Fetal Lead Exposure at Each Stage of Pregnancy and Infant Mental Status
Fetal Lead Exposure at Each Stage of Pregnancy and Infant Mental Status
Background: The impact of prenatal lead exposure on neurodevelopment remains unclear in terms of consistency, the trimester of greatest vulnerability, and the best method for estimating fetal lead exposure.
Objective: We studied prenatal lead exposure's impact on neurodevelopment using repeated measures of fetal dose as reflected by maternal whole blood and plasma lead levels.
Methods: We measured lead in maternal plasma and whole blood during each trimester in 146 pregnant women in Mexico City. We then measured umbilical cord blood lead at delivery and, when offspring were 12 and 24 months of age, measured blood lead and administered the Bayley Scales of Infant Development. We used multivariate regression, adjusting for covariates and 24-month blood lead, to compare the impacts of our pregnancy measures of fetal lead dose.
Results: Maternal lead levels were moderately high with a first-trimester blood lead mean (± SD) value of 7.1 ± 5.1 μg/dL and 14% of values ≥10 μg/dL. Both maternal plasma and whole blood lead during the first trimester (but not in the second or third trimester) were significant predictors (p < 0.05) of poorer Mental Development Index (MDI) scores. In models combining all three trimester measures and using standardized coefficients, the effect of first-trimester maternal plasma lead was somewhat greater than the effect of first-trimester maternal whole blood lead and substantially greater than the effects of second- or third-trimester plasma lead, and values averaged over all three trimesters. A 1-SD change in first-trimester plasma lead was associated with a reduction in MDI score of 3.5 points. Postnatal blood lead levels in the offspring were less strongly correlated with MDI scores.
Conclusions: Fetal lead exposure has an adverse effect on neurodevelopment, with an effect that may be most pronounced during the first trimester and best captured by measuring lead in either maternal plasma or whole blood.
The findings of a wide variety of international studies on the impacts of lead exposure on mental development persuaded many countries to progressively reduce the amount of lead exposure deemed safe during childhood. Since 1991, the U.S. Centers for Disease Control and Prevention (CDC) has recommended 10 μg/dL (0.48 μmol/L) as the pediatric blood lead screening action guideline (CDC 1991), with recent research (Canfield et al. 2003) and pooled analyses of seven prospective studies (Lanphear et al. 2005) prompting consideration of further reductions.
A related issue that has received less attention is the extent to which prenatal lead exposure may produce adverse outcomes. This issue has emerged as a potentially large public health problem because of two recent insights. First, substantial fetal lead exposure can occur from mobilization of maternal skeletal lead stores, which, in turn, can persist many years after external lead exposure has declined (Gulson et al. 2003; Hu and Hernandez-Avila 2002). Second is the growing appreciation of the fetal nervous system's exquisite sensitivity to neurotoxins (Mendola et al. 2002).
Until now, few epidemiologic studies have used designs that allow the neurodevelopmental impacts of prenatal lead exposure to be distinguished from those of postnatal lead exposure. Among these, some have shown an inverse association between prenatal lead exposure and infant neurodevelopment (Bellinger et al. 1987; Dietrich et al. 1987; Ernhart et al. 1987; Shen et al. 1998) and some have not (Cooney et al. 1989; McMichael et al. 1988). Some found associations with neurodevelopment that attenuated over subsequent years (Bellinger et al. 1992; Dietrich et al. 1991; Ernhart et al. 1987), whereas others found relations that were stable over time (Wasserman et al. 1997, 2000).
An important factor that might contribute to inconsistency across studies is variability in the assessment and timing of dose to the fetus. Some studies measured maternal whole blood lead during the second and third trimesters and at delivery (Baghurst et al. 1987; Schnaas et al. 2006), whereas others took measures in the first or second trimester (Dietrich et al. 1987), in mid-pregnancy and at delivery (Wasserman et al. 1997), or at delivery only (Cooney et al. 1989; Ernhart et al. 1986). Some studies relied solely on umbilical cord blood lead level as the index of prenatal exposure (Bellinger et al. 1987). One study measured perinatal maternal bone lead level as an index of mobilizable maternal lead burden during the course of pregnancy (Gomaa et al. 2002).
The toxicokinetics of lead in the maternal-fetal unit are poorly understood. Lead levels in different compartments and at different stages of pregnancy are only modestly correlated, suggesting that each measure captures different aspects of fetal exposure (Baghurst et al. 1987). It is well known from the experimental literature that the vulnerability of developing organ systems, including the brain, to environmental toxicants can vary widely over the course of pregnancy (Mendola et al. 2002). Thus, it is plausible that lead exposure may be particularly neurotoxic during a specific trimester.
Recent evidence also suggests that whole blood lead levels in a pregnant woman might not be the optimal marker for lead concentrations in the fetal brain. Over 99% of lead in whole blood is bound to red cells and thus not available to cross the placenta (Goyer 1990); instead, it is the < 1% of lead in the plasma compartment of blood that is of greatest interest in terms of fetal exposure. Recent data suggest that there are significant interindividual differences in the ratio of red cell lead to plasma lead (Hu 1998; Lamadrid-Figueroa 2006), making maternal whole blood lead levels potentially unreliable as a proxy for plasma lead and fetal exposure (Chuang et al. 2001; Goyer 1990).
To date, no study of fetal lead neurotoxicity has included the biomarker measurements needed to compare whole blood and plasma lead levels during each trimester of pregnancy as predictors of infant neurodevelopment. It is such a comparison that we report here.
Abstract and Introduction
Abstract
Background: The impact of prenatal lead exposure on neurodevelopment remains unclear in terms of consistency, the trimester of greatest vulnerability, and the best method for estimating fetal lead exposure.
Objective: We studied prenatal lead exposure's impact on neurodevelopment using repeated measures of fetal dose as reflected by maternal whole blood and plasma lead levels.
Methods: We measured lead in maternal plasma and whole blood during each trimester in 146 pregnant women in Mexico City. We then measured umbilical cord blood lead at delivery and, when offspring were 12 and 24 months of age, measured blood lead and administered the Bayley Scales of Infant Development. We used multivariate regression, adjusting for covariates and 24-month blood lead, to compare the impacts of our pregnancy measures of fetal lead dose.
Results: Maternal lead levels were moderately high with a first-trimester blood lead mean (± SD) value of 7.1 ± 5.1 μg/dL and 14% of values ≥10 μg/dL. Both maternal plasma and whole blood lead during the first trimester (but not in the second or third trimester) were significant predictors (p < 0.05) of poorer Mental Development Index (MDI) scores. In models combining all three trimester measures and using standardized coefficients, the effect of first-trimester maternal plasma lead was somewhat greater than the effect of first-trimester maternal whole blood lead and substantially greater than the effects of second- or third-trimester plasma lead, and values averaged over all three trimesters. A 1-SD change in first-trimester plasma lead was associated with a reduction in MDI score of 3.5 points. Postnatal blood lead levels in the offspring were less strongly correlated with MDI scores.
Conclusions: Fetal lead exposure has an adverse effect on neurodevelopment, with an effect that may be most pronounced during the first trimester and best captured by measuring lead in either maternal plasma or whole blood.
Introduction
The findings of a wide variety of international studies on the impacts of lead exposure on mental development persuaded many countries to progressively reduce the amount of lead exposure deemed safe during childhood. Since 1991, the U.S. Centers for Disease Control and Prevention (CDC) has recommended 10 μg/dL (0.48 μmol/L) as the pediatric blood lead screening action guideline (CDC 1991), with recent research (Canfield et al. 2003) and pooled analyses of seven prospective studies (Lanphear et al. 2005) prompting consideration of further reductions.
A related issue that has received less attention is the extent to which prenatal lead exposure may produce adverse outcomes. This issue has emerged as a potentially large public health problem because of two recent insights. First, substantial fetal lead exposure can occur from mobilization of maternal skeletal lead stores, which, in turn, can persist many years after external lead exposure has declined (Gulson et al. 2003; Hu and Hernandez-Avila 2002). Second is the growing appreciation of the fetal nervous system's exquisite sensitivity to neurotoxins (Mendola et al. 2002).
Until now, few epidemiologic studies have used designs that allow the neurodevelopmental impacts of prenatal lead exposure to be distinguished from those of postnatal lead exposure. Among these, some have shown an inverse association between prenatal lead exposure and infant neurodevelopment (Bellinger et al. 1987; Dietrich et al. 1987; Ernhart et al. 1987; Shen et al. 1998) and some have not (Cooney et al. 1989; McMichael et al. 1988). Some found associations with neurodevelopment that attenuated over subsequent years (Bellinger et al. 1992; Dietrich et al. 1991; Ernhart et al. 1987), whereas others found relations that were stable over time (Wasserman et al. 1997, 2000).
An important factor that might contribute to inconsistency across studies is variability in the assessment and timing of dose to the fetus. Some studies measured maternal whole blood lead during the second and third trimesters and at delivery (Baghurst et al. 1987; Schnaas et al. 2006), whereas others took measures in the first or second trimester (Dietrich et al. 1987), in mid-pregnancy and at delivery (Wasserman et al. 1997), or at delivery only (Cooney et al. 1989; Ernhart et al. 1986). Some studies relied solely on umbilical cord blood lead level as the index of prenatal exposure (Bellinger et al. 1987). One study measured perinatal maternal bone lead level as an index of mobilizable maternal lead burden during the course of pregnancy (Gomaa et al. 2002).
The toxicokinetics of lead in the maternal-fetal unit are poorly understood. Lead levels in different compartments and at different stages of pregnancy are only modestly correlated, suggesting that each measure captures different aspects of fetal exposure (Baghurst et al. 1987). It is well known from the experimental literature that the vulnerability of developing organ systems, including the brain, to environmental toxicants can vary widely over the course of pregnancy (Mendola et al. 2002). Thus, it is plausible that lead exposure may be particularly neurotoxic during a specific trimester.
Recent evidence also suggests that whole blood lead levels in a pregnant woman might not be the optimal marker for lead concentrations in the fetal brain. Over 99% of lead in whole blood is bound to red cells and thus not available to cross the placenta (Goyer 1990); instead, it is the < 1% of lead in the plasma compartment of blood that is of greatest interest in terms of fetal exposure. Recent data suggest that there are significant interindividual differences in the ratio of red cell lead to plasma lead (Hu 1998; Lamadrid-Figueroa 2006), making maternal whole blood lead levels potentially unreliable as a proxy for plasma lead and fetal exposure (Chuang et al. 2001; Goyer 1990).
To date, no study of fetal lead neurotoxicity has included the biomarker measurements needed to compare whole blood and plasma lead levels during each trimester of pregnancy as predictors of infant neurodevelopment. It is such a comparison that we report here.
