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## L®w°L®w® B Fdftul l L@®<3 in[p)©iyir ®

ivf?@©f t ©o n

Kit e M

. P6©teD©lh , FW 9 KgrWaxgci i Cfl

. KofatKrS , PUnD , Ksfeom l L ll!@m8d)ii©flifii , PW , ^M O 1

. IrteBiramfrmsil , I ©lan)©! ? ©©PD©!? , RflGD , Por J A

. Soi!(g(g®(p 9 HA , m& l^kacrSrSHrns a ©5©r , © A
Fro m the Department

of Environmental

Health, University

ot Cincinnati

College of Medicine, Cincinnati

AUSTIMGT
. A prospectiv e metho dwa s usedin thi s stud

y t o asses s th e effect

s o f feta l lea dexposur e o n neurode

velopmenta

l statu s in 3

- an d6-mont h ol dinfants

. A

t thei r firs t prenatal medica

l appointments , 30

5 lowe r so cioeconomi

c statu s wome

n residin g in predesignate dlead

hazardou s area s o

f Cincinnat i wer e recruited

. Lea

dwas measuredin whol

e bloodin bot

h th e mothe

r andfeto

placenta l uni t (prenata l an dcord ) an dth e neonat

e (ten day s an d3 months)

. Al

l bloodlea dlevel s wer

e les s tha n 3 0 pg/dL

. Infant

developmen

t wa s assessedwit

h the * Bayle y scale s a t 3 an d6 month s o

f age . Multipl e regres- > sio n analyse s whic

h treate dperinatal healt

h factors suc

h a s birth weigh

t an dgestatio n a s confounder s indicate d a n independent , invers e relationship betwee n bot h pre nata l an dneonata

l bloodlea dlevel s an dperformanc e o

n th e Bayle y Menta l Developmenta

l Inde x a t bot h ages . Mal e infant s an dinfant s fro

mth e poores t

familie s ap peare dt o b e especiall

y sensitiv e t o thes e psychoterato

geni c influences

. Further

stud y using astructural equation s approach indicate dtha t neurobehaviora

l deficit s wer e partl y mediatedb

y lead-relate dreduction s i

n birt h weigh t an dgestation

. Pediatrics 1987;80:721-730 ; lead, fetal development, behavior, sex differences, teratology.

ABSS^VIIATOJWS

. MDI , Mental Developmenta l Imfes ; HOME , Home Observation fo

r Measuremento

f th e Environment ; PDI , Psychomoto r Developmental Indss .
I t ha s lon g bee n recognize dtha t lea da t hig h dose s i s a n abortifacien t an dpotentia l terato
gen. 1 ' 3 Lea di s know n t o cros s th e huma n placent a an daccru e i n feta l tissue s durin g gestation. 4 Con

Received for publicatio n Jo n 15,1987 ; accepte d Marc h 13,1987 . Reprin trequest s to (K.ND. ) Ketterin g Laboratory , Universit y o f Cincinnat

i Medica l Center , 322 3 Ede n Ave , Cincinnati , O H 45267-0056 . PEDIATRIC S (ISS N 003 1 4005) . Copyrigh t© 198 7 by th e America n Academ y o f Pediatrics . genita l lea dpoisonin g ha s bee n previousl y reporte d i n neonate s of

wome n workin g i n th e lea dindustr y an di n associatio n wit h th e consumptio n o f non commerciall y produce dspirits. 5 Report s of congen ita l lea dpoisonin g i n infant s fro mthird-worl d countries , wher e lea di s stil l widel y use di n potter y an dcosmetics , continu e t o appear. 6 Today , th e primar y concer n of pediatrician s an d epidemiologist s i s o n level s o f feta l lea dexposur e tha t d o no t normall y resul t

i n miscarriag e o r

ob

viou s neonata l pathologi c conditions

. Ther e i s a growin g bod y o

f dat afro msevera l longitudina l studie s tha t

indicat e tha t

lowe r leve l i n uter o lea d exposur e may b e relate dt o deficit s i n bot h feta l growth an dpostnata l behaviora l development

. Fo r example , Bellinge r

an dhi s colleagues 7 ' 9 i n Bosto n foun dtha t

umbilica l cor dbloo dP b level s o f les s tha n 2 5 -jg/dL were independentl y associate dwit h smal l deficit s i n Bayle y Menta l Developmenta l In

de x (MDI ) a t

6,12 , an d24 month s of

age . I n othe r longitudina l studie s i n Cincinnat i an dPor t Pirie , Australia , lo w leve l feta l lea dexposur e ha s bee n associate dwit h lower

birt h weight, 10,1 1 an dshorte r gestation. 11,1 2 Needlema n an dhi s colleagues 1 3 eval

uate dth e relationshi p betwee n prenata l exposur e t o lea dan dmino r

congenita l anomalie s i n 4,35 4 birth s i n Boston
. Umbilica l cor dbloo dlea dleve l wa s foun dt o b e associated , i n adose-relate dman ner , wit h a n increase dris k for mino r anomalies

. I n thi s paper , w e presen t th e firs t result s of

a majo r longitudina l stud y o

f th e effect s o

f chroni c lo w t o moderat e lea dexposur e o n chil ddevelop

ment. 14 I t wa s hypothesizedtha t

prenata l exposur e t o lead , a s indexe db y maternal , umbilica l cord , an d neonata l bloo dlea dlevels , woul db e relate dt o sen sorimoto r developmenta l deficit s whe n infant s wer e 3 an d6 month s o

f age . I t wa s als o hypothesized tha t Lea d exposur e woul dinterac t wit h othe r

peri

PEDIATRIC S Vol

. 8 0 No

. 5 Novembs r198 7 72 1 iHiAajurn,i i j I.I . IP. 3 

# <'f

nata l ris k factor s suc h a s race , sex , an d socia l class ; thos e fetuse s a thighei j ris k becaus e o f

geneti c o r socia l factor s woul d late r displa y a greate r lead ; relate d behaviora l deficit . Fiffally , i twa s hypothe'- ' size d tha tneurobehaviora l deficit s woul d b e partl y a functio n o f

th e negativ e effec to f prenata l lea d exposur e o n feta l growt h (birt h weight ) an d physi ca l maturatio n (gestationa l ag e a s determine d b y examinatio n o f

th e neonate) . METHOD S Subject s Th e final follow-u p stud y sampl e consiste d o f 30 5 mothers , recruite d betwee n 197 9 an d 1984 , residin g i n predesignate d lead-hazardou s area s o f Cincin nati . Thi s geographica l area ha s a histor y o f havin g a relativel y larg e numbe r o f childre n wit h lea d poisonin g accordin g t o cit y healt h departmen tdata . Result s o f

othe r studie s o n th e Cincinnat i cohor t hav e show n tha tlea d fro m paint , dust , an d gener all y poo r housin g stoc k i s th e majo r contributo r t o bod y burden. 1 5 Informe d consen tfo r participatio n i n th e stud y wa s obtaine d a tprenata l recruitmen t an d agai n a tdeliver y t o obtai n permissio n fo r infan t follow-up . Wome n know n t o b e addicte d t o drugs , alcoholic , o r diabeti c o r thos e wit h prove n neuro logi c disorders , psychoses , o r menta l retardatio n wer e exclude d fro m prenata l recruitment . Exclude d fro m prenata l recruitmen to n thes e base s wer e 48 7 women , an d 2 3 refuse d t o participat e (ie , hav e thei r bloo d sample d fo r lead) . Th e ag e o f enrolle d moth er s a tdeliver y wa s 22. 7 ± 4. 5 year s (mea n ± SD) ; 87 % o f th e mother s wer e single , an d 86 % .wer e o n publi c assistance . Vita l descriptiv e statistic s o n mother s an d infant s i n th e stud y ar e give n i n Tabl e 1 . Infant s o f

les s tha n 3 5 weeks ' gestation , and/o r 1,50 0 g birt h weigh twer e exclude d fro m postnata l recruitment . Furthermore , recruite d infant s mus t hav e ha d a n Apga r scor e o f 6 o r greate r a tfiv e minute s an d hav e n o seriou s medica l conditio n suc h a s Dow n syndrome , phenylketonuria , o r significan t congenita l anomaly . Exclude d fro m postnata l re cruitmen tbase d o n thes e criteri a wer e 7 6 neonates , an d 12 9 familie s refuse d th e 5-yea r postnata l fol low-up . Stud y infant s ha d a mea n birt h weigh to f 3,134. 6 g (S D 462.8 ) an d mea n gestationa l ag e b y physica l examination 1 6 o f 39. 5 week s (S D 1.7) . Ex amination s fo r gestationa l ag e wer e conducte d b y Universit y Hospita l resident s wh o wer e traine d b y J . L . Ballard , MD , th e autho r o f th e protocol . Interexamine r reliabilit y studie s wer e no tcon ducte d fo r th e purpos e o f th e presen tstudy . How ever , th e Ballar d gestatio n estimat e appeare d t o hav e excellen tpredictiv e validit y give n th e stron g TABL E 1 . Descriptiv e Statistic s o n Stud y Sampl e Variabl e Mea

n S D Lo w Hig h J Materna

l age (yr) Social class * Home Observation fo

r Measurementof

th e Environment

2 4 score t No . o f childre n i n home % unmarried Birt h wt(g) Gestational ag

e (wk) $ 5-mi n Apga

r score % blac k % girl s 22. 7 17. 2 31. 5
2. 6 4. 5 5. 4 4.7
1. 5 87. 0 3,134. 6 39. 5 8. 9 462. 8 1. 7 0. 4 84. 9 49. 8 1 5

8 1 7
1 1,81 4 3 5 7 3 9 5 0 4 2
6 4,40 0 4 3 9

* Hollingshea d Four-Facto r Inde x of Social Status. 2 3 tScore s o

f 3 0 o r les s ar e considere d poor . t A s assesse d by standardize d physical examinatio n o f th e neonate. 1 *

an d highl y significan tassociation s wit h menta l an d moto r developmenta l outcome s a t3 an d 6 month s o f age . Descriptiv e statistic s o n mother s an d infant s wh o wer e exclude d fro m th e stud y b y prenatal/postnata l criteri a o r refusa l t o participat e ar e give n i n Tabl e 2 . A compariso n o f

Table s 1 an d 2 sho w tha tstud y dyad s an d exclude d dyad s wer e simila r i n term s o f suc h ke y sociodemographi c variable s a s materna l age , marita l status , an d gravidity . A s on e woul d expect , exclude d neonate s ha d lowe r birt h weights , "gestationa l ages , an d Apga r scores . Ther e wa s als o ' a highe r tendenc y fo r whit e and/o r marrie d familie s t o refus e stud y participation . Assessmen t o f Potentia l Confounder s an d Covariate s Undu e lea d exposur e i s know n t o covar y wit h a numbe r o f

socia l an d biologi c risk s tha tma y mimic , obscure , o r otherwis e interac twit h th e effect s o f toxican texposur e o n chil d development. 17 " 2 0 There fore , a substantia l amoun to f medica l an d socia l backgroun d dat a wer e collecte d o n al l subjects . Th e candidat e confounder s an d covariate s tha twer e selecte d a prior i base d upo n thei r theoretica l and / o r know n empirica l associatio n wit h bot h th e targe t independen tvariabl e (feta l lea d exposure ) and/o r targe tdependen tvariabl e (3 - an d 6-mont h neuro developmenta l status ) ar e liste d i n Fi g 1 . Obstetrica l histor y an d pertinen tperinata l dat a wer e recorde d fro m th e mother' s an d neonate' s charts . Thes e dat a wer e the n code d usin g th e Litt man-Parmele e Obstetrica l an d Postnata l Compli cation s Scales. 2 1 A Composit e Inde x o f Tobacc o an d Alcoho l Consumption , take n fro m th e Proble m Oriented , Perinata l Ris k Assessmen tSystem 2 2 wa s als o used . Th e Composit e Inde x o f Tobacc o an d Alcoho l Consumptio n variabl e wa s dichotomousl y
72 2 FETA L LEA D EXPOSUR E

# IF. Ii * • '

TAEU

E 2 . Descriptiv e Statistic s o n Mother s an d Infant s Exclude d Fro m Stud y Variable/Group Materna l Exclusion s Neonatal

Exclusion s Refusal s Abortions Stillbirth s No . % blac k % unmarried Materna l age (mean yr ± SD ) Gravidit y (mean No . ± SD ) Birth w t(mean g ± SD ) 5-min Apga

r scor e (mean ± SD ) Gestational age b

y examination 1 9 (mean w k ± SD ) 48 7 7 1 7 9 21. 7 ± 5. 9 1. 7 ± 1. 9 3,09 7 ± 57 2 8. 7 ± 0. 9 38. 9 ± 2.7 7 6

8 0 7 9 22. 9 ± 5. 8 2. 1 ± 2. 0 2,20 4 ±89 2 7. 5 ± 2. 5 34. 9 ± 4. 6 152

6 4 6 2 22. 4 ± 4. 1 1. 7 ± 1. 6 3,23 7 ± 49 7 8. 8 ± 0. 6 39. 4 ± 1. 7 43 7 6 7 9 23. 2 ± 5. 8 1. 4 ± 1. 4 16 1 ±0 4 15. 6 ± 0. 5 1 0

6 7 100 19. 9 ± 5. 1 0. 9 ± 1. 2 1^4 6 ±78 9 29. 0 ± 6. 6

i: Perinatal Variables

Birt h w t Gestational afj

a by examinatio n Obstetrica

l Complication s Scal e Postnata l Complication s Scal e Composit e Inde x o f Tobacco an d Alcohol Consump tio n No . o f cigarette s smoked pe r da y Materna l ag e atbirt h o f chil d Gravidit y Parit y Materna l total iron-bindin g capacit y Rac e o f chil d Sa x o f chil d Sociohereditar

y Variables Socioeconomi c statu s Developmenta

l Stimulatio n (Hom e Observation fo r Measuremen

to f th e EnvironmentScale ) No . o f children i n th e hom e
Fi g 1 . Candidat e confounder s and/o r covariates . code dwit h avalu e o f

"1 " indicatin g us e of

tobacco and/o r alcoho l durin g pregnancy . Us e of thes e sub

stance s durin g th e prenata l perio dwa s reporte db y 58 % of stud y mothers

. Informatio n wa s als o gath

ere dthroug h prenata l intervie w o n th e averag e numbe r o f cigarette s smoke dpe r

da y durin g preg nancy . Mos t

smokin g wome n (98% ) reporte dcon sumptio n o

f on e pac k

(2 0 cigarettes ) o r

non e pe r day

. Forty-seve n percen t of th e cohor t

wer e non smokers

. Ther e wa s n o evidenc e o f alcoholis mo r drug-addictio n durin g an y o f th e sampl e pregnan cies

. Th e socioeconomi c statu s of th e infant' s famil y wa s assesse da t

3 month s postpartu mwit h th e Hollingshead 2 3 four-Facto r Inde x o f Socia l Status
. Th e mea n socioeconomi c statu s scor e for stud y mother s o r

familie s wa s 17. 2 (S D 5.4) , reflectin g th e preponderanc e o f

single-parent , low-incom e households

. A s schedule di n th e Cincinnat i proto
col , th e qualit y o

f th e infant' s domesti c environ

men t wa s assesse dwit h th e Hom e Observatio n for Measuremen t

of th e Environmen t

(HOME ) a t

6 an d1 2 month s (B
. M
. Caldwel l an dR
. H
. Bradley , unpublishe ddata , 1978)
. Th e HOM E combine s in

terviewer' s question s wit h direc t observation s to yiel dsubscal e an dtota l HOM E scores . I n general ,

result s o f th e HOM E measur e th e parent' s respon sivenes s an dpersona l involvemen t wit h he r infan t an dth e exten t

to whic h th e physica l environmen t i s stimulatin g an dsafe

. T o procur e amor e stabl e an dreliabl e measur e of

first-year

environmenta l quality , th e mea n of

th e 6

- an d12-mont h HOM E score s wa s calculate dfo r

eac h infan t

an dteste da s apotentia l developmenta l covariat e and/o r con founde r i n regressio n model s wit h lea dvariables

. Al l candidat e covariable s wer e preteste dfor thei r confoundin g potentia l i n a"disease-primar y trait " covarianc e matri x usin g ahighe r tha n standar dP valu e (<.10 ) a s criterio n fo r initia l inclusio n i n regressio n model s wit h lead. 2 5 An y covariabl e as sociate dwit h eithe r

bloo dlea dlevel , behaviora l development , o r

bot h wa s include di n subsequen t regressio n analyses

. AoooooTOtnif

t © ? Lead ) Sxp®w ®

sued ) A critica l tas k

of an y stud y of

thi s kin di s th e accurat e an dreliabl e assessmen t of lea dleve l i n physiologi c compartments
. Th e microanalytica l laborator y a t

th e Universit y of

Cincinnati , Depart

men t o f Environmenta l Health , participate s i n sev era l qualit y contro l program s for th e measuremen t of lea di n whol e blood

. Th e performanc e of thi s laborator y ha s bee n uniforml y superio r throughou t th e cours e of

th e curren t

study. 11 * 8 8 Materna l bloo dsample s wer e collecte db y veni

punctur e a t

th e first prenata l clini c visit

. O

f thes e samples , 50 % were collecte di n th e firs t trimester , an d49 % an d1 % were collecte di n th e secon dan d thir dtrimesters , respectively

. Th e differenc e i n mea n bloo dlea dleve l b y trimeste r of pregnanc y wa s no t statisticall y significan t

(F — .27 , P= .76)
. Therefore , i t

wa s no t deeme dnecessar y to analys e thes e set s of

bloo dlea ddat aseparately

. Cor dbloo d sample s were collecte da t delivery , an dnewbor n infan t sample s were collecte dpostnatall y a t te n day s (correcte dfo

r gestationa l age ) an d3 month s of age . Bloo dwa s draw n fro minfant s b y venipunc

ture , hee l stick , o r

finge r stic k dependin g upo n th e ARTICLE S 73 §

tii*^.iiiMi,iia»i,».i , i.,,1a.. .111, 1 yuiiiiiui i j i jA^, , .,k 

# 1P. 5

physical characteristic s o f th e infant . Contamina tio n o f bloo d sample s draw

n b y a metho d othe r tha n venipunctur e wa s no ta problem becaus e o f thorough presamplin g cleansin g procedure s an d th e controlle d clinica l condition s unde r which phlebo tomy too k place . Studie s comparin g th e results o f finger stic k and venipunctur e method s i n ou r lab orator y hav e show n n o appreciabl e difference s be twee n th e tw o method s whe n thes e stric tpractice s ar e adhered to . Indeed , finger stic k sample s yielde d slightl y lowe r bloo d lea d values , whic h i s opposit e t o whaton e woul d expec ti f contaminatio n wer

e a problem . Prenatal (maternal ) bloo d measurements wer e conducte d b y Environmental Science s Asso ciate s (ESA ) usin g a

n ES A mode

l 201 4 Anodi c Strippin g Voltammete r wit h stri p char trecording . Cor d an d postnata l bloo d sample s wer e analyze d a t th e University o f

Cincinnat

i usin g a n ES A mode

l 301 0 Anodi c Strippin g Voltammeter . T o increas e precisio n o

f measurement , th e instrument' s digital readoutwa s abandone d i n favo r o f pea k heigh t determinatio n usin g a stri p char trecorder . W e rou tinel y conduc tsplit-sampl e analyse s comparin g th e 301 0 results fro

m ou r ow n laborator

y wit h th e 201 4 ES A results . Th e Pearso n rcorrelatio n betwee n thes e tw o method s ha s neve r bee n les s tha n +.97 . Al l bloo d lea d value s wer e correcte d t o a

n average hematocri tfor developmental age , becaus e th e con centratio n o f

erythrocyte s wil l affectth e leve l o f lea d measure d i n whol e blood . Fo r som e analyses , bloo d lead value s wer

e transforme d t o thei r natura l logarithm . Duplicate statistica l analyse s wer e un dertake n to determin e whethe r suc h transforma tion s affecte d th e final regressio n model s or statis tica l significanc e o f

lea d exposure variables . In al l cases , th e final regressio n model s examinin g th e effects o f feta l lead exposure o n behavioral devel opmen tremaine d th e sam e whethe r bloo d lea d wa s expresse d i n micrograms pe r decilite r or natura l lo g units . Statistic s o n bloo d lea d variable s ar e show n i n Tabl e 3 . Mothers ha d a

n arithmeti c mean prenatal bloo d lea d valu e o f

8. 0 /xg/d L (S D = 3.7 ) an d mean umbilical cord bloo d lea d valu e o f 6. 3 pg/d L (S D = 4.5) . Newborn s ha d arithmeti c mean bloo d lea d value s o f 4. 6 -xg/d L (S D = 2.8 ) a tte n day s o f lif e and 5. 9 ng/dL (S D = 3.4 ) a t3 month s o f age . Three TABL E 3
. Descriptiv e Statistic s o n Feta l Lea dExpo

mont h bloo d lea d wa s considere d i n thi s stud y a s anothe r index o

f fetal exposure , althoug h extrau terin e source s o f

lea d i n diet , water , an d atmospher e canno tb e entirel y discounted . Th e intercorrelation s amon g fetal lea d exposure variable s ar

e show n i n Tabl e 4 . Mos tcorrelation s betwee n lea d exposure variable s wer e lo w to mod erate . Thi s wa s probabl

y due , i n part , t o th e lon g period s o f tim e betwee n assessment s (eg , materna l an d umbilical cor

d samples ) an d th e facttha tbloo d wa s take n fro

m differen tpool s (ie , maternal an d neonatal) . In observational studies , dat a ar e ofte n missin g o n on e o r mor

e ke y independen to r dependen tvar iables . Thi s proved to b e th e cas e fo r feta l lead exposure variables . O

f th e 30 5 subjects i n th e sam ple , 26 6 prenatal , 9 6 cord , an d 30 2 newbor n bloo d lea d value s wer

e availabl e fo

r analyses . Prenatal bloo d lea d level s wer

e usuall y missin g becaus e o f th e inability t o obtai n a sampl e atth e tim e o f recruitment . Furthermore , onl y hig h qualit y cord bloo d lea d sample s were considere d suitabl e for analysis ; thos e wit

h clot s or microdot s wer e no t assessed . Newbor

n bloo d lead assessment s wer e missin g a s a resul to f

a misse d postnata l appoint men to r th e inabilit

y to obtai n a sampl e becaus e o f th e physical characteristic s o f th e infant . Neverthe less , analysi s o

f varianc e showe d tha tsubject s with jnissin g prenatal , cord , or newbor n bloo d lea d meas urements di d no tsignificantl y diffe r (P * 5 .10 ) fro m th e res to f th e sampl e o n stud y covariate s or indice s o f behaviora

l development . Behavioral developmen twas assesse d whe n th e infant s wer

e 3 and 6 month s o

f ag e wit h th e MD I an d Psychomoto r Developmenta l Inde x (PDI ) o f th e Bayle y Scale s o f

Infan tDevelopment. 2 1 Th e Bayle y scale s a t3 an d 6 month s provid e differential indicator s o f

th e infant' s neurodevelopmental sta tu s and reflectattentivenes s an d responsivenes s t o stimuli , moto r abilitie s i n th e manipulatio n o f ob jects , an d postural control . Th e Bayle y scale s were administere d i n th e mornin g a ta n inner-city health clini c by on e o f

thre e professionall y traine d psy chometricians . Car

e wa s take n to ensur e tha tth e infan twa s no tnoticeabl y ill , fatigued , hungry , o r receivin g medicatio n whe n examined . Interteste r TABL E 4 . Intercorrelation

s Amon g Feta l Lea d Exposur e Variables* su n vanaoies * Bloo dLea dVariabl e Prenata l (maternal ) Umbilical cor d Newborn (1 0 d) Newbor n ( 3 mo ) * Result s ar e expresse d whol e blood

. No
. Mea n S D Lo

w Hig h 26 6 8. 0 3. 7 1 2 7 9 6 6. 3 4. 5 1 2 8 30 2 4. 6 2. 8 1 2 2 30 2 5. 9 3. 4 1 22 a s microgram s pe r

decilite r of Prenata l bloo dlea d Cor dbloo dlea d 10- d bloo dlea d * Pearso n r . t P - s .001
. Cor d Bloo d Lea d 0.42 t 10-

d Bloo d Lea d 0.30 t 0.38 t Bloo

d Lea d 0.38 t 0.32 t 0.54 t *$

72 4 FETA L LEA D EXPOSUR E 

# 1P. 6

0 reliabilit y wa s assesse dsevera l time s throughou t th e stud y an daverage d.9 6 (Pearso n r) for th e Bayle y MD I an dPDI
. Thi s researc h protoco l wa s reviewe dan dapprove db y th e Committe e o n Hu

ma n Researc h of

th e Universit y of

Cincinnat i Col

leg e o f Medicine

. Dat o AffsaOyeo o Th e dat aanalyti c procedure s use di n thi s stud y were designe dt o achiev e th e bes t possibl e compro mis e betwee n th e conflicting goal s o f reducin g th e probabilit y of

typ e I erro r

(ie , false-positiv e lea d effect) an dtyp e I I erro r

(ie , false-negativ e [no ] lea d effect)

. Th

® analyti c strateg y involve s aprior i spec ificatio n o f

potentia l developmenta l confounders an dcovariates , pretestin g covariable s for confound

in g potentia l (P*

s .10) , backwar deliminatio n of nonsignifican t

covariate s an dconfounder s throug h multipl e regressio n analyse s to atrimme dregres sio n model , and , finally , th e testin g of potentia l dynami c interaction s amon g lea dexposures , bio

logi c outcomes , an dbehaviora l performanc e throug h structura l equatio n analyses

. Multipl e regressio n analyse s allo w for th e evaluatio n o

f th ® contributio n of

toxican t exposur e to development,

. independen t

of covariables

. Structura l equatio n , analyse s g o furthe r

to allo w th e testin g o

f causa l v pathway s wherei n lea dindirectl y affect s neurobe

haviora l statu s throug h it s effec t o n covariable s suc h a s birt h weight , gestation , o r othe r perinata l factors

. TABL I i

. Cwariate-Adjuste d Parameter Estimate s fo

r Feta l Lea dExposur e Variable s o

n 3-Mont h Bayle y Men

tal Developmenta

l Index0

N o significan t

effect s of

feta l lea dexposur e o n Bayle y PD I wer e foun dafte r adjustmen t

for covar iates

. However , bloo dindice s of i n uter o lea dex posur e wer e consistentl y relate dto Bayle y MDI a t 3 an d6 month s of

age . Th e covariate-adjuste d paramete r

estimate s for

feta l lea dexposur e varia

ble s o n 3-mont h Bayle y MD I ar e give n i n Tabl e 5
. Variable s othe r

tha n bloo dlea dwhic h wer e retaine d i n th e fina l model s a s statisticall y significan t pre dictor s o f Bayle y MD I wer e birt h weight , gestation , materna l age , chil drace , chil dsex , an dsocioeco

nomi c status
. Bot h prenata l (maternal ) an dumbilica l cor d bloo dlea dvalue s wer e inversel y relate dto MDI a t 3 months

. Fo r

prenata l bloo dlead , thi s effec t too k th e for mof acovariate-adjuste dreductio n of 0.3 4 MDI point s pe r

microgra mpe r

decilite r of lea di n blood , o r 9. 2 point s acros s th e rang e o f prenata l bloo dlea dvalue s observe di n th e sample

. Each

. microgra mpe r

decilite r increas e i n umbilica l cor d bloo dlea dwa s associate dwit h acovariate-adjuste d Bloo d Sourc e 0 S

E t P Valu e Valu e Rang e o f Effec t Prenatal -.3 4 0.1 7 -1.9 6 .0 5 Umbilica l corf d -.6 0 Newbor n (1 0 d ) .0 6 Newbor n ( 3 mo ) -.2 3 0.2

6 -2.3 0 0.2 2 0.26 0.1 8 -1.3 0 .0 2

.7 9 .2 0 9. 2 16. 3

0 Othe r variable s remaining in fina l model s a s statisti

call y significan

t (P< .05 ) covariate s include dbirt h weight, gestation , materna

l age , chil drace , chil dsex , and socioeconomi

c status
. Neithe

r Composit e Inde x o f To

bacc o an dAlcoho

l Consumptio

n nor quantit y o f ciga

rette s smoke

dpe r da y remainedin th e model s a s statis

ticall y significan

t covariates

. Pvalue calculate db y two
taile dtest
. reductio n o f

0.6 0 MDI points , o r

16. 8 MD I point s acros s th e rang e of

cor dbloo dlea dvalue s observe d i n th e sample

. Non e of

th e newbor n assessment s of bloo dlea dwere associate dwit h 3-mont h MDI afte r covariat e adjustment

. Th e covariate-adjuste dparamete r estimate s for feta l lea dexposur e variable s o n 6-mont h MDI ar e give n i n Tabl e 6
. A s wa s th e cas e for 3-mont h MDI , variable s othe r

tha n bloo dlea dwhic h wer e retaine d i n th e fina l mode l a s statisticall y significan t predic

tor s of Bayle y MD I wer e birt h weight , gestation , materna l age , chil dsex , an dsocioeconomi c status
. Prenata l (maternal ) an dten-da y newbor n bloo d lea dlevel s wer e bot h significantl y relate dto reduc

tion s i n Bayle y MDI a t

6 month s o

f age . Fo r pre nata l bloo dlead , dose-relate ddeficit s i n MD I were mor e pronounce di n boys , a s indicate db y th e sig

nifican t prenata l bloo dlea db y sex . interaction

. Multipl e regressio n analyse s for boy s onl y showe d tha t eac h microgra mpe r

decilite r increas e i n pre nata l bloo dlea dwa s associate dwit h acovariate

adjuste ddecremen t

o f 0.3 4 MDI point s ( P < .01) , o r a n overal l decremen t

of 22. 7 MD I point s acros s th e rang e o f

prenata l bloo dlea dobserve di n th e sample

. Fo r newbor n (ten-day ) bloo dlead , dose-relate d deficit s i n MDI wer e mos t pronounce di n infant s fro mth e poores t

families , a s indicate db y th e sig

nifican t ten-da y bloo dlea db y socioeconomi c statu s interaction

. Multipl e regressio n analyse s fo r infant s wit h score s les s tha n th e media n socioeconomi c statu s scor e showe dtha t

eac h microgra mpe r

deci

lite r increas e i n ten-da y bloo dlea dleve l wa s asso ciate dwit h acovariate-adjuste ddecremen t o f 0.7 3 MDI point s ( P < .03) , o r 16. 1 MD I point s acros s th e rang e of

ten-da y bloo dlea dobserve di n th e sample

. Umbilica l cor dan d3-mont h bloo dlea d value s wer e als o inversel y relate dt o 6-month MD I
ARTICLE S 72 S

* • " --••• - • • •it,**lMfciiii*f c Alt mxt.*.,**.+ .±LMmk„. i .i.i . »> . i .P. 7

TABL E 6 . Covariate-Adjuste

d Paramete

r Estimate s fo r Feta l Lea d Exposur e Variable s o n 6-Mont h Bayle y Menta l Developmenta

l Index * Bloo d Sourc e o r Interactio

n Prenatal (maternal ) Prenatal x chil d se x Umbilical cor

d Newbor n (1 0 d) Newbor n x socioeconomi c statu s Newbor n ( 3 mo ) 0 -0.7 6 1.2 7 -0.6 6 -3.4 9 0.1 8 -0.4 8 S E 0.3 4 0.5 1 0.3 7 1.2 9 0.07 0.27 tValu

e -2.1 6 2.4 9 -1.7 6 2.6 9 2.45 -1.7 8 P

Valu e .02 .0 1 .0 8 .00 7 .0 1 .07 Rang

e o f Effec t 22.7 t 16.l t

* Othe r variable s remainin g i n fina l model s a s statisticall

y significan

t( P < .05) covariate

s include d birt h weight , gestation, materna

l age , chil d race , chil d sex , an d socioeconomi

c status . Neithe

r Composit

e Inde x o f Tobacc o an d Alcoho l Consumptio

n no r quantit y o f cigarette s smoke d pe r da y remaine d i n th e model s a s statisticall

y significan

tcovariates . P valu e calculate d b y two-taile d test. tI n mal e infants . | I n infant s wit h score s les s tha n the media

n socioeconomi

c statu s scor e fo r th e sample . bu twer e no tquite statisticall y significan twhe n usin g a two-tai l test. Nevertheless , th e consistenc y o f a n apparentadvers e neurobehaviora l effec t acros s bloo d lea d variable s was striking . Structura l Equatio n Analyse s Multipl e regressio n analyse s ar e severel y limite d b y th e facttha tthe y ca n onl y evaluate stati c inter action s betwee n toxicantexposure an d othe r factors tha tca n affectneurobehaviora l development. 2 8 Many o f th e variable s considere d a s potentia l co variate s or confounders ma y actuall y b e health outcome s o f

intoxicatio n an d thereb y mediat e late r developmental deficits . Perinatal healt h factors suc h a s birt

h weigh tan d gestational ag e ar e goo d examples . Previou s researc h wit h th e Cincinnat

i dat a bas e ha s demonstrate d tha thighe r materna l bloo d lea d level s ar

e associate d wit

h statisticall y significan treduction s i n weigh ta tbirth. 1 0 Rathe r tha n considerin g birt

h weigh to r othe r perinatal health factors a s confounders o f th e bloo d lead behavio r relationshi p i n multipl e regressio n anal yses , suc h covariable s ma y b e mor e appropriately modeled (bot

h conceptuall y an d statistically ) a s mediators o f

late r neurobehaviora

l deficits . Unti l recently , adequat

e statistica l techniques to estimat e suc h indirec teffect s i n longitudinal studie s hav e no tbee n available . Now , man y o f th e statistica l problem s inheren ti n pat h analysi s have bee n solve d b y th e metho d know n a s structura

l equa tions. 29 * 30 Thi s statistica l metho d i s typicall y use d to test a se to f

specifi c causa

l hypothese s agains ta se to f observe d dat

a (usuall y a covarianc e matrix o f observe d relation s amon g th e variable s i n th e models) . In th e presen tstudy , structura l equatio n analyse s wer

e use d to testth e hypothesi s tha tlead relate d deficit s i n infan tneurodevelopmentatstatu s a t3 an d 6 month s o f

ag e wer e due , i n part , to lead relate d lower birt

h weigh tan d shortene d gesta tiona l age . Prenatal (maternal ) bloo d lea d wa s mod ele d i n thes e analyses , becaus e i twa s mos thighl y correlate d wit

h perinatal outcome s i n previou s wor k with thes e data. 1 0 Th e structura

l analysi s wa s conducte d i n th e followin g manner . Th e variable s show n i n Tabl e 2 wer e ordered accordin g t o th e causal relationship s hypothesize d to exist . Child' s race an d sex , mother' s age , socioeconomi c status , Composit e Inde x o f To bacc o and Alcoho l Consumption , gravidity , an d parit y wer e initiall y include d a s exogenou s (inde pendent) variable s i n al l structura l equations . In addition , th e stati c interactio n o f prenatal bloo d lea d wit h eac h o f

thes e exogenou s variable s wa s initiall y entertaine d i n eac h o f th e structural equa tio n models . Th e endogenou s (dependent) variable s include d i n thes e model s wer e prenatal bloo d lead , gestation , birt

h weight , Obstetrical Complication s Scal e score , Postnata l Complication s Scal e score , and , finally, 3 - o r 6-mont h MD I an d PDI . Thi s lis t reflects th e orderin g o f

posite d causal event s amon g thes e variable s (ie , prenatal bloo d lea d i s hypothe size d to affec

teach o f th e endogenou s variable s tha t follow , whereas MD I an d PD I ar e assume d to b e fina l outcome s i n th e model) . Furthermore , th e variable s o

f birt h weigh tan d gestationa l ag e wer e allowe d to b e noncausall y correlate d wit h th e Ob stetrica l an d Postnata l Complication s Scal e scores . Finally , MDI and PD I wer e treate d a s independent , fina l outcomes , an d no tcorrelate d i n a causal man ner . Prenatal bloo d lea d wa s lo g transformed , be caus e i tserve d a s a n intermediate endogenou s var iabl e an d assumption s o f normalit y o f distributio n neede d t o b e met . From thi s initia l (full y parameterized ) model , nonsignifican tpath s wer e removed fro

m th e struc tura l equation s unti l al l remainin g path s wer e sig nifican tatP

** S .1 0 (two-tai l test). Maximu m like lihoo d estimate s o f

th e remainin g parameter s i n th e mode l wer e the n obtaine d usin g th e Linea r Struc - %

* >


# I

!

72 6 FETA L LEA D EXPOSUR E^Spsp^'^Pff- . "T^T . r^W^ B JtV*AJ lj ,y| . "• " P. 8

tural Relation s (LJSREL ) progra m o f Joresko g an d Sorbom. 3 Any nonsignifican t( P > .05 ) parameters wer e removed fro

m th e model s i n a stepwis e fash ion . An exogenou s variabl e tha twa s no tfound t o b e significantl y relate d to an y endogenou s variabl e withi n th e structural equatio n wa s eliminate d fro m th e model . Similarly , a n endogenou s variabl e tha t wa s no tsignificantl y affecte d b y an y othe r variable , an d di d no tsignificantl y affectany othe r endoge nou s variable , was eliminate d fro m th e model . Thi s strateg y o f

backwar d remova l o f nonsignifi can tparameters wa s used , an d a final mode l wa s derive d fo r both th e 3-mont h an d 6-mont

h devel opmental assessments . Th e onl y remainin g stati c interactio n term wa s prenatal bloo d lea d b y se x o n 6-mont h Bayle y scale s outcome s (a s was th e cas e i n th e standard multipl e regressio n analyses) . Th e final structural mode l derive d fro

m thes e analyse s fo r 3-month MD I an d PD I i s show n i n Fi g 2 . A s predicted , prenatal bloo d lea d wa s inversel y relate d to birt

h weigh t(-15 0 g pe r natura l lo g uni t o f bloo d lead) , which , i n turn , wa s positivel y asso ciate d wit h 3-month MD I an d PDI . (Lo g bloo d lea d value s ranged fro

m 0 to 3.29583 7 whil e antilo g value s range d fro

m 0 to 27. ) Prenata l bloo d lea d was als o inversel y associate d with gestational ag e (-0.4 6 week s pe r lo g uni to f bloo d lead) , which , i n turn , wa s als o positivel y associate d wit h Bayle y developmental outcomes . Therefore , a portio n o f lead' s advers e effec to n behaviora l developmenta t 3 month s o f

ag e was "indirect, " through it s dynami c interactio n with fetal growt h an d maturationa

l var iables . Prenatal bloo d lea d was associate d wit h les s optimal Postnata l Complication s Scal e score s (Fi g 2) . In additio n t o lead , consumptio n o f tobacco and / or alcoho l product

s during pregnanc

y wa s relate d to both highe r prenatal bloo d lea d value s (a s ha s bee n foun d i n othe r studies) , lowere d birt h weight , and , ultimately , lower MDI an d PD I through it s effec to n fetal growth . I ti s interestin g tha tthi s effec tshoul d b e reliabl e i n a sampl e characterize d b y a relativel y low leve l o f consumptio n o f

thes e products an d attest s to th e genera l validit y o f th e Composit e Inde x o f Tobacc o an d Alcoho l Con sumptio n variable . Th e structura

l equatio n analyse s result s fo r 6 - mont h MD I an d PD I ar

e presente d i n Figur

e 3 . Fo r th e mos tpart, th e 3 - an d 6-mont h model s were identical , with th e exceptio n o f race an d mother' s

Sf N Postnata l Cone I les tion s Scal e Horner' s ag e

Parit y

S.t. S

CIU C \"» , " \ -.on(-.iJJ) ^

Rac e -?.4J(-.I49 ) Fi g 2 . Relationship s amon g prenata l lea d (Pb ) expo sure , perinata l outcomes , an d developmenta l variable s a s reveale d throug h structura l equatio n analyse s fo r 3 - mont h Menta l Developmenta l Inde x (MDI ) an d Psy chomoto r Developmenta l Inde x (PDI) . Unstandardize d an d (standardized ) regressio n coefficient s ar e shown . Omnibu s goodness-of-fi ttes tprovide d b y LISREL 3 1 pro Oostetrica l Cow ) I canon s Scal e gra m wa s surveye d a teac h ste p o f eliminatio n procedure . A tn o tim e di d approximat e x 2 squar e valu e fo r goodnes s o f fi texcee d expectation , indicatin g tha tfina l model s s o obtaine d fi tth e dat a well . Abbreviations : S.E.S. , socio economi c status ; CITAC , Composit e Inde x o f Tobacc o an d Alcoho l Consumption .
ARTICLE S 72 7P. 9

Rac e

Postnata l Corelicatton s Scal e Prenata l lloor j P a a $• »

s.c.s .

testatio n

llrt nveign t

Fi g 3 . Relationships amon

g prenata l lea d (Pb ) exposure , perinata l outcomes, an

d developmenta

l variable s a s reveale d throug h structura

l equatio n analyse s fo r 6 - mont h Menta l Developmenta

l Inde x (MDI ) an d Psy chomoto r Developmenta

l Inde x (PDI) . Unstandardize

d an d (standardized

) regressio

n coefficient

s ar e shown . Omnibu s goodness-of-fi

ttes tprovide

d b y LISREL

3 1 proag e predictin g prenatal bloo d lea d valu e i n th e 6 - month model an d th e aforementione d prenatal bloo d lea d b y se x interactio n o n 6-mont h Bayle y developmental outcomes . Also , th e absolute siz e o f th e standardize d an d unstandardize d regressio n coefficients diffe r to a certai n degree becaus e th e variable s i n th e model s themselve s slightl y differed an d th e facttha teac h mode l contain s som e subject

s who ar e uniqu e (ie , asmal l number o f stud y subject

s did no treceiv e a 3-month Bayle y assessmen tan d a fe w di d no treceiv e a 6-mont h Bayle y assessment) . T o summarize , ther e i s ampl e evidenc e i n thes e multipl e regressio n an d structural equatio n anal yse s o f both directan d indirecteffects o f fetal lea d exposure o n earl y neurobehaviora l development . Prenatal , umbilical , an d newbor n bloo d lea d level s wer e directl y relate d to deficits i n Bayle y MD I a t eithe r 3 months , 6 months , o r a tboth assessments . Boy s an d infant s fro

m th e poores tfamilie s ap peare d t o b e mos tsensitiv e t o thes e psychoterato geni c influences . Furthermore , i n uter o exposure to lead , a s indexe d b y prenatal (maternal ) bloo d lea d value , ma

y hav e exerte d additional effects o n de velopmen tthrough decrements i n fetal growt h an d maturation . DISCUSSIO N Indice s o f feta l lea d exposure wer

e mor e strongl y an d consistentl y relate d t o 3 - an d 6-mont h Bayle y Prenata l lim n P O I Se i gra m wa s surveye d a teac h ste p o f eliminatio n procedure

. A tn o tim e di d approximat

e x 2 squar e valu e fo r goodnes s o f fi texcee d expectation, indicatin

g tha tfinal model

s so obtaine d fitth e dat a well. Abbreviations : S.E.S. , socio economi c status ; CITAC

, Composit e Inde x o f Tobacc o an d Alcoho l Consumption

. MD I tha n PDI . Thi s findin g i s i n accord with previou s studies. 7 ' 9 Th e MD I i s als o a mor e reliabl e an d vali d subscal e a tthes e age s tha n th e PDI. 2 7 Therefore , i ti s no tsurprisin g tha tthi s scal e wa s th e mos tsensitiv e o f

developmental outcom e vari able s i n th e investigation . A t3 months , bot

h prenatal an d umbilical cor d bloo d lea d level s wer

e associate d wit

h deficit s i n MD I afte r covariate adjustment . A cavea tma y b e i n order , however , wit

h regar d to th e cord bloo d lea d results . Thi s finding i s base d o n slightl y fewe r tha n on e third o

f th e subjects i n th e study ; there fore , i tma

y no tb e a s reliabl e a n effec ta s tha tfound fo r othe r bloo d lead variables . However , othe r stud ie s hav e reported simila r relationship s betwee n lea d i n cor d bloo d an d neurobehaviora l deficits. 7 " 9 A t6 months , th e result s wer e mor e complex bu t stil l consisten twit

h stud y hypotheses . Tw o key perinatal risk factors appeared to b e operativ e i n modifyin g th e effects o f

fetal exposure to lead . First , mal e infant s expresse d a muc h greate r 6-mont

h neurobehaviora

l defici ti n respons e to fetal expo sur e a s assesse d by materna l bloo d lead . Thi s findin g i s interestin g i n tha tseveral epidemiologi c stud ie s hav e shown tha tth e relativ e risk o f perinatal mortalit y an d morbidit

y i s highe r i n boys, 32,3 3 in cludin g th e ris k o f

poo r reproductive outcome s an d postnata l developmen tdue to fetal exposur e to industrial pollutants. 34,3 5 Thi s "mal e disadvantage " ma y b e due t o slowe r maturatio n an d integratio n .•• * 

## 1 '


# ' I

• i

72 8 FETA L LEA D EXPOSUR E 

# I—**- » •*—1 —p.fl l P.1 0

of orga n system s i n boys. 3 8 Boy s als o hav e ahighe r rat e o f menta l developmenta l disabilit y i n th e gen era l population 37,3 8 an ddispla y mor e profoun din

tellectua l deficit s a s aresul t of cortica l lesions. 39,4 0 Boys , an dperhap s mal e brains , may b e mor e sen sitiv e t o th e toxic effect s of i n uter o chemica l ex posures . Infant s o f

lowe r socia l clas s familie s appeare dt o b e mor e sensitiv e to th e effect s o f feta l exposur e a s indexe db y newbor n (ten-day ) bloo dlea dlevels

. Thi s findin g i s consisten t wit h previou s studie s i n whic h amor e advers e behaviora l effec t of lea d exposur e wa s show n amon g th e lowe r socia l classes. 41,4 2 Neurobehaviora l sequela e a s aresul t of perinata l insul t

ha s bse n show n to b e mor e sever e amon g th e lowe r

social classes

. I t

i s likel y tha t

socia l clas s i s acollectiv e surrogat e fo r avariet y o f

pre nata l stressor s tha t

ma y affec t

reproductiv e fitnes s an dmak e th e expressio n o f neurobehaviora l deficit s mor e likel y i n infant s fro mth e poores t families. 43,4 4 Umbilica l cor dan d3-mont h bloo dlea dlevel s wer e als o inversel y associate dwit h 6-mont h Bayle y MDI , althoug h a t

no t quit e astatisticall y signifi

can t leve l whe n usin g atwo-taile dtest
. Neverthe

less , th e consistenc y o f negativ e relationship s acros s bloo dlea dmeasure s wa s impressive

. Anothe r noteworth y findin g i n thi s stud y was . tha t earl y lead-relate dneurobehaviora l deficit s \ wer e partl y mediate dthroug h birt h weigh t and ^ gestation

. Ther e ar e anumbe r o f studie s i n whic h th e effect s o f

prenata l lea dexposur e o n obstetrica l outcome s wer e evaluated

. Lea dha s bee n show n to affec t placenta l metabolis mi n a n i n vitr o study. 4 6 Ther e i s als o evidenc e tha t prematurity , lowe r

birt h weight , an dprematur e ruptur e of membrane s i s associate dwit h materna l bloo dlea dvalue s of 3 0 Mg/d L o r greater. 4 6 Althoug h on e recen t prospectiv e stud y ha s reporte darelationshi p betwee n low-leve l prenata l lea dexposur e an dprematur e birth, 1 2 thi s i s th e firs t

stud y to repor t

a n independent , invers e relationshi p betwee n prenata l bloo dlea dan dbirt h weigh t a t level s o f

les s tha n 3 0 Mg/d

L of whol e blood

. Th e finding o f

bot h direc t

an dmediate deffect s of low-leve l feta l lea dexposur e o n developmen t suggest s tha t

wha t constitute s saf

e level s of

expo sur e for childre n ma y no t

b e saf e fo r th e fetus

. I t shoul db e stresse dtha t neurobehaviora l deficit s wer e relate dto lea dexposure s i n thi s stud y tha t wer e wel l belo w th e "correctiv e action " leve l a s propose db y th e Center s fo r Diseas e Control. 4 7 In

deed , prenata l (maternal ) bloo dlea dlevel s i n thi s sampl e wer e wel l withi n th e rang e foun dfor U S wome n i n thei r

reproductiv e year s a s assesse db y th e Nationa l Healt h an dNutritio n Examinatio n Survey. 4 8 Thes e finding s als o sugges t tha t in-dept h studie s o f toxican t exposur e durin g th e cours e o f pregnanc y ar e essentia l i n definin g th e "critica l period " of exposur e for

give n effect s an di n under

standin g th e possibl e mechanism s for thes e eari y neurobehaviora l deficits

. Thi s i s b y n o mean s ane w concep t i n th e fieldof

reproductiv e toxicology. 48,5 0 However , becaus e lea di s on e of severa l widel y distribute dtoxicants i n ou r environment , th e finding s of thi s stud y deserv e th e specia l attentio n o f pediatricians , obstetricians , an dpubli c healt h offi

- :
Futur e studie s wit h th e Cincinnat i cohor t wil l hel p to determin e whethe r th e developmenta l ef

fect s of feta l lea dexposur e persis t int o late r

child

hood

. B y virtu e of

thei r geographica l locatio n an d housing , muc h of

th e stud y cohor t

i s a t considerabl e risk fo r clinicall y significan t

elevation s i n bloo d lea dlevels. 1 6 I t

wil l b e importan t

to ascertai n ho w thes e postnata l exposure s affec t curren t behaviora l functionin g an dfutur e intellectua l attainment

.

Thi s research i s supporte db y aProgra mProject gran t fro mth e Nationa

l Institut e o

f Environmenta

l Healt h Science s (P01-ES01566-08) , Pau l B
. Hammond , principa l investigator

. Th e author s than k

th e man y technician s an dsuppor

t staf f a t th e Universit

y o f Cincinnat i Colleg e o f Medicin e andBabie s Mil

k FundAssociation clini c wh o helpedt o mak e thi s research possible

.

1 . Cantaro

w A , Trumper M : Lead

Poisoning. Baltimore , Wil liam s & Wilkin s Co , 1944 " - 2 . Olive r T : Load

Poisoning: From the Industrial, Medical and Social Points of View. Ne w York , Pau l B . Hoeber , 191 4 3 . Ro m WN : Effects o f

lea d o n th e femal e an d reproduction : A review . Mt

Sinai Med

1976;43:542-55 2 4 . Barltro p D : Transfe r o f lead t o th e huma

n fetus , i n Barltro p D (ed) : Mineral

Metabolism in Pediatrics. Oxford, Blcctocel l Scientific , 19S9 , p p 135-15 1 5 . Gershanih JJ , Brooks GG , Littl e JA : Bloo d lea d value s i n pregnantwome

n and thei r offspring . Am J Obstet Gynecol 1974;119:508-51 1 6 . Ghafou

r SY , Khuffaa

h FA , Ibrahi

m HS , e tal : Congenita

l lead intoxicatio n wit

h seizure s due t o prenata l axpoaure. Clin Pediatr1984;23:282-28 3 7 . Bellinge r DC , Needleman HL , Levito n A , e tal : Early csn sorimoto r developmentan d prenata l exposur e t o lead . Neurobshav Toxicol

Teratol 1984;6:387-402 8 . Bellinge r D , Levito n A , Needleman HL , e tal : Lo w leve l Ice

d exposur e an d infantdevelopmenti n th e firstyear . Neurobehav Toxicol Teratol

1986;8:151-16 1 9 . Bellinge r D , Levito n A , Watemau i C , e tal : Lo w leve l lead exposur e and early developmenti n socio-economicall y ad vantage d urba

n infants , i n Smit

h M (ed) : Proceedings of the International

Workshop on Effects of Lead Exposure on Neurobshavioml

Development, i n press , 1987 10 . Bornschei n RL : Th e effecto f low leve l prenatal lea d expo sur e o n feta l growth . Presente d a tth e Environmental Pro tectio n Agency/European Economi c Communit y Conference : Lea d Exposur

e an d Neurobehaviora

l Effects i n Chil dren , Edinburgh , Scotland , Sep t8-12,198 8 11 . Dietric h KN , Kraff

tKM , Bie r U, e tal : Early effects o f feta l lead exposure : Neurobehaviora l finding s a t6 months . Int J Biosot Res 1986;8:2-1 9 12 . McMichae

l AJ , Vimpan

i GV, Robertao

n EF , e tal : Th e PortP.1 1

Piri e cohor

tstudy : Materna

l bloo d lea

d an d pregnanc

y outcome . J

Epidemiol

Community Health 1986;40:18-25 13 . Needleman HL , Rabinowit z M , Levito n A , e tal : Th e rela tionshi p between prenata l exposur e t o lead an d congenita

l anomalies . JAMA 1984;251:2956-299 9 14 . Bornschei n RL , Hammon d PB , Dietrich KN , e tal : Th e Cincinnat i prospectiv e stud

y o f lo w leve l lead exposur

e an d it s effects o n chil d developmen tEnviron Res 1985;38:4-1 8 15 . Clar k CS , Bornschei n RL , Succo p P , e tal : Conditio n and typ e o f housin g a s a

n indicato r o

f potential environmenta

l lead exposure an d pediatri c bloo d lea d levels . Environ Res 1985;38:46-5 3 16 . Ballard JL , Nova

k KK, Driver MA : Simplified score fo r assessmen to

f feta l maturation i n newl

y bor n infanta . J Pediatr1979-95:769-774 17 . Dietrich KN , Kraff

tKM , Pearson DT , e ta

k Contribution o f social and developmenta l factors t o lead exposur

e durin g th e firs tyear o f

life . Pediatric* 1985;75:1114-111 9 18 . Hun tTJ , Hepner R

, Seato n KW : Childhoo d lea d poisonin g an d inadequat

e chil d care . Am J

Dis Child

1982;136:538 - 54 2 19 . Milar CR

, Schroeder SR , Musha

k P , e ta k Contribution o f th e caregivin g environmentt o increase d lead burde n i n children . Am J

Ment Defic 1982;84:339-344 20 . Star k AD , Qua

h RF , Meigs JW , e ta

k Relationshi p o

f sociodemograph k factors t o blood lea d concentration s i n New Haven children . J Epidemiol

Community Health 1982;36:133-13 9 21 . Littman B , Parmelee AH : Medica l correlate s o f

infantde velopmen tPediatrics 1978;61:470-474 22 . Hobel CJ : Developmen to f POPRAS-proble

m oriente d per inatal risk assessmen tsystem , i n Harris T R(ed) : The Use of Computers in Perinatal Medicine. Ne w York

, Praeger, 1980 , p p 117-13 9 23 . Hollingshea d AB : Fou r facto r inde

x o f socia l status , workin

g paper. New Haven , CT , Yale University , 197 5 24 . Delete d i n proo

f 25 . Dale s LG , Ur

y HK : A n imprope

r us e o f statistica l signifi cance testin g i n studyin g covariables . Int J Epidemiol 1978;7:373-375 26 . Hammon

d PB : Measuremen

to f lead . Presente d atth e Roya l Societ y o f Canad a Commission o n Lea

d i n th e Environment, National Researc

h Council , Ottawa, Canada, Marc h 13 , 198 5 27 . Bayley N : The Bayley Scales of Infant Development. Ne w York , Psychologica

l Corporation , 1969 * - 28 . Pearso n DT , Dietric h KN : Th e behaviora l toxicology an d teratolog y o f childhood : Model s method s and implication s fo r intervention . Neurotoxicology 1985;6:165-182 29 . Joresko g KG : Statistica l estimatio n o f structura l model s i n longitudina

l developmenta

l investigations , i n Nesselroad e JR , Balte s P B (eds) : Longitudinal Research in the Study of Behaviorand

Development

Ne w York, Academi

c Press , 1979 , p p 303-35 1 30 . Vino d HD , Ulla h A : Recent Advances in Regression Methods. New York

, Marce l Dekker Inc , 198 1 31 . Joresko g KG, Sorbo

m D : LISREL IV: Analysis of Linear Structural

Relationships by the Method of Maximum Likelihood, User's Guide. Chicago , Internationa l Educationa

l Services , 1985 32 . Abramowic

z M , Barnet

tH L Sex rati o o f

infan tmortality : Trend s o f change . Am J

Dis Child

1970;119:314-31 5 33 . Naey e RL , Bur

tLS , Wrigh

tDL , e tal : Neonatal mortality , th e male disadvantage . Pediatrics 1971,48*902-90 6 34 . Scrag g RKR , McMichae

l AJ , Clar k PD : Pollutio n an d se

x rati o o f births . Med

J Aust 1977;2:6 8 35 . McKeown-Eyssen G E Rued y J , Neim s A : Methyl mercur y exposur e i n Norther

n Quebec : 2 . Neurologi c findings in children . Am J

Epidemiol

1983;118:470-47 9 36 . Khour

y MJ , Mark

s JS , McCarth

y BJ , e tal : Factors affecting th e sex differentia

l i n neonata

l mortality . Th e role o

f res pirator y distres s syndrome . Am J Obsttt Gynecol 1985;151:777-78 2 37 . Gros s MB , Wilso n WC : Minimal Brain Dysfunction: A Clinical Study of Incidence, Diagnosis, and Treatment

in over 1000 Children. New York , Bninner/Maze L 197

4 38 . Schaffer D , Schonfel d I , O'Conno r PA , e tal : Neurologica

l sof tsigns : Thei r relationshi p t o psychiatri c disorder an d intelligenc e i n childhoo d an d adolescence . Arch Gen Psychiatry 1985;42342-35 1 39 . Bornstei n RA , Matarazzo JD : Relationshi p o f sex an d th e effects o f unilatera l lesion s o n th e Wechtle r Intelligenc e Scales : Furthe

r considerations . J

Nerv Ment

Dis 1984;172:707-71 0 40 . Ingti s J , Lawson JS : Sex differences i n th e effects o f unilat era l brai n damag e o n intelligence . Science 1981;212:693-69 6 41 . Harve

y PG , Hamli n MW

, Kuma r R , e tal : Bloo d lead , behavior , and intelligenc e testperformanc e i n preschool children . Sc i Total

Environ 1984;40:45-6 0 42 . Winneke G

, Kraeme r U : Neuropsychologica

l effects o f

lea d i n children : Interaction s wit h social backgroun

d variables . Neuropsychobiology 1984;11:195-202 43 . Broma

n SH , Nichol s PL , Kennedy WA : Preschool IQ: Prenatal and Early Developmental

Correlates. Hillsdale , NJ , Erlbaum, 197

5 44 . Werne

r E , Bierma

n JM , Frenc

h FF : The Children of

Kauai •f Honolulu , Universit

y o f Hawaii , 197 1 4£ . Dawso n EB , Crav

y WD , Clar

k RR , e ta k Effec to f trac e metal s o n placenta

l metabolism . Am J

Obstet Gynecol '• 1969;103:253-25 6 46 . Fahim MS , Fahim Z

, Hal l DG : Effects o f

subtoxi c lea d level s o n pregnan

twome n in th e stat e o f

Missouri . Res Common Chem Pathol

Pharmacol

1976;13:309-33 1 47 . Preventing lead

poisoning in young children: A statement by the Centers forDisease Control U S Departmen to f

Healt h and Huma

n Service s publicatio n No . 99-2230 . Atlanta , Cen ter s fo r Diseas e Control , 1986 48 . Mahaffe

y KR , Annes tJL , Robert

s J , e tal : National esti mate s o f bloo d lea d levels : Unite d States , 1976-1980 . J V Engl J Med 1982;307:573-57 9 49 . Clarkao

n TW , Nordber

g GF , Sage

r PR : Reproductive an

d developmenta

l toxicit y o f metals . Scand

J Work Environ Health 1985;11:145-15 4 50 . Weis s B , Spyker JM : Behaviora l implication s o f

prenata l and early postnatal exposur e t o chemica

l pollutants . Pediatrics 1974;53:851-862 t



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