In utero aspirin exposure and child neurocognitive development: A propensity score-matched analysis.

OBJECTIVE: To evaluate the association between a short-period, high-dose in utero aspirin exposure and child neurocognitive development. DESIGN: A propensity score-matched analysis of a multicentre prospective cohort study. SETTING: The US Collaborative Perinatal Project (1959-1976). POPULATION: A total of 50 565 singleton live births with maternal information. METHODS: We performed a propensity score matching to balance maternal characteristics between women with and without aspirin exposure. Inverse probability-weighted marginal structural models were used to estimate associations between aspirin exposure and child neurocognitive assessments. MAIN OUTCOME MEASURES: Child neurocognitive development was assessed using the Bayley Scales at 8 months, the Stanford Binet Intelligence Scale at 4 years, and the Wechsler Intelligence Scale and Wide-Range Achievement Test (WRAT) at 7 years. RESULTS: Children exposed to aspirin in utero were associated with an 8%-16% reduced risk of having suspect/abnormal or below-average scores in most neurocognitive assessments. A trend of lower risks of having suspect/abnormal or below-average scores was further observed in children with in utero aspirin exposure for more than 7 days, particularly on Bayley Mental (relative risk [RR] 0.82, 95% CI 0.74-0.92), WRAT Reading (RR 0.88, 95% CI 0.78-0.98) and WRAT Arithmetic tests (RR 0.76, 95% CI 0.66-0.86). This association was mainly observed in the second trimester of pregnancy. CONCLUSIONS: In utero aspirin exposure was associated with improved child neurocognitive development in a prospective cohort study. Further studies are warranted to evaluate the impact of long-period and low-dose in utero aspirin exposure on child short- and long-term neurodevelopment.

RNA-Sequencing Reveals Gene Expression and Pathway Signatures in Umbilical Cord Blood Affected by Birth Delivery Mode.

Cesarean section (CS) confers increased risk of type I diabetes, asthma, inflammatory bowel disease, celiac disease, overweight and obesity, etc., in the offspring. However, the underlying mechanism remains unknown. To investigate the influence of CS on gene expression in cord blood, we have performed RNA-sequencing followed by single-gene analysis, gene set enrichment analysis, gene co-expression network analysis, and interacting genes/proteins analysis in eight full-term infants born by elective CS and eight matched vaginally delivered (VD) infants. Crucial genes identified above were further validated in another 20 CS and 20 VD infants. We found for the first time that mRNA expression of genes involved in immune response (IL12A, INFG, IL1B, TNF, MIF, IL4, CA1, IFI27, HLA-DOB and EPHB1) and metabolism (DLK1, CYP2A6 and GATM) were significantly influenced by CS. Notably, serum TNF-α and IFN-γ were remarkably up-regulated in the CS infants (p = 5.0 × 10-4 and 3.0 × 10-3, respectively) compared to the VD infants. It is biologically plausible that CS may exert adverse impacts on offspring health through influencing expression of genes in the above processes. These findings will help understand the potential underlying mechanisms of the adverse health impacts of CS and identify biomarkers for future health of offspring born with different delivery modes. Supplementary Information: The online version contains supplementary material available at 10.1007/s43657-022-00086-7.

Fetal genome predicted birth weight and polycystic ovary syndrome in later life: a Mendelian randomization study.

Associations between lower birth weight and higher polycystic ovary syndrome (PCOS) risk have been reported in previous observational studies, however, the causal relationship is still unknown. Based on decomposed fetal and maternal genetic effects on birth weight (n = 406,063), we conducted a two-sample Mendelian randomization (MR) analysis to assess potential causal relationships between fetal genome predicted birth weight and PCOS risk using a large-scale genome-wide association study (GWAS) including 4,138 PCOS cases and 20,129 controls. To further eliminate the maternally transmitted or non-transmitted effects on fetal growth, we performed a secondary MR analysis by utilizing genetic instruments after excluding maternally transmitted or non-transmitted variants, which were identified in another birth weight GWAS (n = 63,365 parent-offspring trios from Icelandic birth register). Linkage disequilibrium score regression (LDSR) analysis was conducted to estimate the genetic correlation. We found little evidence to support a causal effect of fetal genome determined birth weight on the risk of developing PCOS (primary MR analysis, OR: 0.86, 95% CI: 0.52 to 1.43; secondary MR analysis, OR: 0.86, 95% CI: 0.54 to 1.39). In addition, a marginally significant genetic correlation (rg = -0.14, se = 0.07) between birth weight and PCOS was revealed via LDSR analysis. Our findings indicated that observed associations between birth weight and future PCOS risk are more likely to be attributable to genetic pleiotropy driven by the fetal genome rather than a causal mechanism.

Maternal Polycystic Ovary Syndrome and Offspring Birth Weight: A Mendelian Randomization Study.

CONTEXT: Observational associations between maternal polycystic ovary syndrome (PCOS) and offspring birth weight (BW) have been inconsistent and the causal relationship is still uncertain. OBJECTIVE: We conducted a 2-sample Mendelian randomization (MR) study to estimate the causal effect of maternal PCOS on offspring BW. METHODS: We constructed genetic instruments for PCOS with 14 single nucleotide polymorphisms (SNPs) which were identified in a genome-wide association study (GWAS) meta-analysis including 10 074 PCOS cases and 103 164 controls of European ancestry from 7 cohorts. The genetic associations of these SNPs with the offspring BW were extracted from summary statistics estimated by the Early Growth Genetics consortium (n = 406 063 European ancestry individuals) using the weighted linear model, an approximation method of structural equation model, which separated maternal genetic effects from fetal genetic effects. We used a 2-sample MR design to examine the causal relationship between maternal PCOS and offspring BW. Sensitivity analyses were conducted to assess the robustness of the MR results. RESULTS: We found little evidence for a causal effect of maternal PCOS on offspring BW (-6.1 g, 95% CI -16.8 g, 4.6 g). Broadly consistent results were found in the sensitivity analyses. CONCLUSION: Despite the large scale of this study, our results suggested little causal effect of maternal PCOS on offspring BW. MR studies with a larger sample size of women with PCOS or more genetic instruments that would increase the variation of PCOS explained are needed in the future.

Triglyceride Induced Metabolic Inflammation: Potential Connection of Insulin Resistance and Recurrent Pregnancy Loss.

The underlying correlative mechanisms between Insulin resistance (IR) and recurrent pregnancy loss (RPL) in patients without polycystic ovarian syndrome (PCOS) remain inconclusive. To investigate the association between triglyceride (TG) levels, lymphocyte subsets, and IR in RPL patients without PCOS and obesity. Eighty-nine subjects with an unexplained RPL, independent of PCOS/obesity were enrolled in this study. A 75-g oral glucose tolerance test was performed on each subject with plasma tested for glucose and insulin. The fasting venous blood of all subjects was collected for routine clinical chemistry analysis. Lymphocyte subsets were analyzed by four-color flow cytometry. As a result, TG levels were significantly elevated in RPL patients with IR compared to those without IR. Pearson linear correlation model and receiver operating characteristic (ROC) curve analyses revealed a significant positive association between TG and HOMA-IR index value. In multiple logistic regression analysis, TG was significantly associated with the risk of hyperinsulinemia and increased CD3+CD4+/CD3+CD8+ ratio which was significantly negatively correlated with disposition index (DI30) and DI120, indicators for insulin sensitivity. In addition, DI30 and DI120 were significantly decreased in the higher CD3+CD4+/CD3+CD8+ group. Our findings showed that the elevated TG and altered immune responses in RPL patients with IR are independent of PCOS and obesity, and could be used as an indicator of IR in RPL patients. These results contribute to the understanding of the pathophysiology of IR in RPL for potential prevention and therapeutic targets.

Household mold exposure interacts with inflammation-related genetic variants on childhood asthma: a case-control study.

BACKGROUND: A number of studies have examined the association between mold exposure and childhood asthma. However, the conclusions were inconsistent, which might be partly attributable to the lack of consideration of gene function, especially the key genes affecting the pathogenesis of childhood asthma. Research on the interactions between genes and mold exposure on childhood asthma is still very limited. We therefore examined whether there is an interaction between inflammation-related genes and mold exposure on childhood asthma. METHODS: A case-control study with 645 asthmatic children and 910 non-asthmatic children aged 3-12 years old was conducted. Eight single nucleotide polymorphisms (SNPs) in inflammation-related genes were genotyped using MassARRAY assay. Mold exposure was defined as self-reported visible mold on the walls. Associations between visible mold exposure, SNPs and childhood asthma were evaluated using logistic regression models. In addition, crossover analyses were used to estimate the gene-environment interactions on childhood asthma on an additive scale. RESULTS: After excluding children without information on visible mold exposure or SNPs, 608 asthmatic and 839 non-asthmatic children were included in the analyses. Visible mold exposure was reported in 151 asthmatic (24.8%) and 119 non-asthmatic children (14.2%) (aOR 2.19, 95% CI 1.62-2.97). The rs7216389 SNP in gasdermin B gene (GSDMB) increased the risk of childhood asthma with each C to T substitution in a dose-dependent pattern (additive model, aOR 1.32, 95% CI 1.11-1.57). Children carrying the rs7216389 T allele and exposed to visible mold dramatically increased the risk of childhood asthma (aOR 3.21; 95% CI 1.77-5.99). The attributable proportion due to the interaction (AP: 0.47, 95% CI 0.03-0.90) and the relative excess risk due to the interaction (RERI: 1.49, 95% CI 0-2.99) were statistically significant. CONCLUSIONS: In the present study, there was a significant additive interaction between visible mold exposure and rs7216389 SNP on childhood asthma. Future studies need to consider the gene-environment interactions when exploring the risk factors of childhood asthma.

The impact of cesarean delivery on infant DNA methylation.

BACKGROUND: Mounting evidence suggests that cesarean delivery may have a long-lasting effect on infant health. But the underlying mechanisms remain unclear. This study aims to examine whether cesarean delivery on maternal request without any medical indications (CDMR) impacts DNA methylation status in the umbilical cord blood of the infant. METHODS: A cross-sectional study was conducted in Shanghai, China. A total of 70 CDMR and 70 vaginal deliveries (VD) were recruited in 2012. The cord blood DNA methylation status was measured in 30 CDMR and 30 VD newborns using Illumina Infinium Human Methylation 450 K BeadChip. To validate the results, the cord blood DNA methylation status was measured in another 40 CDMR and 40 VD newborns using targeted bisulfite sequencing assay. A total of 497 CpG sites from 40 genes were included in the analysis. RESULTS: A total of 165 differentially methylated positions (DMPs) exhibited differences in DNA methylation by 10% or more between the CDMR and VD groups, many of which were related to the development of the immune system. Based on the targeted bisulfite sequencing assay, 16 genes (16/22, 72.7%) had higher methylation level in the CDMR group than the VD group. Among them, 5 genes were related to the immune system. After considering the estimation of cell type proportions, there was few significant differences in DNA methylation between CDMR and VD groups. CONCLUSIONS: The DMPs identified between CDMR and VD groups might be largely explained by the cell type proportions. Further studies are needed to examine DNA methylation in each cell type separately.

Incidence and trend of preterm birth in China, 1990-2016: a systematic review and meta-analysis.

OBJECTIVES: To update the WHO estimate of preterm birth rate in China in 1990-2016 and to further explore variations by geographic regions and years of occurrence. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Pubmed, Embase, Cochrane Library and Sinomed databases were searched from 1990 to 2018. ELIGIBILITY CRITERIA: Studies were included if they provided preterm birth data with at least 500 total births. Reviews, case-control studies, intervention studies and studies with insufficient information or published before 1990 were excluded. We estimated pooled incidence of preterm birth by a random effects model, and preterm birth rate in different year, region and by livebirths or all births in subgroup analyses. RESULTS: Our search identified 3945 records. After the removal of duplicates and screening of titles and abstracts, we reviewed 254 studies in full text and excluded 182, leaving 72 new studies. They were combined with the 82 studies included in the WHO report (154 studies, 187 data sets in total for the meta-analysis), including 24 039 084 births from 1990 to 2016. The pooled incidence of preterm birth in China was 6.09% (95% CI 5.86% to 6.31%) but has been steadily increasing from 5.36% (95% CI 4.89% to 5.84%) in 1990-1994 to 7.04% (95% CI 6.09% to 7.99%) in 2015-2016. The annual rate of increase was about 1.05% (95% CI 0.85% to 1.21%). Northwest China appeared to have the highest preterm birth rate (7.3%, 95% CI 4.92% to 9.68% from 1990 to 2016). CONCLUSIONS: The incidence of preterm birth in China has been rising gradually in the past three decades. It was 7% in 2016. Preterm birth rate varied by region with the West having the highest occurrence.

Perfluoroalkyl substances in early pregnancy and risk of hypertensive disorders of pregnancy: A prospective cohort study.

BACKGROUND: Perfluoroalkyl substances (PFASs) were reported to be associated with hypertensive disorders of pregnancy (HDP) but the results were inconsistent and prospective data are scarce. We aimed to examine these associations in a large prospective birth cohort study in Shanghai, China. METHODS: A total of 10 PFASs were measured by high-performance liquid chromatography/tandem mass spectrometry (HPLC/MS-MS) in the plasma samples from 3220 women who were enrolled during early pregnancy and gave birth to a singleton live birth between 2013 and 2016. The outcomes included gestational hypertension (GH), preeclampsia (PE) and overall HDP. Associations of these outcomes with each PFASs were estimated by multivariable logistic regression and expressed as odd ratios (ORs) and 95% confidence intervals (95% CIs). Potential non-linear association between PFASs and HDP was examined with restricted cubic spline model. To handle the potential confounding by correlated PFASs, we applied elastic net regression (ENR) to identify independent PFASs components of outcomes. RESULTS: Among all singleton live births, the incidence rates of GH and PE were 2.0% and 2.2%, respectively. Overall, PFASs did not show a significant and consistent pattern of the associations with GH, PE or overall HDP, both before and after controlling for potential confounders. ENR model confirmed the results that there was no independently predictive role of PFASs on GH, PE or overall HDP. CONCLUSIONS: In this large prospective cohort study, maternal plasma concentration of PFASs in early pregnancy were not associated with GH, PE or overall HDP in singleton livebirths.

The effect of perceived social support during early pregnancy on depressive symptoms at 6 weeks postpartum: a prospective study.

BACKGROUND: Postpartum depression was associated with maternal suffering and diminished functioning, increased risk of marital conflict as well as adverse child outcomes. Perceived social support during pregnancy was associated with postpartum depression among women. However, its causal relationship remains unclear. Therefore, we prospectively evaluate the association between perceived social support during early pregnancy and postpartum depressive symptoms. METHODS: We prospectively examined whether perceived social support during early pregnancy affected depressive symptoms at 6 weeks postpartum in a cohort of 3310 women. Perceived social support and postpartum depression were assessed by ENRICHD Social Support Instrument (ESSI) and the postpartum Edinburgh Postpartum Depression Scale (EPDS), respectively. Prevalence of postpartum depressive symptoms was 11.4% (EPDS cutoff≥10). As a test of heterogeneity of association in subpopulations, logistic regression models were performed to analyze the association between social support and postpartum depressive symptoms in strata which were defined by the potential confounder candidates. After multiple imputation, multivariable logistic regression was performed to assess the effect of social support on postpartum symptoms in individual items and total score. Two models were built. Model I adjusted for the variables associated with social support or postpartum depression and changed the association estimates by ≥10%. Model II adjusted for all variables that may be related to social support or postpartum depression. RESULTS: Significant associations between low perceived social support and postpartum depressive symptoms was found(Model I odds ratio: 1.63, 95% confidence interval: 1.15, 2.30; Model II odds ratio: 1.77, 95% confidence interval: 1.24-2.52). Stratified analyses showed that there was little evidence of heterogeneity of association in subpopulations by basic characteristics of participants. CONCLUSIONS: These findings suggest that early intervention may be able to help protect against depression symptoms at 6 weeks postpartum.

Triclosan and Female Reproductive Health: A Preconceptional Cohort Study.

BACKGROUND: Triclosan (2,4,4'-trichloro-2'-hydroxy-diphenyl ether) is widely used in personal care and household products. Previous in vitro and in vivo studies showed that triclosan may affect female reproductive health. However, evidence from human studies is scarce. OBJECTIVES: To assess the potential effects of triclosan on women's reproductive health. METHODS: A prospective cohort study recruited 1,182 couples who planned to conceive and presented to preconception care clinics for physical examination in Shanghai, China, between 2013 and 2015. These couples were then prospectively followed every 2 months for 12 months. Triclosan was quantified in preconception urine samples at enrollment. The outcomes of interest included menstruation and fecundity. Normal menstruation was defined as a woman who had normal cycle duration between 21 and 35 days, duration of menstrual bleeding between 3 and 7 days, and self-reported normal amount of menstrual bleeding. RESULTS: A total of 698 women were included in the analysis on the association between triclosan and menstruation. Compared with low triclosan levels, high triclosan levels were associated with increased risks of abnormal menstruation [adjusted odds ratio (OR) = 1.47; 95% confidence interval = 1.05, 2.06] and prolonged menstrual cycle (OR = 2.08; 95% confidence interval = 1.00, 2.31). In the analysis on the association between triclosan and fecundability, 648 women were included. Compared with the lowest tertile of triclosan level (<1.1 ng/mL), the highest level (>4.5 ng/mL) was associated with a 23% of reduction in fecundability and there tended to be a dose-response pattern. CONCLUSION: Our findings suggest that triclosan may affect menstruation and reduce female fecundity.

A genetic variant in the placenta-derived MHC class I chain-related gene A increases the risk of preterm birth in a Chinese population.

Preterm birth (PTB) is a predominant contributor to neonatal mortality and morbidity worldwide. However, the pathophysiology of PTB is not well-understood. We tested the hypothesis that single-nucleotide polymorphisms (SNPs) in the placenta-derived MHC class I chain-related gene A (MICA) could disrupt placental development and hence result in PTB. Nineteen selected SNPs in MICA were genotyped in a case-control study of 127 premature infants and 634 term controls in a Chinese Han population. We found that significantly increased PTB risk was associated with homozygosity for the A variant of rs2256318 (adjusted odds ratio = 6.97 and 95% confidence interval = 2.34-20.74 for A/A, compared with G/G genotype, P = 0.001). In addition, the A/A genotype of rs2256318 was associated with decreased placental weight of neonates (ß = -25.331; P = 0.033). Furthermore, stratified analysis demonstrated that the A/A genotype of rs2256318 was associated with increased PTB risk in female group. In addition, we observed statistical interaction between the polymorphism rs2516448 and sex (P = 0.04). No significant differences in the distribution of haplotypes between cases and controls were detected. Our results indicate that the polymorphism of rs2256318 in MICA may contribute to the etiology of PTB through interfering with placental development. These findings need to be further validated in larger and multi-ethnic populations.