1 Cholesterol Center, ABC Building, 3200 Burnet Avenue, Cincinnati, OH 45229, USA
2 To whom correspondence should be addressed. e-mail glueckch{at}healthall.com
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Key words: gestational diabetes/infant development in the first 18 months of life/metformin/pre-eclampsia/polycystic ovary syndrome
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Metformin has beneficial effects on risk factors for the high rate of first trimester SAB in PCOS [hyperinsulinaemia, insulin resistance, hyperandrogenaemia, obesity and hypofibrinolytic high levels of plasminogen activator inhibitor activity (PAI-Fx)] (Glueck et al., 1999a, 2001a, 2002a,b,c, 2004a,b; Jakubowicz et al., 2002
). Within this frame of reference, metformin lowers the rate of first-trimester SAB (Glueck et al., 2001b
, 2002a,b,c, 2004a,b; Jakubowicz et al., 2002
).
Metformin does not appear to be teratogenic whether given to women with type 2 diabetes, gestational diabetes (GD) or PCOS (Coetzee and Jackson, 1979, 1980, 1984, 1985; Jackson and Coetzee, 1979
; Glueck et al., 2001b
, 2002a,b,c, 2004a,b; Heard et al., 2002
; Jakubowicz et al., 2002
).
Beyond reduction in SAB (Glueck et al., 2002c), reduction in pre-eclampsia (Glueck et al., 2004a
) and reduction in macrosomia (Glueck et al., 2004a
), another reason for continuing metformin during pregnancy in women with PCOS is its reduction in GD and its positive effects on the mechanisms of GD (Glueck et al., 2002a
,c, 2004a,b). In a previous study of 95 live births, development of GD in women with PCOS on metformin during pregnancy did not differ from controls [nine out of 95 pregnancies (9.5%) versus 40 out of 251 (15.9%), P = 0.12], (Glueck et al., 2004a
). By reducing pre-conception weight, insulin, insulin resistance and insulin secretion, and by reducing the physiological hyperinsulinaemia of pregnancy, metformin helps to prevent development of GD and improves pregnancy outcomes in women with PCOS (Glueck et al., 2004b
).
Our previous studies suggested that metformin during pregnancy in women with PCOS does not adversely affect their neonates birth weight or length, or growth in the first 6 months of life (Glueck et al., 2002c). In 63 live births to women with PCOS who took metformin through pregnancy, birth weight (P = 0.19) and height (P = 0.14) did not differ from those of normal neonatal populations (Glueck et al., 2002c
). At 6 month follow-up, height was greater than (P = 0.008) and weight did not differ from (P = 0.26) those of normal infant populations; motorsocial development was normal (Glueck et al., 2002c
).
Given the increasing evidence for the value of continuing metformin throughout pregnancy in women with PCOS, in the current study, our specific aim was to assess prospectively birth length and weight, growth and motorsocial development during the first 18 months of life in 126 live births (122 pregnancies) to 109 Midwestern USA women with PCOS who conceived on and continued metformin through pregnancy.
![]() |
Materials and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The diagnosis of PCOS was made using revised 2003 ESHRE/ASRM consensus conference criteria (ESHRE/ASRM, 2004) (two out of three): (i) oligomenorrhea or anovulation; (ii) clinical and/or biochemical signs of hyperandrogenism; and (iii) polycystic ovaries (see also Table I).
|
We used the definitions of Laven et al. (2002) for oligomenorrhoea (bleeding intervals between 35 days and 6 months), or amenorrhoea, bleeding interval >6 months (Table I).
Since 100% of our prospectively studied patients with PCOS conceived on metformin, we did not have access to infants born to a second, potentially informative control group, i.e. women with PCOS who conceived without metformin and, while following the same protein-enriched, carbohydrate-restricted diet, did not take metformin during pregnancy. We also did not have access to infants born to a prospectively studied control group of normal pregnant women, matched to those with PCOS by age, parity and pre-conception body mass index (BMI), followed longitudinally on the same high-protein, low-carbohydrate diet throughout pregnancy.
Women with PCOS
Non-pregnant women were referred to our centre for diagnosis of PCOS and for study of the efficacy and safety of metformin (Glueck et al., 1999b), or metformin and pioglitazone (Glueck et al., 2003
). None of the women, having been offered participation in the metformin treatment study declined participation. The current prospective, open label, single centre, consecutive case series study included 109 women (age 31 ± 5 years, 104 Caucasian, five other) from the Midwestern USA who conceived on metformin, 1.52.55 g/day, and had
1 live birth. The 109 women were enrolled consecutively in the pregnancy follow-up study after they had conceived, and were followed prospectively in Cincinnati or in their hometowns, under our direction, and using our protocol (Glueck et al., 2001b
, 2002c, 2004a,b). Women were included consecutively in the current study irrespective of outcome(s) of their previous pregnancies without metformin, to avoid selection bias based on previous pregnancy outcomes. All pregnancies (historical and current) were conceived with the same partners, which may be important since the issue of differing male partners in previous and current pregnancies potentially could contribute to differing outcomes by virtue of male partner chromosomal translocation or sperm DNA fragmentation.
At pre-metformin baseline, after an overnight fast, blood was obtained for measurements of fasting serum insulin and glucose, the 4G/5G polymorphism of the PAI-1 gene, PAI-Fx and serum sex hormones, using previously reported methods (Velazquez et al., 1994, 1997a,b; Glueck et al., 1999a
,b, 2000, 2001a,b,c). HOMA insulin resistance and insulin secretion were calculated as per Haffner et al. (1996
). Normal limits for pre-conception, pre-treatment systolic and diastolic blood pressure, high-density lipoprotein (HDL) cholesterol and triglycerides were taken from the recent Adult Treatment Panel III guidelines (National Institutes of Health, 2001
).
Pre-conception, PCOS women with BMI <25 kg/m2 or 25 were instructed, respectively, in a 2000 or 1500 calories/day, high-protein (26% of calories), low-carbohydrate (44%) diet (42% of carbohydrate was complex), with 30% of the calories as fat and a polyunsaturate/saturate ratio of 2:1 (Glueck et al., 2002c
). After conception, calorie restrictions were dropped, but continued adherence to the low-carbohydrate, high-protein diet was encouraged. At least 1 month before and throughout pregnancy, folic acid (1 mg/day) was given to reduce the likelihood of neonatal spina bifida (American Academy of Pediatrics, 1999
).
Pre-conception, metformin was started at 1.5 g/day, with the dose increased over 24 months to a target of 2.55 g/day (850 mg with each meal). Although the targeted metformin dose (2.55 g/day) was taken in 74 of 122 pregnancies (61%), in some women we had to reduce metformin to the highest dose level tolerated, 1 g/day in five of 122 pregnancies (4.1%), and 1.52 g/day in 43 of 122 pregnancies (35%). While receiving metformin, the women with PCOS were evaluated every 2 months with serial measurements of fasting serum insulin, PAI-Fx and serum sex hormones. After conception, we recommended that metformin be continued throughout pregnancy, and continued without change in dose, but it could be stopped by the concurrent request of both the patient and her obstetrician.
During pregnancy, women with PCOS made monthly follow-up visits to our centre with measurement of weight, and, after an overnight fast, serum insulin, glucose, testosterone, estradiol, progesterone and PAI-Fx (Glueck et al. 2002c, 2004a,b). At each monthly visit during pregnancy, after a 5 min resting period, seated blood pressure was obtained by a single observer and recorded; diet was reviewed, as was adherence to metformin and metformin dose. All medical aspects of the patients pregnancies were managed directly by the investigators.
At gestation weeks 2628, in collaboration with the patients obstetricians, evaluation for GD was done (OSullivan et al., 1973; American Diabetes Association, 1986
).
Pre-eclampsia was diagnosed by the ISSHP criteria (Brown et al., 2001) which include blood pressure >140/90 mmHg on two separate occasions 4 h apart or a single diastolic pressure
110 mmHg, in association with
2+ proteinuria by dipstick testing, in the absence of renal disease or infection.
At birth, all neonates were examined by paediatricians who had no knowledge of the metformin dose or duration; height and weight were recorded, along with any birth defects. At well-baby visits at 3, 6, 9, 12 and 18 months of life, paediatricians obtained infants heights and weights, reviewed motor and social development, and documented any birth defects which became evident during the first 18 months of life. Parents and paediatricians were asked to report any apparent abnormalities in accretion of height or weight and in motor and/or social development to us. The American Academy of Pediatrics motor and social development questionnaire (1993) was completed by the infants parents and reviewed in detail with the paediatricians and with a principal investigator (C.J.G.). At months 3, 6, 9, 12 and 18, the Academys questionnaire included five, five, five, seven and six questions, respectively. Each question was given an equivalent score of 1, and entirely normal motor and social development had a score of 100%.
Community controls
The 109 women with PCOS were compared with 252 prospectively followed healthy women (age 29 ± 6 years, 226 Caucasian, 25 African-American, one other) not known to have PCOS (Glueck et al., 2004a). These 252 women consecutively delivered 262 live births, 242 singleton and 10 sets of twins, in a suburbanurban community practice of obstetrics (Glueck et al., 2004a
). Although the controls from the community obstetrics practice had regular menses, had no clinical signs of hyperandrogenism and had not been diagnosed by their obstetricians as having PCOS, they did not have serological tests to rule out hyperandrogenism.
Outcome measures
Outcome measures included major birth defects, infant birth weight and height, and growth and motorsocial development during the first 18 months of life. Additional outcome measures included maternal GD and pre-eclampsia.
Statistical analysis
Infants height and weight by gender at birth, 3, 6, 9, 12 and 18 months of age were compared with gender-specific Centers for Disease Control and Prevention (CDC) data for US male and female infants (Kuczmarski et al., 2002) using t-tests (SAS/STAT, 2002
). Comparisons of women with PCOS who conceived on metformin versus community controls were made using
2 tests or Fishers exact tests for categorical variables, and Wilcoxon non-parametric tests for numerical variables (SAS/STAT, 2002
).
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
At the time of this report, these 127 women had 151 pregnancies (156 fetuses). At the time of this report, of the 156 fetuses, there were 126 live births (122 pregnancies), nine ongoing pregnancies (>13 weeks gestation) and 21 first-trimester SABs (13%).
During the 7 year time period, among the 886 women with PCOS, 759 other women with PCOS started participation in the metformindiet programme and did not conceive. Of these 759 women, 310 were single, 368 were married, nine had previous hysterectomy, and 197 used contraceptive methods (barrier, intrauterine device or tubal ligation) and did not wish to become pregnant. Besides the 127 women who conceived, there were 282 women (of 759) who wished to conceive but have not conceived to date.
The 127 women who conceived were relatively thinner than the 282 women who have, to date, failed to conceive (BMI 33.7 ± 7.9 versus 37.7 ± 8.4, P < 0.0001), and younger (31 ± 5 versus 33 ± 5 years, P = 0.0003). The 127 women who conceived did not differ (P 0.2) from the 282 women who failed to conceive in terms of pre-treatment fasting serum insulin (21 ± 16 versus 26 ± 28 uU/ml), HOMA insulin resistance (5.09 ± 5.41 versus 6.77 ± 11.57) and HOMA insulin secretion (296 ± 310 versus 333 ± 335).
On metformin, of the 122 pregnancies in the 109 women, 105 (86%) were conceived spontaneously, two (2%) with artificial insemination, 12 (10%) with 50 mg clomid, two (2%) with IVF and one (1%) with pergonal.
Metformin was continued throughout pregnancy in 104 of the 122 (85%) pregnancies, and discontinued in 18 pregnancies at a median of 12 weeks gestation by womens obstetricians who did not want metformin continued beyond the first trimester. Of the 122 pregnancies (126 live births), metformin 1 g/day was taken in five pregnancies (4.1%), 1.5 g/day was taken in 34 (28%), 1.7 g/day was taken in five (4.1%), 2 g/day was taken in four (3.3%), and 2.55 g/day was taken in 74 (60.7%) pregnancies. There were no differences (P > 0.3) in the number of weeks of gestation, or infants birth height or weight comparing the 104 pregnancies where metformin was continued throughout versus the 18 where it was stopped at (median) 12 weeks gestation.
Characteristics of PCOS in the 109 women with PCOS and 1 live birth
At study entry, in the cohort of 109 women, mean ± SD weight was 92.6 ± 22.3 kg, BMI 33.5 ± 7.6 kg/m2. Of the 109 women, 16% had BMI <25 (normal weight), 16% were overweight (BMI 2530), 50% were obese (BMI
3040) and 19% had extreme obesity (BMI
40) (Flegal et al. 2002
). Using ATP III cutpoints (National Institutes of Health, 2001
), systolic blood pressure was high (
130 mmHg) in 27%, diastolic blood pressure high (
85 mmHg) in 19%, triglycerides high (
150 mg/dl) in 29%, HDL cholesterol low (<50 mg/dl) in 64%, and fasting serum glucose high (>110 mg/dl) in 6%. Fasting serum insulin was high (
17 uU/ml) in 50% of the 109 women.
Of the 109 women, 96 had 6 menses/year, and 11 had 710 menses (Table I). Of the 109 women, 95 (87%) had FerrimanGallwey (FG) (Ferriman and Gallwey, 1961
) scores
7, and 63 (58%) had severe acne. Of the 109 women, 51 (47%) had
1 high androgen level (Table I). Polycystic ovaries had been demonstrated before pregnancy in 94 of the 109 women (Table I).
All 109 women (100%) met the revised 2003 diagnostic criteria for PCOS (ESHRE/ASRM, 2004), having two of the following three findings (oligo-anovulation, clinical and/or biochemical signs of hyperandrogenism and polycystic ovaries) (Table I).
GD and pre-eclampsia
Three (2.8%) of the 109 patients had pre-conception type 2 DM controlled by diet alone, but had normal glucose tolerance testing during pregnancy on metformin. Pre-conception type 2 DM did not differ in patients (2.8%) versus community controls (one out of 252, 0.4%), Fischers P = 0.084. Of the 119 pregnancies in the women with PCOS, where there was no type 2 DM pre-conception; GD was diagnosed in nine (7.6%), less than in the community controls pregnancies (40 out of 251, 15.9%), 2 = 4.93, P = 0.027. In women with PCOS, GD did not differ in pregnancies where metformin was continued throughout (eight out of 102, 7.8%) versus those where it was stopped at a median of 12 weeks gestation (one out of 17, 5.9%), Fishers P = 1. GD was more common in the community controls than in the women with PCOS despite the controls having much lower BMI (25.6 ± 5.9 versus 33.5 ± 7.6 kg/m2, P < 0.0001).
Pre-eclampsia occurred in five of 122 (4.1%) pregnancies in the women with PCOS, not different (P = 0.80) from the community controls (nine out of 252, 3.6%). Pre-eclampsia did not differ in women with PCOS who continued metformin throughout pregnancy (five out of 104, 4.8%) versus those who stopped at a median of 12 weeks gestation (none out of 18, 0%), Fishers P = 1. Pre-eclampsia occurred in two of the 53 women with PCOS who were primigravidas (3.8%), not different (Fishers P = 1) from four of 91 community control primiparous women (4.4%).
Infants height and weight at birth, and at 3, 6, 9, 12 and 18 months follow-up
Of the 126 live births, 101 (80.2%) were term (37 gestational weeks) and 25 were <37 weeks, not different from the community controls, where 206 of 252 births (81.7%) were term, P = 0.71. Of the 126 live births to the women with PCOS, there were two birth defects (1.6%) (one sacrococcygeal teratoma, one tethered spinal cord).
As displayed in Figures 1 and 2, birth weight and height in the total cohort of 52 male infants and the 42 term male infants did not differ from the CDC male infant cohort (Kuczmarski et al., 2002). At 3 months, male infants were shorter than CDC males (Figures 1 and 2). At 12 months, male infants, but not term male infants, were shorter than CDC males (Figures 1 and 2). The male PCOS infant cohort was thinner than CDC males at 3, 6 and 12 months (Figure 2). Term male infants were thinner than CDC males at 3 and 6 months of age, Figure 2.
|
|
|
|
Infants motor and social development
As determined by an American Academy of Pediatrics motorsocial development questionnaire (1993), at 3, 6, 9, 12 and 18 months, of a potential 100% score, mean ± SD scores were 95 ± 13, 98 ± 8, 95 ± 10, 97 ± 8 and 94 ± 6%. No infants were determined to have motor or social developmental delays by this questionnaire or by their paediatricians.
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Importantly, there is no evidence that metformin is teratogenic whether given to women with type 2 DM, GD or PCOS (Coetzee and Jackson, 1979, 1980, 1984, 1985; Jackson and Coetzee, 1979
; Glueck et al., 2001b
, 2002a,b,c, 2004a,b; Jakubowicz et al., 2002
). In the current study, as in the past, metformin use during pregnancy was not associated with increased development of major birth defects, with the birth defect rate of 1.6% not different from the USA national 1.9% rate reported by the CDC for 19901991 (James et al., 2000
), or 4.2% recently reported from Australia (Hansen et al., 2002
).
Although the current study was prospective, women with PCOS were not randomized to a placebodiet versus metformindiet group, and comparisons of the development of pre-eclampsia and GD were made against healthy pregnant women without PCOS. A larger number of live births in a double-blind, placebo-controlled trial of metformindiet versus placebodiet throughout pregnancy would add weight to the current evidence against teratogenicity, would allow an optimal assessment of effects of diet and dietmetformin on pre-eclampsia and GD, and would allow comparison of birth height and weight and subsequent growth in infants from metformindiet and placebodiet groups.
Although calories and carbohydrates were restricted before conception, after conception, calorie restrictions were dropped, but continued adherence to the low-carbohydrate, high-protein diet was encouraged. We doubt that the low-carbohydrate, but calorically unrestricted diet during pregnancy had any major effects on pre-eclampsia, development of GD or neonatal weight. Although many diet and lifestyle interventions for prevention of pre-eclampsia have been carried out, as summarized by Duley (2003) Overall, there is insufficient evidence for any firm conclusion about the effects of any aspect of diet or lifestyle during pregnancy. Although there has been no systematic prospective study of carbohydrate, but not caloric restriction during pregnancy on the subsequent development of GD, carbohydrate restriction in women with diet-controlled GD results in improved glycaemic control, less need for insulin, a decrease in the incidence of large for gestational age infants and a decrease in Caesarian deliveries for macrosomia (Major et al, 1998
).
The prematurity rate of 20% in infants from PCOS mothers did not differ from community controls (18%). There was no neonatal hypoglycaemia.
In women with pre-gestational type 2 DM, Hellmuth et al. (2000) reported an increased prevalence of pre-eclampsia on metformin (32%) versus 7% on sulphonylurea, versus 10% on insulin, and also reported higher perinatal mortality (11.6% on metformin, 1.3% on sulphonylureas or insulin). Hellmuth et al. (2000
) used various treatment schedules initiated over a very wide range of gestation. The retrospectively selected, 42 woman control group (Hellmuth et al., 2000
) was very heterogeneous and included women whose initial treatment dates varied by as much as 32 gestational weeks. In contrast to Hellmuth et al. (2000
), in our recent prospective study of metformin and pre-eclampsia (Glueck et al., 2004a
), there was no increase in pre-eclampsia in primarily non-diabetic women with PCOS versus controls (5.2 versus 3.6%). Moreover, in our recent study (Glueck et al., 2004a
), as had been the case in previous reports (Coetzee and Jackson, 1979
, 1980, 1984, 1985; Jackson and Coetzee, 1979
; Glueck et al., 2001b
, 2002a,b,c, 2004a,b; Jakubowicz et al., 2002
), there was no perinatal mortality, and no fetal loss in either the second or third trimesters. Our recently reported cohort (Glueck et al., 2004a
) was very different from that of Hellmuth et al. (2000
), having PCOS, studied prospectively with prospective controls, and largely non-diabetic, with only 2% of women with pre-conception type 2 DM. The study of Hellmuth et al. (2000
) was retrospective, and included exclusively diabetic pregnancies over a 25 year period (19661991). Our recently reported study of PCOS, and others (Coetzee and Jackson, 1979
, 1980, 1984, 1985; Jackson and Coetzee, 1979
; Glueck et al., 2001b
, 2002a,b,c, 2004a,b; Jakubowicz et al., 2002
) did not reveal the adverse pregnancy outcomes (increased pre-eclampsia, increased perinatal mortality) on metformin as reported by Hellmuth et al. (2000
) in type 2 diabetics.
Since, as above, metformin reduces SAB, GD, macrosomia and pre-eclampsia, it is important to examine birth weight and length, growth and motorsocial development in the first few years of life in neonates born to mothers with PCOS who took metformin during pregnancy. Our previous study of 63 live births to women with PCOS who took metformin during pregnancy (Glueck et al., 2002c) revealed that neither birth weight nor height differed from those of the normal neonatal population. At 6 month follow-up, infant height was greater (P = 0.008) and weight did not differ from the normal USA infant population (Glueck et al., 2002c
). The infants paediatricians reported no cases of growth retardation (Glueck et al., 2002c
). Motor and social development were normal by an American Academy of Pediatrics (1993) development questionnaire (Glueck et al., 2002c
). Mean ± SD motorsocial development scores at 3 (n = 51) and 6 months (n = 47) were, respectively, 95 ± 11 (out of 100 maximum) and 98 ± 6 (Glueck et al., 2002c
). The infants paediatricians reported no cases of significant retardation in motorsocial development (Glueck et al., 2002c
).
In the current study, birth weight and height as well as growth over the first 18 months of life did not differ systematically from CDC normal infant cohorts (Kuczmarski et al., 2002). None of the infants were judged by their paediatricians to have growth retardation. By an American Academy of Pediatrics (1993) motor and social development questionnaire, mean scores, out of a maximum of 100%, ranged from 94 to 98%; no infants were judged by their paediatricians to have abnormal motor and social development.
Since metformin facilitates conception in women with PCOS and subsequently lowers their otherwise high rate of first-trimester SAB (Glueck et al., 2001b, 2002a,b,c, 2004a,b; Jakubowicz et al., 2002
), it is important, as in the current study, that, when continued through pregnancy, metformin was not teratogenic, reduced GD and pre-eclampsia, did not adversely affect birth length or weight, and had no adverse effect on growth or on motorsocial development in the first 18 months of life.
![]() |
Acknowledgements |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
American Academy of Pediatrics. (1999) Practice Guideline. Folic acid for prevention of neural tube defects. Committee on Genetics. Pediatrics 104,325327.
American Diabetes Association. (1986) Position statementgestational diabetes mellitus. Diabetes Care 9,430431.[Medline]
Brown MA, Lindheimer MD, De Swiet M, Van Assche A and Moutquin JM (2001) The classification and diagnosis of the hypertensive disorders of pregnancy: statement from the International Society for the Study of Hypertension in Pregnancy (ISSHP). Hypertens Pregnancy 20,IXXIV.[CrossRef][Medline]
Coetzee EJ and Jackson WP (1979) Metformin in management of pregnant insulin-independent diabetics. Diabetologia 16,241245.[Medline]
Coetzee EJ and Jackson WP (1980) Pregnancy in established non-insulin-dependent diabetics. A five-and-a-half year study at Groote Schuur Hospital. S Afr Med J 58,795802.[Medline]
Coetzee EJ and Jackson WP (1984) Oral hypoglycaemics in the first trimester and fetal outcome. S Afr Med J 65,635637.[Medline]
Coetzee EJ and Jackson WP (1985) The management of non-insulin-dependent diabetes during pregnancy. Diabetes Res Clin Pract 1,281287.[Medline]
Duley L (2003) Pre-eclampsia and the hypertensive disorders of pregnancy. Br Med Bull 67,16176.
ESHRE/ASRM. (2004) Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Fertil Steril 81,1925.[CrossRef][Medline]
Ferriman D and Gallwey JD (1961) Clinical assessment of body hair growth in women. J Clin Endocrinol Metab 21,14401447.
Flegal KM, Carrol MD, Ogden CL and Johnson CL (2002) Prevalence and trends in obesity among US adults, 19992000. J Am Med Assoc 288,17231727.
George SS, George K, Irwin C, Job V, Selvakumar R, Jeyaseelan V and Seshadri MS (2003) Sequential treatment of metformin and clomiphene citrate in clomiphene-resistant women with polycystic ovary syndrome: a randomized, controlled trial. Hum Reprod 18,299304.
Glueck CJ, Wang P, Fontaine RN, Sieve-Smith L, Tracy T and Moore SK (1999a) Plasminogen activator inhibitor activity: an independent risk factor for the high miscarriage rate during pregnancy in women with polycystic ovary syndrome. Metabolism 48,15891595.[Medline]
Glueck CJ, Wang P, Fontaine R, Tracy T and Sieve-Smith L (1999b) Metformin-induced resumption of normal menses in 39 of 43 (91%) previously amenorrheic women with the polycystic ovary syndrome. Metabolism 48,511519.[Medline]
Glueck CJ, Phillips H, Cameron D, Wang P, Fontaine RN, Moore SK, Sieve-Smith L and Tracy T (2000) The 4G/4G polymorphism of the hypofibrinolytic plasminogen activator inhibitor type 1 gene: an independent risk factor for serious pregnancy complications. Metabolism 49,845852.[CrossRef][Medline]
Glueck CJ, Kupferminc MI, Fontaine RN, Wang P, Weksler BB and Eldor A (2001a) Genetic hypofibrinolysis in complicated pregnancies. Obstet Gynecol 97,4448.
Glueck CJ, Phillips H, Cameron D, Sieve-Smith L and Wang P (2001b) Continuing metformin throughout pregnancy in women with polycystic ovary syndrome appears to safely reduce first-trimester spontaneous abortion: a pilot study. Fertil Steril 75,4652.[CrossRef][Medline]
Glueck CJ, Wang P, Fontaine R, Tracy T, Sieve-Smith L (2001c) Metformin to restore normal menses in oligo-amenorrheic teenage girls with polycystic ovary syndrome (PCOS). J Adolesc Health 29,160169.[CrossRef][Medline]
Glueck CJ, Wang P, Kobayashi S, Phillips H and Sieve-Smith L (2002a) Metformin therapy throughout pregnancy reduces the development of gestational diabetes in women with polycystic ovary syndrome. Fertil Steril 77,520525.[CrossRef][Medline]
Glueck CJ, Streicher P and Wang P (2002b) Treatment of polycystic ovary syndrome with insulin-lowering agents. Expert Opin Pharmacother 3,11771189.[Medline]
Glueck CJ, Wang P, Goldenberg N and Sieve-Smith L (2002c) Pregnancy outcomes among women with polycystic ovary syndrome treated with metformin. Hum Reprod 17,28582864.
Glueck CJ., Moreira A, Goldenberg N, Sieve L and Wang P (2003) Pioglitazone and metformin in obese women with polycystic ovary syndrome not optimally responsive to metformin. Hum Reprod 18,16181625.
Glueck CJ, Bornovali S, Goldenberg N, Dharashivkar S, Pranikoff J and Wang P (2004a) Pre-eclampsia, polycytic ovary syndrome, metformin, pregnancy outcomes. Diabetes Med, in press.
Glueck CJ, Goldenberg N, Wang P, Loftspring M and Sherman A (2004b) Metformin during pregnancy reduces insulin, insulin resistance, insulin secretion, weight, testosterone, and development of gestational diabetes: prospective longitudinal study of women with polycystic ovary syndrome from pre-conception through pregnancy. Hum Reprod 19,510521.
Haffner SM, Kennedy E, Gonzalez C, Stern MP and Miettinen H (1996) A prospective analysis of the HOMA model. The Mexico City Diabetes Study. Diabetes Care 19,11381141.[Abstract]
Hansen M, Kurinczuk JJ, Bower C and Webb S (2002) The risk of major birth defects after intracytoplasmic sperm injection and in vitro fertilization. N Engl J Med 346,725730.
Heard MJ, Pierce A, Carson SA and Buster JE (2002) Pregnancies following use of metformin for ovulation induction in patients with polycystic ovary syndrome. Fertil Steril 77,669673.[CrossRef][Medline]
Hellmuth E, Damm P and Molsted-Pedersen L (2000) Oral hypoglycaemic agents in 118 diabetic pregnancies. Diabetes Med 17,507511.[CrossRef][Medline]
Jackson WP and Coetzee EJ (1979) Side-effects of metformin. S Afr Med J 56,11131114.
Jakubowicz DJ, Iuorno MJ, Jakubowicz S, Roberts KA and Nestler JE (2002) Effects of metformin on early pregnancy loss in the polycystic ovary syndrome. J Clin Endocrinol Metab 87,524529.
James LM, Erickson JD and McClearn AB (2000) Prevalence of birth defects. Division of Birth Defects and Developmental Disabilities, National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, Georgia.
Kawadzki JK and Dunaif A (1992) Diagnostic criteria for polycystic ovary syndrome: a rational approach. In Dunaif A, Givens JR, Haseltine F and Merriam GR (eds), Polycystic Ovary Syndrome. Blackwell Scientific, Cambridge, MA, pp. 377384.
Kocak M, Caliskan, E, Simsir C and Haberal A (2002) Metformin therapy improves ovulatory rates, cervical scores, and pregnancy rates in clomiphene citrate-resistant women with polycystic ovary syndrome. Fertil Steril 77,101106.[CrossRef]
Kuczmarski RJ, Ogden CL, Guo SS, Grummer-Strawn LM, Flegal KM, Mei Z, Wei R, Curtin LR, Roche AF and Johnson CL (2002) 2000 CDC growth charts for the United States: methods and development. Vital Health Stat 11,1190.
Laven JS, Imani B, Eijkemans MJ and Fauser BC (2002) New approach to polycystic ovary syndrome and other forms of anovulatory infertility. Obstet Gynecol Surv 57,755767.[CrossRef][Medline]
Major CA, Henry MJ, De Veciana M and Morgan MA (1998) The effects of carbohydrate restriction in patients with diet-controlled gestational diabetes. Obstet Gynecol 91,600604.
Moghetti P, Castello R, Negri C, Tosi F, Perrone F, Caputo M, Zanolin E and Muggeo M (2000) Metformin effects on clinical features, endocrine and metabolic profiles, and insulin sensitivity in polycystic ovary syndrome: a randomized, double-blind, placebo-controlled 6-month trial, followed by open, long-term clinical evaluation. J Clin Endocrinol Metab 85,139146.
Morin-Papunen LC, Koivunen RM, Ruokonen A and Martikainen HK (1998) Metformin therapy improves the menstrual pattern with minimal endocrine and metabolic effects in women with polycystic ovary syndrome. Fertil Steril 69,691696.[CrossRef][Medline]
National Institutes of Health. (2001) Third Report of the National Cholesterol Education Program Expert Panel on detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). NIH Publication 01-3670.
OSullivan JB, Mahan CM, Charles D and Dandrow RV (1973) Screening criteria for high-risk gestational diabetic patients. Am J Obstet Gynecol 116,895900.[Medline]
Pirwany IR, Yates RW, Cameron IT and Fleming R (1999) Effects of the insulin sensitizing drug metformin on ovarian function, follicular growth and ovulation rate in obese women with oligomenorrhoea. Hum Reprod 14,29632968.
SAS/STAT. (2002) Changes and Enhancements Through Release 8.02. SAS Institute, SAS Campus Drive.
Stadtmauer LA, Wong BC and Oehninger S (2002) Should patients with polycystic ovary syndrome be treated with metformin? Benefits of insulin sensitizing drugs in polycystic ovary syndromebeyond ovulation induction. Hum Reprod 17,30163026.
Vandermolen DT, Ratts VS, Evans WS, Stovall DW, Kauma SW and Nestler JE (2001) Metformin increases the ovulatory rate and pregnancy rate from clomiphene citrate in patients with polycystic ovary syndrome who are resistant to clomiphene citrate alone. Fertil Steril 75,310315.[CrossRef][Medline]
Velazquez EM, Mendoza S, Hamer T, Sosa F and Glueck CJ (1994) Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy. Metabolism 43,647654.[Medline]
Velazquez E, Acosta A and Mendoza SG (1997a) Menstrual cyclicity after metformin therapy in polycystic ovary syndrome. Obstet Gynecol 90,392395.
Velazquez EM, Mendoza SG, Wang P and Glueck CJ (1997b) Metformin therapy is associated with a decrease in plasma plasminogen activator inhibitor-1, lipoprotein(a), and immunoreactive insulin levels in patients with the polycystic ovary syndrome. Metabolism 46,454457.[Medline]
Wang JX, Davies MJ and Norman RJ (2001) Polycystic ovarian syndrome and the risk of spontaneous abortion following assisted reproductive technology treatment. Hum Reprod 16,26062609.
Submitted on January 29, 2004; accepted on March 23, 2004.