Association of Breastfeeding and Neonatal Jaundice With Infant Neurodevelopment.

INTRODUCTION: Exclusive breastfeeding is advantageous for infant neurodevelopment. Nevertheless, insufficient human milk supply in exclusively breastfed infants may elevate the risk of neonatal jaundice, which can potentially result in neurological harm. Whether mothers should adhere to exclusive breastfeeding in infants with neonatal jaundice remains unclear. METHODS: Data comes from the Jiangsu Birth Cohort (JBC), a prospective and longitudinal birth cohort study in China. A total of 2,577 infants born from November 2017 to March 2021 were included in the analysis. Multivariate linear regression models were used to analyze the associations between breastfeeding status, neonatal jaundice, and their interaction with infant neurodevelopment. Analysis was performed in 2022. RESULTS: Compared with "exclusive breastfeeding," fine motor scores of infants were lower for "mixed feeding" (ßadj, -0.16; 95% CI, -0.29 to -0.03; p=0.016) and "no breastfeeding" (ßadj, -0.41; 95% CI, -0.79 to -0.03; p=0.034). Compared with "no neonatal jaundice," infants with "severe neonatal jaundice" had lower scores for cognition (ßadj, -0.44; 95% CI, -0.66 to -0.23; p<0.001) and fine motor (ßadj, -0.19; 95% CI, -0.35 to -0.03; p=0.024). In infants with severe neonatal jaundice, the termination of exclusive breastfeeding before 6 months was associated with worse cognition (ßadj, -0.28; 95% CI, -0.57 to 0.01), while this association was not observed in those without neonatal jaundice (ßadj, 0.09; 95% CI, -0.26 to 0.43). CONCLUSIONS: Exclusive breastfeeding for the first 6 months is beneficial to the neurodevelopment of infants, especially in those with severe neonatal jaundice.

Association between PM2.5 exposure and the outcomes of ART treatment: A prospective birth cohort study.

Exposure to fine particulate matter (PM2.5) has been reported to be adversely associated with reproductive health. However, current evidence on PM2.5 exposure adversely influencing pregnancy outcomes remains inconclusive. Women receiving assisted reproductive technology (ART) treatment are under close monitoring with regards to their treatment process, which make them great study population to assess the impact of PM2.5 in the post-implantation period. Therefore, within a prospective cohort study in Jiangsu, China, we assessed the associations between exposure to ambient PM2.5 and the outcomes of ART treatment, including implantation failure, biochemical pregnancy loss, clinical pregnancy and live birth, in 2431 women who underwent the first fresh embryo transfer or frozen embryo transfer cycle. High-performance machine-learning model was performed to estimate daily PM2.5 exposure concentrations at 1 km spatial revolution. Exposure windows were divided into seven periods according to the process of follicular and embryonic development in ART. Generalized estimation equations (GEE) was used to assess the association between PM2.5 and ART outcomes. Higher PM2.5 exposure was associated with decreased probability of clinical pregnancy (RR: 0.98, 95 % CI: 0.96-1.00). Each 10 µg/m3 increase in PM2.5 exposure in the duration from hCG test to 30 days after embryo transfer (Period 7) was positively associated with the risk of biochemical pregnancy loss (RR: 1.06, 95 % CI: 1.00-1.13), and more prominent effects were observed in women undergoing fresh embryo transfer. Null associations were observed between PM2.5 exposure and implantation failure or live birth at any exposure window. Collectively, our study suggested that exposure to PM2.5 increased the risk of adverse treatment outcomes in the ART population. Thus, for women opting for ART treatment, particularly those who select fresh embryo transfer cycles, additional evaluation of PM2.5 exposure before treatment might be of value in decreasing the risk of adverse pregnancy outcomes.

Prenatal titanium exposure and child neurodevelopment at 1 year of age: A longitudinal prospective birth cohort study.

Previous animal studies provided the evidence that prenatal titanium exposure can cause neurotoxicity in their offspring, while human data is vacant. Our aim was to identify the associations of prenatal titanium exposure with the child neurodevelopment. Participants in present study were recruited during early pregnancy between 2014 and 2017. Urinary concentrations of titanium at first trimester were determined. We assessed child neurodevelopment using the Chinese version of Gesell Developmental Schedules at first year follow-up. The multivariable linear regressions and the robust modified Poisson regressions were used to estimate the associations of specific gravity corrected urinary titanium concentrations with the child neurodevelopment. In adjusted models, children's developmental quotient scores in the language domain were 2.03 points (95% CI: -3.66, -0.40) lower in the highest tertile of prenatal urinary titanium than in the lowest tertile. Also, children with prenatal urinary titanium in the highest tertile had 1.42 times (95% CI: 1.17, 1.72) increased risk of language development delay compared to those in the lowest tertile. No statistically significant associations were observed between titanium exposure and child development delay in motor, adaptive and social areas. The findings indicated that prenatal higher titanium exposure was associated with impaired language development, suggesting that titanium might act as developmental neurotoxicants.

Leukocyte telomere length in children born following blastocyst-stage embryo transfer.

Perinatal and childhood adverse outcomes associated with assisted reproductive technology (ART) has been reported, but it remains unknown whether the initial leukocyte telomere length (LTL), which is an indicator of age-related phenotypes in later life, is affected. Here, we estimated the LTLs of 1,137 individuals from 365 families, including 202 children conceived by ART and 205 children conceived spontaneously from two centers of the China National Birth Cohort, using whole-genome sequencing (WGS) data. One-year-old children conceived by ART had shorter LTLs than those conceived spontaneously (beta, -0.36; P = 1.29 × 10-3) after adjusting for plurality, sex and other potential confounding factors. In particular, blastocyst-stage embryo transfer was associated with shorter LTL (beta, -0.54, P = 2.69 × 10-3) in children conceived by ART. The association was validated in 586 children conceived by ART from five centers using different LTL quantification methods (that is, WGS or qPCR). Blastocyst-stage embryo transfer resulted in shorter telomere lengths in mice at postnatal day 1 (P = 2.10 × 10-4) and mice at 6 months (P = 0.042). In vitro culturing of mice embryos did not result in shorter telomere lengths in the late cleavage stage, but it did suppress telomerase activity in the early blastocyst stage. Our findings demonstrate the need to evaluate the long-term consequences of ART, particularly for aging-related phenotypes, in children conceived by ART.

Associations of maternal dietary patterns during pregnancy and fetal intrauterine development.

Dietary pattern is excellent in reflecting an individual's eating conditions. Longitudinal data on fetal growth can reflect the process of intrauterine growth. We aimed to evaluate the associations between maternal dietary patterns and intrauterine parameters in middle and late pregnancy. The present study was conducted within Jiangsu Birth Cohort (JBC) study. Dietary information was assessed with a food frequency questionnaire (FFQ) in the second and third trimester of gestation. B-ultrasound scans were performed to obtain fetal intrauterine parameters, including head circumference (HC), femur length (FL), abdominal circumference (AC), and estimated fetal weight (EFW). Exploratory factor analysis was used to extract dietary patterns. Multiple linear regression and linear mixed-effects model (LMM) were used to investigate the association between maternal dietary patterns and fetal growth. A total of 1,936 pregnant women were eligible for the study. We observed inverse associations of maternal "Vegetables and fish" and "Snack and less eggs" patterns during mid-pregnancy with fetal HC Z-score, respectively ("Vegetables and fish": ß = -0.09, 95% CI -0.12, -0.06; "Snack and less eggs": ß = -0.05, 95% CI -0.08, -0.02). On the contrary, "Animal internal organs, thallophyte and shellfish" pattern in the second trimester was associated with increased HC Z-scores (ß = 0.04, 95% CI 0.02, 0.06). Consistently, score increase in "Vegetables and fish" pattern in the third trimester was inversely associated with the Z-scores of HC (ß = -0.05, 95% CI -0.09, -0.02), while "Meat and less nuts" pattern was positively correlated with the Z-scores of HC (ß = 0.04, 95% CI 0.02, 0.07). As compared to the fetus whose mothers at the lowest tertile of "Snack and less eggs" pattern in both trimesters, those whose mothers at the highest tertile demonstrated 1.08 fold (RR = 2.10, 95% CI 1.34-3.28) increased risk of small HC for gestational age (GA). No correlation was observed between maternal dietary patterns and other intrauterine parameters. Our results suggested the effects of maternal dietary patterns on fetal growth, particularly HC. These findings highlighted the adverse impact of unhealthy dietary pattern on fetal growth, might provide evidence for strategies to prevent intrauterine dysplasia and dietary guidelines during pregnancy.

Association of Maternal Mild Hypothyroidism With Offspring Neurodevelopment in TPOAb-Negative Women: A Prospective Cohort Study.

Objectives: Adequate maternal thyroid hormone availability is crucial for fetal neurodevelopment, but the role of maternal mild hypothyroidism is not clear. We aim to investigate the association of maternal mild hypothyroidism with neurodevelopment in infants at 1 year of age among TPOAb-negative women. Methods: The present study was conducted within the Jiangsu Birth Cohort. A total of 793 mother-infant pairs were eligible for the present study. Maternal thyroid function was assessed by measuring serum thyroid-stimulating hormone, free thyroxine, and thyroid peroxidase antibodies. Neurodevelopment of infants was assessed by using the Bayley Scales of Infant and Toddler Development third edition screening test (Bayley-III screening test). Results: In the multivariate adjusted linear regression analyses, infants of women with subclinical hypothyroidism and isolated hypothyroxinemia were associated with decreased receptive communication scores (ß = -0.68, p = 0.034) and decreased gross motor scores (ß = -0.83, p = 0.008), respectively. Moreover, infants of women with high-normal TSH concentrations (3.0-4.0 mIU/L) and low FT4 concentrations were significantly associated with lower gross motor scores (ß = -1.19, p = 0.032), while no differences were observed in infants when the mothers had a high-normal TSH concentration and normal FT4 levels. Conclusions: Maternal subclinical hypothyroidism is associated with decreased receptive communication scores in infants at 1 year of age. In addition, maternal TSH concentration greater than 4.0 mIU/L and maternal isolated hypothyroxinemia are associated with impaired gross motor ability of infants, especially in infants of women with high-normal TSH concentrations (3.0-4.0 mIU/L).

Maternal PM2.5 exposure during gestation and offspring neurodevelopment: Findings from a prospective birth cohort study.

Emerging data have suggested the potential role of prenatal PM2.5 exposure as a neurotoxin for offspring. However, the existing results are equivocal, and no study has examined the effects of complex chemical constituents of the particular matter on offspring neurodevelopment. Therefore, in a prospective birth cohort study conducted in Jiangsu, China, we aimed to investigate the association between prenatal exposure to PM2.5 and the neurodevelopment in infants, and further assess the effects of specific chemical constituents of PM2.5. A total of 1531 children who had available data on daily prenatal PM2.5 exposure and completed assessment on neurodevelopment at 1 year old were enrolled. We used the high-performance machine-learning model to estimate daily PM2.5 exposure concentrations at 1 km × 1 km spatial resolution. The combined geospatial-statistical model was applied to evaluate average concentrations of six chemical constituents [organic matter (OM), black carbon (BC), sulfate (SO42-), nitrate (NO3-), ammonium (NH4+), and soil dust (Dust)]. The neurodevelopment of children was assessed using Bayley-III Screening Test. After adjusting for confounding factors, the risk of non-optimal gross motor development increased by 31 % for every 10 µg/m3 increase in average PM2.5 exposure during gestation (aRR: 1.31; 95 % CI: 1.04, 1.64). Further analysis of PM2.5 constituents showed that prenatally exposed to high SO42- was associated with the risk of non-optimal gross motor development (aRR: 1.40; 95 % CI: 1.08, 1.81). Null associations were observed for the rest four neurodevelopment domains. Collectively, our study suggested that prenatal exposure to PM2.5, particularly with high SO42- concentration, was associated with children's non-optimal gross motor development at 1 year old. The short- and long-term influences of perinatal PM2.5 exposure on children's neurodevelopment warrant further investigation.

Associations between antenatal corticosteroid exposure and neurodevelopment in infants.

BACKGROUND: It has been well recognized that antenatal administration of dexamethasone to pregnant women at risk of preterm delivery may markedly accelerate fetal maturation and reduce the risk of adverse perinatal outcomes in their preterm infants, particularly for births before 34 weeks of gestation. Since 2015, antenatal corticosteroid administration has been extended beyond 34 weeks of gestation by clinical guidelines, as it might have beneficial effects on fetal maturation and perinatal outcomes. However, concerns regarding the potential influence of antenatal corticosteroid treatment on offspring neurodevelopment have been raised. OBJECTIVE: This study aimed to investigate whether maternal antenatal corticosteroid administration was associated with neurodevelopment in infants at 1 year of age. STUDY DESIGN: In this prospective and longitudinal birth cohort study, women were followed up throughout gestation, and their infants underwent a Bayley Scales of Infant and Toddler Development, Third Edition, screening test at 1 year of age between December 2018 and September 2020. Finally, 1609 pregnant women and 1759 infants were included in the current study. Using a generalized linear mixed model, we examined the association between antenatal corticosteroid exposure and infant neurodevelopment in cognitive, receptive communication, expressive communication, fine motor, and gross motor functions. RESULTS: Of the 1759 infants eligible for this study, 1453 (82.6%) were singletons. A total of 710 infants were exposed to antenatal corticosteroids, among whom 415 were dexamethasone exposed and 483 were prednisone exposed. Dexamethasone was prescribed most often in late pregnancy, whereas prednisone was often used before 8 weeks of gestation among women who conceived through assisted reproductive technology. Compared with those who had no exposure, antenatal corticosteroid exposure was associated with an increased risk of infants being noncompetent in the cognitive development domain after adjusting for conventional risk factors (adjusted risk ratio, 1.53; 95% confidence interval, 1.08-2.18; P=.017). For medication-specific exposure, those exposed vs not exposed to antenatal dexamethasone were 1.62-fold (95% confidence interval, 1.10-2.38; P=.014) more likely to be noncompetent in the cognitive development domain at 1 year. The association did not vary markedly between preterm and term infants, singletons and twins, or assisted reproductive technology-conceived and spontaneously conceived infants (all P>.05 for heterogeneity). In contrast, a null association was observed for the risk of being noncompetent in any domain of neurodevelopment with antenatal prednisone exposure at early pregnancy. CONCLUSION: Here, antenatal corticosteroid, particularly dexamethasone exposure, was markedly associated with an increased risk of infants being noncompetent in the cognitive development domain at 1 year of age. These findings may provide new information when weighing the benefits and potential risks of maternal antenatal corticosteroid administration.

Association of Maternal Dietary Patterns during Gestation and Offspring Neurodevelopment.

The health effects of diet are long term and persistent. Few cohort studies have investigated the influence of maternal dietary patterns during different gestational periods on offspring's health outcomes. This study investigated the associations between maternal dietary patterns in the mid- and late-gestation and infant's neurodevelopment at 1 year of age in the Jiangsu Birth Cohort (JBC) Study. A total of 1178 mother-child pairs were available for analysis. A semiquantitative food frequency questionnaire (FFQ) was used to investigate dietary intake at 22-26 and 30-34 gestational weeks (GWs). Neurodevelopment of children aged 1 year old was assessed using Bayley-Ⅲ Screening Test. Principal component analysis (PCA) and Poisson regression were used to extract dietary patterns and to investigate the association between dietary patterns and infant neurodevelopment. After adjusting for potential confounders, the maternal 'Aquatic products, Fresh vegetables and Homonemeae' pattern in the second trimester was associated with a lower risk of being non-competent in cognitive and gross motor development, respectively (cognition: aRR = 0.84; 95% CI 0.74-0.94; gross motor: aRR = 0.80; 95% CI 0.71-0.91), and the similar pattern, 'Aquatic products and Homonemeae', in the third trimester also showed significant association with decreased risk of failing age-appreciate cognitive and receptive communication development (cognition: aRR = 0.89; 95% CI 0.80-0.98; receptive communication: aRR = 0.91; 95% CI 0.84-0.99). Notably, adherence to the dietary pattern with relatively high aquatic and homonemeae products in both trimesters demonstrated remarkable protective effects on child neurodevelopment with the risk of being non-competent in cognitive and gross motor development decreasing by 59% (95% CI 0.21-0.79) and 63% (95% CI 0.18-0.77), respectively. Our findings suggested that adherence to the 'Aquatic products and Homonemeae' dietary pattern during pregnancy may have optimal effects on offspring's neurodevelopment.

Stress, anxiety, and depression in infertile couples are not associated with a first IVF or ICSI treatment outcome.

BACKGROUND: Psychological distress may exert a negative influence on reproductive function of couples at reproductive age. Couples seeking assisted reproductive technology (ART) treatment may have a higher prevalence of psychological distress than fertile couples. However, whether psychological distress is associated with the outcome of ART treatment remains unknown. We aimed to investigate the association of pre-treatment psychological distress and clinical pregnancy rate among infertility couples undergoing in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) treatment. METHODS: This nested case-control study was conducted based on women who underwent their first fresh IVF or ICSI cycle in the Jiangsu Birth Cohort Study (JBC) between November 2015 and January 2019. A total of 150 women who did not obtain clinical pregnancy after first IVF or ICSI fresh embryo transfer were identified as cases, and a total of 300 age matched women who obtained clinical pregnancy were identified as controls. Conditional logistic regression analyses were used to investigate the association between psychological distress and the outcome of first IVF or ICSI treatment, adjusting for multiple potential confounders. RESULTS: No statistically significant association was observed between score of maternal symptoms of psychological distress and clinical pregnancy. Adjusted ORs of logistic regression were 1.00 (95% CI 0.97-1.03) for anxiety, 0.98 (95% CI 0.95-1.02) for depression, and 0.98 (95% CI 0.95-1.01) for perceived stress, respectively. When treat depression and anxiety as categorical variables, 62 (13.8%) were classified as clinical depression, 11 (2.4%) were classified as clinical anxiety, among 450 women in the present study. Psychological distress symptoms were also not associated with clinical pregnancy rate. Adjusted ORs of logistic regression were 0.27 (95% CI 0.03-2.33) for anxiety, 0.88 (95% CI 0.46-1.68) for depression, respectively. CONCLUSIONS: Our findings firstly indicated that psychological distress experienced prior to IVF/ICSI treatment was not associated with clinical pregnancy.

Assisted reproductive technology and birth defects in a Chinese birth cohort study.

BACKGROUND: It has been consistently shown in several meta-analyses that infants born after ART have an excess of birth defects compared with those after spontaneous conception, however, the prevalence of birth defects among ART offspring in China is incompletely studied. Moreover, it is unclear to what extent the risk of birth defects is associated with parental infertility characteristics, specific ART procedures and twinning. METHODS: In the prospective cohort study, we included women who participated in the cohort, and had pregnancies of at least 20 gestational weeks between August 2016 and May 2019, and followed them until their children reached 1 year of age. Exposures of interest were ART, as well as infertility-related characteristics, certain ART procedures and specific medication usage. The primary outcome was birth defects including both major and minor defects, which we analysed with logistic generalized estimating equations to investigate the association with ART and certain ART characteristics. FINDINGS: A total of 1,825 women with ART-pregnancy and 3,483 women with spontaneous-pregnancy were included in the analysis. The prevalence of any defects was significantly higher among ART-births than their non-ART counterparts at each follow-up, specifically at prenatal screening (2•2% vs. 1•2%), at delivery (4•9% vs. 2•9%), at 6 months (10•4% vs. 5•3%) and 1 year of age (13•9% vs. 7•0%), and the associations between ART and increased risk of birth defects at each follow-up were similarly robust. Among ART-births, GnRH antagonist regimen for ovulation induction in women was associated with an increased risk of birth defects in their offspring after taking into account potential influencing factors (Multivariable model: adjusted risk ratio [aRR] 1•47, 1•04-2•07). Additionally, mediation through twinning accounted for 31•1% of the risk of ART-associated birth defects. INTERPRETATION: The results suggest that ART confers an increased risk for birth defects in offspring. The risk is partly attributable to infertility characteristics, certain ovulation induction regimen, and to some extent mediated by twinning. Our findings highlight the importance of long-term follow-up of children conceived via ART for health conditions. FUNDING: National Key Research and Development Program of China, National Natural Science Foundation of China and Natural Science Foundation of Jiangsu Province.

Association of assisted reproductive technology, germline de novo mutations and congenital heart defects in a prospective birth cohort study.

Emerging evidence suggests that children conceived through assisted reproductive technology (ART) have a higher risk of congenital heart defects (CHDs) even when there is no family history. De novo mutation (DNM) is a well-known cause of sporadic congenital diseases; however, whether ART procedures increase the number of germline DNM (gDNM) has not yet been well studied. Here, we performed whole-genome sequencing of 1137 individuals from 160 families conceived through ART and 205 families conceived spontaneously. Children conceived via ART carried 4.59 more gDNMs than children conceived spontaneously, including 3.32 paternal and 1.26 maternal DNMs, after correcting for parental age at conception, cigarette smoking, alcohol drinking, and exercise behaviors. Paternal DNMs in offspring conceived via ART are characterized by C>T substitutions at CpG sites, which potentially affect protein-coding genes and are significantly associated with the increased risk of CHD. In addition, the accumulation of non-coding functional mutations was independently associated with CHD and 87.9% of the mutations were originated from the father. Among ART offspring, infertility of the father was associated with elevated paternal DNMs; usage of both recombinant and urinary follicle-stimulating hormone and high-dosage human chorionic gonadotropin trigger was associated with an increase of maternal DNMs. In sum, the increased gDNMs in offspring conceived by ART were primarily originated from fathers, indicating that ART itself may not be a major reason for the accumulation of gDNMs. Our findings emphasize the importance of evaluating the germline status of the fathers in families with the use of ART.

Cumulative live birth rates of in vitro fertilization/intracytoplasmic sperm injection after multiple complete cycles in China.

There were few studies of cumulative live birth rates (CLBRs) based on multicenter reproductive clinical data from the general Chinese population. Here we report a retrospective cohort study, including 14 311 women with 17 315 cycles, in three reproductive centers to evaluate two estimated parameters of CLBRs with multiple transfer cycles of in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) in a Chinese population. We found that CLBRs were related to female age and endometrial thickness. By the fourth transfer cycle, the conservative and optimal estimates of CLBRs were 52.95% and 77.30% in women under 30 years of age, and 18.17% and 26.51% in those 37 years of age or older, respectively. The two estimates were 44.70% and 63.15% in women with endometrial thickness more than 7 mm, and 32.05% and 46.18% in those with less than 7 mm, respectively. In addition, body mass index (BMI), duration of infertility, and infertility diagnoses may also be related to CLBRs on certain conditions. The findings from this study on CLBRs after multiple transfer cycles of IVF/ICSI treatment on different conditions in the Chinese population should be beneficial to both infertile couples and clinicians.

Effect of endometrial thickness and embryo quality on live-birth rate of fresh IVF/ICSI cycles: a retrospective cohort study.

BACKGROUND: Successful implantation and delivery require both the functional embryo and receptive endometrium in assisted reproductive technology (ART) cycles. However, little is known about embryo-endometrial interaction on live-birth. We aimed to investigate the independent effect and interaction of endometrial thickness (EMT) and embryo quality on live-birth in fresh embryo transfer (ET) cycles. METHODS: We conducted a retrospective cohort study including 15,012 ART cycles between 2013 and 2016 in three centers in China. Poisson regression with generalized estimating equations was employed to calculate relative risks (RRs) and 95% confidence intervals (CIs). We estimated the interaction of embryo quality and EMT on live-birth rate (LBR). RESULTS: The LBR per cycle was 42.8% overall. LBR increased with increasing EMT and reached a plateau (50.6 to 54.2%) when EMT was 11 mm or thicker. Embryo quality represented by cumulative score was associated with LBR independently of number of embryos transferred and EMT. LBR was not increased with thicker EMT when only Q1 cleavage-stage embryo transferred (aRR 0.95, 95%CI 0.61-1.46). LBR was not increased significantly with thicker EMT with transfer of two good-quality cleavage-stage embryos and any blastocyst combination except Q1 group. There was significant interaction between EMT and embryo quality on LBR for cleavage-stage ETs (P=0.023). CONCLUSIONS: This study demonstrated the nonlinear EMT-LBR association and the EMT cut-off value of 11 mm which may be of more clinical significance for predicting live-birth. Embryo quality is an independent prognostic tool for LBR. Our finding of significant embryo-endometrial interaction indicates combination of EMT and embryos quality might improve the prognostic value in clinical practice for live-birth in patients undergoing transfer of 1-2 fresh cleavage-stage embryos.