Associations Of Maternal Urinary Heavy Metals And Bisphenols Levels With Longitudinally Assessed Fetal Growth

Fetal period is critical for growth and development.Growth during this period is related to health after birth and even in adulthood.Birth weight is the most common used indicator of fetal growth;however,it is a cross-sectional parameter measured at the endpoint of fetal growth.It is not conducive to early detection and intervention of abnormal fetal growth if only birth weight is assessed.Fetal growth parameters obtained from prenatal ultrasound examinations can reflect fetal growth in real time.In recent years,a growing number of studies have focuses on these fetal growth parameters,and used them to identify risk factors associated with abnormal fetal growth,as well as to identify individuals at increased risks of adverse birth outcomes,such as premature and fetal growth restriction.However,the majority of these studies have focused on fetal growth parameters that measured at only one time point during gestation.Studies using data of repeatedly measured fetal growth are scarce.Furthermore,studies on the extent to which fetal growth parameters track in different trimesters are limited.Increasing evidence suggests that prenatal exposure to environmental pollutants could adversely affect fetal growth.Heavy metal is one of the most concerned pollutants.A number of epidemiological studies have explored the associations between metals exposure during pregnancy and fetal growth.However,the majority of these studies assessed the associations between metals exposure and birth weight,and few studies focused on intrauterine growth.In addition,most of these studies were cross-sectional designed,in which metal exposure level was measured at only one time point during gestation;thus,the windows of heightened vulnerability to metals exposure during gestation could not be identified.Besides heavy metals,bisphenol compounds are also important.Bisphenol A（BPA）can be found in a variety consumer products,including plastic bottles,food and beverage cans,and etc.Bisphenol F（BPF）and bisphenol S（BPS）have been widely used in manufacturing a variety of BPA-free products.Studies have shown that the general population is widely exposure to BPA,BPF,and BPS.A number of studies have assessed the associations of prenatal to BPA with fetal growth,but showed inconsistent results.Moreover,most of these studies reported the associations of BPA exposure and birth weight,but few studies focused on intrauterine growth.Additionally,few studies have investigated the associations of prenatal exposure to BPF and BPS with intrauterine growth.The present study was based on a prospective birth cohort study in Wuhan.Longitudinal fetal growth parameters were collected through ultrasound examinations.We investigated the extent to which fetal growth characteristics tracked,and determined the maternal and paternal factors and adverse birth outcomes associated with fetal growth.In addition,we collected maternal urine samples in different periods during pregnancy,and measured urinary concentrations of heavy metals（As,Cd,Cr,Pb,and V）,and bisphenol compounds（BPA,BPF,and BPS）.We assessed the associations of prenatal exposure to these pollutants with fetal growth,and investigated whether there were critical windows of vulnerability to these factors for fetal growth,in order to provide epidemiological evidence for the prevention and control of prenatal exposure to adverse environmental factors.Part 1:Risk factors and adverse birth outcomes associated with fetal growthObjectives:To examine the extent to which fetal growth characteristics track,and whether fetal growth are influenced by maternal and paternal determinants,and are associated with adverse birth outcomes.Methods:The present study was embedded in a longitudinal prenatal cohort in Wuhan from 2013 to 2016.Fetal growth characteristics,including head circumference（HC）,abdominal circumference（AC）,femur length（FL）,and estimated fetal weight（EFW）were measured by ultrasound at 16,24,and 31 weeks of gestation.We calculated gestational age-adjusted standard deviation scores（SDS）for all these characteristics as well as birth weight,birth length,and ponderal index.Information on maternal and paternal physical characteristics and lifestyle habits were obtained in face-to-face interviews and electronic medical records system.Pearson correlations were calculated to assess the tracking of fetal growth characteristics during different periods of pregnancy.We calculated the proportion of fetuses whose EFW/BW remained within the same tertile.Generalized linear regression models were used to evaluate the associations of maternal and paternal physical characteristics and lifestyle habits with fetal growth characteristics.Moreover,multiple logistic regression models were used to assess to association of fetal growth characteristics during different periods of pregnancy with the risks adverse birth outcomes,including low birth weight,macrosomia,small for gestational age,large for gestational age,and preterm birth.Results:Correlation coefficients between fetal growth characteristics at 16 weeks of gestation and birth weight were low（all correlation coefficients<0.24;all P<0.05）.Correlation coefficients between fetal growth characteristics at 31 weeks of gestation and birth weight were relatively higher（correlation coefficients ranged from 0.35 to0.56;all P<0.05）.Tracking birth weight within the same tertile at birth occurred in37.6%of fetuses.Maternal and paternal height,weight,and BMI were positively associated with fetal growth characteristics;furthermore,maternal age,parity,folic acid supplement,gestational diabetes,and hypertension disorders during pregnancy were all related to fetal growth.Fetal growth characteristics during the 3 time periods were negatively associated with the risks of low birth weight and small for gestational age,while were positively associated with the risks of macrosomia and large for gestational age,with the strongest associations presented at the 31 weeks of gestation.Moreover,fetal growth characteristics were not significantly associated with the risk of preterm birth.Conclusions:Fetal growth characteristics track moderately throughout gestation,with stronger tracking coefficients present in later pregnancy.Maternal and paternal physical characteristics and lifestyle habits were related to fetal growth.Fetal growth characteristics were associated with the risks of adverse birth outcomes,with the strongest associations presented in late pregnancy.Part 2:Associations of maternal urinary heavy metals levels with longitudinally assessed fetal growthObjectives:To investigate trimester-specific associations of urinary concentrations of heavy metals,including As,Cd,Cr,Pb,and V,with fetal growth parameters measured repeatedly by ultrasound and birth size.Methods:The present study was embedded in a longitudinal prenatal cohort in Wuhan from 2013 to 2016.Concentrations of the heavy metals were measured in maternal urine samples of 3041 women collected in the 1^st,2^nd,and 3^rd trimesters using an inductively coupled plasma mass spectrometry（ICP-MS）.Urinary specific gravity adjusted urinary metals concentrations were calculated.Because the distributions of urinary metals concentrations were shown to be right-skewed,a natural logarithm（ln-）transformation of data was used to satisfy statistical normality.Linear regressions with generalized estimating equations were applied to estimate trimester-specific associations of urinary metals concentrations with fetal growth parameters and birth weight,birth length,and ponderal index.Results:Geometric means of urinary specific gravity adjusted urinary concentrations of As,Cd,Cr,Pb,and V were 18.8,0.48,1.05,2.44,and 0.80μg/L,respectively.Inverse associations of Cr exposure in the 1^st trimester with fetal growth parameters at 31 weeks of gestation were observed,resulting in significant reduction in AC of-5.4%（95%CI:-9.6%,-1.2%）and EFW of-5.6%（95%CI:-9.8%,-1.4%）per unit increase in Ln-Cr.Urinary Cr concentration in the 2^nd trimester was also associated with reduced AC and EFW at 31 weeks of gestation.Maternal urine concentrations of Cd,Pb,and V in the1^st and 2^nd trimester were all negatively associated with fetal growth parameters at 31weeks of gestation.Besides,urinary concentrations of Cd,Cr,and V in the 1^st trimester were negatively associated with newborns’ponderal index;urinary concentrations of Cr and V in the 2^nd trimester were negatively associated with ponderal index.No significant association was observed between urinary As concentrations and fetal growth parameters or birth size.In stratified analyses by fetal sex,the inverse associations of Cr exposure in the 2^nd trimester with fetal AC and EFW at 31 weeks of gestation were evident in boys but not in girls,and these sex-based differences were statistically significant(P_interaction<0.05).Conclusions:Our findings show that prenatal exposure to Cd,Cr,Pb,and V significantly reduced fetal growth.This is the first study on the trimester-specific association of prenatal to Cr with fetal growth.These findings provide epidemiological evidence for the prevention of heavy metals exposure among pregnant women.Part 3:Associations of maternal urinary bisphenols levels with longitudinally assessed fetal growthObjectives:To investigate trimester-specific associations of urinary concentrations of BPA,BPF,and BPS with fetal growth parameters measured repeatedly by ultrasound and birth size.Methods:The present study was embedded in a longitudinal prenatal cohort study;845women with three urine samples in the 1^st,2^nd,and 3^rd trimesters were recruited between2013 and 2015 in Wuhan,China.Maternal urine concentrations of BPA,BPF,and BPS were measured using ultra-high performance liquid chromatography coupled with triple quadrupole mass spectrometry（UHPLC-MS）.Linear regressions with generalized estimating equations were applied to estimate trimester-specific associations of urinary bisphenol concentrations with fetal growth parameters and birth weight,birth length,and ponderal index.Results:Detection rates of BPA,BPF,and BPS were 76.9%,98.3%,and 86.8%,respectively.Geometric means of SG-adjusted urinary bisphenol concentrations were0.87 ng/mL for BPA,0.68 ng/mL for BPF,and 0.39 ng/mL for BPS.An interquartile range（IQR）increase in urinary concentrations of BPF in the 1^st trimester was associated with a significant reduction in EFW at 24 weeks’gestation of 7.9%（95%CI:-15.6%,-0.2%）and EFW at 31 weeks’gestation of 7.3%（95%CI:-14.3%,-0.3%）,as well as a reduction in BW of 27.3 g（95%CI:-54.5,0.0 g）.Maternal urine concentrations of BPF in the 2^nd and 3^rd trimesters were also inversely associated with fetal growth parameters and birth size.Urinary BPS concentration in the 1^st trimester was inversely associated with AC and EFW at 31 weeks of gestation and newborns’birth weight and ponderal index;urinary BPS concentration in the 2^nd trimester was inversely associated with birth weight and birth length.No significant association was found between urinary BPA concentrations and fetal growth parameters or birth size.Conclusions:Our findings show that prenatal exposure to BPS and BPF significantly reduce fetal growth while no such impact was observed for BPA,suggesting that prenatal exposure to BPS and BPF could be toxic for fetal growth in humans.This is the first study on the trimester-specific association of prenatal to BPF with fetal growth.