Keskosten kasvu ja aikuisiän kognitiiviset taidot ja mielenterveys

Background: Preterm birth (before 37 weeks of gestation) is a major cause of infant mortality and morbidity worldwide, and preventing its burden is a health care priority. Even in adulthood, individuals who were born preterm perform, on average, worse on tests of cognitive functioning than term-born peers do, and may have more mental health problems. Early growth failure is common among preterm individuals, and some studies have suggested that those preterm individuals who grow poorly in infancy have more neurodevelopmental problems later on in childhood. It is unclear whether these associations persist into adulthood and whether they extend beyond the smallest and most immature of preterm infants, to the majority of preterm infants who are born late preterm (at 34-36 completed weeks of gestation). It also remains unknown whether early postnatal growth patterns predict mental health outcomes - some partly conflicting evidence suggests that intrauterine growth restriction at least associates with mental health problems. The mechanisms explaining the associations between growth and neurodevelopment are also unclear. Early growth reflects a number of intertwined early-life environmental factors and individual characteristics, and while altering neonatal nutrition can affect growth, it is not known whether changes in nutrition can improve long-term neurodevelopmental outcomes. It has even been suggested that faster growth and higher nutritional intakes during the early postnatal period can present a trade-off between improved neurodevelopment and increased cardiovascular risk. Methods: The 157 participants of the Helsinki Study of Very Low Birth Weight Adults (HeSVA, birth weight <1500g) and the 108 participants of the Arvo Ylppö Longitudinal Study (AYLS, gestational age 34-36 completed weeks) examined in this thesis were born in Finland between 1978 and 1986. They were invited to adult follow-up visits between 2004 and 2012. Among these young adults, I examined whether growth in weight, length, and head circumference between different early growth periods (between preterm birth, term age, and 12 months of corrected age in HeSVA, and between late preterm birth, 5 and 20 months of corrected age, and 56 months of age in AYLS) was associated with performance in neuropsychological tests, with self-rated symptoms of depression, attention deficit hyperactivity disorder, and other mental health problems, or with diagnosis of mental disorder based on a psychiatric interview in adulthood. In the AYLS cohort, the participants also reported final grade point average and special education in comprehensive school. I further examined whether daily intakes of energy in total, of energy from human milk, and of carbohydrates, protein, and fats during the initial hospitalization, which were relatively low compared to modern recommendations, predicted adult cognitive functioning (HeSVA). As growth variables, I used standardised residual change scores from linear regression models where weight, length, and head circumference z scores were regressed on corresponding measures at previous time points, creating uncorrelated residuals that reflect growth conditional on previous history. These growth variables were then used as independent variables in linear and logistic regression models to predict the outcomes, while taking into account several potential confounders including child and parental background characteristics and neonatal morbidity. Results: Faster growth during the first months of life was associated with better adult cognitive functioning in both cohorts. The size and direction of the effects were similar: for each SD faster growth in weight, head circumference, and length between birth and term age, the HeSVA participants had 0.23-0.41 SD higher general intelligence quotient, executive functioning component, and visual memory scores. For each SD faster weight gain and head growth from birth to 5 months, and head growth from 5 to 20 months, the AYLS participants had 0.19-0.41 SD higher general intelligence quotient and executive functioning component scores and grade point average. Those who grew faster also had lower odds of having received special education at school. Growth after these time periods did not predict cognitive functioning or school outcomes. In contrast, there were no consistent associations between early growth and adult mental health in either cohort. Even when taking into account several important neonatal complications and illnesses, the associations between early growth and adult cognitive functioning could not be wholly explained. Neonatal morbidity however seemed to largely account for the associations between higher energy intake between the first six weeks of life and better cognitive functioning among the HeSVA participants. Conclusions: Faster growth during the first weeks and months of life after preterm birth is associated with better cognitive functioning, and these associations persist into adulthood. The mechanisms explaining these associations are largely unclear, but seem outcome-specific. Early intakes of nutrition may reflect or possibly even mediate the effects of neonatal morbidity on neurodevelopment, however the neonatal morbidities commonly associated with preterm birth do not wholly account for the associations between early growth and long-term neurodevelopment. Keywords: premature birth; infant, very low birth weight; gestational age; birth weight; cognition; intelligence; executive functioning; memory; mental health; depression; attention deficit disorder with hyperactivity; substance-related disorders; anxiety disorders; education; growth; weight gain; body height; cephalometry; energy intake; milk, human; infant; adult; risk factors; follow-up studies; longitudinal studies; developmental origins of health and diseaseTausta: Ennenaikainen syntymä (ennen 37 täyttä raskausviikkoa) on tärkeimpiä pienten lasten kuolleisuuden ja sairastavuuden syitä ympäri maailman, ja sen haittojen ehkäisy on terveydenhuollossa ensiarvoisen tärkeää. Vielä aikuisuudessakin ennenaikaisesti syntyneet suoriutuvat keskimäärin ikätovereitaan heikommin kognitiivisten toimintojen testeissä ja heillä on mahdollisesti enemmän mielenterveysongelmia. Varhainen syntymänjälkeinen kasvuhäiriö on tavallista ennenaikaisesti syntyneillä imeväisillä, ja joidenkin tutkimusten mukaan niillä ennenaikaisesti syntyneillä lapsilla, joiden kasvu on heikkoa imeväisiässä, on myös enemmän kehityksellisiä ongelmia myöhemmin lapsuudessa. On epäselvää, säilyykö tämä yhteys aikuisuuteen, ja koskeeko se pelkästään kaikkein pienimpinä ja ennenaikaisimpina syntyneitä lapsia, vai myös hieman ennenaikaisena syntyneitä (34–36 täyttä raskausviikkoa). Ei myöskään tiedetä, onko varhainen kasvu syntymän jälkeen yhteydessä mielenterveyteen - osittain ristiriitaiset tutkimustulokset viittaavat siihen, että ainakin syntymää edeltävä kasvuhäiriö liittyy mielenterveyden häiriöihin. Mekanismit, jotka selittävät kasvun ja aivojen kehityksen välistä yhteyttä tunnetaan huonosti. Varhainen kasvu heijastelee useita varhaisia, toisiinsa kytkeytyneitä ympäristötekijöitä ja yksilöllisiä ominaisuuksia. Vaikka varhainen ravitsemus voi vaikuttaa kasvuun, ei tiedetä, voidaanko ravitsemusta muuttamalla vaikuttaa myönteisesti ja kestävästi aivojen kehitykseen ja kognitiivisiin taitoihin. On jopa ehdotettu, että nopeampi kasvu ja suurempi energiansaanti imeväisiässä voi vaikuttaa myönteisesti aivojen kehitykseen, mutta toisaalta lisätä sydän- ja verisuonisairastavuuden riskiä. Menetelmät: Tämän väitöskirjan kohteena olevaan kahteen aineistoon kuului Pikku-K-tutkimuksen (engl. Helsinki Study of Very Low Birth Weight Adults) 157 pikkukeskosena syntynyttä osallistujaa (<1500g) ja Arvo Ylppö -tutkimuksen (engl. Arvo Ylppö Longitudinal Study) 108 hieman ennenaikaisena syntynyttä osallistujaa (34–36 täyttä raskausviikkoa). Nämä osallistujat syntyivät Suomessa vuosien 1978 ja 1986 välillä, ja heidät kutsuttiin aikuisiän seurantavaiheeseen vuosien 2004 ja 2012 välillä. Tutkin, miten varhainen painon, pituuden ja päänympäryksen kasvu eri ajanjaksoina ennusti suoriutumista kognitiivisten toimintojen testeissä, itse raportoituja masennuksen ja tarkkaavuus- ja ylivilkkaushäiriön oireita ja muita mielenterveyden ongelmia sekä psykiatrisen haastattelun perusteella diagnosoituja mielenterveyden häiriöitä aikuisuudessa. Lisäksi Arvo Ylppö -tutkimuksessa osallistujat raportoivat peruskoulun päättötodistuksensa keskiarvon ja kertoivat, olivatko saaneet erityisopetusta. Pikku-K-aineistossa tutkitut kasvukaudet sijoittuivat ennenaikaisen syntymän, lasketun ajan ja 12 kk korjattua ikää vastaavan ajankohdan välille. Arvo Ylppö -aineistossa kasvukaudet sijoittuivat hieman ennenaikaisen syntymän, 5 ja 20 kk korjattua ikää vastaavien ajankohtien, sekä 56 kk iän välille. Lisäksi selvitin Pikku-K-aineistossa, ennustaako päivittäinen keskimääräinen energiansaanti ja hiilihydraattien, proteiinin, rasvojen, ja ihmismaidosta saatavan energian määrä syntymää seuranneena sairaalassaoloaikana aikuisiän kognitiivisia taitoja. Nämä ravitsemustasot olivat aineistossani nykypäivän suosituksiin verrattuna matalia. Kasvumuuttujina käytin standardoituja residuaalimuuttujia. Ne olivat peräisin lineaariregressiomalleista, joissa standardoitua paino-, pituus- ja päänympärysmittaa kasvukauden lopussa ennustettiin vastaavilla standardoiduilla mitoilla aiempina ajankohtina. Näin syntyi residuaalimuuttujia, jotka olivat riippumattomia aiemmasta kasvuhistoriasta. Näitä residuaalimuuttujia käytettiin riippumattomina muuttujina lineaari- ja logistisissa regressiomalleissa ennustamaan aikuisiän vastemuuttujia samalla huomioiden useita mahdollisia sekoittavia tekijöitä, kuten lapsen ja hänen vanhempansa taustaan ja varhaiseen sairastavuuteen liittyviä tekijöitä. Tulokset: Nopeampi kasvu ensimmäisten elinkuukausien aikana oli yhteydessä parempaan aikuisiän kognitiiviseen testisuoriutumiseen molemmissa aineistoissa. Näiden yhteyksien kokoluokka ja suunta olivat samankaltaiset: yhden keskihajonnan verran nopeampi painon, päänympäryksen ja pituuden kasvu syntymän ja lasketun ajan välillä oli Pikku-K-aineistossa yhteydessä 0.23–0.41 keskihajontaa suurempaan älykkyysosamäärään sekä toiminnanohjausta ja visuaalista muistia kuvaaviin komponenttipisteisiin. Arvo Ylppö -aineistossa yhden keskihajonnan verran nopeampi painon ja päänympäryksen kasvu syntymän ja 5 kk välillä, ja pään kasvu 5 ja 20 kk välillä oli yhteydessä 0.19–0.41 keskihajontaa korkeampaan älykkyysosamäärään, toiminnanohjauskomponenttipisteisiin ja päättötodistuksen keskiarvoon, ja niillä jotka kasvoivat nopeammin, oli myös pienempi todennäköisyys saada erityisopetusta. Kasvu näiden ajanjaksojen jälkeen ei ennustanut neurokognitiivisia tai koulusuoriutumiseen liittyviä tuloksia. Kasvun ja aikuisiän mielenterveyden välillä ei havaittu johdonmukaisia yhteyksiä kummassakaan aineistossa. Tutkimuksessa otettiin huomioon useita varhaiseen sairastavuuteen liittyviä tekijöitä, jotka eivät kuitenkaan täysin selittäneet kasvun ja aikuisiän kognitiivisten taitojen välistä yhteyttä. Vastasyntyneen sairaudet kuitenkin vaikuttivat selittävän suurelta osin ne yhteydet, jotka havaittiin ensimmäisen kuuden elinviikon aikaisen korkeamman energiansaannin ja paremman aikuisiän neurokognitiivisen suoriutumisen välillä Pikku-K-aineistossa. Johtopäätökset: Nopeampi kasvu ensimmäisten elinviikkojen ja -kuukausien aikana on yhteydessä parempiin kognitiivisiin taitoihin aikuisilla, jotka ovat syntyneet ennenaikaisesti. Kasvun ja kognitiivisten taitojen ja mielenterveyden kehityksen yhteyttä selittävät mekanismit ovat suurelta osin epäselviä, mutta vaikuttavat eroavan riippuen siitä, millaiset aikuisiän ominaisuudet ovat tarkastelun kohteena. Varhainen energiansaanti voi heijastella tai jopa välittää vastasyntyneisyyskauden sairastavuuden vaikutuksia kognitiiviseen kehitykseen, mutta ennenaikaiseen syntymään tavallisesti liittyvät komplikaatiot eivät vaikuta kokonaan selittävän varhaisen kasvun ja aikuisiän kognitiivisten taitojen välisiä yhteyksiä. Avainsanat: ennenaikainen syntymä; pikkukeskonen; raskausviikot; syntymäpaino; kognitio; älykkyys; toiminnanohjaus; muisti; mielenterveys; masennus; tarkkaavuus- ja ylivilkkaushäiriö; päihdehäiriöt; ahdistuneisuushäiriöt; koulutus; kasvu; painonnousu; pituus; päänympäryksen mittaus; energiansaanti; ihmismaito; imeväisikäinen; aikuinen; riskitekijät; seurantatutkimukset; pitkittäistutkimukset; varhainen ohjelmoitumishypotees

Neurocognitive outcome in young adults born late-preterm

Aim This study examined whether late-preterm birth (34+0 to 36+6wks+d gestational age) was associated with neurocognitive deficit in young adulthood, and whether small for gestational age (SGA) birth amplified any adversity. Method Participants derived from the prospective regional cohort study, the Arvo Ylppö Longitudinal Study (n=786; 398 females, 388 males) (mean age 25y 4mo, SD 8mo), born 1985 to 1986 late-preterm (n=119; 21 SGA, <−2 SD) and at term (37+0 to 41+6wks+d; n=667; 28 SGA) underwent tests of intelligence, executive functioning, attention, and memory, and reported their education. Results Those born late-preterm scored −3.71 (95% confidence interval [CI] −6.71 to −0.72) and −3.11 (95% CI −6.01 to −0.22) points lower on Full-scale and Verbal IQ than peers born at term. Compared with those born at term and appropriate for gestational age (≥−2 to <2 SD) Full-scale, Verbal, and Performance IQ scores of those born late-preterm and SGA were −9.45 to −11.84 points lower. After adjustments, differences were rendered non-significant, except that scores in Full-scale and Performance IQ remained lower among those born late-preterm and SGA. Interpretation Late-preterm birth, per se, may not increase the risk of poorer neurocognitive functioning in adulthood. But the double burden of being born late-preterm and SGA seems to increase this risk

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

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

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

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

Maternal Hypertensive Pregnancy Disorders and Mental 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

Nutrition after preterm birth and adult neurocognitive outcomes

Background Preterm birth ( Methods In 86 participants of the Helsinki Study of Very Low Birth Weight Adults (birthweight <1500g), we examined if higher intakes of energy, macronutrients, and human milk during the first nine weeks after preterm birth predict performance in tests of cognitive ability at 25.1 years of age (SD = 2.1). Results 10 kcal/kg/day higher total energy intake at 3 to 6 weeks of age was associated with 0.21 SD higher adult IQ (95% Confidence Interval [CI] 0.07-0.35). Higher carbohydrate and fat intake at 3-6 weeks, and higher energy intake from human milk at 3-6 and at 6-9 weeks were also associated with higher adult IQ: these effect sizes ranged from 0.09 SD (95% CI 0.01-0.18) to 0.34 SD (0.14-0.54) higher IQ, per one gram/kg/day more carbohydrate and fat, and per 10 kcal/kg/day more energy from human milk. Adjustment for neonatal complications attenuated the associations: intraventricular hemorrhage, in particular, was associated with both poorer nutrition and poorer IQ. Conclusion In preterm neonates with very low birth weight, higher energy and human milk intake predict better neurocognitive abilities in adulthood. To understand the determinants of these infants' neurocognitive outcome, it seems important to take into account the role of postnatal nutrition, not just as an isolated exposure, but as a potential mediator between neonatal illness and long-term neurodevelopment.Peer reviewe

Betamethasone administration during pregnancy is associated with placental epigenetic changes with implications for inflammation

Background Glucocorticoids (GCs) play a pivotal role in fetal programming. Antenatal treatment with synthetic GCs (sGCs) in individuals in danger of preterm labor is common practice. Adverse short- and long-term effects of antenatal sGCs have been reported, but their effects on placental epigenetic characteristics have never been systematically studied in humans. Results We tested the association between exposure to the sGC betamethasone (BET) and placental DNA methylation (DNAm) in 52 exposed cases and 84 gestational-age-matched controls. We fine-mapped associated loci using targeted bisulfite sequencing. The association of placental DNAm with gene expression and co-expression analysis on implicated genes was performed in an independent cohort including 494 placentas. Exposure to BET was significantly associated with lower placenta DNAm at an enhancer of FKBP5. FKBP5 (FK506-binding protein 51) is a co-chaperone that modulates glucocorticoid receptor activity. Lower DNAm at this enhancer site was associated with higher expression of FKBP5 and a co-expressed gene module. This module is enriched for genes associated with preeclampsia and involved in inflammation and immune response. Conclusions Our findings suggest that BET exposure during pregnancy associates with few but lasting changes in placental DNAm and may promote a gene expression profile associated with placental dysfunction and increased inflammation. This may represent a pathway mediating GC-associated negative long-term consequences and health outcomes in offspring.Peer reviewe

Cohort profile : InTraUterine sampling in early pregnancy (ITU), a prospective pregnancy cohort study in Finland: study design and baseline characteristics

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.Peer reviewe

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

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

Infant Growth after Preterm Birth and Mental Health in Young Adulthood

Objectives Faster growth after preterm birth benefits long-term cognitive functioning. Whether these benefits extend to mental health remains largely unknown. We examined if faster growth in infancy is associated with better self-reported mental health in young adults born preterm at very low birth weight (VLBW) ( Study Design As young adults, participants of the Helsinki Study of Very Low Birth Weight Adults self-reported symptoms of depression and attention deficit/hyperactivity disorder (ADHD) (n = 157) and other psychiatric problems (n = 104). As main predictors of mental health outcomes in linear regression models, we used infant weight, length, and head circumference at birth, term, and 12 months of corrected age, and growth between these time points. Growth data were collected from records and measures at term and at 12 months of corrected age were interpolated. Additionally, we examined the moderating effects of intrauterine growth restriction. Results Size at birth, term, or 12 months of corrected age, or growth between these time points were not associated with mental health outcomes (p-values >0.05). Intrauterine growth restriction did not systematically moderate any associations. Conclusions Despite the high variability in early growth of VLBW infants, the previously described association between slow growth in infancy and poorer cognitive functioning in later life is not reflected in symptoms of depression, ADHD, and other psychiatric problems. This suggests that the development of cognitive and psychiatric problems may have dissimilar critical periods in VLBW infants.Peer reviewe