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

Martinussen and Eszter Vanky Pediatrics; 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.

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Metformins Effect on First-Year Weight Gain: 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.
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. 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 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.

abstract
BACKGROUND: The impact of metformin medication in pregnant women with polycystic ovary syndrome on weight gain during pregnancy 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 delivery and offspring anthropometry at birth and weight 1 year postpartum 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 in the rst year postpartum compared with women randomized to placebo. Children exposed to metformin weighed more at 1 year of age. Pediatrics 2012;130:e1222e1226

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ARTICLE

The role of metformin treatment in pregnant women with polycystic ovary syndrome (PCOS) is not yet determined. Nonrandomized and retrospective studies and 1 small randomized controlled trial (RCT) indicate positive effects of metformin on pregnancy complications.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 concentrations.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 have any adverse effect on birth length and weight, growth, or motor-social development in the rst 18 months of life compared with a background population.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 subcutaneous fat, but overall body fat was the same as in children whose mothers were treated with insulin alone.11 It is important to establish the possible long-term impact and safety of intrauterine metformin exposure in the offspring, and this can only be done in RCTs. To investigate the possible effect of fetal metformin exposure in utero we performed 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.
PEDIATRICS Volume 130, Number 5, November 2012

METHODS
Study Design The current study is a follow-up of The PregMet study. The PregMet study was a prospective, randomized, doubleblind, multicenter trial that compared metformin 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 ultrasonography. The exclusion criteria were alanine aminotransferase level .90 IU/L, serum creatinine concentration .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 placebo treatment (16 women participated twice). Randomization, blinding, and performed measurements are described in detail elsewhere.8 All participants received written and individual verbal counseling on diet and lifestyle at inclusion. Thereafter treatment 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 the rst week and thereafter 2 tablets twice daily until delivery, when study medication was stopped. To counteract a possible adverse effect of metformin on vitamin B levels, patients were advised to take 0.8 mg of folic acid daily and 1 daily multivitamin tablet containing both vitamin B6 and 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 determined by mid-pregnancy ultrasound examination, measuring biparietal diameter, 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 approved the study. Written informed consent was obtained from each patient before inclusion, and the Declaration 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 contacted after the end of the original study. Of the 274 included pregnancies (in 258 women) in The PregMet Study, 3 patients had miscarriages, 12 dropped out, 1 was excluded due to misdiagnosis, and 2 infants died perinatally. Two hundred forty women with 256 pregnancies were invited to participate 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 system free of charge. The mothers carry a weight card where the infants weights
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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 Institute of Laboratory Medicine, 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 t tests for independent samples. Values are reported as means (SD) or absolute numbers. A x2 test 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 regression 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 Authority 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.

differences were found in baseline data between those 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 did those in the placebo group. However, after delivery, the women in the placebo group lost more weight during the rst 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 rst trimester of pregnancy to 1 year postpartum was +1.0 6 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, birth length, and ponderal index between newborns who were exposed to metformin and those who were exposed 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). However, when adjusted for gestational age, maternal smoking, maternal BMI, and maternal height, these differences disappeared (data not shown).

TABLE 1 Maternal and Offspring Characteristics From the First Trimester of Pregnancy to 1 y
Postpartum
n First trimester Age, y BMI, kg/m2 Smoking, No. Civil status, single/married or cohabitant Education, #12 y/.12 y At the end of pregnancya BMI, kg/m2 BMI gain in pregnancy, kg/m2 Smoking, No. Offspring characteristics at birth Gestational length, d Birth weight, all, g Girls, g Boys, g Birth length. all, cm Girls, cm Boys, cm Ponderal index, all, kg/m3 Girls, kg/m3 Boys, kg/m3 Offspring gender, girls/boys Placenta weight, all, g Girls, g Boys, g 1 y postpartum Maternal BMI, kg/m2 Maternal BMI change from rst trimester to 1 y postpartum, kg/m2 Maternal BMI change from end of pregnancy to 1 y postpartum, kg/m2 Smoking, No. Offspring weight at 1 y, all, kg Girls, kg Boys, kg 102 102 102 99 99 97 97 99 102 102 52 50 101 51 50 101 51 50 102 91 47 44 101 101 96 102 102 52 50 Metformin 29.7 6 4.4 29.5 6 7.1 10 (10) 5/99 31/68 32.7 6 6.9 3.2 6 2.0 5 (5) 277 6 10 3548 6 550 3438 6 539 3662 6 542 50.0 6 2.1 49.4 6 1.9 50.6 6 2.2 28.3 6 2.6 28.5 6 2.6 28.1 6 2.5 52/50 660 6 148 644 6 149 678 6 148 30.6 6 8.1 1.0 6 2.9 22.1 6 3.6 11 (11) 10.2 6 1.2 9.8 6 0.9 10.6 6 1.3 n 97 97 97 96 95 85 85 97 97 97 51 46 95 50 45 95 50 45 97 84 41 43 94 94 82 95 94 50 44 Placebo 29.4 6 4.3 27.6 6 6.1 3 (3) 0/96 34/61 32.0 6 7.3 4.2 6 4.3 2 (2) 274 6 10 3483 6 634 3602 6 560 3350 6 681 49.8 6 2.5 50.0 6 2.4 49.5 6 2.7 28.2 6 2.6 28.8 6 2.6 28.6 6 2.4 51/46 646 6 152 662 6 142 631 6 161 27.6 6 6.1 0.2 6 2.0 24.1 6 4.9 9 (9) 9.7 6 1.1 9.5 6 1.1 10.0 6 1.0 P .61 .04 .08a .06a .54 .51 .03 .44b .08 .44 .13 .01 .49 .18 .03 .77 .68 .30 .89 .54 .57 .17 .004 .03 .003 .82a .003 .09 .01

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

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). b Fisher s exact test.

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Offspring Weight Development At 1 year of age, infants exposed to metformin in utero were 5% heavier compared 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 signicant in a multivariate regression analysis, where we adjusted for gestational age, birth weight, maternal smoking 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).

exposed infants of each gender are heavier than placebo-exposed ones. This weight difference persisted also after adjustment for factors known to inuence weight development and cannot
34.0 33.5 33.0 Body mass index (kg/m2) 32.5 32.0 31.5 31.0 30.5 30.0 29.5 29.0 28.5 28.0 19 24 32 Metformin Placebo

be attributed to a big mothersbig infants phenomenon. Unfortunately, we have no data on body composition of these infants. Accordingly we do not know whether the weight

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 placebo. We have previously reported that metformin treatment in women with PCOS reduced weight gain in pregnancy.8 Contrary to our hypothesis, the current study shows that weight reduction after delivery is less in mothers who were randomized to metformin compared with those randomized to placebo 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, we have adjusted for maternal baseline BMI, and the difference persists between the groups. We believe that higher BMI 1 year after delivery can be attributed to a rebound effect after ceased metformin medication at delivery. At birth, there were no differences in weight or length between the 2 groups. Interestingly, at1 yearof age, metformin-

36

1 year after delivery

Gestional week or time after delivery

FIGURE 1
Weight development in pregnancy and postpartum according to treatment allocation. Medication was stopped at delivery. P value at gestational week 19 = .95; at gestational week 24 = .38; at gestational week 32 = .18, and at gestational week 36 = .03. P value at 1 year postpartum = .03.

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

Models
Univariate n Randomization, metformin = 1; placebo = 2 Birth weight, g Gestational age, d Maternal smoking, no = 1; yes = 2 Maternal BMI 1 y postpartum, kg/m2 Maternal height, cm Exclusive breastfeeding, mo Any breastfeeding, mo Maternal education, 12 y = 1; .12 y = 2 B 95% CI 2.80 to 2.17 P n B Multivariate 95% CI P

195 2.49 195 .001 195 .005 194 .21 191 .02 195 .04 195 2.03 195 2.05 190 2.41

.003 186 2.53 186 186 186 186 186 186 186 186 .001 2.01 2.23 2.00 .03 .02 2.06 2.32

2.84 to 2.22 .001 .00 to .00 2.03 to 2.01 2.78 to .31 2.02 to .02 .00 to .06 2.05 to .10 2.11 to 2.00 2.66 to .03 .001 .07 .40 .83 .03 .54 .04 .07

.00 to .00 ,.001 2.01 to .02 .44 2.32 to .74 .43 2.01 to .04 .14 .001 to .07 .02 2.09 to .02 .26 2.08 to 2.01 .01 2.75 to 2.07 .02

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

Regression Model
Girls n Randomization, metformin = 1; placebo = 2 Birth weight, g Gestational age, d Maternal smoking, no =1; yes = 2 Maternal BMI 1 y postpartum, kg/m2 Maternal height, cm Exclusive breastfeeding, mo Any breastfeeding, mo Maternal education, 12 y = 1; .12 y = 2 97 97 97 97 97 97 97 97 97 B 2.41 .00 2.01 2.16 .00 .01 .07 2.04 2.48 95% CI 2.82 to .00 .00 to .00 2.03 to .01 2.83 to .51 2.02 to .03 2.03 to .05 2.02 to .16 2.11 to .03 2.93 to 2.03 P .05 .55 .22 .63 .91 .71 .12 .22 .03 n 88 88 88 88 88 88 88 88 88 B 2.42 .00 2.02 2.26 2.01 .04 2.00 2.05 2.22 Boys 95% CI 2.85 to .00 .00 to .00 2.04 to .00 21.06 to .54 2.04 to .03 2.04 to .08 2.12 to .11 2.13 to .02 2.71 to .26 P .05 ,.001 .07 .52 .61 .052 .97 .17 .37

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difference represents increased lean body mass, increased fat mass, or both. The probability that metformin may 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 In these girls, treatment with metformin delayed premature menarche and prevented excessive weight gain. The weight effect persisted also after metformin treatment had been stopped.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 of genes.15 This is the rst report providing evidence on metformin inuence on intrauterine 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 and length, at 1 year of age, both boys and girls exposed to metformin had higher weight compared with placebo-exposed boys and girls. Additional studies are needed to conrm and explain our ndings and to establish the safety of intrauterine metformin exposure.

REFERENCES
1. Begum MR, Khanam NN, Quadir E, et al. Prevention of gestational diabetes mellitus by continuing metformin therapy throughout pregnancy in women with polycystic ovary syndrome. J Obstet Gynaecol Res. 2009;35(2):282286 2. Glueck CJ, Phillips H, Cameron D, SieveSmith L, Wang P. Continuing metformin throughout pregnancy in women with polycystic ovary syndrome appears to safely reduce rst-trimester spontaneous abortion: a pilot study. Fertil Steril. 2001;75 (1):4652 3. Glueck CJ, Wang P, Goldenberg N, SieveSmith L. Pregnancy outcomes among women with polycystic ovary syndrome treated with metformin. Hum Reprod. 2002; 17(11):28582864 4. Glueck CJ, Wang P, Kobayashi S, Phillips H, Sieve-Smith L. Metformin therapy throughout pregnancy reduces the development of gestational diabetes in women with polycystic ovary syndrome. Fertil Steril. 2002;77 (3):520525 5. Jakubowicz DJ, Iuorno MJ, Jakubowicz S, Roberts KA, Nestler JE. Effects of metformin on early pregnancy loss in the polycystic ovary syndrome. J Clin Endocrinol Metab. 2002;87(2):524529 6. Nawaz FH, Khalid R, Naru T, Rizvi J. Does continuous use of metformin throughout pregnancy improve pregnancy outcomes in women with polycystic ovarian syndrome? J Obstet Gynaecol Res. 2008;34(5):832837 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):17341740 8. Vanky E, Stridsklev S, Heimstad R, et al. Metformin versus placebo from rst trimester to delivery in polycystic ovary syndrome: a randomized, controlled multicenter study. J Clin Endocrinol Metab. 2010;95(12):E448E455 9. Vanky E, Zahlsen K, Spigset O, Carlsen SM. Placental passage of metformin in women with polycystic ovary syndrome. Fertil Steril. 2005;83(5):15751578 10. Glueck CJ, Goldenberg N, Pranikoff J, Loftspring M, Sieve L, Wang P. Height, weight, and motor-social development during the rst 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): 13231330 11. Rowan JA, Rush EC, Obolonkin V, Battin M, Wouldes T, Hague WM. Metformin in gestational 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 longterm health risks related to polycystic ovary syndrome (PCOS). Hum Reprod. 2004; 19(1):4147 13. Ibez L, Ong K, Valls C, Marcos MV, Dunger DB, de Zegher F. Metformin treatment to prevent early puberty in girls with precocious pubarche. J Clin Endocrinol Metab. 2006;91(8):28882891 14. Ibez L, Valls C, Ong K, Dunger DB, de Zegher F. Metformin therapy during puberty delays menarche, prolongs pubertal growth, and augments adult height: a randomized study in low-birth-weight girls with early-normal onset of puberty. J Clin Endocrinol Metab. 2006;91(6):20682073 15. Germeyer A, Jauckus J, Zorn M, Toth B, Capp E, Strowitzki T. Metformin modulates IL-8, IL-1b, ICAM and IGFBP-1 expression in human endometrial stromal cells. Reprod Biomed Online. 2011;22(4):327334

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

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