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Current Medical Research & Opinion

Article ST-0282.R1/755121
All rights reserved: reproduction in whole or part not permitted

Cholesterol 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;
CJGlueck@health-partners.org
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

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Charles J. Glueck
Naila Goldenberg
Joel Pranikoff
Zia Khan
Jagjit Padda
Ping Wang

Original article
Effects of metformin-diet intervention before
and throughout pregnancy on obstetric and
neonatal outcomes in patients with polycystic
ovary syndrome

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0300-7995
doi:10.1185/03007995.2012.755121

Vol. 29, No. 1, 2013, 5562

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 comparable with other subfertile populations. Palomba et al.11 reported that pregnant
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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 in
PCOS safely reduces otherwise high first trimester miscarriage 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, preeclampsia, preterm delivery, and infants who are small
for gestational age10,21. Pre-pregnancy BMI is an independent predictor of many adverse outcomes of pregnancy22,
very relevant to women with PCOS who, as a group, are
much 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 thrombophilia26, but live births are realized in 61% to 75% of subsequent pregnancies.
In the current prospective follow-up study, our hypothesis was that metformin low GI diet, started before conception and continued throughout pregnancy, would
reduce safely first trimester miscarriage and improve pregnancy 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.
56

Metformin, PCOS, pregnancy outcomes Glueck et al.

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 who
had 1 pregnancy without metformin-diet, and 1 pregnancy on metformin-diet. To avoid bias, multiple pregnancies were not counted, only the first pregnancy of
record by history and on metformin-diet were compared.
Pregnancy outcomes (live births, miscarriages) were compared in the 76 women before metformin-diet and on metformin-diet, with each subject serving as her own
control. Separately, in the 76 women with PCOS on metformin-diet, pregnancy outcomes (gestational diabetes,
pre-eclampsia, length of gestation, fetal weight) were compared to those in 156 healthy women, who had 1 previous 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 previously 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 mellitus, there were 76 with PCOS defined by the Rotterdam
Consensus Criteria27, who had 1 antecedent pregnancy
without metformin-diet, and who subsequently took metformin 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 pregnancy under our direct supervision without selection bias
related to outcomes of previous pregnancies without metformin. There were no physician or office visit charges for
women before or during pregnancy. Adherence to metformin was reviewed at each monthly visit by both the physician and the dietitian.
Pre-conception, PCOS women with BMI 525 and
those 25 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 calorie restrictions were dropped, ad libitum caloric intake was
allowed, but continued adherence to the low GI, low carbohydrate, low saturated fat, high P/S, and high protein
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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 hormone binding globulin, estradiol, progesterone, and quantitative 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 metformindiet, with comparison to their own antecedent pregnancies
without metformin-diet.
Secondary outcome measures included development of
gestational diabetes, pre-eclampsia, eclampsia, birth 532
weeks and 32 to 537 weeks gestation, and birth weight
4000 or 4500 grams, with comparison to current pregnancies 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 detect
change in miscarriage rate at p 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 multiple 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 previous 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 first
pregnancy outcome (live birth, miscarriage) on metformin-diet, with explanatory variables including race, age,
and pre-conception BMI, and the duration of metformindiet 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 pregnancies in controls (n 156). Chi-square tests or Mantel
Haenszel tests were used. Stepwise logistic regressions
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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 metformin-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 androstenedione (230 ng/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 conception, 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 on


metformin-diet
The 76 women had pregnancies both before metformindiet 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 metformindiet. 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 pregnancy outcome (live birth or miscarriage), by stepwise
Metformin, PCOS, pregnancy outcomes Glueck et al.

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Table 1. First pregnancy in 76 women with PCOS on metformin-diet before conception and throughout pregnancy, compared to 156 healthy women with 1
previous pregnancy and 1 live birth current pregnancy delivered in a community obstetrics practice (controls).

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PCOS

Compared with community


controls

76

Race
Diabetes history
Age at conception

74 W (97%), 2 B & O (3%)


7 Type 2 DM
32  5 yrs
525 yrs, n 6 (8%)
25530, n 25 (33%)
30535, n 26 (34%)
35540, n 14 (18%)
40, n 5 (7%)
33.3  7.4 kg/m2
median 32.9

BMI at conception

First pregnancy on metformin-diet with live birth n 62 (82%)


Birth at gestation week
532 weeks, n 1 (2%)
32537 weeks, n 7 (12%)
3742 weeks, n 52 (87%)
(2 missing)
Gestational diabetes (GD)
8/56 not T2DM (14%)
Pre-eclampsia
6/62 (10%)
Birth weight
54000 g, n 51 (84%)
40004500 g, n 8 (13%)
44500 g, n 2 (3%)
(1 missing)

156 had previous and current


pregnancies
142 W (91%), 14 B & O (9%)
no Type 2 DM
30  6 yrs
525 yrs, n 28 (18%)
25530, n 40 (26%)
30535, n 56 (36%)
35540, n 25 (16%)
40, n 7 (4%)
26.9  6.6 kg/m2
median 25.1
Live birth n 156
532 weeks, n 0
32537 weeks, n 16 (11%)
3742 weeks, n 131 (89%)
(9 missing)
23/156 (15%)
5/156 (3%)
54000 g, n 115 (86%)
40004500 g, n 17 (13%)
44500 g, n 2 (1%)
(22 missing)

PCOS vs controls

% W, p 0.07 (2)
p 0.0003 (Fisher)
p 0.026 (Wilcoxon)
MantelHaenszel
p 0.12

p50.0001 (Wilcoxon)

MantelHaenszel
p 0.43
p 0.93 (2)
p 0.08 (Fisher)
MantelHaenszel
p 0.66

W white, 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

47%
Miscarriage
53%
Live birth
pregnancy
Of 76 pregnacies before metformin-diet
40 live birth (53%)
36 miscarriages (47%)

18%
Miscarriage
82%
Live birth
pregnancy

Of 76 pregnacies on metformin-diet
62 live births (82%)
14 miscarriages (18%)

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.

logistic regression, there were no explanatory significant


variables (p50.05) among race, age, pre-conception body
weight, 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).
58

Metformin, PCOS, pregnancy outcomes Glueck et al.

Median weight gain during these live birth pregnancies


on metformin-diet was 3 pounds, with 75% gaining 20
pounds.
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 predictors 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
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logistic regression, among explanatory variables race, age,


pre-conception weight and case/control status, pre-conception weight was a significant predictor for pre-eclampsia; 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, preconception weight and case/control status were not significant predictors for fetal macrosomia, p40.05.
Birth before 32 weeks (2%) and from 32 to 537 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 metformindiet, 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 miscarriage 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 hyperinsulinemia 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
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pregnancy loss. Metformin reduces hyperinsulinemia,


and would be expected to raise35 glycodelin and insulinlike 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 of
adverse 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 resistance16. Pre-pregnancy diet may be associated with GD,
frequent in women with PCOS21,36. We speculate that
beginning our low GI diet before pregnancy optimizes
pregnancy outcomes, via improvement in insulin sensitivity16 and synergism with metformin16. In overweight/obese
premenopausal women with PCOS, an insulin sensitivity
index improved more on a low GI diet than a macronutrient 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. Douglas et al.17 studied three eucaloric diets,
one rich in monounsaturated fatty acids [17% energy], one
low carbohydrate [43%], and one standard (56% carbohydrate, 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 of
metformin before conception, and maintenance throughout pregnancy. Nestler38 hypothesized and MorinPapunen 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 speculated14 that early withdrawal of metformin without continuation 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 metformin could not be assessed separately. Randomized, controlled 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
Metformin, PCOS, pregnancy outcomes Glueck et al.

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study, we believe that using each woman as her own control, 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 additional weakness of our study design is that although the
chances that the next pregnancy after spontaneous abortion 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, congruent
with 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 metformin-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 rate
reported for healthy women6,45. With supportive care in
a dedicated miscarriage clinic, 26% of women with a history of unexplained first trimester miscarriage miscarried
again in their subsequent pregnancy46, and some of our
observed reduction in miscarriage may have been accountable to supportive monthly follow-up in our center.
Maternal obesity is associated with a whole range of
pregnancy complications including miscarriage, preeclampsia, gestational diabetes, and fetal macrosomia22,47,
and new recommendations for total weight gain during
pregnancy22 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 pregnancy and 75% gaining 20 pounds. Hence, on metformin-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 preterm birth (532 weeks), doubling the rate of gestational
diabetes, and fetal macrosomia21,36. By contrast, in the
current study, on metformin-diet, fetal macrosomia, preeclampsia and gestational diabetes did not differ from
healthy controls. In the current study, in contrast to previous 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 trimester49, Vanky et al. reported that the prevalence of
60

Metformin, PCOS, pregnancy outcomes Glueck et al.

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 teratogenic2,5,4952. Growth, and motor and social development during childhood in offspring of metformin-taking
mothers is normal53.

Conclusion
In the current study, metformin-diet before and during
pregnancy in PCOS reduces miscarriage and adverse pregnancy outcomes. Concurrent use of low GI, low carbohydrate 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, reducing the otherwise higher likelihood in women with PCOS
of gestational diabetes mellitus, fetal macrosomia, and preeclampsia, 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 relationships
C.J.G., N.G., J.P., Z.K., J.P., and P.W. have disclosed that they
have no significant relationships with or financial interests in any
commercial companies related to this study or article.
CMRO peer reviewers may have received honoraria for their
review work. The peer reviewers on this manuscript have disclosed that they have no relevant financial relationships.

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