Gestational organophosphate esters (OPEs) exposure in association with placental DNA methylation levels of peroxisome proliferator-activated receptors (PPARs) signaling pathway-related genes.

BACKGROUND: Organophosphate esters (OPEs) exposure could affect offspring health. However, the underlying mechanisms are not well documented. OBJECTIVES: Based on a birth cohort study, we aimed to investigate the associations among gestational OPEs exposure, placental DNA methylation levels of peroxisome proliferator-activated receptor (PPAR) signaling pathway-related genes, and fetal growth. METHODS: We measured the concentrations of eight OPE metabolites in maternal urine samples and neonatal anthropometric measurements in 733 mother-child pairs. In 327 placental samples, we assessed the DNA methylation levels of 14 genes which were involved in the PPARs signaling pathway and expressed in placenta. Multiple linear regression models were used to examine the associations of OPEs exposure with placental DNA methylation, and of OPEs and placental DNA methylation with neonatal anthropometric measurements. Causal mediation analyses were conducted to examine the potential mediating role of placental DNA methylation in the pathway between OPEs exposure and fetal growth. RESULTS: We observed a general pattern of OPEs exposure being associated with hypermethylation of candidate genes, with statistically significant associations identified for several OPEs with RXRA, ACAA1, ACADL, ACADM, PLTP, and NR1H3 methylation. Further, gestational exposure to BCIPP, DPP, BBOEP, ∑NCl-OPEs, and ∑OPEs tended to be associated with lower anthropometric measurements, with more significant associations observed on arm circumference, and abdominal and back skinfold thickness. Notably, RXRA, ACAA1, ACOX1, CPT2, ACADM, and NR1H3 methylation tended to be associated with lower neonatal anthropometric measurements, especially for abdominal and back skinfold thickness. Moreover, mediation analyses showed that 19.42 % of the total effect of DPP on the back skinfold thickness was mediated by changes in RXRA methylation, and there was a significant indirect effect of RXRA methylation. CONCLUSIONS: Gestational OPEs exposure could disrupt the placental DNA methylation levels of PPAR signaling pathway-related genes, which might contribute to the effect of OPEs on fetal growth.

The Role of Placental DNA Methylation at Reproduction-Related Genes in Associations between Prenatal Bisphenol Analogues Exposure and the Digit Ratio in Children at Age 4: A Birth Cohort Study.

Placental DNA methylation (DNAm) may be a potential mechanism underlying the effects of prenatal bisphenol analogues (BPs) exposure on reproductive health. Based on the Shanghai-Minhang Birth Cohort Study (S-MBCS), this study investigated associations of placental DNAm at reproduction-related genes with prenatal BPs exposure and children's digit ratios at age 4 using multiple linear regression models, and mediation analysis was further used to examine the mediating role of placental DNAm in the associations between prenatal BPs exposure and digit ratios among 345 mother-child pairs. Prenatal exposure to bisphenol A (BPA) was associated with hypermethylation at Protocadherin 8 (PCDH8), RBMX Like 2 (RBMXL2), and Sperm Acrosome Associated 1 (SPACA1), while bisphenol F (BPF) exposure was associated with higher methylation levels of Fibroblast Growth Factor 13 (FGF13). Consistent patterns were found in associations between higher DNAm at the 4 genes and increased digit ratios. Further mediation analysis showed that about 15% of the effect of BPF exposure on increased digit ratios was mediated by placental FGF13 methylation. In conclusion, the altered placental DNAm status might be a mediator underlying the feminizing effect of prenatal BPs exposure.

Associations of prenatal exposure to bisphenols with infant anthropometry: A prospective cohort study.

BACKGROUND: Bisphenols (BPs) have been shown to exhibit developmental toxicities. Epidemiological evidence on prenatal BPs exposure and infant growth primarily confined scopes to specific BPs and birth outcomes, with few studies focusing on infant growth and reporting inconsistent findings. The joint effect of prenatal exposure to BPs mixture on infant growth was rarely studied. OBJECTIVE: This study examined associations of prenatal exposure to individual bisphenol A (BPA) and its analogues (bisphenol F [BPF], bisphenol S [BPS], bisphenol AF [BPAF], and tetrachlorobisphenol A [TCBPA]) and their mixture with infant growth. METHODS: Urinary concentrations of BPs in pregnant women were quantified. Weight, body mass index, skinfold thickness, and circumference measurements of infants were collected at birth, 6 and 12 months of age, rapid growth and overweight were further defined. Multiple linear regression models and Bayesian kernel machine regression models (BKMR) were used to analyze associations of exposure to individual BPs and BPs mixture with infants' anthropometric measurements, and to identify the important components among mixture. The risks for rapid growth and overweight of each BP were determined using modified Poisson regression models. RESULTS: A general profile of higher prenatal BPs exposure (mainly BPA, BPF, and BPS) associated with higher anthropometric measurements and higher risks of overweight during infancy was found. We also observed higher risks of rapid growth in infants following prenatal BPs exposure, with risk ratios ranging from 1.46 to 1.91. The joint effect of BPs mixture and single effect of each BP from the BKMR models were consistent with findings from the linear regression models, further suggesting that associations in girls were generally driven by BPA, BPF, or BPS, while in boys mainly by BPF. CONCLUSION: Prenatal exposure to BPs and their mixture could increase anthropometric measurements of offspring during infancy, with implications of altered growth trajectory in future.

Associations between maternal urinary kisspeptin in late pregnancy and decreased fetal growth: a pregnancy-birth cohort study.

Background: Kisspeptin has been indicated to be a biomarker of fetal growth. Although some evidence suggested that maternal kisspeptin concentrations in early pregnancy were associated with increased fetal growth, studies are still limited and the effect of kisspeptin in late pregnancy remains unknown. This study aimed to investigate the associations between maternal kisspeptin in late pregnancy and fetal growth. Methods: Based on the Shanghai-Minhang Birth Cohort study, 724 mother-neonate pairs were included in this study. We measured maternal kisspeptin concentrations in the urine samples collected in late pregnancy and neonatal anthropometric indices at birth. The associations between maternal kisspeptin and neonatal anthropometry were investigated using multiple linear regression models. Results: Higher maternal urinary kisspeptin concentrations were associated with lower neonatal birth weight, head circumference, upper arm circumference, abdominal skinfold thickness, triceps skinfold thickness, and back skinfold thickness. The inverse associations were more pronounced for the highest kisspeptin levels versus the lowest. These patterns were consistent in analyses stratified by neonatal sex, with notably stable associations between maternal kisspeptin concentrations and skinfold thickness. Conclusion: The present study suggested that maternal kisspeptin concentrations in late pregnancy might be inversely associated with fetal growth. The physiological mechanisms of maternal kisspeptin might differ from those in early pregnancy. Further studies are required to assess associations between maternal kisspeptin and energy homeostasis and explore the physiological roles of kisspeptin in late pregnancy.

Association between prenatal exposure to per- and polyfluoroalkyl substances and infant anthropometry: A prospective cohort study.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are a group of synthetic organic chemicals with potential endocrine-disrupting effects, and have been found to impair the physical growth of offspring in both experimental and epidemiological studies. We aimed to investigate the effects of prenatal PFAS exposure on repeated measurements of multiple anthropometric indicators in infants. METHOD: PFAS were measured in serum samples collected from pregnant women at 12-16 gestational weeks. We calculated z-scores for the weight-for-age (WAZ), weight-for-length (WLZ), head circumference-for-age (HCZ), arm circumference-for-age (ACZ), triceps skinfold-for-age (TSZ), and subscapular skinfold-for-age (SSZ) at birth, 6 months, and 12 months of age according to the child growth standards of the World Health Organization (WHO) for anthropometric indicators. A total of 964 mother-infant pairs were included. A multivariate linear regression was performed to examine the associations between prenatal PFAS concentrations and anthropometric indicators at each time point. A generalized estimating equation (GEE) model was used to examine the longitudinal effects of PFAS exposure on repeated measurements of anthropometric indicators. Ultimately, a Bayesian kernel machine regression (BKMR) model was used to assess the joint effects of the PFAS mixture on anthropometric indicators. RESULTS: In GEE models, perfluorododecanoic acid (PFDoA) in the high tertile group was associated with increased WAZ/WLZ, with ß values (95% confidence intervals (CI)) of 0.12 (0.00, 0.23) and 0.18 (0.03, 0.32), respectively. Perfluorononanoic acid (PFNA) was associated with increased ACZ in the middle and high tertile groups. The BKMR models also presented the associations of the PFAS mixture with increased WAZ/WLZ throughout infancy, with more profound effects in females. Meanwhile, a pattern of inverse associations was observed between the perfluorooctanoic acid (PFOA) concentrations in the high tertile group and decreased WAZ, WLZ, and HCZ in males. In addition, the associations between PFAS and increased TSZ/SSZ at birth were identified by both linear regression and BKMR models. CONCLUSION: Prenatal PFAS exposure (PFNA and PFDoA) was associated with increased infant anthropometry, especially in female infants, while prenatal PFOA exposure was associated with decreased weight, and head and arm circumference in male infants. The findings indicate that prenatal PFAS exposure may impair the growth trajectory of offspring.

Prenatal exposure to Per- and polyfluoroalkyl substances and adiposity measures of children at 4 and 6 years: A prospective birth cohort in China.

There is growing evidence that prenatal exposure to Per- and polyfluoroalkyl substances (PFAS) was associated with childhood obesity, but evidence on multiple adiposity measures including arm circumference (AC), and waist circumference (WC) among Chinese children is limited. We investigated the associations of prenatal exposure to PFAS with adiposity measures of children at 4 and 6 years of age in the Shanghai-Minhang Birth Cohort Study. A total of 573 mother-child pairs with maternal PFAS concentrations and at least one measurement of adiposity measures of children were included in the present study. Eleven PFAS were assessed in maternal fasting blood samples. Information on children's weight, height, AC, and WC was collected at follow-ups. Weight for age Z score (WAZ), body mass index for age Z score (BMIz), and children overweight were calculated based on the World Health Organization Child Growth Standards. Multivariate linear regression, Poisson regression with robust error variance, and Bayesian Kernel Machine Regression (BKMR) models were used to examine the associations of prenatal exposure to PFAS with children's adiposity measures. Eight PFAS with detection rates above 85 % were included in the analyses. In the multivariate linear regression models, maternal PFNA concentrations were associated with a greater AC (ß = 0.29, 95 % Confidence Interval (CI): 0.04-0.55) in 4-year-old children and with an increase in WAZ (ß = 0.26, 95 % CI: 0.06-0.46), BMIz (ß = 0.31, 95 % CI: 0.09-0.53), AC (ß = 0.49, 95 % CI: 0.08-0.90), and WC (ß = 1.47, 95 % CI: 0.41-2.52) in 6-year-old children. We also observed the associations of maternal concentrations of PFOS, PFNA, PFUdA, and PFTrDA with the increased risk of children overweight in 6-year-old children. BKMR models further supported the findings from multivariate linear regression and Poisson regression models, and identified PFNA as the most important contributor. Moreover, the associations described above were generally more pronounced in girls. In conclusion, prenatal exposure to PFAS was associated with an increased risk of children's adiposity with a sex-specific manner, and PFNA contributed most to the associations after controlling for the effect of co-exposure to other PFAS compounds, especially among girls at 6 years of age.

Determinants of organophosphate esters exposure in pregnant women from East China.

Organophosphate esters (OPEs) have been broadly used in various industrial and consumer products, resulting in global distribution and human exposure. Gestational exposure to OPEs may adversely affect the health of both pregnant women and their offspring. To better understand OPE exposure in pregnant women, our study determined eight urinary metabolites of major OPEs in pregnant women (n = 733) recruited at 12-16 weeks of gestation from Shanghai, China, and explored the determinants of OPE exposure among various sociodemographic characteristics, lifestyles, and dietary factors. Urinary metabolites of OPEs, including bis (1,3-dichloro-2-propyl) phosphate (BDCPP), bis (2-chloroethyl) phosphate (BCEP), bis (1-chloro-2-propyl) phosphate (BCIPP), dicresyl phosphate (DCP), diphenyl phosphate (DPP), dibutyl phosphate (DBP), bis (2-ethylhexyl) phosphate (BEHP), and bis (2-butoxyethyl) phosphate (BBOEP), exhibited a detection rate ranging from 69.30% to 99.32%. Multivariate linear regression models indicated that pregnant women who were multiparous, had a higher family income per capita, worked in white-collar jobs, and took nutritional supplements such as milk powder and fish oil tended to have higher urinary OPE metabolite concentrations. Besides, independent of sociodemographic characteristics and lifestyle factors, consumption of more aquatic products, soy products, pork, and puffed food, as well as drinking of purified tap water versus tap water, were associated with increased urinary OPEs metabolite concentrations. Our study demonstrated that OPE exposure was ubiquitous in pregnant women from Shanghai, and provided new insights into the potential factors influencing OPE exposure during pregnancy.

Prenatal per- and polyfluoroalkyl substances exposure and gut microbiota of infants: A prospective cohort study.

Prenatal exposure to per- and polyfluoroalkyl substances (PFASs) has been reported to be linked to a series of adverse health outcomes in mothers and their children. As the gut microbiota is a sensitive biomarker for assessing the toxicity of environmental contaminants, this study attempted to investigate whether prenatal PFASs exposure was associated with the gut microbiota of infants. Based on the Shanghai-Minhang Birth Cohort Study, this prospective cohort study included 69 mother-infant pairs. Fasting blood samples were collected from pregnant women for the PFASs assay. We collected fecal samples of infants at 1 year of age and analyzed the V3-V4 hypervariable region of the bacterial 16 S rRNA gene by high-throughput sequencing. Among the detected 11 PFASs, the concentration of perfluorooctanoic acid (22.19 ng/mL) was the highest, followed by perfluorooctane sulfonic acid (12.08 ng/mL). Compared with infants whose mothers' total PFASs concentrations during pregnancy were at the 40th percentile or lower (reference group), the species richness and diversity of microbiota were lower in infants prenatally exposed to a high level of PFASs (the sum of PFASs concentrations above the 60th percentile). Prenatal exposure to PFASs was associated with a higher proportion of Acidaminococcaceae, Acidaminococcus, Megamonas, Megasphaera micronuciformis and Megamonas funiformis in infants. The changes of the species have been suggested to be associated with immune and metabolic dysfunction in humans. Functional alterations of gut microbiota due to PFASs exposure were dominated by an enrichment of butanoate metabolism. Our preliminary findings may shed light on the potential role of the microbiota underlying the well-known impact of prenatal PFASs exposure on health outcomes of humans in later life.

Prenatal exposure to per- and polyfluoroalkyl substances and DNA methylation in the placenta: A prospective cohort study.

Epidemiological studies regarding the relationship between per- and polyfluoroalkyl substances (PFAS) and DNA methylation were limited. We investigated the associations of maternal PFAS concentrations with placental DNA methylation and examined the mediating role of methylation changes between PFAS and infant development. We measured the concentrations of 11 PFAS in maternal plasma during early pregnancy and infant development at six months of age. We analyzed genome-wide DNA methylation in 16 placental samples using reduced representation bisulfite sequencing. Additionally, we measured DNA methylation levels using bisulfite amplicon sequencing in 345 mother-infant pairs for five candidate genes, including carbohydrate sulfotransferase 7 (CHST7), fibroblast growth factor 13 (FGF13), insulin receptor substrate 4 (IRS4), paired like homeobox 2Ap (PHOX2A), and plexin domain containing 1 (PLXDC1). We found that placental DNA methylation profiles related to PFOA mainly enriched in angiogenesis and neuronal signaling pathways. PFOA was associated with hypomethylation of IRS4 and PLXDC1, and PFNA was associated with PLXDC1 hypomethylation. There were positive associations of CHST7 methylation with PFTrDA and IRS4 methylation with PFDoA and PFTrDA. PLXDC1 hypomethylation mediated the association between PFOA and suspected developmental delay in infants. Future studies with larger sample sizes are warranted to confirm these findings.

Per- and Poly-fluoroalkyl Substances and Bile Acid Profiles in Pregnant Women.

Alterations in bile acid (BA) profiles are closely associated with adverse outcomes in pregnant women and their offspring and may be one potential pathway underlying the related metabolic effects of per- and poly-fluoroalkyl substances (PFAS) exposure. However, evidence of associations between PFAS exposure and BA profiles in pregnant women is scarce. This study examined the associations of individual PFAS and PFAS mixture with BA profiles of pregnant women. We obtained quantitative data on the plasma concentrations of 13 PFAS and 15 BAs in 645 pregnant women from the Jiashan birth cohort. In Bayesian kernel machine regression models, the PFAS mixture was associated with increased plasma CA, TCA, TCDCA, and GLCA levels but with decreased GCA and LCA concentrations. Furthermore, the PFAS mixture was associated with increased concentrations of total BAs and the secondary/primary BA ratio but with decreased conjugated/unconjugated and glycine/taurine-conjugated BA ratios. PFHxS, PFUdA, PFOS, PFNA, and PFDA were the dominant contributors. The results of the linear regression analysis of individual PFAS were generally similar. Our findings provide the first epidemiological evidence for the associations of a PFAS mixture with BA profiles in pregnant women and may provide explanatory insights into the biological pathways underlying the related metabolic effects of PFAS exposure.

Prenatal exposures to isoflavones and neurobehavioral development in children at 2 and 4 years of age: A birth cohort study.

Isoflavones (ISOs) are plant-derived estrogen-like compounds, which were already proved with cognition benefits on elderly people. However, studies assessing the associations between prenatal ISOs exposure and children's neurodevelopment are scarce. This study aimed to examine the associations between maternal urinary ISOs concentrations, including genistein (GEN), daidzein (DAD), glycitein (GLY), and metabolite equol (EQU), and children's neurodevelopment, based on a Chinese cohort study. Participants in this study were pregnant women recruited at 12-16 weeks of gestation, and they provided a single spot urine sample for the ISOs assay. Neurodevelopment was measured using the Child Behavior Checklist (CBCL) at 2 and 4 years of age. Negative binomial regression analysis and Generalized Estimating Equation (GEE) were performed to examine the associations between maternal urinary ISOs concentrations and CBCL scores. Associations were observed between moderate levels of prenatal ISOs exposure and decreased risks of childhood neurobehavioral problems, while the highest level of prenatal ISOs exposure was associated with increased risks of neurobehavioral problems among children. The neuroprotective effects were consistently between moderate DAD exposure and specific neurobehavioral problems, across different ages and sexes. For example, compared with the lowest exposure level, the third quartile group was associated with less Anxious/Depressed problems in boys at 2 years of age (RR=0.72 (95%CI: 0.52, 0.99)), girls at 2 years of age (RR=0.70 (95%CI: 0.46, 1.06)), boys at 4 years of age (RR=0.73 (95%CI: 0.55, 0.96)), and girls at 4 years of age (RR=0.95 (95%CI: 0.68, 1.31)).

Relevance of PUFA-derived metabolites in seminal plasma to male infertility.

Aim: This study aims to investigate the biological effects of polyunsaturated fatty acid (PUFA)-derived metabolites in seminal plasma on male fertility and to evaluate the potential of PUFA as a biomarker for normozoospermic male infertility. Methods: From September 2011 to April 2012, We collected semen samples from 564 men aged 18 to 50 years old (mean=32.28 years old)ch., residing in the Sandu County, Guizhou Province, China. The donors included 376 men with normozoospermia (fertile: n=267; infertile: n=109) and 188 men with oligoasthenozoospermia (fertile: n=121; infertile: n=67). The samples thus obtained were then analyzed by liquid chromatography-mass spectrometry (LC-MS) to detect the levels of PUFA-derived metabolites in April 2013. Data were analyzed from December 1, 2020, to May 15, 2022. Results: Our analysis of propensity score-matched cohorts revealed that the concentrations of 9/26 and 7/26 metabolites differed significantly between fertile and infertile men with normozoospermia and oligoasthenozoospermia, respectively (FDR < 0.05). In men with normozoospermia, higher levels of 7(R)-MaR1 (HR: 0.4 (95% CI [0.24, 0.64]) and 11,12-DHET (0.36 (95% CI [0.21, 0.58]) were significantly associated with a decreased risk of infertility, while higher levels of 17(S)-HDHA (HR: 2.32 (95% CI [1.44, 3.79]), LXA5 (HR: 8.38 (95% CI [4.81, 15.24]), 15d-PGJ2 (HR: 1.71 (95% CI [1.06, 2.76]), and PGJ2 (HR: 2.28 (95% CI [1.42, 3.7]) correlated with an increased risk of infertility. Our ROC model using the differentially expressed metabolites showed the value of the area under the curve to be 0.744. Conclusion: The PUFA-derived metabolites 7(R)-MaR1, 11,12-DHET, 17(S)-HDHA, LXA5, and PGJ2 might be considered as potential diagnostic biomarkers of infertility in normozoospermic men.

Prenatal Exposure to Perfluoroalkyl Substances and Cognitive and Neurobehavioral Development in Children at 6 Years of Age.

Epidemiological evidence regarding the effects of prenatal exposure to perfluoroalkyl substances (PFASs) on neurodevelopment in children is inconclusive. In 449 mother-child pairs from the Shanghai-Minhang Birth Cohort Study, we measured the concentrations of 11 PFASs in maternal plasma samples obtained at 12-16 weeks of gestation. We assessed children's neurodevelopment at 6 years of age by the fourth edition of the Chinese Wechsler Intelligence Scale for Children and Child Behavior Checklist for ages 6-18. We evaluated the association between prenatal exposure to PFASs and children's neurodevelopment and the effect modification of maternal dietary factors during pregnancy and the child's sex. We found that prenatal exposure to multiple PFASs was associated with increased scores for attention problems, and the individual effect of perfluorooctanoic acid (PFOA) was statistically significant. However, no statistically significant association between PFASs and cognitive development was observed. Additionally, we found the effect modification of maternal nut intake and child's sex. In conclusion, this study suggests that prenatal exposure to PFASs was associated with more attention problems, and maternal nut intake during pregnancy may alter the potential effect of PFASs. However, these findings were exploratory because of multiple testing and the relatively small sample size.

Prenatal bisphenol exposure and intelligence quotient in children at six years of age: A prospective cohort study.

The effects of prenatal bisphenol A (BPA) exposure on children's cognitive development have been reported; however, relevant evidence on BPA analogues was limited, with rare evidence of the joint effect of their mixture. Among 424 mother-offspring pairs from the Shanghai-Minhang Birth Cohort Study, maternal urinary concentrations of five bisphenols (BPs) were quantified, and children's cognitive function was assessed by the Wechsler Intelligence Scale at six years of age. We assessed the associations of prenatal exposure to individual BPs with children's intelligence quotient (IQ) and analyzed the joint effect of BPs mixture by the Quantile g-computation model (QGC) and Bayesian kernel machine regression model (BKMR). QGC models showed that higher maternal urinary BPs mixture concentrations were associated with lower scores among boys in a non-linear way; however, no association was observed in girls. For individual effects, BPA and BPF were associated with decreased IQ scores in boys and were identified as important contributors to the joint effect of BPs mixture. However, associations of BPA with increased IQ scores in girls, and TCBPA with increased IQ scores in both sexes were observed. Our findings suggested prenatal exposure to BPs mixture may affect children's cognitive function in a sex-specific pattern and provided evidence of the neurotoxicity of BPA and BPF.

Bile acid metabolites in early pregnancy and risk of gestational diabetes mellitus: Results from a prospective cohort study.

AIMS: To evaluate the associations of plasma bile acid metabolites, especially in early pregnancy, with gestational diabetes mellitus (GDM) risk among pregnant women. MATERIALS AND METHODS: Plasma concentrations of 15 bile acid metabolites were measured in 645 women at early pregnancy from the Jiashan Birth Cohort using a liquid chromatography-tandem mass spectrometry metabolomics platform. Using logistic and cubic spline models, we examined associations between baseline plasma bile acid metabolites and GDM risk during mid-late pregnancy. A meta-analysis of prospective studies of bile acid and GDM risk was performed. RESULTS: The linear and nonlinear univariate models identified eight metabolites associated with GDM, including cholic acid, taurocholic acid (TCA), glycocholic acid, glycochenodeoxycholic acid, deoxycholic acid, lithocholic acid (LCA), ursodeoxycholic acid and taurolithocholic acid (all P <0.05). Multivariable analysis indicated that TCA and LCA levels were positively (odds ratio [OR] 2.07, 95% confidential interval [CI] 1.05, 3.96; P = 0.030) and negatively (OR 0.83, 95% CI 0.68, 1.01; P = 0.065) associated with GDM, respectively, after adjusting for confounders. The TCA-GDM association showed a positive linear shaped relationship (OR 2.07, 95% CI 1.05, 3.96; P = 0.030); while LCA was negatively related with GDM risk in linearity (OR 0.83, 95% CI 0.68, 1.01; P = 0.065). The meta-analysis of five studies showed a consistent bile acid and GDM association, with a risk ratio (RR) of 2.43 (1.95, 3.03). CONCLUSIONS: This study indicated that, the levels of circulating bile acids in early pregnancy were associated with risk of GDM, independent of GDM risk factors. Most GDM-associated bile acids were primary conjugated and secondary unconjugated bile acids.

Preterm Birth, Small for Gestational Age, and Large for Gestational Age and the Risk of Atrial Fibrillation Up to Middle Age.

Importance: Adverse birth outcomes, including preterm birth, small for gestational age (SGA), and large for gestational age (LGA) are associated with increased risks of hypertension, ischemic heart disease, stroke, and heart failure, but knowledge regarding their associations with atrial fibrillation (AF) is limited and inconsistent. Objective: To investigate whether preterm birth, SGA, or LGA are associated with increased risks of AF later in life. Design, Setting, and Participants: This multinational cohort study included Danish, Swedish, and Finnish national health registries. Live singleton births in Denmark from 1978 through 2016, in Sweden from 1973 through 2014, and in Finland from 1987 through 2014, who were followed up until December 31, 2016, in Denmark, December 31, 2021, in Sweden, and December 31, 2014, in Finland were included. Data analyses were performed between January 2021 and August 2022. Exposures: Preterm birth (less than 37 gestational weeks), SGA (less than 10th percentile birth weight for gestational age), and LGA (more than 90th percentile birth weight for gestational age) identified from medical birth registers. Main Outcomes and Measures: Diagnosis of AF obtained from nationwide inpatient and outpatient registers. The study team ran multivariable Cox proportional hazard models and flexible parametric survival models to estimate hazard ratios (HRs) and 95% CIs for AF according to preterm birth, SGA, and LGA. Sibling analyses were conducted to control for unmeasured familial factors. Results: The cohort included 8 012 433 study participants (maximum age, 49 years; median age, 21 years; male, 51.3%). In 174.4 million person-years of follow-up, 11 464 participants had a diagnosis of AF (0.14%; median age, 29.3 years). Preterm birth and LGA were associated with increased AF risk in both the full population cohort and in the sibling analyses; the multivariate HRs from the cohort analyses were 1.30 (95% CI, 1.18-1.42) and 1.55 (95% CI, 1.46-1.63), respectively. Preterm birth was more strongly associated with AF in childhood than in adulthood. Children born SGA had an increased risk of AF in the first 18 years of life but not afterwards. Conclusions and Relevance: Preterm births and LGA births were associated with increased risks of AF up to middle age independently of familial confounding factors. Individuals born SGA had an increased AF risk only during childhood.

Rheumatoid arthritis and the risk of postpartum psychiatric disorders: a Nordic population-based cohort study.

BACKGROUND: Postpartum psychiatric disorders (PPD) are common complications of childbirth. A common explanation for their development is that the psychological, hormonal, and immune changes associated with pregnancy and parturition may trigger psychiatric symptoms postpartum. Rheumatoid arthritis (RA) is characterized by abnormalities in the activity of the hypothalamic-pituitary-adrenal axis and of the immune system, but its association with PPD is unknown. We analyzed whether women with RA before childbirth have an increased risk of PPD. METHODS: We conducted a large population-based cohort study including mothers of singleton births in the Danish (1995-2015), Finnish (1997-2013), and Swedish Medical Birth Registers (2001-2013) (N = 3,516,849). We linked data from the Medical Birth Registers with data from several national socioeconomic and health registers. Exposure was defined as having a diagnosis of RA before childbirth, while the main outcome was a clinical diagnosis of psychiatric disorders 90 days postpartum. We analyzed the association between RA and PPD using Cox proportional hazard models, stratified by a personal history of psychiatric disorders. RESULTS: Among women without a history of psychiatric disorders, the PPD incidence rate was 32.2 in the exposed and 19.5 per 1000 person-years in the unexposed group; women with RA had a higher risk of overall PPD than their unexposed counterparts [adjusted hazard ratio (HR) = 1.52, 95% confidence intervals (CI) 1.17 to 1.98]. Similar associations were also observed for postpartum depression (HR = 1.65, 95% CI 1.09 to 2.48) and other PPD (HR = 1.59, 95% CI 1.13 to 2.24). Among women with a history of psychiatric disorders, the incidence rate of overall PPD was 339.6 in the exposed and 346.6 per 1000 person-years in the unexposed group; RA was not associated with PPD. We observed similar associations between preclinical RA (RA diagnosed after childbirth) and PPD to those corresponding to clinical RA. CONCLUSIONS: Rheumatoid arthritis was associated with an increased PPD risk in women without, but not in those with a psychiatric history. If our findings are confirmed in future studies, new mothers with RA may benefit from increased surveillance for new-onset psychiatric disorders postpartum.

Individual and joint effects of phthalates exposure on the risk of early miscarriage.

BACKGROUND: The exposure levels of phthalates in humans have dropped dramatically. Little is known about the individual and joint effects of phthalates exposure at low levels on the risk of early miscarriage. OBJECTIVE: To examine the association between exposure to phthalates individually or as a mixture and early miscarriage. METHODS: A case-control study was conducted in Shanghai, China during 2019-2020. A total of 291 women seeking medical services due to miscarriage (cases) and 308 women planning to terminate an unintended pregnancy (controls) within 12 gestational weeks were recruited. Urinary concentrations of eight phthalate metabolites were determined by ultra-performance liquid chromatography. We included 534 women in the main analysis who had available data on both phthalates exposure and complete information on potential confounders. We used logistic regression and Bayesian kernel machine regression (BKMR) to examine the associations of concentrations of phthalates with miscarriage. RESULTS: Among the phthalate metabolites, mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) had the highest concentration (8.10 ng/mL), followed by mono(2-ethyl-5-oxohexyl) phthalate (MEOHP, 2.68 ng/mL) and monobutyl phthalate (MBP, 2.24 ng/mL). Higher concentrations of MBP, mono(2-ethylhexyl) phthalate (MEHP), MEHHP, MEOHP and the molar sum of di(2-ethylhexyl) phthalate (DEHP) metabolites (∑DEHPm) were associated with an increased risk of miscarriage exhibiting a dose-response relationship. The most evident association of miscarriage was found with ∑DEHPm, with adjusted odds ratio (95% confidence interval) of 1.94 (1.14, 3.31) for the second quartile, 2.83 (1.67, 4.79) for the third quartile and 4.28 (2.49, 7.37) for the fourth quartile compared to the first quartile. Consistently, the phthalate mixture was positively associated with the risk of miscarriage and DEHP was the predominant contributor to the joint effect in BKMR model. IMPACT: Phthalates are a family of synthetic chemicals mainly used as plasticizers, solvents and additives in a large variety of industrial and consumer products, including food packing materials, toys, gloves, medical devices and personal care products. Although exposure levels of phthalates of pregnant women have declined sharply over the past few decades, phthalates exposure was still associated with an increased risk of early miscarriage. Our findings suggest that future researchers and policy makers might need to take low-dose effects of phthalates into account regarding the reproductive toxicity of phthalates exposure in humans. SIGNIFICANCE: Our findings contribute to the awareness of the reproductive toxic potential of phthalates at low levels in humans and support the ongoing efforts to further reduce exposure to phthalates.

Prenatal exposure to ambient PM2.5 and its chemical constituents and child intelligence quotient at 6 years of age.

There are limited studies on the associations between prenatal exposure to constituents of fine particulate matter (PM2.5) and children's intelligence quotient (IQ). Our study aimed to explore the associations between prenatal PM2.5 and its six constituents and the IQ levels of 6-year-old children. We included 512 mother-child pairs. We used a satellite-based modelling framework to estimate prenatal PM2.5 and its six constituents (ammonium, sulfate, nitrate, organic carbon, soil dust, and black carbon). We assessed the children's IQ using the short form of the Wechsler Intelligence Scale. Perceptual Reasoning Index (PRI), Verbal Comprehension Index (VCI), and Full Scale IQ (FSIQ) scores were computed. The multiple informant model (MIM) was applied to explore the trimester specific effects of PM2.5 and its six constituents' exposure on children's PRI, VCI, and FSIQ. To examine whether the duration of breastfeeding and physical activity (PA) could modify the effects of PM2.5 on children's IQ, we stratified the analyses according to the duration of breastfeeding (≤6 and >6 months) and time of outdoor activities after school (≤2 and >2 h/week). The first trimester PM2.5 and its five constituents' exposures were inversely associated with FSIQ [ß = -1.34, 95 % confidence interval [CI] (-2.71, 0.04) for PM2.5] and PRI [ß = -2.18, 95 %CI (-3.80, -0.57) for PM2.5] in children. The associations were magnified among boys and those with less outdoor activities or shorter breastfeeding duration. Our results indicate that prenatal PM2.5 and several of its main constituents' exposure may disrupt cognitive development in children aged 6 years. More PA and longer breastfeeding duration may alleviate the detrimental effects of prenatal PM2.5 exposure on children's cognitive function.

Maternal per- and poly-fluoroalkyl substances exposure and child adiposity measures: A birth cohort study.

Maternal exposure to per- and polyfluoroalkyl substances (PFAS) during pregnancy may have a programming effect on the physical development of the offspring. However, the findings of the association between PFAS and the physical development of offspring were inconsistent, and the overall effects of the PFAS mixture were unclear. In this study, we examined the associations between maternal PFAS exposure and offspring adiposity during the first two years of life. A total of 937 mother-child pairs from the Jiashan Birth Cohort Study were investigated. Thirteen PFASs were analyzed in maternal blood samples. Child weight and length were measured at birth, 1, 3, 6, 8, 12, and 24 months, and the ponderal index (PI) and weight-for-age z-scores (WAZ) were calculated. Longitudinal associations of PFAS concentrations (by quartile) with repeated data of PI and WAZ were examined using linear mixed model, and the overall effect of the PFAS mixture on adiposity measures was evaluated using quantile g-computation (QGC). Maternal PFAS exposure was associated with increased PI in both the linear mixed model and the QGC model. Among the PFAS examined, the associations between maternal PFTrDA exposure and PI were the strongest. Maternal PFAS and WAZ showed similar patterns of association. In the longitudinal cohort study, we found that adiposity in young children is increased by maternal PFAS exposure. The associations between maternal PFASs concentrations and child adiposity may be chemical-specific.