Neurodevelopmental Outcomes After Cardiac Surgery in Infancy

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4-2015

Neurodevelopmental Outcomes After CardiacSurgery in InfancyJ. William GaynorThe Children’s Hospital of Philadelphia

Christian StoppBoston Children’s Hospital

David WypijBoston Children’s Hospital

Dean B. AndropoulosTexas Children’s Hospital

Joseph AtallahStollery Children’s Hospital

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Gaynor, J. William; Stopp, Christian; Wypij, David; Andropoulos, Dean B.; Atallah, Joseph; Atz, Andrew M.; Beca, John; Donofrio,Mary T.; Duncan, Kim; Ghanayem, Nancy S.; Goldberg, Caren S.; Hövels-Gürich, Hedwig; Ichida, Fukiko; Jacobs, Jeffrey P.; Justo,Robert; Latal, Beatrice; Li, Jennifer S.; Mahle, William T.; McQuillen, Patrick S.; Menon, Shaji C.; Pemberton, Victoria L.; Pike, NancyA.; Pizarro, Christian; Shekerdemian, Lara S.; Synnes, Anne; Williams, Ismee; Bellinger, David C.; and Newburger, Jane W.,"Neurodevelopmental Outcomes After Cardiac Surgery in Infancy" (2015). Public Health Resources. Paper 320.http://digitalcommons.unl.edu/publichealthresources/320

AuthorsJ. William Gaynor, Christian Stopp, David Wypij, Dean B. Andropoulos, Joseph Atallah, Andrew M. Atz, JohnBeca, Mary T. Donofrio, Kim Duncan, Nancy S. Ghanayem, Caren S. Goldberg, Hedwig Hövels-Gürich,Fukiko Ichida, Jeffrey P. Jacobs, Robert Justo, Beatrice Latal, Jennifer S. Li, William T. Mahle, Patrick S.McQuillen, Shaji C. Menon, Victoria L. Pemberton, Nancy A. Pike, Christian Pizarro, Lara S. Shekerdemian,Anne Synnes, Ismee Williams, David C. Bellinger, and Jane W. Newburger

This article is available at DigitalCommons@University of Nebraska - Lincoln: http://digitalcommons.unl.edu/publichealthresources/320

Neurodevelopmental Outcomes AfterCardiac Surgery in InfancyJ. William Gaynor, MDa, Christian Stopp, MSb, David Wypij, PhDb, Dean B. Andropoulos, MDc, Joseph Atallah, MD, CM, SM, FRCPCd,Andrew M. Atz, MDe, John Beca, MDf, Mary T. Donofrio, MDg, Kim Duncan, MDh, Nancy S. Ghanayem, MDi, Caren S. Goldberg, MDj,Hedwig Hövels-Gürich, MDk, Fukiko Ichida, MDl, Jeffrey P. Jacobs, MDm, Robert Justo, MDn, Beatrice Latal, MDo, Jennifer S. Li, MDp,William T. Mahle, MDq, Patrick S. McQuillen, MDr, Shaji C. Menon, MDs, Victoria L. Pemberton, RNC, MS, CCRCt, Nancy A. Pike, RN, PhDu,Christian Pizarro, MDv, Lara S. Shekerdemian, MDw, Anne Synnes, MDCMx, Ismee Williams, MDy, David C. Bellinger, PhDb,Jane W. Newburger, MD, MPHb, for the International Cardiac Collaborative on Neurodevelopment (ICCON) Investigators

abstract BACKGROUND: Neurodevelopmental disability is the most common complication for survivors of surgeryfor congenital heart disease (CHD).

METHODS:We analyzed individual participant data from studies of children evaluated with the Bayley Scales ofInfant Development, second edition, after cardiac surgery between 1996 and 2009. The primary outcome wasPsychomotor Development Index (PDI), and the secondary outcome was Mental Development Index (MDI).

RESULTS: Among 1770 subjects from 22 institutions, assessed at age 14.5 6 3.7 months, PDIs andMDIs (77.6 6 18.8 and 88.2 6 16.7, respectively) were lower than normative means (each P , .001).Later calendar year of birth was associated with an increased proportion of high-risk infants(complexity of CHD and prevalence of genetic/extracardiac anomalies). After adjustment for centerand type of CHD, later year of birth was not significantly associated with better PDI or MDI. Risk factorsfor lower PDI were lower birth weight, white race, and presence of a genetic/extracardiac anomaly(all P # .01). After adjustment for these factors, PDIs improved over time (0.39 points/year, 95%confidence interval 0.01 to 0.78; P = .045). Risk factors for lower MDI were lower birth weight,male gender, less maternal education, and presence of a genetic/extracardiac anomaly (all P , .001).After adjustment for these factors, MDIs improved over time (0.38 points/year, 95% confidence interval0.05 to 0.71; P = .02).

CONCLUSIONS: Early neurodevelopmental outcomes for survivors of cardiac surgery in infancy have improvedmodestly over time, but only after adjustment for innate patient risk factors. As more high-risk CHD infantsundergo cardiac surgery and survive, a growing population will require significant societal resources.

WHAT’S KNOWN ON THIS SUBJECT:Neurodevelopmental disabilities are the mostcommon, and potentially the most damaging,sequelae of congenital heart defects. Children withcongenital heart defects undergoing surgery ininfancy have problems with reasoning, learning,executive function, inattention and impulsivebehavior, language skills, and social skills.

WHAT THIS STUDY ADDS: Earlyneurodevelopmental outcomes for survivors ofcardiac surgery in infancy have improved modestlyover time, but only after adjustment for innate patientrisk factors. As more high-risk infants with congenitalheart defects survive cardiac surgery, a growingpopulation will require significant societal resources.

aThe Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania; bBoston Children’s Hospital, Boston,Massachusetts; cTexas Children’s Hospital, Houston, Texas; dStollery Children’s Hospital and the Western CanadianComplex Pediatric Therapies Follow-up Program, Edmonton, Alberta, Canada; eDivision of Pediatric Cardiology,Medical University of South Carolina, Charleston, South Carolina; fStarship Children’s Hospital, Auckland, NewZealand; gChildren’s National Medical Center, Washington, District of Columbia; hChildren’s Hospital and MedicalCenter, Omaha, Nebraska; iMedical College of Wisconsin, Children’s Hospital of Wisconsin, Milwaukee, Wisconsin;jMott’s Children’s Hospital, Ann Arbor, Michigan; kUniversity Hospital Aachen, Aachen, Germany; lToyama UniversityHospital, Toyama, Japan; mJohns Hopkins All Children’s Heart Institute, St. Petersburg, Florida; nUniversity ofQueensland, Brisbane, Australia; oUniversity Children’s Hospital Zurich, Zurich, Switzerland; pDuke UniversityMedical Center, Durham, North Carolina; qChildren’s Healthcare of Atlanta, Atlanta, Georgia; rUniversity ofCalifornia, San Francisco, San Francisco, California; sPrimary Children’s Medical Center, Salt Lake City, Utah;tNational Heart, Lung, and Blood Institute, Bethesda, Maryland; uChildren’s Hospital Los Angeles, Los Angeles,California; vAlfred I. duPont Hospital for Children, Wilmington, Delaware; wThe Royal Children’s Hospital,Melbourne, Australia; xUniversity of British Columbia, Vancouver, British Columbia, Canada; and yNew York-Presbyterian Morgan Stanley Children’s Hospital of New York, New York, New York

Drs Gaynor and Newburger conceptualized and participated in design of the study; Drs Gaynor,Newburger, Bellinger, and Hövels-Gürich and Ms Pemberton contributed to data interpretation; DrsAndropoulos, Atallah, Atz, Beca, Donofrio, Duncan, Ghanayem, Goldberg, Ichida, Jacobs, Justo, Latal,Li, Mahle, McQuillen, Menon, Pike, Pizarro, Shekerdemian, Synnes, and Williams supervised datacollection and submission at their institutions (including participation in the Pediatric HeartNetwork Single Ventricle Reconstruction [SVR] and Infant Single Ventricle [ISV] trials,);

ARTICLE PEDIATRICS Volume 135, number 5, May 2015

Neurodevelopmental disabilities arethe most common, and potentially themost damaging, sequelae ofcomplicated childhood diseases.Although many studies haveevaluated the cognitive andbehavioral status of children whowere born prematurely, few havebeen performed in children sufferingfrom rare conditions includingcomplex congenital heart disease(CHD).1 Small studies at individualinstitutions have shown that childrenwith CHD undergoing surgery ininfancy have more problems withreasoning, learning, executivefunction, inattention and impulsivebehavior, language skills, and socialskills compared with peers withoutCHD.2–5 Lower abilities in these areasmay lead to poor school performance,strained interpersonal relationships,and behavior problems. Survivors ofcardiac surgery in infancy are morelikely than the general population torequire remedial services, includingtutoring and special education, aswell as physical, occupational, andspeech therapy.2,6 As these childrenreach adulthood, neurodevelopmentaldisabilities can limit educationalachievements, employability,insurability, and quality of life.Currently known risk factors explainonly ∼30% of the observed variationin neurodevelopmental outcome aftercardiac surgery in infancy.7

Importantly, these studies haveidentified few modifiable risk factorsfor adverse neurodevelopmentaloutcomes.7–9 In addition, thesestudies usually derive from singlecenters and are limited by smallsample size.

Many centers caring for children withCHD have measured and reportedneurodevelopmental outcomes, oftenusing standardized instruments andcollecting similar data on potentialcovariates and confounders. The useof individual participant data frommultiple studies has beenchampioned as the gold standard forsynthesizing prognostic risk factors inclinical prediction models.10–12

Nevertheless, no studies using thisapproach have been performed inchildren with CHD or have evaluatedneurodevelopmental outcomes. Inthis study, we pooled and analyzedsuch data from earlier studies todescribe neurodevelopmentaloutcomes of infants after opencardiac surgery with regard totemporal trends over a 14-yearinterval.

METHODS

Identification of ParticipatingInstitutions

Participating institutions wereselected based on a literature searchto identify studies reportingneurodevelopmental outcomes aftercardiac surgery in infancy(Supplemental Table 4). The inclusioncriteria were (1) cardiac surgeryusing cardiopulmonary bypass at age#9 months; (2) enrollment ina clinical trial or observational cohortstudy with date of surgery betweenJanuary 1, 1988, and December 31,2009; (3) neurodevelopmentalevaluation between 6 and 30 monthsof age using the Bayley Scales ofInfant Development, first edition(BSID-I), BSID-II, or the Bayley Scalesof Infant and Toddler Development,third edition13,14; and (4) dataavailable on patient and operativemanagement variables. Childrentreated with a primary strategy ofcardiac transplantation were noteligible. Investigators identified bythe initial literature search werecontacted and invited to participate.Additional centers with eligiblesubjects but previously unpublisheddata were identified and invited tocontribute. All invited investigatorsagreed to submit data for thisanalysis.8,9,15–24

Preparation of the Analysis Data Set

Participating institutions reviewedtheir databases to select appropriatesubjects for analysis. Each institutionobtained approval or exemption fromtheir institutional review board.

Center investigators submitteda limited, deidentified standardizeddataset, includingneurodevelopmental outcomemeasures and demographic,preoperative, perioperative, andpostoperative variables(Supplemental Table 5). Investigatorswere asked to code their subjectsaccording to cardiac diagnosis into 1of 4 previously described categoriesthat have been shown to predictperioperative mortality: Class I, 2ventricles with no aortic archobstruction; Class II, 2 ventricles withaortic arch obstruction; Class III,single ventricle without archobstruction; and Class IV, singleventricle with arch obstruction.25

Subjects with d-transposition of thegreat arteries (TGA) or tetralogy ofFallot (TOF) are generally in Class I,whereas subjects with hypoplasticleft heart syndrome (HLHS) are inClass IV. Subgroup analyses wereperformed based on 3 common typesof CHD: TGA with intact ventricularseptum (IVS) or ventricular septaldefect (VSD) (Class I only), TOF withor without pulmonary atresia (PA),and HLHS. Anomalies were classifiedas definite genetic anomalies,suspected genetic anomalies or majorextracardiac anomalies, or absent(normal). Subjects in whom thepresence or absence of an anomalyhad not been specifically noted wereclassified as being normal.

The sample was restricted to subjectsassessed using BSID-II, which was themost commonly used instrument.Although the sample would havebeen larger had other versions of theBayley scales been included, nostandardized methodology exists bywhich scores from different versionsof the Bayley scales can be combined.BSID-II offers a standardizedassessment of cognitive and motordevelopment for children aged 1through 42 months. It yields 2 scores:the Psychomotor Development Index(PDI) and the Mental DevelopmentIndex (MDI). The PDI assesses controlof gross muscle function, including

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crawling and walking, as well as finemuscle skills necessary forprehension, use of writinginstruments, and imitation of handmovements. The MDI assessesmemory, problem solving, earlynumber concepts, generalization,vocalizations, and language and socialskills. The mean 6 SD is 100 6 15 inthe normative population for bothscores. Motor skills (PDI) are usuallymore severely affected in infantsurvivors of cardiac surgery than arecognitive abilities (MDI).15,21

Dataset Preparation and StatisticalAnalysis

Center investigators reviewed theirdata for deidentification, dataaccuracy, data completeness, andoutlying observations beforesubmission to the Data CoordinationCenter (DCC) at Boston Children’sHospital. The DCC performeda standardized integrity examinationof the data to identify inconsistencies,missing data, and outliers acrossinstitutions. Communications wereexchanged with centers until allissues were resolved. Collaborativedecisions between the leadinvestigators (Drs Gaynor andNewburger) were made with respectto group assignment for cardiac class,cardiac diagnosis, race, and geneticanomaly when collapsing acrosscategories of a variable or handlingunique cases. Analyses included onlydata for which all queries had beenresolved. The DCC merged the dataacross institutions into a finalanalysis data set.

Group differences by cardiac classwere assessed by using x2 tests forcategorical variables and analysis ofvariance or Kruskal–Wallis tests forcontinuous variables. Comparisons ofPDI and MDI with normative meanswere made using 1-sample t tests.Primary analyses examined therelationships of PDI and MDI fromBSID-II with year of birth. Pearsoncorrelations were used to examinethese relationships in the full cohortas well as in homogeneous diagnostic

subgroups (ie, TGA, TOF, and HLHS).The types of CHD included in clinicalstudies changed over time. Therefore,linear regression analyses usingcontinuous year of birth andadjusting for center and cardiac classserved as foundation models forpredicting PDI and MDI. Candidatepredictors in multivariable analyseswere preoperative measures andpatient factors, including birthweight, gestational age, race, ethnicity(Hispanic versus not Hispanic),gender, maternal education, geneticor extracardiac anomalies, prenataldiagnosis, preoperative mechanicalventilation, and neonatal status (ageat first surgery #30 days). Factorsrelating to operative management orpostoperative course were notincluded. Predictors were screened toidentify associations witha neurodevelopmental score at theP , .25 level after adjusting forcenter, cardiac class, and year of birth.Predictors meeting this criterion wereincluded in stepwise backwardanalysis in which P , .05 served asthe criterion for retention into the fullmodel. Center, cardiac class, and yearof birth were retained in all modelsregardless of P value. Standardizedmean scores present the predictedPDIs and MDIs adjusting for center,cardiac class, and other statisticallysignificant predictors at the meanvalue of the covariates. Analyses wereperformed using SAS 9.3 (SASInstitute, Cary, NC).

RESULTS

Of the 2501 subjects submitted from26 institutions in 6 countries, 1770subjects born between 1996 and2009 from 22 institutions wereevaluated with BSID-II and form thecohort for this report. The cohort waspredominantly male (61.5%), white(84.0%), and non-Hispanic (92.3%).Cardiac diagnoses and preoperativecharacteristics are shown in Table 1for the overall cohort and each classof CHD. Because of changes ineligibility criteria across studies, the

majority of subjects in the early yearswere in Class I, whereas in later years,the percentage of subjects in Class IVsurpassed that in Class I (Fig 1A). Themost common cardiac defects wereHLHS (n = 549, 31.0%), followed byTGA with IVS (n = 235, 13.3%), othersingle ventricle (n = 203, 11.5%), TOFwithout PA (n = 166, 9.4%), VSD (n =148, 8.4%), and TGA with VSD (n =121, 6.8%). Figure 1B showsvariation over time in the percentageof subjects with a definite orsuspected genetic or majorextracardiac anomaly.

Subjects were assessed at age 14.5 63.7 months. Compared withnormative means, CHD subjects hadsignificantly lower PDIs (77.6 6 18.8)and MDIs (88.2 6 16.7) (each P ,.001). PDIs and MDIs were $1 SDbelow the population mean for63.5% and 36.1% of subjects,respectively, and $2 SD below themean for 36.8% and 15.3% ofsubjects. Higher cardiac class,reflecting more serious heart disease,was significantly associated with lowerPDI, but not with lower MDI (Table 1).

Univariate analyses

For the entire cohort, later year ofbirth was not associated with betterPDI or MDI. Over the study period,unadjusted mean PDIs declined (r =20.17, P , .001), as did unadjustedMDIs (r =20.05, P = .03). Similarly, indiagnostic subgroup analysis (TGAwith IVS or VSD [Class I only], TOFwith or without PA, and HLHS),unadjusted scores did not improveover time in any subgroup. PDIsdeclined over time for subjects withTGA (r = 20.18, P = .001) and TOF(r =20.16, P = .03) but were stable forsubjects with HLHS (r = 0.03, P = .44).MDIs decreased for the TOF group(r =20.16, P = .03) but did not changesignificantly over time among thosewith TGA or HLHS (TGA: r = 20.02,P = .68; HLHS: r = 0.005, P = .91).

Multivariable analyses

Multivariable analyses adjusting forcenter, cardiac class, and year of birth

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(foundation models; see Table 2)were performed to determineadditional independent predictors ofneurodevelopmental outcome, as wellas to examine temporal trends whenconsidering all measured potentialrisk factors. Later year of birth wasnot significantly associated withbetter PDI or MDI when adjusting forcenter and cardiac class.

Independent predictors of lower PDIincluded lower birth weight, white

race, and presence of a definite orsuspected genetic or extracardiacanomaly (full model in Table 2). Thefinal model for PDI included 1675subjects from 22 centers with anadjusted R2 of 24.3% and root meansquare error of 16.2. A statisticallysignificant annual improvement inPDI (0.39 points/year, 95%confidence interval [CI] 0.01 to 0.78;P = .045) was observed in the fullyadjusted model.

Independent predictors of lower MDIincluded lower birth weight, malegender, less maternal education, andpresence of a definite or suspectedgenetic or extracardiac anomaly (fullmodel in Table 2). The final model forMDI included 1717 subjects from22 centers with an adjusted R2 of27.7% and root mean square errorof 14.2. A statistically significantannual improvement in MDI(0.38 points/year, 95% confidence

TABLE 1 Demographic and Preoperative Characteristics and Neurodevelopmental Outcomes by Cardiac Class

Variable Overall (n = 1770) Class I (n = 878) Class II (n = 114) Class III (n = 106) Class IV (n = 672) P

Demographic and preoperative characteristicsCardiac diagnosis —

TGA/IVS 13.3 26.5 1.8 0 0 —

TGA/VSD 6.8 13.3 3.5 0 0 —

TOF 9.4 18.7 0 1.9 0 —

TOF/PA 1.3 1.8 0 6.6 0 —

TAPVC 3.2 6.3 0 0.9 0 —

VSD without IAA/coarctation 8.4 16.9 0 0 0 —

VSD with IAA/coarctation 3.1 0 47.4 0 0.2 —

AVC defects 3.1 5.4 5.3 0.9 0 —

HLHS 31.0 0 0 0 81.7 —

Other functional single ventricle anomaly 11.5 0 0 76.4 18.2 —

Other 9.0 11.2 42.1 13.2 0 —

Birth weight (kg) 3.2 (0.6) 3.2 (0.7) 3.2 (0.6) 3.1 (0.6) 3.3 (0.5) .10Gestational age (wk) 38.7 (1.9) 38.8 (2.1) 38.9 (1.8) 38.4 (1.7) 38.5 (1.5) ,.001Race ,.001White 84.0 83.7 82.5 76.4 85.9 —

Black 7.6 5.6 9.6 13.2 9.1 —

Other 8.4 10.7 7.9 10.4 5.1 —

Hispanic ethnicity 7.7 4.9 2.6 10.5 11.9 ,.001Female gender 38.5 40.1 44.7 36.8 35.6 .15Maternal education ,.001Graduate school 11.3 11.9 11.4 9.4 10.9 —

Completed college 24.4 26.3 28.9 5.7 24.1 —

High school and/or some college 38.8 38.7 33.3 34.0 40.5 —

Less than high school 8.3 8.5 9.6 3.8 8.5 —

Missing or not specified 17.2 14.6 16.7 47.2 16.1 —

Genetic anomaly ,.001Normal or not specified 85.1 86.9 69.3 93.4 84.2 —

Suspected genetic or major extracardiac 6.6 2.9 6.1 1.9 12.2 —

Definite genetic 8.3 10.3 24.6 4.7 3.6 —

Prenatal diagnosis 38.5 16.1 28.4 49.2 70.0 ,.001Preoperative mechanical ventilation 35.2 28.6 39.5 41.4 55.1 ,.001Neonate (age #30 d) at time of surgery 71.9 53.1 80.7 53.8 97.8 ,.001

Neurodevelopmental outcomesAge at assessment (mo) 14.5 (3.7) 14.4 (3.9) 15.6 (5.2) 14.3 (4.0) 14.6 (3.1) ,.001BSID-IIPDI 77.6 (18.8) 80.6 (18.3) 79.2 (20.3) 76.3 (17.8) 73.7 (18.7) ,.001#85 63.5 57.7 62.9 73.8 69.4 ,.001#70 36.8 30.0 31.4 36.9 46.4 ,.001

MDI 88.2 (16.7) 88.3 (16.1) 86.0 (17.3) 90.5 (14.8) 88.0 (17.6) .24#85 36.1 34.8 40.4 26.4 38.7 .05#70 15.3 13.8 20.2 12.3 17.0 .12

Values are expressed as % or mean (SD). Missing ,10% of sample except prenatal diagnosis (n = 1541) and preoperative mechanical ventilation (n = 1305). P values were determined byx2 tests for categorical variables and Kruskal–Wallis tests for continuous variables except the BSID measures, for which analysis of variance was used. Class I, 2 ventricles with no aorticarch obstruction; Class II, 2 ventricles with aortic arch obstruction; Class III, single ventricle with no arch obstruction; and Class IV, single ventricle with arch obstruction. AVC,atrioventricular canal; IAA, interrupted aortic arch; TAPVC, total anomalous pulmonary venous connection.

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interval 0.05 to 0.71; P = .02) wasobserved in the fully adjusted model.Interestingly, gestational age, prenataldiagnosis, and neonatal status werenot significantly associated withPDI or MDI after adjustment for theother variables in the full models.

A graphical presentation of thestandardized mean PDIs and MDIsbased on a model using year of birthcategories and continuous year ofbirth with the corresponding final setof independent predictors is providedin Fig 2. In addition, relationships ofPDIs and MDIs with the correspondingfinal set of independent predictorswere examined for the homogeneousdiagnostic subgroups (Table 3),including adjustment for VSD in TGApatients and adjustment for PA in TOFpatients. After adjustment for patientfactors, an annual improvement inscores was identified only in the TOFgroup.

DISCUSSION

The past 2 decades have seendramatic improvements in survival ofinfants with complex CHD due toadvances in surgical andperioperative care andmanagement.26 Concomitant withdiminishing early mortality rates,neurodevelopmental disabilities havebeen increasingly recognized ina substantial proportion of survivors.In this project, we aggregatedindividual participant patient factorsand neurodevelopmental outcomedata, measured with the sameinstrument, from existing studies tocreate the largest cohort (.1700subjects) reported to date. The use ofindividual participant data providesthe opportunity for extensive datareview, allows the inclusion ofunpublished data to reducepublication bias, and enables furthersubgroup analyses.12 We sought to

use this unique dataset to determinewhether improvements inneurodevelopmental performancemirrored those of survival.

Mean PDIs and MDIs were lower thanexpected compared with the generalpopulation. In unadjusted analyses,improvements over time were notevident in either motor function (PDI)or cognitive function (MDI). Thecomposition of the cohort changedover the study, with an increasingnumber of patients with morecomplex CHD in the later years, likelyaffecting temporal trends.Nonetheless, we could not identifysignificant improvements in outcomesover time, even when restrictingunadjusted analyses to homogeneousdiagnostic subgroups of TGA, TOF, andHLHS. Similarly, in analyses adjustingfor center and complexity of CHD(ie, foundation models), we did notfind improvement in either PDI or MDIover the study period. In contrast, inmultivariable analyses for the wholecohort, incorporating patient andpreoperative medical risk factors,performance for both PDI and MDIshowed statistically significantimprovements, albeit of modestmagnitude. Interestingly, inmultivariable analyses for thediagnostic subgroups, performanceimproved only for the TOF patients,but not for the TGA or HLHS groups.The absence of improved scores overtime in unadjusted analyses orfoundation models, but increasingscores in multivariable analyses,suggests that more patients at greaterrisk for adverse neurodevelopmentaloutcomes are undergoing congenitalheart surgery and/or that high-riskpatients are more often surviving.

There are several potentialexplanations for this finding. Patientand environmental factors, such asprematurity, genetic syndromes, andsocioeconomic status, may be moreimportant determinants ofneurodevelopmental outcomes thanare operative managementstrategies.7,9,24 Brain development is

FIGURE 1A, Distribution of cardiac class in study cohort by year of birth. Class I, 2 ventricles with no aorticarch obstruction; Class II, 2 ventricles with aortic arch obstruction; Class III, single ventricle with noarch obstruction; and Class IV, single ventricle with arch obstruction. B, Distribution of definite orsuspected genetic or major extracardiac anomalies by year of birth.

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abnormal in children with CHD.Magnetic resonance imaging (MRI)studies in CHD fetuses show smallertotal brain volumes (adjusted for

gestational age and weight) andabnormal brain metabolism, as wellas delayed cortical development andfolding.27–31 At birth, brain

maturation in neonates with HLHS orTGA is delayed by ∼1 monthcompared with a normative sample.29

Postnatal MRI studies have shown

TABLE 2 Multivariable Linear Regression of Psychomotor and Mental Development Index With Patient Risk Factors

Variable PDI MDI

Foundation Model Full Model Foundation Model Full Model

Patients (centers), n 1725 (23) 1675 (22) 1768 (23) 1717 (22)Adjusted R2, % 13.3 24.3 10.0 27.7Root MSE 17.5 16.2 15.8 14.2Year of birthb-estimate (P) 0.31 (.14) 0.39 (.045) 0.27 (.15) 0.38 (.02)95% CI 20.10 to 0.72 0.01 to 0.78 20.10 to 0.63 0.05 to 0.71

Center, P ,.001 ,.001 ,.001 ,.001Cardiac class, P ,.001 ,.001 .002 ,.001I Reference Reference Reference ReferenceIIb-estimate (P) 20.6 (.77) 1.5 (.39) 20.9 (.58) 1.3 (.39)95% CI 24.2 to 3.1 21.9 to 5.0 24.1 to 2.3 21.6 to 4.2

IIIb-estimate (P) 25.3 (.006) 26.1 (.001) 20.2 (.90) 0.03 (.99)95% CI 29.1 to 21.5 29.7 to 22.4 23.6 to 3.2 23.1 to 3.2

IVb-estimate (P) 210.7 (,.001) 211.4 (,.001) 24.1 (,.001) 24.9 (,.001)95% CI 213.1 to 28.3 213.6 to 29.1 26.3 to 21.9 26.8 to 22.9

Birth weight (per kg)b-estimate (P) — 3.21 (,.001) — 4.38 (,.001)95% CI — 1.86 to 4.55 — 3.22 to 5.54

Race, P (.01)White — Reference — —

Blackb-estimate (P) — 4.6 (.003) — —

95% CI — 1.5 to 7.7 — —

Otherb-estimate (P) — 1.4 (.36) — —

95% CI — 21.6 to 4.4 — —

Female genderb-estimate (P) — — — 2.4 (,.001)95% CI — — — 1.0 to 3.8

Maternal education, P ,.001Graduate school — — — ReferenceCompleted collegeb-estimate (P) — — — 21.4 (.26)95% CI — — — 23.8 to 1.0

High school and/or some collegeb-estimate (P) — — — 24.7 (,.001)95% CI — — — 27.0 to 22.4

Less than high schoolb-estimate (P) — — — 26.8 (,.001)95% CI — — — 29.9 to 23.6

Missing or not specifiedb-estimate (P) — — — 24.8 (.003)95% CI — — — 27.9 to 21.6

Genetic anomaly, P — ,.001 — ,.001Normal or not specified — Reference — ReferenceSuspected genetic or major extracardiacb-estimate (P) — 28.3 (,.001) — 28.3 (,.001)95% CI — 211.5 to 25.1 — 211.1 to 25.4

Definite geneticb-estimate (P) — 219.9 (,.001) — 220.8 (,.001)95% CI — 222.9 to 216.9 — 223.4 to 218.2

All characteristics from Table 1 except preoperative mechanical ventilation were considered for inclusion in the models. Coefficients for intercepts and center indicator variables are not reported. MSE,mean square error, with root MSE representing the sample SD of the differences between observed and predicted values. CI, confidence interval.—, variable not included in the corresponding model.

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that white matter injury is evident in 1of 5 infants before cardiacsurgery.32–34 Andropoulos et alshowed that a lower brain maturityscore at birth by MRI is associatedwith greater brain injury in both thepreoperative and postoperativeperiods.33 Beca et al recently reportedthat severity of brain immaturity atbirth predicts the severity ofneurodevelopmental impairment at2 years of age after cardiac surgery ininfancy.34 In addition, von Rhein et alshowed that brain volumes remainsmaller into adolescence and that themagnitude of reduction correlateswith neurodevelopmental outcomes.35

Thus, altered brain development dueto CHD may increase vulnerability toperioperative hemodynamic instabilityand intraoperative brain injury due tohypoxia and ischemia. The lack ofgreater improvement in earlyneurodevelopmental outcomes overthe study period, despitecontemporaneous improvements insurvival, surgical strategies, andperioperative care, thus may be due tothe greater effects of innate patientfactors and abnormal brainmaturation, which outweigh theimpact of modifiable managementfactors in determiningneurodevelopmental outcomes ofchildren with CHD.

In the latter years of the study period,a greater percentage of subjects haddefinite genetic anomalies. Severalfactors may explain this finding. Manyof the early developmental studies incardiac patients specifically excludedthose with identified geneticsyndromes. Additionally, genetictesting has become more prevalent inrecent years and is a routinecomponent of clinical care of complexCHD in many clinical centers. Finally,methods of discerning geneticanomalies have become increasinglysensitive, improving the yield oftesting and potentially exposingabnormal genetic underpinnings toCHD that escape recognition onphysical examination by subspecialistsin genetics. For example, a recentstudy showed pathogenic copynumber variants in $10% of childrenwith single ventricle lesions, onlya minority of whom were noted to bedysmorphic on examination bya clinical geneticist.36 If geneticanomalies were ascertained morefrequently over time in our dataset,adjustment for genetic anomalies mayhave caused us to overestimate theimprovement in outcomes over time.

There are limitations to this analysis.This study is not a formalmetaanalysis. To develop as largea dataset as possible, investigators

were asked to submit both publishedand unpublished data from theirinstitutions. We did not formallyassess the quality of study design andexecution for each study. The trends inscores were examined over a relativelybrief time interval of 14 years, duringwhich the BSID-II was thestandardized neurodevelopment testof choice at many centers. The earliestenrolled patients in our studypostdated some important changes inthe management of cardiopulmonarybypass for infants. Our analyses didnot consider subsequent changes inintraoperative management strategies.We cannot exclude the possibilitythat improvement in MDI in themultivariable analyses may bethe result of the Flynn effect, ie, thefinding that, in the general population,cognitive function assessed byneurodevelopmental test scoresimproves over time by 0.3 to 0.5points per year or ∼5 points perdecade.37 In addition, earlyneurodevelopmental testing haslimited predictive value for laterneurodevelopmental outcomes.38,39

Finally, the data are assembled fromexisting data sets of multiple studies.Some studies were clinical trials andothers were observational studies. Thestudy designs and goals, inclusion andexclusion criteria, and data collectedvaried considerably. Furthermore,characteristics of the subjects in thecombined dataset, such as diagnosisand surgical class, changed over thestudy period. Subjects in later yearshad greater disease severity and weremore likely to have an identifiedgenetic syndrome. All of these factorsmay limit generalizability of the studyinferences. However, the strengths ofthis analysis relate to the substantialsample size, and the findingsrepresent the consolidation of nearlyall published information concerningearly neurodevelopmental outcomesin this population.

CONCLUSIONS

In this analysis of pooled individualparticipant data, early

FIGURE 2Standardized PDI and MDI means by year of birth. The standardized means plot the predicted PDIsand MDIs and SE bars based on a model with year of birth category adjusting for center, cardiacclass, and other statistically significant predictors at the mean value of the covariates. Overlaid arestandardized means plots based on continuous year of birth. The horizontal dotted line representsthe normative mean of 100 for both PDI and MDI.

822 GAYNOR et al

neurodevelopmental outcomes aftercardiac surgery in newborns andinfants are below population meansand, even after adjustment for center

and class, have not significantlyimproved in recent years. Afteradjustment for patient andpreoperative medical factors,

however, both PDI and MDI improvedsignificantly by a modest degree(∼5–6 points over 14 years).Multivariable regression analyses

TABLE 3 Multivariable Linear Regression of Psychomotor and Mental Development Index With Patient Risk Factors for Select Homogeneous DiagnosticSubgroups

Variable TGA TOF HLHS

PDI MDI PDI MDI PDI MDI

Patients (centers), n 324 (9) 334 (9) 174 (8) 179 (8) 541 (20) 549 (20)Adjusted R2, % 13.6 22.9 33.6 37.4 11.5 20.3Root MSE 14.6 12.2 15.1 12.5 17.5 15.6Year of birthb-estimate (P) 0.07 (.87) 0.33 (.35) 1.43 (.04) 1.12 (.0497) 0.48 (.19) 20.11 (.73)95% CI 20.76 to 0.90 20.36 to 1.03 0.07 to 2.79 0.002 to 2.25 20.23 to 1.20 20.74 to 0.51

Center, P ,.001 ,.001 .01 ,.001 ,.001 ,.001Cardiac subclassIntact ventricular septuma

b-estimate (P) 3.6 (.04) 20.8 (.59) — — — —

95% CI 0.1 to 7.1 23.7 to 2.1 — — — —

No pulmonary atresiab

b-estimate (P) — — 9.2 (.01) 3.5 (.24) — —

95% CI — — 2.1 to 16.4 22.4 to 9.4 — —

Birth weight (per kg)b-estimate (P) 2.73 (.07) 3.30 (.007) 2.77 (.13) 4.24 (.006) 2.51 (.09) 4.64 (,.001)95% CI 20.17 to 5.63 0.89 to 5.70 20.84 to 6.38 1.26 to 7.22 20.40 to 5.42 2.05 to 7.24

Race, P .37 — .35 — .03 —

White Reference Reference ReferenceBlackb-estimate (P) 25.0 (.32) — 2.1 (.72) — 4.8 (.10) —

95% CI 214.8 to 4.9 — 29.6 to 13.7 — 20.9 to 10.5 —

Otherb-estimate (P) 2.6 (.34) — 5.9 (.15) — 27.3 (.05) —

95% CI 22.8 to 8.0 — 22.2 to 14.1 — 214.7 to 0.1 —

Female genderb-estimate (P) — 6.4 (,.001) — 1.1 (.58) — 2.6 (.07)95% CI — 3.5 to 9.3 — 22.9 to 5.1 — 25.5 to 0.2

Maternal education, P — ,.001 — .049 — .006Graduate school — Reference — Reference — ReferenceCompleted collegeb-estimate (P) — 23.4 (.19) — 6.0 (.03) — 21.7 (.48)95% CI — 28.6 to 1.7 — 0.5 to 11.5 — 26.6 to 3.1

High school and/or some collegeb-estimate (P) — 29.4 (,.001) — 3.0 (.27) — 26.2 (.007)95% CI — 214.3 to 24.4 — 22.3 to 8.3 — 210.8 to 21.7

Less than high schoolb-estimate (P) — 213.1 (,.001) — 2.3 (.61) — 27.9 (.02)95% CI — 219.2 to 26.9 — 26.6 to 11.3 — 214.3 to 21.5

Missing or not specifiedb-estimate (P) — 26.8 (.03) — 213.0 (.10) — 26.8 (.02)95% CI — 213.0 to 20.5 — 228.5 to 2.5 — 212.5 to 21.1

Genetic anomaly, P .01 ,.001 ,.001 ,.001 ,.001 ,.001Normal or not specified Reference Reference Reference Reference Reference ReferenceSuspected genetic or major extracardiacb-estimate (P) 216.8 (.03) 213.8 (.03) 218.6 (.005) 222.4 (,.001) 27.9 (,.001) 26.8 (.001)95% CI 231.7 to 22.0 226.2 to 21.4 231.4 to 25.8 233.1 to 211.6 212.6 to 23.3 210.9 to 22.7

Definite geneticb-estimate (P) 223.2 (.03) 228.3 (,.001) 222.6 (,.001) 220.3 (,.001) 218.5 (,.001) 221.5 (,.001)95% CI 244.2 to 22.3 242.6 to 214.1 229.8 to 215.5 225.9 to 214.6 227.4 to 29.5 229.2 to 213.7

CI, confidence interval; MSE, mean square error, with root MSE representing the sample SD of the differences between observed and predicted values. —, variable not included in thecorresponding model.a In comparison with ventricular septal defect.b In comparison with pulmonary atresia.

PEDIATRICS Volume 135, number 5, May 2015 823

showed that patient factors (race,gender, birth weight, geneticanomalies, type of CHD, and maternaleducation) are important

determinants of neurodevelopmentaloutcomes. To the extent that subjectsin this study reflect true temporaltrends, these data suggest that more

high-risk CHD infants are undergoingcardiac surgery and surviving, creatinga growing population that will requiresignificant societal resources.

Mr Stopp and Dr Wypij coordinated and created the pooled data set and carried out the analyses; Drs Gaynor and Newburger drafted the initial manuscript; and all

authors reviewed and revised the manuscript and approved the final manuscript as submitted.

www.pediatrics.org/cgi/doi/10.1542/peds.2014-3825

DOI: 10.1542/peds.2014-3825

Accepted for publication Feb 24, 2015

Address correspondence to J. William Gaynor, MD, Division of Cardiothoracic Surgery, The Children’s Hospital of Philadelphia, 34th and Civic Center Blvd,

Philadelphia, PA 19104. E-mail: [email protected]

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

Copyright © 2015 by the American Academy of Pediatrics

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

FUNDING: This pooled data analysis project was funded by a grant from the Mend-a-Heart Foundation. The Kostin Family Innovation Fund supplied partial support

for Mr Stopp. Individual studies that contributed data were funded by grants from the American Heart Association (9950480N, 0365018Y), Auckland Medical

Research Fund, Australia and New Zealand Intensive Care Society, Canadian Institutes of Health Research (MOP93780), CReFF (Clinical Research Feasibility Fund)

Grant, Children’s National Medical Center Board of Visitors Grant, Doris Duke Foundation, Ethel Brown Foerderer Fund for Excellence, Farb Family Fund, Food and

Drug Administration’s Office of Orphan Products Development, Green Lane Research and Education Fund, Heart Foundation of New Zealand, Internal Children’s

National Medical Center Grants, Larry L. Hillblom Foundation (2002/3E), March of Dimes Foundation (5-FY2005-1231, 6-FY2009-303), Mercator Foundation Switzerland,

Murdoch Children’s Research Institute, National Center for Research Resources (RR01271, RR02172), National Heart Foundation of Australia, National Heart, Lung,

and Blood Institute (HL41786, HL063411, HL068269, HL068270, HL068279, HL068281, HL068285, HL068288, HL068290, HL068292, HL085057), National Institute of Child

Health and Development (HD18655, HD055501), National Institute of Neurologic Disorders and Stroke (NS35902, NS40117, NS063876), and Prince Charles Hospital

Foundation.

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

COMPANION PAPER: A companion to this article can be found on page 926, and online at www.pediatrics.org/cgi/doi/10.1542/peds.2015-0719.

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PEDIATRICS Volume 135, number 5, May 2015 825

DOI: 10.1542/peds.2014-3825; originally published online April 27, 2015; 2015;135;816Pediatrics

(ICCON) InvestigatorsNewburger and for the International Cardiac Collaborative on Neurodevelopment

Lara S. Shekerdemian, Anne Synnes, Ismee Williams, David C. Bellinger, Jane W. McQuillen, Shaji C. Menon, Victoria L. Pemberton, Nancy A. Pike, Christian Pizarro,

Jacobs, Robert Justo, Beatrice Latal, Jennifer S. Li, William T. Mahle, Patrick S. Ghanayem, Caren S. Goldberg, Hedwig Hövels-Gürich, Fukiko Ichida, Jeffrey P.Atallah, Andrew M. Atz, John Beca, Mary T. Donofrio, Kim Duncan, Nancy S. J. William Gaynor, Christian Stopp, David Wypij, Dean B. Andropoulos, Joseph

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DOI: 10.1542/peds.2014-3825; originally published online April 27, 2015; 2015;135;816Pediatrics

(ICCON) InvestigatorsNewburger and for the International Cardiac Collaborative on Neurodevelopment

Lara S. Shekerdemian, Anne Synnes, Ismee Williams, David C. Bellinger, Jane W. McQuillen, Shaji C. Menon, Victoria L. Pemberton, Nancy A. Pike, Christian Pizarro,

Jacobs, Robert Justo, Beatrice Latal, Jennifer S. Li, William T. Mahle, Patrick S. Ghanayem, Caren S. Goldberg, Hedwig Hövels-Gürich, Fukiko Ichida, Jeffrey P.Atallah, Andrew M. Atz, John Beca, Mary T. Donofrio, Kim Duncan, Nancy S. J. William Gaynor, Christian Stopp, David Wypij, Dean B. Andropoulos, Joseph

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Supplemental InformationSUPPLEMENTAL TABLE 4 International Cardiac Collaborative on

Neurodevelopment (ICCON) Centers and Investigators

Alfred I. Dupont Hospital for Childrena,b

Christian PizarroErica Sood

Boston Children’s Hospitala,c

David C. BellingerCarolyn Dunbar-MastersonRichard A. JonasJane W. NewburgerChristian StoppDavid Wypij

Children’s Healthcare of Atlantaa,b

Dawn IlardiWilliam T. Mahle

Children’s Hospital Los Angelesa

Alan B. LewisNancy A. Pike

Children’s Hospital of Philadelphiaa

Judy BernbaumRobert R. ClancyJ. William GaynorMarsha GerdesGil WernovskyElaine H. Zackai

Children’s Hospital and Medical Center, Omahaa,b

Carman DeMareKim DuncanHoward Needelman

Children’s National Medical Centera

Mary T. DonofrioPenny GlassRichard A. JonasKami B. Skurow-Todd

Cincinnati Children’s Hospital Medical Centera

Duke University Medical Centera

Jennifer S. LiThe Hospital for Sick Children, Torontoa

Johns Hopkins All Children’s Heart Institutea

Jeffrey P. JacobsMedical College of Wisconsina,b

Cheryl L. BrosigNancy S. GhanayemKathleen A. Mussatto

Medical University of South Carolinaa

Andrew M. AtzMott’s Children’s Hospitala

Caren S. GoldbergRichard G. Ohye

Pediatric Heart NetworkGail PearsonVictoria L. Pemberton

New York-Presbyterian Morgan Stanley Children’s Hospital of New Yorka

Ismee WilliamsPrimary Children’s Medical Centera

Shaji C. MenonRoyal Children’s Hospital, Melbourneb

Julia GunnLara S. ShekerdemianMichelle Goldsworthy, RN

PEDIATRICS Volume 135, Number 5, May 2015 SI1

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SUPPLEMENTAL TABLE 4 Continued

Starship Children’s Hospital, Aucklandb

John BecaStollery Children’s Hospital and the Western Canadian Complex Pediatric Therapies Follow-up Programa,b

Joseph AtallahIvan M. RebeykaCharlene M.T. Robertson

Texas Children’s Hospitalb

Dean B. AndropoulosMarie TurcichRobert Voigt

Toyama University Hospitala,b

Keijiro IbukiFukiko IchidaMie MatsuiTachiyo Matsuzaki KakimotoNaoki Yoshimura

University Children’s Hospital, Zuricha

Ingrid BeckWalter KnirschBeatrice Latal

University of British Columbia, Vancouvera

Anne SynnesUniversity of California, San Franciscoa,b

Patrick S. McQuillenSteven P. Miller

University of Queensland, Brisbanea

P.B. ColditzRobert JustoD.R. Robertson

University of Texas Southwestern Medical Centera

University Hospital, AachenHedwig Hövels-Gürich

a BSID, second edition.b Bayley Scales of Infant and Toddler Development, third edition.c BSID, first edition.

SI2 GAYNOR et al

SUPPLEMENTAL TABLE 5 Patient and Demographic Factors

Variable Definition

Cardiac class Class I: Two ventricle/no arch obstructionClass II: Two ventricle/arch obstructionClass III: Single ventricle/no arch obstructionClass IV: Single ventricle/arch obstruction

Cardiac diagnosis d-Transposition of the great arteries with intact ventricularseptum

d-Transposition of the great arteries with ventricular septaldefect

Tetralogy of FallotTetralogy of Fallot with pulmonary atresiaTruncus arteriosusTotal anomalous pulmonary venous connectionVentricular septal defect without interrupted aortic arch andcoarctation

Ventricular septal defect with interrupted aortic arch andcoarctation

Coarctation and arch hypoplasiaAtrioventricular canal defects (partial, transitional, or complete)Pulmonary atresia with intact ventricular septumHypoplastic left heart syndromeOther functional single ventricle anomalyOther cardiac diagnosis

Year of birthBirth weight KilogramsGestational age WeeksRace White

Black/African AmericanOther

Ethnicity Hispanic/Non-HispanicGender Female/maleMaternal education Graduate school

Completed collegeHigh school and/or some collegeLess than high schoolMissing or not specified

Genetic or nongenetic anomaly Normal or anomaly not specifiedSuspected genetic or nongenetic anomalyDefinite genetic anomaly

Description of genetic or majorextracardiac anomaly

Alagille syndromeCHARGE (coloboma, heart defect, atresia choanae, retardedgrowth and development, genital abnormality, and earabnormality)

22q11 deletionsGoldenhar syndromeHolt–Oram syndromeJacobsen syndromeKabuki syndromeNoonan’s syndromeTrisomy 13Trisomy 18Trisomy 21Turner’s syndromeVATER/VACTERL (vertebrae, imperforate anus or anal atresia,cardiac anomalies, tracheoesophageal fistula, renalanomalies, limb anomalies)

Williams syndromeMultiple congenital anomalies, not otherwise specifiedFetal alcohol spectrum disorderAbnormality of genetic testing not otherwise specifiedOther genetic or major extracardiac anomaly

Prenatal diagnosis Yes/noPreoperative mechanical ventilation Yes/no, if onmechanical ventilationwhen taken tooperating room

for surgery

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