Dataset Information

Metformin exposure, maternal PCOS status and fetal venous liver circulation: A randomized, placebo-controlled study.

ABSTRACT:

Background

Metformin is prescribed to women with polycystic ovary syndrome (PCOS) to prevent pregnancy complications. Children exposed to metformin vs. placebo in utero, have increased head circumference at birth and are more overweight and obese at 8 years of age. Also, maternal PCOS-status seems to alter the long-term cardio-metabolic health of offspring. We hypothesized that the long-term effects of metformin-exposure and/or maternal PCOS may be mediated by circulatory adaptations during fetal life.

Material and methods

This is a sub-study of a larger double-blinded, placebo-controlled trial, where women with PCOS were randomized to metformin (2g/day) or placebo in pregnancy, a total of 487 women. A sub-group of participants (N = 58) took part in this sub-study and had an extended ultrasound examination at gestational week 32, including blood flow velocity and diameter measurements of the umbilical vein (UV), the ductus venosus (DV) and the portal vein (PV). Blood flow volume was calculated and adjusted for estimated fetal weight (EFW) (normalized flow). Metformin exposed fetuses were compared to placebo exposed fetuses. Fetuses of mothers with PCOS (metformin [n = 30] and placebo [n = 28]) were compared to a low-risk reference population (N = 160) by z-score statistics.

Results

There was no difference in fetal liver flow between metformin vs. placebo-exposed fetuses. Fetuses of mothers with PCOS had higher EFW (0.63 [95% CI 0.44-0.83] p<0.001), lower normalized UV, DV, PV, and lower total venous liver blood flows than the reference population.

Conclusion

Metformin during pregnancy did not affect fetal liver blood-flow. In our population, maternal PCOS-status was associated with reduced total venous liver blood-flow, which may explain altered growth and metabolism later in life.

SUBMITTER: Grindheim S

PROVIDER: S-EPMC8797196 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectivePolycystic ovary syndrome (PCOS) is a common endocrine disorder, with potential effects on offspring both genetically and through altered intrauterine environment. Metformin, which ameliorate hormonal disturbances in non-pregnant women with PCOS is increasingly used in pregnancy. It passes the placenta, and the evidence on potential consequences for offspring endocrine development is scarce. We explore the potential effects of maternal PCOS status and intrauterine metformin exposure on offspring steroid hormone levels.DesignThis is a follow-up study of 5-10 years old children from the PregMet-study-a randomized controlled trial comparing metformin (2000 mg/day) to placebo during PCOS pregnancies. Of the 255 children invited, 117 (46%) were included.MethodsThere was no intervention in this follow-up study. Outcomes were serum levels of androstenedione, testosterone, SHBG, cortisol, 17-hydroxyprogesterone, 11-deoxycortisol and calculated free testosterone converted to gender-and age adjusted z-scores from a Norwegian reference population. These were compared in i) placebo-exposed children versus children from the reference population (z-score zero) by the deviation in z-score by one-sample t-tests and ii) metformin versus placebo-exposed children by two-sample t-tests. Holm-Bonferroni adjustments were performed to account for multiple endpoints.ResultsGirls of mothers with PCOS (n = 30) had higher mean z-scores of androstenedione (0.73 (95% confidence interval (CI) 0.41 to 1.06), p<0.0001), testosterone (0.76 (0.51 to 1.00), p<0.0001), and free testosterone (0.99 (0.67 to 1.32), p<0.0001) than the reference population. Metformin-exposed boys (n = 31) tended to have higher 11-deoxycortisol z-score than placebo-exposed boys (n = 24) (mean difference 0.65 (95% CI 0.14-1.17), p = 0.014).ConclusionMaternal PCOS status was associated with elevated androgens in 5- to 10-year-old daughters, which might indicate earlier maturation and increased risk of developing PCOS. An impact of metformin in pregnancy on steroidogenesis in children born to mothers with PCOS cannot be excluded. Our findings need confirmation in studies that include participants that have entered puberty.

Project description:BackgroundMaternal 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.MethodsWe 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.FindingsBetween 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).InterpretationMetformin 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.FundingThe Efficacy and Mechanism Evaluation (EME) Programme, a Medical Research Council and National Institute for Health Research partnership.