Fetal Fat Distribution Research Articles

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

BackgroundMaternal 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.ObjectiveTo 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.DesignDouble-blind, placebo-controlled, randomised controlled trial with embedded substudies.SettingFifteen NHS hospitals in the UK.ParticipantsPregnant women aged ≥ 16 years with a singleton fetus and a body mass index of ≥ 30 kg/m2.InterventionMetformin tablets (or placebo) administered between 12 and 16 weeks’ gestation until delivery of the baby.Main outcome measuresThe 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.ResultsWe 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.ConclusionsMetformin 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.Trial registrationCurrent Controlled Trials ISRCTN51279843.FundingThis project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research partnership.

OP20.09: Differences in fetal fat distribution in the presence of abnormal umbilical artery Doppler waveforms

(FGR). Methods: During routine assessment of pregnancies known to be at high risk where there were abnormal umbilical artery Doppler waveforms the amounts of fetal abdominal and mid-thigh fat were calculated (fetal subcutaneous fat layer = total area–lean mass area). These were compared with normative data that were collected as part of a continuing ongoing long-term study of fetal growth parameters in a non-smoking cohort of women with uncomplicated pregnancies. Results: Fifty-two pregancies were studied from 24 weeks’ to 39 weeks’ gestation where the umbilical artery S/D was greater than the 95 th centile for gestation. While there was overall an increase in the numbers of fetuses with abdominal and mid-thigh measurements less than the 50 th centile this was only significant for the abdominal measurements, with 87% being less than the 50 th centile for total abdominal area and abdominal lean mass and 92% being less than the 50 th centile for abdominal fat area (Chi square 36.6, P = 0.000). The main component of the decrease in abdominal area was in the subcutaneous fat layer (with 33% being less than the 5 th centile for gestation). The effect was not as clear for the mid-thigh reduction in measurements (with 62% being < 50th centile) but the main component for the mid-thigh was a reduction in fetal thigh subcutaneous fat (13% < 5th centile). Conclusions: There is a difference in the fetal response to FGR (as indicated by abnormal umbilical artery S/D) between the maintenance of both lean body mass and subcutaneous fat. There appears to be a prefence for the preservation of lean body mass and subcutaneous fat peripherally in comparison, with a more global reduction centrally.