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Attention-deficit and hyperactivity disorder (ADHD) is a common childhood disorder with a substantial genetic component. However, the extent to which epigenetic mechanisms play a role in the etiology of the disorder is unknown. We performed epigenome-wide association studies (EWAS) within the Pregnancy And Childhood Epigenetics (PACE) Consortium to identify DNA methylation sites associated with ADHD symptoms at two methylation assessment periods: birth and school age. We examined associations of both DNA methylation in cord blood with repeatedly assessed ADHD symptoms (age 4–15 years) in 2477 children from 5 cohorts and of DNA methylation at school age with concurrent ADHD symptoms (age 7–11 years) in 2374 children from 9 cohorts, with 3 cohorts participating at both timepoints. CpGs identified with nominal significance ( p  < 0.05) in either of the EWAS were correlated between timepoints ( ρ  = 0.30), suggesting overlap in associations; however, top signals were very different. At birth, we identified nine CpGs that predicted later ADHD symptoms ( p  < 1 × 10 –7 ), including ERC2 and CREB5 . Peripheral blood DNA methylation at one of these CpGs (cg01271805 in the promoter region of ERC2 , which regulates neurotransmitter release) was previously associated with brain methylation. Another (cg25520701) lies within the gene body of CREB5 , which previously was associated with neurite outgrowth and an ADHD diagnosis. In contrast, at school age, no CpGs were associated with ADHD with p  < 1 × 10 −7 . In conclusion, we found evidence in this study that DNA methylation at birth is associated with ADHD. Future studies are needed to confirm the utility of methylation variation as biomarker and its involvement in causal pathways.

Depression and obesity represent two of the most common complications during pregnancy and are associated with severe health risks for both the mother and the child. Although several studies have analysed the individual effects of depression or obesity on the mothers and their children, the effects associated with the co-occurrence of both disorders have so far been poorly investigated. The relationship between depression and obesity is very complex and it is still unclear whether maternal depression leads to obesity or vice versa. It is well known that the intrauterine environment plays an important role in mediating the effects of both depression and obesity in the mother on the fetal programming, increasing the child’s risk to develop negative outcomes.

Early life stress (ELS) may increase the risk of anxiety throughout the life course. Whether this effect extends to late adulthood is poorly known. In our study comprising 1872 participants from the Helsinki Birth Cohort Study born in 1934–1944, we investigated the association of various forms of ELS and their accumulation with self-reported anxiety symptoms at the age of 65–77 years. Data on childhood socioeconomic status and separation from parents were based on national registers for all participants. Information on self-reported emotional and physical trauma, parental divorce, and death of a family member in childhood was obtained from 1277 participants. We found that experiencing emotional trauma, physical trauma, and low socioeconomic status in childhood were associated with increased anxiety symptoms in late adulthood [B = 0.44 (95% CI = 0.31–0.58); B = 0.33 (95% CI = 0.20–0.46); B = 0.10 (95% CI = 0.01–0.19), respectively]. These associations remained significant even after controlling for other forms of ELS. Accumulation of early life stress also increased the levels of late-adulthood anxiety symptoms and the risk of anxiety regarded as clinically significant. Screening for potentially stressful childhood experiences in elderly populations may help identifying individuals with increased anxiety symptoms and planning preventive and therapeutic interventions for those exposed to ELS.

Aims/hypothesisMaternal obesity in pregnancy is associated with cardiovascular disease and mortality rate in the offspring. We aimed to determine whether maternal obesity is also associated with increased incidence of type 2 and type 1 diabetes in the offspring, independently of maternal diabetes as a candidate mechanistic pathway.MethodsBirth records of 118,201 children from 1950 to 2011 in the Aberdeen Maternity and Neonatal Databank were linked to Scottish Care Information–Diabetes, the national register for diagnosed diabetes in Scotland, to identify incident and prevalent type 1 and type 2 diabetes up to 1 January 2012. Maternal BMI was calculated from height and weight measured at the first antenatal visit. The effect of maternal obesity on offspring outcomes was tested using time-to-event analysis with Cox proportional hazards regression to compare outcomes in offspring of mothers in underweight, overweight or obese categories of BMI, compared with offspring of women with normal BMI.ResultsOffspring of obese (BMI ≥30 kg/m2) and overweight (BMI 25–29.9 kg/m2) mothers had an increased hazard of type 2 diabetes compared with mothers with normal BMI, after adjustment for gestation when weight was measured, maternal history of diabetes before pregnancy, maternal history of hypertension, age at delivery, parity, socioeconomic status, and sex of the offspring: HR 3.48 (95% CI 2.33, 5.06) and HR 1.39 (1.06, 1.83), respectively.Conclusions/interpretationMaternal obesity is associated with increased incidence of type 2 diabetes in the offspring. Evidence-based strategies that reduce obesity among women of reproductive age and that might reduce the incidence of diabetes in their offspring are urgently required.

Importance Corticosteroids administered to women at risk of imminent preterm birth is one of the most effective ways to improve the prognosis of infants born preterm. Scant data about long-term neurodevelopmental and neurosensory outcomes among the treatment-exposed children are mixed, suggesting that not all domains of neurodevelopmental and neurosensory function may be equally affected. Moreover, the long-term outcomes may vary according to whether the treatment-exposed children are being born preterm (<37 weeks and 0 days) or term (≥37 weeks and 0 days). Objectives To study whether antenatal corticosteroid treatment is associated with psychological developmental and neurosensory disorders in children born term and preterm and whether the associations persist in a sibling-comparison design. Design, Setting, and Participants This population-based retrospective register-linkage study comprised all singleton live births in Finland between January 1, 2006, and December 31, 2017, followed up until December 31, 2018, as well as a sibling comparison among term sibling pairs. Data were analyzed from March 21, 2021, to July 7, 2022. Exposures Antenatal corticosteroid treatment. Main Outcomes and Measures Cox proportional hazards regression models were used to estimate the associations between antenatal corticosteroid treatment and physician-diagnosed specific developmental disorders of speech and language, scholastic skills, and motor function; pervasive developmental disorder; other or unspecified psychological developmental disorder; disorders of vison and hearing; epilepsy; and cerebral palsy. Results The study population comprised 670 097 singleton children (342 562 boys [51.1%]) followed up for a median of 5.8 years (IQR, 3.1-8.7 years). Of the 14 868 treatment-exposed children (2.2%; 53.9% boys), 6730 (45.3%) were born term, and 8138 (54.7%) were born preterm, and of the 655 229 nonexposed children (97.8%; 51.1% boys), 634 757 (96.9%) were born term, and 20 472 (3.1%) were born preterm. Of the 241 621 eligible maternal sibling pairs born term, 4128 (1.7%) were discordant for treatment exposure. Compared with nonexposure in the entire population, treatment exposure was significantly associated with higher adjusted hazard ratios (aHRs) for specific developmental disorders of speech and language (aHR, 1.38 [95% CI, 1.27-1.50];P < .001), specific developmental disorders of scholastic skills (aHR, 1.32 [95% CI, 1.13-1.54];P = .004), specific developmental disorder of motor function (aHR, 1.32 [95% CI, 1.18-1.49];P < .001), pervasive developmental disorder (aHR, 1.35 [95% CI, 1.17-1.56];P < .001), other or unspecified disorder of psychological development (aHR, 1.88 [95% CI, 1.58-2.25];P < .001), and vision or hearing loss (aHR, 1.22 [95% CI, 1.04-1.43];P = .02). Compared with nonexposure in the term-born group, treatment exposure was significantly associated with higher aHRs for specific developmental disorders of speech and language (aHR, 1.47 [95% CI, 1.31-1.66];P < .001), specific developmental disorders of scholastic skills (aHR, 1.28 [95% CI, 1.01-1.63];P = .04), specific developmental disorder of motor function (aHR, 1.38 [95% CI, 1.12-1.70];P < .001), pervasive developmental disorder (aHR, 1.42 [95% CI, 1.16-1.75];P < .001), other or unspecified disorder of psychological development (aHR, 1.92 [95% CI, 1.51-2.43];P < .001), epilepsy (aHR, 1.57 [95% CI, 1.22-2.01];P < .001), and cerebral palsy (aHR, 2.18 [95% CI, 1.47-3.23];P < .001). The hazard for any psychological developmental and neurosensory disorder was significantly higher for the treatment-exposed sibling compared with the nonexposed cosibling (absolute difference, 1.2% [95% CI, 0.03%-2.4%];P < .001; aHR, 1.22 [95% CI, 1.04-1.42];P = .01). Antenatal corticosteroids were not associated with either significant benefit or risk in the preterm group. Conclusions and Relevance This study suggests that the possible long-term psychological developmental and neurosensory harms warrant careful consideration of risks and benefits when deciding on maternal antenatal corticosteroid treatment.

Prenatal stress exposure is associated with risk for psychiatric disorders later in life. This may be mediated in part via enhanced exposure to glucocorticoids (GCs), which are known to impact neurogenesis. We aimed to identify molecular mediators of these effects, focusing on long-lasting epigenetic changes. In a human hippocampal progenitor cell (HPC) line, we assessed the short- and long-term effects of GC exposure during neurogenesis on messenger RNA (mRNA) expression and DNA methylation (DNAm) profiles. GC exposure induced changes in DNAm at 27,812 CpG dinucleotides and in the expression of 3,857 transcripts (false discovery rate [FDR] ≤ 0.1 and absolute fold change [FC] expression ≥ 1.15). HPC expression and GC-affected DNAm profiles were enriched for changes observed during human fetal brain development. Differentially methylated sites (DMSs) with GC exposure clustered into 4 trajectories over HPC differentiation, with transient as well as long-lasting DNAm changes. Lasting DMSs mapped to distinct functional pathways and were selectively enriched for poised and bivalent enhancer marks. Lasting DMSs had little correlation with lasting expression changes but were associated with a significantly enhanced transcriptional response to a second acute GC challenge. A significant subset of lasting DMSs was also responsive to an acute GC challenge in peripheral blood. These tissue-overlapping DMSs were used to compute a polyepigenetic score that predicted exposure to conditions associated with altered prenatal GCs in newborn’s cord blood DNA. Overall, our data suggest that early exposure to GCs can change the set point of future transcriptional responses to stress by inducing lasting DNAm changes. Such altered set points may relate to differential vulnerability to stress exposure later in life.

Maternal obesity in pregnancy predicts offspring psychopathology risk in childhood but it remains unclear whether maternal obesity or underweight associate with adult offspring mental disorders. We examined longitudinally whether maternal body mass index (BMI) in pregnancy predicted mental disorders in her offspring and whether the associations differed by offspring birth year among 68,571 mother–child dyads of Aberdeen Maternity and Neonatal Databank, Scotland. The offspring were born 1950–1999. Maternal BMI was measured at a mean 15.7 gestational weeks and classified into underweight, normal weight, overweight, moderate obesity and severe obesity. Mental disorders were identified from nationwide registers carrying diagnoses of all hospitalizations and deaths in Scotland in 1996–2017. We found that maternal BMI in pregnancy was associated with offspring mental disorders in a time-dependent manner: In offspring born 1950–1974, maternal underweight predicted an increased hazard of mental disorders [Hazard Ratio (HR) = 1.74; 95% Confidence Interval (CI) = 1.01–3.00)]. In offspring born 1975–1999, maternal severe obesity predicted increased hazards of any mental (HR 1.60; 95% CI 1.08–2.38) substance use (HR 1.91; 95% CI 1.03–3.57) and schizophrenia spectrum (HR 2.80; 95% CI 1.40–5.63) disorders. Our findings of time-specific associations between maternal prenatal BMI and adult offspring mental disorders may carry important public health implications by underlining possible lifelong effects of maternal BMI on offspring psychopathology.

Recent research in economics emphasizes the role of in utero conditions for the health endowment at birth and in early childhood and for social as well as economic outcomes in later life. This paper analyzes the relation between maternal mental health during pregnancy and birth outcomes of the child. In particular, we analyze the relationship between maternal mental health during pregnancy and the probability of giving birth preterm (PT), having a newborn at low birth weight (LBW) or being small for gestational age (SGA). Based on large population-representative data from the German Socio-Economic Panel (SOEP) and cohort data from the National Educational Panel Study (NEPS), we present extensive descriptive evidence on the relationship between maternal mental health and preterm birth by carrying out OLS estimates controlling for a wide range of socioeconomic characteristics. In addition, we apply matching estimators and mother fixed effects models, which bring us closer toward a causal interpretation of estimates. In summary, the results uniformly provide evidence that poor maternal mental health is a risk factor for preterm birth and low birth weight in offspring. In contrast, we find no evidence for an relationship between maternal mental health and small for gestational age at birth.

Maternal depressive symptoms during pregnancy have been associated with child behavioural symptoms of attention-deficit/hyperactivity disorder (ADHD) in early childhood. However, it remains unclear if depressive symptoms throughout pregnancy are more harmful to the child than depressive symptoms only during certain times, and if maternal depressive symptoms after pregnancy add to or mediate any prenatal effects. 1,779 mother-child dyads participated in the Prediction and Prevention of Pre-eclampsia and Intrauterine Growth Restriction (PREDO) study. Mothers filled in the Center of Epidemiological Studies Depression Scale biweekly from 12+0-13+6 to 38+0-39+6 weeks+days of gestation or delivery, and the Beck Depression Inventory-II and the Conners' Hyperactivity Index at the child's age of 3 to 6 years (mean 3.8 years, standard deviation [SD] 0.5). Maternal depressive symptoms were highly stable throughout pregnancy, and children of mothers with consistently high depressive symptoms showed higher average levels (mean difference = 0.46 SD units, 95% Confidence Interval [CI] 0.36, 0.56, p < 0.001 compared to the low group), and proportion (32.1% vs. 14.7%) and odds (odds ratio = 2.80, 95% CI 2.20, 3.57, p < 0.001) of clinically significant ADHD symptoms. These associations were not explained by the effects of maternal depressive symptoms after pregnancy, which both added to and partially mediated the prenatal effects. Maternal depressive symptoms throughout pregnancy are associated with increased ADHD symptomatology in young children. Maternal depressive symptoms after pregnancy add to, but only partially mediate, the prenatal effects. Preventive interventions suited for the pregnancy period may benefit both maternal and offspring mental health.

Background Gestational age is often used as a proxy for developmental maturity by clinicians and researchers alike. DNA methylation has previously been shown to be associated with age and has been used to accurately estimate chronological age in children and adults. In the current study, we examine whether DNA methylation in cord blood can be used to estimate gestational age at birth. Results We find that gestational age can be accurately estimated from DNA methylation of neonatal cord blood and blood spot samples. We calculate a DNA methylation gestational age using 148 CpG sites selected through elastic net regression in six training datasets. We evaluate predictive accuracy in nine testing datasets and find that the accuracy of the DNA methylation gestational age is consistent with that of gestational age estimates based on established methods, such as ultrasound. We also find that an increased DNA methylation gestational age relative to clinical gestational age is associated with birthweight independent of gestational age, sex, and ancestry. Conclusions DNA methylation can be used to accurately estimate gestational age at or near birth and may provide additional information relevant to developmental stage. Further studies of this predictor are warranted to determine its utility in clinical settings and for research purposes. When clinical estimates are available this measure may increase accuracy in the testing of hypotheses related to developmental age and other early life circumstances.