Does Metformin Treatment During Pregnancy Modify the Future Metabolic Profile in Women With PCOS?

Does Metformin Treatment During Pregnancy Modify the Future Metabolic Profile in Women With PCOS? Abstract Context Worldwide, metformin is prescribed to improve pregnancy outcome in polycystic ovary syndrome (PCOS). Metformin may also benefit future health by modulating increased metabolic stress during pregnancy. Objective To investigate whether metformin during pregnancy modified future metabolic health in women with PCOS. Design Follow-up study of a randomized controlled trial that compared metformin with placebo in women with PCOS. Mean follow-up period was 7.7 years (range, 5 to 11 years). Setting Three university hospitals, seven local hospitals, and one gynecological specialist practice. Participants Women with PCOS according to Rotterdam criteria; all former participants in the Metformin in Pregnant PCOS Women Study. Intervention Metformin 2000 mg daily or placebo from first trimester to delivery in the original study. No intervention in the present follow-up study. Main Outcomes and Measures Main outcome measure was weight gain in the follow-up period. Weight, body mass index (BMI), waist and hip circumferences, and blood pressure (BP) were registered. Body composition was assessed by bioelectrical impedance analysis, and fasting lipids, glucose, and insulin were analyzed. Results Of 239 invited women, 131 (55%) participated in the follow-up. Weight gain was similar in women given metformin (2.1 ± 10.5 kg) and women given placebo (1.8 ± 11.2 kg) at 7.7 years’ follow-up after pregnancy (P = 0.834). No difference was found in BMI, waist/hip ratio, BP, body composition, lipids, glucose and insulin levels, or prevalence of metabolic syndrome at follow-up between those treated with metformin and those treated with placebo during pregnancy. Conclusion Metformin treatment during pregnancy did not influence the metabolic profile in women with PCOS at 7.7 years of follow-up. Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in young women (1). Using the Rotterdam criteria, the prevalence of PCOS is estimated to be 10% to 14% in the general population (2, 3). Implications of the syndrome are multifaceted, and PCOS is associated with metabolic impairment and increased risk of pregnancy complications. Data from meta-analyses show a threefold increase in gestational diabetes mellitus (DM) among women with PCOS (4–6). Pregnancy entails metabolic and homeostatic alterations and a physiological increase in insulin resistance, particularly during the third trimester. In a large cohort of women, a history of pregnancy complications such as preeclampsia, gestational diabetes, and giving birth to a small-for-gestational-age infant were indicators of an increased risk of cardiovascular disease (CVD) later in life (7). Awareness of these trajectories provides an opportunity for early identification of women at risk. Excessive weight gain in pregnancy has a negative effect on obstetric outcome (8–10). Women with high gestational weight gain have a threefold increased risk of being overweight at first prenatal visit in a consecutive pregnancy compared with the risk in women with normal or low gestational weight gain (11). Excessive postpartum weight retention at the end of the first year postpartum is a predictor for being overweight 15 years later (12). We previously reported that women with PCOS randomly assigned to metformin 2 g/d gained less weight during pregnancy (13). Insulin resistance, although not a criterion for PCOS, affects the majority of women with the syndrome. Among hirsute women with PCOS in a Danish cohort, increased fasting insulin level was found in 28% of women with body mass index (BMI) ≤25 kg/m2 and in 74% of women with BMI >25 kg/m2 (14). Hyperandrogenism seems to worsen insulin resistance in PCOS, with insulin resistance found in 43% of hyperandrogenic women compared with 14% of normo-androgenic women (15). Metformin is a multipotent drug that exerts its effect on several tissues that are sensitive to insulin, such as liver, skeletal muscle, and adipose tissue. The Endocrine Society guideline on PCOS recommends lifestyle interventions such as physical exercise and weight loss as primary treatment of overweight and obesity in PCOS. Metformin is recommended as second-line treatment when type 2 DM or impaired glucose tolerance is present and lifestyle intervention is insufficient to improve metabolic dysfunction. In addition, metformin is recommended for menstrual irregularity in women with PCOS when treatment with hormonal contraceptives is contraindicated or not tolerated (16). Worldwide, metformin is prescribed in the first trimester and onward in an attempt to improve pregnancy outcome in PCOS. Metformin may also benefit future maternal health by modulating increased metabolic stress during pregnancy To our knowledge, prospective data regarding postpartum metabolic health in women with PCOS have not been published. In the current study, we aimed to explore possible effects of metformin treatment during pregnancy on long-term metabolic health. Materials and Methods The current study is a follow-up to a randomized, controlled, double-blind, multicenter trial. Mothers who participated in the Metformin in Pregnant PCOS Women Study (the PregMet Study) (17) from 2005 to 2009 were eligible for participation in the follow-up. Women with PCOS were randomly assigned to metformin or placebo from the first trimester to delivery to assess whether metformin reduced pregnancy complications. Study design The PregMet Study In all, 257 women with 274 pregnancies were included at 11 study centers in Norway: three university hospitals, seven local hospitals, and one gynecological specialist practice. Randomization, blinding, and examinations are described elsewhere (17). Inclusion criteria for the PregMet Study were (1) PCOS diagnosed according to the Rotterdam criteria (3), (2) age 18 to 45 years, (3) gestational age between 5 and 12 weeks, and (4) a viable singleton fetus shown on ultrasonography. The participants received counseling on lifestyle and diet at inclusion, before randomization to metformin (2 g/d) or placebo. To counteract possible metformin effects on folate or vitamin B12 levels, the participants were advised to take 0.8 mg of folate and one multivitamin tablet daily throughout pregnancy. The follow-up study From April 2014 to July 2016, a total of 239 women were invited to participate in the follow-up. The inclusion criterion was participation in the PregMet Study. Exclusion criteria were ongoing pregnancy and breastfeeding (Fig. 1). Participants who dropped out (n = 12), miscarried (n = 3), or lost their children (n = 3) were not invited. Seventeen of the women participated twice in the PregMet Study. When women participated twice and were randomized equally, data from the first participation were recorded; when they were randomized once to metformin and once to placebo, the data from the metformin-exposed pregnancy were used. Nonresponders received two reminders about 1 to 2 months and 6 to 7 months after the first letter. In all, 131 women (55%) agreed to participate in the follow-up. One hundred seventeen women met for a physical examination and interview, whereas 14 were interviewed by phone and gave self-reported data. Two medical students and a trained midwife examined the participants and collected the data. Standardized interviewer-administered questionnaires were used to obtain self-reported data on former medical and gynecological/obstetric history, contraceptives, ethnicity, education, civil status, smoking, physical activity, and current use of metformin. Figure 1. View largeDownload slide Flowchart showing randomization, dropouts, and exclusions. Figure 1. View largeDownload slide Flowchart showing randomization, dropouts, and exclusions. Blood pressure (BP) was measured three times, 2 minutes apart, with digital devices, with the participant in a sitting position after at least 15 minutes of rest in a chair. The mean of the second and third measurements was calculated. Height and waist and hip circumferences were measured manually and rounded off to the closest 0.5 cm. Body composition and weight were measured using bioelectrical impedance (InBody 720; BIOSPACE, Seoul, South Korea). The examination was performed with the participant wearing light and snug clothes and no shoes. InBody gives an estimate of total body fluids, proteins, minerals, and fat and was validated against dual-energy X-ray absorptiometry. Blood samples were drawn from an antecubital vein between 0800 and 1100 hours after an overnight fast. All analyses except insulin were performed directly, using standard procedures at St. Olavs Hospital, Trondheim, Norway. Insulin was analyzed at Oslo University Hospital, Aker, Norway. The homeostatic model assessment (HOMA) index was computed as [fasting glucose (mmol/L) × fasting insulin concentration (mU/L)] /22.5. HOMA-β was calculated using the following formula: 20 × fasting insulin (mU/L)/fasting glucose (mmol/L) − 3.5. The prevalence of metabolic syndrome (MetS) was estimated according to the Rotterdam consensus (3). Three of the following five criteria were required: waist circumference >88 cm; triglycerides ≥150 mg/dL (1.7 mmol/L); high-density lipoprotein (HDL) ≤50 mg/dL (1.3 mmol/L); systolic BP ≥130 mm Hg and/or diastolic BP ≥85 mm Hg; and fasting glucose 110 to 126 mg/dL (6.11 to 6.99 nmol/L) and/or 2-hour oral glucose tolerance test glucose 140 to 199 mg/dL (7.78 to 11.04 nmol/L). The more widely applicable guideline, the National Cholesterol Education Program–Adult Treatment Panel III definition, requires the presence of at least three of the following five criteria: waist circumference >88 cm; triglycerides ≥150 mg/dL (1.7 mmol/L) or drug treatment of elevated triglycerides; HDL ≤50 mg/dL (1.3 mmol/L) or drug treatment of reduced HDL cholesterol; systolic BP ≥130 mm Hg and/or diastolic BP ≥85 mm Hg or treatment of elevated BP; and fasting glucose ≥100 mg/dL (5.6 nmol/L). Participants were asked if they had been diagnosed with type 2 DM, hypertension, CVD, or depression. Statistical analyses Statistics were performed with SPSS version 24 (IBM Corp., Armonk, NY). Data were reported as mean ± standard deviation or absolute numbers (percentages). Differences between study groups were assessed with two-tailed t tests for independent samples. Fisher exact test was used for evaluation of discrete data. To adjust for multiple testing, we considered significance as a two-tailed P value < 0.01. Ethical approval Written informed consent was obtained from each participant before inclusion, and the Declaration of Helsinki was followed throughout the study. The Regional Committees for Medical and Health Research Ethics Mid-Norway approved the current study (04.04.2014, reference number: 2014/96). Results In all, 131 of 239 invited participants (55%) in the PregMet Study agreed to participate in this follow-up. The only difference between the metformin and the placebo groups at baseline (i.e., at inclusion in the PregMet Study) was lower total cholesterol level in the placebo group (Table 1). Women who participated in the follow-up and those who declined were comparable at baseline, except for a tendency toward more smokers among those who declined, n = 7 vs 15 (P = 0.051) (data not shown). In the PregMet Study, 80% of the participants took >85% of the study medication. Table 1. Baseline Characteristics of Participants (N = 131) at First Trimester of Pregnancy in the PregMet Study Metformin (n = 66) Placebo (n = 65) Age, y 29.5 ± 3.9 30.1 ± 4.1 Weight, kg 79.9 ± 19.5 80.1 ± 17.7 BMI, kg/m2 28.7 ± 6.9 28.5 ± 6.2 Systolic BP, mm Hg 118 ± 12 118 ± 12 Diastolic BP, mm Hg 73 ± 10 72 ± 10 Fasting glucose, mmol/L 4.6 ± 0.5 4.7 ± 0.6 2-h glucose, mmol/L 5.3 ± 1.5 5.4 ± 1.7 Cholesterol, mmol/L 4.8 ± 1.1 4.4 ± 0.7 HDL cholesterol, mmol/L 1.6 ± 0.4 1.6 ± 0.3 Triglycerides, mmol/L 1.2 ± 0.5 1.1 ± 0.5 Hyperandrogenic phenotype, n (%) 48 (72.7) 46 (70.8) Normoandrogenic phenotype, n (%) 18 (27.3) 19 (29.2) Metformin (n = 66) Placebo (n = 65) Age, y 29.5 ± 3.9 30.1 ± 4.1 Weight, kg 79.9 ± 19.5 80.1 ± 17.7 BMI, kg/m2 28.7 ± 6.9 28.5 ± 6.2 Systolic BP, mm Hg 118 ± 12 118 ± 12 Diastolic BP, mm Hg 73 ± 10 72 ± 10 Fasting glucose, mmol/L 4.6 ± 0.5 4.7 ± 0.6 2-h glucose, mmol/L 5.3 ± 1.5 5.4 ± 1.7 Cholesterol, mmol/L 4.8 ± 1.1 4.4 ± 0.7 HDL cholesterol, mmol/L 1.6 ± 0.4 1.6 ± 0.3 Triglycerides, mmol/L 1.2 ± 0.5 1.1 ± 0.5 Hyperandrogenic phenotype, n (%) 48 (72.7) 46 (70.8) Normoandrogenic phenotype, n (%) 18 (27.3) 19 (29.2) Data are presented as mean ± standard deviation or n (%) as appropriate. View Large Table 1. Baseline Characteristics of Participants (N = 131) at First Trimester of Pregnancy in the PregMet Study Metformin (n = 66) Placebo (n = 65) Age, y 29.5 ± 3.9 30.1 ± 4.1 Weight, kg 79.9 ± 19.5 80.1 ± 17.7 BMI, kg/m2 28.7 ± 6.9 28.5 ± 6.2 Systolic BP, mm Hg 118 ± 12 118 ± 12 Diastolic BP, mm Hg 73 ± 10 72 ± 10 Fasting glucose, mmol/L 4.6 ± 0.5 4.7 ± 0.6 2-h glucose, mmol/L 5.3 ± 1.5 5.4 ± 1.7 Cholesterol, mmol/L 4.8 ± 1.1 4.4 ± 0.7 HDL cholesterol, mmol/L 1.6 ± 0.4 1.6 ± 0.3 Triglycerides, mmol/L 1.2 ± 0.5 1.1 ± 0.5 Hyperandrogenic phenotype, n (%) 48 (72.7) 46 (70.8) Normoandrogenic phenotype, n (%) 18 (27.3) 19 (29.2) Metformin (n = 66) Placebo (n = 65) Age, y 29.5 ± 3.9 30.1 ± 4.1 Weight, kg 79.9 ± 19.5 80.1 ± 17.7 BMI, kg/m2 28.7 ± 6.9 28.5 ± 6.2 Systolic BP, mm Hg 118 ± 12 118 ± 12 Diastolic BP, mm Hg 73 ± 10 72 ± 10 Fasting glucose, mmol/L 4.6 ± 0.5 4.7 ± 0.6 2-h glucose, mmol/L 5.3 ± 1.5 5.4 ± 1.7 Cholesterol, mmol/L 4.8 ± 1.1 4.4 ± 0.7 HDL cholesterol, mmol/L 1.6 ± 0.4 1.6 ± 0.3 Triglycerides, mmol/L 1.2 ± 0.5 1.1 ± 0.5 Hyperandrogenic phenotype, n (%) 48 (72.7) 46 (70.8) Normoandrogenic phenotype, n (%) 18 (27.3) 19 (29.2) Data are presented as mean ± standard deviation or n (%) as appropriate. View Large We found no difference in weight-gain (from the first trimester of pregnancy to follow-up), BMI, waist/hip ratio, BP levels, body composition, fasting lipid levels, fasting glucose levels, or HOMA index when comparing metformin-treated women with placebo-treated women at follow-up (Table 2). Prevalence of MetS, type 2 DM, hypertension, CVD, and depression was comparable between the metformin and placebo groups. Participants with hyperandrogenism were comparable to those without hyperandrogenism regarding waist circumference, BP, fasting lipids, glucose, and HOMA index (data not shown). Education level, civil status, and parity were similar in both groups at follow-up (Table 3). Table 2. Anthropometry and Endocrine Characteristics of Women With PCOS at 5- to 11-Year Follow-Up, Categorized According to Use of Metformin or Placebo During Pregnancy Metformin (n = 66) Placebo (n = 65) P Value Follow-up, y 7.6 ± 1.4 7.7 ± 1.2 0.696 Age, y 37.5 ± 4.2 38.5 ± 4.7 0.180 Weight, kg 82.0 ± 19.4 81.9 ± 18.4 0.960 BMI, kg/m2 29.6 ± 6.9 29.3 ± 6.9 0.790 Δ weight: inclusion to follow-up, kg 2.1 ± 10.5 1.8 ± 11.2 0.834 Δ weight per year: inclusion to follow-up, kg 0.30 ± 1.40 0.20 ± 1.48 0.711 Waist, cm 90.7 ± 15.5 89.9 ± 14.4 0.748 Hip, cm 107.3 ± 15.5 108.4 ± 13.1 0.664 Waist/hip ratio 0.90 ± 0.07 0.90 ± 0.08 0.609 Waist >88 cm, n (%) 38 (59) 33 (52) 0.481 Body muscle mass, kg 28.3 ± 4.3 28.8 ± 3.2 0.559 Body fat, kg 31.6 ± 15.0 33.8 ± 16.7 0.521 Body fat, % 36.4 ± 9.4 37.6 ± 10.1 0.575 Visceral fat area, cm2 128.4 ± 64.1 135.6 ± 72.3 0.637 Systolic BP, mm Hg 119 ± 14 119 ± 14 0.817 Diastolic BP, mm Hg 78 ± 10 77 ± 11 0.555 Fasting glucose, mmol/L 5.1 ± 0.5 5.2 ± 0.7 0.329 Fasting insulin, µIU/mL 10.8 ± 7.5 12.0 ± 7.6 0.437 HOMA-IR index 2.4 ± 1.6 2.9 ± 1.9 0.155 HOMA-β 1.3 ± 0.7 1.4 ± 1.1 0.886 c-Peptide, nmol/L 0.67 ± 0.34 0.77 ± 0.37 0.148 HbA1c, % 5.2 ± 0.26 5.2 ± 0.45 0.624 Total cholesterol, mmol/L 4.7 ± 0.8 4.6 ± 0.7 0.234 HDL cholesterol, mmol/L 1.5 ± 0.4 1.5 ± 0.4 0.850 Triglycerides, mmol/L 1.0 ± 0.5 1.0 ± 0.6 0.450 MetS “Rotterdam” criteria, n (%) 12 (18.2) 10 (15.4) 0.816 MetS NCEP-ATPIII 2005, n (%) 15 (22.7) 12 (18.5) 0.667 Type 2 diabetes mellitus, n (%) 0 (0) 3 (4.6) 0.119 Hypertension, n (%) 5 (7.6) 4 (6.2) 1.000 CVD, n (%) 0 (0) 1 (1.5) 0.496 Depression, n (%) 8 (12.1) 9 (13.8) 0.800 Bariatric surgery, n (%) 6 (9.1) 2 (3.1) 0.274 Smoking, n (%) 8 (12.3) 8 (12.3) 1.0 Current use of metformin, n (%) 5 (7.6) 8 (12.3) 0.397 Metformin (n = 66) Placebo (n = 65) P Value Follow-up, y 7.6 ± 1.4 7.7 ± 1.2 0.696 Age, y 37.5 ± 4.2 38.5 ± 4.7 0.180 Weight, kg 82.0 ± 19.4 81.9 ± 18.4 0.960 BMI, kg/m2 29.6 ± 6.9 29.3 ± 6.9 0.790 Δ weight: inclusion to follow-up, kg 2.1 ± 10.5 1.8 ± 11.2 0.834 Δ weight per year: inclusion to follow-up, kg 0.30 ± 1.40 0.20 ± 1.48 0.711 Waist, cm 90.7 ± 15.5 89.9 ± 14.4 0.748 Hip, cm 107.3 ± 15.5 108.4 ± 13.1 0.664 Waist/hip ratio 0.90 ± 0.07 0.90 ± 0.08 0.609 Waist >88 cm, n (%) 38 (59) 33 (52) 0.481 Body muscle mass, kg 28.3 ± 4.3 28.8 ± 3.2 0.559 Body fat, kg 31.6 ± 15.0 33.8 ± 16.7 0.521 Body fat, % 36.4 ± 9.4 37.6 ± 10.1 0.575 Visceral fat area, cm2 128.4 ± 64.1 135.6 ± 72.3 0.637 Systolic BP, mm Hg 119 ± 14 119 ± 14 0.817 Diastolic BP, mm Hg 78 ± 10 77 ± 11 0.555 Fasting glucose, mmol/L 5.1 ± 0.5 5.2 ± 0.7 0.329 Fasting insulin, µIU/mL 10.8 ± 7.5 12.0 ± 7.6 0.437 HOMA-IR index 2.4 ± 1.6 2.9 ± 1.9 0.155 HOMA-β 1.3 ± 0.7 1.4 ± 1.1 0.886 c-Peptide, nmol/L 0.67 ± 0.34 0.77 ± 0.37 0.148 HbA1c, % 5.2 ± 0.26 5.2 ± 0.45 0.624 Total cholesterol, mmol/L 4.7 ± 0.8 4.6 ± 0.7 0.234 HDL cholesterol, mmol/L 1.5 ± 0.4 1.5 ± 0.4 0.850 Triglycerides, mmol/L 1.0 ± 0.5 1.0 ± 0.6 0.450 MetS “Rotterdam” criteria, n (%) 12 (18.2) 10 (15.4) 0.816 MetS NCEP-ATPIII 2005, n (%) 15 (22.7) 12 (18.5) 0.667 Type 2 diabetes mellitus, n (%) 0 (0) 3 (4.6) 0.119 Hypertension, n (%) 5 (7.6) 4 (6.2) 1.000 CVD, n (%) 0 (0) 1 (1.5) 0.496 Depression, n (%) 8 (12.1) 9 (13.8) 0.800 Bariatric surgery, n (%) 6 (9.1) 2 (3.1) 0.274 Smoking, n (%) 8 (12.3) 8 (12.3) 1.0 Current use of metformin, n (%) 5 (7.6) 8 (12.3) 0.397 Data presented as mean ± standard deviation or n (%) as appropriate. Abbreviations: HbA1c, hemoglobin A1c; HOMA-IR, homeostasis model assessment insulin resistance index; NCEP-ATPIII, National Cholesterol Education Program‒Adult Treatment Panel III. View Large Table 2. Anthropometry and Endocrine Characteristics of Women With PCOS at 5- to 11-Year Follow-Up, Categorized According to Use of Metformin or Placebo During Pregnancy Metformin (n = 66) Placebo (n = 65) P Value Follow-up, y 7.6 ± 1.4 7.7 ± 1.2 0.696 Age, y 37.5 ± 4.2 38.5 ± 4.7 0.180 Weight, kg 82.0 ± 19.4 81.9 ± 18.4 0.960 BMI, kg/m2 29.6 ± 6.9 29.3 ± 6.9 0.790 Δ weight: inclusion to follow-up, kg 2.1 ± 10.5 1.8 ± 11.2 0.834 Δ weight per year: inclusion to follow-up, kg 0.30 ± 1.40 0.20 ± 1.48 0.711 Waist, cm 90.7 ± 15.5 89.9 ± 14.4 0.748 Hip, cm 107.3 ± 15.5 108.4 ± 13.1 0.664 Waist/hip ratio 0.90 ± 0.07 0.90 ± 0.08 0.609 Waist >88 cm, n (%) 38 (59) 33 (52) 0.481 Body muscle mass, kg 28.3 ± 4.3 28.8 ± 3.2 0.559 Body fat, kg 31.6 ± 15.0 33.8 ± 16.7 0.521 Body fat, % 36.4 ± 9.4 37.6 ± 10.1 0.575 Visceral fat area, cm2 128.4 ± 64.1 135.6 ± 72.3 0.637 Systolic BP, mm Hg 119 ± 14 119 ± 14 0.817 Diastolic BP, mm Hg 78 ± 10 77 ± 11 0.555 Fasting glucose, mmol/L 5.1 ± 0.5 5.2 ± 0.7 0.329 Fasting insulin, µIU/mL 10.8 ± 7.5 12.0 ± 7.6 0.437 HOMA-IR index 2.4 ± 1.6 2.9 ± 1.9 0.155 HOMA-β 1.3 ± 0.7 1.4 ± 1.1 0.886 c-Peptide, nmol/L 0.67 ± 0.34 0.77 ± 0.37 0.148 HbA1c, % 5.2 ± 0.26 5.2 ± 0.45 0.624 Total cholesterol, mmol/L 4.7 ± 0.8 4.6 ± 0.7 0.234 HDL cholesterol, mmol/L 1.5 ± 0.4 1.5 ± 0.4 0.850 Triglycerides, mmol/L 1.0 ± 0.5 1.0 ± 0.6 0.450 MetS “Rotterdam” criteria, n (%) 12 (18.2) 10 (15.4) 0.816 MetS NCEP-ATPIII 2005, n (%) 15 (22.7) 12 (18.5) 0.667 Type 2 diabetes mellitus, n (%) 0 (0) 3 (4.6) 0.119 Hypertension, n (%) 5 (7.6) 4 (6.2) 1.000 CVD, n (%) 0 (0) 1 (1.5) 0.496 Depression, n (%) 8 (12.1) 9 (13.8) 0.800 Bariatric surgery, n (%) 6 (9.1) 2 (3.1) 0.274 Smoking, n (%) 8 (12.3) 8 (12.3) 1.0 Current use of metformin, n (%) 5 (7.6) 8 (12.3) 0.397 Metformin (n = 66) Placebo (n = 65) P Value Follow-up, y 7.6 ± 1.4 7.7 ± 1.2 0.696 Age, y 37.5 ± 4.2 38.5 ± 4.7 0.180 Weight, kg 82.0 ± 19.4 81.9 ± 18.4 0.960 BMI, kg/m2 29.6 ± 6.9 29.3 ± 6.9 0.790 Δ weight: inclusion to follow-up, kg 2.1 ± 10.5 1.8 ± 11.2 0.834 Δ weight per year: inclusion to follow-up, kg 0.30 ± 1.40 0.20 ± 1.48 0.711 Waist, cm 90.7 ± 15.5 89.9 ± 14.4 0.748 Hip, cm 107.3 ± 15.5 108.4 ± 13.1 0.664 Waist/hip ratio 0.90 ± 0.07 0.90 ± 0.08 0.609 Waist >88 cm, n (%) 38 (59) 33 (52) 0.481 Body muscle mass, kg 28.3 ± 4.3 28.8 ± 3.2 0.559 Body fat, kg 31.6 ± 15.0 33.8 ± 16.7 0.521 Body fat, % 36.4 ± 9.4 37.6 ± 10.1 0.575 Visceral fat area, cm2 128.4 ± 64.1 135.6 ± 72.3 0.637 Systolic BP, mm Hg 119 ± 14 119 ± 14 0.817 Diastolic BP, mm Hg 78 ± 10 77 ± 11 0.555 Fasting glucose, mmol/L 5.1 ± 0.5 5.2 ± 0.7 0.329 Fasting insulin, µIU/mL 10.8 ± 7.5 12.0 ± 7.6 0.437 HOMA-IR index 2.4 ± 1.6 2.9 ± 1.9 0.155 HOMA-β 1.3 ± 0.7 1.4 ± 1.1 0.886 c-Peptide, nmol/L 0.67 ± 0.34 0.77 ± 0.37 0.148 HbA1c, % 5.2 ± 0.26 5.2 ± 0.45 0.624 Total cholesterol, mmol/L 4.7 ± 0.8 4.6 ± 0.7 0.234 HDL cholesterol, mmol/L 1.5 ± 0.4 1.5 ± 0.4 0.850 Triglycerides, mmol/L 1.0 ± 0.5 1.0 ± 0.6 0.450 MetS “Rotterdam” criteria, n (%) 12 (18.2) 10 (15.4) 0.816 MetS NCEP-ATPIII 2005, n (%) 15 (22.7) 12 (18.5) 0.667 Type 2 diabetes mellitus, n (%) 0 (0) 3 (4.6) 0.119 Hypertension, n (%) 5 (7.6) 4 (6.2) 1.000 CVD, n (%) 0 (0) 1 (1.5) 0.496 Depression, n (%) 8 (12.1) 9 (13.8) 0.800 Bariatric surgery, n (%) 6 (9.1) 2 (3.1) 0.274 Smoking, n (%) 8 (12.3) 8 (12.3) 1.0 Current use of metformin, n (%) 5 (7.6) 8 (12.3) 0.397 Data presented as mean ± standard deviation or n (%) as appropriate. Abbreviations: HbA1c, hemoglobin A1c; HOMA-IR, homeostasis model assessment insulin resistance index; NCEP-ATPIII, National Cholesterol Education Program‒Adult Treatment Panel III. View Large Table 3. Socioeconomic Measures at 5- to 11-Year Follow-Up Metformin
(n = 66) Placebo
(n = 65) P Value Education 0.778  10 y primary school 3 (4.6) 1 (1.5)  High school 17 (26.2) 18 (27.7)  College <4 y 22 (33.8) 22 (33.8)  College ≥4 y 23 (35.4) 24 (36.9) Civil status 0.547  Married 35 (53.8) 42 (64.6)  Cohabitant 21 (32.3) 17 (26.2)  Single/divorced 6 (9.2) 5 (7.7)  Other 3 (4.6) 1 (1.5) Parity 0.809  Parity 1 11 (16.7) 9 (13.8)  Parity 2+ 55 (83.3) 56 (86.2) Metformin
(n = 66) Placebo
(n = 65) P Value Education 0.778  10 y primary school 3 (4.6) 1 (1.5)  High school 17 (26.2) 18 (27.7)  College <4 y 22 (33.8) 22 (33.8)  College ≥4 y 23 (35.4) 24 (36.9) Civil status 0.547  Married 35 (53.8) 42 (64.6)  Cohabitant 21 (32.3) 17 (26.2)  Single/divorced 6 (9.2) 5 (7.7)  Other 3 (4.6) 1 (1.5) Parity 0.809  Parity 1 11 (16.7) 9 (13.8)  Parity 2+ 55 (83.3) 56 (86.2) Data are presented as n (%). View Large Table 3. Socioeconomic Measures at 5- to 11-Year Follow-Up Metformin
(n = 66) Placebo
(n = 65) P Value Education 0.778  10 y primary school 3 (4.6) 1 (1.5)  High school 17 (26.2) 18 (27.7)  College <4 y 22 (33.8) 22 (33.8)  College ≥4 y 23 (35.4) 24 (36.9) Civil status 0.547  Married 35 (53.8) 42 (64.6)  Cohabitant 21 (32.3) 17 (26.2)  Single/divorced 6 (9.2) 5 (7.7)  Other 3 (4.6) 1 (1.5) Parity 0.809  Parity 1 11 (16.7) 9 (13.8)  Parity 2+ 55 (83.3) 56 (86.2) Metformin
(n = 66) Placebo
(n = 65) P Value Education 0.778  10 y primary school 3 (4.6) 1 (1.5)  High school 17 (26.2) 18 (27.7)  College <4 y 22 (33.8) 22 (33.8)  College ≥4 y 23 (35.4) 24 (36.9) Civil status 0.547  Married 35 (53.8) 42 (64.6)  Cohabitant 21 (32.3) 17 (26.2)  Single/divorced 6 (9.2) 5 (7.7)  Other 3 (4.6) 1 (1.5) Parity 0.809  Parity 1 11 (16.7) 9 (13.8)  Parity 2+ 55 (83.3) 56 (86.2) Data are presented as n (%). View Large Discussion Metformin use from the first trimester and throughout pregnancy did not modify maternal metabolic profile at 7.7 years postpartum. Postpartum yearly weight increase in women with PCOS was relatively low, independent of randomization. Strengths of the study This study prospectively assessed the long-term metabolic profile in a well-characterized cohort of women with PCOS after randomization to metformin or placebo treatment during pregnancy. Participants in the follow-up were representative of the original study population. Limitations of the study Participants in this follow-up were relatively young to experience serious complications of MetS, such as CVD. Risk factors of CVD may occur at this age and may potentially be modified by metformin intervention. A 55% participation rate is less than we had hoped for, but the percentage is in accordance with that of other clinical follow-up studies. Further assessment of glucose tolerance by an oral glucose tolerance test would be preferable, but this was not possible because of limited resources and for practical reasons. The metformin effect We found no difference in weight gain from the first trimester of pregnancy to the current follow-up on the basis of randomization. Women randomly assigned to metformin gained less weight during pregnancy than those randomly assigned to placebo. However, maternal BMI increase from the first trimester to 1 year postpartum was higher in the metformin group (13). These findings may be explained by weight homeostasis mechanisms restoring prepregnancy weight (18). Interestingly, the average annual weight gain of 0.25 kg (0.44 kg when eight cases of bariatric surgery were excluded) in the follow-up period is relatively small in the current study compared with the background population. In a Norwegian population-based cohort, mean 11-year weight gain was 7.0 kg (0.64 kg/y) in those aged 30 to 39 years (19). A higher baseline weight (mean, 80.0 kg) in women with PCOS compared with that of the Norwegian cohort (mean, 64.1 kg) may partly explain this observation. In an Australian community-based longitudinal cohort of women in their 20s with PCOS, a 10-year weight gain of 6.6 kg (0.66 kg/y) was reported (20). Women participating in the present follow-up were older. Moderate weight increase in the fourth decade of life onward might point to a different pattern of weight changes through life in women with PCOS, who are more susceptible to weight gain in adolescence and the early reproductive years. Another possible explanation may be that all participants (metformin and placebo groups) received counseling on lifestyle and diet when entering the original study. Both the counseling itself and the timing of it, in early pregnancy, might have had a lasting effect on lifestyle and weight management. Contrary to our assumptions, the lower weight gain and metformin treatment as such during pregnancy did not affect maternal metabolic risk factors or lower the trajectory of insulin resistance 7.7 years postpartum. Women with PCOS were reported to have higher gestational weight gain than controls (21). In nonobese women without PCOS, measurement of maternal insulin concentration in the upper quartile in early pregnancy was associated with increased gestational weight gain and higher postpartum weight retention (22). Insulin resistance was reported to remain more pronounced 18 months postpartum in women with PCOS than in women without PCOS but with gestational DM (23). According to the “metabolic memory” theory, in patients with type 2 DM, early intensive glycemic control is proposed to prevent high plasma glucose levels from triggering the known mechanisms of endothelial damage, such as oxidative stress, nonenzymatic glycation of proteins, epigenetic changes, and chronic inflammation. In in vitro studies, metformin, among other pharmaceutical interventions used to prevent long-term consequences of hyperglycemia, showed a strong inhibitory effect on the formation and accumulation of advanced glycation end products after nonenzymatic glycation (24). One could hypothesize that in addition to lowering gluconeogenesis, increasing peripheral glucose use, and delaying glucose absorption, metformin has beneficial effects in suppressing progression of hyperglycemia-induced metabolic memory changes during the pregnant state. Participants in the PregMet Study were diagnosed according to the Rotterdam criteria, and 72% presented with a phenotype that included hyperandrogenism. No difference in metabolic risk factors were detected between hyperandrogenic vs normoandrogenic women at follow-up (data not shown). The prevalence of MetS, type 2 DM, and CVD was low in the current study, as could be expected at a mean age of 37 years. Data on the risk of hard end points such as CVD in postmenopausal women with PCOS is diverging. Some studies suggest that protective factors are activated, prohibiting increased CVD risk factors from translating to CVD (25). Conclusion At follow-up 7.7 years postpartum, the weight and metabolic health of women with PCOS were not influenced by metformin use in pregnancy. Weight increase in the fourth decade of life in women with PCOS was less than that in the general population. Abbreviations: Abbreviations: BMI body mass index BP blood pressure CVD cardiovascular disease DM diabetes mellitus HDL high-density lipoprotein HOMA homeostatic model assessment MetS metabolic syndrome PCOS polycystic ovary syndrome PregMet Study Metformin in Pregnant PCOS Women Study Acknowledgments We thank all participants in the PregMet Study and the present follow-up study for their contributions. Financial Support: The Research Council of Norway and Felles Forskningsutvalg (Norwegian University of Science and Technology, Faculty of Medicine and Health Sciences/St. Olavs Hospital Trust) funded the present follow-up study (to M.O.U.). Novo Nordisk Foundation Norway supported the study (to M.O.U.). None of the funders had a role in the collection, analysis, and interpretation of data or in the writing of the primary reports from these studies or was in any way involved in this follow-up study of the women. Clinical Trial Information: ClinicalTrials.gov nos. NCT00159536 (The PregMet Study) (registered 12 September 2005) and NCT03259919 (the pilot study) (registered October 2000). Disclosure Summary: The authors have nothing to disclose. References 1. Azziz R , Carmina E , Dewailly D , Diamanti-Kandarakis E , Escobar-Morreale HF , Futterweit W , Janssen OE , Legro RS , Norman RJ , Taylor AE , Witchel SF ; Task Force on the Phenotype of the Polycystic Ovary Syndrome of The Androgen Excess and PCOS Society . The Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome: the complete task force report . Fertil Steril . 2009 ; 91 ( 2 ): 456 – 488 . Google Scholar CrossRef Search ADS PubMed 2. March WA , Moore VM , Willson KJ , Phillips DI , Norman RJ , Davies MJ . The prevalence of polycystic ovary syndrome in a community sample assessed under contrasting diagnostic criteria . Hum Reprod . 2010 ; 25 ( 2 ): 544 – 551 . Google Scholar CrossRef Search ADS PubMed 3. Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group . Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome . Fertil Steril . 2004 ; 81 ( 1 ): 19 – 25 . CrossRef Search ADS 4. Boomsma CM , Eijkemans MJ , Hughes EG , Visser GH , Fauser BC , Macklon NS . A meta-analysis of pregnancy outcomes in women with polycystic ovary syndrome . Hum Reprod Update . 2006 ; 12 ( 6 ): 673 – 683 . Google Scholar CrossRef Search ADS PubMed 5. Kjerulff LE , Sanchez-Ramos L , Duffy D . Pregnancy outcomes in women with polycystic ovary syndrome: a metaanalysis . Am J Obstet Gynecol . 2011 ; 204 ( 6 ): 558.e1 – 558.e6 . Google Scholar CrossRef Search ADS 6. Qin JZ , Pang LH , Li MJ , Fan XJ , Huang RD , Chen HY . Obstetric complications in women with polycystic ovary syndrome: a systematic review and meta-analysis . Reprod Biol Endocrinol . 2013 ; 11 ( 1 ): 56 . Google Scholar CrossRef Search ADS PubMed 7. Fraser A , Nelson SM , Macdonald-Wallis C , Cherry L , Butler E , Sattar N , Lawlor DA . Associations of pregnancy complications with calculated cardiovascular disease risk and cardiovascular risk factors in middle age: the Avon Longitudinal Study of Parents and Children . Circulation . 2012 ; 125 ( 11 ): 1367 – 1380 . Google Scholar CrossRef Search ADS PubMed 8. Siega-Riz AM , Viswanathan M , Moos MK , Deierlein A , Mumford S , Knaack J , Thieda P , Lux LJ , Lohr KN . A systematic review of outcomes of maternal weight gain according to the Institute of Medicine recommendations: birthweight, fetal growth, and postpartum weight retention . Am J Obstet Gynecol . 2009 ; 201 ( 4 ): 339.e1 – 339.e14 . Google Scholar CrossRef Search ADS 9. Norman JE , Reynolds RM . The consequences of obesity and excess weight gain in pregnancy . Proc Nutr Soc . 2011 ; 70 ( 4 ): 450 – 456 . Google Scholar CrossRef Search ADS PubMed 10. Kominiarek MA , Peaceman AM . Gestational weight gain . Am J Obstet Gynecol . 2017 ; 217 ( 6 ): 642 – 651 . Google Scholar CrossRef Search ADS PubMed 11. Gunderson EP , Abrams B , Selvin S . The relative importance of gestational gain and maternal characteristics associated with the risk of becoming overweight after pregnancy . Int J Obes Relat Metab Disord . 2000 ; 24 ( 12 ): 1660 – 1668 . Google Scholar CrossRef Search ADS PubMed 12. Linné Y , Dye L , Barkeling B , Rössner S . Long-term weight development in women: a 15-year follow-up of the effects of pregnancy . Obes Res . 2004 ; 12 ( 7 ): 1166 – 1178 . Google Scholar CrossRef Search ADS PubMed 13. Carlsen SM , Martinussen MP , Vanky E . Metformin’s effect on first-year weight gain: a follow-up study . Pediatrics . 2012 ; 130 ( 5 ): e1222 – e1226 . Google Scholar CrossRef Search ADS PubMed 14. Glintborg D , Henriksen JE , Andersen M , Hagen C , Hangaard J , Rasmussen PE , Schousboe K , Hermann AP . Prevalence of endocrine diseases and abnormal glucose tolerance tests in 340 Caucasian premenopausal women with hirsutism as the referral diagnosis . Fertil Steril . 2004 ; 82 ( 6 ): 1570 – 1579 . Google Scholar CrossRef Search ADS PubMed 15. Daan NM , Louwers YV , Koster MP , Eijkemans MJ , de Rijke YB , Lentjes EW , Fauser BC , Laven JS . Cardiovascular and metabolic profiles amongst different polycystic ovary syndrome phenotypes: who is really at risk ? Fertil Steril . 2014 ; 102 ( 5 ): 1444 – 1451.e3 . Google Scholar CrossRef Search ADS PubMed 16. Legro RS , Arslanian SA , Ehrmann DA , Hoeger KM , Murad MH , Pasquali R , Welt CK ; Endocrine Society . Diagnosis and treatment of polycystic ovary syndrome: an Endocrine Society clinical practice guideline . J Clin Endocrinol Metab . 2013 ; 98 ( 12 ): 4565 – 4592 . Google Scholar CrossRef Search ADS PubMed 17. Vanky E , Stridsklev S , Heimstad R , Romundstad P , Skogøy K , Kleggetveit O , Hjelle S , von Brandis P , Eikeland T , Flo K , Berg KF , Bunford G , Lund A , Bjerke C , Almås I , Berg AH , Danielson A , Lahmami G , Carlsen SM . Metformin versus placebo from first trimester to delivery in polycystic ovary syndrome: a randomized, controlled multicenter study . J Clin Endocrinol Metab . 2010 ; 95 ( 12 ): E448 – E455 . Google Scholar CrossRef Search ADS PubMed 18. Greenway FL . Physiological adaptations to weight loss and factors favouring weight regain . Int J Obes . 2015 ; 39 ( 8 ): 1188 – 1196 . Google Scholar CrossRef Search ADS 19. Drøyvold WB , Nilsen TI , Krüger O , Holmen TL , Krokstad S , Midthjell K , Holmen J . Change in height, weight and body mass index: longitudinal data from the HUNT Study in Norway . Int J Obes . 2006 ; 30 ( 6 ): 935 – 939 . Google Scholar CrossRef Search ADS 20. Teede HJ , Joham AE , Paul E , Moran LJ , Loxton D , Jolley D , Lombard C . Longitudinal weight gain in women identified with polycystic ovary syndrome: results of an observational study in young women . Obesity (Silver Spring) . 2013 ; 21 ( 8 ): 1526 – 1532 . Google Scholar CrossRef Search ADS PubMed 21. Sir-Petermann T , Hitchsfeld C , Maliqueo M , Codner E , Echiburú B , Gazitúa R , Recabarren S , Cassorla F . Birth weight in offspring of mothers with polycystic ovarian syndrome . Hum Reprod . 2005 ; 20 ( 8 ): 2122 – 2126 . Google Scholar CrossRef Search ADS PubMed 22. Scholl TO , Chen X . Insulin and the “thrifty” woman: the influence of insulin during pregnancy on gestational weight gain and postpartum weight retention . Matern Child Health J . 2002 ; 6 ( 4 ): 255 – 261 . Google Scholar CrossRef Search ADS PubMed 23. Palomba S , Falbo A , Russo T , Rivoli L , Orio M , Cosco AG , Vero R , Capula C , Tolino A , Zullo F , Colao A , Orio F . The risk of a persistent glucose metabolism impairment after gestational diabetes mellitus is increased in patients with polycystic ovary syndrome . Diabetes Care . 2012 ; 35 ( 4 ): 861 – 867 . Google Scholar CrossRef Search ADS PubMed 24. Rahbar S , Natarajan R , Yerneni K , Scott S , Gonzales N , Nadler JL . Evidence that pioglitazone, metformin and pentoxifylline are inhibitors of glycation . Clin Chim Acta . 2000 ; 301 ( 1-2 ): 65 – 77 . Google Scholar CrossRef Search ADS PubMed 25. Schmidt J , Landin-Wilhelmsen K , Brännström M , Dahlgren E . Cardiovascular disease and risk factors in PCOS women of postmenopausal age: a 21-year controlled follow-up study . J Clin Endocrinol Metab . 2011 ; 96 ( 12 ): 3794 – 3803 . Google Scholar CrossRef Search ADS PubMed Copyright © 2018 Endocrine Society http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Clinical Endocrinology and Metabolism Oxford University Press

Does Metformin Treatment During Pregnancy Modify the Future Metabolic Profile in Women With PCOS?

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Endocrine Society
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Copyright © 2018 Endocrine Society
ISSN
0021-972X
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1945-7197
D.O.I.
10.1210/jc.2018-00485
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Abstract

Abstract Context Worldwide, metformin is prescribed to improve pregnancy outcome in polycystic ovary syndrome (PCOS). Metformin may also benefit future health by modulating increased metabolic stress during pregnancy. Objective To investigate whether metformin during pregnancy modified future metabolic health in women with PCOS. Design Follow-up study of a randomized controlled trial that compared metformin with placebo in women with PCOS. Mean follow-up period was 7.7 years (range, 5 to 11 years). Setting Three university hospitals, seven local hospitals, and one gynecological specialist practice. Participants Women with PCOS according to Rotterdam criteria; all former participants in the Metformin in Pregnant PCOS Women Study. Intervention Metformin 2000 mg daily or placebo from first trimester to delivery in the original study. No intervention in the present follow-up study. Main Outcomes and Measures Main outcome measure was weight gain in the follow-up period. Weight, body mass index (BMI), waist and hip circumferences, and blood pressure (BP) were registered. Body composition was assessed by bioelectrical impedance analysis, and fasting lipids, glucose, and insulin were analyzed. Results Of 239 invited women, 131 (55%) participated in the follow-up. Weight gain was similar in women given metformin (2.1 ± 10.5 kg) and women given placebo (1.8 ± 11.2 kg) at 7.7 years’ follow-up after pregnancy (P = 0.834). No difference was found in BMI, waist/hip ratio, BP, body composition, lipids, glucose and insulin levels, or prevalence of metabolic syndrome at follow-up between those treated with metformin and those treated with placebo during pregnancy. Conclusion Metformin treatment during pregnancy did not influence the metabolic profile in women with PCOS at 7.7 years of follow-up. Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in young women (1). Using the Rotterdam criteria, the prevalence of PCOS is estimated to be 10% to 14% in the general population (2, 3). Implications of the syndrome are multifaceted, and PCOS is associated with metabolic impairment and increased risk of pregnancy complications. Data from meta-analyses show a threefold increase in gestational diabetes mellitus (DM) among women with PCOS (4–6). Pregnancy entails metabolic and homeostatic alterations and a physiological increase in insulin resistance, particularly during the third trimester. In a large cohort of women, a history of pregnancy complications such as preeclampsia, gestational diabetes, and giving birth to a small-for-gestational-age infant were indicators of an increased risk of cardiovascular disease (CVD) later in life (7). Awareness of these trajectories provides an opportunity for early identification of women at risk. Excessive weight gain in pregnancy has a negative effect on obstetric outcome (8–10). Women with high gestational weight gain have a threefold increased risk of being overweight at first prenatal visit in a consecutive pregnancy compared with the risk in women with normal or low gestational weight gain (11). Excessive postpartum weight retention at the end of the first year postpartum is a predictor for being overweight 15 years later (12). We previously reported that women with PCOS randomly assigned to metformin 2 g/d gained less weight during pregnancy (13). Insulin resistance, although not a criterion for PCOS, affects the majority of women with the syndrome. Among hirsute women with PCOS in a Danish cohort, increased fasting insulin level was found in 28% of women with body mass index (BMI) ≤25 kg/m2 and in 74% of women with BMI >25 kg/m2 (14). Hyperandrogenism seems to worsen insulin resistance in PCOS, with insulin resistance found in 43% of hyperandrogenic women compared with 14% of normo-androgenic women (15). Metformin is a multipotent drug that exerts its effect on several tissues that are sensitive to insulin, such as liver, skeletal muscle, and adipose tissue. The Endocrine Society guideline on PCOS recommends lifestyle interventions such as physical exercise and weight loss as primary treatment of overweight and obesity in PCOS. Metformin is recommended as second-line treatment when type 2 DM or impaired glucose tolerance is present and lifestyle intervention is insufficient to improve metabolic dysfunction. In addition, metformin is recommended for menstrual irregularity in women with PCOS when treatment with hormonal contraceptives is contraindicated or not tolerated (16). Worldwide, metformin is prescribed in the first trimester and onward in an attempt to improve pregnancy outcome in PCOS. Metformin may also benefit future maternal health by modulating increased metabolic stress during pregnancy To our knowledge, prospective data regarding postpartum metabolic health in women with PCOS have not been published. In the current study, we aimed to explore possible effects of metformin treatment during pregnancy on long-term metabolic health. Materials and Methods The current study is a follow-up to a randomized, controlled, double-blind, multicenter trial. Mothers who participated in the Metformin in Pregnant PCOS Women Study (the PregMet Study) (17) from 2005 to 2009 were eligible for participation in the follow-up. Women with PCOS were randomly assigned to metformin or placebo from the first trimester to delivery to assess whether metformin reduced pregnancy complications. Study design The PregMet Study In all, 257 women with 274 pregnancies were included at 11 study centers in Norway: three university hospitals, seven local hospitals, and one gynecological specialist practice. Randomization, blinding, and examinations are described elsewhere (17). Inclusion criteria for the PregMet Study were (1) PCOS diagnosed according to the Rotterdam criteria (3), (2) age 18 to 45 years, (3) gestational age between 5 and 12 weeks, and (4) a viable singleton fetus shown on ultrasonography. The participants received counseling on lifestyle and diet at inclusion, before randomization to metformin (2 g/d) or placebo. To counteract possible metformin effects on folate or vitamin B12 levels, the participants were advised to take 0.8 mg of folate and one multivitamin tablet daily throughout pregnancy. The follow-up study From April 2014 to July 2016, a total of 239 women were invited to participate in the follow-up. The inclusion criterion was participation in the PregMet Study. Exclusion criteria were ongoing pregnancy and breastfeeding (Fig. 1). Participants who dropped out (n = 12), miscarried (n = 3), or lost their children (n = 3) were not invited. Seventeen of the women participated twice in the PregMet Study. When women participated twice and were randomized equally, data from the first participation were recorded; when they were randomized once to metformin and once to placebo, the data from the metformin-exposed pregnancy were used. Nonresponders received two reminders about 1 to 2 months and 6 to 7 months after the first letter. In all, 131 women (55%) agreed to participate in the follow-up. One hundred seventeen women met for a physical examination and interview, whereas 14 were interviewed by phone and gave self-reported data. Two medical students and a trained midwife examined the participants and collected the data. Standardized interviewer-administered questionnaires were used to obtain self-reported data on former medical and gynecological/obstetric history, contraceptives, ethnicity, education, civil status, smoking, physical activity, and current use of metformin. Figure 1. View largeDownload slide Flowchart showing randomization, dropouts, and exclusions. Figure 1. View largeDownload slide Flowchart showing randomization, dropouts, and exclusions. Blood pressure (BP) was measured three times, 2 minutes apart, with digital devices, with the participant in a sitting position after at least 15 minutes of rest in a chair. The mean of the second and third measurements was calculated. Height and waist and hip circumferences were measured manually and rounded off to the closest 0.5 cm. Body composition and weight were measured using bioelectrical impedance (InBody 720; BIOSPACE, Seoul, South Korea). The examination was performed with the participant wearing light and snug clothes and no shoes. InBody gives an estimate of total body fluids, proteins, minerals, and fat and was validated against dual-energy X-ray absorptiometry. Blood samples were drawn from an antecubital vein between 0800 and 1100 hours after an overnight fast. All analyses except insulin were performed directly, using standard procedures at St. Olavs Hospital, Trondheim, Norway. Insulin was analyzed at Oslo University Hospital, Aker, Norway. The homeostatic model assessment (HOMA) index was computed as [fasting glucose (mmol/L) × fasting insulin concentration (mU/L)] /22.5. HOMA-β was calculated using the following formula: 20 × fasting insulin (mU/L)/fasting glucose (mmol/L) − 3.5. The prevalence of metabolic syndrome (MetS) was estimated according to the Rotterdam consensus (3). Three of the following five criteria were required: waist circumference >88 cm; triglycerides ≥150 mg/dL (1.7 mmol/L); high-density lipoprotein (HDL) ≤50 mg/dL (1.3 mmol/L); systolic BP ≥130 mm Hg and/or diastolic BP ≥85 mm Hg; and fasting glucose 110 to 126 mg/dL (6.11 to 6.99 nmol/L) and/or 2-hour oral glucose tolerance test glucose 140 to 199 mg/dL (7.78 to 11.04 nmol/L). The more widely applicable guideline, the National Cholesterol Education Program–Adult Treatment Panel III definition, requires the presence of at least three of the following five criteria: waist circumference >88 cm; triglycerides ≥150 mg/dL (1.7 mmol/L) or drug treatment of elevated triglycerides; HDL ≤50 mg/dL (1.3 mmol/L) or drug treatment of reduced HDL cholesterol; systolic BP ≥130 mm Hg and/or diastolic BP ≥85 mm Hg or treatment of elevated BP; and fasting glucose ≥100 mg/dL (5.6 nmol/L). Participants were asked if they had been diagnosed with type 2 DM, hypertension, CVD, or depression. Statistical analyses Statistics were performed with SPSS version 24 (IBM Corp., Armonk, NY). Data were reported as mean ± standard deviation or absolute numbers (percentages). Differences between study groups were assessed with two-tailed t tests for independent samples. Fisher exact test was used for evaluation of discrete data. To adjust for multiple testing, we considered significance as a two-tailed P value < 0.01. Ethical approval Written informed consent was obtained from each participant before inclusion, and the Declaration of Helsinki was followed throughout the study. The Regional Committees for Medical and Health Research Ethics Mid-Norway approved the current study (04.04.2014, reference number: 2014/96). Results In all, 131 of 239 invited participants (55%) in the PregMet Study agreed to participate in this follow-up. The only difference between the metformin and the placebo groups at baseline (i.e., at inclusion in the PregMet Study) was lower total cholesterol level in the placebo group (Table 1). Women who participated in the follow-up and those who declined were comparable at baseline, except for a tendency toward more smokers among those who declined, n = 7 vs 15 (P = 0.051) (data not shown). In the PregMet Study, 80% of the participants took >85% of the study medication. Table 1. Baseline Characteristics of Participants (N = 131) at First Trimester of Pregnancy in the PregMet Study Metformin (n = 66) Placebo (n = 65) Age, y 29.5 ± 3.9 30.1 ± 4.1 Weight, kg 79.9 ± 19.5 80.1 ± 17.7 BMI, kg/m2 28.7 ± 6.9 28.5 ± 6.2 Systolic BP, mm Hg 118 ± 12 118 ± 12 Diastolic BP, mm Hg 73 ± 10 72 ± 10 Fasting glucose, mmol/L 4.6 ± 0.5 4.7 ± 0.6 2-h glucose, mmol/L 5.3 ± 1.5 5.4 ± 1.7 Cholesterol, mmol/L 4.8 ± 1.1 4.4 ± 0.7 HDL cholesterol, mmol/L 1.6 ± 0.4 1.6 ± 0.3 Triglycerides, mmol/L 1.2 ± 0.5 1.1 ± 0.5 Hyperandrogenic phenotype, n (%) 48 (72.7) 46 (70.8) Normoandrogenic phenotype, n (%) 18 (27.3) 19 (29.2) Metformin (n = 66) Placebo (n = 65) Age, y 29.5 ± 3.9 30.1 ± 4.1 Weight, kg 79.9 ± 19.5 80.1 ± 17.7 BMI, kg/m2 28.7 ± 6.9 28.5 ± 6.2 Systolic BP, mm Hg 118 ± 12 118 ± 12 Diastolic BP, mm Hg 73 ± 10 72 ± 10 Fasting glucose, mmol/L 4.6 ± 0.5 4.7 ± 0.6 2-h glucose, mmol/L 5.3 ± 1.5 5.4 ± 1.7 Cholesterol, mmol/L 4.8 ± 1.1 4.4 ± 0.7 HDL cholesterol, mmol/L 1.6 ± 0.4 1.6 ± 0.3 Triglycerides, mmol/L 1.2 ± 0.5 1.1 ± 0.5 Hyperandrogenic phenotype, n (%) 48 (72.7) 46 (70.8) Normoandrogenic phenotype, n (%) 18 (27.3) 19 (29.2) Data are presented as mean ± standard deviation or n (%) as appropriate. View Large Table 1. Baseline Characteristics of Participants (N = 131) at First Trimester of Pregnancy in the PregMet Study Metformin (n = 66) Placebo (n = 65) Age, y 29.5 ± 3.9 30.1 ± 4.1 Weight, kg 79.9 ± 19.5 80.1 ± 17.7 BMI, kg/m2 28.7 ± 6.9 28.5 ± 6.2 Systolic BP, mm Hg 118 ± 12 118 ± 12 Diastolic BP, mm Hg 73 ± 10 72 ± 10 Fasting glucose, mmol/L 4.6 ± 0.5 4.7 ± 0.6 2-h glucose, mmol/L 5.3 ± 1.5 5.4 ± 1.7 Cholesterol, mmol/L 4.8 ± 1.1 4.4 ± 0.7 HDL cholesterol, mmol/L 1.6 ± 0.4 1.6 ± 0.3 Triglycerides, mmol/L 1.2 ± 0.5 1.1 ± 0.5 Hyperandrogenic phenotype, n (%) 48 (72.7) 46 (70.8) Normoandrogenic phenotype, n (%) 18 (27.3) 19 (29.2) Metformin (n = 66) Placebo (n = 65) Age, y 29.5 ± 3.9 30.1 ± 4.1 Weight, kg 79.9 ± 19.5 80.1 ± 17.7 BMI, kg/m2 28.7 ± 6.9 28.5 ± 6.2 Systolic BP, mm Hg 118 ± 12 118 ± 12 Diastolic BP, mm Hg 73 ± 10 72 ± 10 Fasting glucose, mmol/L 4.6 ± 0.5 4.7 ± 0.6 2-h glucose, mmol/L 5.3 ± 1.5 5.4 ± 1.7 Cholesterol, mmol/L 4.8 ± 1.1 4.4 ± 0.7 HDL cholesterol, mmol/L 1.6 ± 0.4 1.6 ± 0.3 Triglycerides, mmol/L 1.2 ± 0.5 1.1 ± 0.5 Hyperandrogenic phenotype, n (%) 48 (72.7) 46 (70.8) Normoandrogenic phenotype, n (%) 18 (27.3) 19 (29.2) Data are presented as mean ± standard deviation or n (%) as appropriate. View Large We found no difference in weight-gain (from the first trimester of pregnancy to follow-up), BMI, waist/hip ratio, BP levels, body composition, fasting lipid levels, fasting glucose levels, or HOMA index when comparing metformin-treated women with placebo-treated women at follow-up (Table 2). Prevalence of MetS, type 2 DM, hypertension, CVD, and depression was comparable between the metformin and placebo groups. Participants with hyperandrogenism were comparable to those without hyperandrogenism regarding waist circumference, BP, fasting lipids, glucose, and HOMA index (data not shown). Education level, civil status, and parity were similar in both groups at follow-up (Table 3). Table 2. Anthropometry and Endocrine Characteristics of Women With PCOS at 5- to 11-Year Follow-Up, Categorized According to Use of Metformin or Placebo During Pregnancy Metformin (n = 66) Placebo (n = 65) P Value Follow-up, y 7.6 ± 1.4 7.7 ± 1.2 0.696 Age, y 37.5 ± 4.2 38.5 ± 4.7 0.180 Weight, kg 82.0 ± 19.4 81.9 ± 18.4 0.960 BMI, kg/m2 29.6 ± 6.9 29.3 ± 6.9 0.790 Δ weight: inclusion to follow-up, kg 2.1 ± 10.5 1.8 ± 11.2 0.834 Δ weight per year: inclusion to follow-up, kg 0.30 ± 1.40 0.20 ± 1.48 0.711 Waist, cm 90.7 ± 15.5 89.9 ± 14.4 0.748 Hip, cm 107.3 ± 15.5 108.4 ± 13.1 0.664 Waist/hip ratio 0.90 ± 0.07 0.90 ± 0.08 0.609 Waist >88 cm, n (%) 38 (59) 33 (52) 0.481 Body muscle mass, kg 28.3 ± 4.3 28.8 ± 3.2 0.559 Body fat, kg 31.6 ± 15.0 33.8 ± 16.7 0.521 Body fat, % 36.4 ± 9.4 37.6 ± 10.1 0.575 Visceral fat area, cm2 128.4 ± 64.1 135.6 ± 72.3 0.637 Systolic BP, mm Hg 119 ± 14 119 ± 14 0.817 Diastolic BP, mm Hg 78 ± 10 77 ± 11 0.555 Fasting glucose, mmol/L 5.1 ± 0.5 5.2 ± 0.7 0.329 Fasting insulin, µIU/mL 10.8 ± 7.5 12.0 ± 7.6 0.437 HOMA-IR index 2.4 ± 1.6 2.9 ± 1.9 0.155 HOMA-β 1.3 ± 0.7 1.4 ± 1.1 0.886 c-Peptide, nmol/L 0.67 ± 0.34 0.77 ± 0.37 0.148 HbA1c, % 5.2 ± 0.26 5.2 ± 0.45 0.624 Total cholesterol, mmol/L 4.7 ± 0.8 4.6 ± 0.7 0.234 HDL cholesterol, mmol/L 1.5 ± 0.4 1.5 ± 0.4 0.850 Triglycerides, mmol/L 1.0 ± 0.5 1.0 ± 0.6 0.450 MetS “Rotterdam” criteria, n (%) 12 (18.2) 10 (15.4) 0.816 MetS NCEP-ATPIII 2005, n (%) 15 (22.7) 12 (18.5) 0.667 Type 2 diabetes mellitus, n (%) 0 (0) 3 (4.6) 0.119 Hypertension, n (%) 5 (7.6) 4 (6.2) 1.000 CVD, n (%) 0 (0) 1 (1.5) 0.496 Depression, n (%) 8 (12.1) 9 (13.8) 0.800 Bariatric surgery, n (%) 6 (9.1) 2 (3.1) 0.274 Smoking, n (%) 8 (12.3) 8 (12.3) 1.0 Current use of metformin, n (%) 5 (7.6) 8 (12.3) 0.397 Metformin (n = 66) Placebo (n = 65) P Value Follow-up, y 7.6 ± 1.4 7.7 ± 1.2 0.696 Age, y 37.5 ± 4.2 38.5 ± 4.7 0.180 Weight, kg 82.0 ± 19.4 81.9 ± 18.4 0.960 BMI, kg/m2 29.6 ± 6.9 29.3 ± 6.9 0.790 Δ weight: inclusion to follow-up, kg 2.1 ± 10.5 1.8 ± 11.2 0.834 Δ weight per year: inclusion to follow-up, kg 0.30 ± 1.40 0.20 ± 1.48 0.711 Waist, cm 90.7 ± 15.5 89.9 ± 14.4 0.748 Hip, cm 107.3 ± 15.5 108.4 ± 13.1 0.664 Waist/hip ratio 0.90 ± 0.07 0.90 ± 0.08 0.609 Waist >88 cm, n (%) 38 (59) 33 (52) 0.481 Body muscle mass, kg 28.3 ± 4.3 28.8 ± 3.2 0.559 Body fat, kg 31.6 ± 15.0 33.8 ± 16.7 0.521 Body fat, % 36.4 ± 9.4 37.6 ± 10.1 0.575 Visceral fat area, cm2 128.4 ± 64.1 135.6 ± 72.3 0.637 Systolic BP, mm Hg 119 ± 14 119 ± 14 0.817 Diastolic BP, mm Hg 78 ± 10 77 ± 11 0.555 Fasting glucose, mmol/L 5.1 ± 0.5 5.2 ± 0.7 0.329 Fasting insulin, µIU/mL 10.8 ± 7.5 12.0 ± 7.6 0.437 HOMA-IR index 2.4 ± 1.6 2.9 ± 1.9 0.155 HOMA-β 1.3 ± 0.7 1.4 ± 1.1 0.886 c-Peptide, nmol/L 0.67 ± 0.34 0.77 ± 0.37 0.148 HbA1c, % 5.2 ± 0.26 5.2 ± 0.45 0.624 Total cholesterol, mmol/L 4.7 ± 0.8 4.6 ± 0.7 0.234 HDL cholesterol, mmol/L 1.5 ± 0.4 1.5 ± 0.4 0.850 Triglycerides, mmol/L 1.0 ± 0.5 1.0 ± 0.6 0.450 MetS “Rotterdam” criteria, n (%) 12 (18.2) 10 (15.4) 0.816 MetS NCEP-ATPIII 2005, n (%) 15 (22.7) 12 (18.5) 0.667 Type 2 diabetes mellitus, n (%) 0 (0) 3 (4.6) 0.119 Hypertension, n (%) 5 (7.6) 4 (6.2) 1.000 CVD, n (%) 0 (0) 1 (1.5) 0.496 Depression, n (%) 8 (12.1) 9 (13.8) 0.800 Bariatric surgery, n (%) 6 (9.1) 2 (3.1) 0.274 Smoking, n (%) 8 (12.3) 8 (12.3) 1.0 Current use of metformin, n (%) 5 (7.6) 8 (12.3) 0.397 Data presented as mean ± standard deviation or n (%) as appropriate. Abbreviations: HbA1c, hemoglobin A1c; HOMA-IR, homeostasis model assessment insulin resistance index; NCEP-ATPIII, National Cholesterol Education Program‒Adult Treatment Panel III. View Large Table 2. Anthropometry and Endocrine Characteristics of Women With PCOS at 5- to 11-Year Follow-Up, Categorized According to Use of Metformin or Placebo During Pregnancy Metformin (n = 66) Placebo (n = 65) P Value Follow-up, y 7.6 ± 1.4 7.7 ± 1.2 0.696 Age, y 37.5 ± 4.2 38.5 ± 4.7 0.180 Weight, kg 82.0 ± 19.4 81.9 ± 18.4 0.960 BMI, kg/m2 29.6 ± 6.9 29.3 ± 6.9 0.790 Δ weight: inclusion to follow-up, kg 2.1 ± 10.5 1.8 ± 11.2 0.834 Δ weight per year: inclusion to follow-up, kg 0.30 ± 1.40 0.20 ± 1.48 0.711 Waist, cm 90.7 ± 15.5 89.9 ± 14.4 0.748 Hip, cm 107.3 ± 15.5 108.4 ± 13.1 0.664 Waist/hip ratio 0.90 ± 0.07 0.90 ± 0.08 0.609 Waist >88 cm, n (%) 38 (59) 33 (52) 0.481 Body muscle mass, kg 28.3 ± 4.3 28.8 ± 3.2 0.559 Body fat, kg 31.6 ± 15.0 33.8 ± 16.7 0.521 Body fat, % 36.4 ± 9.4 37.6 ± 10.1 0.575 Visceral fat area, cm2 128.4 ± 64.1 135.6 ± 72.3 0.637 Systolic BP, mm Hg 119 ± 14 119 ± 14 0.817 Diastolic BP, mm Hg 78 ± 10 77 ± 11 0.555 Fasting glucose, mmol/L 5.1 ± 0.5 5.2 ± 0.7 0.329 Fasting insulin, µIU/mL 10.8 ± 7.5 12.0 ± 7.6 0.437 HOMA-IR index 2.4 ± 1.6 2.9 ± 1.9 0.155 HOMA-β 1.3 ± 0.7 1.4 ± 1.1 0.886 c-Peptide, nmol/L 0.67 ± 0.34 0.77 ± 0.37 0.148 HbA1c, % 5.2 ± 0.26 5.2 ± 0.45 0.624 Total cholesterol, mmol/L 4.7 ± 0.8 4.6 ± 0.7 0.234 HDL cholesterol, mmol/L 1.5 ± 0.4 1.5 ± 0.4 0.850 Triglycerides, mmol/L 1.0 ± 0.5 1.0 ± 0.6 0.450 MetS “Rotterdam” criteria, n (%) 12 (18.2) 10 (15.4) 0.816 MetS NCEP-ATPIII 2005, n (%) 15 (22.7) 12 (18.5) 0.667 Type 2 diabetes mellitus, n (%) 0 (0) 3 (4.6) 0.119 Hypertension, n (%) 5 (7.6) 4 (6.2) 1.000 CVD, n (%) 0 (0) 1 (1.5) 0.496 Depression, n (%) 8 (12.1) 9 (13.8) 0.800 Bariatric surgery, n (%) 6 (9.1) 2 (3.1) 0.274 Smoking, n (%) 8 (12.3) 8 (12.3) 1.0 Current use of metformin, n (%) 5 (7.6) 8 (12.3) 0.397 Metformin (n = 66) Placebo (n = 65) P Value Follow-up, y 7.6 ± 1.4 7.7 ± 1.2 0.696 Age, y 37.5 ± 4.2 38.5 ± 4.7 0.180 Weight, kg 82.0 ± 19.4 81.9 ± 18.4 0.960 BMI, kg/m2 29.6 ± 6.9 29.3 ± 6.9 0.790 Δ weight: inclusion to follow-up, kg 2.1 ± 10.5 1.8 ± 11.2 0.834 Δ weight per year: inclusion to follow-up, kg 0.30 ± 1.40 0.20 ± 1.48 0.711 Waist, cm 90.7 ± 15.5 89.9 ± 14.4 0.748 Hip, cm 107.3 ± 15.5 108.4 ± 13.1 0.664 Waist/hip ratio 0.90 ± 0.07 0.90 ± 0.08 0.609 Waist >88 cm, n (%) 38 (59) 33 (52) 0.481 Body muscle mass, kg 28.3 ± 4.3 28.8 ± 3.2 0.559 Body fat, kg 31.6 ± 15.0 33.8 ± 16.7 0.521 Body fat, % 36.4 ± 9.4 37.6 ± 10.1 0.575 Visceral fat area, cm2 128.4 ± 64.1 135.6 ± 72.3 0.637 Systolic BP, mm Hg 119 ± 14 119 ± 14 0.817 Diastolic BP, mm Hg 78 ± 10 77 ± 11 0.555 Fasting glucose, mmol/L 5.1 ± 0.5 5.2 ± 0.7 0.329 Fasting insulin, µIU/mL 10.8 ± 7.5 12.0 ± 7.6 0.437 HOMA-IR index 2.4 ± 1.6 2.9 ± 1.9 0.155 HOMA-β 1.3 ± 0.7 1.4 ± 1.1 0.886 c-Peptide, nmol/L 0.67 ± 0.34 0.77 ± 0.37 0.148 HbA1c, % 5.2 ± 0.26 5.2 ± 0.45 0.624 Total cholesterol, mmol/L 4.7 ± 0.8 4.6 ± 0.7 0.234 HDL cholesterol, mmol/L 1.5 ± 0.4 1.5 ± 0.4 0.850 Triglycerides, mmol/L 1.0 ± 0.5 1.0 ± 0.6 0.450 MetS “Rotterdam” criteria, n (%) 12 (18.2) 10 (15.4) 0.816 MetS NCEP-ATPIII 2005, n (%) 15 (22.7) 12 (18.5) 0.667 Type 2 diabetes mellitus, n (%) 0 (0) 3 (4.6) 0.119 Hypertension, n (%) 5 (7.6) 4 (6.2) 1.000 CVD, n (%) 0 (0) 1 (1.5) 0.496 Depression, n (%) 8 (12.1) 9 (13.8) 0.800 Bariatric surgery, n (%) 6 (9.1) 2 (3.1) 0.274 Smoking, n (%) 8 (12.3) 8 (12.3) 1.0 Current use of metformin, n (%) 5 (7.6) 8 (12.3) 0.397 Data presented as mean ± standard deviation or n (%) as appropriate. Abbreviations: HbA1c, hemoglobin A1c; HOMA-IR, homeostasis model assessment insulin resistance index; NCEP-ATPIII, National Cholesterol Education Program‒Adult Treatment Panel III. View Large Table 3. Socioeconomic Measures at 5- to 11-Year Follow-Up Metformin
(n = 66) Placebo
(n = 65) P Value Education 0.778  10 y primary school 3 (4.6) 1 (1.5)  High school 17 (26.2) 18 (27.7)  College <4 y 22 (33.8) 22 (33.8)  College ≥4 y 23 (35.4) 24 (36.9) Civil status 0.547  Married 35 (53.8) 42 (64.6)  Cohabitant 21 (32.3) 17 (26.2)  Single/divorced 6 (9.2) 5 (7.7)  Other 3 (4.6) 1 (1.5) Parity 0.809  Parity 1 11 (16.7) 9 (13.8)  Parity 2+ 55 (83.3) 56 (86.2) Metformin
(n = 66) Placebo
(n = 65) P Value Education 0.778  10 y primary school 3 (4.6) 1 (1.5)  High school 17 (26.2) 18 (27.7)  College <4 y 22 (33.8) 22 (33.8)  College ≥4 y 23 (35.4) 24 (36.9) Civil status 0.547  Married 35 (53.8) 42 (64.6)  Cohabitant 21 (32.3) 17 (26.2)  Single/divorced 6 (9.2) 5 (7.7)  Other 3 (4.6) 1 (1.5) Parity 0.809  Parity 1 11 (16.7) 9 (13.8)  Parity 2+ 55 (83.3) 56 (86.2) Data are presented as n (%). View Large Table 3. Socioeconomic Measures at 5- to 11-Year Follow-Up Metformin
(n = 66) Placebo
(n = 65) P Value Education 0.778  10 y primary school 3 (4.6) 1 (1.5)  High school 17 (26.2) 18 (27.7)  College <4 y 22 (33.8) 22 (33.8)  College ≥4 y 23 (35.4) 24 (36.9) Civil status 0.547  Married 35 (53.8) 42 (64.6)  Cohabitant 21 (32.3) 17 (26.2)  Single/divorced 6 (9.2) 5 (7.7)  Other 3 (4.6) 1 (1.5) Parity 0.809  Parity 1 11 (16.7) 9 (13.8)  Parity 2+ 55 (83.3) 56 (86.2) Metformin
(n = 66) Placebo
(n = 65) P Value Education 0.778  10 y primary school 3 (4.6) 1 (1.5)  High school 17 (26.2) 18 (27.7)  College <4 y 22 (33.8) 22 (33.8)  College ≥4 y 23 (35.4) 24 (36.9) Civil status 0.547  Married 35 (53.8) 42 (64.6)  Cohabitant 21 (32.3) 17 (26.2)  Single/divorced 6 (9.2) 5 (7.7)  Other 3 (4.6) 1 (1.5) Parity 0.809  Parity 1 11 (16.7) 9 (13.8)  Parity 2+ 55 (83.3) 56 (86.2) Data are presented as n (%). View Large Discussion Metformin use from the first trimester and throughout pregnancy did not modify maternal metabolic profile at 7.7 years postpartum. Postpartum yearly weight increase in women with PCOS was relatively low, independent of randomization. Strengths of the study This study prospectively assessed the long-term metabolic profile in a well-characterized cohort of women with PCOS after randomization to metformin or placebo treatment during pregnancy. Participants in the follow-up were representative of the original study population. Limitations of the study Participants in this follow-up were relatively young to experience serious complications of MetS, such as CVD. Risk factors of CVD may occur at this age and may potentially be modified by metformin intervention. A 55% participation rate is less than we had hoped for, but the percentage is in accordance with that of other clinical follow-up studies. Further assessment of glucose tolerance by an oral glucose tolerance test would be preferable, but this was not possible because of limited resources and for practical reasons. The metformin effect We found no difference in weight gain from the first trimester of pregnancy to the current follow-up on the basis of randomization. Women randomly assigned to metformin gained less weight during pregnancy than those randomly assigned to placebo. However, maternal BMI increase from the first trimester to 1 year postpartum was higher in the metformin group (13). These findings may be explained by weight homeostasis mechanisms restoring prepregnancy weight (18). Interestingly, the average annual weight gain of 0.25 kg (0.44 kg when eight cases of bariatric surgery were excluded) in the follow-up period is relatively small in the current study compared with the background population. In a Norwegian population-based cohort, mean 11-year weight gain was 7.0 kg (0.64 kg/y) in those aged 30 to 39 years (19). A higher baseline weight (mean, 80.0 kg) in women with PCOS compared with that of the Norwegian cohort (mean, 64.1 kg) may partly explain this observation. In an Australian community-based longitudinal cohort of women in their 20s with PCOS, a 10-year weight gain of 6.6 kg (0.66 kg/y) was reported (20). Women participating in the present follow-up were older. Moderate weight increase in the fourth decade of life onward might point to a different pattern of weight changes through life in women with PCOS, who are more susceptible to weight gain in adolescence and the early reproductive years. Another possible explanation may be that all participants (metformin and placebo groups) received counseling on lifestyle and diet when entering the original study. Both the counseling itself and the timing of it, in early pregnancy, might have had a lasting effect on lifestyle and weight management. Contrary to our assumptions, the lower weight gain and metformin treatment as such during pregnancy did not affect maternal metabolic risk factors or lower the trajectory of insulin resistance 7.7 years postpartum. Women with PCOS were reported to have higher gestational weight gain than controls (21). In nonobese women without PCOS, measurement of maternal insulin concentration in the upper quartile in early pregnancy was associated with increased gestational weight gain and higher postpartum weight retention (22). Insulin resistance was reported to remain more pronounced 18 months postpartum in women with PCOS than in women without PCOS but with gestational DM (23). According to the “metabolic memory” theory, in patients with type 2 DM, early intensive glycemic control is proposed to prevent high plasma glucose levels from triggering the known mechanisms of endothelial damage, such as oxidative stress, nonenzymatic glycation of proteins, epigenetic changes, and chronic inflammation. In in vitro studies, metformin, among other pharmaceutical interventions used to prevent long-term consequences of hyperglycemia, showed a strong inhibitory effect on the formation and accumulation of advanced glycation end products after nonenzymatic glycation (24). One could hypothesize that in addition to lowering gluconeogenesis, increasing peripheral glucose use, and delaying glucose absorption, metformin has beneficial effects in suppressing progression of hyperglycemia-induced metabolic memory changes during the pregnant state. Participants in the PregMet Study were diagnosed according to the Rotterdam criteria, and 72% presented with a phenotype that included hyperandrogenism. No difference in metabolic risk factors were detected between hyperandrogenic vs normoandrogenic women at follow-up (data not shown). The prevalence of MetS, type 2 DM, and CVD was low in the current study, as could be expected at a mean age of 37 years. Data on the risk of hard end points such as CVD in postmenopausal women with PCOS is diverging. Some studies suggest that protective factors are activated, prohibiting increased CVD risk factors from translating to CVD (25). Conclusion At follow-up 7.7 years postpartum, the weight and metabolic health of women with PCOS were not influenced by metformin use in pregnancy. Weight increase in the fourth decade of life in women with PCOS was less than that in the general population. Abbreviations: Abbreviations: BMI body mass index BP blood pressure CVD cardiovascular disease DM diabetes mellitus HDL high-density lipoprotein HOMA homeostatic model assessment MetS metabolic syndrome PCOS polycystic ovary syndrome PregMet Study Metformin in Pregnant PCOS Women Study Acknowledgments We thank all participants in the PregMet Study and the present follow-up study for their contributions. Financial Support: The Research Council of Norway and Felles Forskningsutvalg (Norwegian University of Science and Technology, Faculty of Medicine and Health Sciences/St. Olavs Hospital Trust) funded the present follow-up study (to M.O.U.). Novo Nordisk Foundation Norway supported the study (to M.O.U.). 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Journal of Clinical Endocrinology and MetabolismOxford University Press

Published: Apr 5, 2018

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