Decrease in Birth Weight in Relation to Maternal Bone-Lead Burden

Department of Environmental Health , Harvard University, Cambridge, Massachusetts, United States
PEDIATRICS (Impact Factor: 5.47). 12/1997; 100(5):856-62. DOI: 10.1542/peds.100.5.856
Source: PubMed
Birth weight predicts infant survival, growth, and development. Previous research suggests that low levels of fetal lead exposure, as estimated by umbilical cord blood-lead levels at birth, may have an adverse effect on birth weight. This report examines the relationship of lead levels in cord blood and maternal bone to birth weight.
Umbilical cord and maternal venous blood samples and anthropometric and sociodemographic data were obtained at delivery and 1-month postpartum. Blood-lead levels were analyzed by atomic absorption spectrophotometry. Maternal tibia and patella lead levels were determined at 1-month postpartum with use of a spot-source 109Cd K-X-ray fluorescence instrument. The relationship between birth weight and lead burden was evaluated by multiple regression with control of known determinants of size at birth.
Data on all variables of interest were obtained for 272 mother-infant pairs. After adjustment for other determinants of birth weight, tibia lead was the only lead biomarker clearly related to birth weight. The decline in birth weight associated to increments in tibia lead was nonlinear and accelerated at the highest tibia lead quartile. In the upper quartile, neonates were on average, 156 grams lighter than those in the lowest quartile. Other significant birth weight predictors included maternal nutritional status, parity, education, gestational age, and smoking during pregnancy.
Our results indicate that bone-lead burden is inversely related to birth weight. Taken together with other research indicating that lead can mobilize from bone into plasma without detectable changes in whole blood lead, these findings suggest that bone lead might be a better biomarker than blood lead. Because lead remains in bone for years to decades, mobilization of bone lead during pregnancy may pose a significant fetal exposure with health consequences, long after maternal external lead exposure has declined.


Available from: Howard Hu, Sep 19, 2014
Maternal Bone Lead as an Independent Risk Factor for Fetal
Neurotoxicity: A Prospective Study
Ahmed Gomaa, MD, ScD*‡; Howard Hu, MD, ScD*§; David Bellinger, PhD; Joel Schwartz, PhD*§;
Shirng-Wern Tsaih, ScD*‡; Teresa Gonzalez-Cossio, PhD¶; Lourdes Schnaas#; Karen Peterson, ScD**;
Antonio Aro, PhD*; and Mauricio Hernandez-Avila, MD, ScD¶
ABSTRACT. Objective. A number of prospective
studies have examined lead levels in umbilical cord
blood at birth as predictors of infant mental develop-
ment. Although several have found significant inverse
associations, others have not. Measurement of lead levels
in maternal bone, now recognized as the source of much
fetal exposure, has the potential to serve as a better or
complementary predictor of lead’s effect on the fetus.
Our objective was to compare lead levels in umbilical
cord blood and maternal bone as independent predictors
of infant mental development using a prospective de-
Methods. We recruited women who were giving birth
at 3 maternity hospitals in Mexico City that serve a ho-
mogeneous middle-class community. Umbilical cord
blood lead levels were measured by graphite furnace
atomic absorption spectroscopy, and maternal lead levels
in cortical (tibial) and trabecular (patellar) bone were
measured within 4 weeks of giving birth using a 109-Cd
K-x-ray fluorescence instrument. At 24 months of age,
each infant was assessed using the Bayley Scales of In-
fant Development-II (Spanish Version).
Results. A total of 197 mother-infant pairs completed
this portion of the study and had data on all variables of
interest. After adjustment for other well-known determi-
nants of infant neurodevelopment, including maternal
age, IQ, and education; paternal education; marital status;
breastfeeding duration; infant gender; and infant illness,
lead levels in umbilical cord blood and trabecular bone
were significantly, independently, and inversely associ-
ated with the Mental Development Index (MDI) scores of
the Bayley Scale. In relation to the lowest quartile of
trabecular bone lead, the second, third, and fourth quar-
tiles were associated with 5.4-, 7.2-, and 6.5-point decre-
ments in adjusted MDI scores. A 2-fold increase in cord
blood lead level (eg, from 5 to 10
g/dL) was associated
with a 3.1-point decrement in MDI score, which is com-
parable to the magnitude of effect seen in previous stud-
Conclusion. Higher maternal trabecular bone lead
levels constitute an independent risk factor for impaired
mental development in infants at 24 months of age. This
effect is probably attributable to mobilization of mater-
nal bone lead stores, a phenomenon that may constitute
a significant public health problem in view of the long
residence time of lead in bone. Pediatrics 2002;110:110
118; lead, bone, epidemiology, neurotoxins.
ABBREVIATIONS. K-XRF, K-x-ray fluorescence; BSID, Bayley
Scales of Infant Development; MDI, Mental Development Index;
PDI, Psychomotor Development Index; SD, standard deviation.
he blood lead level considered to be toxic to
children has been revised downward several
times during the past 30 years.
The accumu-
lated body of research that engendered this evolu-
tion in perspective has identified the central nervous
system as particularly vulnerable to the harmful ef-
fects of lead. A key issue that remains to be clarified
is the extent to which the fetal brain is susceptible to
lead toxicity. Although much attention has been paid
to public health efforts to reduce lead exposure in
children between the ages of 6 months and 5 years,
when environmental lead exposures tend to be great-
est, less attention has been paid to understanding the
transfer of lead from mother to fetus and its resulting
health effects.
A major obstacle in assessing the effects of prenatal
lead exposures on neurobehavioral development is
the measurement of fetal dose. A variety of biological
markers of dose have been used or proposed, includ-
ing umbilical cord blood lead level, maternal blood
level at different times during pregnancy, amniotic
fluid lead level, and the concentrations of lead in
cord or placental tissues.
In 1 study, only modest
correlations (0.06 0.38) were found among the
lead levels of such markers (maternal blood at 14 –20
weeks’ gestation, approximately 32 weeks’ gestation,
and delivery; umbilical cord blood; umbilical cord
tissue; and placental tissue).
Because the kinetics of
lead in the maternal-fetal unit are incompletely un-
derstood, these low correlations suggest that these
various biological markers provide largely nonre-
dundant information about fetal exposure. It is im-
portant, therefore, that the utility of such biomarkers
be compared as predictors of fetal risk for adverse
health outcomes.
From the *Department of Environmental Health, Harvard School of Public
Health, Boston, Massachusetts; ‡National Institute for Occupational Safety
and Health, Morgantown, West Virginia; §Channing Laboratory, Depart-
ment of Medicine, Brigham and Women’s Hospital, Harvard Medical
School, Boston, Massachusetts; Neuroepidemiology Unit, Children’s Hos-
pital, Harvard Medical School, Boston, Massachusetts; ¶Centro de Investi-
gaciones en Salud Poblacional, Instituto Nacional de Salud Publica, Cuer-
navaca, Morelos, Mexico; #Department of Developmental Neurobiology,
Instituto Nacional de Perinatologia, Mexico City, Mexico; and **Department
of Nutrition, Department of Environmental Health, Harvard School of
Public Health, Boston, Massachusetts.
Received for publication Aug 23, 2001; accepted Feb 4, 2002.
Reprint requests to (H.H.) Channing Laboratory, 181 Longwood Ave, Bos-
ton, MA 02115. E-mail:
PEDIATRICS (ISSN 0031 4005). Copyright © 2002 by the American Acad-
emy of Pediatrics.
110 PEDIATRICS Vol. 110 No. 1 July 2002
Page 1
Most of the studies that have examined this topic
used maternal venous or umbilical cord blood lead
levels as indicators of fetal lead exposure. Although
some studies reported a significant inverse associa-
tion between fetal lead exposure using these indica-
tors and infant scores on tests of cognitive develop-
others did not.
This inconsistency in
study findings is likely to be the result, at least in
part, of differences in study populations and re-
search methodologies.
An additional possibility is
that lead levels in umbilical cord blood and maternal
venous blood measured at 1 point of time are impre-
cise surrogates of cumulative fetal exposure, result-
ing in varying amounts of exposure misclassification
in the different studies.
It is now recognized that mobilization of maternal
bone lead stores constitutes a major source of fetal
lead exposure. Recent isotopic speciation studies
have demonstrated that the skeletal contribution to
blood lead levels increases from 9% to 65% during
Maternal bone lead levels thus may
serve as a useful biological marker of long-term fetal
lead exposure over the course of pregnancy. With the
development of K-x-ray fluorescence (K-XRF) instru-
ments, it is now possible to make rapid, noninvasive
in vivo measurements of lead in maternal bone.
recent series of studies using this technique, our
group demonstrated that levels of lead in maternal
bone are more strongly associated than either mater-
nal venous blood or umbilical cord blood lead levels
with infant birth weight,
head circumference, and
birth length
and velocity of infant weight gain.
date, the association between maternal bone lead
levels and infant neurobehavior has not been evalu-
In this study, we compared umbilical cord blood
lead levels and maternal bone lead levels with re-
spect to their associations with neurodevelopment of
children at 24 months of age. We also examined the
association between children’s neurodevelopment
and their postnatal blood lead levels.
Study Population
This study was conducted under an established interinstitu-
tional collaboration among Harvard University, the Center for
Population Health Research of the National Institute of Public
Health in Mexico, The American British Cowdray Medical Center,
and the National Institute of Perinatology of Mexico. The study
cohort was recruited from 3 maternity hospitals in Mexico City
that serve a low- to moderate-income population (Mexican Social
Security Institute, Manuel Gea Gonzalez Hospital, and National
Institute of Perinatology).
Baseline information on health status and on social and demo-
graphic characteristics was collected from all eligible participants
at delivery and 1 month postpartum. Anthropometric data from
the mother and newborn, and umbilical cord and maternal venous
blood samples were gathered within 12 hours of delivery. Infor-
mation on estimated gestational age, based on the date of last
menstrual period, and characteristics of the birth and newborn
period were extracted from the medical records. Interviewers
explained the study to and obtained written consent from eligible
women who were willing to participate.
Exclusion criteria included factors that could interfere with
maternal calcium metabolism; medical conditions that could cause
low birth weight; logistic reasons that would interfere with data
collection, such as living in a household outside the metropolitan
area; intention not to breastfeed; prematurity (37 weeks) or an
infant with Apgar score at 5 minutes of 6 or under, a condition
requiring treatment in neonatal intensive care unit, birth weight
2000 g, or serious birth defects; a physician’s diagnosis of mul-
tiple fetuses; preeclampsia, psychiatric, kidney, or cardiac dis-
eases; gestational diabetes; history of repeated urinary infections;
family or personal history of kidney stone formation; seizure
disorder requiring daily medications; ingestion of corticosteroids
or blood pressure 140 mmHg systolic or 90 mmHg diastolic;
and single-parent households.
One month after delivery (5 days), each mother-infant pair
attended the research center for an evaluation that included mea-
surement of maternal bone lead using a spot-source
instrument. Participating mother-infant pairs were subsequently
assessed and interviewed when the infants were 12 and 24 months
of age. At each assessment, attempts were made to collect infant
venous blood for lead measurements and infant development was
assessed using the Bayley Scales of Infant Development II (BSID-
II; Spanish version; Bayley, N. Manual: Bayley Scales of Infant
Development, 2nd Ed. San Antonio, TX: The Psychological Cor-
poration, 1993). Transportation to and from our research center
was provided or reimbursed; no other compensation was offered.
Within 1 month after delivery, all participating mothers received
a detailed explanation of the study and its procedures, as well as
counseling on how to reduce environmental lead exposure. This
research protocol was approved by the Human Subjects Commit-
tees of the National Institute of Public Health of Mexico, the
participating hospitals, and the Harvard School of Public Health.
Blood Lead Measurements
Umbilical blood lead was collected in trace metal-free tubes at
delivery. Infant blood samples for lead analyses were collected in
capillary tubes after a thorough procedure for cleaning sites to be
lanced. Blood samples were analyzed using an atomic absorption
spectrometry instrument (Perkin-Elmer 3000, Chelmsford, MA) at
the metals laboratory of the American British Cowdray Hospital in
Mexico City. External blinded quality control samples provided
throughout the study period by the Maternal and Child Health
Bureau and the Wisconsin State Laboratory of Hygiene Coopera-
tive Blood Lead Proficiency Testing Program were also analyzed.
These analyses demonstrated good precision and accuracy with a
correlation coefficient of 0.99 and a mean difference of 0.17
Bone Lead Measurements
In vivo maternal bone lead measurements were taken within 4
weeks of delivery at 2 bone sites, the mid-tibial shaft (cortical
bone) and the patella (trabecular bone). Although, theoretically, it
would have been desirable to measure bone lead levels during
pregnancy itself instead of right after pregnancy, Mexican law
forbids nonemergency radiologic procedures in women during
pregnancy. In addition, bone lead levels have been shown to
change relatively little over 6 months of lactation,
a physiologic
period accompanied by bone resorption that is at least as strong or
stronger than that of pregnancy,
and there is no reason to believe
that use of postpartum bone lead measurements would introduce
bias into this study. Bone lead was measured noninvasively using
a spot-source
Cd K-XRF instrument constructed at Harvard
University and installed in a research facility in the American
British Cowdray Medical Center. The physical principles, techni-
cal specifications, and validation of this and other similar K-XRF
instruments have been described in detail elsewhere.
this instrument uses a spot-source
-ray source to provoke
the emission of fluorescent photons from target tissue that are then
detected, counted, and arrayed on a spectrum. The net signal is
determined after subtraction of Compton background counts by a
linear least-squares algorithm. The lead fluorescence signal is then
normalized to the elastic or coherently scattered
-ray signal,
which arises predominantly from the calcium and phosphorous
present in bone mineral. Because the instrument provides a con-
tinuous unbiased point estimate that oscillates around the true
bone lead value, negative point estimates are sometimes produced
when true bone lead level is close to 0. The instrument also
provides an estimate of the uncertainty associated with each mea-
surement, derived from a goodness-of-fit calculation of the spec-
trum curve that is equivalent to a single standard deviation. For
this study, 30-minute measurements were taken at the midshaft of
the left tibia and the left patella. Analysis of means and standard
Page 2
deviations of phantom-calibrated measurements did not disclose
any significant shift in accuracy or precision.
Measurements of Child Development and Potential
The BSID-II is a revision and restandardization of the BSID, the
most widely used test of infant development. The revised scale
can be used to assess the development of children between the
ages of 1 and 42 months. Scores have been shown to be sensitive
to a variety of prenatal, perinatal, and postnatal insults, including
lead exposure.
The BSID-II has also been used in numerous
cross-cultural studies of lead and child development .
A Spanish version of the BSID-II was developed by our re-
search group before this study. The team that administered the
BSID-II Spanish Version was led and trained by our group (L.S.
and D.B., respectively), with standardization and quality control
checks conducted through reviews of videotaped interviews.
Mental Development Index (MDI) and Psychomotor Development
Index (PDI) scores at 24 months of age were used as the primary
child development endpoints in this study.
A database was collected on demographic, socioeconomic, and
other factors that may constitute potential cofounders of the rela-
tionship between lead and child development. Maternal IQ was
assessed using the Information, Comprehension, Similarities, and
Block Design components of the Wechsler Adult Intelligence
Score, which has been translated into Spanish and used in Mexico.
Data Analyses
All analyses were performed using the SAS 6.12 (SAS, Inc,
Cary, NC). Descriptive statistics, appropriate transformations, and
identification of outliers were performed before bivariate and
multivariate analyses. Umbilical blood lead concentrations were
converted to their natural logarithmic values to normalize the
skewed distribution. K-XRF bone lead values with measurement
uncertainties exceeding 10 and 15 for tibia and patella, respec-
tively, were excluded from the analyses as part of an established
quality control procedure,
as these values reflect inadequate
sampling and are not correlated with the bone lead concentrations
The associations between MDI scores at 24 months and various
measurements of lead exposure and other covariates were first
examined in bivariate analyses. The adjusted associations between
MDI and biomarkers of lead were then assessed using multiple
linear regression. An initial model was fitted and included mater-
nal IQ, maternal age, child gender, maternal years of education,
paternal years of education, marital status, duration of breastfeed-
ing, and child hospitalization during the first 6 month of life.
Each of the lead biomarkers (umbilical blood lead, tibia bone
lead, and patella bone lead) was then added separately to this
model. A final model was selected using forward, backward, and
stepwise methods to assess for the most stable and robust models.
Variables significantly associated with MDI (P .1) were retained
for entry in forward, stepwise multiple regression with backward
elimination (entry and elimination criteria were P .1 and P .1,
respectively). Regression diagnostics were performed to assess the
effects of multicollinearity and potentially influential data points.
The multivariate linear regression models were repeated: 1)
after excluding potentially influential points, 2) using PDI at 24
months as the dependent variable, and 3) evaluating the interac-
tion between umbilical cord and bone lead levels. We also exam-
ined the associations between child blood lead levels at 12 and 24
months instead of or in addition to umbilical cord or bone lead
measurements in the multivariate models. Because bone lead lev-
els do not have a reference range and do not therefore have an
obvious interpretation, we also reran analyses treating bone lead
as a categorical variable divided into quartiles.
Of 630 mother-infant pairs who were initially eli-
gible for the study, 399 (63%) agreed to participate.
The most common reason for nonparticipation was
the inconvenience of making follow-up visits to the
bone lead research unit. Of these, 278 (70%) attended
the study evaluations through 24 months postpar-
tum, with 197 meeting the study criteria and com-
pleting the study with data on all variables of inter-
est. Of the 81 who attended the study evaluations but
were excluded from subsequent analyses, specific
reasons included birth weight 2000 g (n 3), miss-
ing data for birth weight (n 1), missing data for
gender (n 2), missing data for lactation (n 2),
missing data for maternal education (n 5), missing
data for paternal education (because of single mom
or missing data; n 32), missing data for patella
bone lead (n 24), missing data for tibia bone lead
(n 9), and missing data for maternal IQ (n 3). A
comparison of participants with nonparticipants or
participants with missing data (Table 1) showed no
meaningful differences with respect to maternal IQ,
maternal age, gender of the child, mother’s educa-
tion, father’s education, breastfeeding duration, and
the percentage of children hospitalized during 6
months from delivery. Participants were composed
of fewer parents who were living together (25%; as
TABLE 1. Characteristics of Nonparticipants and Participants in the Lead and Fetal Neurodevelopment Study
Characteristics Eligible Nonparticipants and
Participants With Missing Data
(N 197)
N % Mean (SD) N % Mean (SD) % Mean (SD)
Maternal IQ 458 85.4 (22.2) 261 84.6 (22.9) 86.5 (21.3)
Maternal age 630 24.6 (5.1) 433 24.3 (5.0) 25.1 (5.4)
Gender of the child
Male 340 54 233 55 54
Female 286 46 194 45 46
Mother years of education 621 9.3 (3.1) 424 9.2 (3.0) 9.6 (3.1)
Father years of education 558 9.8 (3.4) 361 9.7 (3.5) 9.9 (3.2)
Marital status
L 222 35 173 40 25
M 408 65 260 60 75
Breastfeeding duration
3mo 53 10 36 12 9
3–6 mo 170 32 95 31 34
6 mo 301 58 178 57 57
Child was hospitalized in the first 6 mo
Yes 69 11 51 12 10
No 561 89 382 88 90
L indicates living together; M, married.
Page 3
opposed to married) compared with nonparticipants
or participants with missing data (40%).
The levels of lead in umbilical cord blood demon-
strated a mean (standard deviation [SD]) value of 6.7
g/dL and ranged from 1.2 to 21.6
g/dL (Ta-
ble 2). The peripartum levels of lead in maternal
patella and tibia bones demonstrated mean (SD) val-
ues of 17.9 (15.2) and 11.5 (11.0)
g/g, respectively.
The blood lead levels of the infants rose slightly as
they grew older, with mean (SD) values of 7.2 (2.8)
and 8.4 (4.6)
g/dL at age 12 and 24 months, respec-
tively (Table 2). The peripartum levels of lead were
intercorrelated to a modest degree, with Spearman
correlation coefficients for lead levels in cord blood
versus tibia bone, cord blood versus patella bone,
and tibia bone versus patella bone of 0.13 (P .07),
0.17 (P .02), and 0.24 (P .001), respectively.
In bivariate analyses of the nonlead covariates,
only maternal IQ, maternal education, and paternal
education were significantly (P .05) associated
with MDI scores (Table 3). Maternal age, duration of
breastfeeding, and duration of child hospitalization
were not significantly associated with MDI scores.
Infants who had higher cord blood lead levels and
infants whose mothers had higher patella bone lead
levels had lower MDI scores (Table 3). When patella
bone lead levels were divided into 4 groups (quar-
tiles), with the lowest group as the reference cate-
gory, each of the higher 3 quartiles was associated
with lower MDI scores (Table 3). Higher tibia lead
levels were associated with lower MDI scores, but
this association was not significant.
In the multivariate analyses (Tables 4 and 5), the
directions of the associations were similar to those in
the bivariate analyses. After adjustment for maternal
IQ, maternal age, gender of the child, maternal and
paternal years of education, marital status, breast-
feeding duration, and child hospitalization status,
higher umbilical cord blood levels were significantly
associated with lower MDI scores. The adjusted as-
sociation between cord blood lead and MDI was
significant and similar in magnitude regardless of
whether patella bone lead was included in the
model, with P values of .02 and .05, respectively
(Table 4, models B and E). Similarly, adjusted patella
bone lead levels were significantly (or borderline
significantly) associated with lower MDI score re-
gardless of whether cord blood lead was included in
the model (Table 4, models C and E). Using the
lowest quartile of patella as the reference group,
patella bone lead levels in the second, third, and
fourth quartiles were associated with 5.1, 7.3, and 6.3
decrements in adjusted MDI scores, respectively (Fig
Adjusted tibia bone lead levels were associated
with lower MDI scores, but the relationship was not
as strong as the one for patella bone lead (Table 4,
model D). Forcing in marital status or excluding
influential points from the analysis did not change
appreciably the significance of the umbilical cord
concentration or patella lead level terms. There were
no apparent interactions among the different biolog-
ical markers of lead exposure.
In the final backward elimination linear regression
model, the only variables that were retained were
maternal IQ, umbilical cord blood lead concentra-
tion, and patella lead level (Table 5). A 2-fold in-
crease in umbilical cord blood lead concentration
was associated with a decrease of 3.1 points in ad-
justed MDI scores, and an increase in patella bone
lead concentration from the lowest to the highest 2
quartiles was associated with an additional decrease
of 6.5 to 7.2 points in adjusted MDI scores.
The adjusted blood lead concentrations at child
ages of 12 and 24 months were not significantly
associated with MDI when added individually to
model A (child blood lead levels at age 12 and 24
months were available only on 86 and 161 of the 197
participants, respectively). The
-coefficients and P
values for blood lead at 24 months were 0.30 and
.21, respectively, for the bivariate analyses, and
0.09 and P .72 for the multivariate analysis,
respectively. When forced into the final models of
MDI scores, neither the 12- nor the 24-month blood
lead values was associated with MDI score and the
effect estimates associated with cord blood lead and
maternal bone lead did not change at all.
When PDI scores at 24 months were used as the
dependent variable instead of MDI scores, the biva-
riate and adjusted associations with biomarkers of
lead exposure were not consistent or significant. In
bivariate analyses, umbilical cord lead levels and
patella bone lead levels were negatively associated
with PDI scores but with P values of .24 and .74,
respectively. Tibia bone lead was not associated with
PDI scores (P .88). In multivariate analyses, um-
bilical cord lead level was negatively associated with
PDI scores, but the P value was .14. Tibia and patella
lead levels were not associated with PDI score (P
.59 and .80, respectively).
TABLE 2. Blood and Bone Lead Levels in the Lead and Fetal Neurodevelopment Study
Peripartum Measurement
(N 197)
Range N (%)
Umbilical cord blood lead (
/dL) 6.7 (3.4) 1.2–21.6
0–4.9 74 (37.6)
5.0–9.9 92 (46.7)
10 31 (15.7)
Maternal patella bone lead (
g/dL) 17.9 (15.2) 1–76.6
Maternal tibia bone lead (
g/dL) 11.5 (11.0) 1–85.9
Childhood Measurements*
Blood lead at 12 mo 7.2 (2.8) 2.3–18.9
Blood lead at 24 mo 8.4 (4.6) 2.5–38.6
* N 86 at 12 months; N 161 at 24 months.
Page 4
The primary biomarker of prenatal lead exposure
used in previous prospective studies of lead and
child development has been the concentration of lead
in whole blood, sampled either from the umbilical
cord at the time of delivery or from maternal venous
blood at various points during pregnancy. We also
used this biomarker in the current study, and our
findings replicate, in 4 major respects, those reported
in some previous prospective studies that constitute
this complex and sometimes confusing literature.
First, as in the Boston
and Shanghai
studies, we
found a significant inverse relationship between the
concentration of lead in umbilical cord blood and
covariate-adjusted MDI scores at 24 months of age on
the BSID. In the Cleveland study,
cord blood lead
level was inversely related to MDI at 6, 12, and 24
months of age but not significantly. Similarly, in the
Yugoslavian study,
cord blood lead level was in
versely but not significantly associated with MDI at
24 months. In contrast, the associations between cord
or prenatal blood lead levels and MDI at 24 months
were neither inverse nor significant in the Cincin-
or Sydney
studies. In the Port Pirie Study,
average antenatal blood lead was inversely but not
significantly associated with MDI at 24 months,
whereas both maternal blood lead at delivery and
cord blood lead were neither inversely nor signifi-
cantly associated with MDI.
Second, the magnitude of the decline in MDI score
with increasing cord blood level, 3.1 points for each
doubling in blood lead level, is comparable to the
decline seen in the studies reporting significant as-
sociations. In the Boston study, for instance, the dif-
ferences between the mean scores of children in the
low (3
g/dL) and high (10
g/dL) cord blood
lead groups was 4 to 8 points in the 6- to 24-month
In the Chinese study of Shen et al,
with cord blood lead levels between 10.7 and 17.5
g/dL achieved MDI scores at 3, 6, and 12 months of
age that were 3 to 6 points lower than children with
cord blood lead levels below 7.4
Third, we found a lack of association between
children’s postnatal blood lead levels and develop-
ment within the first 2 years. The studies in which
such associations have been reported are generally
those in which the study cohorts have the highest
average blood lead levels (eg, Yugoslavia, Port Pirie).
Finally, as in most other studies of infants, prenatal
lead exposure was more strongly associated with
cognitive development scores (MDI) than with motor
development scores (PDI), although Ernhart et al
and Dietrich et al
did find significant associations
between maternal blood lead level during pregnancy
and PDI scores, in the latter study mediated by lead-
associated reductions in birth weight and gestational
The striking similarities and dissimilarities be-
tween the findings of our study and those of others
in this literature provide a context for interpreting
the novel contribution of this study, namely, the
demonstration of the importance of maternal bone
lead level as a biomarker of prenatal lead exposure
that provides information, independent of cord
blood lead level, about a fetus’s risk of reduced de-
velopmental performance in infancy.
In this study, increased levels of lead in maternal
bone were associated with lower MDI scores even
after controlling for cord blood lead level and other
covariates. The inclusion of maternal bone lead in-
creased the explanatory power of the model for men-
tal development from 8.6% to 11.1% (as reflected by
adjusted R
values); moreover, the inclusion of ma
ternal bone lead reduced the effect estimate associ-
ated with umbilical cord blood lead by only 15%
(4.94 to 4.21). Although relatively modest, the
TABLE 3. Bivariate Analyses of MDI in Relation to Maternal Lead Biomarkers and Other Factors
Coefficient Standard
Maternal IQ 0.18 0.05 3.74 .01
Maternal age (y) 0.22 0.19 1.14 .26
Female gender 3.09 2.05 1.50 .13
Mother years of education 3.33 1.10 3.02 .01
Father years of education 2.58 1.10 2.36 .02
Two-parent vs 1-parent household 3.18 2.37 1.34 .18
Duration of breastfeeding*
3–6mo 4.67 3.91 1.19 .23
6mo 1.73 3.74 0.46 .64
Child hospitalized in the first 6 mo 0.11 3.57 0.03 .98
Umbilical cord blood lead level (
g/dL)† 4.52 2.12 2.14 .03
Patella bone lead level (
g/g) 0.19 0.07 2.78 .01
Patella bone lead level
Second quartile 5.51 2.85 1.94 .06
Third quartile 8.63 2.83 3.04 .01
Fourth quartile 8.25 2.85 2.90 .01
Tibia bone lead level‡ 0.15 0.09 0.60 .11
Tibia bone lead level
Second quartile 0.47 2.93 0.16 .87
Third quartile 0.19 2.91 0.07 .95
Fourth quartile 2.37 2.93 0.81 .42
* In relation to 3 months.
† Log transformed.
‡ In relation to first (lowest) quartile.
Page 5
TABLE 4. Linear Regression of MDI in Relation to Maternal Lead Biomarkers and Other Factors
Variable Model
Mother IQ 0.15 0.06 .02 0.15 0.06 .02 0.12 0.06 .05 0.15 0.06 .02 0.13 0.06 .04
Maternal age (y) 0.25 0.19 .19 0.23 0.19 .22 0.15 0.19 .44 0.20 0.20 .32 0.15 0.19 .43
Gender (female vs male) 3.16 2.05 .13 3.06 2.02 .13 2.76 2.03 .18 2.96 2.06 .15 2.74 2.02 .18
Total years in school mom 0.29 1.54 .85 0.47 1.52 .76 0.33 1.52 .83 0.29 1.54 .85 0.48 1.51 .75
Total years in school dad 1.06 1.24 .39 0.95 1.22 .44 1.36 1.23 .27 0.90 1.25 .47 1.21 1.23 .32
Two-parent vs 1-parent household 2.19 2.37 .36 2.25 2.35 .34 2.76 2.36 .25 2.18 2.37 .36 2.71 2.34 .25
Breastfeeding duration (mo) 0.79 1.57 .61 0.48 1.55 .76 0.58 1.55 .71 0.69 1.57 .66 0.35 1.54 .82
Child hospitalization in first 6 mo 0.99 3.52 .78 0.55 3.48 .87 0.10 3.51 .98 0.78 3.52 .83 0.28 3.49 .94
Umbilical cord lead level (
g/dL)† 4.94 2.0653 .0179 4.21 2.09 .05
Maternal patellar lead (
g/g) 0.16 0.07 .03 0.13 0.07 .07
Maternal patellar lead*
Second quartile 5.25 2.81 .06 5.05 2.78 .07
Third quartile 7.66 2.85 .01 7.32 2.83 .01
Fourth quartile 7.20 2.88 .01 6.33 2.88 .03
Maternal tibial lead (
Maternal tibial lead* 0.10 0.10 .30
Second quartile 0.80 2.88 .78
Third quartile 0.18 2.89 .95
Fourth quartile 1.48 2.94 .62
SE indicates standard error.
* In comparison to first (lowest) quartile.
† Log transformed.
Page 6
influence of bone lead is likely underestimated by
this model because the bone lead measurements en-
tail a substantial amount of random error, which
tends to attenuate the apparent magnitude of ef-
In addition, as Gulson et al
pointed out, bone
lead is a source of a substantial fraction of cord blood
lead. Hence, some of the effect of bone lead is being
captured by cord blood lead. Overall, this finding
suggests that the general effect of fetal lead exposure
on subsequent neurodevelopment has been underes-
timated by reliance on cord blood lead levels to
reflect fetal lead exposure.
What does bone lead level that is not captured by
measuring cord blood lead level signify? One possi-
bility is that lead exposure fluctuates substantially
during the course of pregnancy and bone lead levels
capture some of the fetal lead exposure integrated
over time that is not reflected by the cord lead levels.
Multiple measurements of maternal venous blood
lead during the course of pregnancy might capture
the same parameter; this has not been tested, to our
It is noteworthy that in comparison to levels of
lead in the tibia bone, levels of lead in the maternal
patella bone were more closely predictive of MDI
scores. The histomorphometry of patella bone is
mostly trabecular
and in comparison to cortical
bones like the tibia, trabecular bone tends to be more
heavily affected by pregnancy-associated bone re-
Maternal patella bone lead levels had
been previously noted to be superior to tibia bone
lead levels (as well as cord blood lead levels) in
predicting lower infant birth weight
and lower
growth velocity from birth to 1 month of age.
The mean levels of lead that were found in tibia
and patella bone in our population are approxi-
mately 2.5 times higher than those that have been
found in middle- to high-income women who gave
birth in Boston in the early 1990s
and approxi
mately 1.5 times those found in low-income women
TABLE 5. Final Model of MDI in Relation to Lead Biomarkers and Other Related Factors
Coefficient Standard
T Test
Intercept 89.86 5.52 16.27 .01
Maternal IQ 0.17 0.05 3.65 .01
Umbilical cord blood lead level* 4.48 2.04 2.20 .03
Patella bone lead level
Second quartile 5.36 2.75 1.95 .05
Third quartile 7.21 2.75 2.62 .01
Fourth quartile 6.48 2.79 2.33 .02
Total model R
* Natural log of the umbilical cord blood lead concentration.
Fig 1. Maternal bone lead and MDI.
Page 7
from Latin America who emigrated to the Los An-
geles area as recently reported by Rothenberg et al.
Thus, they are high but well within the order of
magnitude of levels being seen in women in this
Maternal bone lead stores are mobilized during
lactation as well as during pregnancy, so it is possi-
ble that the mechanism by which bone lead levels
predict neurobehavioral performance in offspring by
2 years of age is through mobilization into breast
milk with subsequent ingestion and absorption.
However, the postnatal infant blood lead levels in
this study, which presumably would increase if a
suckling infant were absorbing a significant amount
of lead in breast milk, were not predictive of 24-
month MDI, and forcing postnatal blood lead levels
into our regression models of MDI score did not
affect the effect estimates associated with either cord
blood lead or maternal bone lead.
Among the most important limitations of our
study are that we did not have measurements of
maternal blood lead throughout pregnancy (which
would have allowed us to compare maternal bone
lead to a measure of blood lead that was integrated
over pregnancy); we did not have a direct measure of
family socioeconomic status or the caregiving envi-
ronment (eg, the Home Observation for the Measure-
ment of the Environment inventory), which consti-
tute potential confounders of the lead exposure-
mental development relationship; and our final
sample size of 197 mother-infant pairs represented
only 31% of the subjects who were initially eligible
for this study. However, regarding the last 2 issues,
maternal and paternal education have been found to
parallel closely socioeconomic status among families
in Mexico,
and the caregiving environment is likely
to be similar across the homogeneous middle-income
families that compose the patient population for this
study. Finally, our comparison of final participants
with nonparticipants and participants with missing
data did not reveal substantial differences in our
covariates, suggesting that the participants in this
study were representative of the overall cohort.
Our study suggests that fetal development in
women with low current lead exposures can still be
at risk for lead toxicity from long-lived maternal
bone lead stores acquired from previous lead expo-
sures. This is likely to be of particular importance to
women who grew up in heavily lead-contaminated
environments or who worked in occupations associ-
ated with industrial lead exposure and provides ad-
ditional impetus for the general movement in public
health to decrease lead exposure in communities and
workplaces. These results also suggest that there
may be a need to consider potential secondary pre-
vention strategies, ie, measures to prevent maternal
bone lead mobilization during pregnancy. It is inter-
esting that supplementation with calcium during
pregnancy has been noted in some studies to de-
crease maternal bone demineralization,
and pooled
results from a recent randomized crossover trial
found that a nocturnal 1200-
g dietary calcium dose
reduced urinary levels of n-telopeptide of type 1
collagen, a biological marker specific for bone re-
sorption, by an average of 15% in pregnant women
in the third trimester.
Given the relatively benign
nature of calcium supplementation and the lack of a
threshold that has been seen in the relationship be-
tween blood lead and IQ down to a blood lead of 1
supplementation with calcium needs to be
considered as a potential strategy for decreasing fetal
lead exposure in women with a history of significant
lead exposure. Additional research is needed to de-
termine whether implementation of such interven-
tions should be considered on a widespread basis
and, if so, how women who would most benefit
should be identified.
Support for this study was provided by the March of Dimes, US
NIEHS R01ES07821, NIEHS P42 ES-05947 Project 1 (with funding
from the US EPA), NIEHS Center Grant 2 P30 ES-00002, from
Consejo National de Ciencia y Tecnologia (CONACyT) Grant 4150
M9405, and from CONSERVA, Department of Federal District,
We acknowledge the research assistance of Gail Fleischaker,
PhD, Jesus Lozano, Dr Gustavo Olasis, and Dr Francisco Cabral
from the Instituto Nacional de Perinatologia; Dr Dolores Saaver-
dra and the late Dr Carlos Ricalde from the Manuel Gea Gonzalez
Hospital; and the late Dr Rodolofo Munoz from the Hospital de
Ginecologia y Obstetricia No. 4 Luis Castelazo Ayala, Mexican
Social Security Institute.
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“He who knows and knows that he knows is conceited; avoid him.
He who knows not and knows not that he knows not is a fool; instruct him.
He who knows and knows not that he knows is asleep; awaken him.
But he who knows not and knows that he knows not is a wise man; follow him.”
—Arab Proverb
Page 9
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    • "Models were adjusted for measured variables that are recognized as predictors of child stature/length, including: birthlength (cm), breastfeeding (total months), energy intake (Kcal/day), maternal height (cm) and years of education353637. We did not include prenatal lead exposure or prenatal zinc deficiency because these variables may directly affect birth characteristics (weight, length and gestational age) [30]. We chose to restrict our analyses to include only infants with adequate birth weight and normal gestational age. "
    [Show abstract] [Hide abstract] ABSTRACT: Background: Blood lead levels have decreased in Mexico since leaded fuel was banned in 1997, but other sources remain, including the use of lead-glazed ceramics for food storage and preparation. Zinc deficiency is present in almost 30 % of children aged 1-2 years. Previous studies have documented negative associations of both lead exposure and zinc deficiency with stature, but have not considered the joint effects. Given that the prevalence of stunting in pre-school aged children was 13.6 % in 2012, the aim of this study was to evaluate if the relationship between blood lead and child stature was modified by zinc status. Methods: Anthropometry, dietary energy intake, serum zinc and blood lead were measured in 291 children aged 24 months from an ongoing birth cohort study in Mexico City. Child stature was represented by recumbent length as appropriate for this age group. The association between blood lead (BPb) and length-for-age Z score (LAZ) was evaluated using a model stratified by zinc status measured by standard criteria and adjusted for: birth length, breastfeeding practices, energy intake, maternal height and education. Results: Median (IQR) BPb was: 0.17 (0.12-0.26) μmol/L and 17 % of the sample had zinc deficiency (<9.9 μmol/L). BPb was inversely associated with LAZ in the overall sample (β = -0.19, p = 0.02). In stratified models, this negative association was more than three times higher and statistically significant only in the zinc deficient group (β = -0.43, p = 0.04) compared to the zinc replete group (β = -0.12, p = 0.22) (BPb zinc status, p-for-interaction = 0.04). Conclusions: Zinc adequacy is a key factor that may attenuate the negative association of lead on stature in young children.
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    • "Lead has been extensively studied using a variety of matrices (Andrews et al., 1994), with most of the more recent studies of the relationship with SGA using maternal blood, cord blood and placenta . Multiple studies have found an association with SGA (Chen et al., 2006; Odland et al., 1999; Xie et al., 2013; Gundacker et al., 2010; Jelliffe-Pawlowski et al., 2006; Berkowitz et al., 2006; González-Cossío et al., 1997) while others report no relationship (Shirai et al., 2010; Jones et al., 2010; Sowers et al., 2002). The different matrices used and the varying exposure levels may explain the conflicting results. "
    [Show abstract] [Hide abstract] ABSTRACT: Lead, mercury, cadmium and arsenic are some of the most common toxic metals to which Canadians are exposed. The effect of exposure to current low levels of toxic metals on fetal growth restriction is unknown. The aim of this study was to examine relationships between exposure to lead, mercury, cadmium and arsenic during pregnancy, and risk of small for gestational age (SGA) birth. Lead, mercury, cadmium and arsenic levels were measured in blood samples from the first and third trimesters in 1835 pregnant women from across Canada. Arsenic species in first trimester urine were also assessed. Relative risks and 95% confidence intervals were estimated using log binomial multivariate regression. Important covariates including maternal age, parity, pre-pregnancy BMI, and smoking, were considered in the analysis. An exploratory analysis was performed to examine potential effect modification of these relationships by single nucleotide polymorphisms (SNPs) in GSTP1 and GSTO1 genes. No association was found between blood lead, cadmium or arsenic and risk for SGA. We observed an increased risk for SGA for the highest compared to the lowest tertile of exposure for mercury (>1.6µg/L, RR=1.56.; 95% CI=1.04-2.58) and arsenobetaine (>2.25µg/L, RR=1.65; 95% CI=1.10-2.47) after adjustment for the effects of parity and smoking. A statistically significant interaction was observed in the relationship between dimethylarsinic acid (DMA) levels in urinary arsenic and SGA between strata of GSTO1 A104A (p for interaction=0.02). A marginally significant interaction was observed in the relationship between blood lead and SGA between strata of GSTP1 A114V (p for interaction=0.06). These results suggest a small increase in risk for SGA in infants born to women exposed to mercury and arsenic. Given the conflicting evidence in the literature this warrants further investigation in other pregnant populations. Crown Copyright © 2015. Published by Elsevier Inc. All rights reserved.
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    • "Lead in blood is present almost entirely in the cells. Bone lead, which comprises >95 % of adult body lead burden and has a biologic half-life ranging from years to decades, is a better biologic marker for studying chronic toxicity of accumulated exposure and lead burden [79]. In addition, bone lead also serves as an endogenous source of lead exposure for individuals with increased bone turnover [80]. "
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