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SURVIVAL IN INFANTS WITH DOWN SYNDROME, METROPOLITAN ATLANTA,1979-1998

SONJA A. RASMUSSEN, MD, MS, LEE-YANG WONG, MS, ADOLFO CORREA, MD, PHD, DON GAMBRELL, BS, MSHS,AND J. M. FRIEDMAN, MD, PHD

bjective Factors influencing survival among persons with Down syndrome (DS) are not well understood. We sought tovaluate survival of infants with DS and potential prognostic factors.

tudy design Infants with DS who were born alive during 1979 to 1998 were identified using the Metropolitan Atlantaongenital Defects Program (MACDP), a population-based surveillance system. To document vital status, we used data fromospital records, the National Death Index (NDI), and Georgia vital records. We estimated survival probability using theaplan-Meier product limit method and hazard ratios using a Cox proportional hazards model.

esults Survival probability to 1 year was 92.9% (95% CI: 90.9-94.9) and to 10 years was 88.6% (95% CI: 85.0-92.2).nivariate analysis demonstrated that black maternal race, low birth weight, preterm birth, lower paternal education, presencef heart defects, and presence of other major congenital anomalies were important prognostic factors. After multivariatenalysis, maternal race, presence of heart defects, low birth weight, and an interaction between maternal race and presence ofeart defects were significantly associated with mortality risk.

onclusions A racial disparity is apparent in survival for children with Down syndrome. Further study is needed to elucidateossible reasons for the racial disparity. (J Pediatr 2006;148:806-12)

own syndrome (DS) is the most common identified cause of mental retardation,1 occurring in about 1 in 800 births.2

Several studies have demonstrated improving survival in persons with DS.3-8 Improvement in survival was also impliedby a study using US death certificates; median age at death (used as an estimate of survival) in persons with DS

mproved from 25 years in 1983 to 49 years in 1997.9 However, limited information is available on risk factors for mortality inS. Nearly half of children with DS have a congenital heart defect,4,10 and several studies have shown that infants with DS and

ongenital heart defects are at an increased risk for death.4,6,9,11,12

Other risk factors have also been shown to affect survival. In a cohort of infants withS born in Italy,11 two factors in addition to presence of congenital heart defects were

ound to be independently associated with survival: low birth weight and geographicegion of birth. The authors hypothesized that the disparity by geographic region waselated to differences in the quality of medical care provided in these areas. Another studyxamined infant mortality rates in children with DS born in Israel during two timeeriods, 1979 to 1983 and 1987 to 1991.7 Independent risk factors for infant mortalityncluded health status at birth (presence of other conditions, such as congenital heartefects, gastrointestinal malformations, and perinatal conditions), time period (early timeeriod had higher mortality than the later time period), and the residential arrangementf the infant (infants who had been abandoned at the hospital for nonmedical reasons hadigher infant mortality). In addition to an increased risk among infants with congenitaleart defects, survival in Australian aboriginal children with DS was significantly worsehan in non-aboriginal children.6 The study using US death certificates identified aubstantial racial disparity in mortality among persons with DS, with median age at deathn 1997 of 50 years in whites, 25 years in blacks, and 11 years in other racial groups.9,13

owever, reasons for this racial disparity were not identified.We examined survival in DS using a cohort of infants identified through a popu-

S Down syndromeACDP Metropolitan Atlanta Congenital Defects

NDI National Death Index

From the National Center on Birth Defectsand Developmental Disabilities, Centers forDisease Control and Prevention, Atlanta,Georgia; the Health Investigations Branch,Division of Health Studies, Agency forToxic Substances and Disease Registry, At-lanta, Georgia; and the Department ofMedical Genetics, University of British Co-lumbia, Vancouver, Canada.

The findings and conclusions in this manu-script are those of the authors and do notnecessarily represent the views of the Cen-ters for Disease Control and Prevention.

Submitted for publication Jun 2, 2005; lastrevision received Oct 24, 2005; acceptedJan 6, 2006.

Correspondence: Sonja A. Rasmussen, MD,Centers for Disease Control and Preven-tion, 1600 Clifton Road, MS E-86, Atlanta,GA 30333. E-mail: skr9@cdc.gov.

0022-3476/$ - see front matter

Copyright © 2006 Elsevier Inc. All rightsreserved.

Program

06

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ation-based surveillance system for the years 1979 to 1998.everal potential risk factors, including race, sex, maternalge, time period of birth, maternal and paternal education,irth weight, gestational age, presence of major cardiac de-ects, and presence of major noncardiac defects were studiedo better understand their impact on DS survival.

METHODSInfants with DS were ascertained using the Metropol-

tan Atlanta Congenital Defects Program (MACDP), anngoing population-based birth defects surveillance system,or the birth years 1979 to 1998. MACDP has conductedurveillance of major birth defects among fetal deaths and livenfants born to women living in the five-county metropolitantlanta area since 1968. Demographic and clinical informa-

ion is collected by trained abstractors from birth and pedi-tric hospitals, cytogenetics laboratories, and a referral centerhat provides services to children with congenital heart de-ects. Additional information on MACDP has been pub-ished previously.14

We used codes based on the ICD-9-CM (758.000-58.090) to identify cases with possible DS. Cytogeneticata were reviewed on all liveborn infants coded as havingrisomy 21. Only infants whose diagnosis was cytogeneti-ally confirmed were included in the analysis. Infants withree trisomy and Robertsonian translocations were in-luded, but infants with mosaicism and those with partialuplication of chromosome 21 were excluded because these

nfants could be more mildly or more severely affected.nfants were classified as having a heart defect if MACDPisted them as having a code for a heart defect (ICD-9-M-based codes 745.000-747.900). Infants with minor

ardiac defects (eg, patent foramen ovale, patent ductusrteriosus, or tricuspid insufficiency) or unconfirmed car-iac defects were not classified as having a heart defect. Welso classified infants according to the presence or absencef major noncardiac structural birth defects, based on in-ormation from MACDP. Defects were defined as “major”f they had surgical, medical, or serious cosmetic impor-ance.15 Microcephaly was excluded as an additional anom-ly because it is not consistently coded in MACDP amongnfants with DS.

Information on metropolitan Atlanta births recordedn the State of Georgia Certificate of Live Birth was obtainedrom the Maternal and Child Health Division, Georgia De-artment of Human Resources. Birth certificate data hadeen previously linked to MACDP using name and date ofirth of mother, father, baby, and when necessary, otherariables. Information on maternal race and maternal andaternal education was obtained from birth certificates. In-ormation on presence of other major congenital anomaliesheart and noncardiac), date of birth, birth weight, and ges-ational age was obtained from MACDP. Maternal age wasalculated from maternal birth date (from birth certificate, orf absent, from MACDP) and infant date of birth (from

ACDP). e

urvival In Infants With Down Syndrome, Metropolitan Atlanta, 1979-19

When possible, we identified deaths using data fromACDP. To identify additional deaths, we linked MACDP

ases with deaths listed in the National Death Index (NDI),centralized index of US death record information for 1979

hrough 1998 compiled by the National Center for Healthtatistics, and finally, with Georgia vital records. The Centersor Disease Control and Prevention’s institutional reviewoard approved linkage of data from MACDP’s surveillanceystem to data from the NDI. Information on the NDI andts matching process have been described elsewhere.16,17 Forersons with trisomy 21 who had no death record inACDP, Georgia vital records, or the NDI, survival was

ensored for the Kaplan-Meier and Cox analyses on Decem-er 31, 1999.

For persons with DS, we estimated the survival prob-bility by the Kaplan-Meier product-limit method 18 for thentire 20-year study period. We also estimated Kaplan-Meierurvival curves for possible prognostic factors, including timeeriod of birth (1979-1984, 1985-1989, 1990-1994, and995-1998), sex, maternal race (white, black, or other), ma-ernal age (�35 years of age vs �35 years of age), maternalnd paternal education (high school vs more than highchool), low birth weight (�2500 g vs �2500 g), pretermirth (�37 weeks vs. �37 weeks gestation), presence/absencef a major heart defect, and presence/absence of a majoroncardiac congenital defect. We used Greenwood’s methodo calculate the 95% CIs for the estimate of the survivalrobability.19 We used the log-rank test (SAS Institute, Cary,C) to examine variation in survival by period of birth and

ther possible prognostic factors.20 We estimated hazard ra-ios and 95% CIs in relation to possible prognostic factors,aking into account other covariates by means of a Coxroportional hazards model.20 Variables associated with palues �.05 in the univariate analysis were included in theox model.

Because race was an important risk factor for morta-ity 9,13 and race is a potential proxy for effect modifiers suchs socioeconomic status, we examined possible modificationf risk of dying associated with certain prognostic factors byaternal race. To this end, we extended the multivariate

educed regression model (ie, the model with prognosticactors that remained significant after adjustment) to includen interaction term between the presence of heart defects andace and evaluated the improvement in fit of the model.21

We also examined data on underlying cause of deathccording to the NDI by race.

RESULTSThere were 692 liveborn cases coded as having DS

scertained by MACDP for the years 1979 to 1998. Of these,7 cases were excluded for the following reasons: cytogeneticesults not available (22), complex rearrangements involvinghromosome 21 (7), mosaicism (16), and not DS (2). Re-aining for analysis were 645 cases. These included 2 casesith 13;21 Robertsonian translocations, 13 with 14;21 Rob-

rtsonian translocations, 16 with 21;21 Robertsonian trans-

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ocations, and 1 with a 21;22 Robertsonian translocation.uring the 20-year follow-up period, we identified 70 deaths

mong 645 liveborn infants (10.9% case-fatality). MACDPecords captured 32 deaths, NDI linkage identified 38 addi-ional deaths, and linkage with Georgia vital records identi-ed no additional deaths.

The survival probability was 92.9% (95% CI: 90.9%-4.9%) to 1 year of age and 88.6% (95% CI: 85.0%-92.2%) to0 years of age (Figure, A). Univariate analysis of survival byelected demographic and clinical characteristics demon-trated that sex, time period of birth, maternal age, andaternal education were not significant predictors (Table I).aternal race was a statistically significant prognostic factor

or survival (Figure, B), with children born to white mothersurviving longer than those born to black mothers. Other

igure. Children with Down syndrome, metropolitan Atlanta, 1979-1998.hite). C, Survival curve by birth-weight group. D, Survival curve by prese

ignificant risk factors for survival were low birth weight d

08 Rasmussen et al

Figure, C), presence of heart defect (Figure, D), presence ofajor noncardiac congenital defects, preterm birth, and lower

aternal education (Table I).Multivariate analysis using a Cox proportional hazards

odel that included all the significant variables from thenivariate analysis yielded a final reduced model in whichaternal race (black vs white), presence of heart defect, low

irth weight, and an interaction between maternal race andresence of a heart defect were significantly associated withhe risk of mortality (Table II). The interaction betweenaternal race and presence of heart defects revealed that: (1)

ompared with children without heart defects born to whiteothers, children with heart defects born to black mothers

xperienced a 10-fold increased risk of dying; (2) childrenith heart defects born to black mothers had a similar risk of

rvival curve (with 95% CI) B, Survival curve by maternal race (black vsmajor heart defect.

A, Su

ying as children with heart defects born to white mothers;

The Journal of Pediatrics • June 2006

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nd (3) children with or without heart defects who were borno black mothers had a similar risk of dying. When thisnalysis was stratified by birth cohort (1979-1989, 1990-998), similar results were obtained for each cohort (data nothown).

NDI data included information on underlying causef death for 69 cases. Congenital heart defects were noteds the underlying cause of death in 50% and 37% of deathsmong infants born to white and black mothers, respec-ively. Infections were noted as the underlying cause ofeath among similar proportions of infants born to whitend black mothers (13% each). “Down syndrome” wasoted as the underlying cause of death among 16% of

nfants born to black mothers and none of the infants born

able I. Survival probability of children with Down selected demographic and clinical characteristics, me

Risk factors Total

ll 645ime period of birth1979–1984 1471985–1989 1511990–1994 1821995–1998 165

nfant’s sexMale 354Female 291aternal raceWhite 355Black 243Other 47aternal age*�35 years 471�35 years 172aternal education†

High school 279More than high school 349

aternal education‡

High school 193More than high school 330

irth weight�2500 g 152�2500 g 493

reterm birth�37 weeks 129�37 weeks 516

resence of heart defectsYes 266No 379

resence of other non-cardiac defectsYes 103No 542

2 observations with missing values for maternal age.17 observations with missing values for maternal education.122 observations with missing values for paternal education.

o white mothers. t

urvival In Infants With Down Syndrome, Metropolitan Atlanta, 1979-19

DISCUSSION

Our study describes survival in persons with DS born inetropolitan Atlanta from 1979 to 1998 and identifies inde-

endent risk factors associated with lower survival. Studytrengths include its population-based ascertainment and theong time period covered. Availability of cytogenetic datallowed us to exclude persons without a cytogenetic diagnosisf trisomy 21, and NDI data supplemented information oneaths from hospital records or Georgia death certificates.DI data have been previously shown to be accurate and to

dentify a high proportion of deaths.22-24

Our study also has several limitations. Persons withrisomy 21 for whom no dates of death were available in our

ome for the 20-year study period, overall and byolitan Atlanta, 1979–1998

No. deaths(mortality

rate)

Survivalprobability %

(95% CI)p

value

70 (10.9) 87.4 (84.3–90.5).9870

18 (12.2) 87.7 (82.4–93.0)19 (12.6) 87.2 (81.8–92.6)19 (10.4) 89.6 (85.1–94.0)14 (8.5) 91.5 (87.3–95.8)

.355242 (11.9) 85.5 (80.8–90.2)28 (9.6) 89.7 (86.0–93.4)

.000424 (6.8) 91.8 (88.2–95.4)41 (16.9) 80.9 (75.3–86.7)5 (10.6) 87.7 (77.2–98.2)

.512050 (10.6) 88.0 (84.6–91.4)20 (11.6) 85.0 (77.9–92.2)

.190836 (12.9) 84.7 (79.4–90.0)33 (9.5) 89.1 (85.5–92.7)

.006829 (15.0) 80.1 (71.8–88.4)25 (7.6) 91.9 (88.8–95.0)

�.000133 (21.7) 76.5 (69.3–83.8)37 (7.5) 90.7 (87.5–94.0)

.016421 (16.3) 82.5 (75.5–89.4)49 (9.5) 88.7 (85.3–92.1)

�.000145 (16.9) 78.9 (71.5–86.2)25 (6.6) 92.6 (89.7–95.5)

.019918 (17.5) 78.3 (65.4–86.8)52 (9.6) 89.4 (86.2–91.9)

yndrtrop

hree sources were assumed to be alive. Although this may be

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ncorrect, the number of deaths missed is likely to be small,iven that the NDI uses several factors for linkage. By lim-ting our study to cytogenetically confirmed Down syndrome,e might have missed infants who died before cytogenetic

pecimens were obtained or whose specimens were sent to aaboratory to which MACDP does not have access. Cytoge-etic confirmation was available on our cases less frequently inhe earliest time period (1979-1984) compared with the laterhree time periods; however, the total number of infants forhom cytogenetic data were unavailable was small. Our anal-sis of causes of death was limited because only underlyingause of death was available through NDI and was listed asDown syndrome” in 16% of infants of black mothers. Be-ause no information was available on residential arrange-ents, child care services, or medical interventions, we were

nable to address whether these factors impacted survival.vailable information on socioeconomic status was limited.

nformation on race and on maternal and paternal educationas available, but additional factors (eg, family income or

ource of payment for medical services) were not. Althoughace has been used as a proxy for socioeconomic status, it is aelatively poor proxy25; use of education as an indicator ofocioeconomic status also has its limitations.26

Some6,27,28 but not all9,11,29 previous studies havehown increased survival for males with DS compared withemales. In our study, no statistically significant difference waseen. Mortality in low birth weight infants with DS wasigher than among those of normal birth weight, even afterdjusting for other factors. Preterm birth was a significantactor on univariate analysis but was no longer significanthen adjusted for other factors.

Previous studies have shown that paternal risk factorseg, education) are associated with some adverse pregnancyutcomes.30,31 Our study showed an association between sur-ival and paternal but not maternal education. One possiblexplanation for this finding is that paternal education is moremportant than maternal education in determining socioeco-omic status,30,31 but this analysis is limited by the fact that

nformation on education was missing for 19% of fathers.

able II. Adjusted hazard ratios* for death in childreetropolitan Atlanta, 1979–1998

Risk factor

irth weight �2500 g (compared with birth weight �2500 g)lack mother compared with white mother, no heart defectsresence of heart defects compared with no heart defects,white motherlack mother � presence of heart defects compared with whitemother and no heart defectslack mother � presence of heart defects compared with whitemother � presence of heart defectslack mother � presence of heart defects compared with blackmother and no heart defects

Adjusted for statistically significant factors on univariate analysis (maternal race, low biower paternal education).

Previous studies have demonstrated a significant im- r

10 Rasmussen et al

rovement in DS survival by time period,6,32,33 and US deathertificate data showed an improvement in median age ateath from 1983 to 1998.9 In contrast, our cohort, bornuring 1979 to 1998, did not show an improvement in sur-ival by time period. Differences between the results of theS death certificate study and our cohort may be related toifferences in methods; the death certificate analysis usededian age at death and included infants born in earlier years,hereas our analysis is based on a cohort born during 1979 to998. In our study, even in the early time period, infantortality was similar to rates observed in later years in other

tudies, and survival in our study was improved when com-ared with an earlier US study.28 Thus, our inability tobserve an improvement in survival in our study may suggesthat the improvement in early survival occurred before ourtudy began.

Our study shows that nearly 90% of children with DSow survive beyond 10 years of age. This study, along withthers, emphasizes the need to ensure that appropriate med-cal, residential, social, and community services are availableor adults with DS.34 In addition, our study confirms theacial disparity in DS mortality observed in a recent study9,13;owever, the reasons for this racial disparity remain unknown.n our study, presence of a heart defect is a significant riskactor among persons with DS whose mothers are white butot among those whose mothers are black. An increased riskf mortality among blacks compared with whites has beeneported for several birth defects,35,36 and for DS in particu-ar.9,13 In addition, congenital heart defects are known to bessociated with an increased risk of mortality, especiallymong black children.37 We observed that black maternalace was associated with a statistically significant sevenfoldncrease in the risk of dying, but only among children withouteart defects. Similarly, the presence of a heart defect wasssociated with a statistically significant eightfold increase inhe risk of dying, but only among children of white mothers.he reasons for this interaction are unknown. Differences inuality of care, hypothesized to be a prognostic factor in arevious study,11 might explain the observed differences by

ith Down syndrome by selected risk factors,

Adjusted hazard ratio 95% CI

2.91 1.77–4.787.39 2.51–21.758.17 2.79–23.94

10.34 3.53–30.29

1.27 0.68–2.34

1.40 0.75–2.60

ight, presence of heart defect, presence of major noncardiac defects, preterm birth, and

n w

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ace. One possible explanation for the interaction is that

The Journal of Pediatrics • June 2006

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aternal race could be associated with reduced access to orse of specialized health services, such as pediatric cardiologyervices38 or specialized DS clinics. If children of black moth-rs are less likely to have major heart defects diagnosed andreated, then such children would be at increased risk of dyingf serious heart defects without their being recognized as aause of death or important comorbidity. In this scenario, therognostic significance of heart defects would be appreciatednly among children whose defects had been properly diag-osed. Possible underascertainment of congenital heart de-ects among blacks has been suggested in a study of a subsetf the population included in our study 10 as well as in a reportrom the Baltimore-Washington Infant Study.39 In the At-anta study, infants with Down syndrome who had black

others were twice as likely as infants of white mothers toave no information available on cardiac defects, althoughhis difference was not statistically significant.10 Our data alsorovide some support for this hypothesis: 39% of childrenorn to black mothers, compared with 52% of infants born tohite mothers, had a recognized major congenital heart de-

ect.Further study of factors associated with survival may

elp improve the care of persons with DS. Future studieshould include information on socioeconomic status, residen-ial arrangements, and access to specialized medical care,ospitalizations, and surgery to define factors that may con-ribute to decreased survival.

cknowledgments are available at www.jpeds.com.

REFERENCES. Bundey S. Abnormal mental development. In: Rimoin DL, ConnorM, Pyeritz RE, eds. Emery and Rimoin’s Principles and Practice of Medicalenetics. New York: Churchill Livingstone; 1997.

. National Birth Defects Prevention Network. Birth defects surveillanceata from selected states, 1996-2000. Birth Defects Res Part A Clin Moleratol 2003;67:729-818.

. Baird PA, Sadovnick AD. Life expectancy in Down syndrome adults.ancet 1988;2:1354-6.. Frid C, Drott P, Lundell B, Rasmussen F, Anneren G. Mortality inown’s syndrome in relation to congenital malformations. J Intellect Disabiles 1999;43:234-41.. Hayes C, Johnson Z, Thornton L, Fogarty J, Lyons R, O’Connor M,t al. Ten-year survival of Down syndrome births. Int J Epidemiol997;26:822-9.. Leonard S, Bower C, Petterson B, Leonard H. Survival of infants bornith Down’s syndrome: 1980-96. Paediatr Perinat Epidemiol 2000;14:163-71.. Sadetzki S, Chetrit A, Akstein E, Luxenburg O, Keinan L, Litvak I, etl. Risk factors for infant mortality in Down’s syndrome: a nationwide study.aediatri Perinat Epidemiol 1999;13:442-51.. Frid C, Drott P, Otterblad Olausson P, Sundelin C, Anneren G.aternal and neonatal factors and mortality in children with Down

yndrome born in 1973-1980 and 1995-1998. Acta Paediatr004;93:106-12.. Yang Q, Rasmussen SA, Friedman JM. Mortality associated withown’s syndrome in the USA from 1983 to 1997: a population-based study.ancet 2002;359:1019-25.0. Freeman SB, Taft LF, Dooley KJ, Allran K, Sherman SL, Hassold TJ,t al. Population-based study of congenital heart defects in Down syndrome.

m J Med Genet 1998;80:213-7. T

urvival In Infants With Down Syndrome, Metropolitan Atlanta, 1979-19

1. Mastroiacovo P, Bertollini R, Corchia C. Survival of children withown syndrome in Italy. Am J Med Genet 1992;42:208-12.

2. Castilla EE, Rittler M, Dutra MG, Lopez-Camelo JS, Campana H,az JE, et al. Survival of children with Down syndrome in South America.CLAMC- Downsurv Group. Latin American Collaborative Study of Con-enital Malformations. Am J Med Genet 1998;79:108-11.3. Centers for Disease Control and Prevention. Racial disparities in me-ian age at death of persons with Down syndrome—United States, 1968-997. MMWR Morb Mortal Wkly Rep 2001;50:463-5.4. Correa-Villasenor A, Cragan J, Kucik J, O’Leary L, Siffel C, Williams. The Metropolitan Atlanta Congenital Defects Program: 35 years of birthefects surveillance at the Centers for Disease Control and Prevention. Birthefects Res Part A Clin Mol Teratol 2003;67:617-24.

5. Rasmussen SA, Olney RS, Holmes LB, Lin AE, Keppler-NoreuilM, Moore CA. Guidelines for case classification for the National Birthefects Prevention Study. Birth Defects Res A Clin Mol Teratol

003;67:193-201.6. Wentworth DN, Neaton JD, Rasmussen WL. An evaluation of theocial Security Administration master beneficiary record file and the Nationaleath Index in the ascertainment of vital status. Am J Public Health

983;73:1270-4.7. National Center for Health Statistics. National Death Index User Man-al. Hyattsville, Md: National Center for Health Statistics; 2000.8. Kaplan EL, Meier P. Nonparametric estimation from incomplete ob-ervations. J Am Statist Assn 1958;53:457-81.9. Greenwood M. The natural duration of cancer. Reports on the Publicealth and Medical Subjects 1926;33:1-26.

0. Cox DR, Oakes D. Analysis of Survival Data. London: Chapman andall; 1984.

1. Schwartz G. Estimating the dimensions of a model. Ann Stat978;6:461-4.2. Rich-Edwards JW, Corsano KA, Stampfer MJ. Test of the Nationaleath Index and Equifax Nationwide Death Search. Am J Epidemiol

994;140:1016-9.3. Boyle CA, Decoufle P. National sources of vital status information:xtent of coverage and possible selectivity in reporting. Am J Epidemiol990;131:160-8.4. Lash TL, Silliman RA. A comparison of the National Death Index andocial Security Administration databases to ascertain vital status. Epidemi-logy 2001;12:259-61.5. Kawachi I, Daniels N, Robinson DE. Health disparities by race andlass: why both matter. Health Aff (Millwood) 2005;24:343-52.6. Arispe IE, Holmes JS, Moy E. Measurement challenges in developinghe national healthcare quality report and the national healthcare disparitieseport. Med Care 2005;43:I17-23.7. Glasson EJ, Sullivan SG, Hussain R, Petterson BA, Montgomery PD,ittles AH. Comparative survival advantage of males with Down syndrome.m J Human Biol 2003;15:192-5.

8. Fabia J, Drolette M. Life tables up to age 10 for mongols with andithout congenital heart defect. J Ment Defic Res 1970;14:235-42.9. Dupont A, Vaeth M, Videbech P. Mortality and life expectancy ofown’s syndrome in Denmark. J Ment Defic Res 1986;30:111-20.

0. Parker JD, Schoendorf KC. Influence of paternal characteristics on theisk of low birth weight. Am J Epidemiol 1992;136:399-407.1. Hessol NA, Fuentes-Afflick E, Bacchetti P. Risk of low birth weightnfants among black and white parents. Obstet Gynecol 1998;92:814-22.2. Record RG, Smith A. Incidence, mortality, and sex distribution ofongoloid defectives. Brit J Prev Soc Med 1955;9:10-5.

3. Merrick J. Down syndrome in Israel. Downs Syndr Res Pract001;6:128-30.4. Bittles AH, Glasson EJ. Clinical, social, and ethical implications ofhanging life expectancy in Down syndrome. Dev Med Child Neurol004;46:282-6.5. Petrini J, Damus K, Russell R, Poschman K, Davidoff MJ, Mattison D.ontribution of birth defects to infant mortality in the United States.

eratology 2002;66(suppl 1):S3-6.

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6. Berger KH, Zhu BP, Copeland G. Mortality throughout early child-ood for Michigan children born with congenital anomalies, 1992-1998.irth Defects Res Part A Clin Mol Teratol 2003;67:656-61.7. Boneva RS, Botto LD, Moore CA, Yang Q, Correa A, Erickson JD.ortality associated with congenital heart defects in the United States: trends

nd racial disparities, 1979-1997. Circulation 2001;103:2376-81.

12 Rasmussen et al

egional racial and ethnic differences in mortality for congenital hearturgery in children may reflect unequal access to care. Pediatr Cardiol003;24:103-8.9. Correa-Villasenor A, McCarter R, Downing J, Ferencz C. White-lack differences in cardiovascular malformations in infancy and socioeco-omic factors. The Baltimore-Washington Infant Study Group. Am J Epi-

8. Gonzalez PC, Gauvreau K, Demone JA, Piercey GE, Jenkins KJ. demiol 1991;134:393-402.

50 Years Ago in The Journal of PediatricsTREATMENT OF WILMS’ TUMOR

Ng E, Low-Beer B. J Pediatr 1956;49:763-769

In this report, the authors described the clinical features, management, and outcome of a small series of 9 children withWilms’ tumor and reviewed the prior literature. Wilms’ tumor was one of the few childhood cancers which could be curedin the 1950s employing surgery and radiation therapy. The authors reported their success using these strategies, yet whatis noteworthy in this paper is that there is no mention of chemotherapy as the third important treatment modality forthese children. This unintentional oversight suggests that the authors were unaware of work then going on in Boston andfirst reported later in 1956 showing for the first time dramatic resolution of pulmonary metastases in children withWilms’ tumor treated with a new DNA-intercalating agent called Actinomycin D (dactinomycin). This discoveryrevolutionized the treatment of childhood cancer. Prior to that, chemotherapy had been used only for children withleukemia and only hesitantly as single agents and in low doses, resulting in few if any cures. But Dr. Sidney Farber andhis colleagues in Boston and elsewhere recognized that the principles guiding the exploration of chemotherapy in childrenwith leukemia should logically apply to rapidly growing solid neoplasms (such as Wilms’ tumor) as well.1 Shortlyfollowing these initial investigative forays 50 years ago, a firm foundation for the field of pediatric oncology wasestablished, with the realization by the National Cancer Institute that multicenter collaborative clinical trials werenecessary and that a combination of therapeutic agents rather than single drugs was required to overcome drug resistanceand eradicate the tumor. Overall cure rates of Wilms’ tumor now approach 90% in the Western world. Having come thisfar, we owe a great deal to the pioneers of the 1950s such as Drs. Ng and Low-Beer who used existing treatment methods(surgery and radiation) to salvage many of these children.

George R. Buchanan, MDThe University of Texas

Southwestern Medical Center at DallasDallas, Texas 75390

YMPD218810.1016/j.jpeds.2006.04.021

REFERENCE1. Farber, S. Chemotherapy in the treatment of leukemia and Wilms’ tumor. JAMA 1966;198:826.

The Journal of Pediatrics • Month 2006

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ACKNOWLEDGMENTSThe authors wish to acknowledge Dr. Quanhe Yang for

is helpful discussions about this study, Dr. Leslie O’Learyor her assistance in obtaining additional information on

ACDP study patients, and Chenxing Lu for her helpful

ssistance in analyzing interactions. In addition, the authors v

urvival In Infants With Down Syndrome, Metropolitan Atlanta, 1979-19

ish to acknowledge MACDP staff members: Debra Adams,ran Baxter, Jo Anne Croghan, Joann Donaldson, Joan Gar-ia, Debbie Nurmi, Mary Kathryn Peecher, Charlie Maeeters, Wendy Sklenka, Carolyn Sullivan, Karen Thornton,nd Tineka Yowe. Their constant data collection efforts pro-

ide the foundation on which MACDP is built.

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