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

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.publishedVersio

Anthropometrics of neonates born to mothers with PCOS with metformin or placebo exposure in utero

Introduction: Fetal growth may be affected by both maternal polycystic ovary syndrome (PCOS) and metformin therapy. Here, we explore the effect of intrauterine metformin exposure on birth anthropometrics of infants born to women with PCOS. We also investigated whether the effect of metformin on birth anthropometrics is modified by maternal pre-pregnancy body mass index, PCOS hyperandrogenic phenotype, serum androgen levels, preconception use of metformin and offspring sex. Additionally, we assessed newborn anthropometrics in relation to a national reference population. Material and methods: Individual data from three randomized controlled triasl were pooled. The randomized controlled trials investigated the effects of metformin in pregnant women with PCOS. In all, 397 and 403 were randomized to the metformin and placebo groups, respectively. A Scandinavian growth reference was used to calculate sex and gestational age adjusted z-scores. Linear regression models were used to estimate the effect of metformin on offspring z-scores of head circumference, birth length, birthweight, placental weight, body mass index, ponderal index and birthweight:placental weight ratio. S-testosterone, s-androstenedione, and s-sex-hormone binding globulin from four timepoints in pregnancy were analyzed. Results: Compared with the PCOS-placebo group, newborns in the PCOS-metformin group had larger head circumference (head circumference z-score: mean difference = 0.25, 95% CI = 0.11– 0.40). This effect of metformin on head circumference z-score was particularly observed among offspring of overweight/obese mothers and mothers with hyperandrogenic PCOS-phenotype. We observed no difference in other anthropometric measures between the metformin and placebo groups or any clear interaction between maternal androgen levels and metformin. Newborns in the PCOS-placebo group were shorter than in the reference population (birth length z-score: mean = −0.04, 95% CI = –0.05 to −0.03), but head circumference and birthweight were similar. Conclusions: Larger head circumference was observed at birth in metformin-exposed offspring of mothers with PCOS. PCOS-offspring were also shorter, with a similar birthweight to the reference population, indirectly indicating higher weight-to-height ratio at birth.publishedVersio

Metformin in Pregnancy Study (MiPS): Protocol for a systematic review with individual patient data meta-analysis

AbstractIntroduction Gestational diabetes mellitus (GDM) is a common disorder of pregnancy and contributes to adverse pregnancy outcomes. Metformin is often used for the prevention and management of GDM; however, its use in pregnancy continues to be debated. The Metformin in Pregnancy Study aims to use individual patient data (IPD) meta-analysis to clarify the efficacy and safety of metformin use in pregnancy and to identify relevant knowledge gaps.Methods and analysis MEDLINE, EMBASE and all Evidence-Based Medicine will be systematically searched for randomised controlled trials (RCT) testing the efficacy of metformin compared with placebo, usual care or other interventions in pregnant women. Two independent reviewers will assess eligibility using prespecified criteria and will conduct data extraction and quality appraisal of eligible studies. Authors of included trials will be contacted and asked to contribute IPD. Primary outcomes include maternal glycaemic parameters and GDM, as well as neonatal hypoglycaemia, anthropometry and gestational age at delivery. Other adverse maternal, birth and neonatal outcomes will be assessed as secondary outcomes. IPD from these RCTs will be harmonised and a two-step meta-analytic approach will be used to determine the efficacy and safety of metformin in pregnancy, with a priori adjustment for covariates and subgroups to examine effect moderators of treatment outcomes. Sensitivity analyses will assess heterogeneity, risk of bias and the impact of trials which have not provided IPD.Ethics and disseminationAll IPD will be deidentified and studies contributing IPD will have ethical approval from their respective local ethics committees. This study will provide robust evidence regarding the efficacy and safety of metformin use in pregnancy, and may identify subgroups of patients who may benefit most from this treatment modality. Findings will be published in peer-reviewed journals and disseminated at scientific meetings, providing much needed evidence to inform clinical and public health actions in this area.</p

Polycystic ovary syndrome and pregnancy - From a clinical perspective

For decades, infertility and metabolic health challenges have been the main concerns for women diagnosed with polycystic ovary syndrome (PCOS). Poorer pregnancy outcomes and obstetric complications have only recently been recognized as concerns for women with PCOS. Women diagnosed with PCOS are more often overweight and obese, and the prevalence of pregnancy complications in PCOS is influenced by several co-factors such as body mass index, co-morbidities, and ethnicity. The most frequently reported pregnancy complications in PCOS are gestational diabetes, miscarriage and preterm delivery, hypertension, and preeclampsia. This narrative review focuses on existing evidence and clinical practice for prepregnancy screening, antenatal care, and postpartum follow-up of women with PCOS. We also briefly review treatment options, neonatal outcomes, and breastfeeding. Our aim is to increase awareness about obstetric challenges in PCOS

Gestational weight gain, appetite regulating hormones, and metformin treatment in polycystic ovary syndrome: a longitudinal, placebo-controlled study

Objective To explore mechanisms that modulate gestational weight gain (GWG) in women with polycystic ovary syndrome (PCOS) and healthy controls. Design Sub-sample of randomised controlled trials (PCOS) combined with a prospective cohort (controls). Setting Eleven Norwegian, Swedish, and Icelandic hospitals. Population Pregnant women with PCOS treated with metformin (PCOS-M, n = 36) or placebo (PCOS-P, n = 37), and healthy pregnant women (HC, n = 15). Methods Serum levels of the appetite regulating hormones leptin, ghrelin, allopregnanolone, and soluble leptin receptor (sOB-R) were determined in the first and third trimesters. Main Outcome Measures Excessive GWG (eGWG) relative to body mass index according to Institute of Medicine (IOM) guideline. Serum leptin/sOB-R ratio, or free-leptin-index (FLI), as biomarker of leptin sensitivity. Serum ghrelin and allopregnanolone levels. Results The overall prevalence of eGWG was 44% (38/86). Women with eGWG had higher first and third trimester FLI (P < 0.001), and lower third trimester allopregnanolone levels (P = 0.003) versus women with non-eGWG. The prevalence of eGWG was lower in PCOS-M versus PCOS-P (28% versus 62%, odds ratio = 0.4, 95% CI 0.2–0.8, P = 0.005). FLI decreased during pregnancy in PCOS-M (P = 0.01), but remained unaltered in PCOS-P and HC. Ghrelin and allopregnanolone levels were comparable in PCOS-M, PCOS-P and HC throughout pregnancy. Conclusion Excessive GWG is associated with enhanced leptin resistance, and attenuated physiological increase in serum allopregnanolone levels during pregnancy. Metformin reduces the risk for eGWG and improves leptin sensitivity in pregnant women with PCOS

No impact of gestational diabetes mellitus on pregnancy complications in women with PCOS, regardless of GDM criteria used

Polycystic ovary syndrome (PCOS) is characterized by the presence of insulin resistance, and women with PCOS have high prevalence of gestational diabetes (GDM). Both conditions have been associated with increased risk for pregnancy complications such as preterm birth, preeclampsia and increased offspring birth weight. We aimed to estimate the prevalence of GDM in women with PCOS using both previous and new diagnostic criteria, and to analyse whether the risk of pregnancy complications increased with the presence of GDM. In addition, we aimed to assess the response to metformin treatment in PCOS women with GDM. We performed post-hoc analysis of three prospective, double blinded studies of altogether 791 pregnant women with PCOS randomized to either metformin or placebo treatment from first trimester to delivery. Glucose data allowing GDM classification after previous (WHO 1999) and new (WHO 2013 and Norwegian 2017) diagnostic criteria were available for 722 of the women. Complications such as preeclampsia, late miscarriage and preterm birth, birth weight and gestational age were correlated to the presence of GDM and metformin treatment. The prevalence of GDM was 28.3% (WHO 1999), 41.2% (WHO 2013) and 27.2% (Norwegian 2017). Having GDM already in first trimester associated with increased risk for late miscarriage (p<0.01). Having GDM according to newer criteria correlated to increased maternal age and BMI (p<0.001). Otherwise, having GDM (any criteria) correlated neither to the development of preeclampsia, nor to birth weight z-score or the proportion of offspring being large for gestational weight. Maternal age and BMI, parity and gestational weight gain, but not GDM or metformin treatment, were determinants for birth weight z-score. Conclusion: in pregnant women with PCOS, having GDM did not increase the risk for other pregnancy complications except for an increased risk for late miscarriage among those with GDM already in the first trimester

Gestational weight gain, appetite regulating hormones, and metformin treatment in polycystic ovary syndrome : A longitudinal, placebo-controlled study

Objective: To explore mechanisms that modulate gestational weight gain (GWG) in women with polycystic ovary syndrome (PCOS) and healthy controls. Design: Sub-sample of randomised controlled trials (PCOS) combined with a prospective cohort (controls). Setting: Eleven Norwegian, Swedish, and Icelandic hospitals. Population: Pregnant women with PCOS treated with metformin (PCOS-M, n = 36) or placebo (PCOS-P, n = 37), and healthy pregnant women (HC, n = 15). Methods: Serum levels of the appetite regulating hormones leptin, ghrelin, allopregnanolone, and soluble leptin receptor (sOB-R) were determined in the first and third trimesters. Main Outcome Measures: Excessive GWG (eGWG) relative to body mass index according to Institute of Medicine (IOM) guideline. Serum leptin/sOB-R ratio, or free-leptin-index (FLI), as biomarker of leptin sensitivity. Serum ghrelin and allopregnanolone levels. Results: The overall prevalence of eGWG was 44% (38/86). Women with eGWG had higher first and third trimester FLI (P &lt; 0.001), and lower third trimester allopregnanolone levels (P = 0.003) versus women with non-eGWG. The prevalence of eGWG was lower in PCOS-M versus PCOS-P (28% versus 62%, odds ratio = 0.4, 95% CI 0.2–0.8, P = 0.005). FLI decreased during pregnancy in PCOS-M (P = 0.01), but remained unaltered in PCOS-P and HC. Ghrelin and allopregnanolone levels were comparable in PCOS-M, PCOS-P and HC throughout pregnancy. Conclusion: Excessive GWG is associated with enhanced leptin resistance, and attenuated physiological increase in serum allopregnanolone levels during pregnancy. Metformin reduces the risk for eGWG and improves leptin sensitivity in pregnant women with PCOS

Prenatal exposures and birth indices, and subsequent risk of polycystic ovary syndrome: a national registry-based cohort study

Objective To study the associations between prenatal exposures and risk of developing polycystic ovary syndrome (PCOS). Design National registry‐based cohort study. Setting Sweden. Population Girls born in Sweden during the years 1982–1995 (n = 681 123). Methods The girls were followed until the year 2010 for a diagnosis of PCOS. We estimated the associations between maternal body mass index (BMI), smoking, and size at birth with the risk of developing a PCOS diagnosis. Risks were calculated by adjusted hazard ratio (aHR) and 95% confidence intervals (95% CIs). Main outcome measures A diagnosis of PCOS at 15 years of age or later. Results During the follow‐up period 3738 girls were diagnosed with PCOS (0.54%). Girls with mothers who were overweight or obese had 1.5–2.0 times higher risk of PCOS (aHR 1.52, 95% CI 1.36–1.70; aHR 1.97, 95% CI 1.61–2.41, respectively), compared with girls born to mothers of normal weight. The risk of PCOS was increased if the mother smoked during pregnancy (1–9 cigarettes/day, aHR 1.31, 95% CI 1.18–1.47; ≥10 cigarettes/day, aHR 1.44, 95% CI 1.27–1.64). Being born small for gestational age (SGA) was associated with a later diagnosis of PCOS in crude estimates, but the association was not significant after adjusting for maternal factors. Conclusions Maternal smoking and increased BMI appear to increase the risk of PCOS in offspring. The association between SGA and the development of PCOS appears to be mediated by maternal factors. Tweetable abstract Smoking during pregnancy and high maternal BMI are associated with PCOS diagnosis in the offspring

Effects of High Intensity Interval Training and Strenght Training on Metabolic, Cardiovascular and Hormonal Outcomes in Women with Polycystic Ovary Syndrome: A Pilot Study

Background: Polycystic ovary syndrome is a common endocrinopathy in reproductive-age women, and associates with insulin resistance. Exercise is advocated in this disorder, but little knowledge exists on the optimal exercise regimes. We assessed the effects of high intensity interval training and strength training on metabolic, cardiovascular, and hormonal outcomes in women with polycystic ovary syndrome. Materials and Methods: Three-arm parallel randomized controlled trial. Thirty-one women with polycystic ovary syndrome (age 27.2 ± 5.5 years; body mass index 26.7 ± 6.0 kg/m2) were randomly assigned to high intensity interval training, strength training, or a control group. The exercise groups exercised three times weekly for 10 weeks. Results: The main outcome measure was change in homeostatic assessment of insulin resistance (HOMA-IR). HOMA-IR improved significantly only after high intensity interval training, by -0.83 (95% confidence interval [CI], -1.45, -0.20), equal to 17%, with between-group difference (p = 0.014). After high intensity interval training, high-density lipoprotein cholesterol increased by 0.2 (95% CI, 0.02, 0.5) mmol/L, with between group difference (p = 0.04). Endothelial function, measured as flow-mediated dilatation of the brachial artery, increased significantly after high intensity interval training, by 2.0 (95% CI, 0.1, 4.0) %, between-group difference (p = 0.08). Fat percentage decreased significantly after both exercise regimes, without changes in body weight. After strength training, anti-Müllarian hormone was significantly reduced, by -14.8 (95% CI, -21.2, -8.4) pmol/L, between-group difference (p = 0.04). There were no significant changes in high-sensitivity C-reactive protein, adiponectin or leptin in any group. Conclusions: High intensity interval training for ten weeks improved insulin resistance, without weight loss, in women with polycystic ovary syndrome. Body composition improved significantly after both strength training and high intensity interval training. This pilot study indicates that exercise training can improve the cardiometabolic profile in polycystic ovary syndrome in the absence of weight loss

Effects of High Intensity Interval Training and Strength Training on Metabolic, Cardiovascular and Hormonal Outcomes in Women with Polycystic Ovary Syndrome: A Pilot Study

<div><p>Background</p><p>Polycystic ovary syndrome is a common endocrinopathy in reproductive-age women, and associates with insulin resistance. Exercise is advocated in this disorder, but little knowledge exists on the optimal exercise regimes. We assessed the effects of high intensity interval training and strength training on metabolic, cardiovascular, and hormonal outcomes in women with polycystic ovary syndrome.</p><p>Materials and Methods</p><p>Three-arm parallel randomized controlled trial. Thirty-one women with polycystic ovary syndrome (age 27.2 ± 5.5 years; body mass index 26.7 ± 6.0 kg/m²) were randomly assigned to high intensity interval training, strength training, or a control group. The exercise groups exercised three times weekly for 10 weeks.</p><p>Results</p><p>The main outcome measure was change in homeostatic assessment of insulin resistance (HOMA-IR). HOMA-IR improved significantly only after high intensity interval training, by -0.83 (95% confidence interval [CI], -1.45, -0.20), equal to 17%, with between-group difference (p = 0.014). After high intensity interval training, high-density lipoprotein cholesterol increased by 0.2 (95% CI, 0.02, 0.5) mmol/L, with between group difference (p = 0.04). Endothelial function, measured as flow-mediated dilatation of the brachial artery, increased significantly after high intensity interval training, by 2.0 (95% CI, 0.1, 4.0) %, between-group difference (p = 0.08). Fat percentage decreased significantly after both exercise regimes, without changes in body weight. After strength training, anti-Müllarian hormone was significantly reduced, by -14.8 (95% CI, -21.2, -8.4) pmol/L, between-group difference (p = 0.04). There were no significant changes in high-sensitivity C-reactive protein, adiponectin or leptin in any group.</p><p>Conclusions</p><p>High intensity interval training for ten weeks improved insulin resistance, without weight loss, in women with polycystic ovary syndrome. Body composition improved significantly after both strength training and high intensity interval training. This pilot study indicates that exercise training can improve the cardiometabolic profile in polycystic ovary syndrome in the absence of weight loss.</p><p>Trial Registration</p><p>ClinicalTrial.gov <a href="https://clinicaltrials.gov/ct2/show/NCT01919281?term=NCT01919281&rank=1/NCT01919281" target="_blank">NCT01919281</a></p></div