Does brain-derived neurotrophic factor play a role in the association between maternal prenatal mental health and neurodevelopment in 2-year-old children?

OBJECTIVE: To evaluate the role of brain-derived neurotrophic factor (BDNF)-a crucial modulator of neural development and plasticity-in the association between prenatal maternal anxiety, depression, and perceived stress and child neurodevelopment in a prospective cohort study. METHODS: We included 526 eligible mother-child pairs from the Shanghai Birth Cohort in the study. Maternal mental health was assessed at mid-pregnancy using Zung's Self-Rating Anxiety Scale, Center for Epidemiologic Studies Depression Scale, and Perceived Stress Scale. The concentration of BDNF in cord blood was measured by ELISA. The offspring neurodevelopment at 24 months of age was assessed using the Bayley Scales. Linear and non-linear regression models were used. RESULTS: The average cord blood BDNF levels were higher in female newborns and those born via vaginal delivery, full term, and normal birth weight. Prenatal maternal anxiety (ß = -0.32; 95 % CI: -0.55, -0.09), depression (ß = -0.30; 95 % CI: -0.52, -0.08), and perceived stress (ß = -0.41; 95 % CI: -0.71, -0.12) scores were negatively associated with social-emotional performance at 24 months of age. However, no significant associations were found between prenatal maternal anxiety, depression, or perceived stress at mid-pregnancy and cord blood BDNF levels, as well as between cord blood BDNF levels and child neurodevelopment. LIMITATIONS: Maternal mental health at different timepoints during pregnancy and generalizability of the results warrant further assessment. CONCLUSIONS: Prenatal mental health was not associated with cord blood BDNF level and that BDNF may not be a mediator in the association between prenatal mental health and child neurodevelopment.

Interaction of prenatal maternal selenium and manganese levels on child neurodevelopmental trajectories-the Shanghai birth cohort study.

OBJECTIVE: The fetal brain is particularly plastic, and may be concurrently affected by chemical exposure and malnutritional factors. Selenium is essential for the developing brain, and excess manganese exposure may exert neurotoxic effects. However, few epidemiological studies have evaluated the interaction of manganese and selenium assessed in different prenatal stages on postnatal neurodevelopmental trajectories. METHODS: This study contained 1024 mother-child pairs in the Shanghai-birth-cohort study from 2013 to 2016 recruited since early/before pregnancy with complete data on manganese and selenium levels in different prenatal stages and infant neurodevelopmental trajectories. Whole blood manganese and selenium in early pregnancy and around birth were measured by inductively-coupled-plasma-mass-spectrometry (ICP-MS), children's cognitive development was evaluated at 6, 12, and 24 months of age using Age & Stage-Questionnaire (ASQ)-3 and Bayley-III. Multiple linear regression was used to investigate the interaction of prenatal selenium and manganese on neurodevelopmental trajectories. RESULTS: The prenatal manganese and selenium levels were 1.82 ± 0.98 µg/dL and 13.53 ± 2.70 µg/dL for maternal blood in early pregnancy, and 5.06 ± 1.67 µg/dL and 11.81 ± 3.35 µg/dL for umbilical cord blood, respectively. Higher prenatal Se levels were associated with better neurocognitive performances or the consistently-high-level trajectory (P < 0.05), with more significant associations observed in early pregnancy than around birth. However, such positive relationships became non-significant or even adverse in high (vs. low) manganese status, and the effect differences between low and high manganese were more significant in early pregnancy. CONCLUSIONS: Prenatal Selenium was positively associated with child neurodevelopment, but prenatal high manganese may mitigate such favorable effects. The effects were mainly observed in earlier prenatal stage.

Fetal overgrowth and weight trajectories during infancy and adiposity in early childhood.

BACKGROUND: Large-for-gestational age (LGA), a marker of fetal overgrowth, has been linked to obesity in adulthood. Little is known about how infancy growth trajectories affect adiposity in early childhood in LGA. METHODS: In the Shanghai Birth Cohort, we followed up 259 LGA (birth weight >90th percentile) and 1673 appropriate-for-gestational age (AGA, 10th-90th percentiles) children on body composition (by InBody 770) at age 4 years. Adiposity outcomes include body fat mass (BFM), percent body fat (PBF), body mass index (BMI), overweight/obesity, and high adiposity (PBF >85th percentile). RESULTS: Three weight growth trajectories (low, mid, and high) during infancy (0-2 years) were identified in AGA and LGA subjects separately. BFM, PBF and BMI were progressively higher from low- to mid-to high-growth trajectories in both AGA and LGA children. Compared to the mid-growth trajectory, the high-growth trajectory was associated with greater increases in BFM and the odds of overweight/obesity or high adiposity in LGA than in AGA children (tests for interactions, all P < 0.05). CONCLUSIONS: Weight trajectories during infancy affect adiposity in early childhood regardless of LGA or not. The study is the first to demonstrate that high-growth weight trajectory during infancy has a greater impact on adiposity in early childhood in LGA than in AGA subjects. IMPACT: Large-for-gestational age (LGA), a marker of fetal overgrowth, has been linked to obesity in adulthood, but little is known about how weight trajectories during infancy affect adiposity during early childhood in LGA subjects. The study is the first to demonstrate a greater impact of high-growth weight trajectory during infancy (0-2 years) on adiposity in early childhood (at age 4 years) in subjects with fetal overgrowth (LGA) than in those with normal birth size (appropriate-for-gestational age). Weight trajectory monitoring may be a valuable tool in identifying high-risk LGA children for close follow-ups and interventions to decrease the risk of obesity.

Maternal blood concentrations of toxic metal(loid)s and trace elements from preconception to pregnancy and transplacental passage to fetuses.

Intrauterine exposure to heavy metals may adversely affect the developing fetus and health later in life, while certain trace elements may be protective. There is limited data on their dynamic fluctuation in circulating concentration of women from preconception to pregnancy and the degree of transplacental passage to fetus. Such information is critically needed for an optimal design of research studies and intervention strategies. In the present study, we profiled the longitudinal patterns and trajectories of metal(loid)s and trace elements from preconception to late pregnancy and in newborns. We measured whole blood metal(loid)s in women at preconception, 16, 24 and 32 weeks of gestation and in cord blood in 100 mother-newborn pairs. Our data showed that the mean concentrations of mercury (Hg), lead (Pb), rubidium (Rb), manganese (Mn), and iron (Fe) were lower during early-, mid-, and late-pregnancy than at preconception. Copper (Cu), and calcium (Ca) concentrations increased after pregnancy (Cu 798 versus 1353, 1488, and 1464 µg/L). Concentrations at preconception were correlated with those during pregnancy for all examined metal(loid)s. Maternal Hg, Pb, and Se concentrations at late-pregnancy were correlated with those in newborn cord blood in various degrees (correlation coefficients: Hg 0.66, Pb 0.29, Se 0.39). The estimated placental transfer ratio for toxic metal(loid)s ranging from 1.68 (Hg) to 0.18 (Cd). Two trajectory groups were identified for Hg, Pb, Cd, Se concentrations. Hg concentrations may be correlated with maternal education levels. The study is the first to present longitudinal circulating concentration trajectories of toxic metal(loid)s and trace elements from preconception to pregnancy stages. A high degree of transplacental passage was observed in toxic metals Pb and Hg which may pose hazards to the developing fetus.

Maternal Prenatal Factors and Child Adiposity in Associations with Cardiometabolic Risk Factors in Term-Born Chinese Children at the Age of 2 Years.

Early growth has long-lasting associations with adult metabolic health. However, the association of adiposity with cardiometabolic risk factors in toddlers remains poorly understood. This study aimed to examine the association of maternal prenatal factors and child adiposity with child cardiometabolic risk factors among boys and girls aged 2 years. This was a birth cohort study of 549 term-born children in Shanghai, China, with follow-up data at the age of 2-years. Child anthropometric and adiposity measurements included weight, length, and skinfold thickness (triceps, subscapular, and abdominal). Child cardiometabolic risk factors included random morning plasma glucose, serum insulin, lipids, and systolic and diastolic blood pressure (SBP, DBP). At 2 years, overweight/obesity (weight-for-length z score, ZWFL > 2) was associated with 12.6 (95%CI 7.7, 17.4) mmHg higher SBP, and 7.9 (4.1, 11.8) mmHg higher DBP in boys, with similar results observed in girls. Maternal hypertensive disorders of pregnancy were associated with 3.0 (0.1, 5.8) higher SBP, 3.17 (0.90, 5.44) mmHg higher DBP, 0.24 (0.01,0.47) mmol/L higher plasma glucose, and 0.26 (0.01,0.51) mmol/L higher serum triglycerides after adjustment for child age, sex, and ZWFL. Maternal hypertensive disorders of pregnancy and child overweight/obesity were associated with higher SBP and DBP at the age of 2 years.

The association between maternal urinary Bisphenol A levels and neurodevelopment at age 2 years in Chinese boys and girls: A prospective cohort study.

The impact of maternal exposure to Bisphenol A on child cognitive development as well as its sex dimorphism remains uncertain. This study used data of 215 mothers and their children from a birth cohort in Shanghai. Urinary BPA were measured in spot urine samples of mothers at late pregnancy and children at age 2 years. Cognitive development was evaluated by Ages & Stages Questionnaires, Third Edition (ASQ-3) at age 2 years. Urinary BPA was detectable in 98.9% of mothers (geometric mean, GM: 2.6 µg/g. creatinine) and 99.8% children (GM: 3.4 µg/g. creatinine). Relative to the low and medium BPA tertiles, high tertile of maternal urinary BPA concentrations were associated with 4.8 points lower (95% CI: -8.3, -1.2) in gross motor and 3.7 points lower (95% CI: -7.4, -0.1) in problem-solving domain in girls only, with adjustment for maternal age, maternal education, pre-pregnancy BMI, passive smoking during pregnancy, parity, delivery mode, birth-weight for gestational age, child age at ASQ-3 test. This negative association remained with additional adjustment for child urinary BPA concentrations at age 2 years. No association was observed in boys. These results suggested the sex-dimorphism on the associations of maternal BPA exposure with gross motor and problem-solving domains in children at age 2 years. This study also indicated that optimal early child development should start with a healthy BPA-free "in utero" environment.

Urinary antibiotics concentrations, their related affecting factors and infant growth in the first 6 months of life: A prospective cohort study.

Antibiotic exposure even in low-dose could have potential adverse health effects, especially during early life. There is a lack of data on antibiotic burdens in early infancy. We aim to assess antibiotic exposure in infants from birth to 6 months of age, their related affecting factors and the association between antibiotic exposure and infancy growth. Urine samples were collected at ages of 3 days, 42 days, 3 months and 6 months from 197 term-born Chinese infants. A total of 33 representative antibiotics were measured by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Urinary antibiotics were detectable in 69.4%, 63.2%, 75.0% and 84.3% of infants at ages of 3 days, 42 days, 3 and 6 months, respectively. The dominant antibiotic categories detected were: Preferred as Veterinary Antibiotics (PVAs), Human Antibiotics (HAs), and Veterinary Antibiotics (VAs). The detectable rates were 30.6%, 45.8%, 58.9%, and 81.4% for PVAs, 34.1%, 20.8%, 28.6%, and 45.1% for HAs, and 36.5%, 12.5%, 6.3%, and 5.9% for VAs, at age 3 days, 42 days, 3 and 6 months, respectively. Urinary concentrations of HAs and preferred as human antibiotics (PHAs) in newborns at age 3 days were not associated with maternal intrapartum antibiotic prophylaxis. Similarly, no associations were observed between urinary antibiotics concentration and antibiotics use in infants at age 42 days or 6 months. The numbers and concentrations of urine detectable antibiotics were similar between infants with exclusive breastfeeding and infants fed with formula or mixed-feeding at all ages of 42 days, 3 and 6 months. At age of 42 days, infants in the low tertile of total antibiotics concentration or with one antibiotic detected had higher weight-for-length Z score and greater head circumference, compared to infants with no antibiotics detected. No associations were found between urinary antibiotics and any of the infant anthropometric measures at age 6 months. In conclusion, urinary antibiotics were detectable in most infants during the first 6 months of life, and PVAs, HAs and VAs were the most commonly detected antibiotics. This suggested the possibility of a foods-originated antibiotics exposure in children. No strong nor consistent associations were found between urinary antibiotic concentration and infant growth at the first six months of life. Still, attention is needed on the adverse health effect of early life exposure to antibiotics in future studies.

Cord blood fatty acid binding protein 4 and lipids in infants born small- or large-for-gestational-age.

Aim: Adverse (poor or excessive) fetal growth "programs" an elevated risk of type 2 diabetes. Fatty acid binding protein 4 (FABP4) has been implicated in regulating insulin sensitivity and lipid metabolism relevant to fetal growth. We sought to determine whether FABP4 is associated with poor or excessive fetal growth and fetal lipids. Methods: In a nested case-control study in the Shanghai Birth Cohort including 60 trios of small-for-gestational-age (SGA, an indicator of poor fetal growth), large-for-gestational-age (LGA, an indicator of excessive fetal growth) and optimal-for-gestational-age (OGA, control) infants, we measured cord blood concentrations of FABP4 and lipids [high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterols, triglycerides (TG)]. Results: Adjusting for maternal and neonatal characteristics, higher cord blood FABP4 concentrations were associated with a lower odds of SGA [OR = 0.29 (0.11-0.77) per log unit increment in FABP4, P = 0.01], but were not associated with LGA (P = 0.46). Cord blood FABP4 was positively correlated with both LDL (r = 0.29, P = 0.025) and HDL (r = 0.33, P = 0.01) in LGA infants only. Conclusion: FABP4 was inversely associated with the risk of SGA. The study is the first to demonstrate LGA-specific positive correlations of cord blood FABP4 with HDL and LDL cholesterols, suggesting a role of FABP4 in fetal lipid metabolism in subjects with excessive fetal growth.

Docosahexaenoic acid supplementation in gestational diabetes mellitus and neonatal metabolic health biomarkers.

Background and objective: Gestational diabetes mellitus (GDM) "programs" an elevated risk of metabolic dysfunctional disorders in the offspring, and has been associated with elevated leptin and decreased adiponectin levels in cord blood. We sought to assess whether docosahexaenoic acid (DHA) supplementation in GDM affects neonatal metabolic health biomarkers especially leptin and adiponectin. Methods: In a randomized controlled trial, singleton pregnant women with de novo diagnosis of GDM at 24-28 weeks of gestation were randomized to dietary supplementation of 500 mg DHA per day (intervention, n = 30) until delivery or standard care (control, n = 38). The primary outcomes were cord blood leptin and total adiponectin concentrations. Secondary outcomes included high-molecular-weight (HMW) adiponectin and insulin-like growth factor-1 (IGF-1) concentrations in cord blood, maternal glycemic control post-intervention and birth weight (z score). In parallel, 38 euglycemic pregnant women were recruited for comparisons of cord blood biomarkers. Results: There were no significant differences in cord serum leptin, total and HMW adiponectin and IGF-1 concentrations between DHA supplementation and control groups (all p > 0.05). Maternal fasting and 2-h postprandial blood glucose levels at 12-16 weeks post-intervention were similar between the two groups. The newborns in the DHA group had higher birth weight z scores (p = 0.02). Cord blood total and HMW adiponectin concentrations were significantly lower in GDM vs. euglycemic pregnancies. Conclusion: Docosahexaenoic acid supplementation at 500 mg/day in GDM women did not affect neonatal metabolic biomarkers including leptin, adiponectin and IGF-1. The results are reassuring in light of the absence of influence on neonatal adipokines (leptin and adiponectin), and potential benefits to fetal growth and development. Clinical Trial Registration: Clinicaltrials.gov, NCT03569501.

Maternal Pre-Pregnancy Nutritional Status and Infant Birth Weight in Relation to 0-2 Year-Growth Trajectory and Adiposity in Term Chinese Newborns with Appropriate Birth Weight-for-Gestational Age.

Being born with appropriate weight-for-gestational age (AGA, ~80% of newborns) is often considered as low risk for future obesity. This study examined differential growth trajectories in the first two years by considering pre- and peri-natal factors among term-born AGA infants. We prospectively investigated 647 AGA infants and their mothers enrolled during 2012-2013 in Shanghai, China, and obtained repeated anthropometric measures at ages 42 days, 3, 6, 9, and 18 months from postnatal care records, and onsite measurements at age 1 and 2 years (skinfold thickness, mid-upper arm circumference (MUAC)). Birthweight was classified into sex-and gestational age-specific tertiles. Among mothers, 16.3% were overweight/obese (OWO), and 46.2% had excessive gestational weight gain (GWG). The combination of maternal prepregnancy OWO and high birthweight tertile identified a subset of AGA infants with 4.1 mm higher skinfold thickness (95% CI 2.2-5.9), 1.3 cm higher MUAC (0.8-1.7), and 0.89 units higher weight-for-length z-score (0.54, 1.24) at 2 years of age with adjustment for covariates. Excessive GWG was associated with higher child adiposity measures at 2 years of age. AGA infants manifested differential growth trajectories by the combination of maternal OWO and higher birthweight, suggesting that additional attention is needed for those "at increased risk" of OWO in early intervention.

The Associations of Birthweight for Gestational Age Status with Its Differential 0-2 Year Growth Trajectory and Blood Pressure at Two Years of Age in Chinese Boys and Girls.

The first 1000 days of life represents a critical period for lifelong metabolic health. This study prospectively examined the contrasts between the growth trajectories of large, small, and appropriate sizes for gestational age (LGA, SGA, and AGA) term-born infants in their first two years, and their blood pressure at two years. In 2012-2013, 806 Chinese mother-newborn dyads were enrolled in the Shanghai Obesity and Allergy Birth Cohort Study. Repeated anthropometric measures were obtained at age 42 days, and at 3, 6, 9, 12, 18 and 24 months. Systolic and diastolic blood pressure (SBP, DBP) were measured at two years of age. Linear random effect models were employed to evaluate growth trajectory differences between LGA, SGA, and AGA infants. Of the study infants, 12.4% were LGA and 4.0% SGA. Length, weight, and weight-for-length z-score (ZWFL) were all consistently higher in LGA infants and lower in SGA infants than AGA infants. SGA infants had a higher ZWFL (0.11 unit/month; 95% CI: 0.04, 0.19) and a higher BMI (0.19; 95% CI: 0.09, 0.28 kg/m2 per month) growth velocity at age 0-6 months, relative to AGA infants. SGA was associated with 6.4 (0.4-12.4) mmHg higher SBP, and LGA was associated with 2.9 (95% CI -5.2, -0.5) mmHg lower DBP at two years of age in boys, however, not in girls. In conclusion, in this prospective birth cohort with repeated anthropometric measures and BP at two years of age, LGA, SGA, and AGA term-born infants manifested differential patterns of weight growth trajectory and BP, providing new insight into developmental origins of cardiometabolic health.

The impact of maternal depression, anxiety, and stress on early neurodevelopment in boys and girls.

OBJECTIVE: To examine the effects of prenatal maternal depression, anxiety and stress, and postnatal depression on infant early neurodevelopment, and the sex dimorphism. STUDY DESIGN: We used data from 3379 mother-infant pairs from the Shanghai Birth Cohort. Maternal mental health was assessed using the Center for Epidemiological Studies-Depression Scale, Zung Self-Rating Anxiety Scale, Perceived Stress Scale at mid-pregnancy, and the Edinburgh Postnatal Depression Scale at postpartum. Infant neurodevelopment was evaluated using the Ages & Stages Questionnaires and Bayley Scales at ages 6, 12, and 24 months, respectively. Linear mixed models and linear regression models were used. RESULTS: Among 3379 mothers, 11.07 %, 5.42 %, and 34.85 % of women experienced depression, anxiety, and elevated stress, separately. As maternal prenatal mental scores increased per 1SD, infant social-emotional scores decreased -2.82 (-3.86, -1.79) vs -2.86 (-3.94, -1.79) for depression, -2.34 (-3.38, -1.31) vs -2.72 (-3.81, -1.64) for anxiety, and -2.55 (-3.60, -1.50) vs -3.41 (-4.48, -2.35) for stress among boys and girls at age 24 months, respectively. Associations were also observed on social-emotional and communication scores in boys and girls, and fine motor in girls at age 6 and 12 months. These associations were not observed for postpartum depression. LIMITATION: Generalizability of the results to other population remains to be determined. CONCLUSIONS: Prenatal maternal depression, anxiety, and stress were negatively associated with infant early neurodevelopment, which were not observed for postpartum depression. We underscore the importance of maternal prenatal mental health in optimizing infant neuropsychiatric development.

Maternal Thyroid Dysfunction and Neuropsychological Development in Children.

CONTEXT: Thyroid hormones are essential for fetal brain development. The potential effects of maternal gestational thyroid dysfunction on offspring neuropsychological development remain inconclusive. OBJECTIVE: This work aimed to estimate effects of maternal thyroid dysfunction during pregnancy on offspring neuropsychological development in the first 2 years. METHODS: We prospectively examined 1903 mothers and their children from the Shanghai Birth Cohort. Thyroid hormones were assessed at about 12 gestational weeks. Maternal thyroid function was classified into 7 categories: euthyroid, overt/subclinical hyperthyroidism, overt/subclinical hypothyroidism, hyperthyroxinemia, and hypothyroxinemia. Neuropsychological development was assessed by the Ages and Stages Questionnaire at age 6 months, and Bayley Scales at age 24 months. RESULTS: Compared with children of euthyroid mothers, maternal overt hypothyroidism was associated with 7.0 points (95% CI, 1.7-12.4) lower scores in personal-social domain in girls aged 6 months, 7.3 points (95% CI, 2.0-12.6) lower in motor domain, and 7.7 points (95% CI, 1.1-14.2) lower social-emotional scores in boys at age 24 months; maternal subclinical hypothyroidism was associated with 6.5 points (95% CI, 1.0-12.1) poorer social-emotional domain in boys at age 6 months, and 7.4 points (95% CI, 0.1-14.8) poorer adaptive behavior domain in boys at age 24 months; maternal hypothyroxinemia was associated with 9.3 points (95% CI, 3.5-15.1) lower motor scores in boys at age 24 months; and maternal subclinical hyperthyroidism was associated with 6.9 points (95% CI, 0.1-13.7) lower language scores in girls at age 24 months. CONCLUSION: Maternal overt hypothyroidism, subclinical hypothyroidism/hyperthyroidism, and hypothyroxinemia during early pregnancy were associated with weakened neuropsychological development in infancy, and some effects may be sex specific.

Genome-wide placental DNA methylations in fetal overgrowth and associations with leptin, adiponectin and fetal growth factors.

BACKGROUND: Fetal overgrowth "programs" an elevated risk of type 2 diabetes in adulthood. Epigenetic alterations may be a mechanism in programming the vulnerability. We sought to characterize genome-wide alterations in placental gene methylations in fetal overgrowth and the associations with metabolic health biomarkers including leptin, adiponectin and fetal growth factors. RESULTS: Comparing genome-wide placental gene DNA methylations in large-for-gestational-age (LGA, an indicator of fetal overgrowth, n = 30) versus optimal-for-gestational-age (OGA, control, n = 30) infants using the Illumina Infinium Human Methylation-EPIC BeadChip, we identified 543 differential methylation positions (DMPs; 397 hypermethylated, 146 hypomethylated) at false discovery rate < 5% and absolute methylation difference > 0.05 after adjusting for placental cell-type heterogeneity, maternal age, pre-pregnancy BMI and HbA1c levels during pregnancy. Twenty-five DMPs annotated to 20 genes (QSOX1, FCHSD2, LOC101928162, ADGRB3, GCNT1, TAP1, MYO16, NAV1, ATP8A2, LBXCOR1, EN2, INCA1, CAMTA2, SORCS2, SLC4A4, RPA3, UMAD1,USP53, OR2L13 and NR3C2) could explain 80% of the birth weight variations. Pathway analyses did not detect any statistically significant pathways after correcting for multiple tests. We validated a newly discovered differentially (hyper-)methylated gene-visual system homeobox 1 (VSX1) in an independent pyrosequencing study sample (LGA 47, OGA 47). Our data confirmed a hypermethylated gene-cadherin 13 (CDH13) reported in a previous epigenome-wide association study. Adiponectin in cord blood was correlated with its gene methylation in the placenta, while leptin and fetal growth factors (insulin, IGF-1, IGF-2) were not. CONCLUSIONS: Fetal overgrowth may be associated with a large number of altered placental gene methylations. Placental VSX1 and CDH13 genes are hypermethylated in fetal overgrowth. Placental ADIPOQ gene methylations and fetal circulating adiponectin levels were correlated, suggesting the contribution of placenta-originated adiponectin to cord blood adiponectin.

Genome-Wide Placental Gene Methylations in Gestational Diabetes Mellitus, Fetal Growth and Metabolic Health Biomarkers in Cord Blood.

Gestational diabetes mellitus (GDM) "program" an elevated risk of metabolic syndrome in the offspring. Epigenetic alterations are a suspected mechanism. GDM has been associated with placental DNA methylation changes in some epigenome-wide association studies. It remains unclear which genes or pathways are affected, and whether any placental differential gene methylations are correlated to fetal growth or circulating metabolic health biomarkers. In an epigenome-wide association study using the Infinium MethylationEPIC Beadchip, we sought to identify genome-wide placental differentially methylated genes and enriched pathways in GDM, and to assess the correlations with fetal growth and metabolic health biomarkers in cord blood. The study samples were 30 pairs of term placentas in GDM vs. euglycemic pregnancies (controls) matched by infant sex and gestational age at delivery in the Shanghai Birth Cohort. Cord blood metabolic health biomarkers included insulin, C-peptide, proinsulin, IGF-I, IGF-II, leptin and adiponectin. Adjusting for maternal age, pre-pregnancy BMI, parity, mode of delivery and placental cell type heterogeneity, 256 differentially methylated positions (DMPs,130 hypermethylated and 126 hypomethylated) were detected between GDM and control groups accounting for multiple tests with false discovery rate <0.05 and beta-value difference >0.05. WSCD2 was identified as a differentially methylated gene in both site- and region-level analyses. We validated 7 hypermethylated (CYP1A2, GFRA1, HDAC4, LIMS2, NAV3, PAX6, UPK1B) and 10 hypomethylated (DPP10, CPLX1, CSMD2, GPR133, NRXN1, PCSK9, PENK, PRDM16, PTPRN2, TNXB) genes reported in previous epigenome-wide association studies. We did not find any enriched pathway accounting for multiple tests. DMPs in 11 genes (CYP2D7P1, PCDHB15, ERG, SIRPB1, DKK2, RAPGEF5, CACNA2D4, PCSK9, TSNARE1, CADM2, KCNAB2) were correlated with birth weight (z score) accounting for multiple tests. There were no significant correlations between placental gene methylations and cord blood biomarkers. In conclusions, GDM was associated with DNA methylation changes in a number of placental genes, but these placental gene methylations were uncorrelated to the observed metabolic health biomarkers (fetal growth factors, leptin and adiponectin) in cord blood. We validated 17 differentially methylated placental genes in GDM, and identified 11 differentially methylated genes relevant to fetal growth.

The Effect of Early Life Exposure to Triclosan on Thyroid Follicles and Hormone Levels in Zebrafish.

Triclosan (TCS) is an antimicrobial chemical widely used in personal care products. Most of the TCS component is discharged and enters the aquatic ecosystem after usage. TCS has a similar structure as thyroid hormones that are synthesized by thyroid follicular epithelial cells, thus TCS has a potential endocrine disrupting effect. It is still not clear how the different levels of the environmental TCS would affect early development in vivo. This study examines the effects of TCS on thyroid hormone secretion and the early development of zebrafish. The fertilized zebrafish eggs were exposed to TCS at 0 (control), 3, 30, 100, 300, and 900 ng/mL, and the hatching rate and the larvae mortality were inspected within the first 14 days. The total triiodothyronine (TT3), total thyroxine (TT4), free triiodothyronine (FT3), and free thyroxine (FT4) were measured at 7, 14, and 120 days post-fertilization (dpf). The histopathological examinations of thyroid follicles were conducted at 120 dpf. TCS exposure at 30-300 ng/mL reduced the hatching rate of larvae to 34.5% to 28.2 % in the first 48 hours and 93.8 .7 % to 86.8 % at 72 h. Extremely high TCS exposure (900 ng/mL) strongly inhibited the hatching rate, and all the larvae died within 1 day. Exposure to TCS from 3 to 300 ng/mL reduced the thyroid hormones production. The mean TT3 and FT3 levels of zebrafish decreased in 300 ng/mL TCS at 14 dpf (300 ng/mL TCS vs. control : TT3 , 0.19 ± 0.08 vs. 0.39 ± 0.06; FT3, 19.21 ± 3.13 vs. 28.53 ± 1.98 pg/mg), and the FT4 decreased at 120 dpf ( 0.09 ± 0.04 vs. 0.20 ± 0.14 pg/mg). At 120 dpf , in the 300 ng/mL TCS exposure group, the nuclear area and the height of thyroid follicular epithelial cells became greater, and the follicle cell layer got thicker. This happened along with follicle hyperplasia, nuclear hypertrophy, and angiogenesis in the thyroid. Our study demonstrated that early life exposure to high TCS levels reduces the rate and speed of embryos hatching, and induces the histopathological change of thyroid follicle, and decreases the TT3, FT3, and FT4 production in zebrafish.

Effects of single and combined exposure to lead and stress during pregnancy on offspring neurodevelopment.

OBJECTIVE: To assess associations of single and combined exposures to lead and stress during different stages of pregnancy with offspring neurodevelopment. METHODS: We measured prenatal lead (maternal blood-lead in early-pregnancy and umbilical-cord-blood-lead) and maternal stress levels in Shanghai-Birth-Cohort from 2013 to 2016. Maternal stress was assessed using Center-for-Epidemiological-Studies-Depression-Scale and Self-Rating-Anxiety-Scale during mid-pregnancy. The Ages-Stages-Questionnaires-3 (at 6/12-months-of-age) and Bayley-III (at 24-months-of-age) were both used to assess neurodevelopment. RESULTS: A total of 2132 mother-child pairs with both prenatal lead and stress measurements were included. The geometric-means of blood-lead in early-pregnancy and cord-blood-lead were 1.46 µg/dL and 1.33 µg/dL, respectively. Among the study women, 1.89 % and 0.14 % were screened positive for depression and anxiety. Adjusting for related confounders, the combined exposures had stronger adverse associations with offspring social-emotional skills than single exposures; and the combined exposure in early-pregnancy was associated with greater neurodevelopmental differences than combined exposure around-birth, especially in social-emotion at 24 months-of-age [ß (95 %CI): - 10.48(-17.42, -3.54) vs. - 5.95(-11.53, -0.36)]. CONCLUSIONS: Both single and combined prenatal exposures to lead/stress impaired infant neuro-development, and the effects of combined exposure may be more profound than single exposures. Combined exposure in early-pregnancy may be associated with worse neurodevelopmental outcomes than combined exposure around-birth, especially in social-emotional development.

Relationship of maternal obesity and vitamin D concentrations with fetal growth in early pregnancy.

PURPOSE: To evaluate the effects of the association between first trimester vitamin D (VitD) concentrations and increased prepregnancy body mass index (BMI) on early fetal growth restriction (FGR). METHODS: This retrospective cohort study included 15,651 women with singleton pregnancy who delivered at the International Peace Maternity and Child Health Hospital between January 2015 and November 2016. Women were classified in two groups based on their serum 25(OH)D vitamin levels status: VitD sufficient (SUFF) group and VitD insufficient or deficient (INSUFF/DEF). The cut-off point for VitD concentration was 50.00 nmol/L. Comparisons were made between women with normal prepregnancy body weight (BMI 18.5-23.9 kg/m2) and overweight and obese (OWO) women (BMI > 24.0 kg/m2). Early FGR was defined as first-trimester gestational age-adjusted crown-rump length (CRL) in the lowest 20th centile of the population. Multivariate logistic regression was used to evaluate the association between maternal serum 25(OH)D levels and prepregnancy BMI with first trimester CRL and early FGR. RESULTS: In VitD INSUFF/DEF group, the first trimester CRL was decreased (P = 0.005), and the risk of early FGR was increased by 13% (95% CI 1.04-1.24, P = 0.004) compared to the VitD SUFF group. In OWO group, the first trimester CRL was also significantly decreased (P < 0.0001), and the risk of early FGR was significantly increased by 58% (95% CI 1.40-1.78, P < 0.001) compared with normal weight group. Furthermore, there was a significant combined effect of maternal VitD concentrations and OWO on CRL (P for interaction = 0.02) and the risk of early FGR (P for interaction = 0.07). CONCLUSION: Sufficient first trimester serum 25(OH)D concentration was a protective factor for early fetal growth, especially among OWO mothers. Chinese Clinical Trial Registry (Registration number: ChiCTR1900027447 with date of registration on November 13, 2019-retrospectively registered).

Association of maternal exposure to perfluoroalkyl and polyfluroalkyl substances with infant growth from birth to 12 months: A prospective cohort study.

BACKGROUND: Although maternal perfluoroalkyl and polyfluroalkyl substances (PFASs) were associated with adverse birth outcomes, much less is known about their impact on infant growth during early infancy. OBJECTIVES: We investigated the association between maternal PFASs exposure and infant growth during the first 12 months of life. METHODS: Participating 2395 pregnancies were recruited from Shanghai Birth Cohort between 2013 and 2016. Ten PFASs were quantified from maternal plasma collected during early pregnancy (median, 15 gestational weeks). We measured infant length, weight, and head circumference at birth, 42 days, 6 months, and 12 months. Linear mixed regression model was used to estimate the associations between PFAS concentrations and repeated measurements of infant growth. Effect modification by infant sex was estimated. RESULTS: Elevated perfluoroheptanoic acid (PFHpA) concentration was negatively associated with infant length-for-age Z score (LAZ) (ß = -0.06, 95% confidence interval (CI): -0.11, -0.01) during the first year. Adverse associations were also observed for perfluorobutane sulfonate (PFBS) and weight-for-length Z score (WFL) (ß = -0.02, 95% CI: -0.04, -0.00) and BMI-for-age Z score (BAZ) (ß = -0.02, 95% CI: -0.04, -0.00). However, perfluorododecanoic acid (PFDoA) was positively associated with WFL (ß = 0.03, 95% CI: 0.00, 0.06) and BAZ (ß = 0.03, 95% CI: 0.00, 0.06). The adverse association of PFHpA and LAZ was more pronounced among males (ß = -0.06; 95% CI: -0.11, -0.00) than females (ß = 0.06; 95% CI: 0.01, 0.12). CONCLUSIONS: In our study, negative associations were found for maternal PFHpA exposure and infant LAZ, PFBS and WFL and BAZ. Meanwhile, maternal PFDoA exposure was positively related with WFL and BAZ. The adverse association of maternal PFHpA exposure and infant LAZ was more pronounced among males. The results should be interpreted with caution, further prospective cohort studies with longitudinal and detailed measures are warranted to confirm these findings.

Sex-Disparity in the Association Between Birthweight and Cardiovascular Parameters in 4-Year-Old Children: A Chinese Cohort Study.

Background: Sex-related differences in cardiovascular parameters have been well documented in adults, and the impact of birthweight on cardiovascular health in later life has been acknowledged. However, data was limited regarding the association between birthweight and cardiovascular outcomes at an early age, and the sex-disparity in the association remained unclear. Objective: To investigate the association between birthweight and cardiovascular parameters in 4-year-old children. Furthermore, to explore whether sex-disparity exist in this association or in cardiovascular risk. Methods: Follow-up data from the Shanghai Birth Cohort (SBC) was analyzed. Detailed perinatal information including both maternal and offspring datum were recorded. Blood pressure, echocardiography, and anthropometry assessment were conducted during the follow-up of 4-year-old children. Linear regression models were used to analyze the association between birthweight and left ventricle (LV) structure and function changes in each sex and birthweight category. Multivariable logistic regression models were used to compare risk of left ventricular hypertrophy (LVH) in different birthweight subgroups. Results: Overall, macrosomia was significantly associated with thickened LV posterior wall thickness in systole [LVPWs, (ß = 0.26, 95% CI: 0.06, 0.45)] and diastole [LVPWd, (ß = 0.18, 95% CI: 0.06, 0.30)], and thickened interventricular septal thickness in diastole [IVSd, (ß = 0.16, 95% CI: 0.05, 0.28)]. Boys with macrosomia showed a higher left ventricle mass index [LVMI, (ß = 1.29, 95% CI: 0.14, 2.43)], thickened LVPWs (ß = 0.30, 95% CI: 0.05, 0.56) and LVPWd (ß = 0.21, 95% CI: 0.06, 0.36), and thickened IVSd (ß = 0.23, 95% CI: 0.09, 0.36). However, no significant association of structural changes was found in girls. Furthermore, an increased risk of LVH was found solely in macrosomic boys (OR = 2.79, 95% CI: 1.17, 6.63). Conclusion: Children with macrosomia developed cardiovascular changes as early as 4 years of age. Macrosomia was associated with LV structural changes and higher LVH risk in pre-school-aged boys, while no association was found in girls.