DOI: 10.1542/peds.2014-0439; originally published online July 21, 2014; 2014;134;e535Pediatrics

Erick Forno, Omar M. Young, Rajesh Kumar, Hyagriv Simhan and Juan C. CeledónChildhood Asthma

Maternal Obesity in Pregnancy, Gestational Weight Gain, and Risk of  

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located on the World Wide Web at: The online version of this article, along with updated information and services, is

 

of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2014 by the American Academy published, and trademarked by the American Academy of Pediatrics, 141 Northwest Pointpublication, it has been published continuously since 1948. PEDIATRICS is owned, PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

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Maternal Obesity in Pregnancy, Gestational WeightGain, and Risk of Childhood Asthma

abstractBACKGROUND AND OBJECTIVE: Environmental or lifestyle exposures inutero may influence the development of childhood asthma. In this meta-analysis, we aimed to assess whether maternal obesity in pregnancy(MOP) or increased maternal gestational weight gain (GWG) increasedthe risk of asthma in offspring.

METHODS: We included all observational studies published until Octo-ber 2013 in PubMed, Embase, CINAHL, Scopus, The Cochrane Database,and Ovid. Random effects models with inverse variance weights wereused to calculate pooled risk estimates.

RESULTS: Fourteen studies were included (N = 108 321 mother–childpairs). Twelve studies reported maternal obesity, and 5 reported GWG.Age of children was 14 months to 16 years. MOP was associated withhigher odds of asthma or wheeze ever (OR = 1.31; 95% confidenceinterval [CI], 1.16–1.49) or current (OR = 1.21; 95% CI, 1.07–1.37); each1-kg/m2 increase in maternal BMI was associated with a 2% to 3%increase in the odds of childhood asthma. High GWG was associatedwith higher odds of asthma or wheeze ever (OR = 1.16; 95% CI, 1.001–1.34). Maternal underweight and low GWG were not associated withchildhood asthma or wheeze. Meta-regression showed a negativeassociation of borderline significance for maternal asthma history(P = .07). The significant heterogeneity among existing studiesindicates a need for standardized approaches to future studies onthe topic.

CONCLUSIONS:MOP and high GWG are associated with an elevated riskof childhood asthma; this finding may be particularly significant formothers without asthma history. Prospective randomized trials ofmaternal weight management are needed. Pediatrics 2014;134:e535–e546

AUTHORS: Erick Forno, MD, MPH,a,b Omar M. Young, MD,b,c

Rajesh Kumar, MD,d Hyagriv Simhan, MD, MSCR,b,c andJuan C. Celedón, MD, DrPHa,b

aDivision of Pulmonary Medicine, Allergy, and Immunology,Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania;bUniversity of Pittsburgh Medical School, Pittsburgh, Pennsylvania;cDivision of Maternal–Fetal Medicine, Magee-Womens Hospital,Pittsburgh, Pennsylvania; and dDivision of Allergy andImmunology, Lurie Children’s Hospital, Chicago, Illinois

KEY WORDSchildhood asthma, asthma risk factors, maternal obesity,gestational weight gain, meta-analysis

ABBREVIATIONSCI—confidence intervalCINAHL—Cumulative Index to Nursing and Allied Health LiteratureGWG—gestational weight gainMOP—maternal obesity in pregnancyOR—odds ratioSTROBE—Strengthening the Reporting of Observational Studiesin EpidemiologyTNF-a—tumor necrosis factor a

Dr Forno formulated the idea for the study and participated inthe study design, literature searches, study selection, dataabstraction, analysis, and interpretation and the writing of themanuscript; Dr Young participated in the study design, literaturesearches, study selection, data abstraction, analysis, andinterpretation and the writing of the manuscript; Dr Kumarparticipated in the data interpretation and the writing of themanuscript; Dr Simhan contributed to the data analysis andinterpretation and participated in the writing of the manuscript;Dr Celedón contributed to the data analysis and interpretationand participated in the writing of the manuscript; and allauthors approved the final manuscript as submitted. Dr Fornoand Dr Young contributed equally to this manuscript.

This trial has been registered at PROSPERO (www.crd.york.ac.uk/prospero) (identifier CRD42013005490).

www.pediatrics.org/cgi/doi/10.1542/peds.2014-0439

doi:10.1542/peds.2014-0439

Accepted for publication May 6, 2014

Address correspondence to Erick Forno, MD, MPH, Children’sHospital of Pittsburgh, 4401 Penn Avenue, Rangos ResearchBuilding #9130, Pittsburgh, PA 15224. E-mail: erick.forno@chp.edu

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

Copyright © 2014 by the American Academy of Pediatrics

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Obesity is a major public health prob-lem, affecting .35% of the adult pop-ulation in the United States1 andcomplicating up to 20% of pregnanciesin this country.1 Maternal obesity isdefined as a BMI $30 kg/m2, and ma-ternal overweight is defined as a BMIbetween 25 and 29.9 kg/m2.2 Maternalobesity is further stratified into clas-ses: class I (BMI 30–34.9), class II (BMI35–39.9), and class III (BMI $40).3

Maternal obesity in pregnancy (MOP)has been associated with adversepregnancy outcomes, including hy-pertensive disorders of pregnancy,gestational diabetes, and need for op-erative delivery.4,5 Maternal obesityalso has a significant impact on fetaldevelopment, the neonatal period, andoverall childhood development. It hasbeen associated with an elevated in-cidence of fetal neural tube defectssuch as spina bifida and anencephaly.6,7

Moreover, higher gestational weightgain (GWG) increases the risk of smallsize for gestational age and of iatro-genic preterm birth.8

In recent years, there has been grow-ing interest on how in utero expo-sures predispose infants to diseasesthroughout the life span. For example,British epidemiologist David Barker9

reported that people with a history oflow birth weight were at elevated riskof coronary artery disease later in lifeand, in what came to be known as theBarker hypothesis,10 theorized that theorigins of complex diseases may stemfrom intrauterine exposures. Thus,MOP may significantly affect life exutero for years to come. Given thesubstantial impact of maternal obesityon not only maternal but also fetal andneonatal outcomes, in 2009 the In-stitute of Medicine3 recommended thatobese women limit their GWG to be-tween 11 and 20 pounds.

Asthma, a complex disease that affects∼7 million children in the UnitedStates,11 can result from interactions

between hereditary and environmentalfactors12,13 beginning in utero. For ex-ample, maternal smoking during preg-nancy increases the risk of asthmain offspring14 and may hinder age-dependent improvement in airwayhyperreactivity among children withasthma.15

Along these lines, there is growing ev-idence that MOP or high GWG is asso-ciated with elevated risk of asthma orwheeze (a symptom of asthma) in off-spring.16–18 It is thought that in uteroexposure to different dietary patternsor to the proinflammatory milieu ofobesity may affect fetal immune orpulmonary development, thus leadingto asthma.17 Therefore, the aims of thismeta-analysis were to quantitativelyestimate the effect of MOP or GWG onchildhood asthma or wheeze, to gen-erate a pooled analysis of studiesavailable in the literature, and to ex-plore factors that maymodify the effectof MOP on childhood asthma.

METHODS

We prospectively registered the proto-col for this meta-analysis in PROSPEROon September 5, 2013: http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42013005490.

Sources and Study Selection

We searched PubMed, Embase, Cumu-lative Index to Nursing and Allied HealthLiterature, Scopus, the Cochrane Da-tabase, and Ovid for observationalstudies evaluating the association be-tween MOP or GWG and asthma orwheeze in childhood, published up toOctober 2013. Initial inclusion criteriawere as follows:

� Study design: Observational stud-ies published in English (or in lan-guages other than English whenable to translate into English orwhen enough information wasavailable in an English abstractfor use in the data analysis).

� Population: Children in whom out-comes were measured betweenbirth and ,18 years of age. Moth-ers in whom BMI at the beginningof pregnancy was ascertained di-rectly or by report at some pointduring pregnancy or whose GWGwas ascertained directly or by re-port in the third trimester of preg-nancy.

� Outcomes: Wheeze or asthma dur-ing childhood, determined by re-port, doctor’s diagnosis, medicalrecord review, or evaluation bythe study team. When .1 timepoint for such assessment existed,only the latest point available wasincluded.

Two authors (E.F. and O.M.Y.) in-dependently retrieved and screened allstudies according to these pre-determined selection criteria. In addi-tion, we manually screened referencesin the selected articles for additionalrelevant studies. Initial selection wasbased on title and abstract screening,and final selection was performed us-ing full texts. Exclusion criteria wereineligible study design (eg, interven-tional study for management of MOP orGWG or for prevention of childhoodasthma or wheeze), ineligible pop-ulation (eg, adults), ineligible outcomes(eg, other than childhood asthma orwheeze), and insufficient information inEnglish to determine inclusion criteriaand abstract risk estimates. Differ-ences of opinion for inclusion wereresolved by discussion.

Data Extraction and QualityAssessment

Using a uniform data extraction form,2 of the authors (E.F. and O.M.Y.) in-dependently extracted from full-textarticles all data on references (firstauthor, year of publication), number ofparticipants, timing of MOP or GWGdetermination (eg, gestational age atwhich “final” maternal weight was

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ascertained), BMI or GWG (means orcategories) as reported by the originalstudies, outcome definitions, ages atwhich outcomes were measured, totalnumber of participants, number ofparticipants with and without the out-comes when available, odds ratios(ORs) or risk ratios with their corre-sponding confidence intervals (CIs),and relevant covariates as reported inthe original studies (eg, mean mater-nal age, race, smoking exposure duringpregnancy or childhood). Disagree-ments on data extraction between the 2authors were resolved through mutualdiscussion and, if needed, consultationwith a third author (J.C.C.). Agreementbetween the reviewers on study selec-tion was determined by using theCohen k statistic (k). The quality ofreporting in the included studies wasassessed by using the Strengtheningthe Reporting of Observational Studiesin Epidemiology (STROBE) statementchecklist.19 Studies were graded as A(.85% of STROBE criteria fulfilled), B(50–85%), or C (,50%).

Analysis

Data collected were pooled to generatesummary estimates; each study wasweighed by its inverse effect size vari-ant. To evaluate the association of MOPor GWG, we calculated ORs for the de-velopment of childhood asthma orwheeze. Many studies provided differ-ent categories for MOP and GWG;therefore, when possible we contactedthe corresponding authors of theoriginal studies to provide us withestimates for BMI and GWG (in kilo-grams) as continuous variables. Wetested for heterogeneity in resultsacross studies by using a Cochran Qstatistic; the I2 statistic was used toquantify the extent of true heteroge-neity. ORs and their CIs were calculatedby using random effects models. Eggertests were used to assess for potentialpublication bias. Subgroup analyses byoutcome definition and age group and

meta-regression analyses were con-ducted to explore potential sources ofheterogeneity and assess effect modi-fication by different covariates such asmaternal age, race, and smoking ex-posure. All analyses were performed inStata version 12 (Stata Corp, CollegeStation, TX), and a P of .05 was con-sidered statistically significant.

RESULTS

A total of 474 studies were identified(Fig 1): 398 from PubMed, 31 fromEmbase, 28 from Scopus, 7 from Cu-mulative Index to Nursing and AlliedHealth Literature, 1 from the CochraneDatabase, and 9 from Ovid; no addi-tional references were identified fromreviewing references in relevant arti-cles. Of these, 14 studies with a total of108 321 mother–child pairs were in-cluded in the meta-analysis16–18,20–30

(Table 1). There was complete agree-

ment on 469 of 474 articles after titleand abstract screening (interreaderagreement k = .90) and on 40 of 42articles after full-text screening (k =.89).

Characteristics of Included Studies

Included studies were published be-tween March 1996 and October 2013.Twelve studies reported maternal BMI(continuous or categorical) closelybefore or at the beginning of preg-nancy16–18,20–23,25–27,29,30 and were in-cluded in the analysis of MOP; 5 studieswere included in the analysis ofGWG.20,21,23,24,28 Although many studiescategorized MOP and GWG in differentways, response from the authors of theoriginal studies was very positive, andthe majority of them provided us withestimates for continuous BMI18,20–23,27

and GWG (in kilograms)20,21 (or kindlyresponded that continuous data were

FIGURE 1Flowchart of study selection. k indicates Cohen’s k agreement coefficient (1.0 = perfect agreement).(Flowchart adapted from the Preferred Reporting Items for Systematic Reviews and Meta-AnalysesStatement for systematic reviews and meta-analyses.50)

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TABLE1

Characteristicsof

StudiesIncluded

intheMeta-analysis

Reference

NAgeofChildrenat

Outcom

eCityor

Country

Ascertainm

entof

Exposure;Outcome

Risk

Estim

ates

asOriginally

Reported

Comments

Quality

Scorea

Caudrietal2013

163963

8y

Netherlands

Self-report;self-

report

Persistent

wheeze:Continuous

prepregnancy

BMI,OR

=1.26

(CI,1.01–1.57).

Adjusted

forgender,parentalallergy,sm

oke

exposure,breastfeeding,daycare,pregnancy

duration,oldersiblings,birthwt,maternalage,

studyregion,parentaleducation,andmaternal

asthma.

A

Guerra

etal2013

171107

14mo

Spain

Self-report

Frequent

wheeze:Continuous

BMI,

OR=1.08

(CI,1.01–1.15).BM

Icategories:BMI,

18.5,OR=1.7

(CI,0.3–8.3);BMI25–30,OR=1.0

(CI,0.4–2.6);BMI.

30,OR=4.2

(CI,1.5–11.3).

Adjusted

formaternalsocioeconom

icstatus,

child’sgender

andwtfor

length,typeof

delivery,pretermbirth,birthwt,daycare,

breastfeeding,maternalage,parity,and

smoking,andparentalasthma.

A

Håberg

etal2009

1832

281

18mo

Norw

aySelf-report;

self-report

Wheeze:BM

Icategories:BM

I25–30,

RD=0.4(CI,–1.1,1.8);BMI.

30,

RD=3.3(CI,1.2,5.3).

Adjusted

formaternalage,parity,education,

income,asthma,andsm

okinginpregnancy,

parentalsm

okingafterbirth,breastfeeding,

daycare,child’sgender,low

birthwt,preterm

birth,andcesarean

section.Continuous

data

obtained

directlyfrom

theauthor.

A

Halonenetal2013

20261

9y

UnitedStates

(Tucson,

AZ)

Medicalrecords;

measured

Asthma:Prepregnancy

BMItertiles:

Middletertile

OR=0.5(CI,0.2–1.3);

high

OR=0.4(CI,0.2–1.1).GWG

categories:HighGW

G,OR

=3.4

(CI,1.6–7.2).

Adjusted

formaternalage,ethnicity,and

parity,

parentalsm

oking,andchild’sgender.

Continuous

dataobtained

directlyfrom

the

author.

A

Harpsøeetal2013

2138

874

7y

Denm

ark

Self-report;

self-report

Asthmaever:BMIcategories:BM

I,18.5,OR=1.03

(CI,0.88–1.22);

BMI25–30,OR=1.22

(CI,1.12–1.33);

BMI30–35,OR=1.56

(CI,1.36–1.79);

BMI.

35,OR=1.55

(CI,1.23–1.95).

Adjusted

formaternalage,race,socioeconomic

status,smokingduring

pregnancy,atopy,day

careuse,atopy,cesarean

delivery,child

gender,

andnumberofsiblings.Continuous

data

obtained

directlyfrom

theauthor.

A

GWGcategories:,

5kg,OR=1.17

(CI,0.94–1.45);5–9kg,OR=1.02

(CI,0.91–1.15);16–19

kg,OR=0.97

(CI,0.89–1.06);20–24

kg,OR=1.15

(CI,1.05–1.27);.25

kg,OR=1.19

(CI,1.04–1.35).

Currentasthma:BM

Icategories:BM

I,18.5,OR=1.07

(CI,0.85–1.34);BM

I25–30,OR=1.24

(CI,1.10–1.38);BM

I30–35,OR=1.58

(CI,1.32–1.90);

BMI.

35,OR=1.48

(CI,1.08–2.04).

GWGcategories:,

5kg,OR=0.84

(CI,0.60–1.17);5–9kg,OR=1.11

(CI,0.96–1.29);16–19

kg,OR=0.90

(CI,0.80–1.02);20–24

kg,OR=1.15

(CI,1.01–1.31);.25

kg,OR=1.23

(CI,1.03–1.46).

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TABLE1

Continued

Reference

NAgeofChildrenat

Outcom

eCityor

Country

Ascertainm

entof

Exposure;Outcome

Risk

Estim

ates

asOriginally

Reported

Comments

Quality

Scorea

Kumar

etal2010

221191

3y

UnitedStates

(Boston,

MA)

Self-report

Recurrentw

heezing:BM

Icategories:

BMI25–30,OR=1.58

(CI,0.75–3.30);

BMI.

30,OR=3.51

(CI,1.68–7.32).

Adjusted

formaternalage,race,education,atopy,

child’sgender,prematuredelivery,sm

oking

during

pregnancyandathome,fetalgrowth

retardation,andlargesizeforgestationalage.

Continuous

dataobtained

directlyfrom

the

author.

A

Leermakersetal2013

234656

4y

Netherlands

Self-report;

measured

Currentwheeze:

Studyincluded

2subgroups.Adjusted

for

maternalage,parity,ethnicity,education,

smokingduring

pregnancy,pets,gestational

complications,gestationalage

atmeasurement,child’sgender,gestationalage

atbirth,birthwt,breastfeeding,daycare,and

child’sheight

andwtatfollow-up.Continuous

dataobtained

directlyfrom

theauthor.

ANo

family

history:Continuous

BMI,

OR=1.02

(CI,0.95–1.08).Categories:

BMI,

20,OR=0.93

(CI,0.79–1.09);

BMI25–30,OR=1.09

(CI,0.95–1.26);

BMI.

30,OR=0.93

(CI,0.73–1.19).

Continuous

GWGOR

=1.10

(CI,

1.03–1.16).

Positivefamily

history:Continuous

BMI,

OR=1.06

(CI,0.98–1.43).Categories:

BMI,

20,OR=1.19

(CI,0.98–1.43),

BMI25–30,OR=0.95

(CI,0.80–1.14),

BMI.

30,OR=1.41

(CI,1.06–1.87).Continuous

GWG,OR

=1.09

(CI,1.01–1.17).

Olivetietal1996

24262

4–9y

UnitedStates

(Cleveland,OH)

Medicalrecords

Asthma:GW

Gcategory

(,9kg):

OR=3.42

(CI,1.72–6.79).

Adjusted

formaternalasthm

ahistory,

bronchiolitis,m

aternalsmoking,lack

ofprenatalcare,use

ofoxygen

atbirth,

prem

aturity,low

birthwt,

2500

g,and5-min

Apgarscore.

B

Pateletal20122

56945

15–16

yNorthern

Finland

Medicalrecords

Wheezeever:BMIcategoriesforwheeze

(ever)or

asthma(ever):BMI,

18.5,

OR=0.80

(CI,0.58–1.09);BM

I25–30,

OR=1.18

(CI,0.95–1.47);BM

I,30,

OR=0.99

(CI,0.66–1.48).Continuous

BMI,OR

=1.028(CI,1.005–1.051).

Adjusted

forsocioeconomicstatus,m

arital

status,m

aternaleducation,maternalasthm

a,birthwt,parentalsm

okingduring

gestation,

andadolescent

BMIatage

15y.

A

Currentwheeze:BM

Icategoriesfor

wheeze(current)or

asthma(current):

BMI,

18.5,OR=0.87

(CI,0.57–1.04);

BMI25–30,OR=1.13

(CI,0.85–1.30);

BMI,

30,OR=1.54

(CI,0.97–2.44).

Continuous

BMI,OR

=1.047

(CI,1.019–1.077).

Pike

etal2013

26940

6y

UnitedKingdom

Measured

Continuous

BMI:

Adjusted

formaternaleducation,asthma,

smokinginpregnancy,parity,child’sgender,

birthwt,breastfeeding,andotheroutcom

e-specificcovariates.

AAsthmaever:OR=1.06

(CI,0.91–1.24).

Currentasthma:OR

=1.10

(CI,0.92–1.32).

Wheezeever:OR=1.08

(CI,1.02–1.13).

Currentwheeze:OR

=1.02

(CI,0.87–1.20).

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not available28). For prepregnancy BMI,7 studies used maternal self-report ofheight or weight,16–18,21–23,29 and 5 usedmedical records or directly measuredboth.20,25–27,30 For GWG, 4 studies usedthe difference between weight in thethird trimester and that in the first tri-mester,20,23,24,28 and 1 used maternalreport of weight gain.21 Outcomesreported varied and includedwheezing (ever, current, transient, orpersistent) and asthma (ever orcurrent); 12 studies used self-report(of which 3 studies specified “reportof physician-diagnosed asthma”20,21,27),and 2 studies reported using physi-cian diagnosis or medical record re-view.22,24 For comparability purposes,we grouped (when possible) the out-comes into 2 broader categories:“asthma/wheeze ever”17,18,20–22,25–30 and“current asthma/wheeze.”21,23–26,29

Maternal Obesity During Pregnancy

Table 1 shows the original studies withthe MOP as reported (categorical orcontinuous) and the reported out-comes. Given heterogeneity of out-comes, we grouped them into “asthma/wheeze ever” and “current asthma/wheeze.” Figure 2 shows the pooledanalysis by BMI categories. Comparedwith children from mothers of normalweight, those whose mothers wereobese had higher odds of asthma orwheeze ever (OR = 1.49; 95% CI, 1.22–1.83; P , .001) and current asthma orwheeze (OR = 1.36; 95% CI, 1.08–1.68;P = .008). Maternal overweight showednonsignificant trends for asthmaor wheeze ever (OR = 1.13; 95% CI,0.99–1.29; P = .06) and current asth-ma or wheeze (OR = 1.11; 95% CI,0.98–1.25; P = .09). When analyzed to-gether, maternal overweight or obese(BMI .25) led to higher odds ofasthma or wheeze ever (OR = 1.31;95% CI, 1.16–1.49; P , .001) andcurrent asthma or wheeze (OR = 1.21;95% CI, 1.07–1.37; P = .003) (Supple-mental Figure 6). Maternal underweightTA

BLE1

Continued

Reference

NAgeofChildrenat

Outcom

eCityor

Country

Ascertainm

entof

Exposure;Outcome

Risk

Estim

ates

asOriginally

Reported

Comments

Quality

Scorea

Reichm

anand

Nepomnyaschy2008

271971

3y

UnitedStates

Medicalrecords

Asthmaever:BMI.

30,OR=1.34

(CI,1.03–1.76).

Adjusted

formaternalage,education,income,

race,smokingduring

pregnancy,parental

smoking,pretermdelivery,child

age,gender,

andBM

I.Continuous

dataobtained

directly

from

theauthor.

A

Rusconietal20072

815

609

6–7y

Italy

Self-report;self-

report

Persistent

wheezing:GW

G,9kg,OR=

1.08

(CI,0.84–1.39).GW

G.15

kg,

OR=1.20

(CI,0.98–1.48).

Adjusted

formaternalage,education,sm

oking,

studycenter,parentalasthm

aor

atopy,child

gender,low

birthwt,siblings,socioeconom

icstatus,season,andperson

who

completed

the

questionnaire.Authorrespondedbut

continuous

datanotavailable.

B

Scholtens

etal2010

293963

8y

Netherlands

Self-report

Continuous

BMI,no

family

history:

Adjusted

formaternaleducation,sm

oking,

asthma,breastfeeding,modeofdelivery,birth

wt,andchild’sBM

Iat8

yofage.

AAsthma:OR

=0.98

(CI,0.94–1.02).

Wheeze:OR

=1.01

(CI,0.69–1.07).

Continuous

BMI,positivefamily

history:

Asthma:OR

=1.05

(CI,1.01–1.10).

Wheeze:OR

=1.06

(CI,1.01–1.12).

Wrightetal20133

0261

2y

UnitedStates

(Boston,

MA)

Measured

Repeated

wheeze:BM

I.30,OR=2.65

(CI,1.01–6.95).

Adjusted

formaternalage,race,education,

prenatalsm

oking,atopy,child’sgender,birth

wtadjustedforgestationalage,and

serum

cortisollevels(afternoonslope).Continuous

dataunavailable.

A

Tableshow

scharacteristicsofindividualstudies,includingoutcom

e,obesity

categories,and

ORsas

definedandreported

intheoriginalmanuscript,as

wellasreported

covariates

used

intheiradjusted

models.

aQuality

ofreportingassessmentbasedon

STROBE

statem

entcriteria.19

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was not associated with asthma orwheeze (P = .71).

Figure 3 shows the pooled analysis ofmaternal BMI and asthma or wheeze.In this analysis, maternal BMI was sig-nificantly associated with higher oddsof asthma or wheeze ever (OR = 1.03per each 1 kg/m2 increase; 95% CI,

1.02–1.05; P , .001) and currentasthma or wheeze (OR = 1.02 per kg/m2;95% CI, 1.01–1.04; P = .009). There wassignificant heterogeneity for both out-comes (asthma or wheeze ever, I2 =70.4%; current asthma or wheeze,I2 = 66.3%). The Egger test showedthere could be significant publication

bias for asthma or wheeze ever (P = .04)but not for current asthma or wheeze(P = .99).

Gestational Weight Gain

Table 1 shows the original studies withGWG as reported (categories or con-tinuous). Figure 4 shows the pooled

FIGURE 2PooledanalysisbyBMIcategoriesandchildhoodasthmaorwheeze.MaternalobesitybyBMIcategorieswassignificantlyassociatedwithasthmaorwheezeeverand current asthmaorwheeze during childhood.Maternal overweight categories showednonsignificant trends toward increasedasthmaorwheeze. Note thatORs are for each category as comparedwith the “normal weight” category (BMI∼18.5–24.9). Some studies had 2 subgroups (with andwithout family history ofasthma or atopy) and may have 2 entries for the same weight category. Maternal underweight was not significantly associated with childhood asthma orwheeze.

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analysis by reported GWG categories.Children whose mothers were in thehigher GWG categories had signifi-cantly higher odds of asthma orwheeze ever (OR = 1.16; 95% CI, 1.001–1.34; P = .049) but not of currentasthma or wheeze (OR = 1.08; 95% CI,0.89–1.31; P = .45). Figure 5 shows thepooled analysis of maternal (continu-ous) GWG and asthma or wheeze. Inthis analysis, maternal GWG was sig-nificantly associated with higher oddsof current asthma or wheeze (OR =1.015 per 1-kg increase in GWG; 95% CI,1.01–1.02; P , .001) but not withasthma or wheeze ever (OR = 1.04 perkg; 95% CI, 0.97–1.11; P = .27). Both forGWG categories and for continuousGWG, the number of studies was small(n = 2–3). The Egger test showed nosignificant evidence of publication biasfor current asthma or wheeze (P = .52),but it could not be calculated forasthma or wheeze ever because of thesmall number of studies. SubnormalGWG was not associated with asthma

or wheeze (P = .19; Supplemental Fig-ure 7), but the number of studiesreporting was small (n = 3).

Subgroup Analysis andMeta-regression

Meta-regression was performed forBMI with covariates available for ex-traction fromtheoriginalstudies(at thestudy level [eg, mean or median ma-ternal age in the study] or at the cate-gory level when available [eg, mean ormedian maternal age within each BMIcategory in the study]). For continuousBMI, meta-regression showed a nega-tive association of borderline signifi-cance between maternal history ofasthma and the study effect size: Therisk of childhood asthma or wheezewith increasing maternal BMI washigherwhen theprevalenceofmaternalasthma was lower (b = 0.90; 95% CI,0.80–1.01; P = .07); this effect modifi-cation explained part of the study het-erogeneity (I2 decreased to 33.6%; R2 =81.5%). We were unable to perform

subgroup analysis or meta-regressionfor GWG because of the small numberof studies.

DISCUSSION

In this meta-analysis, we report thatchildren whose mothers were obeseduring pregnancy (defined by BMI cat-egories or by higher continuous BMI)are at higher risk of asthma or wheeze.Maternal underweight did not appearto increasetheriskofasthmaorwheezein childhood, although this analysisincluded only a few studies with smallsample sizes and may have been un-derpowered.

Maternal obesity could influence therisk of asthma in the offspring throughseveral mechanisms. Obesity is asso-ciated with a chronic, low-grade in-flammatory state.31 For example, it hasbeen associated with elevated levels ofinflammatory cytokines implicated inasthma, such as tumor necrosis factora (TNF-a), interleukin 6, and trans-forming growth factor b-1. Leptin,a proinflammatory adipokine, not onlyis elevated in the maternal circulationof pregnant obese women but also ishigher in the cord blood of their chil-dren than in children whose mothersare not obese.32 Conversely, adipo-nectin, which has antiinflammatoryproperties and has shown inverseassociations with asthma symptoms33

and airway inflammation,34 is de-creased in obesity and is also de-creased in newborns of obesemothers.35

Alternatively, maternal obesity mayinfluence the pathogenesis of asth-ma through exposure of the de-veloping fetus to different dietarypatterns.36 For example, obese womenare more likely to have low serum lev-els of vitamin D,37 andmaternal vitaminD insufficiency or deficiency has beenassociated with elevated risk of child-hood asthma.38 Similarly, maternalconsumption of other foods duringpregnancy (eg, meat, dairy, or fats) has

FIGURE 3Pooled analysis by continuous BMI and asthma or wheeze. Increasing maternal BMI was significantlyassociated with both asthma or wheeze ever and current asthma or wheeze during childhood. Note thatORs are for each unit increase in BMI. Some studies23,29 had 2 subgroups (with and without familyhistory of asthma or atopy) and may have 2 entries.

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been associated with childhoodasthma.39,40 Finally, shared geneticpolymorphisms or epigenetic changesas a result of maternal obesity could becausing, mediating, or modifying theelevated risk of asthma in their off-spring.

Individual studies assessing whethermaternal history of asthma modifiesthe effect of MOP on childhood asthmahave shown conflicting results.23,25,29

In our meta-regression analysis, therewas significant modification of the ef-fect of MOP on asthma by maternalasthma: There was a more pronouncedincrease in the risk of childhoodasthma when the prevalence of ma-ternal asthma was lower. Althoughsuch analysis is only exploratory andshould be interpreted with caution, itcould indicate that the risk conferred

by the mother’s asthma supersedesthat conferred by maternal obesity. Theheritability of asthma has been esti-mated to be ∼0.82–0.91,12,41 and stud-ies with higher prevalence of maternalasthma could be underpowered to de-tect an effect of maternal obesity. Al-ternatively, this finding may suggestthat the risk from maternal obesity isstronger for nonatopic asthma. Many42–44

but not all45 studies of obesity and asthmahave reported this association to bestronger among nonatopic children oradults.

GWG was reported in fewer studies.Although there seems to be a higherrisk of asthma or wheeze with higherGWG, the observed associations varieddepending on theway the exposurewasreported (categorical or continuousGWG) and the definition of asthma or

wheeze. GWG has also been associatedwith elevated maternal46,47 and cordblood47 leptin levels. Halonen et al20

reported that persistently elevatedTNF-a from birth to 3 months of agewas associated with asthma and de-creased lung function at age 9 yearsand that maternal GWG was the stron-gest predictor of an elevated TNF-alevel. These findings suggest that GWGand maternal obesity may contributeto the onset of childhood asthma viasimilar proinflammatory mechanisms.Additional studies are needed to reachmore definitive conclusions in regardto GWG and childhood asthma orwheeze.

Studies addressing maternal obesityand childhood asthma that did notmeetinclusion criteria for our meta-analysisshould be mentioned. In a Swedish

FIGURE 4Pooled analysis by GWG categories and asthma or wheeze. High maternal GWG was significantly associated with asthma or wheeze ever but not with currentasthma or wheeze (P = .47) during childhood. Note that categories of GWG vary between studies. Subnormal GWG was not significantly associated withchildhood asthma or wheeze (see Supplemental Fig 7).

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cohort of ∼431 000 first-born children,Lowe et al48 reported that MOP wasassociated with greater use of inhaledcorticosteroid use in boys and girls upto age 12 years and in girls up to age 16years; these results suggest that MOPmay also be a risk factor for more se-vere or persistent childhood asthma.Furthermore, in a study by Watson andMcDonald,49 both maternal baselineskinfold thickness (as a surrogate ofpercentage body fat) and increase inskinfold thickness during pregnancywere independently associated withgreater risk of asthma in childhood,whereas BMI was not significant. Theauthors proposed that skinfold mea-surement may be more sensitive thanBMI; this extends to maternal obesity inour recent report that for studies ofasthma, the child’s BMI may not be thebest or sole indicator of adiposity.45

The current study has several limi-tations. We included only articles pub-lished in English or with sufficientinformation in English to abstract datafor analysis, which may not fully rep-resent all studies conducted on thesubject. There was high variabilityamong studies. We dealt with this var-iability in 3 ways: To account for effectsize variability, we used random effectsmodels; to account for the variability inthe way BMI and GWG were categorizedin the original studies, we obtainedeffect sizes using continuous BMI orGWG from many of the authors of theoriginal reports; and we performedmeta-regression analyses to detectsignificant effectmodifiers. However, aswith anymeta-analysis,wewere limitedto the covariates available to us fromthe original articles. Finally, maternalobesity is also a risk factor for

childhood obesity, and the elevatedrisk of asthma could result partlyfrom the child’s own obesity; however,such confounding is unlikely giventhat most of the included studies ad-justed for birth weight16,17,22,23,25,26,29,30

or for the child’s weight or BMI atthe time of assessment of the out-come.17,23,25,27,29

CONCLUSIONS

We report that MOP is a significant riskfactor for the development of childhoodasthma or wheeze. GWG may also in-crease the risk of childhood asthmaor wheeze, but we were limited bythe small number of studies. The ef-fect of maternal obesity on childhoodasthmamay be more pronounced whenthe prevalence of maternal asthma islower.

FIGURE 5Pooled analysis by continuous GWG and asthma or wheeze. Increasing GWG (in kg) was significantly associated with current asthma or wheeze but not withasthma or wheeze ever (P = .27) during childhood. Note that ORs are for each 1-kg increase in GWG. Note the small number of studies in each outcome (n = 2).

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REFERENCES

1. Ogden CL, Carroll MD, Kit BK, Flegal KM.Prevalence of obesity among adults: UnitedStates, 2011–2012. NCHS Data Brief. 2013;131:1–8. PubMed PMID: 24152742

2. World Health Organization (WHO). Obesityand overweight: WHO. Fact sheet no. 311.2013. Available at: www.who.int/media-centre/factsheets/fs311/en/. AccessedApril 17, 2014

3. Institute of Medicine (IOM). Weight GainDuring Pregnancy: Reexamining theGuidelines. Washington, DC: National Acad-emy of Sciences, Institute of Medicine; 2009

4. Cedergren MI. Maternal morbid obesityand the risk of adverse pregnancy out-come. Obstet Gynecol. 2004;103(2):219–224

5. American College of Obstetricians andGynecologists. ACOG committee opinion no.549: obesity in pregnancy. Obstet Gynecol.2013;121(1):213–217

6. Waller DK, Mills JL, Simpson JL, et al. Areobese women at higher risk for producingmalformed offspring? Am J Obstet Gynecol.1994;170(2):541–548

7. Rasmussen SA, Chu SY, Kim SY, Schmid CH,Lau J. Maternal obesity and risk of neuraltube defects: a metaanalysis. Am J ObstetGynecol. 2008;198(6):611–619

8. Kiel DW, Dodson EA, Artal R, Boehmer TK,Leet TL. Gestational weight gain and preg-nancy outcomes in obese women: howmuch is enough? Obstet Gynecol. 2007;110(4):752–758

9. Barker DJ, Winter PD, Osmond C, MargettsB, Simmonds SJ. Weight in infancy anddeath from ischaemic heart disease. Lan-cet. 1989;2(8663):577–580

10. Paneth N, Susser M. Early origin of coro-nary heart disease (the “Barker hypothe-sis”). BMJ. 1995;310(6977):411–412

11. Akinbami LJ, Moorman JE, Bailey C, et al.Trends in asthma prevalence, health careuse, and mortality in the United States,2001–2010. NCHS Data Brief. 2012;94:1–8.PubMed PMID: 22617340

12. Thomsen SF, van der Sluis S, Kyvik KO,Skytthe A, Skadhauge LR, Backer V. In-crease in the heritability of asthma from1994 to 2003 among adolescent twins.Respir Med. 2011;105(8):1147–1152

13. Scirica CV, Celedón JC. Genetics of asthma:potential implications for reducing asthmadisparities. Chest. 2007;132(5 suppl):770S–781S

14. Gilliland FD, Li YF, Peters JM. Effects ofmaternal smoking during pregnancy andenvironmental tobacco smoke on asthma

and wheezing in children. Am J Respir CritCare Med. 2001;163(2):429–436

15. Cohen RT, Raby BA, Van Steen K, et al;Childhood Asthma Management ProgramResearch Group. In utero smoke exposureand impaired response to inhaled cortico-steroids in children with asthma. J AllergyClin Immunol. 2010;126(3):491–497

16. Caudri D, Savenije OEM, Smit HA, et alPerinatal risk factors for wheezing pheno-types in the first 8 years of life. Clin ExpAllergy. 2013;43(12):1395–1405

17. Guerra S, Sartini C, Mendez M, et al. Ma-ternal prepregnancy obesity is an inde-pendent risk factor for frequent wheezing ininfants by age 14 months. Paediatr PerinatEpidemiol. 2013;27(1):100–108

18. Håberg SE, Stigum H, London SJ, Nystad W,Nafstad P. Maternal obesity in pregnancyand respiratory health in early childhood.Paediatr Perinat Epidemiol. 2009;23(4):352–362

19. von Elm E, Altman DG, Egger M, Pocock SJ,Gøtzsche PC, Vandenbroucke JP; STROBEInitiative. The Strengthening the Reportingof Observational Studies in Epidemiology(STROBE) statement: guidelines for report-ing observational studies. J Clin Epidemiol.2008;61(4):344–349

20. Halonen M, Lohman IC, Stern DA, Ellis WL,Rothers J, Wright AL. Perinatal tumor ne-crosis factor-a production, influenced bymaternal pregnancy weight gain, predictschildhood asthma. Am J Respir Crit CareMed. 2013;188(1):35–41

21. Harpsøe MC, Basit S, Bager P, et al. Ma-ternal obesity, gestational weight gain, andrisk of asthma and atopic disease in off-spring: a study within the Danish NationalBirth Cohort. J Allergy Clin Immunol. 2013;131(4):1033–1040

22. Kumar R, Story RE, Pongracic JA, et al.Maternal pre-pregnancy obesity and re-current wheezing in early childhood. PediatrAllergy Immunol Pulmonol. 2010;23(3):183–190. PubMed PMID: 22375278. PubMed Cen-tral PMCID: 3281288

23. Leermakers ET, Sonnenschein-van der VoortAM, Gaillard R, et al. Maternal weight, gesta-tional weight gain and preschool wheezing.The Generation R Study. Eur Respir J. 2013;42(5):1234–1243. PubMed PMID: 23471348

24. Oliveti JF, Kercsmar CM, Redline S. Pre- andperinatal risk factors for asthma in innercity African-American children. Am J Epi-demiol. 1996;143(6):570–577

25. Patel SP, Rodriguez A, Little MP, et al.Associations between pre-pregnancy obe-

sity and asthma symptoms in adolescents.J Epidemiol Community Health. 2012;66(9):809–814

26. Pike KC, Inskip HM, Robinson SM, et al;Southampton Women’s Survey Study Group.The relationship between maternal adiposityand infant weight gain, and childhood wheezeand atopy. Thorax. 2013;68(4):372–379

27. Reichman NE, Nepomnyaschy L. Maternalpre-pregnancy obesity and diagnosis ofasthma in offspring at age 3 years. MaternChild Health J. 2008;12(6):725–733

28. Rusconi F, Galassi C, Forastiere F, et al.Maternal complications and procedures inpregnancy and at birth and wheezingphenotypes in children. Am J Respir CritCare Med. 2007;175(1):16–21

29. Scholtens S, Wijga AH, Brunekreef B, et al.Maternal overweight before pregnancy andasthma in offspring followed for 8 years.Int J Obes (Lond). 2010;34(4):606–613

30. Wright RJ, Fisher K, Chiu YH, et al. Dis-rupted prenatal maternal cortisol, mater-nal obesity, and childhood wheeze. Insightsinto prenatal programming. Am J RespirCrit Care Med. 2013;187(11):1186–1193

31. Fantuzzi G. Adipose tissue, adipokines, andinflammation. J Allergy Clin Immunol. 2005;115(5):911–919, quiz 920

32. Ferretti G, Cester A, Bacchetti T, et al. Leptinand paraoxonase activity in cord blood fromobese mothers [published online ahead ofprint October 23, 2013]. J Matern FetalNeonatal Med. 2013. PubMed PMID: 24147648

33. Kattan M, Kumar R, Bloomberg GR, et al.Asthma control, adiposity, and adipokinesamong inner-city adolescents. J Allergy ClinImmunol. 2010;125(3):584–592

34. Shore SA, Terry RD, Flynt L, Xu A, Hug C.Adiponectin attenuates allergen-inducedairway inflammation and hyperrespon-siveness in mice. J Allergy Clin Immunol.2006;118(2):389–395

35. Vega-Sanchez R, Barajas-Vega HA, Rozada G,Espejel-Nuñez A, Beltran-Montoya J, Vadillo-Ortega F. Association between adiposity andinflammatory markers in maternal and fetalblood in a group of Mexican pregnantwomen. Br J Nutr. 2010;104(12):1735–1739

36. Kumar R. Prenatal factors and the de-velopment of asthma. Curr Opin Pediatr.2008;20(6):682–687

37. Scholl TO, Chen X. Vitamin D intake duringpregnancy: association with maternalcharacteristics and infant birth weight.Early Hum Dev. 2009;85(4):231–234

38. Maslova E, Hansen S, Jensen CB, Thorne-Lyman AL, Strøm M, Olsen SF. Vitamin D

REVIEW ARTICLE

PEDIATRICS Volume 134, Number 2, August 2014 e545 at UNIVERSITY OF TOLEDO LIBRARIES on September 30, 2014pediatrics.aappublications.orgDownloaded from

intake in mid-pregnancy and child allergicdisease: a prospective study in 44,825Danish mother–child pairs. BMC PregnancyChildbirth. 2013;13(1):199

39. Chatzi L, Garcia R, Roumeliotaki T, et al;INMA Study Group; RHEA Study Group.Mediterranean diet adherence duringpregnancy and risk of wheeze and eczemain the first year of life: INMA (Spain) andRHEA (Greece) mother–child cohort stud-ies. Br J Nutr. 2013;110(11):2058–2068

40. Miyake Y, Tanaka K, Okubo H, Sasaki S,Arakawa M. Maternal fat intake duringpregnancy and wheeze and eczema inJapanese infants: the Kyushu Okinawa Ma-ternal and Child Health Study. Ann Epi-demiol. 2013;23(11):674–680

41. van Beijsterveldt CE, Boomsma DI. Geneticsof parentally reported asthma, eczema andrhinitis in 5-yr-old twins. Eur Respir J. 2007;29(3):516–521

42. Visness CM, London SJ, Daniels JL, et al.Association of childhood obesity with atopic

and nonatopic asthma: results from theNational Health and Nutrition ExaminationSurvey 1999–2006. J Asthma. 2010;47(7):822–829

43. Fenger RV, Gonzalez-Quintela A, Vidal C,et al. Exploring the obesity–asthma link: doall types of adiposity increase the risk ofasthma? Clin Exp Allergy. 2012;42(8):1237–1245

44. Telenga ED, Tideman SW, Kerstjens HA, et al.Obesity in asthma: more neutrophilic in-flammation as a possible explanation fora reduced treatment response. Allergy.2012;67(8):1060–1068

45. Forno E, Acosta-Perez E, Brehm J, et alObesity and adiposity indicators, asthma,and atopy in Puerto Rican children. JAllergy Clin Immunol. 2014;133(5):1308–1314

46. Ferraro ZM, Qiu Q, Gruslin A, Adamo KB.Excessive gestational weight gain andobesity contribute to altered expression ofmaternal insulin-like growth factor binding

protein-3. Int J Womens Health. 2013;5:657–665. PubMed PMID: 24124394. PubMedCentral PMCID: 3794982

47. Karakosta P, Georgiou V, Fthenou E, et al.Maternal weight status, cord blood leptinand fetal growth: a prospective mother–child cohort study (Rhea study). PaediatrPerinat Epidemiol. 2013;27(5):461–471

48. Lowe AJ, Ekeus C, Bråbäck L, Rajaleid K,Forsberg B, Hjern A. Impact of maternalobesity on inhaled corticosteroid use inchildhood: a registry based analysis of firstborn children and a sibling pair analysis.PLoS ONE. 2013;8(6):e67368

49. Watson PE, McDonald BW. Subcutaneousbody fat in pregnant New Zealand women:association with wheeze in their infants at18 months. Matern Child Health J. 2013;17(5):959–967

50. Moher D, Liberati A, Tetzlaff J, Altman DG;PRISMA Group. Preferred reporting itemsfor systematic reviews and meta-analyses:the PRISMA statement. BMJ. 2009;339:b2535

(Continued from first page)

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

FUNDING: Dr Forno was supported by NIH grant K12-HD052892. Dr Celedón was supported by NIH grants HL079966 and HL117191 and an endowment from the HeinzFoundation. Funded by the National Institutes of Health (NIH).

POTENTIAL CONFLICT OF INTEREST: Dr Celedón served as a one-time consultant for Genentech in 2011 on an issue unrelated to this manuscript; the other authorshave indicated they have no potential conflicts of interest to disclose.

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DOI: 10.1542/peds.2014-0439; originally published online July 21, 2014; 2014;134;e535Pediatrics

Erick Forno, Omar M. Young, Rajesh Kumar, Hyagriv Simhan and Juan C. CeledónChildhood Asthma

Maternal Obesity in Pregnancy, Gestational Weight Gain, and Risk of  

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