Offspring Outcomes Research Articles

Maternal dietary deficiencies in folic acid or choline reduce primary neuron viability after exposure to hypoxia through increased levels of apoptosis.

Objective: Ischemic stroke is the leading cause of death and disability globally. By addressing modifiable risk factors, particularly nutrition, the prevalence of stroke and its dire consequences can be mitigated. One-carbon (1C) metabolism is a critical biosynthetic process that is involved in neural tube closure, DNA synthesis, plasticity, and cellular proliferation. Folates and choline are two active components of 1C metabolism. We have previously demonstrated that maternal dietary deficiencies during pregnancy and lactation in folic acid or choline result in worse stroke outcomes in offspring. However, there is insufficient data to understand the neuronal mechanisms involved.Methods: Using C57Bl/6J female mice maintained on control, folic acid (0.3 mg/kg) or choline (choline bitrate 300 mg/kg) deficient diets we collected embryonic primary neurons from offspring and exposed them to hypoxic conditions for 6 hours. To determine whether increased levels of either folic acid or choline can rescue reduced neuronal viability, we supplemented cell media with folic acid and choline prior to and after exposure to hypoxia.Results: Our results suggest that maternal dietary deficiencies in either folic acid or choline during pregnancy negatively impacts offspring neuronal viability after hypoxia. Furthermore, increasing levels of folic acid (250 mg/ml) or choline chloride (250 mg/ml) prior to and after hypoxia have a beneficial impact on neuronal viability.Conclusion: The findings contribute to our understanding of the intricate interplay between maternal dietary factors, 1C metabolism, and the outcome of offspring to hypoxic events, emphasizing the potential for nutritional interventions in mitigating adverse outcomes.

Pregnancy and offspring outcomes after prepregnancy bariatric surgery

BackgroundBariatric surgery is internationally performed as a treatment option in obesity to achieve significant and sustained weight loss. There is an increasing number of women having pregnancies after bariatric surgery with mixed maternal and fetal outcomes, with a limited number of large, matched studies. ObjectiveThis study aimed to describe the type of pre-pregnancy bariatric surgery, to analyse maternal, pregnancy and offspring outcomes compared to matched women and to assess the impact of pre-pregnancy bariatric surgery on fetal growth, particularly proportions of small for gestational (SGA) and large for gestational age (LGA). Study DesignA statewide hospital and perinatal data register linked cross-sectional matched study was performed. In total, n=2,018 births in n=1,677 women with pre-pregnancy bariatric surgery were registered between 2013 and 2018, of those n=1,282 were included and analysed with 1:10 to age, parity, smoking status and Body Mass Index (BMI) matched women without bariatric surgery. The first singleton pregnancy following bariatric surgery for each woman was used for analysis. Pregnancy and neonatal outcomes from International Statistical Classification of Diseases Tenth revision codes (ICD-10AM) and neonatal birth records for outcomes of interest were analysed. Multivariable logistic regression was used to estimate the association between SGA and LGA and pre-pregnancy bariatric surgery. ResultsOf the n=1,282 women, 93% had undergone laparoscopic sleeve gastrectomy. Offspring had lower absolute birthweight (3223g ± 605g vs 3418g ± 595g; p<0.001), fewer LGA (8.6% vs 14.1%; p<0.001) and more SGA infants (10.7% vs 7.3%; p<0.001) than offspring born to matched women. Offspring were more likely to be born preterm (10.5% vs 7.8%; p=0.007) to mothers with pre-pregnancy bariatric surgery. Fewer women with previous bariatric surgery were diagnosed with GDM (15% vs 20%; p<0.001) or pregnancy induced hypertension (3.7% vs 5.4%; p=0.01). In the adjusted model, pre-pregnancy bariatric surgery was associated with a lower risk of LGA (OR 0.54, 95% CI 0.44-0.66) and higher risk of SGA (OR 1.78, 95% CI 1.46-2.17). ConclusionsThese data suggest that pre-pregnancy bariatric surgery was associated with a reduction in several obesity related pregnancy complications at the expense of more pre-term births and SGA offspring.

Placental inflammation and early antecedents of health on risk of adverse pregnancy and offspring outcomes

Placental inflammation and early antecedents of health on risk of adverse pregnancy and offspring outcomes

The Effect of Seminal Plasma on the Equine Endometrial Transcriptome.

The establishment of pregnancy involves a fine-tuned balance between protection and tolerance within the maternal immune system, as the female needs to accept a foreign antigen (the semi-allogenic fetus) while still being able to combat pathogens from the uterus. In the horse, the first uterine exposure to paternal antigens is during mating when sperm is introduced to the tissue and draining lymphatics of the uterus. Additionally, it has been suggested that seminal plasma and its proteins within it play an essential role in preparing the female tract for a suitable immunologic environment but this has not been confirmed in the horse. Therefore, the objective of this study was to evaluate the endometrial transcriptome following insemination either with seminal plasma or with reduced seminal plasma. We hypothesised that reduced seminal plasma would alter the endometrial transcriptome and affect transcripts relating to immunotolerance, antigen presentation and embryo growth and development. To do so, six (n = 6) mares were inseminated in a randomised switch-back design over the course of four oestrous cycles. Mares were rectally palpated and scanned via ultrasonography for the detection of a pre-ovulatory follicle (>35 mm) alongside increasing uterine oedema and relaxed cervix, and then treated with one of four treatment groups including (1) 30 mL lactated Ringers solution (LRS; NegCon), (2) 500 × 106 spermatozoa in conjunction with 30 mL seminal plasma (SP+), (3) 30 mL lactated Ringers solution (LRS; wash out) and (4) 500 × 106 spermatozoa with seminal plasma reduced via gradient centrifugation and resuspended in 30 mL LRS (SP-). Human chorionic gonadotropin (hCG) was administered to standardise the time to ovulation and endometrial biopsies were collected 7 days after insemination. RNA was isolated utilising Trizol, and RNA-Seq was performed by Novogene, with 97.79% total mapping and 40 million read depth. p value was set to <0.05. When comparing SP+ to SP-, 158 differentially expressed genes (DEGs) were identified. Biological processes impacted included antigen processing and regulation, cholesterol synthesis, and immune/inflammatory response. Gene ontology (GO) enrichment analysis using DAVID v6.8 revealed that many of these DEGs were involved in biological process such as antigen presentation (HLA-DM beta chain, HLA-DRB, HLA-DQA and RASGRP1), immune cell signalling (CXCL9, CXCL1, DEFB1 and MIP-2B), embryo growth and development (INHA, KLF2, RDH10, LAMA3 and SLC34A2) and embryo metabolism (ABCA1, ABCA2, APOA1, LDL, INSR, IGFBP2 and IGFBP3). Overall, reduction of seminal plasma from the insemination dose impacted the endometrial transcriptome at the time of early embryonic exposure to the uterine environment. Further work is justified to evaluate these alterations impact on embryo maturation, placental development, pregnancy outcome and development of offspring.

Mapping prenatal predictors and neurobehavioral outcomes of an epigenetic marker of neonatal inflammation – A longitudinal population-based study

BackgroundDNA methylation levels at specific sites can be used to proxy C-reactive protein (CRP) levels, providing a potentially more stable and accurate indicator of sustained inflammation and associated health risk. However, its use has been primarily limited to adults or preterm infants, and little is known about determinants for − or offspring outcomes of − elevated levels of this epigenetic proxy in cord blood. The aim of this study was to comprehensively map prenatal predictors and long-term neurobehavioral outcomes of neonatal inflammation, as assessed with an epigenetic proxy of inflammation in cord blood, in the general pediatric population. MethodsOur study was embedded in the prospective population-based Generation R Study (n = 2,394). We created a methylation profile score of CRP (MPS-CRP) in cord blood as a marker of neonatal inflammation and validated it against serum CRP levels in mothers during pregnancy, as well as offspring at birth and in childhood. We then examined (i) which factors (previously associated with sustained inflammation) explain variability in MPS-CRP at birth, including a wide range of prenatal lifestyle and clinical conditions, pro-inflammatory exposures, as well as child genetic liability to elevated CRP levels; and (ii) whether MPS-CRP at birth associates with child neurobehavioral outcomes, including global structural MRI and DTI measures (child mean age 10 and 14 years) as well as psychiatric symptoms over time (Child Behavioral Checklist, at mean age 1.5, 3, 6, 10 and 14 years). ResultsMPS-CRP at birth was validated with serum CRP in cord blood (cut-off > 1 mg/L) (AUC = 0.72). Prenatal lifestyle pro-inflammatory factors explained a small part (i.e., < 5%) of the variance in the MPS-CRP at birth. No other prenatal predictor or the polygenic score of CRP in the child explained significant variance in the MPS-CRP at birth. The MPS-CRP at birth prospectively associated with a reduction in global fractional anisotropy over time on mainly a nominal threshold (β = -0.014, SE = 0.007, p = 0.032), as well as showing nominal associations with structural differences (amygdala [(β = 0.016, SE = 0.006, p = 0.010], cerebellum [(β = -0.007, SE = 0.003, p = 0.036]). However, no associations with child psychiatric symptoms were observed. ConclusionPrenatal exposure to lifestyle-related pro-inflammatory factors was the only prenatal predictor that accounted for some of the individual variability in MPS-CRP levels at birth. Further, while the MPS-CRP prospectively associated with white matter alterations over time, no associations were observed at the behavioral level. Thus, the relevance and potential utility of using epigenetic data as a marker of neonatal inflammation in the general population remain unclear. In the future, the use of epigenetic proxies for a wider range of immune markers may lend further insights into the relationship between neonatal inflammation and adverse neurodevelopment within the general pediatric population.

Genetic Insights Into Perinatal Outcomes of Maternal Antihypertensive Therapy During Pregnancy

Limited information exists regarding the impact of pharmacotherapy in pregnancy due to ethical concerns of unintended fetal harm. Yet, maternal prescriptive drug use for chronic conditions such as hypertension is common. To investigate potential causal relationships between perturbing maternal genetic variants influencing antihypertensive drug targets and perinatal outcomes among offspring using mendelian randomization (MR). This 2-sample MR study used individual-level single-nucleotide variation (SNV) outcome data from mother-father-offspring trios with complete genetic and phenotypic information from the Norwegian Mother, Father and Child Cohort Study (MoBa) and summary-level SNV exposure data from UK Biobank participants sourced from the Integrative Epidemiology Unit OpenGWAS project. Pregnant individuals were recruited across Norway during their routine ultrasonography examination at 18 weeks' gestation between June 1999 and December 2008, and mothers, fathers, and offspring were followed up after birth. Novel genetic instruments for maternal antihypertensive drug targets that act via systolic blood pressure (SBP) were derived from individual-level data analyzed in January 2018. Two-sample multivariable MR analysis of these maternal drug targets and offspring outcomes were performed between January 2023 and April 2024. Maternal genetic variants associated with drug targets for treatments of hypertension, as specified in the National Health Service dictionary of medicines and devices. Offspring outcomes were Apgar score at 1 minute and 5 minutes, offspring developmental score at 6 months, birth length, birth weight z score, gestational age, head circumference, and congenital malformation. Maternal hypertensive disorders of pregnancy were a positive control. The MoBa sample contained 29 849 family trios, with a mean (SD) maternal age of 30.2 (18.6) years and a mean (SD) paternal age of 32.8 (13.1) years; 51.1% of offspring were male. Seven independent SNVs were identified as influencing maternal SBP via the antihypertensive drug target instruments. For higher levels of maternal SBP acting through the CACNB2 calcium channel blocker target, the estimated change in gestational age was 3.99 days (95% CI, 0.02-7.96 days) per 10-mm Hg decrease in SBP. There was no evidence of differential risk for measured perinatal outcomes from maternal SBP acting through drug targets for multiple hypertensive subclasses, such as between the ADRB1 β-adrenoceptor-blocking target and risk of congenital malformation (estimated odds ratio, 0.28 [95% CI, 0.02-4.71] per 10-mm Hg decrease in SBP). Maternal and paternal SBP acting through the EDNRA vasodilator antihypertensive target did not have a potential causal effect on birth weight z score, with respective β estimates of 0.71 (95% CI, -0.09 to 1.51) and 0.72 (95% CI, -0.08 to 1.53) per 10-mm Hg decrease in SBP. The findings provided little evidence to indicate that perturbation of maternal genetic variants for SBP that influence antihypertensive drug targets had potential causal relationships with measures of perinatal development and health within this study. These findings may be triangulated with existing literature to guide physicians and mothers in decisions about antihypertensive use during pregnancy.

The association between maternal sleep and circadian rhythms during pregnancy and infant sleep and socioemotional outcomes.

Studies have established that maternal sleep and circadian rhythm disturbances during pregnancy are associated with poor prenatal and perinatal outcomes for mothers and offspring. However, little work has explored its effects on infant sleep or socioemotional outcomes. The current study examined the relationship between maternal sleep and circadian rhythm disturbances during pregnancy and infant sleep and socioemotional outcomes in a diverse sample of N = 193 mothers and their infants (51% White; 52% Female; Mage = 11.95months). Maternal sleep and circadian rhythms during pregnancy were assessed using self-reports and actigraphy. Mothers reported on infants' sleep and socioemotional outcomes when infants were one year old. When controlling for infant sex, age, gestational age at birth, family income-to-needs ratios, and maternal depression, mothers who reported more sleep problems during pregnancy had infants with more sleep disturbances when they were one year old. Moreover, mothers who had later sleep timing (i.e., went to bed and woke up later, measured via actigraphy) during pregnancy had infants with more dysregulation (e.g., increased feeding difficulties, sensory sensitivities) and externalizing problems, and mothers with increased intra-daily variability in rest-activity rhythms (as measured via actigraphy) had infants with more externalizing problems. Findings suggest that maternal sleep and circadian rhythm disturbances during pregnancy may be a risk factor for infant sleep problems and socioemotional difficulties.

Maternal smoking DNA methylation risk score associated with health outcomes in offspring of European and South Asian ancestry

Background:Maternal smoking has been linked to adverse health outcomes in newborns but the extent to which it impacts newborn health has not been quantified through an aggregated cord blood DNA methylation (DNAm) score. Here, we examine the feasibility of using cord blood DNAm scores leveraging large external studies as discovery samples to capture the epigenetic signature of maternal smoking and its influence on newborns in White European and South Asian populations.Methods:We first examined the association between individual CpGs and cigarette smoking during pregnancy, and smoking exposure in two White European birth cohorts (n=744). Leveraging established CpGs for maternal smoking, we constructed a cord blood epigenetic score of maternal smoking that was validated in one of the European-origin cohorts (n=347). This score was then tested for association with smoking status, secondary smoking exposure during pregnancy, and health outcomes in offspring measured after birth in an independent White European (n=397) and a South Asian birth cohort (n=504).Results:Several previously reported genes for maternal smoking were supported, with the strongest and most consistent association signal from the GFI1 gene (6 CpGs with p&lt;5 × 10-5). The epigenetic maternal smoking score was strongly associated with smoking status during pregnancy (OR = 1.09 [1.07, 1.10], p=5.5 × 10-33) and more hours of self-reported smoking exposure per week (1.93 [1.27, 2.58], p=7.8 × 10-9) in White Europeans. However, it was not associated with self-reported exposure (p&gt;0.05) among South Asians, likely due to a lack of smoking in this group. The same score was consistently associated with a smaller birth size (–0.37±0.12 cm, p=0.0023) in the South Asian cohort and a lower birth weight (–0.043±0.013 kg, p=0.0011) in the combined cohorts.Conclusions:This cord blood epigenetic score can help identify babies exposed to maternal smoking and assess its long-term impact on growth. Notably, these results indicate a consistent association between the DNAm signature of maternal smoking and a small body size and low birth weight in newborns, in both White European mothers who exhibited some amount of smoking and in South Asian mothers who themselves were not active smokers.Funding:This study was funded by the Canadian Institutes of Health Research Metabolomics Team Grant: MWG-146332.

Maternal smoking DNA methylation risk score associated with health outcomes in offspring of European and South Asian ancestry.

Maternal smoking has been linked to adverse health outcomes in newborns but the extent to which it impacts newborn health has not been quantified through an aggregated cord blood DNA methylation (DNAm) score. Here, we examine the feasibility of using cord blood DNAm scores leveraging large external studies as discovery samples to capture the epigenetic signature of maternal smoking and its influence on newborns in White European and South Asian populations. We first examined the association between individual CpGs and cigarette smoking during pregnancy, and smoking exposure in two White European birth cohorts (n=744). Leveraging established CpGs for maternal smoking, we constructed a cord blood epigenetic score of maternal smoking that was validated in one of the European-origin cohorts (n=347). This score was then tested for association with smoking status, secondary smoking exposure during pregnancy, and health outcomes in offspring measured after birth in an independent White European (n=397) and a South Asian birth cohort (n=504). Several previously reported genes for maternal smoking were supported, with the strongest and most consistent association signal from the GFI1 gene (6 CpGs with p<5 × 10-5). The epigenetic maternal smoking score was strongly associated with smoking status during pregnancy (OR = 1.09 [1.07, 1.10], p=5.5 × 10-33) and more hours of self-reported smoking exposure per week (1.93 [1.27, 2.58], p=7.8 × 10-9) in White Europeans. However, it was not associated with self-reported exposure (p>0.05) among South Asians, likely due to a lack of smoking in this group. The same score was consistently associated with a smaller birth size (-0.37±0.12 cm, p=0.0023) in the South Asian cohort and a lower birth weight (-0.043±0.013 kg, p=0.0011) in the combined cohorts. This cord blood epigenetic score can help identify babies exposed to maternal smoking and assess its long-term impact on growth. Notably, these results indicate a consistent association between the DNAm signature of maternal smoking and a small body size and low birth weight in newborns, in both White European mothers who exhibited some amount of smoking and in South Asian mothers who themselves were not active smokers. This study was funded by the Canadian Institutes of Health Research Metabolomics Team Grant: MWG-146332.

Psychiatric Diagnoses in Parents and Psychiatric, Behavioral, and Psychosocial Outcomes in Their Offspring: A Swedish Population-Based Register Study.

Associations were examined between six psychiatric diagnoses in parents and a broad range of psychiatric and nonpsychiatric outcomes in their offspring. All individuals born in Sweden between 1970 and 2000 were linked to their biological parents (N=3,286,293) through Swedish national registers. A matched cohort design, with stratified Cox regression and conditional logistic regression analyses, was used examine associations between six psychiatric diagnoses in the parents and 32 outcomes in their offspring. All children, including those exposed and those not exposed to parents with psychiatric diagnoses, were followed from their date of birth to the date of emigration from Sweden, death, or December 31, 2013, when the offspring were 14-44 years old. In terms of absolute risk, most children who had parents with psychiatric diagnoses were not diagnosed in specialist care themselves, and the proportion of offspring having any of the 16 types of psychiatric conditions ranged from 22.17% (of offspring exposed to parental depression) to 25.05% (of offspring exposed to parental drug-related disorder) at the end of follow-up. Nevertheless, in terms of relative risk, exposure to any of the six parental psychiatric diagnoses increased probabilities of the 32 outcomes among the offspring, with hazard ratios that ranged from 1.03 to 8.46 for time-to-event outcomes and odds ratios that ranged from 1.29 to 3.36 for binary outcomes. Some specificities were observed for parental diagnoses of psychosis and substance-related disorders, which more strongly predicted psychotic-like and externalizing-related outcomes, respectively, in the offspring. The intergenerational transmission of parental psychiatric conditions appeared largely transdiagnostic and extended to nonpsychiatric outcomes in offspring. Given the broad spectrum of associations with the outcomes, service providers (e.g., psychiatrists, teachers, and social workers) should consider clients' broader psychiatric family history when predicting prognosis and planning interventions or treatment.

Maternal hypothyroidism and subsequent metabolic outcomes in children: a systematic review and meta-analysis

IntroductionAs the fetus relies on maternal thyroid hormones in early pregnancy, maternal hypothyroidism plays an important role in fetal development. However, the association between maternal hypothyroidism and metabolic disease in offspring is unclear.ObjectiveTo examine the association between maternal hypothyroidism in pregnancy and metabolic outcomes (obesity, hypertension, type 2 diabetes mellitus, and dyslipidemia) in children < 18 years.MethodsWe systematically searched 5 databases from inception to May 2023. Eligible studies included cohort, case-control, and randomized controlled trials involving children born to mothers with or without hypothyroidism in pregnancy. Data were pooled across studies using random-effects models for outcomes reported in at least three studies. Quality assessment was performed using the ROBINS-E tool for observational studies and the Cochrane Risk of Bias tool for trials.ResultsThe search identified 3221 articles, of which 7 studies were included (1 trial, 6 observational). All studies were conducted outside of North America and ranged in size from 250 to > 1 million children. The follow-up time ranged from 6 to 20 years. Included studies support an increased risk of hypertension and glucose dysregulation in offspring exposed to maternal hypothyroidism (hypertension: OR 1.08, 95% CI 0.75, 1.57 and HR 1.81, 95% CI 1.21, 2.69; diabetes: RR 2.7, 95% CI 0.7, 10). In the pooled analysis, maternal hypothyroidism was not associated with obesity in offspring (OR 1.04, 95% CI 0.64, 1.70).ConclusionThis study found inconsistent evidence on the association between maternal hypothyroidism in pregnancy and metabolic outcomes in offspring, though associations with hypertension and glucose dysregulation are possible.

Association between blood lipid levels in early pregnancy and urinary organophosphate metabolites in the Japan Environment and Children’s Study

BackgroundHigh low-density lipoprotein cholesterol levels (LDL-C) during pregnancy have been associated with adverse pregnancy and offspring outcomes. While previous studies have suggested a potential link between organophosphate pesticide (OPP) exposure and higher LDL-C in the general population and agricultural workers, the relationship in pregnant women and the effect of body mass index on this relationship remain unclear. We examined the association between the urinary concentrations of OPP metabolites (dialkylphosphates) and blood lipid levels in pregnant women. MethodsWe used data from the Japan Environment and Children’s Study, which included 5,169 pregnant women with urinary dialkylphosphate data. We examined the association between urinary concentrations of six dialkylphosphates (DEP, DETP, DEDTP, DMP, DMTP, DMDTP) and blood lipid levels (LDL-C, total cholesterol, high-density lipoprotein cholesterol, and triglycerides) during the first trimester using multiple linear regression under a Bayesian paradigm. We examined the association between high LDL-C, defined as ≥90th percentile of LDL-C, and urinary dialkylphosphate concentrations, using multiple logistic regression under a Bayesian paradigm. These analyses were repeated in underweight, normal-weight, and overweight participants. ResultsDEP, DMP, and DMTP were detected in >50 % of the participants. Multiple linear regression analyses did not show associations between LDL-C and these dialkylphosphates. Stratified analyses showed a positive association between DEP and LDL-C in overweight women (beta coefficient = 2.13, 95 % credible interval = 0.86–3.38, probability of direction (PD) = 100 %); however, the association was not significant (percentage in region of practical equivalence (% in ROPE) = 84.0). Higher DEP was significantly associated with high LDL-C (odds ratio = 1.32, 95 % credible interval = 1.13–1.55, PD = 100 %, % in ROPE = 0.2). ConclusionsAmong overweight pregnant women in the first trimester, higher urinary DEP concentrations were associated with high LDL-C. The effects of OPP on blood lipid profiles merit further investigation.

Vitamin K Antagonists for Pregnant Women With Antiphospholipid Antibodies: A Scoping Review.

To describe characteristics of published research on the safety and efficacy of vitamin K antagonists (VKA) for pregnant patients with antiphospholipid antibodies (aPL), including their methodological characteristics and knowledge gaps. This study followed the Joanna Briggs Institute methodology for scoping reviews and used the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews protocol system. Studies were primarily identified through searching electronic databases including MEDLINE, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials. Study characteristics and outcomes were reported and described using customized charting tables. Of 1528 publications, 17 remained in the final analysis. These reported up to 190 VKA-treated aPL-positive pregnancies diagnosed as antiphospholipid syndrome (APS); pregnancy cases were likely overlapping in some publications. In the 17 reports, there were 723 individuals in comparison groups, including healthy pretreatment pregnancies and women with APS treated with standard therapies without VKA. However, only 4 (23.5%) of the 17 publications stated a study objective focusing on VKA use, of which only one was a full-length article. In addition, information on VKA doses, disease diagnostic criteria, and the long-term outcomes of offspring were largely absent. The current evidence is insufficient to assess VKA efficacy and safety profiles in aPL-positive pregnant patients. Studies with a defined focus on VKA use in this population are lacking, and reporting of key information is not consistent. The relative lack of knowledge of VKA use in pregnant women with APS is concerning, and efficacy and safety questions remain.

Maternal high-fat diet alters Tet-mediated epigenetic regulation during heart development

Imbalanced dietary intake, such as a high-fat diet (HFD) during pregnancy, has been associated with adverse offspring outcomes. Metabolic stress from imbalanced food intake alters the function of epigenetic regulators, resulting in abnormal transcriptional outputs in embryos to cause congenital disorders. We report herein that maternal HFD exposure causes metabolic changes in pregnant mice and non-compaction cardiomyopathy (NCC) in E15.5 embryos, accompanied by decreased 5-hydroxymethylcytosine (5hmC) levels and altered chromatin accessibility in embryonic heart tissues. Remarkably, maternal vitamin C supplementation mitigates these detrimental effects, likely by restoring iron, a cofactor for Tet enzymes, in a reduced state. Using a genetic approach, we further demonstrated that the cardioprotective benefits of vitamin C under HFD conditions are attributable to enhanced Tet activity. Our results highlight an interaction between maternal diet, specifically HFD or vitamin C, and epigenetic modifications during early heart development, emphasizing the importance of balanced maternal nutrition for healthy embryonic development.

Prenatal exposure to common infections and newborn DNA methylation: A prospective, population-based study

BackgroundInfections during pregnancy have been robustly associated with adverse mental and physical health outcomes in offspring, yet the underlying molecular pathways remain largely unknown. Here, we examined whether exposure to common infections in utero associates with DNA methylation (DNAm) patterns at birth and whether this in turn relates to offspring health outcomes in the general population. MethodsUsing data from 2,367 children from the Dutch population-based Generation R Study, we first performed an epigenome-wide association study to identify differentially methylated sites and regions at birth associated with prenatal infection exposure. We also examined the influence of infection timing by using self-reported cumulative infection scores for each trimester. Second, we sought to develop an aggregate methylation profile score (MPS) based on cord blood DNAm as an epigenetic proxy of prenatal infection exposure and tested whether this MPS prospectively associates with offspring health outcomes, including psychiatric symptoms, BMI, and asthma at ages 13–16 years. Third, we investigated whether prenatal infection exposure associates with offspring epigenetic age acceleration – a marker of biological aging. Across all analysis steps, we tested whether our findings replicate in 864 participants from an independent population-based cohort (ALSPAC, UK). ResultsWe observed no differentially methylated sites or regions in cord blood in relation to prenatal infection exposure, after multiple testing correction. 33 DNAm sites showed suggestive associations (p < 5e10 − 5; of which one was also nominally associated in ALSPAC), indicating potential links to genes associated with immune, neurodevelopmental, and cardiovascular pathways. While the MPS of prenatal infections associated with maternal reports of infections in the internal hold out sample in the Generation R Study (R2incremental = 0.049), it did not replicate in ALSPAC (R2incremental = 0.001), and it did not prospectively associate with offspring health outcomes in either cohort. Moreover, we observed no association between prenatal exposure to infections and epigenetic age acceleration across cohorts and clocks. ConclusionIn contrast to prior studies, which reported DNAm differences in offspring exposed to severe infections in utero, we do not find evidence for associations between self-reported clinically evident common infections during pregnancy and DNAm or epigenetic aging in cord blood within the general pediatric population. Future studies are needed to establish whether associations exist but are too subtle to be statistically meaningful with present sample sizes, whether they replicate in a cohort with a more similar infection score as our discovery cohort, whether they occur in different tissues than cord blood, and whether other biological pathways may be more relevant for mediating the effect of prenatal common infection exposure on downstream offspring health outcomes.

Dissecting the Impact of Maternal Androgen Exposure on Developmental Programming through Targeting the Androgen Receptor.

Women with polycystic ovary syndrome (PCOS) exhibit sustained elevation in circulating androgens during pregnancy, an independent risk factor linked to pregnancy complications and adverse outcomes in offspring. Yet, further studies are required to understand the effects of elevated androgens on cell type-specific placental dysfunction and fetal development. Therefore, a PCOS-like mouse model induced by continuous androgen exposure is examined. The PCOS-mice exhibited impaired placental and embryonic development, resulting in mid-gestation lethality. Co-treatment with the androgen receptor blocker, flutamide, prevents these phenotypes including germ cell specification. Comprehensive profiling of the placenta by whole-genome bisulfite and RNA sequencing shows a reduced proportion of trophoblast precursors, possibly due to the downregulation of Cdx2 expression. Reduced expression of Gcm1, Synb, and Prl3b1 is associated with reduced syncytiotrophoblasts and sinusoidal trophoblast giant cells, impairs placental labyrinth formation. Importantly, human trophoblast organoids exposed to androgens exhibit analogous changes, showing impaired trophoblast differentiation as a key feature in PCOS-related pregnancy complications. These findings provide new insights into the potential cellular targets for future treatments.

Association of Beverage Consumption during Pregnancy with Adverse Maternal and Offspring Outcomes.

As the global consumption of sugary and non-sugar sweetened beverages continues to rise, there is growing concern about their health impacts, particularly among pregnant women and their offspring. This study aimed to investigate the consumption patterns of various beverages among pregnant women in Shanghai and their potential health impacts on both mothers and offspring. We applied a multi-stage random sampling method to select participants from 16 districts in Shanghai. Each district was categorised into five zones. Two towns were randomly selected from each zone, and from each town, 30 pregnant women were randomly selected. Data were collected through face-to-face questionnaires. Follow-up data on births within a year after the survey were also obtained. The consumption rates of total beverages (TB), sugar-sweetened beverages (SSB), and non-sugar sweetened beverages (NSS) were 73.2%, 72.8%, and 13.5%, respectively. Logistic regression analysis showed that compared to non-consumers, pregnant women consuming TB three times or less per week had a 38.4% increased risk of gestational diabetes mellitus (GDM) (OR = 1.384; 95% CI: 1.129-1.696) and a 64.2% increased risk of gestational hypertension (GH) (OR = 1.642; 95% CI: 1.129-2.389). Those consuming TB four or more times per week faced a 154.3% higher risk of GDM (OR = 2.543; 95% CI: 2.064-3.314) and a 169.3% increased risk of GH (OR = 2.693; 95% CI: 1.773-4.091). Similar results were observed in the analysis of SSB. Regarding offspring health, compared to non-consumers, TB consumption four or more times per week was associated with a substantial increase in the risk of macrosomia (OR = 2.143; 95% CI: 1.304-3.522) and large for gestational age (LGA) (OR = 1.695; 95% CI: 1.219-2.356). In the analysis of NSS, with a significantly increased risk of macrosomia (OR = 6.581; 95% CI:2.796-13.824) and LGA (OR = 7.554; 95% CI: 3.372-16.921). The high level of beverage consumption among pregnant women in Shanghai needs attention. Excessive consumption of beverages increases the risk of GDM and GH, while excessive consumption of NSS possibly has a greater impact on offspring macrosomia and LGA.

Prenatal depression outcomes in the next generation: A critical review of recent DOHaD studies and recommendations for future research

Prenatal depression, a common pregnancy-related risk with a prevalence of 10–20 %, may affect in utero development and socioemotional and neurodevelopmental outcomes in the next generation. Although there is a growing body of work that suggests prenatal depression has an independent and long-lasting effect on offspring outcomes, important questions remain, and findings often do not converge. The present review examines work carried out in the last decade, with an emphasis on studies focusing on mechanisms and leveraging innovative technologies and study designs to fill in gaps in research. Overall, the past decade of research continues to suggest that prenatal depression increases risk for offspring socioemotional problems and may alter early brain development by affecting maternal-fetal physiology during pregnancy. However, important limitations remain; lack of diversity in study samples, inconsistent consideration of potential confounders (e.g., genetics, postnatal depression, parenting), and restriction of examination to narrow time windows and single exposures. On the other hand, exciting work has begun uncovering potential mechanisms underlying transmission, including alterations in mitochondria functioning, epigenetics, and the prenatal microbiome. We review the evidence to date, identify limitations, and suggest strategies for the next decade of research to detect mechanisms as well as sources of plasticity and resilience to ensure this work translates into meaningful, actionable science that improves the lives of families.

Childhood obesity from the genes to the epigenome.

The prevalence of obesity and its associated comorbidities has surged dramatically in recent decades. Especially concerning is the increased rate of childhood obesity, resulting in diseases traditionally associated only with adulthood. While obesity fundamentally arises from energy imbalance, emerging evidence over the past decade has revealed the involvement of additional factors. Epidemiological and murine studies have provided extensive evidence linking parental obesity to increased offspring weight and subsequent cardiometabolic complications in adulthood. Offspring exposed to an obese environment during conception, pregnancy, and/or lactation often exhibit increased body weight and long-term metabolic health issues, suggesting a transgenerational inheritance of disease susceptibility through epigenetic mechanisms rather than solely classic genetic mutations. In this review, we explore the current understanding of the mechanisms mediating transgenerational and intergenerational transmission of obesity. We delve into recent findings regarding both paternal and maternal obesity, shedding light on the underlying mechanisms and potential sex differences in offspring outcomes. A deeper understanding of the mechanisms behind obesity inheritance holds promise for enhancing clinical management strategies in offspring and breaking the cycle of increased metabolic risk across generations.

P-638 Paternal Consumption of Caloric and Non-Caloric Sweeteners is Associated with Sex-Specific Differences in Reproductive outcomes in offspring

Abstract Study question Does paternal pre-conception consumption of caloric or non-caloric sweeteners (NCS) coupled with high fat diets (HFD) predispose offspring to early puberty onset in mice? Summary answer Paternal prenatal consumption of the NCS Rebaudioside A(RebA) resulted in early puberty onset in female offspring only compared to water and caloric sweetener groups. What is known already A growing body of evidence suggests that the paternal diet also influences health and disease onset in offspring. Early puberty onset is associated with metabolic syndrome, type 2 diabetes, and cardiovascular disease later in adulthood. NCS are often promoted as heathier alternatives to caloric sweeteners. Evidence examining the impact of NCS on male reproductive function and offspring health outcomes, including pubertal timing are lacking. Few studies have shown maternal HFD can contribute to early puberty onset in female offspring however to our knowledge this is the first study to investigate paternal diet and offspring reproductive outcomes. Study design, size, duration 32 6-week-old C57/BL6 male mice were randomly assigned to receive a control diet (CD) or HF plus water (Con), fructose (Fr), Acesulfame K (Ak) or RebA). After 8 weeks, mice were mated. Litters were standardised to 2 males and 2 females per group and fed a standard laboratory diet. Participants/materials, setting, methods Puberty onset was measured in females by vaginal opening (from postnatal day (PN28) and in males by preputial separation (from PN35). Oral glucose tolerance tests were carried out at PN70. Mice were culled from PN80. Data were analysed by repeated measures or 2-way ANOVA. Main results and the role of chance There were no significant differences in birth weight, sex ratio or organ weights across groups. There was an overall effect of paternal NCS on male but not female offspring weight[CR1] at cull(p &amp;lt; 0.05), with male CDRebA offspring having increased BW (29.52g±1.5) compared with CDAk at PN80 (26.4g±3; p &amp;lt; 0.05). Females from paternal HF and CD RebA group [CR2] entered puberty significantly earlier (31.8d±1) than Fr (34d±1;p&amp;lt;0.01) and Con (34±1;p&amp;lt;0.05) groups. Male offspring from HFAk had lower glucose AUC (913±31) compared with CDCon (1289±48;p&amp;lt;0.001). Female offspring from CDRebA (1263±84) and CDFr (1273±67) groups had lower glucose AUC compared with CDCon group (1445±56;p&amp;lt;0.05). Limitations, reasons for caution This study was carried out on mice therefore direct translatability to humans is limited. examining the impact of paternal NCS intakes on molecular pathways in the ovary and testes to assess offspring reproductive health later in life and to evaluate pregnancy success following mating would essential for providing further insight. Wider implications of the findings The present study adds to the experimental evidence to date suggesting that NCS may not be beneficial alternatives to sugar-sweetened products consumed preconceptionally on the health of the offspring. This study also highlights the importance of including paternal diet in research when looking at transgenerational effects. Trial registration number not applicable