Metformin's Effect on First-Year Weight Gain: A Follow-up Study
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Metformin’s Effect on First-Year Weight Gain:
A Follow-up Study
WHAT’S KNOWN ON THIS SUBJECT: The use of metformin in AUTHORS: Sven M. Carlsen, MD, PhD,a,b Marit P.
pregnancy is increasing in the treatment of both gestational Martinussen, MD, PhD,c and Eszter Vanky, MD, PhDc,d
diabetes and polycystic ovary syndrome. Metformin crosses the aUnit for Applied Clinical Research, Institute for Cancer Research
placenta. Teratogenicity is not reported. Possible long-term and Molecular Medicine, Norwegian University of Science and
effects are undetermined. Technology, Trondheim, Norway; Departments of bEndocrinology,
and cObstetrics and Gynecology, St Olav’s Hospital, Trondheim
University Hospital, Trondheim, Norway; and dInstitute for
WHAT THIS STUDY ADDS: Intrauterine metformin exposure seems Laboratory Medicine, Children’s and Women’s Health, Norwegian
to have long-term effects on infant weight. At 1 year of age, infants University of Science and Technology, Trondheim, Norway
born to women and exposed to metformin weigh more than those KEY WORDS
exposed to placebo in utero. PCOS, metformin, pregnancy, weight development, children
ABBREVIATIONS
PCOS—polycystic ovary syndrome
PregMet—The Metformin treatment in pregnant PCOS women study
RCT—randomized controlled trial
abstract Dr Carlsen made substantial contributions to the conception
and design, analysis, and interpretation of data, in addition to
BACKGROUND: The impact of metformin medication in pregnant writing the article and approving the version to be published. Dr
women with polycystic ovary syndrome on weight gain during preg- Martinussen provided analysis and interpretation of data, in
addition to drafting the article or revising it critically for
nancy and after delivery and the impact on growth of the offspring important intellectual content and providing final approval of
are essentially unexplored. the version to be published. Dr Vanky made substantial
contributions to the conception and design, acquisition of data,
METHODS: This is a follow-up study of a randomized controlled trial and analysis and interpretation of data, in addition to drafting
(The Metformin treatment in pregnant PCOS women study), conducted the article or revising it critically for important intellectual
in 11 secondary care centers. Women with PCOS were randomized to content and providing final approval of the version to be
metformin (2000 mg daily) or placebo from first trimester to delivery. published.
Questionnaires were sent to 256 participants 1 year postpartum. This trial has been registered at www.clinicaltrials.gov
(identifier NCT00159536).
Maternal weight development in pregnancy and the first year after de-
www.pediatrics.org/cgi/doi/10.1542/peds.2012-0346
livery and offspring anthropometry at birth and weight 1 year postpar-
doi:10.1542/peds.2012-0346
tum were registered.
Accepted for publication Jun 26, 2012
RESULTS: Women randomized to metformin gained less weight during
Correspondence to Eszter Vanky, Department of Obstetrics and
pregnancy compared with those in the placebo group. In the newborns, Gynecology, St Olavs Hospital, University Hospital of Trondheim,
there was no difference between the 2 groups in weight or length. One Olav Kyrres gt 16, 7006 Trondheim, Norway. E-mail: eszter.
year postpartum, women who used metformin in pregnancy lost less vanky@ntnu.no
weight and their infants were heavier than those in the placebo group PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
(10.2 6 1.2 kg vs 9.7 6 1.1 kg, P = .003). Copyright © 2012 by the American Academy of Pediatrics
CONCLUSIONS: Women randomized to metformin were heavier in the FINANCIAL DISCLOSURE: The authors have indicated they have
no financial relationships relevant to this article to disclose.
first trimester, gained less weight in pregnancy, and lost less weight in
the first year postpartum compared with women randomized to pla- FUNDING: The Liaison Committee between the Central Norway
Regional Health Authority and the Norwegian University of
cebo. Children exposed to metformin weighed more at 1 year of age. Science and Technology (NTNU) funded the study. Weifa A/S
Pediatrics 2012;130:e1222–e1226 (Oslo, Norway) supplied metformin and placebo tablets free of
charge.
e1222 CARLSEN et al
Downloaded from pediatrics.aappublications.org by guest on October 13, 2015ARTICLE
The role of metformin treatment in METHODS reported data on education, smoking
pregnant women with polycystic ovary habits, and study medication. Height
Study Design
syndrome (PCOS) is not yet deter- was recorded at inclusion and weight at
mined. Nonrandomized and retrospec- The current study is a follow-up of The each prescheduled visit. Body weight
tive studies and 1 small randomized PregMet study. The PregMet study was was recorded with light clothes on and
controlled trial (RCT) indicate positive a prospective, randomized, double- without shoes. Gestational age was de-
effects of metformin on pregnancy blind, multicenter trial that compared termined by mid-pregnancy ultrasound
complications.1–7 A large RCT did not metformin 2000 mg daily with placebo examination, measuring biparietal diam-
support these results.8 from the first trimester to delivery.8 eter, femur length, and mean abdominal
Although not approved in pregnancy, In the PregMet study the inclusion diameter of the fetus.
metformin is widely used. Metformin criteria were (1) PCOS diagnosed The Committee for Medical Research
crosses the placenta and is present in according to The Rotterdam Criteria,12 Ethics of Health Region IV, Norway, and
fetal circulation in therapeutic con- (2) age 18 to 45 years, (3) gestational The Norwegian Medicines Agency ap-
centrations.9 So far, no negative effects age between 5 and 12 weeks, and (4) proved the study. Written informed
of metformin have been reported in a singleton viable fetus shown on ul- consent was obtained from each
the mother or in the offspring. Infants trasonography. The exclusion criteria patient before inclusion, and the Dec-
born to mothers with PCOS who used were alanine aminotransferase level laration of Helsinki was followed
metformin in pregnancy did not have .90 IU/L, serum creatinine concen- throughout the study. The study was
any adverse effect on birth length tration .130 mmol/L, known alcohol conducted according to principles of
and weight, growth, or motor-social abuse, previously diagnosed diabetes “Good Clinical Practice,” and the trial is
development in the first 18 months of mellitus or fasting serum glucose .7.0 registered at www.clinicaltrials.gov as
life compared with a background pop- mmol/L at the time point of inclusion, NCT00159536.
ulation.10 treatment with oral glucocorticoids, or
use of drugs known to interfere with The Follow-up Study
In an RCT for women with gestational
metformin.
diabetes, randomized to metformin or The participants in The PregMet Study
insulin, 2-year-old children exposed to Two hundred seventy-four pregnancies gave their written consent to be con-
metformin in utero had more sub- (in 258 women) were randomly tacted after the end of the original
cutaneous fat, but overall body fat was the assigned to either metformin or pla- study. Of the 274 included pregnan-
same as in children whose mothers were cebo treatment (16 women participated cies (in 258 women) in The PregMet
treated with insulin alone.11 It is impor- twice). Randomization, blinding, and Study, 3 patients had miscarriages, 12
tant to establish the possible long-term performed measurements are de- dropped out, 1 was excluded due to
impact and safety of intrauterine met- scribed in detail elsewhere.8 misdiagnosis, and 2 infants died peri-
formin exposure in the offspring, and All participants received written and natally. Two hundred forty women with
this can only be done in RCTs. individual verbal counseling on diet and 256 pregnancies were invited to par-
To investigate the possible effect of fetal lifestyle at inclusion. Thereafter treat- ticipate in the follow-up study. One year
metformin exposure in utero we per- ment with metformin hydrochloride 500 after delivery, a questionnaire and
formed a follow-up investigation of mg (Metformin; Weifa AS, Oslo, Norway) prepaid envelope was sent by mail. A
offspring and mothers from a previous or identically coated placebo tablets reminder was sent about 2 to 3 weeks
RCT, in which women with PCOS were was initiated. The participants took 1 later to nonrespondents. At this time
treated with metformin in pregnancy tablet twice daily during the first week point, the participants were not aware
(The Metformin treatment in pregnant and thereafter 2 tablets twice daily until of whether they had been randomized to
PCOS women [PregMet] study).8 We delivery, when study medication was metformin or to placebo.
hypothesized that 1 year postpartum, stopped. To counteract a possible ad- The participants were asked about
(1) mothers in the metformin group verse effect of metformin on vitamin B their own weight and the infant’s weight
would weigh less (as they did during levels, patients were advised to take 0.8 (registered at the child`s weight card)
pregnancy) compared with those in the mg of folic acid daily and 1 daily mul- at 12 months’ postpartum. In Norway,
placebo group and (2) infants exposed tivitamin tablet containing both vitamin newborns and older infants are closely
to metformin in utero would weigh B6 and B12. followed up in a public health care sys-
less compared with those exposed to Standardized interviewer-administered tem free of charge. The mothers carry a
placebo. questionnaires were used to obtain self- “weight card” where the infant’s weights
PEDIATRICS Volume 130, Number 5, November 2012 e1223
Downloaded from pediatrics.aappublications.org by guest on October 13, 2015are regularly registered at different time differences were found in baseline data kg/m2 in the placebo group (P = .03)
points after birth by a public health nurse, between those who were randomized to (Table 1).
also at 12 months of age. metformin or placebo treatment in
pregnancy (Table 1). Offspring Anthropometry at Birth
Statistical Analyses There were no differences in birth
Maternal Weight Development weight, birth length, and ponderal index
All data entry, data management, and
data analyses were performed at Women in the metformin group gained between newborns who were exposed
the Institute of Laboratory Medicine, less weight in pregnancy than did those to metformin and those who were ex-
Children’s and Women’s, Norwegian in the placebo group. However, after posed to placebo in utero. Boys in
University of Science and Technology. delivery, the women in the placebo the metformin group had higher birth
The data were analyzed according to group lost more weight during the first weight, were longer, and had larger
the intention-to-treat principle. PASW year and had a lower BMI than did those head circumference at birth compared
statistics version 18.0 for Windows in the metformin group 1 year after with the placebo group (Table 1). How-
(IBM SPSS Inc USA, Chicago, IL) was delivery (Fig 1). The change in BMI from ever, when adjusted for gestational age,
used. The differences between the the first trimester of pregnancy to 1 maternal smoking, maternal BMI, and
study groups were compared with year postpartum was +1.0 6 2.9 kg/m2 maternal height, these differences dis-
2-tailed t tests for independent samples. in the metformin group vs +0.2 6 2.0 appeared (data not shown).
Values are reported as means (SD) or
absolute numbers. A x2 test was used TABLE 1 Maternal and Offspring Characteristics From the First Trimester of Pregnancy to 1 y
to test differences between the groups. Postpartum
If the smallest expected value in a cell n Metformin n Placebo P
was ,5, we used the Fisher exact test. First trimester
Associations were investigated with 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
univariate and multivariate linear re- Smoking, No. 102 10 (10) 97 3 (3) .08a
gression analyses. Two-tailed tests were Civil status, single/married or cohabitant 99 5/99 96 0/96 .06a
used throughout, and P , .05 was Education, #12 y/.12 y 99 31/68 95 34/61 .54
considered significant. No adjustments At the end of pregnancya
BMI, kg/m2 97 32.7 6 6.9 85 32.0 6 7.3 .51
for multiple testing were performed. 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
Role of the Funding Source Gestational length, d 102 277 6 10 97 274 6 10 .08
The Liaison Committee between the Birth weight, all, g 102 3548 6 550 97 3483 6 634 .44
Girls, g 52 3438 6 539 51 3602 6 560 .13
Central Norway Regional Health Au- Boys, g 50 3662 6 542 46 3350 6 681 .01
thority and the Norwegian University of Birth length. all, cm 101 50.0 6 2.1 95 49.8 6 2.5 .49
Science and Technology funded the 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
study. Weifa AS (Oslo, Norway) supplied
Ponderal index, all, kg/m3 101 28.3 6 2.6 95 28.2 6 2.6 .77
the study drug free of charge. None of Girls, kg/m3 51 28.5 6 2.6 50 28.8 6 2.6 .68
the funding sources had a role in the Boys, kg/m3 50 28.1 6 2.5 45 28.6 6 2.4 .30
collection, analysis, and interpretation Offspring gender, girls/boys 102 52/50 97 51/46 .89
Placenta weight, all, g 91 660 6 148 84 646 6 152 .54
of the data or in writing and deciding to Girls, g 47 644 6 149 41 662 6 142 .57
submit the report. 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
RESULTS Maternal BMI change from first 101 1.0 6 2.9 94 0.2 6 2.0 .03
trimester to 1 y postpartum, kg/m2
Baseline Characteristics Maternal BMI change from end 96 22.1 6 3.6 82 24.1 6 4.9 .003
of pregnancy to 1 y postpartum, kg/m2
Of the 256 (78%) women with PCOS who Smoking, No. 102 11 (11) 95 9 (9) .82a
participated in The PregMet Study, 199 Offspring weight at 1 y, all, kg 102 10.2 6 1.2 94 9.7 6 1.1 .003
responded to the questionnaire, 1 year 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
postpartum. Except for a higher BMI at
inclusion (in the first trimester of
a Last 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).
pregnancy, before randomization), no b Fisher’s exact test.
e1224 CARLSEN et al
Downloaded from pediatrics.aappublications.org by guest on October 13, 2015ARTICLE
Offspring Weight Development exposed infants of each gender are be attributed to a “big mothers–big
At 1 year of age, infants exposed to met- heavier than placebo-exposed ones. This infants” phenomenon.
formin in utero were 5% heavier com- weight difference persisted also after Unfortunately, we have no data on body
pared with those exposed to placebo adjustment for factors known to in- composition of these infants. Accord-
(10.2 6 1.2 kg vs 9.7 6 1.1 kg; P = .003) fluence weight development and cannot ingly we do not know whether the weight
(Table 1). The difference remained sig-
nificant in a multivariate regression 34.0
Metformin
analysis, where we adjusted for gesta- 33.5 Placebo
33.0
tional age, birth weight, maternal smok-
32.5
Body mass index (kg/m2)
ing in pregnancy, maternal BMI, maternal
32.0
height, and duration of breastfeeding 31.5
(P = .001) (Table 2). Both boys and girls 31.0
exposed to metformin tended to be 30.5
heavier at 1 year of age (Table 3). 30.0
29.5
29.0
DISCUSSION
28.5
The most important findings of the 28.0
current study are that (1) maternal BMI 19 24 32 36 1 year after delivery
Gestional week or time after delivery
is higher at 1 year after delivery in
participants who were randomized to FIGURE 1
Weight development in pregnancy and postpartum according to treatment allocation. Medication was
metformin in pregnancy and stopped stopped at delivery. P value at gestational week 19 = .95; at gestational week 24 = .38; at gestational
medication at delivery than in those week 32 = .18, and at gestational week 36 = .03. P value at 1 year postpartum = .03.
randomized to placebo and (2) infants
exposed to metformin in utero had TABLE 2 Offspring’s Weight (kg) at 1 y Postpartum in Univariate and Multivariate Regression
Models
higher body weight at 1 year of age
Univariate Multivariate
compared with those exposed to pla-
cebo. n B 95% CI P n B 95% CI P
We have previously reported that met- Randomization, metformin = 1; 195 2.49 2.80 to 2.17 .003 186 2.53 2.84 to 2.22 .001
placebo = 2
formin treatment in women with PCOS Birth weight, g 195 .001 .00 to .00 ,.001 186 .001 .00 to .00 .001
reduced weight gain in pregnancy.8 Gestational age, d 195 .005 2.01 to .02 .44 186 2.01 2.03 to 2.01 .07
Contrary to our hypothesis, the current 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
study shows that weight reduction af- Maternal height, cm 195 .04 .001 to .07 .02 186 .03 .00 to .06 .03
ter delivery is less in mothers who Exclusive breastfeeding, mo 195 2.03 2.09 to .02 .26 186 .02 2.05 to .10 .54
were randomized to metformin com- 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; 190 2.41 2.75 to 2.07 .02 186 2.32 2.66 to .03 .07
pared with those randomized to pla-
.12 y = 2
cebo during pregnancy. It could reflect
that women in the metformin group at
baseline were more overweight and TABLE 3 Offspring’s Weight (kg) at 1 y Postpartum According to Gender in a Multivariate
gained more weigh after a pregnancy Regression Model
and postpartum period. However, we Girls Boys
have adjusted for maternal baseline n B 95% CI P n B 95% CI P
BMI, and the difference persists be- Randomization, metformin = 1; 97 2.41 2.82 to .00 .05 88 2.42 2.85 to .00 .05
tween the groups. We believe that placebo = 2
higher BMI 1 year after delivery can 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
be attributed to a rebound effect af- Maternal smoking, no =1; yes = 2 97 2.16 2.83 to .51 .63 88 2.26 21.06 to .54 .52
ter ceased metformin medication at Maternal BMI 1 y postpartum, kg/m2 97 .00 2.02 to .03 .91 88 2.01 2.04 to .03 .61
delivery. 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
At birth, there were no differences in Any breastfeeding, mo 97 2.04 2.11 to .03 .22 88 2.05 2.13 to .02 .17
weight or length between the 2 groups. Maternal education, 12 y = 1; 97 2.48 2.93 to 2.03 .03 88 2.22 2.71 to .26 .37
Interestingly, at1 yearof age, metformin- .12 y = 2
PEDIATRICS Volume 130, Number 5, November 2012 e1225
Downloaded from pediatrics.aappublications.org by guest on October 13, 2015difference represents increased lean this indicates that metformin, when have long-term metabolic or endocrine
body mass, increased fat mass, or both. used during a critical time window, effects in the offspring.
The probability that metformin may have might induce long-term endocrine and/
lasting effects in children, as seen in the or metabolic changes. Imprinting of CONCLUSIONS
current study, is supported by data genes may be the mechanism involved. Although there were no differences in
from small-for-gestational age girls It has been shown that metformin has birth weight and length, at 1 year of age,
with premature adrenarche. 13 In the potential to affect transcription of both boys and girls exposed to met-
these girls, treatment with metfor- genes.15 formin had higher weight compared
min delayed premature menarche and This is the first report providing evi- with placebo-exposed boys and girls.
prevented excessive weight gain. The dence on metformin influence on in- Additional studies are needed to con-
weight effect persisted also after trauterine development. Interestingly, firm and explain our findings and to
metformin treatment had been stop- this effect persists at least 1 year after establish the safety of intrauterine
ped.14 Taken together with our data, birth, indicating that metformin may metformin exposure.
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e1226 CARLSEN et al
Downloaded from pediatrics.aappublications.org by guest on October 13, 2015Metformin's Effect on First-Year Weight Gain: A Follow-up Study
Sven M. Carlsen, Marit P. Martinussen and Eszter Vanky
Pediatrics 2012;130;e1222; originally published online October 15, 2012;
DOI: 10.1542/peds.2012-0346
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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1948. PEDIATRICS is owned, published,
and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk
Grove Village, Illinois, 60007. Copyright © 2012 by the American Academy of Pediatrics. All
rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
Downloaded from pediatrics.aappublications.org by guest on October 13, 2015Metformin's Effect on First-Year Weight Gain: A Follow-up Study
Sven M. Carlsen, Marit P. Martinussen and Eszter Vanky
Pediatrics 2012;130;e1222; originally published online October 15, 2012;
DOI: 10.1542/peds.2012-0346
The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/130/5/e1222.full.html
PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1948. PEDIATRICS is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2012 by the American Academy
of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
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