Prenatal Parental Exposure to Metals and Birth Defects: A Prospective Birth Cohort Study.

While maternal exposure to high metal levels during pregnancy is an established risk factor for birth defects, the role of paternal exposure remains largely unknown. We aimed to assess the associations of prenatal paternal and maternal metal exposure and parental coexposure with birth defects in singletons. This study conducted within the Jiangsu Birth Cohort recruited couples in early pregnancy. We measured their urinary concentrations for 25 metals. A total of 1675 parent-offspring trios were included. The prevalence of any birth defects among infants by one year of age was 7.82%. Paternal-specific gravity-corrected urinary concentrations of titanium, vanadium, chromium, manganese, cobalt, nickel, copper, and selenium and maternal vanadium, chromium, nickel, copper, selenium, and antimony were associated with a 21-91% increased risk of birth defects after adjusting for covariates. These effects persisted after mutual adjustment for the spouse's exposure. Notably, when assessing the parental mixture effect by Bayesian kernel machine regression, paternal and maternal chromium exposure ranked the highest in relative importance. Parental coexposure to metal mixture showed a pronounced joint effect on the risk of overall birth defects, as well as for some specific subtypes. Our findings suggested a couple-based prevention strategy for metal exposure to reduce birth defects in offspring.

Maternal Hypertensive Disorder in Pregnancy and Childhood Strabismus in Offspring.

Importance: Maternal hypertensive disorder in pregnancy (HDP) might affect ocular health in offspring; however, its association with strabismus remains unclear. Objective: To examine the association of maternal HDP with overall and type-specific strabismus in offspring. Design, Setting, and Participants: In the Jiangsu Birth Cohort study, a population-based study in China, pregnant women were recruited from April 24, 2014, to November 30, 2018. A total of 6195 offspring had maternal HDP diagnosis information, of whom 3078 were excluded due to having no information on ocular alignment or due to having ocular diseases other than strabismus or refractive error. Offspring underwent ocular examinations at 3 years of age, completed May 21, 2022. Data were analyzed from May 28, 2022, through December 15, 2023. Exposure: Maternal HDP, categorized into hypertension and preeclampsia or with blood pressure (BP) well controlled (systolic BP, <130; diastolic BP, <80 mm Hg) and poorly controlled (systolic BP, ≥130; diastolic BP, ≥80 mm Hg). Main Outcomes and Measures: The primary outcome was the incidence of strabismus in offspring. Poisson generalized linear mixed models were used to estimate the association between maternal HDP and strabismus. Results: Among the included 3117 children (mean [SD] age, 36.30 [0.74] months; 1629 boys [52.3%]), 143 (4.6%) were exposed to maternal HDP and 368 (11.8%) had strabismus. Offspring exposed to maternal HDP had an 82% increased risk of overall strabismus (relative risk [RR], 1.82 [95% CI, 1.21-2.74]), an 82% increased risk of exophoria (RR, 1.82 [95% CI, 1.11-3.00]), and a 136% increased risk of intermittent exotropia (RR, 2.36 [95% CI, 1.13-4.93]) compared with unexposed offspring. When considering the type of maternal HDP, the risk for all strabismus was high for offspring exposed to preeclampsia (RR, 2.38 [95% CI, 1.39-4.09]) compared with unexposed offspring. When considering the BP control level of maternal HDP, the risk for all strabismus was high for offspring born to mothers with HDP and poorly controlled BP (RR, 2.07 [95% CI, 1.32-3.24]) compared with unexposed offspring. Conclusions and Relevance: These findings suggest that maternal HDP is associated with an increased risk of offspring strabismus. Early screening of strabismus might be recommended for offspring with maternal HDP. Further exploration of the underlying mechanism of the association between HDP and strabismus is warranted.

Association of prenatal multiple metal exposures with child neurodevelopment at 3 years of age: A prospective birth cohort study.

Prenatal exposures to toxic metals and trace elements have been linked to childhood neurodevelopment. However, existing evidence remains inconclusive, and further research is needed to investigate the mixture effects of multiple metal exposures on childhood neurodevelopment. We aimed to examine the associations between prenatal exposure to specific metals and metal mixtures and neurodevelopment in children. In this prospective cohort study, we used the multivariable linear regressions and the robust modified Poisson regressions to explore the associations of prenatal exposure to 25 specific metals with neurodevelopment among children at 3 years of age in 854 mother-child pairs from the Jiangsu Birth Cohort (JBC) Study. The Bayesian kernel machine regression (BKMR) was employed to assess the joint effects of multiple metals on neurodevelopment. Prenatal manganese (Mn) exposure was negatively associated with the risk of non-optimal cognition development of children, while vanadium (V), copper (Cu), zinc (Zn), antimony (Sb), cerium (Ce) and uranium (U) exposures were positively associated with the risk of non-optimal gross motor development. BKMR identified an interaction effect between Sb and Ce on non-optimal gross motor development. Additionally, an element risk score (ERS), representing the mixture effect of multiple metal exposures including V, Cu, Zn, Sb, Ce and U was constructed based on weights from a Poisson regression model. Children with ERS in the highest tertile had higher probability of non-optimal gross motor development (RR = 2.37, 95 % CI: 1.15, 4.86) versus those at the lowest tertile. Notably, Sb [conditional-posterior inclusion probabilities (cPIP) = 0.511] and U (cPIP = 0.386) mainly contributed to the increased risk of non-optimal gross motor development. The findings highlight the importance of paying attention to the joint effects of multiple metals on children's neurodevelopment. The ERS score may serve as an indicator of comprehensive metal exposure risk for children's neurodevelopment.

Impact of low-dose aspirin exposure on obstetrical outcomes: a meta-analysis.

OBJECTIVE: To assess the impact of low-dose aspirin (LDA) on obstetrical outcomes through a meta-analysis of placebo-controlled randomized controlled trials (RCTs). METHODS: A systematic search of the PubMed, Cochrane Library, Web of Science and Embase databases from inception to January 2024 was conducted to identify studies exploring the role of aspirin on pregnancy, reporting obstetrical-related outcomes, including preterm birth (PTB, gestational age <37 weeks), small for gestational age (SGA), low birth weight (LBW, birthweight < 2500g), perinatal death (PND), admission to the neonatal intensive care unit (NICU), 5-min Apgar score < 7 and placental abruption. Relative risks (RRs) were estimated for the combined outcomes. Subgroup analyses were performed by risk for preeclampsia (PE), LDA dosage (<100 mg vs. ≥100 mg) and timing of onset (≤20 weeks vs. >20 weeks). RESULTS: Forty-seven studies involving 59,124 participants were included. Compared with placebo, LDA had a more significant effect on low-risk events such as SGA, PTB and LBW. Specifically, LDA significantly reduced the risk of SGA (RR = 0.91, 95% CI: 0.87-0.95), PTB (RR = 0.93, 95% CI: 0.89-0.97) and LBW (RR = 0.94, 95% CI: 0.89-0.99). For high-risk events, LDA significantly lowered the risk of NICU admission (RR = 0.93, 95% CI: 0.87-0.99). On the other hand, LDA can significantly increase the risk of placental abruption (RR = 1.72, 95% CI: 1.23-2.43). Subgroup analyses showed that LDA significantly reduced the risk of SGA (RR = 0.86, 95% CI: 0.77-0.97), PTB (RR = 0.93, 95% CI: 0.88-0.98) and PND (RR = 0.65, 95% CI: 0.48-0.88) in pregnant women at high risk of PE, whereas in healthy pregnant women LDA did not significantly improve obstetrical outcomes, but instead significantly increased the risk of placental abruption (RR = 5.56, 95% CI: 1.92-16.11). In pregnant women at high risk of PE, LDA administered at doses ≥100 mg significantly reduced the risk of SGA (RR = 0.77, 95% CI: 0.66-0.91) and PTB (RR = 0.56, 95% CI: 0.32-0.97), but did not have a statistically significant effect on reducing the risk of NICU, PND and LBW. LDA started at ≤20 weeks significantly reduced the risk of SGA (RR = 0.76, 95% CI: 0.65-0.89) and PTB (RR = 0.56, 95% CI: 0.32-0.97). CONCLUSIONS: To sum up, LDA significantly improved neonatal outcomes in pregnant women at high risk of PE without elevating the risk of placental abruption. These findings support LDA's clinical application in pregnant women, although further research is needed to refine dosage and timing recommendations.

Assisted reproductive technology and neurodevelopment in children at 1 year of age: a longitudinal birth cohort study.

BACKGROUND: With remarkable advancements in assisted reproductive technology (ART), the number of ART-conceived children continues to increase. Despite increased research investigating the outcomes of ART children, evidence on neurodevelopment remains controversial. OBJECTIVE: The aim of this study was to investigate the association between ART use and neurodevelopment in children at 1 year of age and to determine whether the characteristics of parental infertility and specific ART procedures affect neurodevelopment in children. STUDY DESIGN: The Jiangsu Birth Cohort enrolled couples who received ART treatment and who conceived spontaneously (2014-2020) in Jiangsu Province, China. In this study, we included 3531 pregnancies with 3840 cohort children who completed neurodevelopment assessment at 1 year of age, including 1906 infants conceived by ART (including 621 twins). Poisson regressions were fitted to estimate unadjusted and adjusted risk ratios (RRs) and 95% confidence intervals (CIs) for ART use with neurodevelopmental outcomes (cognition, receptive communication, expressive communication, fine motor, and gross motor) in children. RESULTS: Among singletons, ART use was associated with a 24% to 34% decrease in the risk for noncompetent development in 3 domains (cognition, adjusted RR, 0.66; 95% CI, 0.53-0.82; receptive communication, 0.76; 0.64-0.91; expressive communication, 0.69; 0.51-0.93) after adjustment for conventional covariates. However, an inverse association was observed in the gross motor domain, with ART singletons having a greater risk of being noncompetent in gross motor development than their non-ART counterparts (adjusted RR, 1.41; 95% CI, 1.11-1.79). Compared with singletons, twins resulting from ART treatment demonstrated compromised neurodevelopment in several domains. Furthermore, we continued to observe that the transfer of 'poor' quality embryos was associated with greater risks for noncompetent development in receptive communication (adjusted RR, 1.50; 95% CI, 1.05-2.14) and gross motor domains (1.55; 1.02-2.36) among ART singletons. CONCLUSION: These results generally provide reassuring evidence among singletons born after ART in the cognition, communication, and fine motor domains, but drawn attention to their gross motor development. The quality of transferred embryos in ART treatment might be associated with offspring neurodevelopment; however, the potential associations warrant further validation in independent studies, and the clinical significance needs careful interpretation.

Inter- and trans-generational impacts of real-world PM2.5 exposure on male-specific primary hypogonadism.

Exposure to PM2.5, a harmful type of air pollution, has been associated with compromised male reproductive health; however, it remains unclear whether such exposure can elicit transgenerational effects on male fertility. Here, we aim to examine the effect of paternal exposure to real-world PM2.5 on the reproductive health of male offspring. We have observed that paternal exposure to real-world PM2.5 can lead to transgenerational primary hypogonadism in a sex-selective manner, and we have also confirmed this phenotype by using an external model. Mechanically, we have identified small RNAs (sRNAs) that play a critical role in mediating these transgenerational effects. Specifically, miR6240 and piR016061, which are present in F0 PM sperm, regulate intergenerational transmission by targeting Lhcgr and Nsd1, respectively. We have also uncovered that piR033435 and piR006695 indirectly regulate F1 PM sperm methylation by binding to the 3'-untranslated region of Tet1 mRNA. The reduced expression of Tet1 resulted in hypermethylation of several testosterone synthesis genes, including Lhcgr and Gnas, impaired Leydig cell function and ultimately led to transgenerational primary hypogonadism. Our findings provide insights into the mechanisms underlying the transgenerational effects of paternal PM2.5 exposure on reproductive health, highlighting the crucial role played by sRNAs in mediating these effects. The findings underscore the significance of paternal pre-conception interventions in alleviating the adverse effects of environmental pollutants on reproductive health.

Relative effectiveness of a heterologous booster dose with adenovirus type 5 vectored COVID-19 vaccine versus three doses of inactivated COVID-19 vaccine in adults during a nationwide outbreak of omicron predominance, in China: a retrospective, individually matched cohort-control study.

Effectiveness of heterologous booster regimes with ad5 vectored COVID-19 vaccine in a large, diverse population during the national-scale outbreak of SARS-CoV-2 omicron predominance in China has not been reported, yet. We conducted a large-scale cohort-control study in six provinces in China, and did a retrospective survey on the COVID-19 attack risk during this outbreak. Participant aged ≥18 years in five previous trials who were primed with 1 to 3 doses of ICV received heterologous booster with either intramuscular or orally inhaled ad5 vectored COVID-19 vaccine were included in the heterologous-trial cohort. We performed propensity score-matching at a ratio of 1:4 to match participants in the heterologous-trial cohort individually with the community individuals who received three-dose of ICV as a control (ICV-community cohort). From February 4 to April 10, 2023, 41504 (74.5%) of 55710 individuals completed the survey. The median time since the most recent vaccination to the onset of the symptoms of COVID-19 was 303.0 days (IQR 293.0-322.0). The attack rate of COVID-19 in the heterologous-trial cohort was 55.8%, while that in the ICV-community cohort was 64.6%, resulting in a relative effectiveness of 13.7% (95% CI 11.9 to 15.3). In addition, a higher relative effectiveness against COVID-19 associated outpatient visits, and admission to hospital was demonstrated, which was 25.1% (95% CI 18.9 to 30.9), and 48.9% (95% CI 27.0 to 64.2), respectively. The heterologous booster with ad5 vectored COVID-19 vaccine still offered some additional protection in preventing COVID-19 breakthrough infection versus homologous three-dose regimen with ICV, 10 months after vaccination.

Phthalate and DINCH exposure and ovarian reserve markers among women seeking infertility care.

Phthalate exposure can adversely impact ovarian reserve, yet investigation on the influence of its alternative substance, the non-phthalate plasticizer diisononyl-cyclohexane-1,2-dicarboxylate (DINCH), on ovarian reserve is very sparce. We aimed to investigate the associations of phthalate and DINCH exposure as well as their combined mixture with ovarian reserve. This present study included 657 women seeking infertility care in Jiangsu, China (2015-2018). Urine samples during enrollment prior to infertility treatment were analyzed using high-performance liquid chromatography-isotope dilution tandem mass spectrometry (UPLC-MS/MS) to quantify 17 phthalate metabolites and 3 DINCH metabolites. Multivariate linear regression models, Poisson regression models and weighted quantile sum (WQS) regression were performed to access the associations of 17 urinary phthalate metabolites and 3 DINCH metabolites with ovarian reserve markers, including antral follicle count (AFC), anti-Mullerian hormone (AMH), and follicle-stimulating hormone (FSH). We found that the most conventional phthalates metabolites (DMP, DnBP, DiBP, DBP and DEHP) were inversely associated with AFC, and the DINCH metabolites were positively associated with serum FSH levels. The WQS index of phthalate and DINCH mixtures was inversely associated with AFC (% change = -8.56, 95 % CI: -12.63, -4.31) and positively associated with FSH levels (% change =7.71, 95 % CI: 0.21, 15.78). Our findings suggest that exposure to environmental levels of phthalate and DINCH mixtures is inversely associated with ovarian reserve.

Maternal Dietary Cholesterol and Egg Intake during Pregnancy and Large-for-Gestational-Age Infants: A Prospective Cohort Study.

BACKGROUND: Cholesterol plays a vital role in fetal growth and development during pregnancy. There remains controversy over whether pregnant females should limit their cholesterol intake. OBJECTIVES: The objective of this study was to investigate the association between maternal dietary cholesterol intake during pregnancy and infant birth weight in a Chinese prospective cohort study. METHODS: A total of 4146 mother-child pairs were included based on the Jiangsu Birth Cohort study. Maternal dietary information was assessed with a semiquantitative food-frequency questionnaire. Birth weight z-scores and large-for-gestational-age (LGA) infants were converted by the INTERGROWTH-21st neonatal weight-for-gestational-age standard. Poisson regression and generalized estimating equations were employed to examine the relationships between LGA and maternal dietary cholesterol across the entire pregnancy and trimester-specific cholesterol intake, respectively. RESULTS: The median intake of maternal total dietary cholesterol during the entire pregnancy was 671.06 mg/d, with eggs being the main source. Maternal total dietary cholesterol and egg-sourced cholesterol were associated with an increase in birth weight z-score, with per standard deviation increase in maternal total and egg-sourced dietary cholesterol being associated with an increase of 0.16 [95% confidence interval (CI): 0.07, 0.25] and 0.06 (95% CI: 0.03, 0.09) in birth weight z-score, respectively. Egg-derived cholesterol intake in the first and third trimesters was positively linked to LGA, with an adjusted relative risk of 1.11 (95% CI: 1.04, 1.18) and 1.09 (95% CI: 1.00, 1.18). Compared with mothers consuming ≤7 eggs/wk in the third trimester, the adjusted relative risk for having an LGA newborn was 1.37 (95% CI: 1.09, 1.72) for consuming 8-10 eggs/wk and 1.45 (95% CI: 1.12, 1.86) for consuming >10 eggs/wk (P-trend = 0.015). CONCLUSIONS: Maternal total dietary cholesterol intake, as well as consuming over 7 eggs/wk during pregnancy, displayed significant positive relationships with the incidence of LGA, suggesting that mothers should avoid excessive cholesterol intake during pregnancy to prevent adverse birth outcomes.

Effect of thyroid function on offspring neurodevelopment in people receiving ART therapy: a prospective cohort study.

CONTEXT: Adequate maternal thyroid hormone is vital for fetal neurodevelopment. Abnormal thyroid function can cause developmental defects in offspring from spontaneous pregnancies; however, research in assisted reproduction is lacking. OBJECTIVES: To investigate the association between thyroid disorders and offspring neurodevelopment from assisted reproduction. DESIGN: Prospective cohort study. SETTING AND PARTICIPANTS: In this prospective and longitudinal birth cohort study (Jiangsu, China), we included 729 women who had their thyroid function tested before ART cycle and delivered liveborn babies between November 2015 and June 2020. MAIN OUTCOME MEASURES: Maternal thyroid function was assessed by measuring thyroid antibodies, free thyroxine, and serum thyroid-stimulating hormone. The third edition Bayley Scales of Infant and Toddler Development screening test (Bayley-III screening test) is used to assess the infant's neurodevelopment. RESULTS: In multivariate corrected linear regression analysis, infants of women with subclinical hypothyroidism demonstrated a significantly lower receptive communication score (ß = -0.63, 95% CI [-1.12, -0.14], P = 0.013), with stratified analysis showing a significant association among female offspring (ß = -0.87, 95% CI [-1.59, -0.15], P = 0.018) but null association among male offspring (ß = -0.44, 95% CI [-1.03, 0.15], P = 0.145). No significant differences were found in assisted pregnancy population with normal thyroid function and positive antibodies according to the diagnostic cut-offs applied to normal pregnant women. CONCLUSIONS: Subclinical hypothyroidism in assisted pregnancies correlates with lower communication scores in 1-year-olds, especially in girls. Recommending medication for subclinical hypothyroidism throughout, regardless of thyroid autoantibody status.