Obesity and co-morbid hypertensive and diabetic disorders in pregnancy and early manifestations of neurodevelopmental adversity in the offspring : Prediction and Prevention of Pre-eclampsia and Intrauterine Growth Restriction (PREDO) Study

The prevalence of women entering pregnancy with overweight and obesity is growing worldwide reaching epidemic proportions. Apart from the risks of maternal and fetal morbidity associated with overweight and obesity, excessive weight is also an essential risk factor for diabetic and hypertensive disorders occurring before and during pregnancy. Maternal obesity and co-morbid hypertensive and diabetic disorders affect fetal development and have been linked with compromised neurodevelopment of the offspring; however, previous findings are not entirely consistent. Further, due to high co-morbidity between maternal overweight/obesity and hypertensive and diabetic disorders, it is difficult to disentangle their individual effects on child neurodevelopment. In addition, the mechanisms underlying associations between maternal overweight/obesity and co-morbid disorders and child neurodevelopment remain elusive. This thesis examines the effects of maternal overweight/obesity and co-morbid hypertensive and diabetic disorders on early manifestations of neurodevelopmental adversity and on developmental delay in early childhood. It also examines whether DNA methylation (DNAm) biomarker of gestational age (GA) at birth reflects prenatal exposure to maternal overweight/obesity and co-morbid hypertensive and diabetic disorders, and hence, has a potential to identify individuals at risk for neurodevelopmental adversity already at birth. This thesis capitalizes on the Prediction and Prevention of Pre-eclampsia and Intrauterine Growth Restriction (PREDO) birth cohort comprising 4777 women and their singleton children born in Finland between 2006 and 2010. Data on maternal early pregnancy BMI, pre-pregnancy and gestational hypertension, pre-eclampsia, type 1 diabetes and gestational diabetes mellitus (GDM) were derived from the Finnish Medical Birth Register (MBR). DNAm gestational age (DNAm GA) was calculated using the method based on the methylation profile of 148 selected cytosine-phosphate-guanine (CpG) sites on DNA. Regulatory behavior problems in infancy were measured using Neonatal Perception Inventory (NPI) at the infant’s mean age of 16.9 (SD=7.6) days. Developmental milestones were measured using Ages and Stages Questionnaire (ASQ) Third edition at the child’s mean age of 42.1 (SD=8.2) months. In comparison to the infants born to normal weight mothers, infants born to overweight/obese mothers displayed more regulatory behavior problems and were more likely to display regulatory behavior problems in multiple areas of self-regulation. These effects were independent of the co-morbid hypertensive and diabetic disorders (Study II). Children of overweight and obese mothers were more likely to display more severe and pervasive developmental delay in comparison to the children on normal weight mothers. The effects of maternal overweight and obesity on severity and pervasiveness of developmental delay in early childhood were also independent of the co-morbid hypertensive and diabetic disorders (Study III). Infant regulatory behavior problems partially mediated the association between maternal overweight/obesity and child neurodevelopmental milestones (Study II). Maternal pre-eclampsia was marginally associated with infant regulatory problems in multiple areas of self-regulation in normal weight non-diabetic women, but its effect was not significant in overweight/obese women and/or women with GDM (Study II). Maternal pre-eclampsia increased the odds of more severe and pervasive developmental delay in early childhood, and these effects were lower in the presence of overweight/obesity and diabetic disorders (Study III). GDM was not associated with infant regulatory behavior problems (Study II). The effect of GDM on severity and pervasiveness of developmental delay in early childhood was partially driven by maternal overweight/obesity and/or pre-eclampsia (Study III). Gestational and chronic hypertension were not associated with infant regulatory behavior problems and developmental delay(Studies II and III). Maternal BMI was not associated with variation in DNAm GA (Study IV). Maternal pre-eclampsia was associated with DNAm GA acceleration (Study IV). GDM in index pregnancy was not associated with variation in DNAm GA, however, insulin treated GDM in previous pregnancy was associated with DNAm GA deceleration (Study IV). These study findings suggest that maternal overweight and obesity affect child neurodevelopment independently of the co-morbid hypertensive and diabetic disorders, and that the trajectory of this effect can partially be traced from infant regulatory behavior problems to developmental delay in early childhood. Hence, infant regulatory behavior problems may represent an early manifestation of neurodevelopmental adversity due to prenatal exposure to maternal overweight/obesity. Pre-eclampsia increases the risk of developmental delay in early childhood independently of maternal overweight, obesity and diabetic disorders and its adverse effects on child neurodevelopment have a potential to be detected already at birth by assessing DNAm GA. Adverse effects of gestational diabetes on child neurodevelopment can be partially accounted for by highly co-morbid maternal overweight/ obesity and pre-eclampsia. Efforts aimed at weight management among women of reproductive age and prevention of pre-eclampsia during pregnancy are likely to reduce the burden of neurological morbidity in the future.Yhä useampi hedelmällisessä iässä oleva nainen ympäri maailmaa on ylipainoinen tai lihava. Ylipaino on tärkeä diabeteksen ja verenpainesairauksien riskitekijä sekä yleisesti että raskauden aikana, ja näitä häiriöitä voidaankin kuvata ylipainon ja lihavuuden liitännäissairauksiksi. Aiempien tutkimusten perusteella äidin lihavuus ja nämä liitännäissairaudet vaikuttavat sikiön kehitykseen ja voivat mahdollisesti lisätä lapsen käytös- ja tunnehäiriöiden ja muiden kehityksellisten ongelmien riskiä, mutta nämä aiemmat tulokset ovat osin ristiriidassa keskenään. Lisäksi on vaikeaa arvioida, mikä on yksittäisten riskitekijöiden itsenäinen merkitys lapsen kehityksen kannalta, sillä äidin lihavuus ja ylipaino, diabetes ja verenpainesairaudet esiintyvät usein yhdessä. On myös huomattava, että mekanismit, jotka selittävät äidin ylipainon tai lihavuuden ja sen liitännäissairauksien yhteyttä lapsen kehitykseen ovat edelleen varsin epäselviä. Tässä väitöskirjassa tarkastellaan äidin ylipainon ja lihavuuden sekä diabeteksen ja verenpainehäiriöiden vaikutusta lapsen varhaisiin käytös- ja tunnehäiriöiden ilmentymiin sekä kehitysviivästymiin. Lisäksi väitöskirjassa tarkastellaan vastasyntyneen perimäaineksen epigeneettisiä muutoksia, eli DNA:ssa ennen syntymää tapahtuneita muokkauksia, joiden johdosta emäsjärjestys ei muutu, mutta jotka voivat vaikuttaa solujen toimintaan. Epigeneettisten muutosten osalta selvitetään, ovatko ne yhteydessä äidin raskauden aikaiseen lihavuuteen, ylipainoon ja liitännäissairauksiin. Lisäksi selvitetään, voitaisiinko epigeneettisiä muutoksia tutkimalla auttaa tunnistamaan mahdollisimman varhaisessa vaiheessa ne lapset, joilla on kohonnut kehityksen häiriöiden riski. Väitöskirja on toteutettu osana suomalaista Predo-tutkimusta. Predo (Pre-eklampsian ennustaminen ja ehkäisy) on seurantatutkimus, johon kuuluu 4777 äitiä sekä heidän lastaan, jotka syntyivät Suomessa 2006-2010. Äidin varhaisraskauden painoindeksiä, diabetesta ja verenpainesairauksia koskeva tieto kerättiin Terveyden ja Hyvinvoinnin laitoksen ylläpitämästä kansallisesta Syntyneiden lasten rekisteristä. Epigeneettisten muutosten osalta tarkasteltiin syntymän yhteydessä otettuja napanuoran verinäytteitä, joista on mahdollista tutkia vastasyntyneen soluja. Tutkimuksessa valittiin vastasyntyneen DNA:sta 148 sytosiini-fosfaatti-guaniini-kohtaa, joiden metylaatioaste heijastelee raskauden kestoa, ja näiden kohtien metylaatioastetta tarkasteltiin suhteessa äidin painoon, sairauksiin sekä lapsen kehitykseen. Itsesäätelyvaikeuksia imeväisiässä mitattiin Neonatal Perception Inventory -kyselylomakkeella, jonka vastasyntyneiden äidit täyttivät keskimäärin 17 päivää synnytyksen jälkeen. Kehitysviivästymiä arvioitiin Ages and Stages -kyselylomakkeella, jonka äidit täyttivät lapsen ollessa keskimäärin 42 kuukauden ikäinen. Tutkimuksessa havaittiin, että äidin ylipaino ja lihavuus vaikuttavat lapsen kehitykseen riippumatta liitännäissairauksista eli myös silloin, kun diabeteksen ja verenpainesairauksien vaikutus lapseen on huomioitu. Äidin ylipaino ja lihavuus olivat tutkimuksessa yhteydessä sekä vastasyntyneen varhaisiin itsesäätelyn vaikeuksiin että kehitysviivästymiin varhaislapsuudessa. Tutkimuslöydösten perusteella vastasyntyneen itsesäätelyvaikeudet voivat olla äidin ylipainon ja lihavuuden haittavaikutusten varhainen ilmentymä lapsessa. Tutkimuksessa havaittiin lisäksi, että pre-eklampsia – raskaushäiriö, joka aiheuttaa muun muassa verenpaineen nousua ja jota on kutsuttu Suomessa myös raskausmyrkytykseksi – lisää lapsen varhaisen kehitysviivästymän riskiä riippumatta äidin ylipainosta, lihavuudesta tai diabeteksesta. Tulosten perusteella on mahdollista, että pre-eklampsian haitalliset vaikutukset lapsen kehitykseen voidaan havaita jo varhain tutkimalla vastasyntyneen perimäaineksessa tapahtuneita epigeneettisiä muutoksia. Hedelmällisessä iässä olevien naisten painonhallintaan ja pre-eklampsian ehkäisyyn tähtäävät toimet voisivat vähentää psykiatristen ja neurologisten sairauksien kuormaa tulevaisuudessa

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. Summary 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.Peer reviewe

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.Peer reviewe

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 multiplep-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.Peer reviewe

The epigenetic clock and pubertal, neuroendocrine, psychiatric, and cognitive outcomes in adolescents

Abstract 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

Maternal postpartum depressive symptoms partially mediate the association between preterm birth and mental and behavioral disorders in children

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.Peer reviewe

Maternal Hypertensive Pregnancy Disorders and Mental Disorders in Children

The associations of maternal hypertensive pregnancy disorders with offspring mental disorders remain unclear. We examined whether maternal hypertensive disorders and maximum blood pressure during pregnancy predict offspring childhood mental disorders, whether the associations are independent of maternal and paternal mental disorders and paternal hypertensive disorders, independent of or additive with maternal early pregnancy overweight/obesity and diabetes mellitus disorders, and mediated or moderated by preterm birth, small-for-gestational-age birth and neonatal intensive care unit admission. Our prospective study comprised 4743 mother-child dyads of Prediction and Prevention of Preeclampsia and Intrauterine Growth Restriction study. Women were recruited to the study in early pregnancy at Finnish maternity hospitals. Children were born 2006 to 2010 and followed-up until December 31, 2016, to ages 6.4 to 10.8 years. Hypertensive pregnancy disorders were identified from medical records, Medical Birth Register, and Care Register for Health Care. Systolic and diastolic blood pressure were measured at antenatal clinics and hospital visits. Mental disorder diagnoses were identified from Care Register for Health Care. Maternal gestational and chronic hypertension, preeclampsia and its severity increased offspring hazard of any childhood mental disorder. The associations of preeclampsia (hazard ratio=1.66 [95% CI, 1.14-2.42]) and severe preeclampsia (hazard ratio=2.01 [95% CI, 1.08-3.73]) were independent of all covariates. Maternal hypertensive and diabetes mellitus disorders and overweight/obesity also additively increased offspring hazard of mental disorders. Preterm and small-for-gestational-age births and neonatal intensive care unit admission partially mediated the effects of any and severe preeclampsia on offspring mental disorders. To conclude, maternal hypertensive pregnancy disorders carry adverse consequences for offspring mental health.Peer reviewe

Effect of Vitamin D3Supplementation in the First 2 Years of Life on Psychiatric Symptoms at Ages 6 to 8 Years : A Randomized Clinical Trial

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 D3supplementation 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 D3levels; 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 D3supplementation 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 D3dose 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 D3supplementation 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).Peer reviewe

The Epigenetic Clock at Birth : Associations With Maternal Antenatal Depression and Child Psychiatric Problems

Objective: Maternal antenatal depression may compromise the fetal developmental milieu and contribute to individual differences in aging and disease trajectories in later life. We evaluated the association between maternal antenatal depression and a novel biomarker of aging at birth, namely epigenetic gestational age (GA) based on fetal cord blood methylation data. We also examined whether this biomarker prospectively predicts and mediates maternal effects on early childhood psychiatric problems. Method: A total of 694 mothers from the Prediction and Prevention of Preeclampsia and Intrauterine Growth Restriction (PREDO) Study provided information on history of depression diagnosed before pregnancy; 581 completed the Center for Epidemiological Studies Depression Scale throughout pregnancy, and 407 completed the Child Behavior Checklist at child's age 3.7 years (SD = 0.75 year). DNA methylation (DNAm) GA of fetal cord blood DNA was based on the methylation profile of 148 selected cytosine linked to guanine by phosphate (CpG) sites. Epigenetic GA was calculated as the arithmetic difference between DNAm GA and chronological GA and adjusted for chronological GA. Results: Maternal history of depression diagnosed before pregnancy (mean difference = -0.25 SD units, 95% CI = -0.46 to -0.03) and greater antenatal depressive symptoms (-0.08 SD unit per I-SD unit increase, 95% CI = -0.16 to -0.004) were associated with child's lower epigenetic GA. Child's lower epigenetic GA, in turn, prospectively predicted total and internalizing problems and partially mediated the effects of maternal antenatal depression on internalizing problems in boys. Conclusion: Maternal antenatal depression is associated with lower epigenetic GA in offspring. This lower epigenetic GA seems to be associated with a developmental disadvantage for boys, who, in early childhood, show greater psychiatric problems.Peer reviewe