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### EP A AI R DOCKE T b e presente d Draf t o f manuscrip t to " Conferenc e o f Prospectiv e Studie s Septembe r 6-12 , 1986
. 

# %o<x>>

a t th e Thir d Internationa l o f Lead , Edinburgh , Scotland ,

Environmenta l Lead , Reproductio nandInfan t Developmen t

J . Grassiano* , D
. Popovac" , M
. Murphy* , A
. Mehmeti' v , J
. Kline** , C
. Ahmcsdi^ , P
. Shrout** , Z
. Zvicer" , G
. Wasserman** , E
. Gashi" , Z
. Stein** , B
. Rajovic^ , L
. Belmont** , B
. Colakovic" , R
. Bozo

vic" , R
. Haxhiu" , L
. Radovic~ , R
. Vlaskovic^ , D
. Nenezic A , an d N
. Lolacono *

•Columbi a University , Colleg e o f Physician s & Surgeons , NY , NY "Medicinisk i Facultet , Universit yo f Kosovo , Pristina , Yugoslavi a ^Medicinisk i Centar , Titov a Mitrovica , Yugoslavi a **Ne wYor k Stat e Psychiatri c Institute , NY , NY

# ti l P.3
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I

ABSTRACT :
We ar e studyin g th e relatio no f chroni c lead<Pb ) exposur e t o advers e pregnanc y outcome an

dinfan t development . Thi s study draw s upo na uniqu e communit y surroundin g a P bsmelter , refiner y an dbatter y

plan t i nTitov a Mitrovica , Yugoslavia . Contro l subject s are bein g studie di nPristina , a non-Pb-expose dtow n4 0 k m t o th e south . Recruitmen t o f wome na t 12-2 0 week s gestatio nwil l terminat e i n January , 1987 , a t whic htime w e wil l hav e entere dapproxi matel y 100 0 wome nfro

m eac htow

nint o th e study . Preliminar y dat a fro

m 45 6 wome ni nMitrovic a an d65 0 wome ni nPristin a indicat e that , a t mid-pregnancy , th e bloo dP bconcentration s (BPb's ) i nMitrovic a rang e fro m 2-4 7 ug/dl , wit ha mea no f 17. 4 ug/dl . Th e majo r determinan t o f elevate dBP bi s geographi c proximit y

t o th e P bindustry . InPristina , mid-pregnanc y BPb' s range , fro

m 1-2 3 ug/dl , wit ha mea no f 5. 4 ug/dl . Thu s far , 20 7 pregnancie s hav e come t o ter m i nMitrovica , an d26 8 i nPristina . Ther e i s a stron g associatio nbetwee nmaterna l BP ba t deliver y an dcor dBPb' s ove r a wid e rang e o f BPb's . InMitrovica , th e mea ncor dBP bi s 19. 0 ug/dl , whil e i nPristin a i t i s 5. 4 ug/dl . Th e socioeconomic , ethni c andmaterna l physica l characteristic s ar e quit e comparabl e betwee nth e tw o towns , a nimportan t asse t i n a stud y o f thi s type . A study o f infan t developmen t ha s bee ninitiate di nsubset s o f infant s bor nt o wome ni nth e pregnanc y outcome study . I n Mitrovica , infant s wit hhigh , mid-range , andlo w cor dBPb' s ar e bein g selecte dfo r follow-up ; thu s far , th e mea ncor dBPb' s o f thes e group s are 25.2 , 17.3 , an d11. 2 ug/dl , respectively . In Pristina , a contro l grou po f infant s matche dt o th e Mitrovic a hig hBP bgrou ponSES ha s a mea ncor dBP bo f 3. 9 ug/dl . Anothe r contro l grou pi nPristina , matche dt o th e Mitrovic a lo w BP bgrou p onSE S andcor dBPb , ha s a mea ncor dBP bo f 8. 2 ug/dl .P. 4

IHTR0DUCTX0E3 S Th e autonomou s provinc e o f Kosovo , Yugoslavia , i s a mountainou s farmregio n i n th

® proces s o f industrializatio n becaus e o f it s ric h minera l resources . Th ®cit yo f Titov a Mitrovica 9 approxi

matel y4 0 k

m nort h o f Pristina , th ®capito l o f th

®province , i s th ®sit ®

o f on®

o f th

®larges t lea d ( Pb ) smeltor o A n Europe
. Approximatel y100 ? 00 0 peopl e ar ®expose d t o P b (amission s fro mth e P b ©melter , o f who m60?00 0 liv e i n th ©highl yexpose d cit yare a whic h lie ©i n a valle ya t th e convergenc e o f th ©Xba r an d Sitnic a rivers

. I n 1982 9 KI® reporte d a n alarmin g prevalenc e o f elevate d bloo d P b concentration s (BPb's ) amon g childre n an d adult s i n Mitrovic a (1)
. A t tha t tim® , th ©mea n ai r P b concentration , measure d monthl ya t fiv ©location s i n th ©town , range d fro m21. 3 t o 29„ 2 u/m3 ° I n 1983 9 prio r t o th e initiatio n o f thi s study , a ne wfiltratio n syste mwen t o n lin e a t th ©smelter ? sinc e tha t time , th e mea n ai r P b concentratio n ha s bee n reduce d t o 7. 0 ug/m3 , stil l 1 0 time s th ©allowabl e limi t o f 0. 7 ug/m 3 i n Yugoslavia

. Thus , ©levate d BP b remain s a proble mi n Mitrovica

. Afte r reviewin g th e literatur e concernin g possibl e effect s o f P b o n huma n pregnanc youtcom e (2) , w e becam e convince d o f th ©nee d fo r specifi c effect s t o b e explore d i n relatio n t o precis e measure s o f BP b durin g pregnancy . I n particular , previou s studie s ha d generall yfaile d t o adequatel ycontro l fo r know n ris k factor s suc h a s materna l weight , height 9 parity 9 previou s reproductiv e history 9 smokin g an d socia l class
. Th e population s o f Mitrovic a an d Pristina , wit h thei r comparabl e socia l struc

ture s bu t wid©l ydivergen t range s o f BPb°© 9 provid e a n opportun

it yfo r suc h a study
. Fo r simila r reasons , the yals o provid®a uniqu e opportunit yfo r a prospectiv e stud yregardin g th e influ

enc e o f prenata l an d post-nata l P b exposur e o n infan t develop

ment
. Yh<s Pir©giraairac

yQuatcoja

© Steadie s Recruitmen t o f approximatel y100 0 pregnan t wome n (12=2 0 week s gestation ) i n eac h tow n bega n i n May 9 198 5 an d wil l terminat e i n January 9 1987
. Sinc e th e stud yi s ongoing , w e provid ©i n thi s repor t onl ydescriptiv®dat a abou t thos e case s recruite d an d analyze d t o date 9 i.®. 9 45 6 wome n i n Mitrovic a an d 65 0 wome n i n Pristina

. W e wil l ultimatel yexamin e whethe r exposur e t o Pb , assesse d by SP b an d erythrocyt e proto

porphyri n (EP ) a t mid-pregnanc yan d a t term , i s associate d wit h a n increase d ris k o f selecte d advers e pregnanc youtcomes ? lat e spontaneou s abortio n an d stillbirth , prematur e delivery , intrauterin e growt h retardation , an d congenita l malformations

. Th e possibl e interactio n betwee n iro n deficienc yan d P b toxicit y wil l b e examine d utilizin g concurren t measurement s o f serum ferriti n an d hemoglobi n concentrations

. Factor s know n t o influenc e reproductiv e outcome , suc h a s socia l class 9 pas t reproductiv e histor yan d genera l healt h statu s ar e bein g assesse d throug h questionnaires

. Feta l P b exposur e wil l b e determine d b y measurement s o f BP b an d E P i n umbilica l cor d blood , serum ferriti n an d hemoglobi n concentration s ar e als o bein g measured
. Th e possibl e influenc e o f exposur e t o othe r heavymetal s wil l b e

i**.*. . u*. *.L,lL.ih ^P. 5

examine db

y analysi s o f variou s element s i nplacenta l tissu e obtaine da t delivery . Evaluatio no f th e newbor ninclude s gestationa l ag e assessmen t (3 ) an da carefull y

structure d physica l examinatio nfo r congenita l malformations . Multivariat e analyse s o f thi s dat a se t shoul dultimatel y revea l importan t informatio nconcernin g th e dose-respons e relationship s betwee nP b exposur e an

dpregnanc y

outcomes . Preliminar y

analyse s o f dat a fro m th e mid-pregnanc y interview s sugges t tha t thes e two population s ar e simila r wit hrespec t t o parenta l ag e an

deducation , materna l heigh t an dweight , gravid ity , ethnicit y

andsocioeconomi c status . The y ar e somewha t dissimila r wit hrespec t t o th e highe r proportio no f wome n reportin g smoking , an y alcoho l drinkin g an dworkin g i nPristin a (Tabl e 1) . O f thes e latte r thre e characteristics , smokin g i s know nt o influenc e birthweigh t (4) ; finding s fo r alcoho l drinker s (5 ) an dmaterna l occupatio ni nrelatio nt o birthweigh t ar e inconsistent . Th e relation s o f thes e factor s an dother s t o birthweigh t an

dlat e feta l deat hi nth e study pregnancie s wil l b e examined , andanalyti c adjustmen t wil l b e mad e fo r thei r effect s i nassessin g th e influenc e o f locatio nan dBP bo nth e variou s pregnanc y

outcomes . Tabl e 1 . Sociodenographi c Characteristic s

andHabit s o f th e Population s

Materna l Materna l Paterna l Paterna l Materna l Materna l TitQY B riitrQYica .

N ag e (yr s ) education(yrs ) ag e (yrs ) educatio n(yrs ) weigh t (kg ) heigh t (cm ) 45 6 26. 3 9. 5 30. 6 12. 1 66. 7 163. 2 Pristin a 65 0 26. 9 9. 3 30. 7 1 1 . 7 66. 8 166. 1

X X X X Albania n Serbia n Othe r No answe r 55. 9

24. 8 17. 8 1 . 5 Tota l numbe r o f pregnancie s 3. 3 3. 3 Ethnicity : XAlbania n55. 9 59. 4 24. 9 14. 9 0. 7
Xcigarett e smoker s 23. 0 29. 8 Xo f wome nwh o drin k an y alcoho l 5. 7 9. 5 Xo f wome nwit hjob s 30. 5 45. 8 Th e mid-pregnanc y questionnaire s hav e show nsocia l characteris tic s to b e similar , particularl y wit hregar dt o socioeconomi c statu s (Tabl e 2) .



## VTalbl © 2 o SoeiLa l Cteairact<sri£3tie o @< FteDno P@iptta2.a

t 2

. ©BB © P 6

Titov a Mitrovic a H Numbe r o f adult s i n hom e Numbe r o f childre n i n hom e Numbe r o f room s i n hom e Monthl yfamil yincom e (million s o f ol d dinars ) 45 6 4. 5 2. 1 3. 4 7o 0

Th e distributio n o f mid-pregnanc yBPb' s i n th ® focAfiSJsXm 6 5 0 4 , 2

. 3 < 7 <

t w o . 4

, 1

, 2

, 1

town s a r e illustrate d graphicall yi n Figur e Mitrovic a i s 17. 4 ug/d l whil e th e ug/dl
. Th

© mea n E P i o Mitrovic a Pristin a i s 32. 5 ug/dl § th e mea n 1
. Thu s far „ th e mea n BP b i n m©a n BP b i n Pristin a i s 5. 4 i o 49. 8 ug/dl 9 whil e tha t i n serumferriti n concentration © ar<B identica l i n th © tw o towns , 19. 8 ng/dl
. Th®firs t birth s t o otud yparticipant s occurro d i n October , 1985
. T o dat® , BP b dat a hav e bee n compile d fro m20 7 maternal/in

fan t pair s i n Mitrovic a an d 26 8 pair ®i n Pristina

. I n Mitrovica , thu s far , th e mea n materna l BP b a t ter mi s 21. 4 ug/dl 9 whil e th © mea n umbilica l cor d BP b i s 19. 0 ug/dl
. S n Pristina , th ©mea n materna l BP b a t ter mi o 6. 7 ug/dl 9 whil e th ©mean , umbilica l cor d BP b i s 5. 4 ug/dl
. Th©distribution s o f materna l BPb' s a t ter m arm illustrate d i n Figur e 2 9 whil e th ©distribution s o f umbilica l eor d BPb' o ar e illustrate d i n Figur e 3
. Whil e numerou s oth© r studie s hav ©describe d a n associatio n betwee n materna l an d feta l BPb' s (reviewe d i n 6) 9 non e hav © involve d a populatio n wit h ouc h a wid e rang e o f BPb's
. Th e placent a appear s t o b ® a vtsiry wea k barrie r t o P b ove r a wid ® rang e © f BPb'® 9 a s evidence d byth ©stron g associatio n betwee n materna l an d umbilica l cor d BPb' o i n Mitrovic a show n i n Figur e 4 ( r « 0.86 § P < .001 8 olop © = 0.87> § onc e additiona l dat a ar e accumulated , w e wil l determin e whethe r th ©associatio n involve s non-linea r a o wel l a s linea r components
. Th ©averag e materna l mid-pregnanc yBPb's , materna l BPb' o a t delivory 9 an d umbilica l cor d BPb' s fo r ou r case s tha t hav e eem ©t o ter mar ©presente d i n Tabl e 3
. Tatol ©3 § Avairag

® ° o I Titov a Mitrovic a N* 20 7 ffoirCass © C<aa © feo Team s

N • 26 8 

### Materna l Mid-Pregnanc y 17 , Materna l Deliver y 21 , Umbilica l Cor d19 , 6 5. 4 6. 7 5. 4 Thus , becaus e o f th e wid ©rang e o f BPb's , th e apparen t lac k o f confoundin g by spcia l class , an d th ©larg e numbe r o f wome n involved , thi s prospectiv e stud ypromise s t o answe r man yissue s surroundin g th e possibl e influenc e o f P b exposur e o n pregnanc y

*i . JM.*J*iA ••MMMIB W i*i*..iMmt.Jkk-iUikaiiLi.* . fa " — - ----- H>a.^, J iM.i,^ mP. 7

outcome . I t i s stil l to o early , however , fo r definitiv e dat a concernin g pregnanc y outcome . u s t o presen t an y

Th e Infan t Developaen t Study : environmenta l P bexposur e onph y linguisti c developmen t durin g subset s o f infant s bor nt o women outcome study . Th e infant s wil l month s o f age . A t eac hvisit , ferenc e wil l b e measured ; a ped i andbloo dwil l b e collecte d hemoglobi nandseru m ferriti n assessment s wil l b e carrie dout : Inorde r t o asses s th e effect s o f sical , behaviora l andcognitive earl y life , w e ar e followin g wh o participat e i nth e pregnanc y b e examine da t 6 , 12 , 1 8 and2 4 weight , height , andhea dcircum atri c histor y

wil l b e performe d fo r th e measuremen t o f BPb , EP, Inaddition , th e followin g

6 mont hvisit : Bayle y Scale s o f Infan t Developmen t (7 ) Bate s Infan t Characteristic s Questionnair e (8 ) 1 2 mont hvisit : Bayle y Scale s o f Infan t Developmen t Bate s Infan t Characteristic s Questionnair e 1 8 mont hvisit :

2 4 mont hvisit : Bayle y Scale s o f Infan t Developmen t Memor y fo r Location s Tas k (9 ) Bayle y Scale s o f Infan t Developmen t Bate s Infan t Characteristic s Questionnair e Memor y fo r Location s Tas k Receptiv e Languag e Assessmen t (10 )

a . Selectio no f Subjects : InMitrovica , 38 4 infant s wil l b e selecte do nth e basi s o f cor dBPb's . W e wil l selec t th e follow in g cases :

Grou pa ) th e 14 4 infant s wit hth e highes t cor dBPb's ;

cor dBPb' s o f 2 0 ug/d l o r mor e ar e eligibl e fo r entr y

int o thi s group . Grou pb ) th e 12 0 infant s wit hth e lowes t cor dBPb's ;

cor dBPb' s o f < 1 5 ug/d l ar e eligible . Grou pc ) a rando m sampl e o f 12 0 infant s fro m th e remainin g births , wit hBPb' s o f > 1 5 ug/d l and< 2 0 ug/dl . I nPristina , 26 4 infant s wil l b e selecte dfo r comparativ e purposes : Grou pd ) 14 4 infant s wil l b e matche dt o th e "high " cor dBP bgrou p(Grou pa ) fo r SES . Th e hypothesize deffect s o f P b onmenta l developmen t i nth e firs t year s o f lif e ar e likel y t o b e see ni nthi s comparison . I t i s likel y tha t onl y

minima l adjustmen t fo r SES wil l b e require di nth e statistica l analysis .

Grou pe ) 12 0 infant s wil l b e matche dt o th e "low " cor d BP bgrou p(Grou pb ) fo r SE S an dcor dBPb . B

y virtu e o f thei rP. 8

tow no f residence , i t i s likel y tha t th e BPb' s o f infant s i n childre ni ngrou pbwil l ris e durin g th e firs t tw o year s o f life , whil e thos e o f grou pe wil l not . Thus , thi s contro l group wil l enabl e u s t o attemp t t o distinguis hprenata l fro m post-nata l P beffects . W e hav e establishe dtha t ther e i s a stron g associatio nbetwee n parenta l educatio nan dothe r indicator s o f SE S suc ha s famil y income , rooms/home , numbe r o f residents/home , etc . W e hav e therefor e use dmaterna l an dpaterna l educatio na s th e SE S selectio nfactors . Inorde r t o minimiz e los s t o follow-up , infant s livin g mor e tha n1 0 k m fro m th e hospita l hav e bee n exclude di neac htown . Othe r exclusio ncriteri a includ e twins , majo r centra l nervou s system defects , chromosoma l abnormalitie s o r othe r condition s (e.g. , microcephaly , hydrocephaly ) likel y t o profoundl y

affec t growt ho r menta l development . Thu s far , 24 3 hav e bee nselecte dfo r follow-u pfro m birth s whic h occurre ddurin g th e interva l o f October , 196 5 throug hMarch , 1986 . O f those , 15 0 hav e bee nevaluate da t 6 month s o f age . Th e mea ncor dBPb' s o f group s a- e ar e illustrate di nTabl e 4 . Tabl e 4 : Mea nCor dBPb' s <ug/dl ) o f Selecte dInfant s Titov a Mitrovic a Pfigtinf l Grou pa : 25. 2

Grou pb : 11. 2 Grou pd : 3. 9 (Matche dt o groupa onSES ) Grou pe : 8. 2 (Matche dt o grou pbonSES an dBPb ) Grou pc : 17. 3 Othe r characteristic s o f group s a- e ar e show ni nTabl e 5 . Tabl e 5 : Othe r Characteristic s o f Selecte dInfant s

Grou pa Grou pbGrPU P C GrQU P dGrgU P 6
BP b(ug/dl ) 25. 2 1 1 . 2 17. 3 3. 9 8. 2
Materna l Educatio n(yrs )
Paterna l Educatio n(yrs ) Famil y Incom e 9. 6

11. 1
5. 7 8. 3

12. 2
5. 0 9. 2

12. 0
5. 6 9. 5

1 1 . 3
6. 3 9. 3

1 1 . 3
5. 9 (1 0 dinars/month ) Birthweigh t (grams ) 333 7 329 5 331 0 323 2 331 0P. 9

Insummary , w e ar e studyin g th e influenc e o f P bexposur e on pregnanc y

outcom e an

dinfan t developmen t i ntw o population s wit h anexceptionall y

wid e rang e o f BPb's . Th e socioeconomi c charac teristic s o f th e two town s appea r t o b e quit e similar . Thus , i n thi s study , P bexposur e i s no t linke dt o a particula r socia l clas s o r ethni c group , a nimportan t limitatio no f many othe r previou s andongoin g studies . Becaus e thi s study i s stil l i nth e proces s o f dat a collection , th e presentatio no f dat a concernin g outcome s o f interes t mus t awai t th e nex t conference . References : 1 . Popovac , D , Graziano , J , Seaman , C , Kaul , B , Colakovic , B , Popovac , R , Osmani , I , Haxhiu , M , Begraca , M , Bozovic , Z , Mikic , M : Elevate dbloo dleadi na populatio nnea r a leadsmelte r i n Kosovo , Yugoslavia . Arc hEnviro nHealt h37 : 19-23 , 1982 . 2 . Graziano , JH , Popovac , D , Murphy , MJ , Colakovic , B , Stein , Z , Mehmeti , A , Kline , J , Ahmedi , G , Rajovic , B , Gashi , E , Haxhiu , R , Radovic , L , Hoxha , I , Zvicer , Z , Popovac , R , Bozovic , R , Shrout , P , Lolacono , N : Environmenta l leadan dpregnanc y

outcome . Pro c Fift hInt Con f Heav y Metal s i nth e Enviro n(Athens ) 1 : 414-416 , 1985 . 3 . Ballard , JL , Novak , KK , Driver , M : A simplifie dscor e fo r assessmen t o f feta l maturatio no f newl y bor ninfants . J Pediat r 95 : 769-774 , 1979 . 4 . Abel , EL : Smokin g durin g pregnancy : A review

o f effect s on growt handdevelopmen t o f offspring . Huma nBio l 52 : 593-625 , 1980 . 5 . Stein , Z , Kline , J : Smoking , alcoho l andreproduction . Ame r J Publi c Healt h73 : 1154-1156 , 1983 . 6 . Bell , JU , Thomas , JA : Effect s o f leado nmammalia nreproduc tion . In , Lea dToxicity . R L Singha l andJ A Thoma s (eds) , pp . 169-186 , Urba n4 Schwartzenberg , Baltimore , 1980 . 7 . Bayley , N : Manua l fo r th e Bavle v Scale s o f Infan t DevelopElfill£ . New

York : Psychologica l Corporation , 1969 . 6 . Bates , JE , Freeland , CA , Lounsbury , ML : Measuremen t o f infan t difficultness . Chil dDevelo p50 : 794-803 , 1979 . 9 . Kagan , J : Th e SecondYear : Th e Emergenc e o f Self-Aware Hfififi . Cambridge , MA : Harvar dUniversit y Press , 1981 . 10 . Hedrick , DL , Prather , EM , Tobin , AR : Th e Sequence dInven tory o f Communicativ e Development . 2n dedition . Seattle : Seattl e Universit y Press , 1984 . Figures : Figure s 1- 4 wil l b e distribute da t th e meeting .

### iw

# Frequency Distributio n o fBloo d Lea d Concentration s at Mid-Pregnancy

Pristina , N = 65 0 E S Titova Mitrovica , N B Overla p

0 2 4 6 8 1 0 1 2 1 4 1 6 1 8 2 0 2 2 2 4 2 6 2 8 3 0 3 2 3 4 3 6 3 8 4 0 4 2 4 4 4 6 4 8 5 0 5 2 5 4 5 6 5 8i r.: • •'_'* :



# o

tz <D 

# fi < D D L 

# Frequenc y Distributio n o fMaterna l Bloo d Lea d Concentration s 50r - a t Deliver y

Pristina , N = 26 8 Titova Mitrovica , N = 20 9 Overla p

SIsL-jra
. T—i— r 0 2 4 6 8 1 0 1 2 1 4 1 6 1 8 2 0 2 2 2 4 2 6 2 8 3 0 3 2 3 4 3 6 3 8 4 0 4 2 4 4 4 6 4 8 5 0 5 2 5 4 5 6 56 t aa \.- r •'i-ir-* ' ' " '! • ••vinin- n « •

C O



# . 2

c C D O 

### Q 5 

## C L 

# Frequency Distributio n o fUmbilica l Cord Bloo d Lead Concentration s

B Pristina , N = 26 8 0 Titova Mitrovica , N = 20 7 B Overla p

0 2 4 6 I •••• •rH—i—i—i—i—| - 

## 8 1 0 1 2 1 4 1 6 1 8 2 0 2 2 2 4 2 6 2 8 3 0 3 2 3 4 3 6 3 8 4 0 4 2 4 4 4 6 4 8 5 0 5 2 5 4 5 6 5 8



# Bloo dLea d(pg/dl ) i-*<?o£C \P.1 3



## CDR DBP B <UG/DL )

C > . - VX —M M I a 

## K m U l P I


## • ? ¥ £_ ? £—*.— ? ¥ - - ¥

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### m •r » z •3 3 a e z a r -

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