Title: 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.
Funder: Chief Scientist Office (Scotland)

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. 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 in maternity hospitals in the UK.TARGET POPULATION: Obese (BMI>30kg/m2) pregnant women.INTERVENTIONS BEING EVALUATED: Metformin an insulin sensitising agent or matched placebo initiated between 12 and 16 weeks gestation. PRIMARY OUTCOME: Efficacy outcome – z-score corresponding to the gestational age and sex adjusted birth weight centiles of the baby. SECONDARY OUTCOMES: (i) Mechanistic outcome - maternal insulin resistance (IR) at 36 weeks gestation. (ii) 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. (iii) Biological mechanisms of metformin action including (a) change in whole body IR; hepatic and skeletal insulin sensitivity (b) maternal and neonatal inflammatory and lipid indices including CRP IL-6 leptin lipids triglycerides and PAI1/PAI2 ratio (c) placental glucocorticoid receptor expression (d) maternal brachial arterial endothelial dependent flow mediated dilatation (FMD) (e) in vitro measurements of maternal myometrial contractility.(iv) Maternal fetal and neonatal anthrometry. (v) Adverse pregnancy outcomes as a composite; incidence of low birthweight centile. (vi) Gas chromatography mass spectrometry measurements of metformin in maternal plasma to determine compliance.MEASUREMENT OF OUTCOME AND DURATION OF FOLLOW UP: Birth weight will be measured by clinical staff the result prospectively transferred from the clinical birth record to a case report form and Z score of birth weight centile calculated using www.gestation.net. Maternal IR at 36 weeks gestation will be expressed as the HOMA-IR score and derived from sampling during a glucose tolerance test. Fasting glucose insulin and 2 hour glucose from the glucose tolerance test will also be recorded prior to randomisation at 28 weeks gestation and 36 weeks gestation. 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. Initial follow up will cease once the woman and baby have been seen for a 3 month postnatal follow-up visit although we anticipate further funding applications to continue neonatal follow up into early childhood.SAMPLE SIZE: (1) BIRTH WEIGHT CENTILE. In a previous study the mean (SD) birth weight in a cohort of obese women (mean BMI 34) was 4.0kg (0.6kg). We hypothesise that metformin will reduce mean birth weight by 200g corresponding to a reduction in birthweight centile of 0.3 SD. We believe that this reduction in birth weight centile is clinically relevant but is a relatively conservative estimate of likely reduction in birth weight centile induced by metformin given that mean birth weight in the study described above in a parallel non obese cohort was 3.4kg. A sample size of 143 in each group will have 80% power to detect a difference in means birth weight centile of 0.3 SD (the difference between a placebo mean of 4.0kg and a metformin mean of 3.8kg) at the 5% significance level using a two group t-test; a sample size of 163 in each group will give the study 85% power to detect these differences. In practice we will recruit 200 women to each group to allow loss to follow up (anticipated < 5% by extrapolation from our previous studies) and suboptimal compliance. (2) INSULIN RESISTANCE. In our previous study of obese women with PCOS fasting insulin was lowered by 25% after 6 months treatment with metformin 1500mg daily consistent with meta-analyses. Based on published levels of fasting insulin in obese pregnant women 26.9 IU/L and deriving the standard deviation as 15.7 IU/L from the published standard error of 3.5 IU/L with n=20 if a reduction in mean fasting insulin of 22% (5.4 IU/L)is achieved by metformin in pregnancy in pregnancy a sample size of 306 will be required for the study to have 85% power to demonstrate differences between the placebo and metformin group at the 5% significance level. In practice we will use the Matsuda index a more accurate measure of IR so actual power of the study should be greater. PLANNED ANALYSES: Mean birthweight centile will be compared between the groups using essentially a two-sample t test but with the analysis stratified for the same factors as the randomization. Correlations within the metformin and placebo groups will be used to determine association between IR and adverse pregnancy outcomes. TIMETABLE: Set up 6 months recruit over 2 years (1-2 participants per week in each centre) follow up 1 year analysis 6 months. EXPERTISE IN TEAM: Clinical trials mechanisms of obesity programming vascular biology in vitro measurements of uterine contractility and statistical analysis.


Research activity codes: 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH