Prenatal lead exposure and fetal growth: Smaller infants have heightened susceptibility

doi:10.1016/j.envint.2016.11.023

Environment International

Volume 99, February 2017, Pages 228-233

https://doi.org/10.1016/j.envint.2016.11.023 Get rights and content

Highlights

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Evidence on the association between prenatal lead exposure and fetal growth is inconsistent.
•
Elevated lead levels were associated with lower birthweight and increased odds of small-for-gestational age birth.
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Quantile regression revealed that infants with poor fetal growth are more susceptible to the effects of lead.
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We encourage the use of quantile regression when assessing the impact of prenatal lead exposure on fetal growth.

Abstract

Background

As population lead levels decrease, the toxic effects of lead may be distributed to more sensitive populations, such as infants with poor fetal growth.

Objectives

To determine the association of prenatal lead exposure and fetal growth; and to evaluate whether infants with poor fetal growth are more susceptible to lead toxicity than those with normal fetal growth.

Methods

We examined the association of second trimester maternal blood lead levels (BLL) with birthweight-for-gestational age (BWGA) z-score in 944 mother-infant participants of the PROGRESS cohort. We determined the association between maternal BLL and BWGA z-score by using both linear and quantile regression. We estimated odds ratios for small-for-gestational age (SGA) infants between maternal BLL quartiles using logistic regression. Maternal age, body mass index, socioeconomic status, parity, household smoking exposure, hemoglobin levels, and infant sex were included as confounders.

Results

While linear regression showed a negative association between maternal BLL and BWGA z-score (β = − 0.06 z-score units per log₂ BLL increase; 95% CI: − 0.13, 0.003; P = 0.06), quantile regression revealed larger magnitudes of this association in the < 30th percentiles of BWGA z-score (β range [− 0.08, − 0.13] z-score units per log₂ BLL increase; all P values < 0.05). Mothers in the highest BLL quartile had an odds ratio of 1.62 (95% CI: 0.99–2.65) for having a SGA infant compared to the lowest BLL quartile.

Conclusions

While both linear and quantile regression showed a negative association between prenatal lead exposure and birthweight, quantile regression revealed that smaller infants may represent a more susceptible subpopulation.

Introduction

Poor fetal growth precedes ~ 60% of neonatal deaths (Black et al., 2008) and leads to adverse fetal growth outcomes such as low birthweight and small-for-gestational age (SGA) (Victora et al., 2008). Low birthweight (< 2500 g) and SGA (< 10th percentile of the birthweight-for-gestational age distribution) infants, term and preterm, have an increased risk of chronic developmental and cardiometabolic disorders later in life (Lawn et al., 2014), and impose a substantial socioeconomic burden worldwide (Bhutta et al., 2014). The prevalence of low birthweight globally is estimated to be 20 million infants and of SGA about 32 million infants (of whom ~ 10 million are term low birthweight), with particularly high prevalence in low and middle income countries (Lee et al., 2013). Numerous preventable risk factors have been linked to poor fetal growth, including prenatal lead exposure (Jelliffe-Pawlowski et al., 2006).

Lead is a toxic heavy metal that is widespread in the environment. While exposure to lead has dropped dramatically in the last 30 years, toxic effects are still reported even in populations with blood lead levels (BLL) once believed to be safe (i.e. < 5 μg/dL). During pregnancy, maternal lead can cross the placenta and enter the fetal blood circulation (Lin et al., 1998). Due to similar physicochemical properties, lead competes with calcium for deposition into the bone, which might lead to impaired fetal growth (Potula and Kaye, 2005). Lead also binds to sulfhydryl groups and inhibits enzymes involved in heme synthesis, which is important for cellular respiration and metabolism, as well as hemoglobin synthesis (Flora et al., 2012). Several epidemiological studies have shown inconsistent associations of prenatal lead exposure and fetal growth (Burris et al., 2011, Cantonwine et al., 2010, Gonzalez-Cossio et al., 1997, Jelliffe-Pawlowski et al., 2006, Nishioka et al., 2014, Wigle et al., 2007, Zhang et al., 2015, Zhu et al., 2010). These studies used traditional regression methods, also known as ordinary least squares (OLS) regression, to estimate the conditional mean response of the association between prenatal lead exposure and fetal growth. Because OLS methods model the mean response of an outcome in relation to the exposure, any differences that occur in the magnitude and direction of the exposure-outcome association (e.g., prenatal lead exposure and birthweight) across different percentiles of the outcome may not be captured (Koenker, 2005).

The value of quantile regression, which allows for effects of the exposure (e.g., lead) to vary across the distribution of the outcome (e.g., birthweight), has been demonstrated previously in lead poisoning with regards to school performance. Burgette et al., showed that childhood lead exposure is predictive of poorer performance on standardized state tests, with more pronounced effects in the lower percentiles of the test score distribution (Burgette et al., 2011). We built upon this research by testing whether prenatal lead exposure predicts lower birthweight more prominently at the lower range of birthweight-for-gestational age distribution. In other words: are infants with poor fetal growth more susceptible to lead toxicity than infants with normal fetal growth? Fetal growth is a complex and dynamic process, with infants at the tails of the outcome (e.g., birthweight) distribution suffering a disproportionate burden of perinatal morbidities (Barker et al., 2002, Barker, 2006, Fabricius-Bjerre et al., 2011). We hypothesized that OLS regression analysis may not capture any differences in the associations between prenatal lead exposure and birthweight-for-gestational age that occur for instance at the tails of the outcome distribution (e.g., small-for-gestational age infants), and that these associations could be revealed by using quantile regression.

We used data from the Programming Research in Obesity, Growth Environment and Social Stress (PROGRESS) prospective cohort study of 946 mother-infant pairs in Mexico City to determine the association between prenatal lead exposure at second trimester and fetal growth as measured by birthweight-for-gestational age and risk of SGA. Lead exposure is still a major public health problem in Mexico (Caravanos et al., 2014) and the prevalence of both low birthweight and SGA, which are measures of poor fetal growth, is relatively high (~ 10%) in the Mexican population (Lee et al., 2013).

Section snippets

Study population

Study participants were enrolled as part of the PROGRESS birth cohort project in Mexico City, Mexico, between 2007 and 2011. Details of the cohort's profile and enrollment are described in previous publications (Braun et al., 2014, Burris et al., 2013). In brief, pregnant women who attended the Mexican Social Security Institute (Instituto Mexicano del Seguro Social) clinics for their prenatal care were enrolled. Eligibility criteria for participation in the study were singleton pregnancy,

Results

Second trimester maternal BLL was 3.7 ± 2.7 μg/dL (median 2.8, IQR: 1.9–4.5, range: 0.5–22.9 μg/dL) (Table 1), with 21% of the participants with BLL above the reference level (> 5 μg/dL) for pregnant women recommended by the U.S. Centers for Disease Control and Prevention (Centers for Disease Control and Prevention, CDC, 2010). When we log₂-transformed the maternal BLL data, the range spanned through five log₂ unit increments. Women with higher BLL had lower socioeconomic status, were older in age

Discussion

We found a negative association of prenatal lead exposure at the second trimester with birthweight-for-gestational age. Quantile regression revealed different magnitudes of the association across the birthweight-for-gestational age distribution, suggesting that susceptibility to lead varied based on differences in fetal growth conditions. In particular, the magnitude of the association was larger in the lower percentiles of the birthweight-for-gestational age distribution indicating that

Conclusions

Quantile regression revealed significant shifts in birthweight-for-gestational age distribution associated with prenatal lead exposure, which were not fully captured by linear regression models. Our findings indicate that the magnitude of this association is larger in the lower percentiles of the birthweight-for-gestational age distribution and provide evidence that infants with poorer fetal growth may represent a sensitive subpopulation for lead exposure. Improvements in maternal lead exposure

Competing financial interests

Authors have no competing financial interests.

Acknowledgments

This work was supported by the Harvard T. H. Chan School of Public Health-NIEHS Center for Environmental Health (ES000002) and the National Institute of Environmental Health Sciences grants ES013744, ES014930, ES021357, ES020268, ES023515, and ES009089. We thank the faculty and staff of the American British Cowdray (ABC) Hospital who provided space and valuable assistance in the data collection.

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Full length articlePrenatal lead exposure and fetal growth: Smaller infants have heightened susceptibility

Highlights

Abstract

Background

Objectives

Methods

Results

Conclusions

Introduction

Section snippets

Study population

Results

Discussion

Conclusions

Competing financial interests

Acknowledgments

Clin. Chim. Acta

Lancet

Lancet

J. Pediatr.

Ann. Glob. Health

Toxicology

Lancet

Lancet Glob. Health

Reprod. Toxicol.

Reprod. Toxicol.

Lancet

Reprod. Toxicol.

Adult consequences of fetal growth restriction

Clin. Obstet. Gynecol.

Fetal origins of adult disease: strength of effects and biological basis

Int. J. Epidemiol.

Relationships between lead biomarkers and diurnal salivary cortisol indices in pregnant women from Mexico City: a cross-sectional study

Environ. Health

Exploratory quantile regression with many covariates: an application to adverse birth outcomes

Epidemiology

Racial/ethnic disparities in preterm birth: clues from environmental exposures

Curr. Opin. Pediatr.

Association between birth weight and DNA methylation of IGF2, glucocorticoid receptor and repetitive elements line-1 and alu

Epigenomics

Full length article
Prenatal lead exposure and fetal growth: Smaller infants have heightened susceptibility