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The placenta, a pivotal player in the prenatal environment, holds crucial insights into early developmental pathways and future health outcomes. In this study, we explored genetic molecular regulation in chorionic villus samples (CVS) from the first trimester and placenta tissue at birth. We assessed quantitative trait locus (QTL) mapping on DNA methylation and gene expression data in a Finnish cohort of 574 individuals. We found more QTLs in birth placenta than in first-trimester placenta. Nevertheless, a substantial amount of associations overlapped in their effects and showed consistent direction in both tissues, with increasing molecular genetic effects from early pregnancy to birth placenta. The identified QTLs in birth placenta were most enriched in genes with placenta-specific expression. Conducting a phenome-wide-association study (PheWAS) on the associated SNPs, we observed numerous overlaps with genome-wide association study (GWAS) hits (spanning 57 distinct traits and 23 SNPs), with notable enrichments for immunological, skeletal, and respiratory traits. The QTL-SNP rs1737028 (chr6:29737993) presented with the highest number of GWAS hits. This SNP was related to HLA-G expression via DNA methylation and was associated with various immune, respiratory, and psychiatric traits. Our findings implicate increasing genetic molecular regulation during the course of pregnancy and support the involvement of placenta gene regulation, particularly in immunological traits. This study presents a framework for understanding placenta-specific gene regulation during pregnancy and its connection to health-related traits., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Children who have a parent with a psychotic disorder present an increased risk of developing psychosis. It is unclear to date, however, what proportion of all psychosis cases in the population are captured by a familial high-risk for psychosis (FHR-P) approach. This is essential information for prevention research and health service planning, as it tells us the total proportion of psychosis cases that this high-risk approach would prevent if an effective intervention were developed. Through a prospective cohort study including all individuals born in Finland between January 1, 1987 and December 31, 1992, we examined the absolute risk and total proportion of psychosis cases captured by FHR-P and by a transdiagnostic familial risk approach (TDFR-P) based on parental inpatient hospitalization for any mental disorder. Outcomes of non-affective psychosis (ICD-10: F20-F29) and schizophrenia (ICD-10: F20) were identified in the index children up to December 31, 2016. Of the index children (N=368,937), 1.5% (N=5,544) met FHR-P criteria and 10.3% (N=38,040) met TDFR-P criteria. By the study endpoint, 1.9% (N=6,966) of the index children had been diagnosed with non-affective psychosis and 0.5% (N=1,846) with schizophrenia. In terms of sensitivity, of all non-affective psychosis cases in the index children, 5.2% (N=355) were captured by FHR-P and 20.6% (N=1,413) by TDFR-P approaches. The absolute risk of non-affective psychosis was 6.4% in those with FHR-P, and 3.7% in those with TDFR-P. There was notable variation in the sensitivity and total proportion of FHR-P and TDFR-P cases captured based on the age at which FHR-P/TDFR-P were determined. The absolute risk for psychosis, however, was relatively time invariant. These metrics are essential to inform intervention strategies for psychosis risk requiring pragmatic decision-making., (© 2024 World Psychiatric Association.)

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.

Context: Maternal obesity, hypertensive pregnancy disorders, and gestational diabetes (GDM) are linked to an increased risk of negative offspring health outcomes. This association may be mediated by maternal hypothalamic-pituitary-adrenal axis (HPA axis) activity, resulting in elevated maternal cortisol levels and fetal exposure, but evidence remains scarce., Objective: We (1) examined maternal diurnal cortisol profiles longitudinally across gestation, and (2) explored associations with maternal cardiometabolic complications., Methods: Women in the InTraUterine sampling in early pregnancy (ITU) study (n = 667) provided 7 salivary cortisol samples from awakening to bedtime up to 3 times during pregnancy (median gestational week 19.3, 25.7, and 38.1; n = 9356 samples). Changes in cortisol awakening response (CAR) and diurnal slope (indicative of HPA axis activity) and their associations with maternal body mass index (BMI), hypertensive pregnancy disorders and GDM were examined using linear mixed models., Results: The CAR declined in 60% to 67% of women, and the diurnal slope attenuated from early to late pregnancy (b = 0.006; P = .001). Higher BMI was associated with less decline in CAR (b = 0.031; P = .0004) and less attenuation in diurnal slope from early to late pregnancy (b = -0.001; P = .006). Hypertensive pregnancy disorders and GDM were not significantly associated with diurnal cortisol profiles., Conclusion: The attenuation in CAR and diurnal slope support HPA axis hyporesponsivity during pregnancy. Less attenuation of both markers in women with a higher BMI may indicate reduced adaption of the HPA axis to pregnancy, presenting a mechanistic link to offspring health outcomes., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: Evidence regarding metabolic alterations associated with maternal antenatal depression (AD) is limited, and their role as potential biomarkers that improve the prediction of AD and adverse childbirth, neurodevelopmental, and mental health outcomes remains unexplored., Methods: In a cohort of 331 mother-child dyads, we studied associations between AD (a history of medical register diagnoses and/or a Center for Epidemiological Studies Depression Scale score during pregnancy ≥ 20) and 95 metabolic measures analyzed 3 times during pregnancy. We tested whether the AD-related metabolic measures increased variance explained in AD over its risk factors and in childbirth, neurodevelopmental, and mental health outcomes over AD. We replicated the findings in a cohort of 416 mother-child dyads., Results: Elastic net regression identified 15 metabolic measures that collectively explained 25% (p < .0001) of the variance in AD, including amino and fatty acids, glucose, inflammation, and lipids. These metabolic measures increased the variance explained in AD over its risk factors (32.3%, p < .0001 vs. 12.6%, p = .004) and in child gestational age (9.0%, p < .0001 vs. 0.7%, p = .34), birth weight (9.0%, p = .03 vs. 0.7%, p = .33), developmental milestones at the age of 2.3 to 5.7 years (21.0%, p = .002 vs. 11.6%, p < .001), and any mental or behavioral disorder by the age of 13.1 to 16.8 years (25.2%, p = .03 vs. 5.0%, p = .11) over AD, child sex, and age. These findings were replicated in the independent cohort., Conclusions: AD was associated with alterations in 15 metabolic measures, which collectively improved the prediction of AD over its risk factors and birth, neurodevelopmental, and mental health outcomes in children over AD. These metabolic measures may become biomarkers that can be used to identify at-risk mothers and children for personalized interventions., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

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.

Objective: Prenatal maternal symptoms of depression and anxiety are associated with an increased risk for child socioemotional and behavioral difficulties, supporting the fetal origins of mental health hypothesis. However, to date, studies have not considered specific genomic risk as a possible confound., Method: The Avon Longitudinal Study of Parents and Children (ALSPAC) cohort (n = 5,546) was used to test if child polygenic risk score for attention-deficit/hyperactivity disorder (ADHD), schizophrenia, or depression confounds or modifies the impact of prenatal maternal depression and anxiety on child internalizing, externalizing, and total emotional/behavioral symptoms from age 4 to 16 years. Longitudinal child and adolescent symptom data were analyzed in the ALSPAC cohort using generalized estimating equations. Replication analyses were done in an independent cohort (Prevention of Preeclampsia and Intrauterine Growth Restriction [PREDO] cohort; n = 514) from Finland, which provided complementary measures of maternal mental health and child psychiatric symptoms., Results: Maternal depression and anxiety and child polygenic risk scores independently and additively predicted behavioral and emotional symptoms from childhood through mid-adolescence. There was a robust prediction of child and adolescent symptoms from both prenatal maternal depression (generalized estimating equation estimate = 0.093, 95% CI 0.065-0.121, p = 2.66 × 10 -10 ) and anxiety (generalized estimating equation estimate = 0.065, 95% CI 0.037-0.093, p = 1.62 × 10 -5 ) after adjusting for child genomic risk for mental disorders. There was a similar independent effect of maternal depression (B = 0.156, 95% CI 0.066-0.246, p = .001) on child symptoms in the PREDO cohort. Genetically informed sensitivity analyses suggest that shared genetic risk only partially explains the reported association between prenatal maternal depression and offspring mental health., Conclusion: These findings highlight the genomic contribution to the fetal origins of mental health hypothesis and further evidence that prenatal maternal depression and anxiety are robust in utero risks for child and adolescent psychiatric symptoms., Plain Language Summary: Depression and anxiety affect approximately 15% of pregnant women, and children exposed to maternal depression or anxiety during pregnancy are at higher risk of developing mental health problems. However, the degree to which shared genetics explains the association between maternal and child mental health is unknown. In this study the authors generated polygenic risk scores (PRS), which provide a single measure of genetic risk for complex traits, to investigate the impact of shared genetic risk on the development of childhood mental health problems. Utilizing two longitudinal studies (n = 6,060), the authors found that PRS only partially explained the association between prenatal maternal depression and childhood mental health problems. These analyses show prenatal maternal depression remained a significant predictor of childhood mental health problems after accounting for shared genetic risk, further highlighting that prenatal maternal mental health is a robust predictor of child and adolescent mental health problems., (Copyright © 2023 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Maternal psychological distress during pregnancy is associated with infant temperament. Whether associations persist into late childhood, whether maternal distress is associated with temperament change from infancy to late childhood, whether associations are independent of maternal concurrent distress, and whether maternal distress has sensitive exposure periods on child temperament remain unclear., Methods: Our study includes mother-child dyads from Finnish, prospective Prediction and Prevention of Preeclampsia and Intrauterine Growth Restriction study. The mothers completed the Center for Epidemiologic Studies Depression Scale, State Anxiety Inventory and Perceived Stress Scale: biweekly up to 14 times during pregnancy; once in infancy (at child age 4-12 months); and once in late childhood (at child age 7-11 years). They also completed the Infant Behavior Questionnaire Revised at the infancy ( n  = 2538) and Temperament in Middle Childhood Questionnaire at the late childhood ( n  = 2004; 1693 children had data at both follow-ups) follow-up on child negative affectivity, extraversion and effortful control. We examined the associations of maternal distress with child temperament with linear regression, linear mixed and Bayesian relevant lifecourse exposure models., Results: Maternal distress during pregnancy was associated with higher negative affectivity and lower effortful control in children in infancy and late childhood. Maternal distress during pregnancy was also associated with increases in negative affectivity, decreases in effortful Control, and smaller decreases in extraversion from infancy to late childhood. The associations with late childhood temperament and temperament change were independent of maternal concurrent distress. Late childhood was a sensitive period for lifetime-to-date effects of maternal distress on late childhood negative affectivity and effortful control. Distress during pregnancy and infancy had smaller contributions., Conclusions: Maternal psychological distress during pregnancy is associated with individual differences and change in child temperament from infancy to late childhood. However, distress during pregnancy has a smaller effect on late childhood temperament than maternal concurrent distress., Competing Interests: The authors have declared that they have no competing or potential conflicts of interest., (© 2024 The Authors. JCPP Advances published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

Glucocorticoids are important for proper organ maturation, and their levels are tightly regulated during development. Here, we use human cerebral organoids and mice to study the cell-type-specific effects of glucocorticoids on neurogenesis. We show that glucocorticoids increase a specific type of basal progenitors (co-expressing PAX6 and EOMES) that has been shown to contribute to cortical expansion in gyrified species. This effect is mediated via the transcription factor ZBTB16 and leads to increased production of neurons. A phenome-wide Mendelian randomization analysis of an enhancer variant that moderates glucocorticoid-induced ZBTB16 levels reveals causal relationships with higher educational attainment and altered brain structure. The relationship with postnatal cognition is also supported by data from a prospective pregnancy cohort study. This work provides a cellular and molecular pathway for the effects of glucocorticoids on human neurogenesis that relates to lasting postnatal phenotypes., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Roughly more than one in six adults worldwide suffer from psychiatric conditions. Sporadic studies have associated parental psychiatric disorders with autism spectrum disorder in offspring. Comprehensively examining the association between parental psychiatric disorders and offspring autism spectrum disorder is needed to guide health policies, and to inform etiologic studies., Methods: We included all children born in Sweden and Finland 1997-2016. Diagnoses were clinically ascertained from National Registers through 2017. We calculated adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for autism spectrum disorder in offspring of fathers and mothers with psychiatric disorders, in both parents jointly and across co-occurring conditions., Findings: Among 2,505,842 children, 33,612 were diagnosed with autism spectrum disorder, of which 20% had a parent with psychiatric disorders. The risk of autism spectrum disorder was increased across all psychiatric disorders in fathers (Sweden: aHR = 2.02, 95% CI = 1.92-2.12; Finland: aHR = 1.63, 95% CI = 1.50-1.77), mothers (Sweden: aHR = 2.34, 95% CI = 2.24-2.43; Finland aHR = 2.12, 95% CI = 1.92-2.28), or both parents (Sweden: aHR = 3.76, 95% CI = 3.48-4.07; Finland aHR = 3.61, 95% CI = 3.20-4.07), compared to neither parents. Co-occurrence of parental psychiatric disorders further increased risk (e.g., Sweden: for one, two or ≥three different diagnostic categories compared to no diagnosis, in fathers aHR = 1.81, 2.07, 2.52; in mothers aHR = 2.05, 2.63, 3.57)., Interpretation: Psychiatric disorders in both parents conveyed the highest risk of offspring autism spectrum disorder, followed by mothers and then fathers. The risk increased with number of co-occurring disorders. All parental psychiatric disorders were associated with increased the risk of autism spectrum disorder. To reliably assess the risk of autism spectrum disorder in children, a comprehensive history incorporating the full range of parental psychiatric disorders is needed beyond solely focusing on familial autism spectrum disorder., Funding: Swedish-Research-Council-2021-0214., Competing Interests: Dr. Yin reports funding from KI Research Foundation Grant 2022–02021. Dr. Kolevzon reports support from American Psychiatric Publishing, Phelan-McDermid Syndrome Foundation – Spain and Phelan-McDermid Syndrome Foundation – Brazil, consulting fees from RitrovaTherapeutics, CureSHANK, Aelis Farma, Acadia, Alkermes, Jaguar Therapeutics, GW Pharmaceuticals, Neuren Pharmaceuticals, Clinilabs Drug Development Corporation, Scioto Biosciences, Biogen, PYC Therapeutics, stock or stock options from Ovid Therapeutics, and payment for expert testimony from Anthone v Franciscan Health System (Deposition) FAVROS LAW 701 Fifth Avenue, Suite 4750, Seattle, WA 98104, Ting v. Christina Ring, MD (Deposition) CARDONE & RUTBERG, PC, 3773 Cherry Creek North Drive, Suite 680W, Denver, Colorado, 80,209, Palmquist v. Hain Celestial Group (Trial only), COVINGTON & BURLING LLP, One CityCenter, 850 Tenth Street, NW, Washington, DC 20001–4956, Anderson v. The Johns Hopkins System (Deposition), GOODELL, DEVRIES, LEECH, & DANN, LLP, One South Street, 20th Floor, Baltimore, MD, and Acetaminophen – ASD-ADHD Product Liability Litigation (Deposition), BUTLER SNOW LLP, 810 7th Avenue, Suite 1105, New York, NY, 10,019. Dr. Kolevzon also reports participation in Vagal nerve stimulation in eating and weight disorders. Dr. Ludvigsson has coordinated an unrelated study on behalf of the Swedish IBD quality register (SWIBREG). That study received funding from Janssen corporation. Dr Ludvigsson has also received financial support from MSD developing a paper reviewing national healthcare registers in China. Dr Ludvigsson has an ongoing research collaboration on celiac disease with Takeda. Dr. Kajantie reports support from Academy of Finland, European Commission, Sigrid Jusélius Foundation, Foundation for Pediatric Research, Signe and Ane Gyllenberg Foundation, Yrjö Jahnsson Foundation, Novo Nordisk Foundation, Jalmari and Rauha Ahokas Foundation and Finnish Medical Foundation. Dr. Sandin reports funding from Swedish Research council Grant #2021–0214 and payment for acting as opponent at PhD defense in University of Oslo, Norway. Dr Sandin is a member of DSMB for Vagus Nerve Stimulation for Treatment of Eating Disorders at Mount Sinai Hospital, New York STUDY-21-01790. All authors confirm the independence of researchers from funders. Transparency statement The guarantor of this study affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained. Ethical approval The study was approved by the national Swedish ethics review board, Sweden (2017/1875–31/1; 2018/1864–32; 2019–06314) and the Institutional review board of The Finnish Institute for Health and Welfare (THL/1984/6.02.01/2018 and THL/4309/6.02.01/2022). No individual level consent was required, and all data used were anonymized. Patient and public involvement statement Patients or the public were not involved in the design, conduct, or reporting, or dissemination of our research. Availability of data and material Data cannot be shared publicly because of restrictions by law. Access to the Swedish data can be requested from the Swedish registers (https://www.socialstyrelsen.se/en/statistics-and-data/registers/; socialstyrelsen@socialstyrelsen.se). Access to the Finnish data can be requested from Finnish Social and Health Data Permit Authority Findata (info@findata.fi)., (© 2024 The Author(s).)

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., (© 2024. The Author(s).)

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/m 2 ) or normal weight(18.5-24.99 kg/m 2 ) 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., (© 2024. The Author(s).)

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., (© 2022. The Author(s).)

Context: In non-pregnant population, nonobese individuals with obesity-related metabolome have increased risk for type 2 diabetes and cardiovascular diseases. The risk of these diseases is also increased after gestational diabetes., Objective: This work aimed to examine whether nonobese (body mass index [BMI] < 30) and obese (BMI ≥ 30) women with gestational diabetes mellitus (GDM) and obese non-GDM women differ in metabolomic profiles from nonobese non-GDM controls., Methods: Levels of 66 metabolic measures were assessed in early (median 13, IQR 12.4-13.7 gestation weeks), and across early, mid (20, 19.3-23.0), and late (28, 27.0-35.0) pregnancy blood samples in 755 pregnant women from the PREDO and RADIEL studies. The independent replication cohort comprised 490 pregnant women., Results: Nonobese and obese GDM, and obese non-GDM women differed similarly from the controls across early, mid, and late pregnancy in 13 measures, including very low-density lipoprotein-related measures, and fatty acids. In 6 measures, including fatty acid (FA) ratios, glycolysis-related measures, valine, and 3-hydroxybutyrate, the differences between obese GDM women and controls were more pronounced than the differences between nonobese GDM or obese non-GDM women and controls. In 16 measures, including HDL-related measures, FA ratios, amino acids, and inflammation, differences between obese GDM or obese non-GDM women and controls were more pronounced than the differences between nonobese GDM women and controls. Most differences were evident in early pregnancy, and in the replication cohort were more often in the same direction than would be expected by chance alone., Conclusion: Differences between nonobese and obese GDM, or obese non-GDM women and controls in metabolomic profiles may allow detection of high-risk women for timely targeted preventive interventions., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Importance: Vitamin D is associated with neurodevelopment, but causality, critical windows, and potentials for modification remain unknown., Objective: To determine the impact of high-dose (1200 IU) vs standard-dose (400 IU) vitamin D3 supplementation during the first 2 years on psychiatric symptoms at ages 6 to 8 years and whether the impact is different in children with lower vs higher maternal vitamin D3 levels; lower vs higher levels were defined as 25-hydroxyvitamin D (25[OH]D) less than 30 ng/mL vs 30 ng/mL or greater., Design, Setting, and Participants: This study was a long-term follow-up of the double-blind randomized clinical trial (RCT) Vitamin D Intervention in Infants (VIDI) conducted at a single center in Helsinki, Finland, at 60 degrees north latitude. Recruitment for VIDI took place in 2013 to 2014. Follow-up data for secondary data analysis were collected 2020 to 2021. VIDI originally included 987 term-born infants; 546 of these individuals participated in the follow-up at ages 6 to 8 years, among whom 346 individuals had data on parent-reported psychiatric symptoms. Data were analyzed from June 2022 to March 2023., Interventions: There were 169 infants randomized to receive 400-IU and 177 infants randomized to receive 1200-IU oral vitamin D3 supplementation daily from ages 2 weeks to 24 months., Main Outcomes and Measures: Primary outcomes were internalizing, externalizing, and total problems scores, with clinically significant problems defined as T scores of 64 or greater in the Child Behavior Checklist questionnaire., Results: Among 346 participants (164 females [47.4%]; mean [SD] age, 7.1 [0.4] years), the vitamin D3 dose was 400 IU for 169 participants and 1200 IU for 177 participants. Clinically significant internalizing problems occurred in 10 participants in the 1200-IU group (5.6% prevalence) compared with 20 participants (11.8%) in the 400-IU group (odds ratio, 0.40; 95% CI, 0.17-0.94; P = .04) after adjustment for sex, birth season, maternal depressive symptoms at birth, and parental single status at follow-up. In a post hoc subgroup analysis, 48 children in the 400-IU group with maternal 25(OH)D concentrations less than 30 ng/mL had higher internalizing problems scores compared with children in the 1200-IU group, including 44 children with maternal 25(OH)D concentrations below 30 ng/mL (adjusted mean difference, 0.49; 95% CI, 0.09-0.89; P = .02) and 91 children with maternal concentrations above 30 ng/mL (adjusted mean difference, 0.37; 95% CI, 0.03-0.72; P = .04). Groups did not differ in externalizing or total problems., Conclusions and Relevance: This randomized clinical trial found that higher-than-standard vitamin D3 supplementation in the first 2 years decreased risk of internalizing problems at ages 6 to 8 years., Trial Registration: ClinicalTrials.gov Identifiers: NCT01723852 (VIDI) and NCT04302987 (VIDI2).

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., (© 2022 The Authors. Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

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., (© 2022. The Author(s).)

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., (© 2021. The Author(s).)

Background: Antenatal corticosteroids (ACS) are widely prescribed to improve outcomes following preterm birth. Significant knowledge gaps surround their safety, long-term effects, optimal timing and dosage. Almost half of women given ACS give birth outside the "therapeutic window" and have not delivered over 7 days later. Overtreatment with ACS is a concern, as evidence accumulates of risks of unnecessary ACS exposure., Methods: The Consortium for the Study of Pregnancy Treatments (Co-OPT) was established to address research questions surrounding safety of medications in pregnancy. We created an international birth cohort containing information on ACS exposure and pregnancy and neonatal outcomes by combining data from four national/provincial birth registers and one hospital database, and follow-up through linked population-level data from death registers and electronic health records., Results and Discussion: The Co-OPT ACS cohort contains 2.28 million pregnancies and babies, born in Finland, Iceland, Israel, Canada and Scotland, between 1990 and 2019. Births from 22 to 45 weeks' gestation were included; 92.9% were at term (≥ 37 completed weeks). 3.6% of babies were exposed to ACS (67.0% and 77.9% of singleton and multiple births before 34 weeks, respectively). Rates of ACS exposure increased across the study period. Of all ACS-exposed babies, 26.8% were born at term. Longitudinal childhood data were available for 1.64 million live births. Follow-up includes diagnoses of a range of physical and mental disorders from the Finnish Hospital Register, diagnoses of mental, behavioural, and neurodevelopmental disorders from the Icelandic Patient Registers, and preschool reviews from the Scottish Child Health Surveillance Programme. The Co-OPT ACS cohort is the largest international birth cohort to date with data on ACS exposure and maternal, perinatal and childhood outcomes. Its large scale will enable assessment of important rare outcomes such as perinatal mortality, and comprehensive evaluation of the short- and long-term safety and efficacy of ACS., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Frier et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Faba bean, processed into ingredients (flour, protein concentrate, protein isolate), can be extruded to meat alternatives with a fibrous texture. Despite its importance for consumer acceptance, not enough is known about the flavor of faba bean ingredients nor about the chemical and sensory changes caused by high-moisture extrusion. Therefore, the aim of this work was to describe the flavor of faba bean ingredients and the corresponding extrudates and to understand how their composition affects the perception of sensory attributes. Firstly, faba bean protein ingredients and extrudates were characterized for lipid-degrading enzymatic activities, flavor precursors, and volatile and non-volatile flavor-active compounds. Secondly, sensory profiling was conducted. Thirdly, partial least squares regression was applied to understand the relationship between chemical and sensory data. This study showed that faba bean protein concentrate had the strongest taste and aftertaste (respectively 7 and 6, on a 0-10 intensity scale), bitterness (6-7), and pea flavor and odor (respectively 6 and 5), whereas faba bean protein isolate had the strongest cereal flavor (4) and odor (4), and off-flavor (2) and off-odor (3). Faba bean flour had the mildest flavor. High-moisture extrusion brought several chemical changes to the ingredients, including the formation of several volatile compounds and inactivation of lipid-degrading enzymes. Only traces of tannins were found in extrudates. The presence of free phenolics, vicine, and convicine was linked to strong taste and aftertaste, bitterness, and a drying sensation of the mouth, whereas lipid oxidation products were related to pea, cereal, and off-odors and flavors., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: A decade after stroke, young stroke survivors continue to suffer from cognitive impairment. However, it is not known whether this long-term cognitive outcome is caused in part by further cognitive decline or solely by incomplete recovery from the acute effects of ischemic stroke. We studied changes in three cognitive domains over a 9-year follow-up period after first-ever and only ischemic stroke., Patients and Methods: In this prospective, two-center cohort study, we recruited consecutive 18-65 year-old patients with acute stroke between 2007 and 2009, along with demographically matched stroke-free controls. We performed comprehensive neuropsychological assessments at 3 months, 2, and 9 years after stroke, and we also performed neurological examinations at the time of inclusion and at the 9-year follow-up. We assessed the associations among stroke, follow-up time and long-term cognitive outcomes using repeated-measures analysis of variance., Results: The subjects comprised 85 patients who had had their first-ever and only ischemic stroke (mean age 53 years at inclusion), along with 31 stroke-free demographic controls. We compared the cognitive changes in patients to those in controls over a 9-year follow-up. After initial recovery between 3 months and 2 years after stroke, patients showed a decline in memory between 2 and 9 years after stroke compared to controls within the same time interval (immediate recall p < 0.001; delayed recall p < 0.001; list learning p < 0.001). Other than memory, we found no difference in cognitive changes between poststroke patients and controls., Discussion: Our main finding was memory decline over a decade in young first-ever stroke patients with no further stroke or neurodegenerative disease. Our study extends the previous results of further memory decline in elderly stroke survivors to young stroke survivors., Conclusion: Young stroke survivors might be at risk of memory decline over the decade following the stroke., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Laari, Turunen, Kauranen, Mustanoja, Lahti-Pulkkinen, Tatlisumak and Poutiainen.)

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., (© 2022. The Author(s).)

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.

Substantial genetic correlations have been reported across psychiatric disorders and numerous cross-disorder genetic variants have been detected. To identify the genetic variants underlying general psychopathology in childhood, we performed a genome-wide association study using a total psychiatric problem score. We analyzed 6,844,199 common SNPs in 38,418 school-aged children from 20 population-based cohorts participating in the EAGLE consortium. The SNP heritability of total psychiatric problems was 5.4% (SE = 0.01) and two loci reached genome-wide significance: rs10767094 and rs202005905. We also observed an association of SBF2, a gene associated with neuroticism in previous GWAS, with total psychiatric problems. The genetic effects underlying the total score were shared with common psychiatric disorders only (attention-deficit/hyperactivity disorder, anxiety, depression, insomnia) (rG > 0.49), but not with autism or the less common adult disorders (schizophrenia, bipolar disorder, or eating disorders) (rG < 0.01). Importantly, the total psychiatric problem score also showed at least a moderate genetic correlation with intelligence, educational attainment, wellbeing, smoking, and body fat (rG > 0.29). The results suggest that many common genetic variants are associated with childhood psychiatric symptoms and related phenotypes in general instead of with specific symptoms. Further research is needed to establish causality and pleiotropic mechanisms between related traits., Competing Interests: The authors have declared that no competing interests exist.

Demand for plant-based meat alternatives has increased in recent years due to concerns about health, ethics, the environment, and animal welfare. Nevertheless, the market share of plant-based meat alternatives must increase significantly if they are to support sustainable food production and consumption. Flavor is an important limiting factor of the acceptability and marketability of plant-based meat alternatives. Undesirable chemosensory perceptions, such as a beany flavor, bitter taste, and astringency, are often associated with plant proteins and products that use them. This study reviewed 276 articles to answer the following five research questions: (1) What are the volatile and nonvolatile compounds responsible for off-flavors? (2) What are the mechanisms by which these flavor compounds are generated? (3) What is the influence of thermal extrusion cooking (the primary structuring technique to transform plant proteins into fibrous products that resemble meat in texture) on the flavor characteristics of plant proteins? (4) What techniques are used in measuring the flavor properties of plant-based proteins and products? (5) What strategies can be used to reduce off-flavors and improve the sensory appeal of plant-based meat alternatives? This article comprehensively discusses, for the first time, the flavor issues of plant-based meat alternatives and the technologies available to improve flavor and, ultimately, acceptability., (© 2022 The Authors. Comprehensive Reviews in Food Science and Food Safety published by Wiley Periodicals LLC on behalf of Institute of Food Technologists.)

Purpose: To assess the ability of 2D-Shear wave elastography (2D-SWE) to evaluate its reproducibility, to define the optimal orientation and size of the region of interest (ROI), and to differentiate benign from malignant inguinal lymph nodes (LNs)., Method: Thirty-two suspicious inguinal LNs from 21 patients were evaluated with 2D-SWE. SWE measurements were obtained in two orthogonal planes. To investigate reproducibility, sensitivity and specificity, circular ROIs with a diameter of 1 mm, 2 mm, 3 mm and 5 mm were placed on the cortex of the LNs. Additionally, one freehand ROI was drawn covering majority of the LN. Two observers performed five sets of SWE measurements for each ROI size. All LNs underwent core needle biopsy or were surgically removed., Results: The 3 mm ROI for Mean-E in axial plane showed high interrater agreement [intraclass correlation coefficient (ICC) 0.899] with the cut-off value of 7.31 kPa resulting in 88.9% sensitivity and 60.9% specificity for differentiating malignant from benign LNs. In benign LNs, mean elasticity of the ROI was lower (7.68 ± 3.82 kPa; range, 3.41-15.40 kPa) compared to the malignant LNs (15.81 ± 10.61 kPa; range, 3.86-36.45 kPa)., Conclusions: The most reproducible way to measure stiffness in inguinal LNs is a 3 mm circular ROI centered on the cortex of the LN in axial plane. Elasticity values were higher in the malignant LNs reflecting the stiffer nature of the metastatic LNs. 2D-SWE offers a noninvasive ultrasonographic tool to assess superficial inguinal lymph nodes with high reproducibility., Competing Interests: The authors have declared that no competing interests exist.

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., (© 2022. The Author(s).)

Purpose: The InTraUterine sampling in early pregnancy (ITU) is a prospective pregnancy cohort study. The overarching aim of ITU is to unravel genomic, epigenomic, transcriptomic, endocrine, inflammatory and metabolic maternal-placental-fetal mechanisms involved in the programming of health and disease after exposure to prenatal environmental adversity, such as maternal malnutrition, cardiometabolic disorders, infections, medical interventions, mental disorders and psychosocial stress. This paper describes the study protocol, design and baseline characteristics of the cohort., Participants: We included 944 pregnant Finnish women, their partners and children born alive between April 2012 and December 2017. The women were recruited through the national, voluntary trisomy 21 screening between 9 +0 and 21 +6 gestational weeks. Of the participating women, 543 were screen positive and underwent fetal chromosomal testing. Test result of these women suggested no fetal chromosomal abnormality. Further, we recruited 401 women who were screen negative and who did not undergo fetal chromosomal testing., Findings to Date: We have collected chorionic villi and amniotic fluid from the screen-positive women; blood, urine, buccal swabs and diurnal salivary samples from all women; blood and buccal swabs from all partners; and placenta, cord blood and buccal swabs from all newborns for analyses of the genome, epigenome, transcriptome, and endocrine, inflammatory and metabolic markers. These data are coupled with comprehensive phenotypes, including questions on demographic characteristics, health and well-being of the women and their partners during pregnancy and of the women and their children at the child's age of 1.7 and 3 years. Data also come from patient records and nationwide registers covering health, lifestyle and medication data., Future Plans: Multiple layers of ITU data allow integrative data analyses, which translate to biomarker identification and allow risk stratification and understanding of the biological mechanisms involved in prenatal programming of health and disease., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Preterm birth has been linked with postpartum depressive (PPD) disorders and high symptom levels, but evidence remains conflicting and limited in quality. It remains unclear whether PPD symptoms of mothers with preterm babies were already elevated before childbirth, and whether PPD symptoms mediate/aggravate the effect of preterm birth on child mental disorders. We examined whether preterm birth associated with maternal PPD symptoms, depressive symptoms trajectories from antenatal to postpartum stage, and whether PPD symptoms mediated/aggravated associations between preterm birth and child mental disorders. Mothers of preterm (n = 125) and term-born (n = 3033) children of the Prediction and Prevention of Preeclampsia and Intrauterine Growth Restriction study reported depressive symptoms four times within 8 weeks before and twice within 12 months after childbirth. Child mental and behavioral disorder diagnoses until age 8.4-12.8 years came from medical register. Preterm birth associated with higher PPD symptoms (mean difference = 0.19 SD, 95% CI 0.01, 0.37, p = 0.04), and higher odds (odds ratio = 2.23, 95% CI 1.22, 4.09, p = 0.009) of the mother to belong to a group that had consistently high depressive symptoms levels trajectory from antenatal to postpartum stage. PPD symptoms partially mediated and aggravated the association between preterm birth and child mental disorders. Preterm birth, maternal PPD symptoms and child mental disorders are associated, calling for timely prevention interventions., (© 2022. The Author(s).)