Exploring Distribution Of Environmental Multiple Metals And Associations With Birth Weight And Gestational Age

Background:Fetuses are exposure to various chemicals in utero.Previous epidemiological studies indicated that prenatal exposure to individual toxic metals（e.g.cadmium,arsenic,lead）affect fetal growth.However,knowledge about the associations of essential elements with birth weight and gestational age remain limited.In addition,most of the previous studies,due to the limitation of the traditional statistical methods,only restricted to explore the influence of an individual metal on birth weight and gestational age,by employing the ordinary least squares regression method.Metal exposures in humans never occur in isolation,thus the single-metal model resulted in a one-dimensional judgment of exposures and health effect.Moreover,the previous studies that used ordinary regression based on the assumption that the magnitudes of the impact of exposure on all range distribution of the outcome were uniform.However,infants at the tails of birth weight and gestational age distribution may suffer a disproportionate burden of prenatal morbidities.Objective:We aimed to explore the distribution of multiple metals in cord blood and its relative factors,and the associations of individual metal and metal mixtures with birth weight z-score,small-for-gestational-age（SGA）,gestational age,and preterm birth.Methods:A total of 16 metals were analyzed in 734 cord samples from a Chinese cohort study.Information on maternal lifestyle habits among pregnant and demographic and socio-economic characteristics were collected before delivery.The effects of sociodemographic characteristics and lifestyle on the concentration of individual metals in cord blood were analyzed by multivariate linear regression model.We used generalized linear regression and quantile regression to evaluate the associations of individual metals with birth weight z-score and gestational age.We used logistic regression to evaluate the associations of individual metals with SGA and premature.Weighted quantile sum regression（WQSR）was used to explore the relationships between metal mixtures and birth outcomes,and identify the stronger contributors of the mixtures to the associations.Results:Our study found that nutrition supplementations were important factors affecting the concentrations of metals in umbilical cord blood.Folic acid supplementation was related to decreased the concentrations of As,Pb,and Al in cord blood,but increased the concentration of Cd.Calcium supplementation was negatively associated to the concentrations of Cd and Al in cord blood.In addition,the higher levels of Ni and Mn in cord blood was found in maternal pre-pregnant BMI≥24.0.And the mothers with higher household income and multipara were negatively related to the concentration of Ni in cord blood.The generalized linear regression found that one unit increase of ln-transformed concentration of Cu,Mn,and Cd,the birth weight z-score decreased 0.50（95%CI:-0.70,-0.29）,0.13（95%CI:-0.24,-0.01）,and 0.02（95%CI:-0.04,-0.001）respectively.Quantile regression showed stronger relations in the tails of birthweight z-score distribution[e.g.the associations of Cu at specific birth weight z-score quantiles were:the 10^th percentile-0.78（95%CI:-1.16,-0.40）,the 20^th percentile-0.81（95%CI:-1.04,-0.59）,the 90^th percentile-0.32（95%CI:-0.59,-0.05）].And the logistic regression model found that one unit increase of ln-transformed concentrations of Cu and Cr were associated with an increased risk of SGA[OR（95%CI）:4.65（2.25,9.62）for Cu;1.32（0.99,1.75）for Cr].The WQS index composed by Cu（39.7%）,Ni（18.3%）,Mn（14.0%）,and Cd（13.1%）,was related to decreased birth weight z-score[β（95%CI）:-0.31（-0.42,-0.20）].The WQSR identified Cu（40.2%）and Cr（10.4%）were the important contributors to the metal mixtures that was associated with an increased risk of SGA[OR（95%CI）:2.34（1.50,3.67）].The generalized linear regression found one unit increase in ln-transformed concentration of Cu,Se,and As,the gestational age increased 5.87（95%CI:4.24,7.49）days,3.30（95%CI:0.86,5.75）days,0.27（95%CI:0.01,0.53）days,respectively.While the gestational age decreased 3.01（95%CI:-5.32,-0.70）day with the increased ln-transformed Zn concentration.Quantile regression showed stronger relations in the tails of gestational age distribution[e.g.the associations of Zn at specific gestational age quantiles were:the 10^th percentile-6.93（95%CI:-10.5,-3.41）days,the 20^thpercentile-5.07（95%CI:-7.92,-2.23）days,the 90^th percentile 1.48（95%CI:-1.38,4.35）days].And we found ln-transformed Zn was associated with an increased risk of preterm birth[OR（95%CI）:52.1（5.11,521）],while Cu was associated with a decreased risk of preterm birth[OR（95%CI）:0.04（0.01,0.28）].The WQS index composed by Zn（64.7%）and Mn（12.4%）,was related to an increased risk of preterm birth[OR（95%CI）:3.90（1.63,9.30）].The WQSR identified Cu（54.9%）and Se（19.9%）were the important contributors to the metal mixtures that was associated with a decreased risk of preterm birth[OR（95%CI）:0.26（0.11,0.65）].Conclusion:We found nutrition supplementation were associated with decreased concentrations of toxic metals in umbilical cord blood.In this study,we found the essential elements of Cu,Zn,and Mn were mainly contributors to the associations between metal mixtures and birth outcomes,which combined the results of individual metal and multiple metal exposure models.Co-exposure to Cu,Mn,Ni,and Cd were associated to decreased birth weight z-score.Co-exposure to Cu and Cr were associated to an increased risk of SGA.Co-exposure to Zn and Mn were associated with an increased risk of preterm birth.The further studies are needed to explore the mechanism of multiple metal exposures with birth outcomes.Meanwhile,quantile regression found that the magnitudes of the associations with Cu and Zn were stronger at the lower birthweight z-score distribution and shorter gestational age distribution respectively,providing evidence that smaller infants may be more sensitive to metal exposure.