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Current Medical Research & Opinion Vol. 29, No. 1, 2013, 5562

0300-7995 Article ST-0282.R1/755121

doi:10.1185/03007995.2012.755121 All rights reserved: reproduction in whole or part not permitted

Original article

Effects of metformin-diet intervention beforeand throughout pregnancy on obstetric andneonatal outcomes in patients with polycysticovary syndrome

Charles J. GlueckNaila GoldenbergJoel PranikoffZia KhanJagjit PaddaPing WangCholesterol Center, Jewish Hospital of Cincinnati,

Cincinnati, OH, USA

Address for correspondence:

Charles J. Glueck MD, UC Health Building, 3200

Burnet Avenue, Cincinnati, OH 45229, USA.

Tel.: 1 513-924-8261; Fax: 1 513-924-8273;

[email protected]

Keywords:

Fetal macrosomia Gestational diabetes

Metformin-diet Miscarriage Polycystic ovary

syndrome (PCOS) Pre-eclampsia

Accepted: 20 November 2012; published online: 12 December 2013

Citation:Curr Med Res Opin 2013; 29:5562

Abstract

Objective:

Prospectively assess whether metformin/diet pre-conception and throughout pregnancy would safely

reduce first trimester miscarriage and improve pregnancy outcomes in women with polycystic ovary

syndrome (PCOS).

Research design and methods:

In 76 PCOS women, first pregnancy miscarriage and live birth were compared before and on metformin/

diet, started 6.8 months (median) before conception, continued throughout pregnancy. On metformin

22.55 g/day, low glycemic index diet, first pregnancy outcomes in PCOS were compared with 156

community obstetric practice women (controls).

Main outcome measures:Live births, miscarriage, birth537 weeks gestation, gestational diabetes, pre-eclampsia, fetal macrosomia.

Results:

In 76 PCOS women before metformin-diet, there were 36 miscarriages (47%) and 40 live births vs. 14

(18%) miscarriages and 62 live births on metformin-diet 6.8 months before conception and throughout

pregnancy, p 0.0004, OR 3.99, 95% CI 1.918.31. On metformin-diet, PCOS women did not differ

(p40.08) from controls for birth 537 weeks gestation, gestational diabetes, pre-eclampsia, or fetal

macrosomia.

Conclusions:

Metformin-diet before and during pregnancy in PCOS reduces miscarriage and adverse pregnancy

outcomes. Study limitation: individual benefits of the diet alone and diet plus metformin could not be

assessed separately. Randomized, controlled clinical trials now need to be done with a larger number of

patients.

Introduction

As shown by most17 but not all8,9 studies, there is a high miscarriage rate in

women with polycystic ovary syndrome (PCOS), amplified by obesity, age, and

duration of infertility. However, the 2011 Consensus Statement on PCOS10

concluded . . . data in relation to risk of miscarriage in women with PCOS

are conflicting, although miscarriage rates are generally thought to be compa-

rable with other subfertile populations. Palomba et al.11 reported that pregnant

! 2013 Informa UK Ltd www.cmrojournal.com Metformin, PCOS, pregnancy outcomes Glueck et al. 55


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patients with PCOS have impaired decidual trophoblast

invasion, directly related to markers of insulin resistance

and testosterone levels, which might promote frequent

first trimester miscarriage in women with PCOS.

In small prospective1,2,5,12 and retrospective3,13 studies,

continuation of metformin throughout pregnancy inPCOS safely reduces otherwise high first trimester miscar-

riage rates. In a meta-analysis of 17 randomized controlled

clinical trials, Palomba et al.14 reported that metformin

had no effect on the spontaneous abortion risk in PCOS

patients when administered before pregnancy, and then

withdrawn after conception. Conversely, Morin-Papunen

et al. reported that metformin (3 months pre-conception

through week 12 of pregnancy) significantly improved live

birth rates (41.9% vs. 28.8%), with benefits especially

marked in obese women15. Improved live birth rates

have also been reported in non-obese women with

PCOS pretreated with metformin for 3 months before

In Vitro Fertilization/Intracytoplasmic Sperm Injection(IVF/ICSI)8.

Low glycemic index (GI), low carbohydrate, low fat,

low saturated fat, high protein diets, the type of diet used

in the current study, are important in management of

PCOS by themselves16,1720, and may be synergistic with

metformin16.

Compared to women without PCOS, women

with PCOS have significantly more gestational diabetes

mellitus (GD), pregnancy-induced hypertension, pre-

eclampsia, preterm delivery, and infants who are small

for gestational age10,21. Pre-pregnancy BMI is an indepen-

dent predictor of many adverse outcomes of pregnancy22,

very relevant to women with PCOS who, as a group, aremuch more obese than normal women23.

Miscarriage in an initial pregnancy is associated with an

increased risk of miscarriage in subsequent pregnancies in

unselected women24,25 and in women with thrombophi-

lia26, but live births are realized in 61% to 75% of subse-

quent pregnancies.In the current prospective follow-up study, our hypoth-

esis was that metformin low GI diet, started before con-

ception and continued throughout pregnancy, would

reduce safely first trimester miscarriage and improve preg-

nancy outcomes in PCOS.

Patients and methods

Study design

Our research protocol was approved by our Institutional

Review Board with signed informed consent from patients.

The study was prospective from the diagnosis of PCOS

through pre-conception therapy with metformin-diet

(metformin 22.55 g/day, low glycemic index diet), and

then on metformin-diet throughout pregnancy.

The diagnosis of PCOS was made by the ESHRE/

ASRM Rotterdam consensus criteria27. Exclusion criteria

included type 1 diabetes mellitus, pituitary insufficiency,

persistent hyperprolactinemia, and adult onset congenital

adrenal hyperplasia.

The study cohort included 76 women with PCOS whohad 1 pregnancy without metformin-diet, and 1 preg-

nancy on metformin-diet. To avoid bias, multiple preg-

nancies were not counted, only the first pregnancy of

record by history and on metformin-diet were compared.

Pregnancy outcomes (live births, miscarriages) were com-

pared in the 76 women before metformin-diet and on met-

formin-diet, with each subject serving as her own

control. Separately, in the 76 women with PCOS on met-

formin-diet, pregnancy outcomes (gestational diabetes,

pre-eclampsia, length of gestation, fetal weight) were com-

pared to those in 156 healthy women, who had 1 previ-

ous pregnancy, not known to have PCOS, consecutively

delivered in a suburban/urban community practice.Although a detailed history of pre-conception and

within-pregnancy cigarette smoking was obtained in the

cases, it was not systematically recorded in controls.

Pre-eclampsia28 and eclampsia were defined as previ-

ously described29.

Study protocol

Between 1997 and 2012, 1686 women were referred to our

center for a study of efficacy and safety of metformin in

PCOS. After excluding women with Type 1 diabetes mel-

litus, there were 76 with PCOS defined by the RotterdamConsensus Criteria27, who had 1 antecedent pregnancy

without metformin-diet, and who subsequently took met-

formin 22.55 g per day in combination with a low GI diet

before conception, conceived without fertility treatment,

and continued this regime through pregnancy. These 76

women were consecutively enrolled after conception and

were prospectively followed monthly throughout preg-

nancy under our direct supervision without selection bias

related to outcomes of previous pregnancies without met-

formin. There were no physician or office visit charges for

women before or during pregnancy. Adherence to metfor-

min was reviewed at each monthly visit by both the phy-

sician and the dietitian.Pre-conception, PCOS women with BMI 525 and

those25 kg/m2 were respectively instructed by registered

dietitians on a 1500 or 1200 calorie/day diet (low GI, low

carbohydrate [44%], high protein [26%], low fat [30%], low

saturated fat, polyunsaturated to saturated fat ratio [P/S]

2/1). Diet adherence was reinforced at visits every month

before pregnancy. After conception, the antecedent calo-

rie restrictions were dropped, ad libitum caloric intake was

allowed, but continued adherence to the low GI, low car-

bohydrate, low saturated fat, high P/S, and high protein

Current Medical Research & Opinion Volume 29, Number 1 January 2013

56 Metformin, PCOS, pregnancy outcomesGlueck et al. www.cmrojournal.com ! 2013 Informa UK Ltd


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diet was encouraged and emphasized by monthly follow-up

throughout gestation with a dietitian.

During pregnancy, women with PCOS made monthly

follow up visits to our center with measurement of weight,

complete blood count with platelet count, fasting serum

insulin, glucose, testosterone, free testosterone, sex hor-mone binding globulin, estradiol, progesterone, and quan-

titative HCG. Plasminogen activator inhibitor activity

(PAI-Fx) was measured at the first three visits during the

pregnancy. At each monthly visit, after a 5 minute rest,

seated blood pressure was obtained, and metformin dose

was recorded.

Outcome measures

In women with PCOS, primary outcome measures were

live birth or first trimester miscarriage on metformin-

diet, with comparison to their own antecedent pregnancies

without metformin-diet.Secondary outcome measures included development of

gestational diabetes, pre-eclampsia, eclampsia, birth532

weeks and 32 to537 weeks gestation, and birth weight

4000 or 4500 grams, with comparison to current preg-

nancies in controls.

Statistical analyses

Power analysis based on a decrease in miscarriage from

40%3,7 to 20% on metformin-diet suggested that in

women with PCOS, 45 pregnancies would be needed

before metformin-diet and on metformin-diet to detectchange in miscarriage rate atp 0.05 with power 0.8.

Patients and controls were compared by the Wilcoxon

test for continuous measures, and by chi-square test or

Fishers test for dichotomous characters. For ordinal mul-

tiple level characters, the MantelHaenszel test was used

to detect the levels shift.

The first pregnancy outcome (live birth, miscarriage)

on metformin-diet was compared with the patients previ-

ous first pregnancy outcome without metformin-diet.

McNemars test was used to detect the change of incident

tendency. Odds ratios and 95% confidence intervals were

also calculated. Stepwise logistic regression was used to

determine significant explanatory variables for the firstpregnancy outcome (live birth, miscarriage) on metfor-

min-diet, with explanatory variables including race, age,

and pre-conception BMI, and the duration of metformin-

diet before conception.

To compare gestational diabetes, pre-eclampsia, length

of gestation, and fetal macrosomia, the first pregnancies

with live births on metformin-diet in PCOS women

(n 62) were compared with current live birth pregnan-

cies in controls (n 156). Chi-square tests or Mantel

Haenszel tests were used. Stepwise logistic regressions

were used with gestational diabetes, pre-eclampsia,

length of gestation, and fetal macrosomia as dependent

variables, and race, age and weight before conception,

and case/control status as explanatory variables.

Results

Characteristics of PCOS women before

metformin-diet

In the 76 women with PCOS at study entry, before met-

formin-diet, median and 25th75th percentile values for

age were 31 (2834) years, weight 207 (182238) pounds,

and BMI 34.6 (29.439.3) kg/m2. More than 75% of the

PCOS cohort had BMI above normal (overweight 25 or

obese 30 kg/m2), more than 50% had high testosterone

(42 ng/dl), and more than 25% had high androstenedi-

one (230ng/dl), low sex hormone binding globulin(26 nmol/l), and high DHEAS (205 ug/dl).

Characteristics of PCOS women on

metformin-diet

Compared to healthy controls, women with PCOS were

more likely to be older at the time of conception (32 5

vs. 30 6 years [p 0.026]), and were much heavier at the

time of conception (BMI 33.3 7.4 [median 32.9] vs.

26.9 6.6 [median 25.1] kg/m2,p50.0001) (Table 1).In the 76 women with PCOS, from study entry to con-

ception, the median and 25th75th percentile period on

metformin-diet was 6.8 (1.515) months. In 9 of the 76

women (12%), metformin-diet was started at the time of

documentation of pregnancy.

Type 2 diabetes (T2DM) was present in 7 of 76 women

with PCOS at the time of conception on metformin-diet,

and in 0 of 156 younger and thinner community controls

(Table 1). Metformin was the only therapy for T2DM in

the 7 women with PCOS with T2DM at study entry.

Pregnancies before metformin-diet and onmetformin-diet

The 76 women had pregnancies both before metformin-diet and on metformin-diet for a median of 6.8 months

before conception, with metformin-diet then continued

throughout pregnancy (Figure 1). Of these 76 women,

first pregnancy outcomes without metformin-diet included

36 (47%) miscarriages and 40 live births vs. 14 (18%) first

pregnancy miscarriages and 62 live births on metformin-

diet. McNemars S 12.7, p 0.0004, odds ratio 3.99,

95% confidence interval 1.918.31 (Figure 1).Of the 76 pregnancies on metformin-diet, for the preg-

nancy outcome (live birth or miscarriage), by stepwise




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logistic regression, there were no explanatory significant

variables (p50.05) among race, age, pre-conception bodyweight, and duration of metformin-diet treatment before

conception. Pregnancy outcomes did not differ (p 0.6)

by metformin dosage (38 women receiving 2.55 g/day,

3852.55 g/day).

Gestational diabetes, pre-eclampsia, neonatal

birth weight, duration of gestation

In women with PCOS, of 76 first pregnancies on

metformin-diet, 62 resulted in live births (Figure 1).

Median weight gain during these live birth pregnancies

on metformin-diet was 3 pounds, with 75% gaining 20pounds.

Gestational diabetes in 8 (14%) live birth pregnancies

in 56 PCOS women without T2DM on metformin-diet did

not differ from that in community controls (15%)

(Table 1). Using stepwise logistic regression, race, age,

weight and case/control status were not significant predic-

tors for gestational diabetes,p40.05.

Pre-eclampsia did not differ (p 0.08) between PCOS

patients on metformin-diet and current pregnancies in

community controls (10% vs. 3%) (Table 1). By stepwise

Table 1. First pregnancy in 76 women with PCOS on metformin-diet before conception and throughout pregnancy, compared to 156 healthy women with1

previous pregnancy and 1 live birth current pregnancy delivered in a community obstetrics practice (controls).

PCOS Compared with communitycontrols

PCOS vs controls

n 76 156 had previous and current

pregnanciesRace 74 W (97%), 2 B & O (3%) 142 W (91%), 14 B & O (9%) % W, p 0.07 (2)Diabetes history 7 Type 2 DM no Type 2 DM p 0.0003 (Fisher)Age at conception 32 5 yrs 30 6yrs p 0.026 (Wilcoxon)

525 yrs,n 6 (8%) 525 yrs,n 28 (18%) MantelHaenszelp 0.1225530,n 25 (33%) 25530,n 40 (26%)

30535,n 26 (34%) 30535,n 56 (36%)35540,n 14 (18%) 35540,n 25 (16%)40,n 5 (7%) 40,n 7 (4%)

BMI at conception 33.3 7.4kg/m2

median 32.926.9 6.6kg/m2

median 25.1p50.0001 (Wilcoxon)

First pregnancy on metformin-diet with live birth n 62 (82%) Live birthn 156Birth at gestation week 532 weeks,n 1 (2%) 532 weeks,n 0 MantelHaenszel

p 0.4332537 weeks,n 7 (12%) 32537 weeks,n 16 (11%)3742 weeks, n 52 (87%)

(2 missing)3742 weeks,n 131 (89%)

(9 missing)

Gestational diabetes (GD) 8/56 not T2DM (14%) 23/156 (15%) p 0.93 (2

)Pre-eclampsia 6/62 (10%) 5/156 (3%) p 0.08 (Fisher)Birth weight 54000 g,n 51 (84%) 54000 g,n 115 (86%) MantelHaenszel

p 0.6640004500 g,n 8 (13%) 40004500 g,n 17 (13%)44500 g,n 2 (3%)(1 missing)

44500 g,n 2 (1%)(22 missing)

Wwhite, B black, O other, DM diabetes mellitus, T2DM type 2 diabetes mellitus.

Live births and Miscarriages in 76 Women with PCOS

the first pregnancy before matformin-diet and the first pregnancy on metoformin-diet

McNemar S=12.7, p=.0004. Odds Ratio=3.99, 95% CI 1.91-8.31

Of 76 pregnacies before metformin-diet40 live birth (53%)

36 miscarriages (47%)

Of 76 pregnacies on metformin-diet62 live births (82%)

14 miscarriages (18%)

18%

Miscarriage

47%

Miscarriage82%Live birthpregnancy

53%Live birth

pregnancy

Figure 1. Comparison of first pregnancy outcomes. Seventy-six first pregnancies in 76 women with PCOS who had pregnancies before metformin-diet and

subsequently on metformin-diet for a median of 6.8 months before conception and then throughout pregnancy.




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logistic regression, among explanatory variables race, age,

pre-conception weight and case/control status, pre-con-

ception weight was a significant predictor for pre-eclamp-

sia; for 1 kg increase in pre-conception weight, the odds

ratio was 1.03, 95% CI 1.0031.054, p 0.03. There were

no cases of eclampsia.The percentage of neonates with fetal macrosomia

(birth weight 44000 g) did not differ between neonates

born to PCOS mothers on metformin-diet and controls

(Table 1). By stepwise logistic regression, race, age, pre-

conception weight and case/control status were not signif-

icant predictors for fetal macrosomia, p40.05.

Birth before 32 weeks (2%) and from 32 to537 weeks

(12%) in women with PCOS on metformin-diet not differ

from healthy controls (0%, 11%), p 0.43 (Table 1). By

stepwise logistic regression, race, age, weight and case/

control status were not significant predictors for preterm

birth, p40.05.

Safety

During pregnancy, gastrointestinal upset and/or diarrhea

associated with metformin use occurred intermittently in

women with PCOS, but were not severe enough to cause

them to discontinue therapy.

On metformin, there was no maternal lactic acidosis

and no maternal or neonatal hypoglycemia.

Of the 62 first pregnancy live births in women with

PCOS on metformin-diet (Figure 1), there was one

major birth defect (sacrococcygeal teratoma) determined

by pediatricians without knowledge of metformin dose or

duration.

Discussion

Our principal findings were that in women with PCOS,

compared to antecedent pregnancy without metformin-

diet, metformin-diet before conception and continued

throughout pregnancy reduces miscarriage, and reduces

birth before 37 weeks, gestational diabetes, pre-eclampsia,

and fetal macrosomia to levels observed in healthy

women in a community practice of obstetrics. Why

should metformin-diet use before conception, during the

first trimester15, and throughout pregnancy reduce miscar-riage rates1,2 and promote live birth rates15? Metformin use

before conception improves the quality of the oocyte30,31.

Hypofibrinolysis, mediated by high levels of PAI-Fx, is a

significant independent predictor for miscarriage in

women with PCOS7 and metformin reduces hyperinsuli-

nemia and high PAI-Fx3,32,33. Metformin reduces uterine

artery impedance between 1219 weeks gestation34.

Reduced serum glycodelin and insulin-like growth factor

binding protein-1 in women with PCOS during the first

trimester of pregnancy35 may contribute to early

pregnancy loss. Metformin reduces hyperinsulinemia,

and would be expected to raise35 glycodelin and insulin-

like growth factor binding protein-1.

The low GI diet started pre-conception and continued

throughout pregnancy along with metformin may have

contributed to reduction of miscarriage and reduction ofadverse pregnancy outcomes and is a strength of this study.

The low GI diet is important in management of PCOS,

primarily by improving insulin sensitivity16, and may be

synergistic with metformin in reducing insulin resis-

tance16. Pre-pregnancy diet may be associated with GD,

frequent in women with PCOS21,36. We speculate that

beginning our low GI diet before pregnancy optimizespregnancy outcomes, via improvement in insulin sensitiv-

ity16 and synergism with metformin16. In overweight/obese

premenopausal women with PCOS, an insulin sensitivity

index improved more on a low GI diet than a macronutri-

ent matched healthy diet16. Women on the low GI diet

had improved menstrual cyclicity (95% vs. 63%,p 0.03)16. There was also a significant dietmetformin

interaction16. Douglaset al.17 studied three eucaloric diets,

one rich in monounsaturated fatty acids [17% energy], one

low carbohydrate [43%], and one standard (56% carbohy-

drate, 31% fat). Fasting insulin was lower following the low

carbohydrate vs. standard diet; acute insulin response to

glucose was lower relative to the monounsaturated fat

diet17. Low GI diets37 favorably affect neonatal birth

weight. The dietary glycemic load is positively related to

risk of gestational diabetes19. Low fat (30% of calories,high P/S) diets have been recommended for women with

PCOS20.

The second strength of the study was the initiation ofmetformin before conception, and maintenance through-

out pregnancy. Nestler38 hypothesized and Morin-

Papunen et al.15 documented that 3 months treatment

with metformin before conception optimizes effects on

hyperinsulinemia and improves fertility outcomes. In

four randomized controlled clinical trials where metformin

had no effect on early miscarriage rates, metformin was

given 1 month before conception, and was continued

only until a positive pregnancy test3942. Palomba et al.14

concluded that pre-conception metformin which was

withdrawn before or at the diagnosis of pregnancy had

no effect on abortion risk in PCOS patients and specu-

lated14 that early withdrawal of metformin without con-tinuation during pregnancy could affect its potential

benefits.

The major limitation of the current study is that the

individual benefits of the diet alone and diet plus metfor-

min could not be assessed separately. Randomized, con-

trolled clinical trials now need to be done with a larger

number of patients. Optimally, at least 3 months before

conception15 and throughout pregnancy, half of the

women should be randomized to diet with metformin,

and half to diet with placebo. Short of a placebo-controlled




6/8

study, we believe that using each woman as her own con-

trol, comparing antecedent pregnancy outcomes without

metformin and subsequent outcomes on metformin-diet

pre-conception and throughout pregnancy provides a

good comparison, eliminating between subject variance

(weight, degree of insulin resistance, PAI-Fx levels,degree of hyperandrogenism, etc). However an addi-

tional weakness of our study design is that although the

chances that the next pregnancy after spontaneous abor-

tion will again end in abortion are increased, 61% to

75% of the next pregnancies will be live birth

pregnancies24,25,43,26.

In the current report in women with PCOS, congruentwith many15,44 but not all studies3941, metformin-diet,

taken for an average of 6.8 months before conception,

sharply reduced the miscarriage rate, from 47% before met-

formin-diet to 18% on metformin-diet. Our finding of 18%

miscarriage on metformin-diet in women with PCOS falls

within the 15% to 31% first trimester miscarriage ratereported for healthy women6,45. With supportive care in

a dedicated miscarriage clinic, 26% of women with a his-

tory of unexplained first trimester miscarriage miscarried

again in their subsequent pregnancy46, and some of our

observed reduction in miscarriage may have been account-

able to supportive monthly follow-up in our center.

Maternal obesity is associated with a whole range of

pregnancy complications including miscarriage, pre-

eclampsia, gestational diabetes, and fetal macrosomia22,47,

and new recommendations for total weight gain duringpregnancy22 include 15 to 25 pounds for overweight

women (BMI 2529.9 kg/m2) and 11 to 20 pounds for

obese women (BMI 30 kg/m2). Prior to conception,more than half of our cohort had BMI 30, with

mean SD BMI 33.3 7.4 kg/m2. Median weight gain

throughout pregnancy on metformin-diet was 3 pounds,

with 50% of the cohort gaining 3 pounds during preg-

nancy and 75% gaining 20 pounds. Hence, on metfor-

min-diet, weight gain during pregnancy in half of our

PCOS cohort was less than the lower limit (11 pounds)

suggested for obese women, and 75% of our cohort had

weight gain less than the recommended upper normal

limit of 20 pounds for obese women22.

Without metformin before and during pregnancy,

PCOS is strongly associated with pre-eclampsia, very pre-

term birth (532 weeks), doubling the rate of gestationaldiabetes, and fetal macrosomia21,36. By contrast, in the

current study, on metformin-diet, fetal macrosomia, pre-

eclampsia and gestational diabetes did not differ from

healthy controls. In the current study, in contrast to pre-

vious reports21,48, premature delivery (532 weeks, 32 to

537 weeks) was not more common in PCOS patients on

metformin than in controls. However, in a randomized,

controlled clinical trial in women with PCOS who first

started metformin-diet therapy at the end of the first tri-

mester49, Vanky et al. reported that the prevalence of

pre-eclampsia, gestational diabetes mellitus, pre-term

delivery, and a composite of these outcomes did not

differ in metformin treated vs. placebo groups.

Metformin continued throughout pregnancy is not ter-

atogenic2,5,4952. Growth, and motor and social develop-

ment during childhood in offspring of metformin-takingmothers is normal53.

Conclusion

In the current study, metformin-diet before and during

pregnancy in PCOS reduces miscarriage and adverse preg-

nancy outcomes. Concurrent use of low GI, low carbohy-

drate diet before and throughout pregnancy, by reducing

insulin resistance, and synergistic with metformin16, may

be important in improving pregnancy outcomes.

Moreover, the beneficial effects of metformin-diet, reduc-

ing the otherwise higher likelihood in women with PCOSof gestational diabetes mellitus, fetal macrosomia, and pre-

eclampsia, appears to have broad utility during pregnancy

in women with PCOS.

Transparency

Declaration of funding

This manuscript was supported in part by the Lipoprotein

Research Fund of the Jewish Hospital of Cincinnati.

Declaration of financial/other relationshipsC.J.G., N.G., J.P., Z.K., J.P., and P.W. have disclosed that they

have no significant relationships with or financialinterests in any

commercial companies related to this study or article.

CMROpeer reviewers may have received honoraria for their

review work. The peer reviewers on this manuscript have dis-

closed that they have no relevant financial relationships.

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