Sex differences in DNA methylation across gestation: a large scale, cross-cohort, multi-tissue analysis.

Biological sex is a key variable influencing many physiological systems. Disease prevalence as well as treatment success can be modified by sex. Differences emerge already early in life and include pregnancy complications and adverse birth outcomes. The placenta is a critical organ for fetal development and shows sex-based differences in the expression of hormones and cytokines. Epigenetic regulation, such as DNA methylation (DNAm), may underlie the previously reported placental sexual dimorphism. We associated placental DNAm with fetal sex in three cohorts. Individual cohort results were meta-analyzed with random-effects modelling. CpG-sites differentially methylated with sex were further investigated regarding pathway enrichment, overlap with methylation quantitative trait loci (meQTLs), and hits from phenome-wide association studies (PheWAS). We evaluated the consistency of findings across tissues (CVS, i.e. chorionic villus sampling from early placenta, and cord blood) as well as with gene expression. We identified 10,320 epigenome-wide significant sex-differentially methylated probes (DMPs) spread throughout the epigenome of the placenta at birth. Most DMPs presented with lower DNAm levels in females. DMPs mapped to genes upregulated in brain, were enriched for neurodevelopmental pathways and significantly overlapped with meQTLs and PheWAS hits. Effect sizes were moderately correlated between CVS and placenta at birth, but only weakly correlated between birth placenta and cord blood. Sex differential gene expression in birth placenta was less pronounced and implicated genetic regions only marginally overlapped with those associated with differential DNAm. Our study provides an integrative perspective on sex-differential DNAm in perinatal tissues underscoring the possible link between placenta and brain.

Associations of polymetabolic risk of high maternal pre-pregnancy body mass index with pregnancy complications, birth outcomes, and early childhood neurodevelopment: findings from two pregnancy cohorts.

BACKGROUND: A substantial proportion of maternal pregnancy complications, adverse birth outcomes and neurodevelopmental delay in children may be attributable to high maternal pre-pregnancy Body Mass Index (BMI). However, BMI alone is insufficient for the identification of all at-risk mothers and children as many women with non-obesity(< 30 kg/m2) or normal weight(18.5-24.99 kg/m2) and their children may suffer from adversities. Evidence suggests that BMI-related metabolic changes during pregnancy may predict adverse mother-child outcomes better than maternal anthropometric BMI. METHODS: In a cohort of 425 mother-child dyads, we identified maternal BMI-defined metabolome based on associations of 95 metabolic measures measured three times during pregnancy with maternal pre-pregnancy BMI. We then examined whether maternal BMI-defined metabolome performed better than anthropometric BMI in predicting gestational diabetes, hypertensive disorders, gestational weight gain (GWG), Caesarian section delivery, child gestational age and weight at birth, preterm birth, admission to neonatal intensive care unit (NICU), and childhood neurodevelopment. Based on metabolic measures with the highest contributions to BMI-defined metabolome, including inflammatory and glycolysis-related measures, fatty acids, fluid balance, ketone bodies, lipids and amino acids, we created a set of maternal high BMI-related polymetabolic risk scores (PMRSs), and in an independent replication cohort of 489 mother-child dyads tested their performance in predicting the same set of mother-child outcomes in comparison to anthropometric BMI. RESULTS: BMI-defined metabolome predicted all of the studied mother-child outcomes and improved their prediction over anthropometric BMI, except for gestational hypertension and GWG. BMI-related PMRSs predicted gestational diabetes, preeclampsia, Caesarian section delivery, admission to NICU, lower gestational age at birth, lower cognitive development score of the child, and improved their prediction over anthropometric BMI. BMI-related PMRSs predicted gestational diabetes, preeclampsia, Caesarean section delivery, NICU admission and child's lower gestational age at birth even at the levels of maternal non-obesity and normal weight. CONCLUSIONS: Maternal BMI-defined metabolome improves the prediction of pregnancy complications, birth outcomes, and neurodevelopment in children over anthropometric BMI. The novel, BMI-related PMRSs generated based on the BMI-defined metabolome have the potential to become biomarkers identifying at-risk mothers and their children for timely targeted interventions even at the level of maternal non-obesity and normal weight.

Maternal social support during and after pregnancy and child cognitive ability: examining timing effects in two cohorts.

BACKGROUND: Maternal anxiety, depression, and stress during and after pregnancy are negatively associated with child cognitive development. However, the contribution of positive maternal experiences, such as social support, to child cognitive development has received less attention. Furthermore, how maternal experience of social support during specific developmental periods impacts child cognitive development is largely unknown. METHODS: Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC; n = 5784) and the Prediction and Prevention of Preeclampsia and Intrauterine Growth Restriction study (PREDO; n = 420), we investigated the associations between maternal perceived social support during and after pregnancy and child's general cognitive ability at 8 years of age, assessed with the Wechsler Intelligence Scale for Children (WISC). Bayesian relevant life course modeling was used to investigate timing effects of maternal social support on child cognitive ability. RESULTS: In both cohorts, higher maternal perceived social support during pregnancy was associated with higher performance on the WISC, independent of sociodemographic factors and concurrent maternal symptoms of depression and anxiety. In ALSPAC, pregnancy emerged as a sensitive period for the effects of perceived social support on child cognitive ability, with a stronger effect of social support during pregnancy than after pregnancy on child cognitive ability. CONCLUSIONS: Our findings, supported from two prospective longitudinal cohorts, suggest a distinct role of maternal perceived social support during pregnancy for cognitive development in children. Our study suggests that interventions aimed at increasing maternal social support during pregnancy may be an important strategy for promoting maternal and child well-being.

Maternal early-pregnancy body mass index-associated metabolomic component and mental and behavioral disorders in children.

Maternal pre-pregnancy obesity and/or higher body mass index (BMI) have been associated with neurodevelopmental and mental health adversities in children. While maternal metabolomic perturbations during pregnancy may underpin these associations, the existing evidence is limited to studying individual metabolites, not capturing metabolic variation specific to maternal BMI, and not accounting for the correlated nature of the metabolomic measures. By using multivariate supervised analytical methods, we first identified maternal early-pregnancy BMI-associated metabolomic component during pregnancy. We then examined whether this component was associated with mental and behavioral disorders in children, improved the prediction of the child outcomes over maternal BMI, and what proportion of the effect of maternal BMI on the child outcomes this component mediated. Early-pregnancy BMI of 425 mothers participating in the PREDO study was extracted from the national Medical Birth Register. During pregnancy, mothers donated up to three blood samples, from which a targeted panel of 68 metabolites were measured. Mental and behavioral disorders in children followed-up from birth until 8.4-12.8 years came from the Care Register for Health Care. Of the 68 metabolites averaged across the three sampling points, 43 associated significantly with maternal early-pregnancy BMI yielding a maternal early-pregnancy BMI-associated metabolomic component (total variance explained, 55.4%; predictive ability, 52.0%). This metabolomic component was significantly associated with higher hazard of any mental and behavioral disorder [HR 1.45, 95%CI(1.15, 1.84)] and relative risk of having a higher number of co-morbid disorders [RR 1.43, 95%CI(1.12, 1.69)] in children. It improved the goodness-of-model-fit over maternal BMI by 37.7-65.6%, and hence the predictive significance of the model, and mediated 60.8-75.8% of the effect of maternal BMI on the child outcomes. Maternal BMI-related metabolomic perturbations during pregnancy are associated with a higher risk of mental and behavioral disorders in children. These findings may allow identifying metabolomic targets for personalized interventions.

ADHD symptoms and diagnosis in adult preterms: systematic review, IPD meta-analysis, and register-linkage study.

BACKGROUND: This study examined differences in ADHD symptoms and diagnosis between preterm and term-born adults (≥18 years), and tested if ADHD is related to gestational age, birth weight, multiple births, or neonatal complications in preterm borns. METHODS: (1) A systematic review compared ADHD symptom self-reports and diagnosis between preterm and term-born adults published in PubMed, Web of Science, and PROQUEST until April 2021; (2) a one-stage Individual Participant Data(IPD) meta-analysis (n = 1385 preterm, n = 1633 term; born 1978-1995) examined differences in self-reported ADHD symptoms[age 18-36 years]; and (3) a population-based register-linkage study of all live births in Finland (01/01/1987-31/12/1998; n = 37538 preterm, n = 691,616 term) examined ADHD diagnosis risk in adulthood (≥18 years) until 31/12/2016. RESULTS: Systematic review results were conflicting. In the IPD meta-analysis, ADHD symptoms levels were similar across groups (mean z-score difference 0.00;95% confidence interval [95% CI] -0.07, 0.07). Whereas in the register-linkage study, adults born preterm had a higher relative risk (RR) for ADHD diagnosis compared to term controls (RR = 1.26, 95% CI 1.12, 1.41, p < 0.001). Among preterms, as gestation length (RR = 0.93, 95% CI 0.89, 0.97, p < 0.001) and SD birth weight z-score (RR = 0.88, 95% CI 0.80, 0.97, p < 0.001) increased, ADHD risk decreased. CONCLUSIONS: While preterm adults may not report higher levels of ADHD symptoms, their risk of ADHD diagnosis in adulthood is higher. IMPACT: Preterm-born adults do not self-report higher levels of ADHD symptoms, yet are more likely to receive an ADHD diagnosis in adulthood compared to term-borns. Previous evidence has consisted of limited sample sizes of adults and used different methods with inconsistent findings. This study assessed adult self-reported symptoms across 8 harmonized cohorts and contrasted the findings with diagnosed ADHD in a population-based register-linkage study. Preterm-born adults may not self-report increased ADHD symptoms. However, they have a higher risk of ADHD diagnosis, warranting preventive strategies and interventions to reduce the presentation of more severe ADHD symptomatology in adulthood.

Positive maternal mental health during pregnancy and mental and behavioral disorders in children: A prospective pregnancy cohort study.

BACKGROUND: The role of positive maternal mental health during pregnancy in child mental health remains largely unknown. We investigated whether positive maternal mental health during pregnancy is associated with lower hazards of mental and behavioral disorders in children and mitigates the adverse effects of negative maternal mental health. METHODS: Among 3,378 mother-child dyads of the Prediction and Prevention of Preeclampsia and Intrauterine Growth Restriction study, mothers reported their positive mental health biweekly throughout pregnancy with the Positive and Negative Affect Schedule, the Spielberger State Anxiety Inventory Curiosity scale, and a visual analogue scale for social support, and negative mental health with the Center for Epidemiologic Studies Depression Scale. We extracted data on their mental and behavioral disorder diagnoses from a nationwide medical register. This register provided data on their children's mental and behavioral disorder diagnoses as well, from birth until 8.4-12.8 (Median = 10.2, Interquartile Range 9.7-10.8) years of age. RESULTS: A positive maternal mental health composite score during pregnancy was associated with a lower hazard of any mental and behavioral disorder among all children [Hazard Ratio (HR) = 0.79, 95% Confidence Interval (CI) 0.71 - 0.87] and among children of mothers experiencing clinically relevant depressive symptoms during pregnancy [HR = 0.80, 95%CI 0.64 - 1.00] and/or mental and behavioral disorders before or during pregnancy [HR = 0.69, 95%CI 0.55-0.86]. These associations were independent of covariates. CONCLUSIONS: Children whose mothers had more positive mental health during pregnancy were less likely to develop mental and behavioral disorders. Protective effects were seen also among children of mothers facing mental health adversities before or during pregnancy.

Reliability of a novel approach for reference-based cell type estimation in human placental DNA methylation studies.

The placenta is a central organ during early development, influencing trajectories of health and disease. DNA methylation (DNAm) studies of human placenta improve our understanding of how its function relates to disease risk. However, DNAm studies can be biased by cell type heterogeneity, so it is essential to control for this in order to reduce confounding and increase precision. Computational cell type deconvolution approaches have proven to be very useful for this purpose. For human placenta, however, an assessment of the performance of these estimation methods is still lacking. Here, we examine the performance of a newly available reference-based cell type estimation approach and compare it to an often-used reference-free cell type estimation approach, namely RefFreeEWAS, in placental genome-wide DNAm samples taken at birth and from chorionic villus biopsies early in pregnancy using three independent studies comprising over 1000 samples. We found both reference-free and reference-based estimated cell type proportions to have predictive value for DNAm, however, reference-based cell type estimation outperformed reference-free estimation for the majority of data sets. Reference-based cell type estimations mirror previous histological knowledge on changes in cell type proportions through gestation. Further, CpGs whose variation in DNAm was largely explained by reference-based estimated cell type proportions were in the proximity of genes that are highly tissue-specific for placenta. This was not the case for reference-free estimated cell type proportions. We provide a list of these CpGs as a resource to help researchers to interpret results of existing studies and improve future DNAm studies of human placenta.

Positive maternal mental health during pregnancy and psychiatric problems in children from early childhood to late childhood.

Negative maternal mental health during pregnancy increases the risk of psychiatric problems in children, but research on the potential benefits of positive maternal mental health during pregnancy is scarce. We investigated associations between positive maternal mental health composite score, based on reports of maternal positive affect, curiosity, and social support during pregnancy, and children's psychiatric problems (Child Behavior Checklist) at ages 1.9-5.9 and 7.1-12.1 years among 2636 mother-child dyads of the Prediction and Prevention of Preeclampsia and Intrauterine Growth Restriction study. For each standard deviation higher positive maternal mental health score during pregnancy, total psychiatric problems were 1.37 (95% confidence interval (CI) -1.79,-0.95) t-scores lower in early childhood and 1.75 (95% CI -2.24,-1.26) t-scores lower in late childhood. These associations were independent of covariates and of negative maternal mental health. Total psychiatric problems remained stably lower from early childhood to late childhood in children of mothers with higher positive mental health during pregnancy, whereas they increased in children of mothers with lower positive mental health. Positive maternal mental health in child's late childhood partially mediated the effects of positive maternal mental health during pregnancy on children's psychiatric problems. Supporting positive maternal mental health may benefit mothers and children.

Prenatal maternal and cord blood vitamin D concentrations and negative affectivity in infancy.

Higher maternal vitamin D concentration during pregnancy is associated with better child mental health. Negative affectivity, an early-emerging temperamental trait, indicates an increased risk of psychopathology. We investigated if maternal early/mid-pregnancy 25-hydroxyvitamin D (25(OH)D) and neonatal cord blood 25(OH)D concentrations are associated with Negative affectivity in infancy. We studied term-born infants from the vitamin D Intervention in Infants study (VIDI, n = 777, follow-up rate 80%, Finland), and the Generation R Study (n = 1505, follow-up rate 40%, Netherlands). We measured maternal serum 25(OH)D at 6-27 weeks (VIDI) or 18-25 weeks (Generation R) of pregnancy, and cord blood 25(OH)D at birth (both cohorts). Caregivers rated infant Negative affectivity at 11.7 months (VIDI) or 6.5 months (Generation R) using the Revised Infant Behavior Questionnaire. Using linear regression, we tested associations between 25(OH)D and Negative affectivity adjusted for infant age, sex, season of 25(OH)D measurement, maternal age, education, smoking, and body-mass-index. Per 10 nmol/l increase in maternal early/mid-pregnancy 25(OH)D, infant Negative affectivity decreased by 0.02 standard deviations (95% confidence interval [CI] - 0.06, - 0.004) in VIDI, and 0.03 standard deviations (95% CI - 0.03, - 0.01) in Generation R. Cord blood 25(OH)D was associated with Negative affectivity in Generation R (- 0.03, 95% CI - 0.05, - 0.01), but not VIDI (0.00, 95% CI - 0.02, 0.02). Lower maternal 25(OH)D concentrations were consistently associated with higher infant Negative affectivity, while associations between cord blood 25(OH)D concentrations and Negative affectivity were less clear. Maternal vitamin D status during early- and mid-pregnancy may be linked with early-emerging differences in offspring behavior.

Maternal exposure to childhood maltreatment and mental and behavioral disorders in children.

Exposure to maltreatment in childhood is associated with lifelong risk of mental and behavioral disorders. Whether the effects extend to the next generation remains unclear. We examined whether maternal exposure to childhood abuse and neglect in her own childhood were associated with mental and behavioral disorders and psychiatric symptoms in her children, and whether maternal lifetime mental and behavioral disorders or lower education level mediated or added to the effects. Mothers (n = 2252) of the Prediction and Prevention of Preeclampsia and Intrauterine Growth Restriction cohort study completed the Childhood Trauma Questionnaire and reported on their education and their 7.0-12.1-year-old children's psychiatric symptoms using the Strengths and Difficulties Questionnaire. We identified lifetime mental and behavioral disorder diagnoses for the mothers and diagnoses for their children from birth (2006-2010) until 8.4-12.8 years (12/31/2018) from Care Register for Health Care. We found that maternal exposure to childhood abuse, but not neglect, was associated with higher hazards of mental and behavioral disorders (hazard ratio 1.20, 95% confidence interval 1.06-1.37) in children. These associations were partially mediated by maternal mental and behavioral disorders and education (proportion of effect size mediated: 23.8% and 15.1%, respectively), which together with maternal exposure to childhood abuse added to the hazard of mental and behavioral disorders in children. Similar associations were found for maternal exposure to childhood abuse and neglect with psychiatric symptoms in children. To conclude, maternal exposure to childhood maltreatment is associated with mental and behavioral disorders and psychiatric symptoms in children. Our findings call for interventions to prevent intergenerational transmission.

Genome-Wide Copy Number Variant and High-Throughput Transcriptomics Analyses of Placental Tissues Underscore Persisting Child Susceptibility in At-Risk Pregnancies Cleared in Standard Genetic Testing.

Several studies have shown that children from pregnancies with estimated first-trimester risk based on fetal nuchal translucency thickness and abnormal maternal serum pregnancy protein and hormone levels maintain a higher likelihood of adverse outcomes, even if initial testing for known genetic conditions is negative. We used the Finnish InTraUterine cohort (ITU), which is a comprehensively characterized perinatal cohort consisting of 943 mothers and their babies followed throughout pregnancy and 18 months postnatally, including mothers shortlisted for prenatal genetic testing but cleared for major aneuploidies (cases: n = 544, 57.7%) and control pregnancies (n = 399, 42.3%). Using genome-wide genotyping and RNA sequencing of first-trimester and term placental tissue, combined with medical information from registry data and maternal self-report data, we investigated potential negative medical outcomes and genetic susceptibility to disease and their correlates in placenta gene expression. Case mothers did not present with higher levels of depression, perceived stress, or anxiety during pregnancy. Case children were significantly diagnosed more often with congenital malformations of the circulatory system (4.12 (95% CI [1.22−13.93]) higher hazard) and presented with significantly more copy number duplications as compared to controls (burden analysis, based on all copy number variants (CNVs) with at most 10% frequency, 823 called duplications in 297 cases versus 626 called duplications in 277 controls, p = 0.01). Fifteen genes showed differential gene expression (FDR < 0.1) in association with congenital malformations in first-trimester but not term placenta. These were significantly enriched for genes associated with placental dysfunction. In spite of normal routine follow-up prenatal testing results in early pregnancy, case children presented with an increased likelihood of negative outcomes, which should prompt vigilance in follow-up during pregnancy and after birth.

Maternal Hypertensive Pregnancy Disorders and Mental and Behavioral Disorders in the Offspring: a Review.

PURPOSE OF REVIEW: We review here recent original research and meta-analytic evidence on the associations of maternal hypertensive pregnancy disorders and mental and behavioral disorders in the offspring. RECENT FINDINGS: Seven meta-analyses and 11 of 16 original research studies published since 2015 showed significant associations between maternal hypertensive pregnancy disorders and offspring mental and behavioral disorders. Evidence was most consistent in meta-analyses and high-quality cohort studies. The associations, independent of familial confounding, were observed on different mental and behavioral disorders in childhood and schizophrenia in adulthood. Preterm birth and small-for-gestational age birth emerged as possible moderators and mediators of the associations. Cross-sectional and case-control studies yielded inconsistent findings, but had lower methodological quality. Accumulating evidence from methodologically sound studies shows that maternal hypertensive pregnancy disorders are associated with an increased risk of mental and behavioral disorders in the offspring in childhood. More studies on adult mental disorders are needed.

Maternal depression and inflammation during pregnancy.

BACKGROUND: Maternal depression during pregnancy increases the risk for adverse developmental outcomes in children. However, the underpinning biological mechanisms remain unknown. We tested whether depression was associated with levels of and change in the inflammatory state during pregnancy, if early pregnancy overweight/obesity or diabetes/hypertensive pregnancy disorders accounted for/mediated these effects, and if depression added to the inflammation that typically accompanies these conditions. METHODS: We analyzed plasma high-sensitivity C-reactive protein (hsCRP) and glycoprotein acetyls at three consecutive stages during pregnancy, derived history of depression diagnoses before pregnancy from Care Register for Healthcare (HILMO) (N = 375) and self-reports (N = 347) and depressive symptoms during pregnancy using the Center for Epidemiological Studies Depression Scale completed concurrently to blood samplings (N = 295). Data on early pregnancy body mass index (BMI) and diabetes/hypertensive pregnancy disorders came from medical records. RESULTS: Higher overall hsCRP levels, but not change, during pregnancy were predicted by history of depression diagnosis before pregnancy [HILMO: mean difference (MD) = 0.69 standard deviation (s.d.) units; 95% confidence interval (CI) 0.26-1.11, self-report: MD = 0.56 s.d.; 95% CI 0.17-0.94] and higher depressive symptoms during pregnancy (0.06 s.d. per s.d. increase; 95% CI 0.00-0.13). History of depression diagnosis before pregnancy also predicted higher overall glycoprotein acetyls (HILMO: MD = 0.52 s.d.; 95% CI 0.12-0.93). These associations were not explained by diabetes/hypertensive disorders, but were accounted for and mediated by early pregnancy BMI. Furthermore, in obese women, overall hsCRP levels increased as depressive symptoms during pregnancy increased (p = 0.006 for interaction). CONCLUSIONS: Depression is associated with a proinflammatory state during pregnancy. These associations are mediated by early pregnancy BMI, and depressive symptoms during pregnancy aggravate the inflammation related to obesity.

Associations of antenatal glucocorticoid exposure with mental health in children.

BACKGROUND: Synthetic glucocorticoids, to enhance fetal maturation, are a standard treatment when preterm birth before 34 gestational weeks is imminent. While morbidity- and mortality-related benefits may outweigh potential neurodevelopmental harms in children born preterm (<37 gestational weeks), this may not hold true when pregnancy continues to term (⩾37 gestational weeks). We studied the association of antenatal betamethasone exposure on child mental health in preterm and term children. METHODS: We included 4708 women and their children, born 2006-2010, from the Prediction and Prevention of Pre-eclampsia and Intrauterine Growth Restriction Study with information on both antenatal betamethasone treatment and child mental and behavioral disorders from the Finnish Hospital Discharge Register from the child's birth to 31 December 2016. Additional follow-up data on mother-reported psychiatric problems and developmental milestones were available for 2640 children at 3.5 (s.d. = 0.07) years-of-age. RESULTS: Of the children, 187 were born preterm (61 betamethasone-exposed) and 4521 at term (56 betamethasone-exposed). The prevalence of any mental and behavioral, psychological development, emotional and behavioral, and comorbid disorders was higher in the betamethasone-exposed, compared to non-exposed children [odds ratio 2.76 (95% confidence interval 1.76-4.32), 3.61 (2.19-5.95), 3.29 (1.86-5.82), and 6.04 (3.25-11.27), respectively]. Levels of psychiatric problems and prevalence of failure to meet the age-appropriate development in personal-social skills were also higher in mother-reports of betamethasone-exposed children. These associations did not vary significantly between preterm and term children. CONCLUSIONS: Antenatal betamethasone exposure may be associated with mental health problems in children born preterm and in those who end up being born at term.

Polygenic prediction of the risk of perinatal depressive symptoms.

BACKGROUND: Perinatal depression carries adverse effects on maternal health and child development, but genetic underpinnings remain unclear. We investigated the polygenic risk of perinatal depressive symptoms. METHODS: About 742 women from the prospective Prediction and Prevention of Pre-eclampsia and Intrauterine Growth Restriction cohort were genotyped and completed the Center for Epidemiologic Studies Depression scale 14 times during the prenatal period and twice up to 12 months postpartum. Polygenic risk scores for major depressive disorder, bipolar disorder, schizophrenia, and cross-disorder were calculated using multiple p-value thresholds. RESULTS: Polygenic risk scores for major depressive disorder, schizophrenia, and cross-disorder, but not bipolar disorder, were associated with higher prenatal and postpartum depressive symptoms (0.8%-1% increase per one standard deviation increase in polygenic risk scores). Prenatal depressive symptoms accounted for and mediated the associations between the polygenic risk scores and postpartum depressive symptoms (effect size proportions-mediated: 52.2%-88.0%). Further, the polygenic risk scores were associated with 1.24-1.45-fold odds to belong to the group displaying consistently high compared with consistently low depressive symptoms through out the prenatal and postpartum periods. CONCLUSIONS: Polygenic risk scores for major depressive disorder, schizophrenia, and cross-disorder in non-perinatal populations generalize to perinatal depressive symptoms and may afford to identify women for timely preventive interventions.

Consequences of being overweight or obese during pregnancy on diabetes in the offspring: a record linkage study in Aberdeen, Scotland.

AIMS/HYPOTHESIS: Maternal 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. METHODS: Birth 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. RESULTS: Offspring 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/INTERPRETATION: Maternal 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.

Fetal programming of neuropsychiatric disorders by maternal pregnancy depression: a systematic mini review.

BACKGROUND: Maternal depression complicates a large proportion of pregnancies. Current evidence shows numerous harmful effects on the offspring. Reviews, which include depression, concluded that stress has harmful effects on the offspring's outcomes neuro-cognitive development, temperament traits, and mental disorders. OBJECTIVE: This mini review of recent studies, sought to narrow the scope of exposure and identify studies specifically assessing prenatal depression and offspring neuropsychiatric outcomes. STUDY ELIGIBILITY CRITERIA: The review included longitudinal, cohort, cross-sectional, clinical, quasi-experimental, epidemiological, or intervention study designs published in English from 2014 to 2018. PARTICIPANTS: Study populations included mother-child dyads, mother-father-child triads, mother-alternative caregiver-child triads, and family studies utilizing sibling comparisons. METHODS: We searched PubMED and Web of Science. Study inclusion and data extraction were based on standardized templates. The quality of evidence was assessed using the Newcastle-Ottawa Scale (NOS). RESULTS: Thirteen studies examining neuropsychiatric outcomes were included. We judged the evidence to be moderate to high quality. CONCLUSIONS: Our review supports that maternal prenatal depression is associated with neuropsychiatric adversities in children. IMPLICATIONS: Future investigations should unravel the biological underpinnings and target timely interventions as early in pregnancy as possible to prevent offspring neuropsychiatric harms.

Schizotypal traits are associated with sleep spindles and rapid eye movement in adolescence.

Research suggests an association between schizophrenia and a decrease in sleep spindle activity, as well as a change in sleep architecture. It is unknown how the continuum of psychotic symptoms relates to different features in the sleep electroencephalogram. We set out to examine how sleep architecture and stage 2 spindle activity are associated with schizotypy in a healthy adolescent population. The participants in our study (n = 176, 61% girls) came from a community-based cohort. Schizotypal traits were evaluated using the Schizotypal Personality Scale (STA) in early adolescence (mean age 12.3 years, SD = 0.5) and the participants underwent ambulatory overnight polysomnography at mean age 16.9 years (SD = 0.1). Sleep was scored in 30-s epochs into stages 1, 2, 3 and rapid eye movement (REM) sleep. Stage 2 spindles were detected using an automated algorithm. Spindle analyses from central and frontal derivations included spindle duration and density for slow (10-13 Hz) and fast (13-16 Hz) ranges. Covariates included sex and age. Those with the highest STA scores had a higher percentage of REM (B = 2.07 [95% CI, 0.17, 4.0]; p = .03) than those with the lowest scores. Those with the highest scores had shorter spindle duration, as derived from the frontal regions, and a slower oscillation range (B = -0.04 [95% CI, -0.07, -0.01]; p = .023) than those with the lowest scores. We conclude that high levels of schizotypy characteristics measured in early adolescence may be associated with distinguished features of sleep architecture, namely with spindle morphology and a higher proportion of REM sleep.

Genetic risk factors for schizophrenia associate with sleep spindle activity in healthy adolescents.

Schizophrenia has been associated with disturbed sleep, even before the onset of the disorder, and also in non-schizophrenic first-order relatives. This may point to an underlying genetic influence. Here we examine whether weighted polygenic risk scores (PRS) for schizophrenia are associated with sleep spindle activity in healthy adolescents. Our sample comes from a community-based cohort of 157 non-schizophrenic adolescents (57% girls) having both genetic data and an overnight sleep EEG measurement available. Based on a recent genome-wide association study, we calculated PRS for schizophrenia across the whole genome. We also calculated PRS for the CACNA1l gene region, which has been associated with both schizophrenia and sleep spindle formation. We performed an overnight sleep EEG at the homes of the participants. Stage two sleep spindles were detected using an automated algorithm. Sleep spindle amplitude, duration, intensity and density were measured separately for central and frontal derivations and for fast (13-16 Hz) and slow (10-13 Hz) spindles. PRS for schizophrenia was associated with higher fast spindle amplitude (p = 0.04), density (p = 0.006) and intensity (p = 0.04) at the central derivation, and PRS in the CACNA1l region associated with higher slow spindle amplitude (p = 0.01), duration (p = 0.03) and intensity (p = 0.002) at the central derivation. A positive association between genetic variants for schizophrenia and sleep spindle activity among healthy adolescents supports a view that sleep spindles and schizophrenia share similar genetic pathways. This study suggests that altered sleep spindle activity might serve as an endophenotype of schizophrenia.

Infant regulatory behavior problems during first month of life and neurobehavioral outcomes in early childhood.

Whether infant regulatory behavior problems already in the first month of life indicate an increased risk of childhood neurobehavioral problems, and whether maternal depression in the postpartum and early childhood underpins these associations remain unclear. Altogether, 2049-2364 mothers from the Prediction and Prevention of Pre-eclampsia and Intrauterine Growth Restriction (PREDO) study completed the Neonatal Perception Inventory on regulatory behavior problems at the infant's age of 15.6 days (SD 3.2, range 1-30), the Infant Behavior Questionnaire-Revised on temperament at 6.5 months (SD 0.9, range 4.2-12.4), and the Ages and Stages Questionnaire-3 on developmental milestones and the Child Behavior Checklist on behavioral problems at 3.5 years (SD 0.7, range 1.9-6.0). Maternal depressive symptoms were measured by the Center for Epidemiological Studies Depression Scale (infancy follow-ups) and Beck Depression Inventory-II (childhood follow-up). Father-rated infant temperament and paternal depressive symptoms were also available (n = 1474). Higher levels of infant regulatory behavior problems predicted higher levels of mother- and father-rated negative affectivity temperament (0.13 SD units per SD unit, 95% confidence interval 0.09-0.17; and 0.09, 0.04-0.14, respectively), lower levels of mother-rated orienting/regulation temperament (- 0.09, - 0.13 to - 0.05) and problem-solving skills (- 0.12, - 0.21 to - 0.04), and higher levels of Externalizing (0.07, 0.03-0.11) and Total behavioral problems (0.07, 0.03-0.11). Regulatory behaviors partially mediated the effect of maternal depressive symptoms. Regulatory behavior problems already during the first month of life predict neurobehavioral outcomes, and partially mediate the effect of maternal depressive symptoms. Our study may inform design of interventions aimed at timely prevention in children at risk.