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Abstract Context Comprehensive assessment of metabolism in maternal obesity and pregnancy disorders can provide information about the shared maternal-fetal milieu and give insight into both maternal long-term health and intergenerational transmission of disease burden. Objective To assess levels, profiles, and change in the levels of metabolic measures during pregnancies complicated by obesity, gestational diabetes (GDM), or hypertensive disorders. Design, Setting and Participants A secondary analysis of 2 study cohorts, PREDO and RADIEL, including 741 pregnant women. Main Outcome Measures We assessed 225 metabolic measures by nuclear magnetic resonance in blood samples collected at median 13 [interquartile range (IQR) 12.4-13.7], 20 (IQR 19.3-23.0), and 28 (27.0-35.0) weeks of gestation. Results Across all 3 time points women with obesity [body mass index (BMI) ≥ 30kg/m2] in comparison to normal weight (BMI 18.5-24.99 kg/m2) had significantly higher levels of most very-low-density lipoprotein-related measures, many fatty and most amino acids, and more adverse metabolic profiles. The change in the levels of most metabolic measures during pregnancy was smaller in obese than in normal weight women. GDM, preeclampsia, and chronic hypertension were associated with metabolic alterations similar to obesity. The associations of obesity held after adjustment for GDM and hypertensive disorders, but many of the associations with GDM and hypertensive disorders were rendered nonsignificant after adjustment for BMI and the other pregnancy disorders. Conclusions This study shows that the pregnancy-related metabolic change is smaller in women with obesity, who display metabolic perturbations already in early pregnancy. Metabolic alterations of obesity and pregnancy disorders resembled each other suggesting a shared metabolic origin.

Abstract 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.

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.

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.

Abstract Context Prepregnancy body mass index (pBMI) is associated with the maternal metabolome during pregnancy. However, evidence remains inconclusive whether pBMI is also associated with alterations in the fetal cord blood metabolome, and whether pBMI modifies the associations between maternal and fetal metabolomes. Objective This work aimed to examine whether pBMI is associated with the fetal cord blood metabolome and whether maternal and fetal metabolomes are associated and vary according to the degree of maternal pBMI. Methods We derived pBMI from medical records and tested it in relation to 95 cord blood metabolic measures of 1702 newborns in the PREDO, RADIEL, and ITU studies. We tested the associations between maternal and fetal metabolomes and moderation by pBMI in 556 mother-child dyads of the PREDO and RADIEL studies contributing maternal blood samples at 3 time points during pregnancy. Results In the meta-analysis of the 3 studies, higher pBMI was associated with 12 of the 95 cord blood metabolic measures, including lower levels of high-density lipoprotein–associated measures and higher levels of branched-chain and aromatic amino acids, as well as ketone bodies. Associations between maternal and fetal metabolomes were significant for 61 of the 95 measures; 26 of the 95 associations were modified by maternal pBMI, being stronger among mothers with obesity than those without. Conclusion Maternal pBMI is associated with alterations in fetal cord blood metabolome. Maternal and fetal metabolomes are associated, and associations vary according to maternal pBMI.

Purpose of ReviewWe 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 FindingsSeven 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.SummaryAccumulating 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.

Preterm birth(<37 gestational weeks) is associated with numerous adversities, however, data on positive developmental outcomes remain limited. We examined if preterm and term born(≥37 gestational weeks) adults differ in dispositional optimism/pessimism, a personality trait associated with health and wellbeing. We assessed if birth weight z-score, neurosensory impairments and parental education modified the outcome. We systematically searched PubMed and Web of Science for cohort or case-control studies(born ≥ 1970) with data on gestational age and optimism/pessimism reported using the Life-Orientation-Test-Revised in adulthood(≥18 years). The three identified studies(Helsinki Study of Very Low Birth Weight Adults; Arvo Ylppö Longitudinal Study; Avon Longitudinal Study of Parents and Children) provided data for the two-step random-effects linear regression Individual-Participant-Data meta-analysis. Preterm and term borns did not differ on optimism(p = 0.76). Preterms scored higher on pessimism than term borns(Mean difference = 0.35, 95%Confidence Interval 0.36, 0.60, p = 0.007), although not after full adjustment. Preterm born participants, but not term born participants, with higher birth weight z-score, had higher optimism scores (0.30 raw score units per standard deviation increase, 95% CI 0.10, 0.49, p = 0.003); preterm vs term x birth weight z-score interaction p = 0.004). Preterm and term born adults display similar optimism. In preterms, higher birth weight may foster developmental trajectories promoting more optimistic life orientations.

Background Molecular aging biomarkers, such as epigenetic age predictors, predict risk factors of premature aging, and morbidity/mortality more accurately than chronological age in middle-aged and elderly populations. Yet, it remains elusive if such biomarkers are associated with aging-related outcomes earlier in life when individuals begin to diverge in aging trajectories. We tested if the Horvath epigenetic age predictor is associated with pubertal, neuroendocrine, psychiatric, and cognitive aging-related outcomes in a sample of 239 adolescents, 11.0–13.2 years-old. Results Each year increase in epigenetic age acceleration (AA) was associated with 0.06 SD units higher weight-for-age, 0.08 SD units taller height-for-age, -0.09 SD units less missed from the expected adult height, 13 and 16% higher odds, respectively, for each stage increase in breast/genitals development on the Tanner Staging Questionnaire and pubertal stage on the Pubertal Development Scale, 4.2% higher salivary cortisol upon awakening, and 18 to 34% higher odds for internalizing and thought problems on the Child Behavior Checklist ( p values <  0.045). AA was not significantly associated with cognition. Conclusions Our findings suggest that already in adolescence, AA is associated with physiological age acceleration, which may index risk of earlier aging. AA may identify individuals for preventive interventions decades before aging-related diseases become manifest.

Background A recent study has shown that it is possible to accurately estimate gestational age (GA) at birth from the DNA methylation (DNAm) of fetal umbilical cord blood/newborn blood spots. This DNAm GA predictor may provide additional information relevant to developmental stage. In 814 mother-neonate pairs, we evaluated the associations between DNAm GA and a number of maternal and offspring characteristics. These characteristics reflect prenatal environmental adversity and are expected to influence newborn developmental stage. Results DNAm GA acceleration (GAA; i.e., older DNAm GA than chronological GA) of the offspring at birth was associated with maternal age of over 40 years at delivery, pre-eclampsia and fetal demise in a previous pregnancy, maternal pre-eclampsia and treatment with antenatal betamethasone in the index pregnancy, lower neonatal birth size, lower 1-min Apgar score, and female sex. DNAm GA deceleration (GAD; i.e., younger DNAm GA than chronological GA) of the offspring at birth was associated with insulin-treated gestational diabetes mellitus (GDM) in a previous pregnancy and Sjögren’s syndrome. These findings were more accentuated when the DNAm GA calculation was based on the raw difference between DNAm GA and GA than on the residual from the linear regression of DNAm GA on GA. Conclusions Our findings show that variations in the DNAm GA of the offspring at birth are associated with a number of maternal and offspring characteristics known to reflect exposure to prenatal environmental adversity. Future studies should be aimed at determining if this biological variation is predictive of developmental adversity.

Abstract Background Fetal or prenatal programming, i.e. the process in which environmental events during pregnancy are shaping and determining the development of the embryo, can be embedded by epigenetic changes including DNA methylation. Apart from environment, also the genome plays an important role and a variety of studies which identified meQTLs (methylation quantitative trait loci, i.e. SNPs which are associated with methylation levels) have been published. Methods Focusing on variably methylated regions (VMRs), we investigated if genotype (G), prenatal environment (E) or the combination of both (GxE, G+E) best explain cordblood DNA methylation in sample of 817 Finnish neonates. Furthermore, we used an epigenetic clock predictor to evaluate if accelerated or decelerated epigenetic age was associated with prenatal environment or with childhood psychiatric problems at age 3. Results We found that SNP genotype alone best explained methylation status in 44%, SNP x environment in 32% and SNP and prenatal environment in 24% of all VMRs. While functionally relevant meQTLs were located in close proximity to the specific CpG-site, functionally relevant SNPs involved in interaction models showed much broader peaks. Concerning the epigenetic clock, lower gestational age was associated with maternal depression diagnosis and greater depressive symptoms throughout pregnancy. Epigenetic age deceleration was associated with pre-eclampsia. Furthermore, lower epigenetic gestational age was significantly associated with greater total and internalizing problems in boys. Discussion Not only environment but also genotype should be considered in epigenetic studies. Furthermore, our results suggest that long-distance effects are present in GxE interactions. The epigenetic clock which mirrors prenatal environment is partially predictive for future development of the child. Lower epigenetic gestational age seems to be developmentally disadvantageous for boys, who in early childhood show greater psychiatric problems.