Full length articlePrenatal lead exposure and fetal growth: Smaller infants have heightened susceptibility
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.
References (37)
- et al.
Low level lead exposure and oxidative stress: current opinions
Clin. Chim. Acta
(2007) - et al.
Can available interventions end preventable deaths in mothers, newborn babies, and stillbirths, and at what cost?
Lancet
(2014) - et al.
Maternal and child undernutrition: global and regional exposures and health consequences
Lancet
(2008) - et al.
A simplified method for diagnosis of gestational age in the newborn infant
J. Pediatr.
(1978) - et al.
Blood lead levels in Mexico and pediatric burden of disease implications
Ann. Glob. Health
(2014) - et al.
Interaction of metals and thiols in cell damage and glutathione distribution: potentiation of mercury toxicity by dithiothreitol
Toxicology
(2001) - et al.
Every newborn: progress, priorities, and potential beyond survival
Lancet
(2014) - et al.
National and regional estimates of term and preterm babies born small for gestational age in 138 low-income and middle-income countries in 2010
Lancet Glob. Health
(2013) - et al.
Evidence that birth weight is decreased by maternal lead levels below 5 μg/dl in male newborns
Reprod. Toxicol.
(2014) - et al.
Changes in low levels of lead over the course of pregnancy and the association with birth outcomes
Reprod. Toxicol.
(2014)
Maternal and child undernutrition: consequences for adult health and human capital
Lancet
Prenatal exposure to lead in relation to risk of preterm low birth weight: a matched case-control study in China
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
Cited by (41)
Maternal exposure to metal mixtures during early pregnancy and fetal growth in the Jiangsu Birth Cohort, China
2022, Environmental ResearchCitation Excerpt :The fetal period is a critical stage for embryo development, in which fetuses are vulnerable to environmental contaminants (Segal and Giudice, 2019). It has been widely demonstrated that many toxic metals can easily cross the placental barrier or accumulate in the placental tissues (Esteban-Vasallo et al., 2012; Goyer, 1990), and then inhibit fetal development by exerting toxic effects on placenta or fetus directly (Meakin et al., 2020; Rodosthenous et al., 2017; Xiong et al., 2021). A growing number of epidemiological studies have revealed that prenatal metal exposure is associated with reduced fetal growth, such as Pb (Lamichhane et al., 2018; Rodosthenous et al., 2017; Srivastava et al., 2001; Sun et al., 2019; Zhu et al., 2010), As (Liao et al., 2018; Sun et al., 2019), Hg (Ballester et al., 2018; Murcia et al., 2016; Vigeh et al., 2018), Cd (Barn et al., 2019; Kippler et al. 2012a, 2012b; Liu et al., 2021; Shirai et al., 2010), Cr (Cabrera-Rodriguez et al., 2018; Freire et al., 2019; Peng et al., 2018), vanadium (V) (Hu et al., 2018; Sun et al., 2019; Zhou et al., 2019), thallium (Tl) (Xia et al., 2016) and barium (Ba) (Goodrich et al., 2019; Howe et al., 2021).
Prenatal phthalates, gestational weight gain, and long-term weight changes among Mexican women
2022, Environmental ResearchPrenatal lead exposure, telomere length in cord blood, and DNA methylation age in the PROGRESS prenatal cohort
2022, Environmental ResearchAssociation between prenatal metal exposure and adverse respiratory symptoms in childhood
2022, Environmental ResearchCitation Excerpt :Pb and Mn can cross the placental barrier which indicates that fetal lung development could be impaired by maternal exposure during pregnancy (Claus Henn et al., 2017). In utero exposure to Pb is associated with lower birth weight for gestational age (Rodosthenous et al., 2017) and preterm birth (Ashrap et al., 2020), which are risk factors for later lung dysfunction and alterations in lung development (Briana and Malamitsi-Puchner, 2013; Smith et al., 2010). BPb has been associated with increased bronchial hyperresponsiveness (Min et al., 2008).