Adverse Offspring Outcomes Research Articles

Obesity Impairs Embryonic Myogenesis by Enhancing BMP Signaling within the Dermomyotome.

Obesity during pregnancy leads to adverse health outcomes in offspring. However, the initial effects of maternal obesity (MO) on embryonic organogenesis have yet to be thoroughly examined. Using unbiased single‐cell transcriptomic analyses (scRNA‐seq), the effects of MO on the myogenic process is investigated in embryonic day 9.5 (E9.5) mouse embryos. The results suggest that MO induces systematic hypoxia, which is correlated with enhanced BMP signaling and impairs skeletal muscle differentiation within the dermomyotome (DM). The Notch‐signaling effectors, HES1 and HEY1, which also act down‐stream of BMP signaling, suppress myogenic differentiation through transcriptionally repressing the important myogenic regulator MEF2C. Moreover, the major hypoxia effector, HIF1A, enhances expression of HES1 and HEY1 and blocks myogenic differentiation in vitro. In summary, this data demonstrate that MO induces hypoxia and impairs myogenic differentiation by up‐regulating BMP signaling within the DM, which may account for the disruptions of skeletal muscle development and function in progeny.

Epigenetic regulation of oxidative and inflammatory phenotypes in women with gestational diabetes and offspring

Abstract Background Hyperglycemia-induced oxidative stress and inflammation are potent drivers of atherosclerotic cardiovascular disease (ASCVD). Gestational diabetes (GDM) is characterized by chronic hyperglycemia during pregnancy and may represent a clinical model to study the mechanisms of oxidative stress and inflammation induced by hyperglycemia. GDM is associated with a range of adverse perinatal and long-term outcomes for both mother and offspring. In this perspective, it is emerging a putative association between maternal GDM and offspring's epigenetic trait. Purpose To investigate the link between histone modifications, oxidative stress and inflammatory phenotype as well as the transmission of epigenetic signatures to the offspring. Methods We analyzed peripheral blood mononuclear cells (PBMC) from GDM and control mothers as well as human umbilical vein endothelial cells (HUVEC) and cord blood mononuclear cells (CBMC) isolated from newborn umbilical cords obtained at delivery from both groups. Histone methyltransferase MLL1-dependent trimethylation of histone 3 at lysine 4 amino residue (H3K4me3) on NF-kB p65 subunit promoter region was assessed by chromatin immunoprecipitation (ChIP) and real-time qPCR in HUVEC, PBMC and CBMC, respectively. MLL1 and downstream inflammatory and redox genes were determined by real-time qPCR and immunocytochemistry in the presence and in the absence of MLL1 inhibitor MM-102. Measurement of reactive oxygen species (ROS) was performed by electron spin resonance spectroscopy. Results For the first time, we demonstrated a significant increase of MLL1 expression with subsequent MLL1-induced upregulation of NF-kB p65 gene via H3K4me3 in GDM as compared to control cells. MLL1-driven epigenetic remodeling of NF-kB p65 promoter is upstream to the activation of inflammatory pathway. Indeed, treatment with MM-102 decreased H3K4me3 and blunted expression of NF-kB p65 as well as VCAM-1, MCP-1 and IL-6 genes. We also found that expression of ROS scavenger aldehyde dehydrogenase 2 is reduced, whereas pro-oxidant nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit NOX4 is upregulated. Interestingly, the increased ROS generation observed in GDM is involved in the upregulation of MLL1 as shown by the restoring effect of antioxidant vitamin C on MLL1 expression levels. Conclusions Our results suggest that a complex interplay between oxidative stress and histone modifications are responsible for the GDM maternal inflammatory and oxidative phenotypes and its transmission to the offspring. The deciphering of epigenetic-induced chromatin remodelling opens the perspective for pharmacological reprogramming of adverse chromatin changes to reduce the burden of early development of metabolic phenotypes and ASCVD. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): University G. d'Annunzio MIUR fundings Schematic figure

Increased maternal inflammation and poorer infant neurobehavioural competencies in women with a history of major depressive disorder from the psychiatry research and motherhood – Depression (PRAM-D) study

IntroductionStress in pregnancy is associated with adverse outcomes in offspring, and developmental programming is a potential mechanism. We have previously shown that depression in pregnancy is a valid and clearly defined stress paradigm, and both maternal antenatal and offspring stress-related biology is affected. This study aims to clarify whether maternal biology in pregnancy and offspring outcomes can also be influenced by a history of a prior depression, in the absence of depression in pregnancy. Our primary hypothesis is that, similarly to women with depression in pregnancy, women with a history of depression but who are not depressed in pregnancy will have increased cortisol secretion and markers of immune system function, and that their offspring will have poorer neuro-developmental competencies and increased cortisol stress response. MethodsA prospective longitudinal design was used in 59 healthy controls and 25 women with a past history of depression who were not depressed in pregnancy, named as ‘history-only’, and their offspring. Maternal antenatal stress-related biology (cortisol and markers of immune system function) and offspring outcomes (gestational age at birth, neonatal neurobehaviour (Neonatal Behavioural Assessment Scale, NBAS), cortisol stress response and basal cortisol at 2 and 12 months) and cognitive, language and motor development (Bayley Scales of Infant and Toddler Development (BSID)) were measured. ResultsCompared with healthy pregnant women, those with a history of depression who remain free of depression in pregnancy exhibit increased markers of immune system function in pregnancy: IL-8 (d = 0.63, p = 0.030), VEGF (d = 0.40, p = 0.008) and MCP-1 (d = 0.61, p = 0.002) and have neonates with lower neurobehavioural scores in most areas, reaching statistical significance in thesocial-interactive (d = 1.26, p = 0.015) cluster. However, there were no differences in maternal or offspring HPA axis function or in infant development at 12 months. ConclusionOur study indicates that pregnant women with a history of depression have increased markers of immune system function, and their offspring show behavioural alterations that may be the effects of in utero programming, epigenetic factors or genetic predisposition.

Gestational diabetes mellitus: Major risk factors and pregnancy-related outcomes: A cohort study.

BackgroundGestational diabetes mellitus (GDM) is a major pregnancy endocrine problem that has several confirmed risk factors and is associated with adverse pregnancy-related outcomes (PRO).ObjectiveTo evaluate the relationship between GDM diagnosis and the associated risk factors of PRO (maternal, intrapartum, perinatal, and neonatal) in accordance with International Association of Diabetes and Pregnancy Study Groups criteria.Materials and MethodsThis prospective cohort study was performed with 531 singleton parturient (265 GDM and 266 non-GDM). They were selected consecutively from referral hospitals, and the maternal, intrapartum, perinatal, and neonatal outcomes were assessed.ResultsThe major risk factors influencing the GDM diagnosis were maternal age, obesity, family history of diabetes, previous history of GDM, and previous history of macrosomia. In the comparison of PRO between the groups, significant associations were detected for emergency cesarean delivery, preeclampsia, polyhydramnios, premature rupture of membrane, preterm delivery, and neonatal hyperbilirubinemia in the GDM group. In the multivariate logistic regression analysis, a previous history of stillbirth was significantly associated with maternal and perinatal outcomes. The odds ratios (CI 95%) of the PRO in the women with a GDM diagnosis were: maternal = 2.43 (1.51-3.90), intrapartum = 2.05 (1.35-3.11), perinatal = 2.00 (1.29-3.10), and neonatal = 1.68 (1.08-2.62). The PRO was significantly correlated with GDM diagnosis, but not with the risk factors.Conclusion The adverse pregnancy outcomes were significantly correlated with GDM diagnosis, and the outcomes were not directly affected by the risk factors. Given the related adverse outcomes for mothers and offspring, early screening and management of GDM is necessary especially in Asians and in low-/middle-income countries.

Developmental programming by maternal obesity: Lessons from animal models.

The obesity epidemic has led to more women entering pregnancy overweight or obese. In addition to adverse short-term outcomes, maternal obesity and/or gestational diabetes predispose offspring to developing obesity, type 2 diabetes and cardiovascular disease in adulthood through developmental programming. Human epidemiological studies, although vital in identifying associations, are often unable to address causality and mechanistic studies can be limited by the lack of accessibility of key metabolic tissues. Furthermore, multi-generational studies take many years to complete. Integration of findings from human studies with those from animal models has therefore been critical in moving forward this field that has been termed the 'Developmental Origins of Health and Disease'. This review summarises the evidence from animal models and highlights how animal models provide valuable insight into the maternal factors responsible for developmental programming, potential critical developmental windows, sexual dimorphism, molecular mechanisms and age-related offspring outcomes throughout life. Moreover, we describe how animal models are vital to explore clinically relevant interventions to prevent adverse offspring outcomes in obese or glucose intolerant pregnancy, such as antioxidant supplementation, exercise and maternal metformin treatment.

TH4. A CAUSAL ROLE FOR ATTENTION DEFICIT/ HYPERACTIVITY DISORDER ON RISK-TAKING BEHAVIOURS, ACADEMIC AND FINANCIAL PROBLEMS AND MAJOR DEPRESSION

Previous studies have suggested associations between maternal smoking during pregnancy (MSDP) and a range of adverse outcomes in offspring. However, evidence reporting adverse effects on poor academic performance in adolescence is scant.This register-based cohort study used linked data obtained from New South Wales (NSW) educational and health registries in Australia. MSDP was assessed using self-reports of smoking during pregnancy. Offspring’s educational performance was assessed using the National Assessment Program for Literacy and numeracy (NAPLAN), when students were in grade 9 and approximately aged 14 years. We used multivariable logistic regression models to explore associations.Adolescent offspring exposed to MSDP were at an increased risk of substandard academic performance in all domains, with the highest odds for spelling [OR, 3.12 (95%CI 2.98–3.26)] followed by writing [OR, 2.97 (95%CI 2.84–3.11)], reading [OR, 2.49 (95%CI 2.37–2.62)], and numeracy [OR, 2.43 (95%CI 2.30–2.58)]. In our sex-stratified analysis, MSDP displayed stronger effects on the academic performance of female offspring in all domains.Our findings showed that MSDP was associated with an increased risk of reduced academic performance in adolescent offspring. The different effects of MSDP on the academic performance of male and female offspring is a new finding, which needs further investigation.

Brief Hydromorphone Exposure During Pregnancy Sufficient to Induce Maternal and Neonatal Microbial Dysbiosis.

Prenatal opioid exposure is associated with significantly adverse medical, developmental, and behavioral outcomes in offspring, though the underlying mechanisms driving these impairments are still unclear. Accumulating evidence implicates gut microbial dysbiosis as a potential modulator of these adverse effects. However, how opioid exposure during pregnancy alters the maternal and neonatal microbiome remain to be elucidated. Here, we utilize a murine model of brief hydromorphone exposure during pregnancy (gestation day 11-13; i.p.; 10mg/kg) to examine its impact on the maternal and neonatal microbiome. Fecal samples were collected at various timepoints in dams (4days post hydromorphone exposure, birth, and weaning) and offspring (2, 3, and 5weeks) to interrogate longitudinal changes in the microbiome. Stomach contents at 2weeks were also collected as a surrogate for breastmilk and microbial analysis was performed using 16S rRNA sequencing. Alongside alterations in the maternal gut microbial composition, offspring gut microbiota exhibited distinct communities at 2 and 3weeks. Furthermore, functional profiling of microbial communities revealed significant differences in microbial community-level phenotypes gram-negative, gram-positive, and potentially pathogenic in maternal and/or neonatal hydromorphone exposed groups compared with controls. We also observed differences in stomach microbiota in opioid-exposed vs non-exposed offspring, which suggests breast milk may also play a role in shaping the development of the neonatal gut microbiota. Together, we provide evidence of maternal and neonatal microbial dysbiosis provoked even with brief hydromorphone exposure during pregnancy.

Associations of maternal bisphenol urine concentrations during pregnancy with neonatal metabolomic profiles

BackgroundFetal exposure to bisphenols is associated with altered fetal growth, adverse birth outcomes and childhood cardio-metabolic risk factors. Metabolomics may serve as a tool to identify the mechanisms underlying these associations. We examined the associations of maternal bisphenol urinary concentrations in pregnancy with neonatal metabolite profiles from cord blood.MethodsIn a population-based prospective cohort study among 225 mother–child pairs, maternal urinary bisphenol A, S and F concentrations in first, second and third trimester were measured. LC–MS/MS was used to determine neonatal concentrations of amino acids, non-esterified fatty acids (NEFA), phospholipids (PL), and carnitines in cord blood.ResultsNo associations of maternal total bisphenol concentrations with neonatal metabolite profiles were present. Higher maternal average BPA concentrations were associated with higher neonatal mono-unsaturated alkyl-lysophosphatidylcholine concentrations, whereas higher maternal average BPS was associated with lower neonatal overall and saturated alkyl-lysophosphatidylcholine (p-values < 0.05).Trimester-specific analyses showed that higher maternal BPA, BPS and BPF were associated with alterations in neonatal NEFA, diacyl-phosphatidylcholines, acyl-alkyl-phosphatidylcholines, alkyl-lysophosphatidylcholine, sphingomyelines and acyl-carnitines, with the strongest effects for third trimester maternal bisphenol and neonatal diacyl-phosphatidylcholine, sphingomyeline and acyl-carnitine metabolites (p-values < 0.05). Associations were not explained by maternal socio-demographic and lifestyle characteristics or birth characteristics.DiscussionHigher maternal bisphenol A, F and S concentrations in pregnancy are associated with alterations in neonatal metabolite profile, mainly in NEFA, PL and carnitines concentrations. These findings provide novel insight into potential mechanisms underlying associations of maternal bisphenol exposure during pregnancy with adverse offspring outcomes but need to be replicated among larger, diverse populations.

Maternal mental distress and cortisol levels in pregnancies with congenital heart disease.

Prenatal maternal stress is associated with adverse offspring outcomes, which may be mediated by maternal stress hormones. However, evidence supporting the association between maternal stress and cortisol levels in high-risk pregnancies is limited. This study aims to determine the relationship between self-reported maternal mental distress and maternal salivary cortisol levels in pregnancies complicated by foetal CHD compared with healthy pregnancies. We recruited women with pregnancies complicated by foetal CHD and healthy pregnancies. Maternal saliva was collected between 22 and 40 gestational weeks. Standardized questionnaires measuring stress, depression, and anxiety were completed by patients. Generalized estimating equation was used to evaluate associations between maternal mental distress scales and cortisol levels. We studied 165 women (55 CHD, 110 controls) and collected 504 cortisol samples (160 CHD, 344 controls). Women carrying CHD foetuses had higher stress, anxiety, and depression scores compared to women carrying healthy foetuses. However, maternal cortisol levels did not significantly differ in CHD and controls. Cortisol levels were higher in women carrying foetuses with functionally single-ventricle versus two-ventricle CHD. In both CHD and controls, there was no significant association between maternal stress, depression or anxiety scores and cortisol levels. Our data suggest that self-reported maternal stress, anxiety, and depression are not associated with maternal salivary cortisol levels in CHD and healthy pregnancies. The impact of maternal mental distress on foetal health may be through other mediating pathways other than maternal cortisol concentrations.

Comparative epidemiology of gestational diabetes in ethnic Chinese from Shanghai birth cohort and growing up in Singapore towards healthy outcomes cohort

BackgroundGestational diabetes mellitus (GDM) has been associated with adverse health outcomes for mothers and offspring. Prevalence of GDM differs by country/region due to ethnicity, lifestyle and diagnostic criteria. We compared GDM rates and risk factors in two Asian cohorts using the 1999 WHO and the International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria.MethodsThe Shanghai Birth Cohort (SBC) and the Growing Up in Singapore Towards healthy Outcomes (GUSTO) cohort are prospective birth cohorts. Information on sociodemographic characteristics and medical history were collected from interviewer-administered questionnaires. Participants underwent a 2-h 75-g oral glucose tolerance test at 24–28 weeks gestation. Logistic regressions were performed.ResultsUsing the 1999 WHO criteria, the prevalence of GDM was higher in GUSTO (20.8%) compared to SBC (16.6%) (p = 0.046). Family history of hypertension and alcohol consumption were associated with higher odds of GDM in SBC than in GUSTO cohort while obesity was associated with higher odds of GDM in GUSTO. Using the IADPSG criteria, the prevalence of GDM was 14.3% in SBC versus 12.0% in GUSTO. A history of GDM was associated with higher odds of GDM in GUSTO than in SBC, while being overweight, alcohol consumption and family history of diabetes were associated with higher odds of GDM in SBC.ConclusionsWe observed several differential risk factors of GDM among ethnic Chinese women living in Shanghai and Singapore. These findings might be due to heterogeneity of GDM reflected in diagnostic criteria as well as in unmeasured genetic, lifestyle and environmental factors.

Trends in Gestational Diabetes at First Live Birth by Race and Ethnicity in the US, 2011-2019

Gestational diabetes is associated with adverse maternal and offspring outcomes. To determine whether rates of gestational diabetes among individuals at first live birth changed from 2011 to 2019 and how these rates differ by race and ethnicity in the US. Serial cross-sectional analysis using National Center for Health Statistics data for 12 610 235 individuals aged 15 to 44 years with singleton first live births from 2011 to 2019 in the US. Gestational diabetes data stratified by the following race and ethnicity groups: Hispanic/Latina (including Central and South American, Cuban, Mexican, and Puerto Rican); non-Hispanic Asian/Pacific Islander (including Asian Indian, Chinese, Filipina, Japanese, Korean, and Vietnamese); non-Hispanic Black; and non-Hispanic White. The primary outcomes were age-standardized rates of gestational diabetes (per 1000 live births) and respective mean annual percent change and rate ratios (RRs) of gestational diabetes in non-Hispanic Asian/Pacific Islander (overall and in subgroups), non-Hispanic Black, and Hispanic/Latina (overall and in subgroups) individuals relative to non-Hispanic White individuals (referent group). Among the 12 610 235 included individuals (mean [SD] age, 26.3 [5.8] years), the overall age-standardized gestational diabetes rate significantly increased from 47.6 (95% CI, 47.1-48.0) to 63.5 (95% CI, 63.1-64.0) per 1000 live births from 2011 to 2019, a mean annual percent change of 3.7% (95% CI, 2.8%-4.6%) per year. Of the 12 610 235 participants, 21% were Hispanic/Latina (2019 gestational diabetes rate, 66.6 [95% CI, 65.6-67.7]; RR, 1.15 [95% CI, 1.13-1.18]), 8% were non-Hispanic Asian/Pacific Islander (2019 gestational diabetes rate, 102.7 [95% CI, 100.7-104.7]; RR, 1.78 [95% CI, 1.74-1.82]), 14% were non-Hispanic Black (2019 gestational diabetes rate, 55.7 [95% CI, 54.5-57.0]; RR, 0.97 [95% CI, 0.94-0.99]), and 56% were non-Hispanic White (2019 gestational diabetes rate, 57.7 [95% CI, 57.2-58.3]; referent group). Gestational diabetes rates were highest in Asian Indian participants (2019 gestational diabetes rate, 129.1 [95% CI, 100.7-104.7]; RR, 2.24 [95% CI, 2.15-2.33]). Among Hispanic/Latina participants, gestational diabetes rates were highest among Puerto Rican individuals (2019 gestational diabetes rate, 75.8 [95% CI, 71.8-79.9]; RR, 1.31 [95% CI, 1.24-1.39]). Gestational diabetes rates increased among all race and ethnicity subgroups and across all age groups. Among individuals with a singleton first live birth in the US from 2011 to 2019, rates of gestational diabetes increased across all racial and ethnic subgroups. Differences in absolute gestational diabetes rates were observed across race and ethnicity subgroups.

Maternal postnatal depression and offspring depression at age 24 years in a UK-birth cohort: the mediating role of maternal nurturing behaviours concerning feeding, crying and sleeping

Background: Maternal postnatal depression (PND) is a risk factor for offspring depression in adulthood. However, few longitudinal studies have examined the role of maternal nurturing parenting behaviours in the association between maternal PND and offspring depression in adulthood. Methods: We examined pathways from maternal PND measured using self-reported Edinburgh Postnatal Depression Scale at 8 weeks to offspring ICD-10 depression diagnosed using the Clinical Interview Schedule-Revised computerised assessment at 24 years through maternal-reported nurturing behaviours concerning feeding, sleeping and crying measured from pregnancy to age 3 years 6 months in 5,881 members of the UK-based birth cohort study, the Avon Longitudinal Study of Parents and Children. Results: The fully adjusted model revealed an indirect effect from PND to adult offspring depression through the combination of all parenting factors (probit regression coefficient [ B]=0.038, 95% confidence interval [CI] 0.005, 0.071); however, there was no evidence of a direct effect from early maternal PND to offspring depression once the indirect effect via parenting factors was accounted for ( B=0.009, 95%CI -0.075, 0.093). Specificity analyses revealed indirect effects through maternal worries about feeding ( B=0.019, 95%CI 0.003, 0.035, p=0.010) and maternal perceptions and responses to crying ( B=0.018, 95%CI 0.004, 0.032, p=0.012). Conclusions: The adverse impact of maternal PND on offspring depression in early adulthood was explained by maternal nurturing behaviours concerning feeding, crying and sleeping in early childhood. Residual confounding and measurement error likely limit reliable conclusions. If found causal, interventions providing support to reduce worries around maternal nurturing behaviours and treating depression could reduce adverse outcomes in adult offspring of depressed mothers.

Maternal smoking during pregnancy and poor academic performance in adolescent offspring: A registry data-based cohort study

BackgroundPrevious studies have suggested associations between maternal smoking during pregnancy (MSDP) and a range of adverse outcomes in offspring. However, evidence reporting adverse effects on poor academic performance in adolescence is scant. MethodsThis register-based cohort study used linked data obtained from New South Wales (NSW) educational and health registries in Australia. MSDP was assessed using self-reports of smoking during pregnancy. Offspring’s educational performance was assessed using the National Assessment Program for Literacy and numeracy (NAPLAN), when students were in grade 9 and approximately aged 14 years. We used multivariable logistic regression models to explore associations. ResultsAdolescent offspring exposed to MSDP were at an increased risk of substandard academic performance in all domains, with the highest odds for spelling [OR, 3.12 (95%CI 2.98–3.26)] followed by writing [OR, 2.97 (95%CI 2.84–3.11)], reading [OR, 2.49 (95%CI 2.37–2.62)], and numeracy [OR, 2.43 (95%CI 2.30–2.58)]. In our sex-stratified analysis, MSDP displayed stronger effects on the academic performance of female offspring in all domains. ConclusionsOur findings showed that MSDP was associated with an increased risk of reduced academic performance in adolescent offspring. The different effects of MSDP on the academic performance of male and female offspring is a new finding, which needs further investigation.

Maternal postnatal depression and offspring depression at age 24 years in a UK-birth cohort: the mediating role of maternal nurturing behaviours concerning feeding, crying and sleeping.

Background: Maternal postnatal depression (PND) is a risk factor for offspring depression in adulthood. However, few longitudinal studies have examined the role of maternal nurturing parenting behaviours in the association between maternal PND and offspring depression in adulthood. Methods: We examined pathways from maternal PND measured using self-reported Edinburgh Postnatal Depression Scale at 8 weeks to offspring ICD-10 depression diagnosed using the Clinical Interview Schedule-Revised computerised assessment at 24 years through maternal-reported nurturing behaviours concerning feeding, sleeping and crying measured from pregnancy to age 3 years 6 months in 5,881 members of the UK-based birth cohort study, the Avon Longitudinal Study of Parents and Children. Results: The fully adjusted model revealed an indirect effect from PND to adult offspring depression through the combination of all parenting factors (probit regression coefficient [ B]=0.038, 95% confidence interval [CI] 0.005, 0.071); however, there was no evidence of a direct effect from early maternal PND to offspring depression once the indirect effect via parenting factors was accounted for ( B=0.009, 95%CI -0.075, 0.093). Specificity analyses revealed indirect effects through maternal worries about feeding ( B=0.019, 95%CI 0.003, 0.035, p=0.010) and maternal perceptions and responses to crying ( B=0.018, 95%CI 0.004, 0.032, p=0.012). Conclusions: The adverse impact of maternal PND on offspring depression in early adulthood was explained by maternal nurturing behaviours concerning feeding, crying and sleeping in early childhood. Residual confounding and measurement error likely limit reliable conclusions. If found causal, interventions providing support to reduce worries around maternal nurturing behaviours and treating depression could reduce adverse outcomes in adult offspring of depressed mothers.

Association of pre-pregnancy cardiovascular risk factor burden with adverse maternal and offspring outcomes

Association of pre-pregnancy cardiovascular risk factor burden with adverse maternal and offspring outcomes

The association between birth by caesarean section at term and offspring cognitive and academic performance: A birth cohort study.

Caesarean section (CS) is associated with an increased risk of adverse health outcomes for both mothers and offspring. The evidence for an association between CS and reduced offspring cognitive and academic performance has been inconsistent, with considerable limitations. The aim of this study is to compare cognitive and academic performance in childhood and early adulthood in offspring delivered by CS with those delivered vaginally at term. Data on 4327 mothers and offspring from a longitudinal birth cohort study were analysed. Offspring cognitive performance was measured by the Picture Peabody Vocabulary Test-Revised (PPVT-R) at ages five and 21 and the Raven's Standard Progressive Matrices at age 14. Academic achievement was assessed using the Wide Range Achievement Test at age 14. After adjustment for confounding factors, there was no statistically significant association between cognitive performance and offspring birth mode at age five (P=0.11). The adjusted difference of mean scores at five years on the PPVT-R for elective CS birth compared to those born by vaginal delivery was -2.2 (95% confidence interval (CI) -4.3 to -0.2), whereas for emergency CS it was 0.0 (95% CI -2.0 to 2.0). There were no differences in cognitive or academic performance at ages 14 and 21. Birth mode was not significantly associated with offspring cognitive or academic performance. Our study does not support concerns that CS is associated with a reduction in cognitive performance.

Screening, Diagnosis, and Management of GDM

Gestational diabetes mellitus (GDM) is characterized by an imbalance between insulin supply and resistance, resulting in maternal hyperglycemia first diagnosed during pregnancy. The increasing incidence of GDM parallels the obesity epidemic. There is no universal consensus on optimal screening and diagnostic criteria but it is widely accepted that pregnancies complicated by GDM are at high risk of short- and long-term adverse outcomes for both mother and offspring. Early intervention with lifestyle changes and medical treatment has been shown to prevent perinatal complications. At the same time, the application of clinical guidelines to real world clinical practice may be challenging as it is affected by socioeconomic diversities.

The Association Between High Birth Weight and Long-Term Outcomes—Implications for Assisted Reproductive Technologies: A Systematic Review and Meta-Analysis

Background: Studies have shown that the prevalence of children born with high birth weight or large for gestational age (LGA) is increasing. This is true for spontaneous pregnancies; however, children born after frozen embryo transfer (FET) as part of assisted reproductive technology (ART) also have an elevated risk. In recent years, the practice of FET has increased rapidly and while the perinatal and obstetric risks are well-studied, less is known about the long-term health consequences.Objective: The aim of this systematic review was to describe the association between high birth weight and LGA on long-term child outcomes.Data Sources: PubMed, Scopus, and Web of Science were searched up to January 2021. Exposure included high birth weight and LGA. Long-term outcome variables included malignancies, psychiatric disorders, cardiovascular disease, and diabetes.Study Selection: Original studies published in English or Scandinavian languages were included. Studies with a control group were included while studies published as abstracts and case reports were excluded.Data Extraction: The methodological quality, in terms of risk of bias, was assessed by pairs of reviewers. Robins-I (www.methods.cochrane.org) was used for risk of bias assessment in original articles. For systematic reviews, AMSTAR (www.amstar.ca) was used. For certainty of evidence, we used the GRADE system. The systematic review followed PRISMA guidelines. When possible, meta-analyses were performed.Results: The search included 11,767 articles out of which 173 met the inclusion criteria and were included in the qualitative analysis, while 63 were included in quantitative synthesis (meta-analyses). High birth weight and/or LGA was associated with low to moderately elevated risks for certain malignancies in childhood, breast cancer, several psychiatric disorders, hypertension in childhood, and type 1 and 2 diabetes.Conclusions: Although the increased risks for adverse outcome in offspring associated with high birth weight and LGA represent serious health effects in childhood and in adulthood, the size of these effects seems moderate. The identified risk association should, however, be taken into account in decisions concerning fresh and frozen ART cycles and is of general importance in view of the increasing prevalence in high birthweight babies.

Association of medically assisted reproduction with offspring cord blood DNA methylation across cohorts.

STUDY QUESTIONIs cord blood DNA methylation associated with having been conceived by medically assisted reproduction?SUMMARY ANSWERThis study does not provide strong evidence of an association of conception by medically assisted reproduction with variation in infant blood cell DNA methylation.WHAT IS KNOWN ALREADYMedically assisted reproduction consists of procedures used to help infertile/subfertile couples conceive, including ART. Due to its importance in gene regulation during early development programming, DNA methylation and its perturbations associated with medically assisted reproduction could reveal new insights into the biological effects of assisted reproductive technologies and potential adverse offspring outcomes.STUDY DESIGN, SIZE, DURATIONWe investigated the association of DNA methylation and medically assisted reproduction using a case–control study design (N = 205 medically assisted reproduction cases and N = 2439 naturally conceived controls in discovery cohorts; N = 149 ART cases and N = 58 non-ART controls in replication cohort).PARTICIPANTS/MATERIALS, SETTINGS, METHODSWe assessed the association between medically assisted reproduction and DNA methylation at birth in cord blood (205 medically assisted conceptions and 2439 naturally conceived controls) at >450 000 CpG sites across the genome in two sub-samples of the UK Avon Longitudinal Study of Parents and Children (ALSPAC) and two sub-samples of the Norwegian Mother, Father and Child Cohort Study (MoBa) by meta-analysis. We explored replication of findings in the Australian Clinical review of the Health of adults conceived following Assisted Reproductive Technologies (CHART) study (N = 149 ART conceptions and N = 58 controls).MAIN RESULTS AND THE ROLE OF CHANCEThe ALSPAC and MoBa meta-analysis revealed evidence of association between conception by medically assisted reproduction and DNA methylation (false-discovery-rate-corrected P-value < 0.05) at five CpG sites which are annotated to two genes (percentage difference in methylation per CpG, cg24051276: Beta = 0.23 (95% CI 0.15,0.31); cg00012522: Beta = 0.47 (95% CI 0.31, 0.63); cg17855264: Beta = 0.31 (95% CI 0.20, 0.43); cg17132421: Beta = 0.30 (95% CI 0.18, 0.42); cg18529845: Beta = 0.41 (95% CI 0.25, 0.57)). Methylation at three of these sites has been previously linked to cancer, aging, HIV infection and neurological diseases. None of these associations replicated in the CHART cohort. There was evidence of a functional role of medically assisted reproduction-induced hypermethylation at CpG sites located within regulatory regions as shown by putative transcription factor binding and chromatin remodelling.LIMITATIONS, REASONS FOR CAUTIONSWhile insufficient power is likely, heterogeneity in types of medically assisted reproduction procedures and between populations may also contribute. Larger studies might identify replicable variation in DNA methylation at birth due to medically assisted reproduction.WIDER IMPLICATIONS OF THE FINDINGSNewborns conceived with medically assisted procedures present with divergent DNA methylation in cord blood white cells. If these associations are true and causal, they might have long-term consequences for offspring health.STUDY FUNDING/COMPETING INTERESTS(S)This study has been supported by the US National Institute of Health (R01 DK10324), the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013)/ERC Grant agreement no. 669545, European Union’s Horizon 2020 research and innovation programme under Grant agreement no. 733206 (LifeCycle) and the NIHR Biomedical Centre at the University Hospitals Bristol NHS Foundation Trust and the University of Bristol. The UK Medical Research Council and Wellcome (Grant ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. Methylation data in the ALSPAC cohort were generated as part of the UK BBSRC funded (BB/I025751/1 and BB/I025263/1) Accessible Resource for Integrated Epigenomic Studies (ARIES, http://www.ariesepigenomics.org.uk). D.C., J.J., C.L.R. D.A.L and H.R.E. work in a Unit that is supported by the University of Bristol and the UK Medical Research Council (Grant nos. MC_UU_00011/1, MC_UU_00011/5 and MC_UU_00011/6). B.N. is supported by an NHMRC (Australia) Investigator Grant (1173314). ALSPAC GWAS data were generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. The Norwegian Mother, Father and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research, NIH/NIEHS (Contract no. N01-ES-75558), NIH/NINDS (Grant nos. (i) UO1 NS 047537-01 and (ii) UO1 NS 047537-06A1). For this work, MoBa 1 and 2 were supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01-ES-49019) and the Norwegian Research Council/BIOBANK (Grant no. 221097). This work was partly supported by the Research Council of Norway through its Centres of Excellence funding scheme, Project no. 262700.D.A.L. has received support from national and international government and charity funders, as well as from Roche Diagnostics and Medtronic for research unrelated to this study. The other authors declare no conflicts of interest.TRIAL REGISTRATION NUMBERN/A.

A Role for the Pregravid Maternal Milieu in the Intergenerational Transmission of Obesity

ObjectivesMaternal obesity increases the risk for adverse pregnancy and offspring outcomes; however, with large heterogeneity. We hypothesize that in mothers with obesity, the heterogeneity of offspring adiposity is due to prolonged exposure to excess maternal substrates, namely glucose and triglycerides, which promote fetal fat accretion. The aims of this prospective observational study were to 1) examine the maternal metabolic milieu in pregnant women with metabolically unhealthy obesity, MUO and metabolically healthy obesity, MHO; and 2) identify if these maternal metabolic phenotypes in women with obesity influence infant adiposity. MethodsDuring early pregnancy, 51 women with obesity were classified to have MUO (n = 9) or MHO (n = 13) based on the presence of zero (MHO) or ≥ 2 (MUO) risk factors for metabolic syndrome (SBP > 130 or DBP > 85, HDL < 50 mg/dL, LDL ≥ 100 mg/dL, triglycerides ≥ 150 mg/dL, and glucose ≥ 100 mg/dL). Area under the pregnancy concentration curve (AUC) for glucose and triglycerides, gestational weight gain (GWG), fat accretion, and energy intake and expenditure from early (13–16 wks), mid (24–27 wks) to late (35–37 wks) pregnancy and infant fat mass were compared between groups. ResultsCompared to women with MHO, women with MUO were not different with respect to maternal BMI, GWG, fat accretion, energy and macronutrient intake, and energy expenditure. In both groups, maternal substrates changed similarly from ∼13 to ∼37 weeks of pregnancy, however MUO resulted in greater pregnancy AUC for glucose (+2169.7 ± 381.5 p < 0.001 mg/dL · day) and triglycerides (+12,210.5 ± 3916.1 mg/dL · day, p < 0.001). The offspring of women with MHO had significantly lower birth weight (–620.8 ± 204.6 g, p = 0.01), body fat percentage (–5.8 ± 2.1%, p = 0.02), and total fat mass (–268.8 ± 88.4 g, p = 0.01). ConclusionsDiffering obesity phenotypes in pregnancy may explain the heterogeneity of offspring adiposity. Metabolically unhealthy obesity resulted in a more prolonged exposure of fetal fat promoting substrates and increased adiposity at birth. This study identifies a population of women with obesity most in need of prenatal interventions and suggests that obesity phenotypes need to be considered when evaluating intervention effect on offspring outcomes. Funding SourcesR01DK099175.