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1.  Prenatal urinary phthalate metabolites levels and neurodevelopment in children at two and three years of age 
Previous studies suggest that prenatal phthalate exposure affects neurodevelopment and behavior during the first years of life.
To evaluate the effect of maternal urinary concentrations of phthalate metabolites during pregnancy on mental and psychomotor development in children 24-36 months of age.
This analysis was conducted on the first three years of life among a subsample of 136 mother-child pairs from the ELEMENT cohort studies conducted in Mexico City. Maternal urine samples collected during the third trimester of pregnancy were analyzed for 9 phthalate metabolites: Mono-ethyl phthalate (MEP), Mono-n-butyl phthalate (MnBP), mono-isobutyl phthalate (MiBP), mono-benzyl phthalate (MBzP), Mono-3-carboxypropyl phthalate (MCPP), and four di-2-ethylhexyl phthalate (DEHP) metabolites [mono-2-ethylhexyl-phthalate (MEHP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), and mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP)]. Among the 136 children, 135 (99.3%) completed the study period. Child neurodevelopment was assessed using mental and psychomotor development indexes (MDI and PDI) from a Bayley (BSID II) test at 24, 30, and 36 months of age. The effect of prenatal phthalate exposure on neurodevelopment was estimated using linear regression models for longitudinal data clustered at the individual level.
No significant associations were observed among all children combined, but differential effects by gender were found. Among girls, there was a negative association between MDI and DEHP metabolites MEHP (β = −2.11 [95% CI: −3.73, −0.49]), MEHHP (β = −1.89 [95% CI: −3.64, −0.15]), MEOHP (β = −1.80 [95% CI: −3.58, −0.03]) MECPP (β = −2.52 [95% CI: −4.44, −0.61]), and DEHP (β = −3.41 [95% CI: −5.26, −1.55]); there was no significant effect among boys. Male PDI was positively related to MBzP (β = 1.79 [95% CI: 0.14, 3.45]) and MCPP (β = 1.64 [95% CI: 0.15, 3.12]); there was no significant effect on PDI among girls.
This study demonstrates that sex plays a role of an effect modifier in the association between prenatal phthalate exposure and neurodevelopment.
PMCID: PMC3735862  PMID: 23747553
Prenatal Exposure; Biomarkers; Phthalates; Child Development; Longitudinal Study
2.  Windows of lead exposure sensitivity, attained height, and BMI at 48 months 
The Journal of Pediatrics  2012;160(6):1044-1049.
To examine longitudinal association of prenatal, infancy, and early childhood lead exposure during sensitive periods with height and BMI.
Study design
The 773 participants were recruited between 1994 and 2005 in Mexico City. We constructed lead exposure history categories for prenatal (maternal patella lead), infancy and childhood periods (mean child blood lead between birth to 24 months and 30 to 48 months, respectively). Linear regression models were used to study lead exposure history with height and BMI at 48 months.
Children with blood lead levels higher than the median during infancy attained a mean height at 48 months that was significantly shorter (−0.84 cm, 95% CI= −1.42 to −0.25) than children with levels lower than the median. Prenatal lead exposure was not associated with height at 48 months. Results for attained BMI were in general in the same direction as for height.
Our study suggests an effect of early life lead exposure on height attainment at 48 months with an exposure window of greatest sensitivity occurring in infancy.
PMCID: PMC3360798  PMID: 22284921
3.  Bias correction by use of errors-in-variables regression models in studies with K-X ray fluorescence bone lead measurements1 
Environmental research  2010;111(1):17-20.
In-vivo measurement of bone lead by means of K-X ray fluorescence (KXRF) is the preferred biological marker of chronic exposure to lead. Unfortunately, considerable measurement error associated with KXRF estimations can introduce bias in estimates of the effect of bone lead when this variable is included as the exposure in a regression model. Estimates of uncertainty reported by the KXRF instrument reflect the variance of the measurement error and, although they can be used to correct the measurement error bias, they are seldom used in epidemiological statistical analyses. Errors-in-variables regression (EIV) allows for correction of bias caused by measurement error in predictor variables, based on the knowledge of the reliability of such variables. The authors propose a way to obtain reliability coefficients for bone lead measurements from uncertainty data reported by the KXRF instrument and compare, by use of Monte Carlo simulations, results obtained using EIV regression models versus those obtained by the standard procedures. Results of the simulations show that Ordinary Least Square (OLS) regression models provide severely biased estimates of effect, and that EIV provides nearly unbiased estimates. Although EIV effect estimates are more imprecise, their mean squared error is much smaller than that of OLS estimates. In conclusion, EIV is a better alternative than OLS to estimate the effect of bone lead when measured by KXRF.
PMCID: PMC3026095  PMID: 21092947
Lead; KXRF; measurement error; errors-in-variables model; simulations
4.  Prenatal Lead Exposure and Weight of 0- to 5-Year-Old Children in Mexico City 
Environmental Health Perspectives  2011;119(10):1436-1441.
Background: Cumulative prenatal lead exposure, as measured by maternal bone lead burden, has been associated with smaller weight of offspring at birth and 1 month of age, but no study has examined whether this effect persists into early childhood.
Objective: We investigated the association of perinatal maternal bone lead, a biomarker of cumulative prenatal lead exposure, with children’s attained weight over time from birth to 5 years of age.
Methods: Children were weighed at birth and at several intervals up until 60 months. Maternal tibia and patella lead were measured at 1 month postpartum using in vivo K-shell X-ray fluorescence. We used varying coefficient models with random effects to assess the association of maternal bone lead with weight trajectories of 522 boys and 477 girls born between 1994 and 2005 in Mexico City.
Results: After controlling for breast-feeding duration, maternal anthropometry, and sociodemographic characteristics, a 1-SD increase in maternal patella lead (micrograms per gram) was associated with a 130.9-g decrease in weight [95% confidence interval (CI), –227.4 to –34.4 g] among females and a 13.0-g nonsignificant increase in weight among males (95% CI, –73.7 to 99.9 g) at 5 years of age. These associations were similar after controlling for concurrent blood lead levels between birth and 5 years.
Conclusions: Maternal bone lead was associated with lower weight over time among female but not male children up to 5 years of age. Given that the association was evident for patellar but not tibial lead levels, and was limited to females, results need to be confirmed in other studies.
PMCID: PMC3230436  PMID: 21715242
bone lead; growth; weight
Neurotoxicology  2007;29(2):278-285.
The notion that maternal personality characteristics influence cognitive development in their children has been grounded in stress moderation theory. Maternal personality traits, such as self-esteem, may buffer maternal stressors or lead to improved maternal-child interactions that directly impact neurodevelopment. This can be extended to suggest that maternal personality may serve to attenuate or exacerbate the effects of other neurotoxicants, although this has not been studied directly. We examined whether mothers’ self-esteem had a direct or main effect on their children's cognitive outcomes. We also explored the modifying effects of maternal self-esteem on the association between exposure to lead and neurodevelopment in these children. Study participants included 379 mother-child pairs from Mexico City. Data included the Coopersmith self-esteem scale in mothers, children's Bayley's Scale of Infant Development (BSID) scores, and sociodemographic information. Linear regression was used to model the relationship between maternal self-esteem and the Bayley's Mental Development Index (MDI) and Psychomotor Development Index (PDI) scores at age 24 months using regression models stratified by levels of maternal self-esteem. In adjusted models, each point increase in maternal self-esteem was associated with children having 0.2 higher score on the Bayley's MDI (p=0.04). Similar results were observed using the PDI outcome. Moreover, there was evidence that maternal self-esteem attenuated the negative effects of lead exposure, although the interaction fell short of conventional levels of statistical significance.
PMCID: PMC2495770  PMID: 18261800
child; cognition; lead; neurotoxicology; mother-child relations
6.  Effect of Calcium Supplementation on Blood Lead Levels in Pregnancy: A Randomized Placebo-Controlled Trial 
Prenatal lead exposure is associated with deficits in fetal growth and neurodevelopment. Calcium supplementation may attenuate fetal exposure by inhibiting mobilization of maternal bone lead and/or intestinal absorption of ingested lead.
Our goal was to evaluate the effect of 1,200 mg dietary calcium supplementation on maternal blood lead levels during pregnancy.
In a double-blind, randomized, placebo-controlled trial conducted from 2001 through 2003 in Mexico City, we randomly assigned 670 women in their first trimester of pregnancy to ingest calcium (n = 334) or placebo (n = 336). We followed subjects through pregnancy and evaluated the effect of supplementation on maternal blood lead, using an intent-to-treat analysis by a mixed-effects regression model with random intercept, in 557 participants (83%) who completed follow-up. We then conducted as-treated analyses using similar models stratified by treatment compliance.
Adjusting for baseline lead level, age, trimester of pregnancy, and dietary energy and calcium intake, calcium was associated with an average 11% reduction (0.4 μg/dL) in blood lead level relative to placebo (p = 0.004). This reduction was more evident in the second trimester (−14%, p < 0.001) than in the third (−8%, p = 0.107) and was strongest in women who were most compliant (those who consumed ≥ 75% calcium pills; −24%, p < 0.001), had baseline blood lead > 5 μg/dL (−17%, p < 0.01), or reported use of lead-glazed ceramics and high bone lead (−31%, p < 0.01).
Calcium supplementation was associated with modest reductions in blood lead when administered during pregnancy and may constitute an important secondary prevention effort to reduce circulating maternal lead and, consequently, fetal exposure.
PMCID: PMC2627861  PMID: 19165383
calcium; diet; lead; pregnancy; randomized trial; supplementation
7.  Association between the plasma/whole blood lead ratio and history of spontaneous abortion: a nested cross-sectional study 
Blood lead has been associated with an elevated risk of miscarriage. The plasmatic fraction of lead represents the toxicologically active fraction of lead. Women with a tendency to have a higher plasma/whole blood Pb ratio could tend towards an elevated risk of miscarriage due to a higher plasma Pb for a given whole blood Pb and would consequently have a history of spontaneous abortion.
We studied 207 pregnant Mexico City residents during the 1st trimester of pregnancy, originally recruited for two cohorts between 1997 and 2004. Criteria for inclusion in this study were having had at least one previous pregnancy, and having valid plasma and blood Pb measurements. Pb was measured in whole blood and plasma by inductively coupled plasma mass spectrometry using ultra-clean techniques. History of miscarriage in previous pregnancies was obtained by interview. The incidence rate of spontaneous abortion was defined as the proportion of previous pregnancies that resulted in miscarriage. Data were analyzed by means of Poisson regression models featuring the incidence rate of spontaneous abortion as the outcome and continuous or categorized plasma/blood Pb ratios as predictor variables. All models were adjusted for age and schooling. Additionally, logistic regression models featuring inclusion in the study sample as the outcome were fitted to assess potential selection bias.
The mean number of miscarriages was 0.42 (range 0 to 4); mean Pb concentrations were 62.4 and 0.14 μg/L in whole blood and plasma respectively. Mean plasma/blood Pb ratio was 0.22%. We estimated that a 0.1% increment in the plasma/blood Pb ratio lead was associated to a 12% greater incidence of spontaneous abortion (p = 0.02). Women in the upper tertile of the plasma/blood Pb ratio had twice the incidence rate of those in the lower tertile (p = 0.02). Conditional on recruitment cohort, inclusion in the study sample was unrelated to observable characteristics such as number of abortions, number of pregnancies, blood Pb levels, age schooling, weight and height.
Women with a large plasma/whole blood Pb ratio may be at higher risk of miscarriage, which could be due to a greater availability of placental barrier-crossing Pb.
PMCID: PMC2148053  PMID: 17900368

Results 1-7 (7)