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Article ST-0282.R1/755121
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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
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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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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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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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).
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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
76
Race
Diabetes history
Age at conception
BMI at conception
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
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.
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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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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
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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.
References
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