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From the Department of Environmental Health, University ot Cincinnati College of 

Medicine, Cincinnati 

AUSTIMGT. A prospective method was used in this study 

to assess the effects of fetal lead exposure on neurodevelopmental status in 3- and 6-month old infants. At 

their first prenatal medical appointments, 305 lower socioeconomic status women residing in predesignated leadhazardous areas of Cincinnati were recruited. Lead was 

measured in whole blood in both the mother and fetoplacental unit (prenatal and cord) and the neonate (ten 

days and 3 months). All blood lead levels were less than 

30 pg/dL. Infant development was assessed with the* 

Bayley scales at 3 and 6 months of age. Multiple regres-> 

sion analyses which treated perinatal health factors such 

as birth weight and gestation as confounders indicated 

an independent, inverse relationship between both prenatal and neonatal blood lead levels and performance on 

the Bayley Mental Developmental Index at both ages. 

Male infants and infants from the poorest families appeared to be especially sensitive to these psychoteratogenic influences. Further study using a structural equations approach indicated that neurobehavioral deficits 

were partly mediated by lead-related reductions in birth 

weight and gestation. Pediatrics 1987;80:721-730; lead, 

fetal development, behavior, sex differences, teratology. 

ABSS^VIIATOJWS. MDI, Mental Developmental Imfes; HOME, 

Home Observation for Measurement of the Environment; PDI, 

Psychomotor Developmental Indss. 

It has long been recognized that lead at high 

doses is an abortifacient and potential teratogen.1

'

3

 Lead is known to cross the human placenta 

and accrue in fetal tissues during gestation.4 ConReceived for publication Jon 15,1987; accepted March 13,1987. 

Reprint requests to (K.ND.) Kettering Laboratory, University 

of Cincinnati Medical Center, 3223 Eden Ave, Cincinnati, OH 

45267-0056. 

PEDIATRICS (ISSN 0031 4005). Copyright © 1987 by the 

American Academy of Pediatrics. 

genital lead poisoning has been previously reported 

in neonates of women working in the lead industry 

and in association with the consumption of noncommercially produced spirits.5

 Reports of congenital lead poisoning in infants from third-world 

countries, where lead is still widely used in pottery 

and cosmetics, continue to appear.6 

Today, the primary concern of pediatricians and 

epidemiologists is on levels of fetal lead exposure 

that do not normally result in miscarriage or obvious neonatal pathologic conditions. There is a 

growing body of data from several longitudinal 

studies that indicate that lower level in utero lead 

exposure may be related to deficits in both fetal 

growth and postnatal behavioral development. For 

example, Bellinger and his colleagues7'

9

 in Boston 

found that umbilical cord blood Pb levels of less 

than 25 -jg/dL were independently associated with 

small deficits in Bayley Mental Developmental Index (MDI) at 6,12, and 24 months of age. In other 

longitudinal studies in Cincinnati and Port Pirie, 

Australia, low level fetal lead exposure has been 

associated with lower birth weight,10,11 and shorter 

gestation.11,12 Needleman and his colleagues13 evaluated the relationship between prenatal exposure 

to lead and minor congenital anomalies in 4,354 

births in Boston. Umbilical cord blood lead level 

was found to be associated, in a dose-related manner, with an increased risk for minor anomalies. 

In this paper, we present the first results of a 

major longitudinal study of the effects of chronic 

low to moderate lead exposure on child development.14 It was hypothesized that prenatal exposure 

to lead, as indexed by maternal, umbilical cord, and 

neonatal blood lead levels, would be related to sensorimotor developmental deficits when infants were 

3 and 6 months of age. It was also hypothesized 

that Lead exposure would interact with other periPEDIATRICS Vol. 80 No. 5 Novembsr 1987 721 

iHiAajurn,ii j I.I. I 
P.3 

<'f 

natal risk factors such as race, sex, and social class; 

those fetuses at higheij risk because of genetic or 

social factors would later display a greater lead; 

related behavioral deficit. Fiffally, it was hypothe'-' 

sized that neurobehavioral deficits would be partly 

a function of the negative effect of prenatal lead 

exposure on fetal growth (birth weight) and physical maturation (gestational age as determined by 

examination of the neonate). 

METHODS 

Subjects 

The final follow-up study sample consisted of 305 

mothers, recruited between 1979 and 1984, residing 

in predesignated lead-hazardous areas of Cincinnati. This geographical area has a history of having 

a relatively large number of children with lead 

poisoning according to city health department data. 

Results of other studies on the Cincinnati cohort 

have shown that lead from paint, dust, and generally poor housing stock is the major contributor to 

body burden.15 Informed consent for participation 

in the study was obtained at prenatal recruitment 

and again at delivery to obtain permission for infant 

follow-up. Women known to be addicted to drugs, 

alcoholic, or diabetic or those with proven neurologic disorders, psychoses, or mental retardation 

were excluded from prenatal recruitment. Excluded 

from prenatal recruitment on these bases were 487 

women, and 23 refused to participate (ie, have their 

blood sampled for lead). The age of enrolled mothers at delivery was 22.7 ± 4.5 years (mean ± SD); 

87% of the mothers were single, and 86% .were on 

public assistance. Vital descriptive statistics on 

mothers and infants in the study are given in Table 

1. 

Infants of less than 35 weeks' gestation, and/or 

1,500 g birth weight were excluded from postnatal 

recruitment. Furthermore, recruited infants must 

have had an Apgar score of 6 or greater at five 

minutes and have no serious medical condition such 

as Down syndrome, phenylketonuria, or significant 

congenital anomaly. Excluded from postnatal recruitment based on these criteria were 76 neonates, 

and 129 families refused the 5-year postnatal follow-up. Study infants had a mean birth weight of 

3,134.6 g (SD 462.8) and mean gestational age by 

physical examination16 of 39.5 weeks (SD 1.7). Examinations for gestational age were conducted by 

University Hospital residents who were trained by 

J. L. Ballard, MD, the author of the protocol. 

Interexaminer reliability studies were not conducted for the purpose of the present study. However, the Ballard gestation estimate appeared to 

have excellent predictive validity given the strong 

TABLE 1. Descriptive Statistics on Study Sample 

Variable Mean SD Low High 

J Maternal age (yr) 

Social class* 

Home Observation for 

Measurement of the 

Environment24 scoret 

No. of children in home 

% unmarried 

Birth wt (g) 

Gestational age (wk)$ 

5-min Apgar score 

% black 

% girls 

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 

15 

8 

17 

1 

1,814 

35 

7 

39 

50 

42 

6 

4,400 

43 

9 

* Hollingshead Four-Factor Index of Social Status.23 

t Scores of 30 or less are considered poor. 

t As assessed by standardized physical examination of 

the neonate.1* 

and highly significant associations with mental and 

motor developmental outcomes at 3 and 6 months 

of age. 

Descriptive statistics on mothers and infants who 

were excluded from the study by prenatal/postnatal 

criteria or refusal to participate are given in Table 

2. A comparison of Tables 1 and 2 show that study 

dyads and excluded dyads were similar in terms of 

such key sociodemographic variables as maternal 

age, marital status, and gravidity. As one would 

expect, excluded neonates had lower birth weights, 

"gestational ages, and Apgar scores. There was also 

'a higher tendency for white and/or married families 

to refuse study participation. 

Assessment of Potential Confounders and 

Covariates 

Undue lead exposure is known to covary with a 

number of social and biologic risks that may mimic, 

obscure, or otherwise interact with the effects of 

toxicant exposure on child development.17"

20

 Therefore, a substantial amount of medical and social 

background data were collected on all subjects. The 

candidate confounders and covariates that were 

selected a priori based upon their theoretical and/ 

or known empirical association with both the target 

independent variable (fetal lead exposure) and/or 

target dependent variable (3- and 6-month neurodevelopmental status) are listed in Fig 1. 

Obstetrical history and pertinent perinatal data 

were recorded from the mother's and neonate's 

charts. These data were then coded using the Littman-Parmelee Obstetrical and Postnatal Complications Scales.21

 A Composite Index of Tobacco 

and Alcohol Consumption, taken from the Problem 

Oriented, Perinatal Risk Assessment System22 was 

also used. The Composite Index of Tobacco and 

Alcohol Consumption variable was dichotomously 

722 FETAL LEAD EXPOSURE 
IF. 

Ii* •' 

TAEUE 2. Descriptive Statistics on Mothers and Infants Excluded From Study 

Variable/Group Maternal 

Exclusions 

Neonatal 

Exclusions 

Refusals Abortions Stillbirths 

No. 

% black 

% unmarried 

Maternal age (mean yr ± SD) 

Gravidity (mean No. ± SD) 

Birth wt (mean g ± SD) 

5-min Apgar score (mean ± SD) 

Gestational age by examination19 

(mean wk ± SD) 

487 

71 

79 

21.7 ± 5.9 

1.7 ± 1.9 

3,097 ± 572 

8.7 ± 0.9 

38.9 ± 2.7 

76 

80 

79 

22.9 ± 5.8 

2.1 ± 2.0 

2,204 ±892 

7.5 ± 2.5 

34.9 ± 4.6 

152 

64 

62 

22.4 ± 4.1 

1.7 ± 1.6 

3,237 ± 497 

8.8 ± 0.6 

39.4 ± 1.7 

43 

76 

79 

23.2 ± 5.8 

1.4 ± 1.4 

161 ±04 

15.6 ± 0.5 

10 

67 

100 

19.9 ± 5.1 

0.9 ± 1.2 

1^46 ±789 

29.0 ± 6.6 

i: 

Perinatal Variables 

Birth wt 

Gestational afja by examination 

Obstetrical Complications Scale 

Postnatal Complications Scale 

Composite Index of Tobacco and Alcohol Consumption 

No. of cigarettes smoked per day 

Maternal age at birth of child 

Gravidity 

Parity 

Maternal total iron-binding capacity 

Race of child 

Sax of child 

Sociohereditary Variables 

Socioeconomic status 

Developmental Stimulation (Home Observation for 

Measurement of the Environment Scale) 

No. of children in the home 

Fig 1. Candidate confounders and/or covariates. 

coded with a value of "1 " indicating use of tobacco 

and/or alcohol during pregnancy. Use of these substances during the prenatal period was reported by 

58% of study mothers. Information was also gathered through prenatal interview on the average 

number of cigarettes smoked per day during pregnancy. Most smoking women (98%) reported consumption of one pack (20 cigarettes) or none per 

day. Forty-seven percent of the cohort were nonsmokers. There was no evidence of alcoholism or 

drug-addiction during any of the sample pregnancies. 

The socioeconomic status of the infant's family 

was assessed at 3 months postpartum with the 

Hollingshead23 four-Factor Index of Social Status. 

The mean socioeconomic status score for study 

mothers or families was 17.2 (SD 5.4), reflecting 

the preponderance of single-parent, low-income 

households. As scheduled in the Cincinnati protocol, the quality of the infant's domestic environment was assessed with the Home Observation for 

Measurement of the Environment (HOME) at 6 

and 12 months (B. M. Caldwell and R. H. Bradley, 

unpublished data, 1978). The HOME combines interviewer's questions with direct observations to 

yield subscale and total HOME scores. In general, 

results of the HOME measure the parent's responsiveness and personal involvement with her infant 

and the extent to which the physical environment 

is stimulating and safe. To procure a more stable 

and reliable measure of first-year environmental 

quality, the mean of the 6- and 12-month HOME 

scores was calculated for each infant and tested as 

a potential developmental covariate and/or confounder in regression models with lead variables. 

All candidate covariables were pretested for their 

confounding potential in a "disease-primary trait" 

covariance matrix using a higher than standard P 

value (<.10) as criterion for initial inclusion in 

regression models with lead.25 Any covariable associated with either blood lead level, behavioral 

development, or both was included in subsequent 

regression analyses. 

AoooooTOtnift ©? Lead) Sxp®w® sued) 

A critical task of any study of this kind is the 

accurate and reliable assessment of lead level in 

physiologic compartments. The microanalytical 

laboratory at the University of Cincinnati, Department of Environmental Health, participates in several quality control programs for the measurement 

of lead in whole blood. The performance of this 

laboratory has been uniformly superior throughout 

the course of the current study.11*

88 

Maternal blood samples were collected by venipuncture at the first prenatal clinic visit. Of these 

samples, 50% were collected in the first trimester, 

and 49% and 1% were collected in the second and 

third trimesters, respectively. The difference in 

mean blood lead level by trimester of pregnancy 

was not statistically significant (F — .27, P = .76). 

Therefore, it was not deemed necessary to analyse 

these sets of blood lead data separately. Cord blood 

samples were collected at delivery, and newborn 

infant samples were collected postnatally at ten 

days (corrected for gestational age) and 3 months 

of age. Blood was drawn from infants by venipuncture, heel stick, or finger stick depending upon the 

ARTICLES 73§ 

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

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physical characteristics of the infant. Contamination of blood samples drawn by a method other 

than venipuncture was not a problem because of 

thorough presampling cleansing procedures and the 

controlled clinical conditions under which phlebotomy took place. Studies comparing the results of 

finger stick and venipuncture methods in our laboratory have shown no appreciable differences between the two methods when these strict practices 

are adhered to. Indeed, finger stick samples yielded 

slightly lower blood lead values, which is opposite 

to what one would expect if contamination were a 

problem. Prenatal (maternal) blood measurements 

were conducted by Environmental Sciences Associates (ESA) using an ESA model 2014 Anodic 

Stripping Voltammeter with strip chart recording. 

Cord and postnatal blood samples were analyzed at 

the University of Cincinnati using an ESA model 

3010 Anodic Stripping Voltammeter. To increase 

precision of measurement, the instrument's digital 

readout was abandoned in favor of peak height 

determination using a strip chart recorder. We routinely conduct split-sample analyses comparing the 

3010 results from our own laboratory with the 2014 

ESA results. The Pearson r correlation between 

these two methods has never been less than +.97. 

All blood lead values were corrected to an average 

hematocrit for developmental age, because the concentration of erythrocytes will affect the level of 

lead measured in whole blood. For some analyses, 

blood lead values were transformed to their natural 

logarithm. Duplicate statistical analyses were undertaken to determine whether such transformations affected the final regression models or statistical significance of lead exposure variables. In all 

cases, the final regression models examining the 

effects of fetal lead exposure on behavioral development remained the same whether blood lead was 

expressed in micrograms per deciliter or natural log 

units. 

Statistics on blood lead variables are shown in 

Table 3. Mothers had an arithmetic mean prenatal 

blood lead value of 8.0 /xg/dL (SD = 3.7) and mean 

umbilical cord blood lead value of 6.3 pg/dL (SD = 

4.5). Newborns had arithmetic mean blood lead 

values of 4.6 -xg/dL (SD = 2.8) at ten days of life 

and 5.9 ng/dL (SD = 3.4) at 3 months of age. ThreeTABLE 3. Descriptive Statistics on Fetal Lead Expomonth blood lead was considered in this study as 

another index of fetal exposure, although extrauterine sources of lead in diet, water, and atmosphere 

cannot be entirely discounted. 

The intercorrelations among fetal lead exposure 

variables are shown in Table 4. Most correlations 

between lead exposure variables were low to moderate. This was probably due, in part, to the long 

periods of time between assessments (eg, maternal 

and umbilical cord samples) and the fact that blood 

was taken from different pools (ie, maternal and 

neonatal). 

In observational studies, data are often missing 

on one or more key independent or dependent variables. This proved to be the case for fetal lead 

exposure variables. Of the 305 subjects in the sample, 266 prenatal, 96 cord, and 302 newborn blood 

lead values were available for analyses. Prenatal 

blood lead levels were usually missing because of 

the inability to obtain a sample at the time of 

recruitment. Furthermore, only high quality cord 

blood lead samples were considered suitable for 

analysis; those with clots or microdots were not 

assessed. Newborn blood lead assessments were 

missing as a result of a missed postnatal appointment or the inability to obtain a sample because of 

the physical characteristics of the infant. Nevertheless, analysis of variance showed that subjects with 

jnissing prenatal, cord, or newborn blood lead measurements did not significantly differ (P *5 .10) from 

the rest of the sample on study covariates or indices 

of behavioral development. 

Behavioral development was assessed when the 

infants were 3 and 6 months of age with the MDI 

and Psychomotor Developmental Index (PDI) of 

the Bayley Scales of Infant Development.21 The 

Bayley scales at 3 and 6 months provide differential 

indicators of the infant's neurodevelopmental status and reflect attentiveness and responsiveness to 

stimuli, motor abilities in the manipulation of objects, and postural control. The Bayley scales were 

administered in the morning at an inner-city health 

clinic by one of three professionally trained psychometricians. Care was taken to ensure that the 

infant was not noticeably ill, fatigued, hungry, or 

receiving medication when examined. Intertester 

TABLE 4. Intercorrelations Among Fetal Lead Exposure Variables* 

sun vanaoies* 

Blood Lead Variable 

Prenatal (maternal) 

Umbilical cord 

Newborn (10 d) 

Newborn (3 mo) 

* Results are expressed 

whole blood. 

No. Mean SD Low High 

266 8.0 3.7 1 27 

96 6.3 4.5 1 28 

302 4.6 2.8 1 22 

302 5.9 3.4 1 22 

as micrograms per deciliter of 

Prenatal blood lead 

Cord blood lead 

10-d blood lead 

* Pearson r. 

t P -s .001. 

Cord 

Blood 

Lead 

0.42t 

10-d 

Blood 

Lead 

0.30t 

0.38t 

Blood 

Lead 

0.38t 

0.32t 

0.54t 

*$ 

724 FETAL LEAD EXPOSURE 1 
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0 

reliability was assessed several times throughout 

the study and averaged .96 (Pearson r) for the 

Bayley MDI and PDI. This research protocol was 

reviewed and approved by the Committee on Human Research of the University of Cincinnati College of Medicine. 

Dato AffsaOyeoo 

The data analytic procedures used in this study 

were designed to achieve the best possible compromise between the conflicting goals of reducing the 

probability of type I error (ie, false-positive lead 

effect) and type II error (ie, false-negative [no] lead 

effect). Th® analytic strategy involves a priori specification of potential developmental confounders 

and covariates, pretesting covariables for confounding potential (P *s .10), backward elimination of 

nonsignificant covariates and confounders through 

multiple regression analyses to a trimmed regression model, and, finally, the testing of potential 

dynamic interactions among lead exposures, biologic outcomes, and behavioral performance 

through structural equation analyses. Multiple 

regression analyses allow for the evaluation of th® 

contribution of toxicant exposure to development,. 

independent of covariables. Structural equation , 

analyses go further to allow the testing of causal v 

pathways wherein lead indirectly affects neurobehavioral status through its effect on covariables 

such as birth weight, gestation, or other perinatal 

factors. 

TABLI i. Cwariate-Adjusted Parameter Estimates for 

Fetal Lead Exposure Variables on 3-Month Bayley Mental Developmental Index0 

No significant effects of fetal lead exposure on 

Bayley PDI were found after adjustment for covariates. However, blood indices of in utero lead exposure were consistently related to Bayley MDI at 

3 and 6 months of age. The covariate-adjusted 

parameter estimates for fetal lead exposure variables on 3-month Bayley MDI are given in Table 5. 

Variables other than blood lead which were retained 

in the final models as statistically significant predictors of Bayley MDI were birth weight, gestation, 

maternal age, child race, child sex, and socioeconomic status. 

Both prenatal (maternal) and umbilical cord 

blood lead values were inversely related to MDI at 

3 months. For prenatal blood lead, this effect took 

the form of a covariate-adjusted reduction of 0.34 

MDI points per microgram per deciliter of lead in 

blood, or 9.2 points across the range of prenatal 

blood lead values observed in the sample. Each. 

microgram per deciliter increase in umbilical cord 

blood lead was associated with a covariate-adjusted 

Blood Source 0 SE t P 

Value Value 

Range 

of 

Effect 

Prenatal -.34 0.17 -1.96 .05 

Umbilical corfd -.60 

Newborn (10 d) .06 

Newborn (3 mo) -.23 

0.26 -2.30 

0.22 0.26 

0.18 -1.30 

.02 

.79 

.20 

9.2 

16.3 

0

 Other variables remaining in final models as statistically significant (P < .05) covariates included birth 

weight, gestation, maternal age, child race, child sex, and 

socioeconomic status. Neither Composite Index of Tobacco and Alcohol Consumption nor quantity of cigarettes smoked per day remained in the models as statistically significant covariates. P value calculated by twotailed test. 

reduction of 0.60 MDI points, or 16.8 MDI points 

across the range of cord blood lead values observed 

in the sample. None of the newborn assessments of 

blood lead were associated with 3-month MDI after 

covariate adjustment. 

The covariate-adjusted parameter estimates for 

fetal lead exposure variables on 6-month MDI are 

given in Table 6. As was the case for 3-month MDI, 

variables other than blood lead which were retained 

in the final model as statistically significant predictors of Bayley MDI were birth weight, gestation, 

maternal age, child sex, and socioeconomic status. 

Prenatal (maternal) and ten-day newborn blood 

lead levels were both significantly related to reductions in Bayley MDI at 6 months of age. For prenatal blood lead, dose-related deficits in MDI were 

more pronounced in boys, as indicated by the significant prenatal blood lead by sex. interaction. 

Multiple regression analyses for boys only showed 

that each microgram per deciliter increase in prenatal blood lead was associated with a covariateadjusted decrement of 0.34 MDI points (P < .01), 

or an overall decrement of 22.7 MDI points across 

the range of prenatal blood lead observed in the 

sample. 

For newborn (ten-day) blood lead, dose-related 

deficits in MDI were most pronounced in infants 

from the poorest families, as indicated by the significant ten-day blood lead by socioeconomic status 

interaction. Multiple regression analyses for infants 

with scores less than the median socioeconomic 

status score showed that each microgram per deciliter increase in ten-day blood lead level was associated with a covariate-adjusted decrement of 0.73 

MDI points (P < .03), or 16.1 MDI points across 

the range of ten-day blood lead observed in the 

sample. Umbilical cord and 3-month blood lead 

values were also inversely related to 6-month MDI 

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TABLE 6. Covariate-Adjusted Parameter Estimates for Fetal Lead Exposure Variables 

on 6-Month Bayley Mental Developmental Index* 

Blood Source or Interaction 

Prenatal (maternal) 

Prenatal x child sex 

Umbilical cord 

Newborn (10 d) 

Newborn x socioeconomic status 

Newborn (3 mo) 

0 

-0.76 

1.27 

-0.66 

-3.49 

0.18 

-0.48 

SE 

0.34 

0.51 

0.37 

1.29 

0.07 

0.27 

t Value 

-2.16 

2.49 

-1.76 

2.69 

2.45 

-1.78 

P Value 

.02 

.01 

.08 

.007 

.01 

.07 

Range of 

Effect 

22.7t 

16.lt 

* Other variables remaining in final models as statistically significant (P < .05) covariates 

included birth weight, gestation, maternal age, child race, child sex, and socioeconomic 

status. Neither Composite Index of Tobacco and Alcohol Consumption nor quantity of 

cigarettes smoked per day remained in the models as statistically significant covariates. P 

value calculated by two-tailed test. 

t In male infants. 

| In infants with scores less than the median socioeconomic status score for the sample. 

but were not quite statistically significant when 

using a two-tail test. Nevertheless, the consistency 

of an apparent adverse neurobehavioral effect 

across blood lead variables was striking. 

Structural Equation Analyses 

Multiple regression analyses are severely limited 

by the fact that they can only evaluate static interactions between toxicant exposure and other factors 

that can affect neurobehavioral development.28 

Many of the variables considered as potential covariates or confounders may actually be health 

outcomes of intoxication and thereby mediate later 

developmental deficits. Perinatal health factors 

such as birth weight and gestational age are good 

examples. Previous research with the Cincinnati 

data base has demonstrated that higher maternal 

blood lead levels are associated with statistically 

significant reductions in weight at birth.10 Rather 

than considering birth weight or other perinatal 

health factors as confounders of the blood leadbehavior relationship in multiple regression analyses, such covariables may be more appropriately 

modeled (both conceptually and statistically) as 

mediators of later neurobehavioral deficits. Until 

recently, adequate statistical techniques to estimate 

such indirect effects in longitudinal studies have 

not been available. Now, many of the statistical 

problems inherent in path analysis have been 

solved by the method known as structural equations.29*

30

 This statistical method is typically used 

to test a set of specific causal hypotheses against a 

set of observed data (usually a covariance matrix of 

observed relations among the variables in the 

models). In the present study, structural equation 

analyses were used to test the hypothesis that leadrelated deficits in infant neurodevelopmentatstatus 

at 3 and 6 months of age were due, in part, to leadrelated lower birth weight and shortened gestational age. Prenatal (maternal) blood lead was modeled in these analyses, because it was most highly 

correlated with perinatal outcomes in previous work 

with these data.10 

The structural analysis was conducted in the 

following manner. The variables shown in Table 2 

were ordered according to the causal relationships 

hypothesized to exist. Child's race and sex, mother's 

age, socioeconomic status, Composite Index of Tobacco and Alcohol Consumption, gravidity, and 

parity were initially included as exogenous (independent) variables in all structural equations. In 

addition, the static interaction of prenatal blood 

lead with each of these exogenous variables was 

initially entertained in each of the structural equation models. The endogenous (dependent) variables 

included in these models were prenatal blood lead, 

gestation, birth weight, Obstetrical Complications 

Scale score, Postnatal Complications Scale score, 

and, finally, 3- or 6-month MDI and PDI. This list 

reflects the ordering of posited causal events among 

these variables (ie, prenatal blood lead is hypothesized to affect each of the endogenous variables that 

follow, whereas MDI and PDI are assumed to be 

final outcomes in the model). Furthermore, the 

variables of birth weight and gestational age were 

allowed to be noncausally correlated with the Obstetrical and Postnatal Complications Scale scores. 

Finally, MDI and PDI were treated as independent, 

final outcomes, and not correlated in a causal manner. Prenatal blood lead was log transformed, because it served as an intermediate endogenous variable and assumptions of normality of distribution 

needed to be met. 

From this initial (fully parameterized) model, 

nonsignificant paths were removed from the structural equations until all remaining paths were significant at P **S .10 (two-tail test). Maximum likelihood estimates of the remaining parameters in the 

model were then obtained using the Linear Struc-

% 

*> 

I 

! 

726 FETAL LEAD EXPOSURE 
^Spsp^'^Pff-. "T^T. r^W^B

JtV*AJlj,y|. "•" P.8 

tural Relations (LJSREL) program of Joreskog and 

Sorbom.3 Any nonsignificant (P > .05) parameters 

were removed from the models in a stepwise fashion. An exogenous variable that was not found to 

be significantly related to any endogenous variable 

within the structural equation was eliminated from 

the model. Similarly, an endogenous variable that 

was not significantly affected by any other variable, 

and did not significantly affect any other endogenous variable, was eliminated from the model. 

This strategy of backward removal of nonsignificant parameters was used, and a final model was 

derived for both the 3-month and 6-month developmental assessments. The only remaining static 

interaction term was prenatal blood lead by sex on 

6-month Bayley scales outcomes (as was the case 

in the standard multiple regression analyses). 

The final structural model derived from these 

analyses for 3-month MDI and PDI is shown in Fig 

2. As predicted, prenatal blood lead was inversely 

related to birth weight (-150 g per natural log unit 

of blood lead), which, in turn, was positively associated with 3-month MDI and PDI. (Log blood lead 

values ranged from 0 to 3.295837 while antilog 

values ranged from 0 to 27.) Prenatal blood lead 

was also inversely associated with gestational age 

(-0.46 weeks per log unit of blood lead), which, in 

turn, was also positively associated with Bayley 

developmental outcomes. Therefore, a portion of 

lead's adverse effect on behavioral development at 

3 months of age was "indirect," through its dynamic 

interaction with fetal growth and maturational variables. Prenatal blood lead was associated with less 

optimal Postnatal Complications Scale scores (Fig 

2). 

In addition to lead, consumption of tobacco and/ 

or alcohol products during pregnancy was related 

to both higher prenatal blood lead values (as has 

been found in other studies), lowered birth weight, 

and, ultimately, lower MDI and PDI through its 

effect on fetal growth. It is interesting that this 

effect should be reliable in a sample characterized 

by a relatively low level of consumption of these 

products and attests to the general validity of the 

Composite Index of Tobacco and Alcohol Consumption variable. 

The structural equation analyses results for 6-

month MDI and PDI are presented in Figure 3. For 

the most part, the 3- and 6-month models were 

identical, with the exception of race and mother's 

SfN 

Postnatal ConeI lest ions 

Scale 

Horner's age 

Parity 

S.t.S 

CIUC 

\"» , 

" \ 

-.on(-.iJJ)^ 

Race 

-?.4J(-.I49) 

Fig 2. Relationships among prenatal lead (Pb) exposure, perinatal outcomes, and developmental variables as 

revealed through structural equation analyses for 3-

month Mental Developmental Index (MDI) and Psychomotor Developmental Index (PDI). Unstandardized 

and (standardized) regression coefficients are shown. 

Omnibus goodness-of-fit test provided by LISREL31 proOostetrical Cow) I canons 

Scale 

gram was surveyed at each step of elimination procedure. 

At no time did approximate x2 square value for goodness 

of fit exceed expectation, indicating that final models so 

obtained fit the data well. Abbreviations: S.E.S., socioeconomic status; CITAC, Composite Index of Tobacco 

and Alcohol Consumption. 

ARTICLES 727 
P.9 

Race 

Postnatal Corelicattons 

Scale 

Prenatal lloorj Pa 

a $•» 

s.c.s. 

testation 

llrtn veignt 

Fig 3. Relationships among prenatal lead (Pb) exposure, perinatal outcomes, and developmental variables as 

revealed through structural equation analyses for 6-

month Mental Developmental Index (MDI) and Psychomotor Developmental Index (PDI). Unstandardized 

and (standardized) regression coefficients are shown. 

Omnibus goodness-of-fit test provided by LISREL31 proage predicting prenatal blood lead value in the 6-

month model and the aforementioned prenatal 

blood lead by sex interaction on 6-month Bayley 

developmental outcomes. Also, the absolute size of 

the standardized and unstandardized regression 

coefficients differ to a certain degree because the 

variables in the models themselves slightly differed 

and the fact that each model contains some subjects 

who are unique (ie, a small number of study subjects 

did not receive a 3-month Bayley assessment and a 

few did not receive a 6-month Bayley assessment). 

To summarize, there is ample evidence in these 

multiple regression and structural equation analyses of both direct and indirect effects of fetal lead 

exposure on early neurobehavioral development. 

Prenatal, umbilical, and newborn blood lead levels 

were directly related to deficits in Bayley MDI at 

either 3 months, 6 months, or at both assessments. 

Boys and infants from the poorest families appeared to be most sensitive to these psychoteratogenic influences. Furthermore, in utero exposure to 

lead, as indexed by prenatal (maternal) blood lead 

value, may have exerted additional effects on development through decrements in fetal growth and 

maturation. 

DISCUSSION 

Indices of fetal lead exposure were more strongly 

and consistently related to 3- and 6-month Bayley 

Prenatal limn PO 

I Sei 

gram was surveyed at each step of elimination procedure. 

At no time did approximate x2 square value for goodness 

of fit exceed expectation, indicating that final models so 

obtained fit the data well. Abbreviations: S.E.S., socioeconomic status; CITAC, Composite Index of Tobacco 

and Alcohol Consumption. 

MDI than PDI. This finding is in accord with 

previous studies.7'

9

 The MDI is also a more reliable 

and valid subscale at these ages than the PDI.27 

Therefore, it is not surprising that this scale was 

the most sensitive of developmental outcome variables in the investigation. 

At 3 months, both prenatal and umbilical cord 

blood lead levels were associated with deficits in 

MDI after covariate adjustment. A caveat may be 

in order, however, with regard to the cord blood 

lead results. This finding is based on slightly fewer 

than one third of the subjects in the study; therefore, it may not be as reliable an effect as that found 

for other blood lead variables. However, other studies have reported similar relationships between lead 

in cord blood and neurobehavioral deficits.7"

9 

At 6 months, the results were more complex but 

still consistent with study hypotheses. Two key 

perinatal risk factors appeared to be operative in 

modifying the effects of fetal exposure to lead. First, 

male infants expressed a much greater 6-month 

neurobehavioral deficit in response to fetal exposure as assessed by maternal blood lead. This finding is interesting in that several epidemiologic studies have shown that the relative risk of perinatal 

mortality and morbidity is higher in boys,32,33 including the risk of poor reproductive outcomes and 

postnatal development due to fetal exposure to 

industrial pollutants.34,35 This "male disadvantage" 

may be due to slower maturation and integration 

.•• * 

1' 

'I 

•i 

728 FETAL LEAD EXPOSURE I 
—**- » •*—1 — p.fl l P.10 

of organ systems in boys.38 Boys also have a higher 

rate of mental developmental disability in the general population37,38

 and display more profound intellectual deficits as a result of cortical lesions.39,40 

Boys, and perhaps male brains, may be more sensitive to the toxic effects of in utero chemical exposures. 

Infants of lower social class families appeared to 

be more sensitive to the effects of fetal exposure as 

indexed by newborn (ten-day) blood lead levels. 

This finding is consistent with previous studies in 

which a more adverse behavioral effect of lead 

exposure was shown among the lower social 

classes.41,42 Neurobehavioral sequelae as a result of 

perinatal insult has bsen shown to be more severe 

among the lower social classes. It is likely that social 

class is a collective surrogate for a variety of prenatal stressors that may affect reproductive fitness 

and make the expression of neurobehavioral deficits 

more likely in infants from the poorest families.43,44 

Umbilical cord and 3-month blood lead levels 

were also inversely associated with 6-month Bayley 

MDI, although at not quite a statistically significant level when using a two-tailed test. Nevertheless, the consistency of negative relationships 

across blood lead measures was impressive. 

Another noteworthy finding in this study was. 

that early lead-related neurobehavioral deficits \ 

were partly mediated through birth weight and^ 

gestation. There are a number of studies in which 

the effects of prenatal lead exposure on obstetrical 

outcomes were evaluated. Lead has been shown to 

affect placental metabolism in an in vitro study.46 

There is also evidence that prematurity, lower birth 

weight, and premature rupture of membranes is 

associated with maternal blood lead values of 30 

Mg/dL or greater.46 Although one recent prospective 

study has reported a relationship between low-level 

prenatal lead exposure and premature birth,12 this 

is the first study to report an independent, inverse 

relationship between prenatal blood lead and birth 

weight at levels of less than 30 Mg/dL of whole 

blood. 

The finding of both direct and mediated effects 

of low-level fetal lead exposure on development 

suggests that what constitutes safe levels of exposure for children may not be safe for the fetus. It 

should be stressed that neurobehavioral deficits 

were related to lead exposures in this study that 

were well below the "corrective action" level as 

proposed by the Centers for Disease Control.47 Indeed, prenatal (maternal) blood lead levels in this 

sample were well within the range found for US 

women in their reproductive years as assessed by 

the National Health and Nutrition Examination 

Survey.48 These findings also suggest that in-depth 

studies of toxicant exposure during the course of 

pregnancy are essential in defining the "critical 

period" of exposure for given effects and in understanding the possible mechanisms for these eariy 

neurobehavioral deficits. This is by no means a new 

concept in the field of reproductive toxicology.48,50 

However, because lead is one of several widely 

distributed toxicants in our environment, the findings of this study deserve the special attention of 

pediatricians, obstetricians, and public health offi-

: 

Future studies with the Cincinnati cohort will 

help to determine whether the developmental effects of fetal lead exposure persist into later childhood. By virtue of their geographical location and 

housing, much of the study cohort is at considerable 

risk for clinically significant elevations in blood 

lead levels.16 It will be important to ascertain how 

these postnatal exposures affect current behavioral 

functioning and future intellectual attainment. 

This research is supported by a Program Project grant 

from the National Institute of Environmental Health 

Sciences (P01-ES01566-08), Paul B. Hammond, principal 

investigator. 

The authors thank the many technicians and support 

staff at the University of Cincinnati College of Medicine 

and Babies Milk Fund Association clinic who helped to 

make this research possible. 

1. Cantarow A, Trumper M: Lead Poisoning. Baltimore, Williams & Wilkins Co, 1944 " -

2. Oliver T: Load Poisoning: From the Industrial, Medical and 

Social Points of View. New York, Paul B. Hoeber, 1914 

3. Rom WN: Effects of lead on the female and reproduction: 

A review. Mt Sinai Med 1976;43:542-552 

4. Barltrop D: Transfer of lead to the human fetus, in Barltrop 

D (ed): Mineral Metabolism in Pediatrics. Oxford, Blcctocell 

Scientific, 19S9, pp 135-151 

5. Gershanih JJ, Brooks GG, Little JA: Blood lead values in 

pregnant women and their offspring. Am J Obstet Gynecol 

1974;119:508-511 

6. Ghafour SY, Khuffaah FA, Ibrahim HS, et al: Congenital 

lead intoxication with seizures due to prenatal axpoaure. 

Clin Pediatr 1984;23:282-283 

7. Bellinger DC, Needleman HL, Leviton A, et al: Early csnsorimotor development and prenatal exposure to lead. Neurobshav Toxicol Teratol 1984;6:387-402 

8. Bellinger D, Leviton A, Needleman HL, et al: Low level Iced 

exposure and infant development in the first year. Neurobehav Toxicol Teratol 1986;8:151-161 

9. Bellinger D, Leviton A, Watemaui C, et al: Low level lead 

exposure and early development in socio-economically advantaged urban infants, in Smith M (ed): Proceedings of the 

International Workshop on Effects of Lead Exposure on 

Neurobshavioml Development, in press, 1987 

10. Bornschein RL: The effect of low level prenatal lead exposure on fetal growth. Presented at the Environmental Protection Agency/European Economic Community Conference: Lead Exposure and Neurobehavioral Effects in Children, Edinburgh, Scotland, Sept 8-12,1988 

11. Dietrich KN, Krafft KM, Bier U, et al: Early effects of fetal 

lead exposure: Neurobehavioral findings at 6 months. Int J 

Biosot Res 1986;8:2-19 

12. McMichael AJ, Vimpani GV, Robertaon EF, et al: The Port 
P.11 

Pirie cohort study: Maternal blood lead and pregnancy 

outcome. J Epidemiol Community Health 1986;40:18-25 

13. Needleman HL, Rabinowitz M, Leviton A, et al: The relationship between prenatal exposure to lead and congenital 

anomalies. JAMA 1984;251:2956-2999 

14. Bornschein RL, Hammond PB, Dietrich KN, et al: The 

Cincinnati prospective study of low level lead exposure and 

its effects on child development Environ Res 1985;38:4-18 

15. Clark CS, Bornschein RL, Succop P, et al: Condition and 

type of housing as an indicator of potential environmental 

lead exposure and pediatric blood lead levels. Environ Res 

1985;38:46-53 

16. Ballard JL, Novak KK, Driver MA: Simplified score for 

assessment of fetal maturation in newly born infanta. J 

Pediatr 1979-95:769-774 

17. Dietrich KN, Krafft KM, Pearson DT, et ak Contribution 

of social and developmental factors to lead exposure during 

the first year of life. Pediatric* 1985;75:1114-1119 

18. Hunt TJ, Hepner R, Seaton KW: Childhood lead poisoning 

and inadequate child care. Am J Dis Child 1982;136:538-

542 

19. Milar CR, Schroeder SR, Mushak P, et ak Contribution of 

the caregiving environment to increased lead burden in 

children. Am J Ment Defic 1982;84:339-344 

20. Stark AD, Quah RF, Meigs JW, et ak Relationship of 

sociodemographk factors to blood lead concentrations in 

New Haven children. J Epidemiol Community Health 

1982;36:133-139 

21. Littman B, Parmelee AH: Medical correlates of infant development Pediatrics 1978;61:470-474 

22. Hobel CJ: Development of POPRAS-problem oriented perinatal risk assessment system, in Harris TR (ed): The Use 

of Computers in Perinatal Medicine. New York, Praeger, 

1980, pp 117-139 

23. Hollingshead AB: Four factor index of social status, working 

paper. New Haven, CT, Yale University, 1975 

24. Deleted in proof 

25. Dales LG, Ury HK: An improper use of statistical significance testing in studying covariables. Int J Epidemiol 

1978;7:373-375 

26. Hammond PB: Measurement of lead. Presented at the Royal 

Society of Canada Commission on Lead in the Environment, 

National Research Council, Ottawa, Canada, March 13, 

1985 

27. Bayley N: The Bayley Scales of Infant Development. New 

York, Psychological Corporation, 1969 *-

28. Pearson DT, Dietrich KN: The behavioral toxicology and 

teratology of childhood: Models methods and implications 

for intervention. Neurotoxicology 1985;6:165-182 

29. Joreskog KG: Statistical estimation of structural models in 

longitudinal developmental investigations, in Nesselroade 

JR, Baltes PB (eds): Longitudinal Research in the Study of 

Behavior and Development New York, Academic Press, 

1979, pp 303-351 

30. Vinod HD, Ullah A: Recent Advances in Regression Methods. 

New York, Marcel Dekker Inc, 1981 

31. Joreskog KG, Sorbom D: LISREL IV: Analysis of Linear 

Structural Relationships by the Method of Maximum Likelihood, User's Guide. Chicago, International Educational 

Services, 1985 

32. Abramowicz M, Barnett HL Sex ratio of infant mortality: 

Trends of change. Am J Dis Child 1970;119:314-315 

33. Naeye RL, Burt LS, Wright DL, et al: Neonatal mortality, 

the male disadvantage. Pediatrics 1971,48*902-906 

34. Scragg RKR, McMichael AJ, Clark PD: Pollution and sex 

ratio of births. Med J Aust 1977;2:68 

35. McKeown-Eyssen GE Ruedy J, Neims A: Methyl mercury 

exposure in Northern Quebec: 2. Neurologic findings in 

children. Am J Epidemiol 1983;118:470-479 

36. Khoury MJ, Marks JS, McCarthy BJ, et al: Factors affecting 

the sex differential in neonatal mortality. The role of respiratory distress syndrome. Am J Obsttt Gynecol 

1985;151:777-782 

37. Gross MB, Wilson WC: Minimal Brain Dysfunction: A Clinical Study of Incidence, Diagnosis, and Treatment in over 

1000 Children. New York, Bninner/MazeL 1974 

38. Schaffer D, Schonfeld I, O'Connor PA, et al: Neurological 

soft signs: Their relationship to psychiatric disorder and 

intelligence in childhood and adolescence. Arch Gen Psychiatry 1985;42342-351 

39. Bornstein RA, Matarazzo JD: Relationship of sex and the 

effects of unilateral lesions on the Wechtler Intelligence 

Scales: Further considerations. J Nerv Ment Dis 

1984;172:707-710 

40. Ingtis J, Lawson JS: Sex differences in the effects of unilateral brain damage on intelligence. Science 1981;212:693-696 

41. Harvey PG, Hamlin MW, Kumar R, et al: Blood lead, 

behavior, and intelligence test performance in preschool 

children. Sci Total Environ 1984;40:45-60 

42. Winneke G, Kraemer U: Neuropsychological effects of lead 

in children: Interactions with social background variables. 

Neuropsychobiology 1984;11:195-202 

43. Broman SH, Nichols PL, Kennedy WA: Preschool IQ: Prenatal and Early Developmental Correlates. Hillsdale, NJ, 

Erlbaum, 1975 

44. Werner E, Bierman JM, French FF: The Children of Kauai 

•f Honolulu, University of Hawaii, 1971 

4£. Dawson EB, Cravy WD, Clark RR, et ak Effect of trace 

metals on placental metabolism. Am J Obstet Gynecol 

'• 1969;103:253-256 

46. Fahim MS, Fahim Z, Hall DG: Effects of subtoxic lead levels 

on pregnant women in the state of Missouri. Res Common 

Chem Pathol Pharmacol 1976;13:309-331 

47. Preventing lead poisoning in young children: A statement by 

the Centers for Disease Control US Department of Health 

and Human Services publication No. 99-2230. Atlanta, Centers for Disease Control, 1986 

48. Mahaffey KR, Annest JL, Roberts J, et al: National estimates of blood lead levels: United States, 1976-1980. JV Engl 

J Med 1982;307:573-579 

49. Clarkaon TW, Nordberg GF, Sager PR: Reproductive and 

developmental toxicity of metals. Scand J Work Environ 

Health 1985;11:145-154 

50. Weiss B, Spyker JM: Behavioral implications of prenatal 

and early postnatal exposure to chemical pollutants. Pediatrics 1974;53:851-862 

t 

a I 

730 FETAL LEAD EXPOSURE