obesity causes adverse pregnancy outcomes, with a particular focus on insulin resistance (IR). |DESIGN: Double blind placebo controlled randomised clinical trial. |SETTING: Antenatal clinics specialising in the care of obese pregnant women in two large maternity hospitals in the UK (Edinburgh and Liverpool). |TARGET POPULATION: Obese pregnant women.|INTERVENTIONS BEING EVALUATED: Metformin, an insulin sensitising agent or matched placebo initiated between 12 and 16 weeks gestation. |PRIMARY OUTCOMES: (i) Efficacy outcome - z-score corresponding to the gestational age and sex adjusted birthweight centiles of the baby (ii) Mechanistic outcome - maternal insulin resistance (IR) at 36 weeks gestation which will be correlated with adverse pregnancy outcomes. |SECONDARY OUTCOMES: (A) More detailed measurements of neonatal body composition at birth including ponderal index; skinfold thicknesses; and (Edinburgh babies only) neonatal fat mass measured using air displacement plethysmography. (B) Biological mechanisms of metformin action including (i) change in IR; hepatic and skeletal insulin sensitivity (ii) maternal and neonatal inflammatory and lipid indices including CRP, IL-6, leptin, lipids, triglycerides and PAI1/PAI2 ratio (iii) placental glucocorticoid receptor expression (iv) maternal brachial arterial endothelial dependent flow mediated dilatation (FMD) (v) in vitro measurements of maternal myometrial contractility [4] (vi) changes in maternal anthrometry. (C) Adverse pregnancy outcomes as a composite; incidence of low birthweight centile. (D) Gas chromatography mass spectrometry measurements of metformin in maternal plasma to determine compliance.|MEASUREMENT OF OUTCOME AND DURATION OF FOLLOW UP. Birthweight will be measured by clinical staff, the result prospectively transferred from the clinical birth record to a case report form and Z score of birthweight centile calculated using www.gestation.net. Maternal IR at 36 weeks gestation will be expressed as the Matsuda index [5] (the best correlate with the gold standard the hyperinsulinaemic euglycaemic clamp in pregnant women)[6], and derived from multiple sampling during a glucose tolerance test. Change in IR will be expressed as changes in a logarithmic and reciprocal transformation of a single fasting glucose and insulin value (QUICKI), measured during a glucose tolerance test at baseline (prior to treatment), at 28 weeks and at 36 weeks gestation [6]. |In a subgroup of women (n = 20 in each group) insulin resistance will be measured by the hyperinsulinaemic euglycaemic clamp, to characterise the relative effects of metformin on hepatic and peripheral skeletal muscle insulin sensitivity. Endothelial dependent FMD will be measured in a subset (n = 30 each group) at 36 weeks gestation using a non invasive, validated, and reproducible method suitable for use in pregnancy [7 8]. Initial follow up will cease once the woman and baby have been discharged postnatally, although we anticipate further funding applications to continue neonatal follow up into early childhood.|SAMPLE SIZE: |(1) BIRTHWEIGHT CENTILE. In a previous study, the mean (SD) birthweight in a cohort of obese women (mean BMI 34) was 4.0kg (0.6kg)[9]. We hypothesise that metformin will reduce mean birthweight by 200g, corresponding to a reduction in birthweight centile of 0.3 SD. We believe that this reduction in birthweight centile is clinically relevant, but is a relatively conservative estimate of likely reduction in birthweight centile induced by metformin, given that m