Cholesterol Center, Jewish Hospital, Cincinnati, Ohio

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1 HYPERANDROGENISM FERTILITY AND STERILITY VOL. 77, NO. 3, MARCH 2002 Copyright 2002 American Society for Reproductive Medicine Published by Elsevier Science Inc. Printed on acid-free paper in U.S.A. Metformin therapy throughout pregnancy reduces the development of gestational diabetes in women with polycystic ovary syndrome C. J. Glueck, M.D., Ping Wang, Ph.D., Suichi Kobayashi, M.D., Harvey Phillips, M.D., and Luann Sieve-Smith Cholesterol Center, Jewish Hospital, Cincinnati, Ohio Objective: To assess whether metformin safely reduced development of gestational diabetes in women with the polycystic ovary syndrome (PCOS). Design: Prospective and retrospective study. Setting: Outpatient clinical research center. Patient(s): The prospective study included 33 nondiabetic women with PCOS who conceived while taking metformin and had live births; of these, 28 were taking metformin through delivery. The retrospective study included 39 nondiabetic women with PCOS who had live birth pregnancies without metformin therapy. Intervention(s): Metformin, 2.55 g/d, throughout pregnancy in women with PCOS. Main Outcome Measure(s): Development of gestational diabetes in women with PCOS. Result(s): Before metformin therapy, after covariance adjustment for age, the two cohorts did not differ in height, weight, basal metabolic index, insulin, insulin resistance, or insulin secretion. Both cohorts had high fasting insulin, were insulin resistant, and had high insulin secretion. Among the 33 women who received metformin, gestational diabetes developed in 1 of 33 (3%) pregnancies versus 8 of 12 (67%) of their previous pregnancies without metformin. Among the 39 women who did not take metformin, gestational diabetes developed in 14 of 60 (23%) pregnancies. When all live births were combined, gestational diabetes occurred in 22 of 72 pregnancies (31%) in women who did not take metformin versus 1 of 33 pregnancies (3%) in those who took metformin. With gestational diabetes as the response variable and age at delivery and treatment group (metformin or no metformin) as explanatory variables, the odds ratio for gestational diabetes in women with metformin versus without metformin was (95% CI: to 0.795). With gestational diabetes in 93 pregnancies as the response variable and age at delivery and treatment group (metformin no metformin) as explanatory variables, the odds ratio of gestational diabetes in pregnancies in women taking metformin versus without metformin was (95% CI: to 0.938). Conclusion(s): In PCOS, use of metformin is associated with a 10-fold reduction in gestational diabetes (31% to 3%). It also reduces insulin resistance and insulin secretion, thus decreasing the secretory demands imposed on pancreatic -cells by insulin resistance and pregnancy. (Fertil Steril 2002;77: by American Society for Reproductive Medicine.) Key Words: Gestational diabetes mellitus, polycystic ovary syndrome, pregnancy, insulin resistance Received May 22, 2001; revised and accepted October 5, Reprint requests: C. J. Glueck, M.D., Cholesterol Center, ABC Building, 3200 Burnet Avenue, Cincinnati, Ohio (FAX: ; glueckch@ healthall.com) /02/$22.00 PII S (01) Gestational diabetes mellitus (1) was detected in 3.52% of pregnancies in women years of age in a cross-sectional sample of live births in the United States (2). Gestational diabetes, which is related to increasing insulin resistance during pregnancy, is associated with increased later risk for type 2 diabetes (1). Risk factors for gestational diabetes include obesity, age, genetic background, and ethnicity (1, 2). Fetal macrosomia in gestational diabetes increases rates of birth trauma and cesarean section (3, 4). Diagnosis and management of gestational diabetes may reduce perinatal, neonatal, and long-term pediatric complications (1, 3, 4). Polycystic ovary syndrome (PCOS) affects 5% 10% of women (5 13). It is defined as the association of anovulation with clinical or biochemical hyperandrogenism in women with polycystic ovarian morphology on ultrasonog- 520

2 raphy (5 18). However, (U.S.) physicians have not uniformly accepted ovarian morphology as a diagnostic criterion. Women with PCOS are characterized by obesity, insulin resistance, and hyperinsulinemia (5 19), all of which are risk factors for gestational diabetes. Women in whom gestational diabetes develops are likely to have underlying polycystic ovaries (20 22), and women with PCOS are likely to develop gestational diabetes (19, 23 26). The insulin-sensitizing drug metformin is a safe, effective, and rational treatment for the metabolic and endocrine abnormalities in PCOS (5 13, 15). In women with type 2 diabetes, women with gestational diabetes (27), and nondiabetic patients with PCOS (15), metformin was not teratogenic and reduced the otherwise high (65%) likelihood (16) of first-trimester miscarriage in PCOS by 10-fold (15). Most women with gestational diabetes mellitus can be treated satisfactorily with diet alone. However, some require insulin or (experimentally) metformin or sulfonlyureas to achieve proper metabolic control (1, 3, 4, 27 29). We sought to determine whether metformin therapy safely reduced development of gestational diabetes in women with PCOS. MATERIALS AND METHODS Design and Participants This work was performed after obtaining signed informed consent from all participants, according to a protocol approved by the Jewish Hospital Institutional Review Board. We assessed 72 women with well-defined PCOS (6, 12 17) who had a mean ( SD) age of 34 8 years, were nondiabetic before their pregnancies, and had 1 live births. The development of gestational diabetes was studied prospectively in 33 women with PCOS who conceived while taking metformin, 2.55 g/d. Of these women, 28 took metformin throughout pregnancy. Thirty-four live births occurred. Development of gestational diabetes mellitus was studied retrospectively in 39 women with PCOS who had previously conceived without taking metformin; these women had 64 live births and information on gestational diabetes was available for 60 births. At baseline, pre metformin therapy and pre diet therapy height, weight, serum glucose and insulin level, insulin resistance, and insulin secretion were compared in two cohorts. At entry and at every 2-month follow-up visit, after an 8-hour overnight fast, weight, systolic and diastolic blood pressure, glucose, lipids, estradiol, progesterone, LH, FSH, androstenedione, DHEAS, testosterone, sex hormone binding globulin, serum insulin, and lactic acid were measured (6). Homeostasis model assessment (HOMA) formulae (30) were used to calculate insulin resistance and -cell function. At entry, 17-hydroxyprogesterone, prolactin, T 4, TSH, and cortisol were measured to rule out diseases that can mimic PCOS or affect its presentation (6, 17). In the prospective cohort, all women were instructed in a 1500-calorie/d, high-protein (26% of calories), low-carbohydrate (44%) diet, with 30% of calories as fat. After conception, calorie restrictions were dropped and continued adherence to the low-carbohydrate, high-protein diet was encouraged. Before and throughout pregnancy, folic acid (1 mg/d) was given. Patients with PCOS The diagnosis of PCOS (5 19) was based on the 1990 National Institutes of Health criteria (17): oligomenorrhea or amenorrhea, biochemical or clinical hyperandrogenism (31), or polycystic ovaries on ultrasonography and exclusion of disorders that mimic PCOS (17). Homeostasis model assessment insulin resistance (30) and hyperinsulinemia (6, 15, 32) were not required criteria for entry into the study. Exclusion criteria (6, 15) were serum creatinine level 1.5 mg/dl, other virilizing endocrinopathies, pituitary insufficiency, type 1 diabetes, and type 2 diabetes mellitus requiring pharmacologic therapy. Women taking drugs known to affect endogenous sex hormones or lipids and those taking valproic acid (33) in the 2 prestudy months were also excluded. Diagnosis of Gestational Diabetes Screening for gestational diabetes was done in conjunction with the patients obstetricians between the 26th and 28th weeks by using the criteria of the American Diabetes Association (34) and the National Diabetes Data Group s conversion of O Sullivan et al. s diagnostic criteria for the 100-g glucose challenge (35). Statistical Analysis Pretreatment height, weight, body mass index (BMI), glucose, insulin, insulin resistance, and insulin secretion in the two cohorts were compared after adjusting for age by analysis of variance (36). In the prospective cohort, levels before and during metformin therapy were compared by using paired nonparametric, Wilcoxon tests (36), since most of the data were not normally distributed. To compare gestational diabetes in the two cohorts, logistic regression analysis (36) was performed in which gestational diabetes (present or not present) was the response variable (70 women) and treatment (metformin or no metformin) and age at delivery (averaged age if a woman had 1 pregnancy) as the explanatory variables. A second logistic regression model assessed the odds ratio for gestational diabetes in pregnancies conceived during metformin therapy (n 33) versus those conceived without metformin therapy (60 pregnancies in 39 women). The response variable was gestational diabetes (yes or no) in 93 pregnancies, and the explanatory variables were treatment (metformin or no metformin) and age at delivery. The Fisher exact test (36) FERTILITY & STERILITY 521

3 was used to compare the frequency of gestational diabetes in women or pregnancies with or without metformin. Age- and sex-specific percentiles for height and weight in term neonates were assigned by using Centers for Disease Control and Prevention growth charts for the United States published in Sex- and gestational age specific percentiles for neonates born before 37 weeks of gestation were obtained from the study by Lubschenco et al. (37). In women with PCOS, percentile distributions of preconception BMI were determined by using age- and sex-specific data from normal Lipid Research Clinics samples (38). RESULTS Women With PCOS Who Conceived During Metformin Therapy and Had Live Births Of the 32 white women and 1 Latina who conceived while taking metformin and had live births, 18 (55%) were amenorrheic and 14 (42%) were oligomenorrheic in the year before our evaluation. Only 1 of 33 (3%) had 10 menses/y. By selection, these women had oligomenorrhea or amenorrhea, biochemical or clinical hyperandrogenism, or polycystic ovarian morphology on ultrasonography. Of these 33 women, 15 could not conceive before metformin therapy; 18 had 46 previous pregnancies without metformin, from which 12 live births (26%) and 34 miscarriages (74%) resulted. Gestational diabetes developed in 8 of these 12 previous pregnancies (67%) without metformin. In the current study, the mean duration of preconception metformin treatment in these 33 women was months (median, 5.8 months). Women With PCOS Who Previously Had Live Births Without Metformin Of the 37 white and 2 African-American women who had previous live births without metformin therapy, 21 (54%) were amenorrheic and 15 (38%) were oligomenorrheic. Three of 39 (8%) had 10 menses in the year before our evaluation. By selection, they had oligomenorrhea or amenorrhea, biochemical or clinical hyperandrogenism, or polycystic ovarian morphology on ultrasonography. These 39 women had 94 previous pregnancies without metformin therapy, resulting in 64 live births (68%), 26 miscarriages (28%), and 4 elective abortions. Studies for gestational diabetes had been done in 37 women in 60 of the 64 pregnancies resulting in live births, none of which was conceived or carried to term during metformin therapy. Insulin and Glucose Levels, HOMA Insulin Resistance, and HOMA -Cell Function Before Metformin Therapy At baseline before treatment, the 39 women in the retrospective study were older than the 33 women in the prospective study (mean [ SD], years vs years; P.0001), but at the time of delivery, the former cohort was younger ( years vs years). After covariance adjustment for age at baseline before treatment, the two cohorts did not differ in height, weight, BMI, fasting serum insulin level, insulin resistance, and insulin secretion (P.1 for all); the least-squares mean fasting glucose level was higher in the prospective cohort than the retrospective cohort (98 vs. 89 mg/dl; P.047). Both cohorts were very obese. The median weight was 90 kg and 89 kg and median BMI was 33.5 kg/m 2 and 33.6 kg/m 2 in the prospective and retrospective cohorts, respectively. Sixty-six percent of the 33 women in the prospective cohort and 54% of the 39 women in the retrospective cohort had BMI greater than or equal to the Lipid Research Clinics (38) age- and sex-specific 95th percentile. The fasting insulin level was high in the prospective and retrospective cohorts (median, 22 uu/ml and 19 uu/ml, respectively). Insulin resistance ( 90th percentile in 161 healthy normal women [5.54]) was present in 39% of the prospective cohort and in 36% of the retrospective cohort. -Cell function (insulin secretion) was high ( 361, the 90th percentile for 161 controls) in 36% and 28% of the prospective and retrospective cohorts, respectively. Development of Gestational Diabetes Gestational diabetes developed in 1 of 33 (3%) women who took metformin and in 10 of 37 (27%) without metformin (P.0074, Fisher test). Gestational diabetes developed in 1 of 33 pregnancies (3%) in the 33 women who took metformin versus 14 of 60 (23%) pregnancies in the 39 women who did not take metformin (P.016, Fisher test). When all live births without metformin were combined (gestational diabetes in 14 of 60 pregnancies in retrospective cohort and 8 of 12 previous pregnancies in the prospective cohort), gestational diabetes occurred in 22 of 72 pregnancies (31%) without metformin therapy and 1 of 33 pregnancies (3%) with metformin therapy (P.0009, Fisher test). In logistic regression analysis, after adjustment for age at delivery, the odds ratio for gestational diabetes in women who received metformin vs. those who did not receive metformin was (95% CI: to 0.795) (P.03). The odds ratio for gestational diabetes in pregnancies during metformin therapy versus those during no metformin therapy was (95% CI: to 0.938) (P.04). Gestational Age, Weight, and Height In Neonates of the Prospective Cohort The mean and median gestation of the 33 pregnancies in women taking metformin were and 39.7 weeks, respectively. Five women delivered before 37 weeks (1 each at 26, 29, and 33 weeks and 2 at 35 weeks). The distribution of height and weight in the 34 neonates (1 twin pair and 32 singleton births) closely approximated a normal distribution. For weight, 58% of neonates were in the bottom 50% of the distribution and 42% were in the top 50%. For height, 47% of neonates were in the bottom 50% of the distribution and 53% were in the top 50%. 522 Glueck et al. Metformin reduces gestational diabetes Vol. 77, No. 3, March 2002

4 Effects of Metformin In Weight, BMI, Insulin, Insulin Resistance, and Insulin Secretion In 21 of the 33 women who conceived while taking metformin, complete data was available for weight, BMI, insulin, insulin resistance, and insulin secretion. We compared values before metformin therapy with values at the last preconception visit while taking metformin. In these 21 women, median weight decreased from 94 to 88 kg (P.0001), BMI from 33.6 to 29.6 kg/m 2 (P.0001), insulin level from 23 to 14 uu/ml (P.001), insulin resistance from 5.33 to 2.87 (P.0005), and insulin secretion from 274 to 226 (P.04) after metformin therapy. In 15 women who received metformin throughout pregnancy, complete data were available before metformin therapy, baseline before pregnancy, at the last preconception visit during metformin therapy, at the first visit at 4 6 weeks of gestation during metformin therapy, and the mean of subsequent visits during pregnancy while taking metformin (Fig. 1). From baseline to the last visit while taking metformin before conception, median weight decreased from 102 to 88 kg (P.0001), BMI from 33.9 to 30.3 kg/m 2 (P.0001), insulin from 23 to 15 uu/ml (P.04), and insulin resistance from 4.82 to 3.18 (P.03) (Fig. 1). These effects were maintained without significant change (P 0.05) throughout pregnancy (Fig. 1). Maternal and Fetal Safety During Metformin Therapy Of the 33 women taking metformin, none developed lactic acidosis. Intermittent diarrhea or gastritis were common in the first 3 weeks of metformin therapy but resolved spontaneously and were not limiting factors. No major fetal malformations or fetal hypoglycemia occurred in the 34 live births. FIGURE 1 Median weight, body mass index (BMI), fasting serum insulin level, and insulin resistance (IR) in 15 women with the polycystic ovary syndrome before metformin therapy, at their last preconception evaluation during metformin therapy, at their first visit after conception during metformin therapy (4 6 weeks of gestation), and throughout the remainder of their pregnancy during metformin therapy. Paired Wilcoxon tests of difference were done to compare values at baseline with those at prepregnancy during metformin therapy, values at prepregnancy during metformin therapy with those at the first visit after conception during metformin therapy, and values at the first visit after conception during metformin therapy with those during remainder of pregnancy during metformin therapy). DISCUSSION In most (19, 26) but not all (39) studies, women with PCOS develop gestational diabetes more often than healthy women, 20% vs. 8.9% (19), and 41% vs. 3% (26). Moreover, of women without previously diagnosed PCOS who develop gestational diabetes, 44% to 52% have been reported subsequently to have polycystic ovarian morphology (20 22). In our study, the prevalence of gestational diabetes in pregnancies in women not taking metformin (31%) was comparable to that in previous reports (19, 23 26). The 3% prevalence of gestational diabetes in women taking metformin approximates that in the general population 3.52% (2) and represents a 10-fold reduction (31% to 3%) compared with pregnancies in women with PCOS who did not take metformin. The odds ratio for gestational diabetes mellitus was (95% CI: to 0.795) in women taking metformin versus those not taking metformin (P.03) and (95% CI: to 0.938) for pregnancies in women taking metformin versus those not taking metformin Glueck. Metformin reduces gestational diabetes. Fertil Steril (P.04). After covariance adjustment for age at delivery, metformin was associated with about a 10-fold reduction in the rate of gestational diabetes in women with PCOS. Gestational diabetes develops because pregnancy increases requirements for insulin secretion while increasing insulin resistance, which in turn increases demands on pancreatic -cells (1, 20 26). Before pregnancy, women with PCOS commonly have insulin resistance (5 13) and obesity, which are major risk factors for gestational diabetes (1, 2). Because they often have infertility (15, 16), women with PCOS are older than the general population at conception, which is another risk factor (2) for gestational diabetes. In agreement with previous reports (5 13), we found that before pregnancy, metformin and diet decreased weight, FERTILITY & STERILITY 523

5 BMI, insulin, insulin resistance, and insulin secretion; these decreases should reduce demands on the pancreatic -cells. In women taking metformin, these effects were maintained throughout pregnancy. Without caloric restriction during pregnancy, the median body weight of women taking metformin did not increase (P.1); this, along with the lowcarbohydrate diet (44% of calories), may have contributed (1) to reduced development of gestational diabetes. Women with gestational diabetes often have impaired pancreatic -cell compensation for insulin resistance (40). Troglitazone (another insulin-sensitizing drug) improves insulin sensitivity in women with gestational diabetes (41). It is not surprising that metformin therapy during pregnancy reduces the rate of gestational diabetes mellitus by 10-fold. We speculate that metformin, Like troglitazone (42), may protect pancreatic -cells from failure, thus decreasing the risk for developing type 2 diabetes mellitus later. Prevention of gestational diabetes mellitus reduces development of macrosomia, with its attendant neonatal morbidity and mortality (3, 4), and may reduce the risk for subsequent development of type 2 diabetes, which occurs more commonly in women with gestational diabetes than in those without the disease (1, 40, 41). If data from our study were used to design a blinded, placebo-controlled clinical trial, 102 live births (51 randomized to metformin and 51 to placebo) stratified by age and BMI will be required to have a 95% chance of showing that metformin decreases the development of gestational diabetes in women with PCOS (at P.05). In women who were diabetic before conception, Hellmuth et al. 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