Prenatal Cannabis Exposure and The Risk for Neuropsychiatric Anomalies in the Offspring: A Systematic Review and Meta-Analysis.

OBJECTIVE: To evaluate the association between cannabis use during pregnancy and the risk for long-term neuropsychiatric pathology in the offspring. DATA SOURCES: MEDLINE, EMBASE, and Cochrane library databases were systematically searched until January 22, 2024, with no language or date restrictions. STUDY ELIGIBILITY CRITERIA: Studies were eligible for inclusion if they reported quantitative data on any long-term neuropsychiatric outcome in offspring whose mothers used cannabis during pregnancy for medical or recreational use, by any route and at any trimester, in comparison to offspring of women who abstained from cannabis use during pregnancy. All observational study designs were included in the analysis. STUDY APPRAISAL AND SYNTHESIS METHODS: A systematic review and meta-analysis were performed according to the PRISMA and MOOSE guidelines. The data was extracted independently by two reviewers. The following offspring outcomes were of interest: attention-deficit/ hyperactivity disorder (ADHD), autism spectrum disorder (ASD), depression, anxiety, psychotic disorders, as well as cannabis and other substance use. Odds ratios (OR) and 95% confidence intervals (CI) were pooled for each neuropsychiatric outcome in the offspring of women exposed to cannabis during pregnancy compared with non-exposed. Data were pooled using random-effects models. RESULTS: Eighteen eligible observational studies were included in the systematic review, and seventeen were included in the final quantitative analysis, representing 534,445 participants. After adjusting for confounders, the pooled OR for ADHD was 1.13 (95% CI 1.01-1.26); for ASD, the pooled OR was 1.04 (95% CI 0.74-1.46); for psychotic symptoms, the pooled OR was 1.29 (95% CI 0.97-1.72); for anxiety, the pooled OR was 1.34 (95% CI 0.79-2.29); for depression, the pooled OR was 0.72 (95% CI 0.11-4.57); and for offspring's cannabis use the pooled OR was 1.20 (95% CI 1.01-1.42). CONCLUSIONS: Prenatal cannabis exposure is not associated with an increased risk of ASD, psychotic symptoms, anxiety, or depression in offspring. However, it may slightly elevate the risk of ADHD and predispose offspring to cannabis consumption. Despite these findings, caution is warranted regarding cannabis use during pregnancy. Further research is imperative, especially given the increasing potency of cannabis in recent years.

The association of maternal gestational weight gain with cardiometabolic risk factors in offspring: a systematic review and meta-analysis.

CONTEXT: Gestational weight gain (GWG) is known to be a risk factor for offspring obesity, a precursor of cardiometabolic diseases. Accumulating studies have investigated the association of GWG with offspring cardiometabolic risk factors (CRFs), leading to inconsistent results. OBJECTIVE: This study synthesized available data from cohort studies to examine the effects of GWG on offspring CRFs. DATA SOURCE: Four electronic databases, including PubMed, Web of Science, Scopus, and Embase, were searched through May 2023. DATA EXTRACTION: Cohort studies evaluating the association between GWG and CRFs (fat mass [FM], body fat percentage [BF%], waist circumference [WC], systolic blood pressure [SBP] and diastolic blood pressure, high-density-lipoprotein cholesterol [HDL-C] and low-density-lipoprotein cholesterol, triglyceride [TG], total cholesterol, fasting blood glucose, and fasting insulin levels) were included. Regression coefficients, means or mean differences with 95% confidence intervals [CIs], or standard deviations were extracted. DATA ANALYSIS: Thirty-three cohort studies were included in the meta-analysis. Higher GWG (per increase of 1 kg) was associated with greater offspring FM (0.041 kg; 95% CI, 0.016 to 0.067), BF% (0.145%; 95% CI, 0.116 to 0.174), WC (0.154 cm; 95% CI, 0.036 to 0.272), SBP (0.040 mmHg; 95% CI, 0.010 to 0.070), and TG (0.004 mmol/L; 95% CI, 0.001 to 0.007), and with lower HDL-C (-0.002 mmol/L; 95% CI, -0.004 to 0.000). Consistently, excessive GWG was associated with higher offspring FM, BF%, WC, and insulin, and inadequate GWG was associated with lower BF%, low-density lipoprotein cholesterol, total cholesterol, and TG, compared with adequate GWG. Most associations went non-significant or attenuated with adjustment for offspring body mass index or FM. CONCLUSIONS: Higher maternal GWG is associated with increased offspring adiposity, SBP, TG, and insulin and decreased HDL-C in offspring, warranting a need to control GWG and to screen for cardiometabolic abnormalities of offspring born to mothers with excessive GWG. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no. CRD42023412098.

The interplay of maternal and offspring obesogenic diets: the impact on offspring metabolism and muscle mitochondria in an outbred mouse model.

Consumption of obesogenic (OB) diets increases the prevalence of maternal obesity worldwide, causing major psychological and social burdens in women. Obesity not only impacts the mother's health and fertility but also elevates the risk of obesity and metabolic disorders in the offspring. Family lifestyle is mostly persistent through generations, possibly contributing to the growing prevalence of obesity. We hypothesized that offspring metabolic health is dependent on both maternal and offspring diet and their interaction. We also hypothesized that the sensitivity of the offspring to the diet may be influenced by the match or mismatch between offspring and maternal diets. To test these hypotheses, outbred Swiss mice were fed a control (C, 10% fat, 7% sugar, and n = 14) or OB diet (60% fat, 20% sugar, and n = 15) for 7 weeks and then mated with the same control males. Mice were maintained on the same corresponding diet during pregnancy and lactation, and the offspring were kept with their mothers until weaning. The study focused only on female offspring, which were equally distributed at weaning and fed C or OB diets for 7 weeks, resulting in four treatment groups: C-born offspring fed C or OB diets (C ¼ C and C ¼ OB) and OB-born offspring fed C or OB diets (OB ¼ C and OB ¼ OB). Adult offspring's systemic blood profile (lipid and glucose metabolism) and muscle mitochondrial features were assessed. We confirmed that the offspring's OB diet majorly impacted the offspring's health by impairing the offspring's serum glucose and lipid profiles, which are associated with abnormal muscle mitochondrial ultrastructure. Contrarily, maternal OB diet was associated with increased expression of mitochondrial complex markers and mitochondrial morphology in offspring muscle, but no additive effects of (increased sensitivity to) an offspring OB diet were observed in pups born to obese mothers. In contrast, their metabolic profile appeared to be healthier compared to those born to lean mothers and fed an OB diet. These results are in line with the thrifty phenotype hypothesis, suggesting that OB-born offspring are better adapted to an environment with high energy availability later in life. Thus, using a murine outbred model, we could not confirm that maternal obesogenic diets contribute to female familial obesity in the following generations.

The influence of maternal prepregnancy weight and gestational weight gain on the umbilical cord blood metabolome: a case-control study.

BACKGROUND: Maternal overweight/obesity and excessive gestational weight gain (GWG) are frequently reported to be risk factors for obesity and other metabolic disorders in offspring. Cord blood metabolites provide information on fetal nutritional and metabolic health and could provide an early window of detection of potential health issues among newborns. The aim of the study was to explore the impact of maternal prepregnancy overweight/obesity and excessive GWG on cord blood metabolic profiles. METHODS: A case control study including 33 pairs of mothers with prepregnancy overweight/obesity and their neonates, 30 pairs of mothers with excessive GWG and their neonates, and 32 control mother-neonate pairs. Untargeted metabolomic profiling of umbilical cord blood samples were performed using UHPLC‒MS/MS. RESULTS: Forty-six metabolites exhibited a significant increase and 60 metabolites exhibited a significant reduction in umbilical cord blood from overweight and obese mothers compared with mothers with normal body weight. Steroid hormone biosynthesis and neuroactive ligand‒receptor interactions were the two top-ranking pathways enriched with these metabolites (P = 0.01 and 0.03, respectively). Compared with mothers with normal GWG, in mothers with excessive GWG, the levels of 63 metabolites were increased and those of 46 metabolites were decreased in umbilical cord blood. Biosynthesis of unsaturated fatty acids was the most altered pathway enriched with these metabolites (P < 0.01). CONCLUSIONS: Prepregnancy overweight and obesity affected the fetal steroid hormone biosynthesis pathway, while excessive GWG affected fetal fatty acid metabolism. This emphasizes the importance of preconception weight loss and maintaining an appropriate GWG, which are beneficial for the long-term metabolic health of offspring.

The current 'dramatically' high paternal ages at childbirth are not unprecedented.

There is strong individual-level evidence that late fatherhood is related to a wide range of health disorders and conditions in offspring. Over the last decades, mean paternal ages at childbirth have risen drastically. This has alarmed researchers from a wide range of fields. However, existing studies have an important shortcoming in that they lack a long-term perspective. This article is a step change in providing such a long-term perspective. We unveil that in many countries the current mean paternal ages at childbirth and proportions of fathers of advanced age at childbirth are not unprecedented. Taking the detected U-shaped trend pattern into account, we discuss individual- and population-level implications of the recent increases in paternal ages at childbirth and highlight important knowledge gaps. At the individual level, some of the biological mechanisms that are responsible for the paternal age-related health risk might, at least to some degree, be counterbalanced by various social factors. Further, how these individual-level effects are linked to population health and human cognitive development might be influenced by various factors, including technical advances and regulations in prenatal diagnostics.

Paternal aging impacts expression and epigenetic markers as early as the first embryonic tissue lineage differentiation.

BACKGROUND: Advanced paternal age (APA) is associated with adverse outcomes to offspring health, including increased risk for neurodevelopmental disorders. The aim of this study was to investigate the methylome and transcriptome of the first two early embryonic tissue lineages, the inner cell mass (ICM) and the trophectoderm (TE), from human blastocysts in association with paternal age and disease risk. High quality human blastocysts were donated with patient consent from donor oocyte IVF cycles from either APA (≥ 50 years) or young fathers. Blastocysts were mechanically separated into ICM and TE lineage samples for both methylome and transcriptome analyses. RESULTS: Significant differential methylation and transcription was observed concurrently in ICM and TE lineages of APA-derived blastocysts compared to those from young fathers. The methylome revealed significant enrichment for neuronal signaling pathways, as well as an association with neurodevelopmental disorders and imprinted genes, largely overlapping within both the ICM and TE lineages. Significant enrichment of neurodevelopmental signaling pathways was also observed for differentially expressed genes, but only in the ICM. In stark contrast, no significant signaling pathways or gene ontology terms were identified in the trophectoderm. Despite normal semen parameters in aged fathers, these significant molecular alterations can adversely contribute to downstream impacts on offspring health, in particular neurodevelopmental disorders like autism spectrum disorder and schizophrenia. CONCLUSIONS: An increased risk for neurodevelopmental disorders is well described in children conceived by aged fathers. Using blastocysts derived from donor oocyte IVF cycles to strategically control for maternal age, our data reveals evidence of methylation dysregulation in both tissue lineages, as well as transcription dysregulation in neurodevelopmental signaling pathways associated with APA fathers. This data also reveals that embryos derived from APA fathers do not appear to be compromised for initial implantation potential with no significant pathway signaling disruption in trophectoderm transcription. Collectively, our work provides insights into the complex molecular mechanisms that occur upon paternal aging during the first lineage differentiation in the preimplantation embryo. Early expression and epigenetic markers of APA-derived preimplantation embryos highlight the susceptibility of the future fetus to adverse health outcomes.

Future in the past: paternal reprogramming of offspring phenotype and the epigenetic mechanisms.

That certain preconceptual paternal exposures reprogram the developmental phenotypic plasticity in future generation(s) has conceptualized the "paternal programming of offspring health" hypothesis. This transgenerational effect is transmitted primarily through sperm epigenetic mechanisms-DNA methylation, non-coding RNAs (ncRNAs) and associated RNA modifications, and histone modifications-and potentially through non-sperm-specific mechanisms-seminal plasma and circulating factors-that create 'imprinted' memory of ancestral information. The epigenetic landscape in sperm is highly responsive to environmental cues, due to, in part, the soma-to-germline communication mediated by epididymosomes. While human epidemiological studies and experimental animal studies have provided solid evidences in support of transgenerational epigenetic inheritance, how ancestral information is memorized as epigenetic codes for germline transmission is poorly understood. Particular elusive is what the downstream effector pathways that decode those epigenetic codes into persistent phenotypes. In this review, we discuss the paternal reprogramming of offspring phenotype and the possible underlying epigenetic mechanisms. Cracking these epigenetic mechanisms will lead to a better appreciation of "Paternal Origins of Health and Disease" and guide innovation of intervention algorithms to achieve 'healthier' outcomes in future generations. All this will revolutionize our understanding of human disease etiology.

Advances in the study of the correlation between insulin resistance and infertility.

This is a narrative review of the progress of research on the correlation between insulin resistance and infertility. Insulin resistance (IR) is not only involved in the development of various metabolic diseases, but also affects female reproductive function, and to some extent is closely related to female infertility. IR may increase the risk of female infertility by activating oxidative stress, interfering with energy metabolism, affecting oocyte development, embryo quality and endometrial tolerance, affecting hormone secretion and embryo implantation, as well as affecting assisted conception outcomes in infertile populations and reducing the success rate of assisted reproductive technology treatment in infertile populations. In addition, IR is closely associated with spontaneous abortion, gestational diabetes and other adverse pregnancies, and if not corrected in time, may increase the risk of obesity and metabolic diseases in the offspring in the long term. This article provides a review of the relationship between IR and infertility to provide new ideas for the treatment of infertility.

Associations between Paternal Obesity and Cardiometabolic Alterations in Offspring via Assisted Reproductive Technology.

CONTEXT: Both assisted reproductive technology (ART) and obesity are associated with adverse cardiometabolic alterations in offspring. However, the combined effects of paternal obesity and ART on offspring cardiometabolic health are still unclear. OBJECTIVE: To clarify cardiometabolic changes in offspring of obese fathers conceived using ART. DESIGN: Retrospective cohort study conducted between June 2014 and October 2019. SETTING: Center for reproductive medicine. PATIENTS: A total of 2890 singleton visits aged 4-10 years were followed. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Age-and sex-specific z-score of body mass index(BMI), blood pressure, insulin resistance and lipid profile were examined. RESULTS: We observed a strong association between paternal BMI categories and offspring BMI, blood pressure, and insulin resistance. Compared to offspring of fathers with normal weight, multivariable-adjusted mean difference for BMI z-score were 0.53 (95%CI: 0.37-0.68) for obese fathers, 0.17 (95%CI: 0.05-0.30) for overweight fathers, and -0.55 (95%CI: -0.95--0.15) for underweight fathers; corresponding values for systolic blood pressure z-score were 0.21(95%CI: 0.07-0.35), 0.10 (95%CI: -0.01-0.21), and -0.24 (95%CI: -0.59-0.11), and corresponding values for HOMA-IR z-score were 0.31(95%CI: 0.16-0.46), 0.09(95%CI: -0.02-0.21), and -0.11 (95%CI: -0.48-0.28), respectively. The mediation analyses suggested that 57.48% to 94.75% of the associations among paternal obesity and offspring cardiometabolic alterations might be mediated by offspring BMI. CONCLUSIONS: Paternal obesity was associated with an unfavourable cardiometabolic profile in ART-conceived offspring. Mediation analyses indicated that offspring BMI was a possible mediator of the association between paternal obesity and the offspring impaired metabolic changes.

Environmental chemical TCPOBOP exposure alters milk liposomes and offspring growth trajectories in mice.

Exposure to environmental endocrine disruptors (EEDs) has become a global health concern, and EEDs are known to be potent inducers of constitutive androstane receptor (CAR). 1,4-bis [2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP, hereafter abbreviated as TC), a specific ligand for CAR, has been considered as a potential EED. Here, we analyzed the effect of TC exposure to female mice on the histological morphology of their alveoli in the basic unit of lactation. We quantified differences in the milk metabolome of the control and TC-exposed group while assessing the correlations between metabolites and neonatal growth. Mammary histological results showed that TC exposure inhibited alveolar development. Based on the milk metabolomic data, we identified a total of 1505 differential metabolites in both the positive and negative ion mode, which indicated that TC exposure affected milk composition. As expected, the differential metabolites were significantly enriched in the drug metabolism pathway. Further analyses revealed that differential metabolites were significantly enriched in multiple lipid metabolic pathways, such as fatty acid biosynthesis, suggesting that most differential metabolites were concentrated in lipids. Simultaneously, a quantitative analysis showed that TC exposure led to a decrease in the relative abundance of total milk lipids, affecting the proportion of some lipid subclasses. Notably, a portion of lipid metabolites were associated with neonatal growth. Taken together, these findings suggest that TC exposure may affect milk lipidomes, resulting in the inability of mothers to provide adequate nutrients, ultimately affecting the growth and health of their offspring.

Association between maternal pre-pregnancy body mass index and offspring's outcomes at 9 to 15 years of age.

OBJECTIVE: Maternal pre-pregnancy underweight, overweight and obesity might increase the risk for worse short- and long-term outcome in the offspring. There is a need for further study into the relationship between maternal pre-pregnancy body mass index (BMI) and the combined outcome of physical development, state of health and social behavior in children. QUESTION: Is maternal pre-pregnancy BMI associated with the child outcome in terms of physical development, state of health and social behavior (school and leisure time behavior) at the age of 9 to 15 years? METHODS: In the population-based birth cohort study Survey of Neonates in Pomerania (SNIP) children at the age 9-15 years and their families were re-examined by questionnaire-based follow-up. 5725 mother-child pairs were invited to SNiP-follow-up. This analysis is based on the recall fraction of 24.1% (n = 1379). Based on the maternal pre-pregnancy BMI (ppBMI), 4 groups were formed: underweight (ppBMI < 19 kg/m2, n = 117), normal weight (ppBMI 19-24.99 kg/m2, n = 913, reference), overweight (ppBMI 25-30 kg). /m2, n = 237) and obesity (ppBMI > 30 kg/m2, n = 109). RESULTS: In the multiple regression model, the BMI-z-score for children of mothers in the underweight group was -0.50 lower, and 0.50/1.07 higher in the overweight/obese group (p < 0.001) compared to reference at median age of 12 years. No differences were found in children of underweight mothers with regard to social behavior (interaction with friends and family), school and sports performance (coded from "very good" to "poor"), other leisure activities (watching television, using mobile phones, gaming), and health (occurrence of illnesses) compared to children of normal weight mothers. In contrast, maternal pre-pregnancy overweight and obesity were associated with lower school and sports performance, and higher screen time (smart phone, gaming, television) compared to children of normal weight mothers. CONCLUSION: Maternal pre-pregnancy overweight and obesity but not underweight was negatively associated with school performance and leisure time behavior in the offspring at 9-15 years of age.

Relationship between degree of methylation of sperm long interspersed nuclear element-1 (LINE-1) gene and alteration of sperm parameters and age: a meta-regression analysis.

INTRODUCTION: The long interspersed nuclear element-1 (LINE1) gene is a retrotransposon whose methylation status appears to play a role in spermatogenesis, the outcome of assisted reproductive techniques (ART), and even in recurrent pregnancy loss (RPL). Advanced paternal age appears associated with altered sperm parameters, RPL, poor ART outcomes, and compromised offspring health. The methylation status of LINE1 has been reported to be affected by age. The latest meta-analysis on the LINE1 methylation pattern in spermatozoa found no significant differences in methylation levels between infertile patients and fertile controls. However, to the best of our knowledge, no updated meta-analysis on this topic has been published recently. Furthermore, no comprehensive meta-regression analysis was performed to investigate the association between sperm LINE1 methylation pattern and age. OBJECTIVES: To provide an updated and comprehensive systematic review and meta-analysis on sperm LINE1 gene methylation degree in patients with abnormal sperm parameters compared to men with normal sperm parameters and to probe the association between sperm LINE1 methylation status and age and/or sperm concentration. METHODS: This meta-analysis was registered in PROSPERO (registration n. CRD42023397056). It was performed according to the MOOSE guidelines for Meta-analyses and Systematic Reviews of Observational Studies and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols (PRISMA-P). Only original articles evaluating LINE1 gene methylation in spermatozoa from patients with infertility or abnormalities in one or more sperm parameters compared to fertile or normozoospermic men were included. RESULTS: Of 192 abstracts evaluated for eligibility, only 5 studies were included in the quantitative synthesis, involving a total of 340 patients and 150 controls. Our analysis showed no significant difference in LINE1 gene methylation degree in patients with infertility and/or abnormal sperm parameters compared to fertile controls and/or men with normal sperm parameters, although there was significant heterogeneity across studies. No significant evidence of publication bias was found, and no study was sensitive enough to alter the results. In meta-regression analysis, we found that the results were independent of both ages and sperm concentration. A sub-analysis examining patients and controls separately was also conducted and we found a trend for a positive correlation between LINE1 methylation and sperm concentration in the control group only. CONCLUSIONS: The results of this systematic review and meta-analysis do not suggest a determining role of sperm LINE1 gene methylation degree in patients with infertility and/or abnormal sperm parameters. Therefore, we do not suggest including LINE1 in the genetic panel of prospective studies aimed at identifying the most representative and cost-effective genes to be analyzed in couples undergoing ART cycles.

Protocol for a 20-year follow-up after a randomized controlled trial of a Mediterranean diet in pregnancy: maternal and offspring risk factors for cardiovascular disease.

Background: An inadequate maternal diet during pregnancy can impair offspring health and may increase the risk of cardiovascular disease later in life. The purpose of the proposed study is to assess the risk factors associated with cardiovascular disease in both mothers and their offspring 20 years following their participation in a Mediterranean diet intervention trial during pregnancy. Methods: The "Cardiovascular Risk Reduction Diet In Pregnancy" (CARRDIP) study was a randomized controlled trial performed between 1999 and 2001. The participants were randomized to adhere to either a Mediterranean diet or their regular diet during pregnancy. An extensive amount of data such as diet information, ultrasound measurements, anthropometry, and biomarkers from these mothers during pregnancy and their offspring in the neonatal period were collected. The mother-offspring pairs (n = 269) from the CARRDIP study will be invited to participate in a clinical examination and blood sample collection. This follow-up study, conducted 20 years after the original CARRDIP study, will investigate cardiovascular risk factors in mothers and offspring. The primary outcome will be the blood pressure of the offspring. In addition, the study will explore various aspects of cardiovascular health, including metabolic and inflammatory status, clinical history, and body composition of the participants. Discussion: Previous studies investigating the effects of nutrition during pregnancy on maternal and offspring health have been either observational studies, animal studies, or randomized controlled trials with a follow-up period of less than 5 years. This project aims to study the long-term effects of dietary intervention during pregnancy on maternal and offspring cardiovascular risk markers. Clinical Trial Registration: Clinicaltrials.gov, identifier (NCT05030922).

Maternal caffeine consumption during pregnancy and offspring cord blood DNA methylation: an epigenome-wide association study meta-analysis.

Background: Prenatal caffeine exposure may influence offspring health via DNA methylation, but no large studies have tested this. Materials & methods: Epigenome-wide association studies and differentially methylated regions in cord blood (450k or EPIC Illumina arrays) were meta-analyzed across six European cohorts (n = 3725). Differential methylation related to self-reported caffeine intake (mg/day) from coffee, tea and cola was compared with assess whether caffeine is driving effects. Results: One CpG site (cg19370043, PRRX1) was associated with caffeine and another (cg14591243, STAG1) with cola intake. A total of 12-22 differentially methylated regions were detected with limited overlap across caffeinated beverages. Conclusion: We found little evidence to support an intrauterine effect of caffeine on offspring DNA methylation. Statistical power limitations may have impacted our findings.

Current guidelines recommend pregnant women to limit caffeine intake to less than 200 mg daily, even though there is no clear proof of its effects on human development. A biological explanation for how exposure to caffeine during pregnancy influences development would help clarify if recommended limits are justified. An epigenetic mechanism, called DNA methylation (DNAm), has been suggested as a potential biological explanation for how caffeine intake during pregnancy influences health development. DNAm can switch genes 'on' or 'off' in response to environmental influences and therefore act as a bridge between genes and the environment. Studies have found that smoking during pregnancy is connected to over 6000 changes in DNAm at birth, with lasting effects into adulthood. To explore the link between caffeine intake during pregnancy and DNAm at birth, we analyzed data from 3725 mother­child pairs living in different European countries. We looked at effects from coffee, tea and cola intake during pregnancy on children's DNAm at birth. We found one change in DNAm to be connected to total caffeine and another to cola consumption during pregnancy. These few connections do not provide convincing evidence that caffeine intake during pregnancy impacts children's DNAm at birth. However, because mothers in our study consumed little caffeine, it is possible that results would be different in studies with participants consuming high amounts of caffeine during pregnancy. Potentially, our study did not include enough people to find very small changes in DNAm that are connected to caffeine consumption during pregnancy.

Association of caesarean delivery with offspring health outcomes in full-cohort versus sibling-comparison studies: a comparative meta-analysis and simulation study.

BACKGROUND: Full-cohort and sibling-comparison designs have yielded inconsistent results about the impacts of caesarean delivery on offspring health outcomes, with the effect estimates from the latter being more likely directed towards the null value. We hypothesized that the seemingly conservative results obtained from the sibling-comparison design might be attributed to inadequate adjustment for non-shared confounders between siblings, particularly maternal age at delivery. METHODS: A systematic review and meta-analysis was first conducted. PubMed, Embase, and the Web of Science were searched from database inception to April 6, 2022. Included studies (1) examined the association of caesarean delivery, whether elective or emergency, with offspring health outcomes; (2) simultaneously conducted full-cohort and sibling-comparison analyses; and (3) reported adjusted effect estimates with 95% confidence intervals (95% CIs). No language restrictions were applied. Data were extracted by 2 reviewers independently. Three-level meta-analytic models were used to calculate the pooled odds ratios (ORs) and 95% CIs for caesarean versus vaginal delivery on multiple offspring health outcomes separately for full-cohort and sibling-comparison designs. Subgroup analyses were performed based on the method of adjustment for maternal age at delivery. A simulation study was then conducted. The simulated datasets were generated with some key parameters derived from the meta-analysis. RESULTS: Eighteen studies involving 21,854,828 individuals were included. The outcomes assessed included mental and behavioral disorders; endocrine, nutritional and metabolic diseases; asthma; cardiorespiratory fitness; and multiple sclerosis. The overall pooled OR for estimates from the full-cohort design was 1.14 (95% CI: 1.11 to 1.17), higher than that for estimates from the sibling-comparison design (OR = 1.08; 95% CI: 1.02 to 1.14). Stratified analyses showed that estimates from the sibling-comparison design varied considerably across studies using different methods to adjust for maternal age at delivery in multivariate analyses, while those from the full-cohort design were rather stable: in studies that did not adjust maternal age at delivery, the pooled OR of full-cohort vs. sibling-comparison design was 1.10 (95% CI: 0.99 to 1.22) vs. 1.06 (95% CI: 0.85 to 1.31), in studies adjusting it as a categorical variable, 1.15 (95% CI: 1.11 to 1.19) vs. 1.07 (95% CI: 1.00 to 1.15), and in studies adjusting it as a continuous variable, 1.12 (95% CI: 1.05 to 1.19) vs. 1.12 (95% CI: 0.98 to 1.29). The severe underestimation bias related to the inadequate adjustment of maternal age at delivery in sibling-comparison analyses was fully replicated in the simulation study. CONCLUSIONS: Sibling-comparison analyses may underestimate the association of caesarean delivery with multiple offspring health outcomes due to inadequate adjustment of non-shared confounders, such as maternal age at delivery. Thus, we should be cautious when interpreting the seemingly conservative results of sibling-comparison analyses in delivery-related studies.

Maternal Obesity and Kawasaki Disease-like Vasculitis: A New Perspective on Cardiovascular Injury and Inflammatory Response in Offspring Male Mice.

Maternal obesity affects the risk of cardiovascular disease and inflammatory response in offspring. However, the impact of maternal obesity on offspring with Kawasaki disease (KD), the leading cause of childhood acquired heart disease, is still an understudied area. This study aimed to elucidate the impact of maternal obesity on offspring in KD-like vasculitis and the underlying mechanisms. Offspring of obese female mice and normal diet dams were randomly divided into two subgroups. The pups were injected intraperitoneally with either Candida albicans water-soluble fraction (CAWS) or phosphate buffered saline (PBS) to establish the obesity (OB)-CAWS group, OB group, wild type (WT)-CAWS group, and WT group. Their weight was monitored during the study. After four weeks, echocardiography was applied to obtain the alternation of cardiac structures. Mouse cytokine panel, Hematoxylin-Eosin (HE) staining, western blot, and real-time qPCR were used to study the pathological changes and protein and RNA expression alternations. Based on the study of pathology, serology and molecular biology, maternal obesity lead to more severe vasculitis and induced altered cardiac structure in the offspring mice and promoted the expression of pro-inflammatory cytokines through activating the NF-κB signaling pathway. Maternal obesity aggravated the inflammatory response of offspring mice in KD-like vasculitis.

Obstetrical and Perinatal Outcomes Are Not Associated with Advanced Paternal Age in IVF or ICSI Pregnancies with Autologous Oocytes.

BACKGROUND: In recent years, there has been an evident delay in childbearing and concerns have been raised about whether this increase in age affects reproductive outcomes. This study aimed to evaluate the effect of paternal age on obstetrical and perinatal outcomes in couples undergoing in vitro fertilization or intracytoplasmic sperm injection using autologous sperm and oocytes. METHODS: This retrospective study evaluated obstetrical and perinatal outcomes from 14,125 couples that were arbitrarily divided into three groups according to paternal age at conception: ≤30 (n = 1164), 31-40 (n = 11,668) and >40 (n = 1293). Statistics consisted of a descriptive analysis followed by univariate and multivariate models, using the youngest age group as a reference. RESULTS: The study showed significantly longer pregnancies for the fathers aged 31-40 compared to ≤30 years. However, there were no significant differences for the type of delivery, gestational diabetes, anaemia, hypertension, delivery threat, premature rupture of membranes, preterm birth, very preterm birth, and the neonate's sex, weight, low birth weight, very low birth weight, length, cranial perimeter, Apgar score and neonatal intensive care unit admission. CONCLUSION: Despite our promising results for older fathers, as paternal age was not associated with clinically relevant obstetrical and perinatal outcomes, future well-designed studies are necessary as it has been associated with other important disorders.

Diet quality and nutrient density in pregnant women according to adherence to Mediterranean diet.

Background and aims: The dietary pattern followed during pregnancy, specifically healthy dietary patterns such as the Mediterranean diet, is a key factor in the mother's and the offspring's health. Pregnant women dietary intake is not enough to cover the micronutrient requirements of pregnancy, and higher adherence to the Mediterranean diet may improve dietary quality and nutritional density. The aim of the present study was to describe the dietary nutrient intake and diet quality during pregnancy and to evaluate whether a high adherence to Mediterranean diet was associated with a more adequate intake of micronutrients. Methods: This was a cross-sectional study with 1,356 pregnant women selected during the routine second trimester ultrasound scan (19-23 weeks' gestation). Energy and nutrient intake were calculated using a validated 151-item semi-quantitative food frequency questionnaire and nutrient density was estimated dividing the absolute nutrient intake by total energy intake. Adherence to the Mediterranean diet was evaluated with a 17-item Mediterranean diet adherence score. The criterion used for risk of inadequate nutrient intake has been set below two thirds (2/3) of the dietary reference intakes. The differences were assessed by multivariate linear regression models adjusted for confounders. Results: A significant proportion of pregnant women had an inadequate intake of macro and micronutrient that was lower in those with high adherence to the Mediterranean diet (≥12 points, n = 122, 19%), including calcium (the Mediterranean diet high adherence 2.5% vs. low adherence 26.7%, p < 0.001), magnesium (0% vs. 7.6%, p = 0.001), iron (24.5% vs. 74.1%, p < 0.001), and vitamin B9 (0% vs. 29.8%, p < 0.001), vitamin C (0% vs. 1.9%, p = 0.033), and vitamin D (61.5% vs. 92.8%, p < 0.001) intake. High adherence to Mediterranean diet was associated with higher intake of protein, monounsaturated fatty acids, fiber, vitamins (B1, B9, C, D), calcium, magnesium, iron, zinc, phosphor, potassium, essential fatty acids, and α-linolenic acid, and with a lower intake of α-linoleic acid and trans fatty acids as compared to low adherence to Mediterranean diet. Conclusion: High adherence to Mediterranean diet was associated with higher diet quality and lower proportion of inadequate micro and macronutrient intake. The Mediterranean diet promotion, particularly among pregnant women, may be a useful and public health strategy to avoid overweight and nutrient deficiencies.

Can Cryopreservation in Assisted Reproductive Technology (ART) Induce Epigenetic Changes to Gametes and Embryos?

Since the birth of Louise Brown in 1978, more than nine million children have been conceived using assisted reproductive technologies (ARTs). While the great majority of children are healthy, there are concerns about the potential epigenetic consequences of gametes and embryo manipulation. In fact, during the preimplantation period, major waves of epigenetic reprogramming occur. Epigenetic reprogramming is susceptible to environmental changes induced by ovarian stimulation, in-vitro fertilization, and embryo culture, as well as cryopreservation procedures. This review summarizes the evidence relating to oocytes and embryo cryopreservation and potential epigenetic regulation. Overall, it appears that the stress induced by vitrification, including osmotic shock, temperature and pH changes, and toxicity of cryoprotectants, might induce epigenetic and transcriptomic changes in oocytes and embryos. It is currently unclear if these changes will have potential consequences for the health of future offspring.