Pediatrics 2012 aja nie

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DOI: 10.1542/peds.2012-0346; originally published online October 15, 2012;Pediatrics

Sven M. Carlsen, Marit P. Martinussen and Eszter VankyMetformin's Effect on First-Year Weight Gain: A Follow-up Study

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Metformins Effect on First-Year Weight Gain:

A Follow-up Study

WHATS KNOWN ON THIS SUBJECT: The use of metformin inpregnancy is increasing in the treatment of both gestational

diabetes and polycystic ovary syndrome. Metformin crosses the

placenta. Teratogenicity is not reported. Possible long-term

effects are undetermined.

WHAT THIS STUDY ADDS: Intrauterine metformin exposure seems

to have long-term effects on infant weight. At 1 year of age, infants

born to women and exposed to metformin weigh more than those

exposed to placebo in utero.

abstractBACKGROUND: The impact of metformin medication in pregnant

women with polycystic ovary syndrome on weight gain during preg-

nancy and after delivery and the impact on growth of the offspring

are essentially unexplored.

METHODS:This is a follow-up study of a randomized controlled trial

(The Metformin treatment in pregnant PCOS women study), conducted

in 11 secondary care centers. Women with PCOS were randomized to

metformin (2000 mg daily) or placebo from rst trimester to delivery.

Questionnaires were sent to 256 participants 1 year postpartum.Maternal weight development in pregnancy and the rst year after de-

livery and offspring anthropometry at birth and weight 1 year postpar-

tum were registered.

RESULTS:Women randomized to metformin gained less weight during

pregnancy compared with those in the placebo group. In the newborns,

there was no difference between the 2 groups in weight or length. One

year postpartum, women who used metformin in pregnancy lost less

weight and their infants were heavier than those in the placebo group

(10.2 6 1.2 kg vs 9.7 6 1.1 kg, P= .003).

CONCLUSIONS:Women randomized to metformin were heavier in the

rst trimester, gained less weight in pregnancy, and lost less weight inthe rst year postpartum compared with women randomized to pla-

cebo. Children exposed to metformin weighed more at 1 year of age.

Pediatrics 2012;130:e1222e1226

AUTHORS:Sven M. Carlsen, MD, PhD,

a,b

Marit P.Martinussen, MD, PhD,c and Eszter Vanky, MD, PhDc,d

aUnit for Applied Clinical Research, Institute for Cancer Research

and Molecular Medicine, Norwegian University of Science and

Technology, Trondheim, Norway; Departments of bEndocrinology,

and cObstetrics and Gynecology, St Olavs Hospital, Trondheim

University Hospital, Trondheim, Norway; and dInstitute for

Laboratory Medicine, Childrens and Womens Health, Norwegian

University of Science and Technology, Trondheim, Norway

KEY WORDS

PCOS, metformin, pregnancy, weight development, children

ABBREVIATIONS

PCOSpolycystic ovary syndrome

PregMetThe Metformin treatment in pregnant PCOS women study

RCTrandomized controlled trial

Dr Carlsen made substantial contributions to the conception

and design, analysis, and interpretation of data, in addition to

writing the article and approving the version to be published. Dr

Martinussen provided analysis and interpretation of data, in

addition to drafting the article or revising it critically for

important intellectual content and providing nal approval of

the version to be published. Dr Vanky made substantial

contributions to the conception and design, acquisition of data,

and analysis and interpretation of data, in addition to drafting

the article or revising it critically for important intellectual

content and providing nal approval of the version to be

published.

This trial has been registered at www.clinicaltrials.gov

(identier NCT00159536).

www.pediatrics.org/cgi/doi/10.1542/peds.2012-0346

doi:10.1542/peds.2012-0346

Accepted for publication Jun 26, 2012

Correspondence to Eszter Vanky, Department of Obstetrics and

Gynecology, St Olavs Hospital, University Hospital of Trondheim,

Olav Kyrres gt 16, 7006 Trondheim, Norway. E-mail: eszter.

[email protected]

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright 2012 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: The authors have indicated they have

no nancial relationships relevant to this article to disclose.

FUNDING: The Liaison Committee between the Central Norway

Regional Health Authority and the Norwegian University of

Science and Technology (NTNU) funded the study. Weifa A/S

(Oslo, Norway) supplied metformin and placebo tablets free of

charge.

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The role of metformin treatment in

pregnant women with polycystic ovary

syndrome (PCOS) is not yet deter-

mined. Nonrandomized and retrospec-

tive studies and 1 small randomized

controlled trial (RCT) indicate positive

effects of metformin on pregnancycomplications.17 A large RCT did not

support these results.8

Although not approved in pregnancy,

metformin is widely used. Metformin

crosses the placenta and is present in

fetal circulation in therapeutic con-

centrations.9 So far, no negative effects

of metformin have been reported in

the mother or in the offspring. Infants

born to mothers with PCOS who used

metformin in pregnancy did not haveany adverse effect on birth length

and weight, growth, or motor-social

development in the rst 18 months of

life compared with a background pop-

ulation.10

In an RCT for women with gestational

diabetes, randomized to metformin or

insulin, 2-year-old children exposed to

metformin in utero had more sub-

cutaneousfat,butoverallbodyfatwasthe

sameas in children whose mothers weretreated with insulin alone.11 It is impor-

tant to establish the possible long-term

impact and safety of intrauterine met-

formin exposure in the offspring, and

this can only be done in RCTs.

Toinvestigate the possibleeffect of fetal

metformin exposure in utero we per-

formed a follow-up investigation of

offspring and mothers from a previous

RCT, in which women with PCOS were

treated with metformin in pregnancy(The Metformin treatment in pregnant

PCOS women [PregMet] study).8 We

hypothesized that 1 year postpartum,

(1) mothers in the metformin group

would weigh less (as they did during

pregnancy) compared with those in the

placebo group and (2) infants exposed

to metformin in utero would weigh

less compared with those exposed to

placebo.

METHODS

Study Design

The current study is a follow-up of The

PregMet study. The PregMet study was

a prospective, randomized, double-

blind, multicenter trial that comparedmetformin 2000 mg daily with placebo

from the rst trimester to delivery.8

In the PregMet study the inclusion

criteria were (1) PCOS diagnosed

according to The Rotterdam Criteria,12

(2) age 18 to 45 years, (3) gestational

age between 5 and 12 weeks, and (4)

a singleton viable fetus shown on ul-

trasonography. The exclusion criteria

were alanine aminotransferase level

.90 IU/L, serum creatinine concen-

tration .130 mmol/L, known alcohol

abuse, previously diagnosed diabetes

mellitus or fasting serum glucose.7.0

mmol/L at the time point of inclusion,

treatment with oral glucocorticoids, or

use of drugs known to interfere with

metformin.

Two hundred seventy-four pregnancies

(in 258 women) were randomly

assigned to either metformin or pla-

cebotreatment(16womenparticipatedtwice). Randomization, blinding, and

performed measurements are de-

scribed in detail elsewhere.8

All participants received written and

individual verbal counseling on dietand

lifestyle at inclusion. Thereafter treat-

mentwithmetforminhydrochloride500

mg (Metformin; Weifa AS, Oslo, Norway)

or identically coated placebo tablets

was initiated. The participants took 1

tablet twice daily during the rst weekandthereafter2 tablets twice daily until

delivery, when study medication was

stopped. To counteract a possible ad-

verse effect of metformin on vitamin B

levels, patients were advised to take 0.8

mg of folic acid daily and 1 daily mul-

tivitamin tablet containing both vitamin

B6and B12.

Standardized interviewer-administered

questionnaires were usedto obtain self-

reported data on education, smoking

habits, and study medication. Height

wasrecorded at inclusion andweight at

each prescheduled visit. Body weight

was recorded with light clothes on and

without shoes. Gestational age was de-

termined by mid-pregnancy ultrasoundexamination, measuring biparietal diam-

eter, femur length, and mean abdominal

diameter of the fetus.

The Committee for Medical Research

Ethics of Health Region IV, Norway, and

The Norwegian Medicines Agency ap-

proved the study. Written informed

consent was obtained from each

patient before inclusion, and the Dec-

laration of Helsinki was followed

throughout the study. The study wasconducted according to principles of

Good Clinical Practice,and the trial is

registered at www.clinicaltrials.govas

NCT00159536.

The Follow-up Study

The participants in The PregMet Study

gave their written consent to be con-

tacted after the end of the original

study. Of the 274 included pregnan-

cies (in 258 women) in The PregMetStudy, 3 patients had miscarriages, 12

dropped out, 1 was excluded due to

misdiagnosis, and 2 infants died peri-

natally. Two hundred forty women with

256 pregnancies were invited to par-

ticipate in the follow-up study. One year

after delivery, a questionnaire and

prepaid envelope was sent by mail. A

reminder was sent about 2 to 3 weeks

later to nonrespondents. At this time

point, the participants were not awareof whether theyhad beenrandomizedto

metformin or to placebo.

The participants were asked about

their own weight and the infantsweight

(registered at the child`s weight card)

at 12 months postpartum. In Norway,

newborns and older infants are closely

followed up in a public health care sys-

tem free of charge. The mothers carry a

weight cardwhere the infants weights

ARTICLE

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are regularly registered at different time

points after birth by a public health nurse,

also at 12 months of age.

Statistical Analyses

All data entry, data management, and

data analyses were performed at

the Inst itute of Laborat ory Medi cine ,

Childrens and Womens, Norwegian

University of Science and Technology.

The data were analyzed according to

the intention-to-treat principle. PASW

statistics version 18.0 for Windows

(IBM SPSS Inc USA, Chicago, IL) was

used. The differences between the

study groups were compared with

2-tailed ttests for independent samples.

Values are reported as means (SD) orabsolute numbers. A x

2test was used

to test differences between the groups.

If the smallest expected value in a cell

was ,5, we used the Fisher exact test.

Associations were investigated with

univariate and multivariate linear re-

gression analyses. Two-tailed tests were

used throughout, and P , .05 was

considered signicant. No adjustments

for multiple testing were performed.

Role of the Funding Source

The Liaison Committee between the

Central Norway Regional Health Au-

thority and the Norwegian University of

Science and Technology funded the

study. Weifa AS (Oslo, Norway) supplied

the study drug free of charge. None of

the funding sources had a role in the

collection, analysis, and interpretation

of the data or in writing and deciding to

submit the report.

RESULTS

Baseline Characteristics

Of the 256 (78%) women with PCOS who

participated in The PregMet Study, 199

responded to the questionnaire, 1 year

postpartum. Except for a higher BMI at

inclusion (in the rst trimester of

pregnancy, before randomization), no

differences were foundin baseline data

betweenthose who were randomized to

metformin or placebo treatment in

pregnancy (Table 1).

Maternal Weight Development

Women in the metformin group gained

less weight in pregnancy than didthose

in the placebo group. However, after

delivery, the women in the placebo

group lost more weight during the rst

yearand had a lower BMI thandid those

in the metformin group 1 year after

delivery (Fig 1). The change in BMI from

the rst trimester of pregnancy to 1

year postpartum was +1.06 2.9 kg/m2

in the metformin group vs +0.2 6 2.0

kg/m2

in the placebo group (P = .03)

(Table 1).

Offspring Anthropometry at Birth

There were no differences in birth

weight, birthlength,and ponderalindex

between newborns who were exposed

to metformin and those who were ex-

posed to placebo in utero. Boys in

the metformin group had higher birth

weight, were longer, and had larger

head circumference at birth compared

with the placebo group (Table 1). How-

ever, when adjusted for gestational age,

maternal smoking, maternal BMI, and

maternal height, these differences dis-

appeared (data not shown).

TABLE 1 Maternal and Offspring Characteristics From the First Trimester of Pregnancy to 1 yPostpartum

n Metformin n Placebo P

First trimester

Age, y 102 29.7 6 4.4 97 29.4 6 4.3 .61

BMI, kg/m2 102 29.5 6 7.1 97 27.6 6 6.1 .04

Smoking, No. 102 10 (10) 97 3 (3) .08a

Civil status, single/married or cohabitant 99 5/99 96 0/96 .06a

Education,#12 y/.12 y 99 31/68 95 34/61 .54

At the end of pregnancya

BMI, kg/m2

97 32.7 6 6.9 85 32.0 6 7.3 .51

BMI gain in pregnancy, kg/m2

97 3.2 6 2.0 85 4.2 6 4.3 .03

Smoking, No. 99 5 (5) 97 2 (2) .44b

Offspring characteristics at birth

Gestational length, d 102 277 6 10 97 274 6 10 .08

Birth weight, all, g 102 3548 6 550 97 3483 6 634 .44

Girls, g 52 3438 6 539 51 3602 6 560 .13

Boys, g 50 3662 6 542 46 3350 6 681 .01

Birth length. all, cm 101 50.0 6 2.1 95 49.8 6 2.5 .49

Girls, cm 51 49.4 6 1.9 50 50.0 6 2.4 .18

Boys, cm 50 50.6 6 2.2 45 49.5 6 2.7 .03

Ponderal index, all, kg/m3

101 28.3 6 2.6 95 28.2 6 2.6 .77

Girls, kg/m3

51 28.5 6 2.6 50 28.8 6 2.6 .68

Boys, kg/m3

50 28.1 6 2.5 45 28.6 6 2.4 .30

Offspring gender, girls/boys 102 52/50 97 51/46 .89

Placenta weight, all, g 91 660 6 148 84 646 6 152 .54

Girls, g 47 644 6 149 41 662 6 142 .57

Boys, g 44 678 6 148 43 631 6 161 .17

1 y postpartum

Maternal BMI, kg/m2

101 30.6 6 8.1 94 27.6 6 6.1 .004

Maternal BMI change from rst

trimester to 1 y postpartum, kg/m2101 1.0 6 2.9 94 0.2 6 2.0 .03

Maternal BMI change from end

of pregnancy to 1 y postpartum, kg/m2

96 22.1 6 3.6 82 24.1 6 4.9 .003

Smoking, No. 102 11 (11) 95 9 (9) .82a

Offspring weight at 1 y, all, kg 102 10.2 6 1.2 94 9.7 6 1.1 .003

Girls, kg 52 9.8 6 0.9 50 9.5 6 1.1 .09

Boys, kg 50 10.6 6 1.3 44 10.0 6 1.0 .01

a Lastmeasured in pregnancy(ie, for those who passed gestation week 36,it wasgestation week 36; for thosewho gave birth

after gestational week 24 but before gestational week 36, it was the last visit before birth).b Fishers exact test.

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Offspring Weight Development

At 1 year of age, infants exposed to met-

formin in utero were 5% heavier com-

pared with those exposed to placebo

(10.2 6 1.2 kg vs 9.7 6 1.1 kg;P= .003)

(Table 1). The difference remained sig-

nicant in a multivariate regression

analysis, where we adjusted for gesta-

tional age, birth weight, maternal smok-

ing in pregnancy, maternal BMI, maternal

height, and duration of breastfeeding

(P= .001) (Table 2). Both boys and girls

exposed to metformin tended to be

heavier at 1 year of age (Table 3).

DISCUSSION

The most important ndings of the

current study are that (1) maternal BMI

is higher at 1 year after delivery in

participants who were randomized to

metformin in pregnancy and stopped

medication at delivery than in those

randomized to placebo and (2) infants

exposed to metformin in utero had

higher body weight at 1 year of age

compared with those exposed to pla-

cebo.

We have previously reported that met-

formin treatment in women with PCOSreduced weight gain in pregnancy.8

Contrary to our hypothesis, the current

study shows that weight reduction af-

ter delivery is less in mothers who

were randomized to metformin com-

pared with those randomized to pla-

cebo during pregnancy. It could reect

that women in the metformin group at

baseline were more overweight and

gained more weigh after a pregnancy

and postpartum period. However, wehave adjusted for maternal baseline

BMI, and the difference persists be-

tween the groups. We believe that

higher BMI 1 year after delivery can

be attributed to a rebound effect af-

ter ceased metformin medication at

delivery.

At birth, there were no differences in

weight or length between the 2 groups.

Interestingly, at1 year ofage,metformin-

exposed infants of each gender are

heavier thanplacebo-exposed ones.This

weight difference persisted also after

adjustment for factors known to in-

uence weight development and cannot

be attributed to a big mothersbig

infantsphenomenon.

Unfortunately, we have no data on body

composition of these infants. Accord-

ingly we do not know whethertheweight

28.0

28.5

29.0

29.5

30.0

30.5

31.0

31.5

32.0

32.5

33.0

33.5

34.0

Bodymassindex(kg/m2)

19 24 32 36 1 year after delivery

Gestional week or time after delivery

Metformin

Placebo

FIGURE 1Weight development in pregnancy and postpartum according to treatment allocation. Medication was

stopped at delivery.Pvalue at gestational week 19 = .95; at gestational week 24 = .38; at gestational

week 32 = .18, and at gestational week 36 = .03. Pvalue at 1 year postpartum = .03.

TABLE 2 Offsprings Weight (kg) at 1 y Postpartum in Univariate and Multivariate RegressionModels

Univariate Multivariate

n B 95% CI P n B 95% CI P

Randomization, metformin = 1;

placebo = 2

195 2.49 2.80 to 2.17 .003 186 2.53 2.84 to 2.22 .001

Birth weight, g 195 .001 .00 to .00 ,.001 186 .001 .00 to .00 .001

Gestational age, d 195 .005 2.01 to .02 .44 186 2.01 2.03 to 2.01 .07

Maternal smoking, no = 1; yes = 2 194 .21 2.32 to .74 .43 186 2.23 2.78 to .31 . 40

Maternal BMI 1 y postpartum, kg/m2

191 .02 2.01 to .04 .14 186 2.00 2.02 to .02 . 83

Maternal height, cm 195 .04 .001 to .07 .02 186 .03 .00 to .06 .03

Exclusive breastfeeding, mo 195 2.03 2.09 to .02 .26 186 .02 2.05 to .10 . 54

Any breastfeeding, mo 195 2.05 2.08 to 2.01 .01 186 2.06 2.11 to 2.00 .04

Maternal education, 12 y = 1;

.12 y = 2

190 2.41 2.75 to 2.07 .02 186 2.32 2.66 to .03 . 07

TABLE 3 Offsprings Weight (kg) at 1 y Postpartum According to Gender in a MultivariateRegression Model

Girls Boys

n B 95% CI P n B 95% CI P

Randomization, metformin= 1;

placebo = 2

97 2.41 2.82 to .00 .05 88 2.42 2.85 to .00 .05

Birth weight, g 97 .00 .00 to .00 .55 88 .00 .00 to .00 ,.001

Gestational age, d 97 2.01 2.03 to .01 .22 88 2.02 2.04 to .00 .07

Maternal smoking, no =1; yes = 2 97 2.16 2.83 to .51 .63 88 2.26 21.06 to . 54 . 52

Maternal BMI 1 y postpartum, kg/m2

97 .00 2.02 to .03 .91 88 2.01 2.04 to .03 .61

Maternal height, cm 97 .01 2.03 to .05 .71 88 .04 2. 04 to .08 . 052

Exclusive breastfeeding , mo 97 .07 2.02 to .16 .12 88 2.00 2.12 to .11 .97

Any breastfeeding, mo 97 2.04 2.11 to .03 .22 88 2.05 2.13 to .02 .17

Maternal education, 12 y = 1;

.12 y = 2

97 2.48 2.93 to 2.03 .03 88 2.22 2.71 to .26 .37

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difference represents increased lean

body mass, increased fat mass, or both.

Theprobability that metforminmay have

lasting effects in children, as seen in the

current study, is supported by data

from small-for-gestational age girls

with premature adrenarche.13 Inthese girls, treatment with metfor-

min delayed premature menarche and

prevented excessive weight gain. The

weight effect persisted also after

metformin treatment had been stop-

ped.14 Taken together with our data,

this indicates that metformin, when

used during a critical time window,

might induce long-term endocrine and/

or metabolic changes. Imprinting of

genes may be the mechanism involved.

It has been shown that metformin has

the potential to affect transcription ofgenes.15

This is the rst report providing evi-

dence on metformin inuence on in-

trauterine development. Interestingly,

this effect persists at least 1 year after

birth, indicating that metformin may

have long-term metabolic or endocrine

effects in the offspring.

CONCLUSIONS

Although there were no differences in

birth weight andlength,at 1 year of age,

both boys and girls exposed to met-formin had higher weight compared

with placebo-exposed boys and girls.

Additional studies are needed to con-

rm and explain our ndings and to

establish the safety of intrauterine

metformin exposure.

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DOI: 10.1542/peds.2012-0346; originally published online October 15, 2012;Pediatrics

Sven M. Carlsen, Marit P. Martinussen and Eszter VankyMetformin's Effect on First-Year Weight Gain: A Follow-up Study

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