Metformin's Effect on First-Year Weight Gain: A Follow-up Study

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A Follow-up Study

WHAT’S KNOWN ON THIS SUBJECT: The use of metformin in pregnancy 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.

abstract

BACKGROUND: 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 fromfirst trimester to delivery. Questionnaires were sent to 256 participants 1 year postpartum. Maternal weight development in pregnancy and thefirst 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 (10.261.2 kg vs 9.761.1 kg,P= .003).

CONCLUSIONS:Women randomized to metformin were heavier in the

first trimester, gained less weight in pregnancy, and lost less weight in thefirst year postpartum compared with women randomized to pla-cebo. Children exposed to metformin weighed more at 1 year of age.

Pediatrics2012;130:e1222–e1226

AUTHORS:Sven M. Carlsen, MD, PhD,a,bMarit P.

Martinussen, MD, PhD,cand 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 ofbEndocrinology,

andcObstetrics and Gynecology, St Olavs Hospital, Trondheim

University Hospital, Trondheim, Norway; anddInstitute for

Laboratory Medicine, Children’s and Women’s Health, Norwegian University of Science and Technology, Trondheim, Norway

KEY WORDS

PCOS, metformin, pregnancy, weight development, children

ABBREVIATIONS

PCOS—polycystic ovary syndrome

PregMet—The Metformin treatment in pregnant PCOS women study RCT—randomized 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 providingfinal 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 providingfinal approval of the version to be published.

This trial has been registered at www.clinicaltrials.gov (identifier 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. vanky@ntnu.no

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 nofinancial relationships relevant to this article to disclose.

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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 pregnancy complications.1–7 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.9So 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 have any adverse effect on birth length and weight, growth, or motor-social development in thefirst 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-cutaneous fat, but overall body fat was the same as in children whose mothers were treated with insulin alone.11It 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.

To investigate the possible effect 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 compared metformin 2000 mg daily with placebo from thefirst 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-cebo treatment (16 women participated twice). Randomization, blinding, and performed measurements are de-scribed in detail elsewhere.8

All participants received written and individual verbal counseling on diet and lifestyle at inclusion. Thereafter treat-ment with metformin hydrochloride 500 mg (Metformin; Weifa AS, Oslo, Norway) or identically coated placebo tablets was initiated. The participants took 1 tablet twice daily during thefirst week and thereafter 2 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 used to obtain

self-reported data on education, smoking habits, and study medication. Height was recorded at inclusion and weight at each prescheduled visit. Body weight was recorded with light clothes on and without shoes. Gestational age was de-termined by mid-pregnancy ultrasound examination, 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 was conducted according to principles of

“Good Clinical Practice,”and the trial is registered at www.clinicaltrials.gov as 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 PregMet Study, 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 aware of whether they had been randomized to metformin or to placebo.

The participants were asked about their own weight and the infant’s weight (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 card”where the infant’s weights

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also at 12 months of age.

Statistical Analyses

All data entry, data management, and data analyses were performed at the Institute of Laboratory Medicine, Children’s and Women’s, 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-tailedttests for independent samples. Values are reported as means (SD) or absolute numbers. Ax2test 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 significant. 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 first trimester of pregnancy, before randomization), no

metformin or placebo treatment in pregnancy (Table 1).

Maternal Weight Development

Women in the metformin group gained less weight in pregnancy than did those in the placebo group. However, after delivery, the women in the placebo group lost more weight during thefirst year and had a lower BMI than did those in the metformin group 1 year after delivery (Fig 1). The change in BMI from the first trimester of pregnancy to 1 year postpartum was +1.062.9 kg/m2 in the metformin group vs +0.262.0

Offspring Anthropometry at Birth

There were no differences in birth weight, birth length, and ponderal index 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 y Postpartum

n Metformin n Placebo P

First trimester

Age, y 102 29.764.4 97 29.464.3 .61

BMI, kg/m2 102 29.567.1 97 27.666.1 .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 32.766.9 85 32.067.3 .51 BMI gain in pregnancy, kg/m2 97 3.262.0 85 4.264.3 .03

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

Offspring characteristics at birth

Gestational length, d 102 277610 97 274610 .08 Birth weight, all, g 102 35486550 97 34836634 .44

Girls, g 52 34386539 51 36026560 .13

Boys, g 50 36626542 46 33506681 .01

Birth length. all, cm 101 50.062.1 95 49.862.5 .49 Girls, cm 51 49.461.9 50 50.062.4 .18

Boys, cm 50 50.662.2 45 49.562.7 .03

Ponderal index, all, kg/m3 101 28.362.6 95 28.262.6 .77

Girls, kg/m3 51 28.562.6 50 28.862.6 .68

Boys, kg/m3 50 28.162.5 45 28.662.4 .30

Offspring gender, girls/boys 102 52/50 97 51/46 .89 Placenta weight, all, g 91 6606148 84 6466152 .54

Girls, g 47 6446149 41 6626142 .57

Boys, g 44 6786148 43 6316161 .17

1 y postpartum

Maternal BMI, kg/m2 101 30.668.1 94 27.666.1 .004 Maternal BMI change fromfirst

trimester to 1 y postpartum, kg/m2

101 1.062.9 94 0.262.0 .03

Maternal BMI change from end of pregnancy to 1 y postpartum, kg/m2

96 22.163.6 82 24.164.9 .003

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

Offspring weight at 1 y, all, kg 102 10.261.2 94 9.761.1 .003

Girls, kg 52 9.860.9 50 9.561.1 .09

Boys, kg 50 10.661.3 44 10.061.0 .01

aLast measured in pregnancy (ie, for those who passed gestation week 36, it was gestation week 36; for those who gave birth

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

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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 (10.261.2 kg vs 9.761.1 kg;P= .003) (Table 1). The difference remained sig-nificant 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 findings 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 PCOS reduced 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 reflect that women in the metformin group at baseline were more overweight and gained more weigh after a pregnancy and postpartum period. However, we have 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, at 1 year of age,

metformin-exposed infants of each gender are heavier than placebo-exposed ones. This weight difference persisted also after adjustment for factors known to

in-fluence weight development and cannot

be attributed to a “big mothers–big infants”phenomenon.

Unfortunately, we have no data on body composition of these infants. Accord-ingly we do not know whether the weight

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

Bo

d

y ma

ss i

n

d

e

x

(kg

/m

2

)

19 24 32 36 1 year after delivery

Gestional week or time after delivery Metformin

Placebo

FIGURE 1

Weight 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 Offspring’s Weight (kg) at 1 y Postpartum in Univariate and Multivariate Regression Models

Univariate Multivariate

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

Randomization, metformin = 1; placebo = 2

195 2.49 2.80 to2.17 .003 186 2.53 2.84 to2.22 .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 to2.01 .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 to2.01 .01 186 2.06 2.11 to2.00 .04 Maternal education, 12 y = 1;

.12 y = 2

190 2.41 2.75 to2.07 .02 186 2.32 2.66 to .03 .07

TABLE 3 Offspring’s Weight (kg) at 1 y Postpartum According to Gender in a Multivariate Regression 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 to2.03 .03 88 2.22 2.71 to .26 .37

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lasting effects in children, as seen in the current study, is supported by data from small-for-gestational age girls with premature adrenarche.13 In

these 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,

or metabolic changes. Imprinting of genes may be the mechanism involved. It has been shown that metformin has the potential to affect transcription of genes.15

This is the first report providing evi-dence on metformin influence on in-trauterine development. Interestingly, this effect persists at least 1 year after birth, indicating that metformin may

CONCLUSIONS

Although there were no differences in birth weight and length, 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-firm and explain our findings and to establish the safety of intrauterine metformin exposure.

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2. Glueck CJ, Phillips H, Cameron D, Sieve-Smith L, Wang P. Continuing metformin throughout pregnancy in women with polycystic ovary syndrome appears to safely reduce first-trimester spontaneous abortion: a pilot study.Fertil Steril. 2001;75 (1):46–52

3. Glueck CJ, Wang P, Goldenberg N, Sieve-Smith L. Pregnancy outcomes among women with polycystic ovary syndrome treated with metformin.Hum Reprod. 2002; 17(11):2858–2864

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J Obstet Gynaecol Res. 2008;34(5):832–837 7. Vanky E, Salvesen KA, Heimstad R, Fougner KJ, Romundstad P, Carlsen SM. Metformin reduces pregnancy complications without affecting androgen levels in pregnant polycystic ovary syndrome women: results of a randomized study.Hum Reprod. 2004; 19(8):1734–1740

8. Vanky E, Stridsklev S, Heimstad R, et al. Met-formin versus placebo fromfirst trimester to delivery in polycystic ovary syndrome: a ran-domized, controlled multicenter study.J Clin Endocrinol Metab. 2010;95(12):E448–E455 9. Vanky E, Zahlsen K, Spigset O, Carlsen SM.

Placental passage of metformin in women with polycystic ovary syndrome. Fertil Steril. 2005;83(5):1575–1578

10. Glueck CJ, Goldenberg N, Pranikoff J, Loft-spring M, Sieve L, Wang P. Height, weight, and motor-social development during the

first 18 months of life in 126 infants born to 109 mothers with polycystic ovary syndrome who conceived on and continued metformin through pregnancy.Hum Reprod. 2004;19(6): 1323–1330

11. Rowan JA, Rush EC, Obolonkin V, Battin M, Wouldes T, Hague WM. Metformin in ges-tational diabetes: the offspring follow-up (MiG TOFU): body composition at 2 years of age. Diabetes Care. 2011;34(10):2279– 2284

12. Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS).Hum Reprod. 2004; 19(1):41–47

13. Ibáñez L, Ong K, Valls C, Marcos MV, Dunger DB, de Zegher F. Metformin treatment to prevent early puberty in girls with pre-cocious pubarche.J Clin Endocrinol Metab. 2006;91(8):2888–2891

14. Ibáñez L, Valls C, Ong K, Dunger DB, de Zegher F. Metformin therapy during pu-berty delays menarche, prolongs pubertal growth, and augments adult height: a ran-domized study in low-birth-weight girls with early-normal onset of puberty.J Clin Endocrinol Metab. 2006;91(6):2068–2073 15. Germeyer A, Jauckus J, Zorn M, Toth B,

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

2012;130;e1222

Pediatrics

Sven M. Carlsen, Marit P. Martinussen and Eszter Vanky

Metformin's Effect on First-Year Weight Gain: A Follow-up Study

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

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Figure

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

TABLE 1

Maternal and Offspring Characteristics From the First Trimester of Pregnancy to 1 yPostpartum p.3
FIGURE 1

FIGURE 1

p.4
TABLE 3 Offspring’s Weight (kg) at 1 y Postpartum According to Gender in a MultivariateRegression Model

TABLE 3

Offspring’s Weight (kg) at 1 y Postpartum According to Gender in a MultivariateRegression Model p.4
TABLE 2 Offspring’s Weight (kg) at 1 y Postpartum in Univariate and Multivariate RegressionModels

TABLE 2

Offspring’s Weight (kg) at 1 y Postpartum in Univariate and Multivariate RegressionModels p.4

References