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We sought to estimate the prevalence of autism spectrum disorder (ASD) in children born extremely preterm relative to the U.S. population risk of 1.5% [CDC, 2014] using the best-available diagnostic procedures and minimizing confounding with other neurodevelopmental impairments. Eight hundred and eighty nine of 966 (92%) 10-year-old children from the Extremely Low Gestational Age Newborn birth cohort, delivered at 23-27 weeks gestation in 2002-2004, participated. Children meeting ASD screening criteria on the Social Communication Questionnaire were evaluated with the Autism Diagnostic Interview-Revised (ADI-R). Those meeting ADI-R criteria were assessed with the Autism Diagnostic Observation Schedule-2 (ADOS-2). A positive ADOS-2 score was the criterion for ASD. Twenty-six participants were not assessed for ASD because of severe sensory or motor impairment. In the remaining sample, 61 children met criteria for ASD, resulting in a prevalence of 7.1% (95% CI = 5.5-9.0). ASD risk decreased with increasing gestational age, from 15.0% (95% CI = 10.0-21.2) for 23-24 weeks, 6.5% (95% CI = 4.2-9.4) for 25-26 weeks, to 3.4% (95% CI = 1.6-6.1) for 27 weeks gestational age, and this association was independent of IQ. Among children with ASD, 40% had intellectual disability. The male-to-female ratio of children with ASD was 2.1:1 (95% CI = 1.2:1-3.5:1), lower than in the general population (4:1). ASD prevalence in the ELGAN cohort was four times higher than in the general population, and was strongly associated with gestational age, underscoring the need for enhanced ASD screening of children born preterm, and suggesting that some risk factors associated with preterm birth may also play a role in the etiology of autism. Autism Res 2017, 10: 224-232. © 2016 International Society for Autism Research, Wiley Periodicals, Inc., (© 2016 International Society for Autism Research, Wiley Periodicals, Inc.)

Objective: To evaluate the hypothesis that elevated levels of inflammation-related proteins in early postnatal blood predict impaired mental and motor development in extremely preterm infants., Study Design: We measured concentrations of 25 inflammation-related proteins in blood collected on postnatal days 1, 7, and 14 from 939 infants born before 28 weeks gestation. An elevated level was defined as a concentration in the highest quartile for gestational age and day of blood collection. We identified impaired development at age 24 months using the Bayley Scales of Infant Development, Second Edition. The primary outcomes were scores on the Mental Scale or the Motor Scale of <55 (more than 3 SDs below the mean)., Results: For 17 of the 25 inflammation-related proteins, 1 or more statistically significant associations (P<.01) was found between an elevated blood level of the protein and a developmental impairment. Elevations on multiple days were more often associated with developmental impairment than were elevations present for only 1 day. The highest number of predictive elevations was found in day-14 blood., Conclusion: In extremely preterm infants, elevated levels of inflammation-related proteins in blood collected on postnatal days 7 and 14, especially when sustained, are associated with impaired mental and motor development at age 2 years., (Copyright © 2012 Mosby, Inc. All rights reserved.)

The Modified Checklist for Autism in Toddlers (M-CHAT) has yielded elevated rates of screening failure for children born preterm or with low birthweight. We extended these findings with a detailed examination of M-CHAT items in a large sample of children born at extremely low gestational age. The sample was grouped according to children's current limitations and degree of impairment. The aim was to better understand how disabilities might influence M-CHAT scores. Fourteen participating institutions of the Extremely Low Gestational Age Newborns (ELGAN) Study prospectively collected information about 1086 infants who were born before the 28th week of gestation and had an assessment at age 24-months. The 24-month visit included a neurological assessment, the Bayley Scales of Infant Development, Second edition (BSID-II), M-CHAT and a medical history form. Outcome measures included the distribution of failed M-CHAT items among groups classified according to cerebral palsy diagnosis, gross motor function, BSID-II scores and vision or hearing impairments. M-CHAT items were failed more frequently by children with concurrently identified impairments (motor, cognitive, vision and hearing). In addition, the frequency of item failure increased with the severity of impairment. The failed M-CHAT items were often, but not consistently, related to children's specific impairments. Importantly, four of the six M-CHAT 'critical items' were commonly affected by presence and severity of concurrent impairments. The strong association between impaired sensory or motor function and M-CHAT results among extremely low gestational age children suggests that such impairments might give rise to false positive M-CHAT screening., (© 2011 Blackwell Publishing Ltd.)

Background: We wanted to assess to what extent concentrations of circulating proteins appear to be developmentally regulated, and to what extent such regulation is influenced by intra-uterine inflammation., Methods: We measured 22 proteins in blood obtained on postnatal days 1, 7, and 14 from 818 children born before the 28th week of gestation for whom we also had information about placenta morphology., Results: Within the narrow gestational age range of this sample, some protein concentrations increase in blood with increasing gestational age. More commonly, the concentrations of inflammation-related proteins decrease with increasing gestational age. We observed this inverse pattern both in children whose placenta was and was not inflamed. CONCLUSIONS/INFERENCES: Regardless of whether or not the placenta is inflamed, the concentrations of inflammation-related proteins in early blood specimens appear to be developmentally regulated with the most common pattern being a decrease with increasing gestational age., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Aim: To see whether disorders prevalent in infants born extremely preterm cluster., Design: Observational cohort study., Setting:   University-affiliated newborn intensive care nurseries., Subjects:   One thousand two hundred and twenty-three infants born before the 28th week of gestation who survived until 36 weeks postmenstrual age when the diagnosis of bronchopulmonary dysplasia (BPD) could be made., Interventions:   None., Main Outcome Measures:   Cerebral white matter damage (an echolucent lesion, or moderate or severe ventriculomegaly on a protocol cranial ultrasound scan), BPD, retinopathy of prematurity (ROP), necrotizing enterocolitis (NEC) and early and late bacteremia., Results: After adjustment for gestational age, children who had severe NEC (Bell stage IIIb) were at increased risk of cerebral white matter damage, severe ROP (stage 3+), and severe BPD (defined as both oxygen and ventilator dependent). Children who had early bacteremia were at increased risk of late bacteremia and severe ROP. Those who had severe ROP were at increased risk of severe BPD and both early and late bacteremia., Conclusions:   Necrotizing enterocolitis is the disorder common to most of the clusters, but we do not know if its onset occurred before the others. Organ-damage-promoting substances, however, have been found in the circulation of newborn animals with bowel inflammation, supporting the view that NEC contributes to the damage of other organs., (© 2010 The Author(s)/Acta Paediatrica © 2010 Foundation Acta Paediatrica.)

Background: Studies of the relationship between ultrasound images from preterm newborns and developmental delay most often are based on small samples defined by birth weight and exclude infants not testable with standardized assessments., Methods: We evaluated associations between ultrasound-defined lesions of the brain and developmental delays at 24 months' corrected age in 1017 children born before the 28th postmenstrual week. Brain ultrasound scans were read for concordance on 4 lesions: intraventricular hemorrhage, moderate/severe ventriculomegaly, white matter echodense/hyperechoic lesions, and white matter echodense/hypoechoic lesions and 2 diagnoses-periventricular leukomalacia and periventricular hemorrhagic infarction. Certified examiners, who were not aware of the infants' ultrasound findings, administered the Bayley Scales of Infant Development-Second Edition. Children with an impairment (eg., blindness) that precluded testing with the Bayley Scales and those for whom >2 test items were omitted were classified using the Vineland Adaptive Behavior Scales Motor Skills Domain instead of the Psychomotor Development Index and the Adaptive Behavior Composite instead of the Mental Development Index., Results: Fully 26% of all of the children had delayed mental development (ie, Mental Development Index < 70), and 31% had delayed psychomotor development (ie, Psychomotor Development Index < 70). Ultrasound abnormalities were more strongly associated with low Psychomotor Development Index than with low Mental Development Index. Children without cranial ultrasound abnormality had the lowest probability (23% and 26%) of delayed mental or psychomotor development. Moderate/severe ventriculomegaly was associated with a more than fourfold increase in the risk of psychomotor delay and an almost threefold increase in the risk of mental delay. Echolucency was the next best predictor of delayed mental and psychomotor development. The probability of low scores varied with the number of zones involved and with the location of echolucency. At particularly high risk were infants with bilateral cerebellar hemorrhage, co-occurring ventriculomegaly and echolucency bilateral echolucency, or echolucency located posteriorly., Conclusions: Focal white matter damage, as characterized by echolucent/hypoechoic lesion, and diffuse damage, as suggested by late ventriculomegaly, are associated with delayed mental and psychomotor development.

Prenatal exposure to toxic metals is associated with altered placental function and adverse infant and child health outcomes. Adverse outcomes include those that are observed at the time of birth, such as low birthweight, as well as those that arise later in life, such as neurological impairment. It is often the case that these adverse outcomes show sex-specific responses in relation to toxicant exposures. While the precise molecular mechanisms linking in utero toxic metal exposures with later-in-life health are unknown, placental inflammation is posited to play a critical role. Here, we sought to understand whether in utero metal exposure is associated with alterations in the expression of the placental proteome by identifying metal associated proteins (MAPs). Within the Extremely Low Gestational Age Newborns (ELGAN) cohort (n = 230), placental and umbilical cord tissue samples were collected at birth. Arsenic (As), cadmium (Cd), lead (Pb), selenium (Se), and manganese (Mn) concentrations were measured in umbilical cord tissue samples via ICP-MS/MS. Protein expression was examined in placental samples using an LC-MS/MS-based, global, untargeted proteomics analysis measuring more than 3400 proteins. MAPs were then evaluated for associations with pregnancy and neonatal outcomes, including placental weight and gestational age. We hypothesized that metal levels would be positively associated with the altered expression of inflammation/immune-associated pathways and that sex-specific patterns of metal-associated placental protein expression would be observed. Sex-specific analyses identified 89 unique MAPs expressed in female placentas and 41 unique MAPs expressed in male placentas. Notably, many of the female-associated MAPs are known to be involved in immune-related processes, while the male-associated MAPs are associated with intracellular transport and cell localization. Further, several MAPs were significantly associated with gestational age in males and females and placental weight in males. These data highlight the linkage between prenatal metal exposure and an altered placental proteome, with implications for altering the trajectory of fetal development. [ABSTRACT FROM AUTHOR]

Background: Health outcomes among children born prematurely are known to be sexually dimorphic, with male infants often more affected, yet the mechanism behind this observation is not clear. CpG methylation levels in the placenta and blood also differ by sex and are associated with adverse health outcomes. We contrasted CpG methylation levels in the placenta and neonatal blood (n = 358) from the Extremely Low Gestational Age Newborn (ELGAN) cohort based on the EPIC array, which assays over 850,000 CpG sites across the epigenome. Sex-specific epigenome-wide association analyses were conducted for the placenta and neonatal blood samples independently, and the results were compared to determine tissue-specific differences between the methylation patterns in males and females. All models were adjusted for cell type heterogeneity. Enrichment pathway analysis was performed to identify the biological functions of genes related to the sexually dimorphic CpG sites. Results: Approximately 11,500 CpG sites were differentially methylated in relation to sex. Of these, 5949 were placenta-specific and 5361 were blood-specific, with only 233 CpG sites overlapping in both tissues. For placenta-specific CpG sites, 90% were hypermethylated in males. For blood-specific CpG sites, 95% were hypermethylated in females. In the placenta, keratinocyte differentiation biological pathways were enriched among the differentially methylated genes. No enrichment pathways were observed for blood. Conclusions: Distinct methylation patterns were observed between male and female children born extremely premature, and keratinocyte differentiation pathways were enriched in the placenta. These findings provide new insights into the epigenetic mechanisms underlying sexually dimorphic health outcomes among extremely premature infants. [ABSTRACT FROM AUTHOR]

As the master regulator in utero, the placenta is core to the Developmental Origins of Health and Disease (DOHaD) hypothesis but is historically understudied. To identify placental gene-trait associations (GTAs) across the life course, we perform distal mediator-enriched transcriptome-wide association studies (TWAS) for 40 traits, integrating placental multi-omics from the Extremely Low Gestational Age Newborn Study. At P < 2.5 × 10 − 6 , we detect 248 GTAs, mostly for neonatal and metabolic traits, across 176 genes, enriched for cell growth and immunological pathways. In aggregate, genetic effects mediated by placental expression significantly explain 4 early-life traits but no later-in-life traits. 89 GTAs show significant mediation through distal genetic variants, identifying hypotheses for distal regulation of GTAs. Investigation of one hypothesis in human placenta-derived choriocarcinoma cells reveal that knockdown of mediator gene EPS15 upregulates predicted targets SPATA13 and FAM214A, both associated with waist-hip ratio in TWAS, and multiple genes involved in metabolic pathways. These results suggest profound health impacts of placental genomic regulation in developmental programming across the life course. The impact of placental transcriptomics on fetal traits throughout development is not well understood. Here, the authors apply distal-SNP-enriched transcriptome-wide association studies to detect genetic contributions, mediated through fetal placental genomics, to developmental programming of complex traits across the life course. [ABSTRACT FROM AUTHOR]

The authors hypothesized that the risk of cerebral palsy at 2 years in children born extremely preterm to overweight and obese women is increased relative to the risk among children born to neither overweight nor obese women. In a multicenter prospective cohort study, the authors created multinomial logistic regression models of the risk of diparetic, quadriparetic, and hemiparetic cerebral palsy that included the prepregnancy body mass index of mothers of 1014 children born extremely preterm, cerebral palsy diagnoses of children at 2 years, as well as information about potential confounders. Overweight and obese women were not at increased risk of giving birth to a child who had cerebral palsy. The risk ratios associated with overweight varied between 1.1 for quadriparesis (95% CI = 0.5, 2.1) to 2.0 for hemiparesis (95% CI = 0.4, 9.8). The risk ratios associated with obesity varied between 0.7 for diparesis (95% CI = 0.2, 2.5) to 2.5 for hemiparesis (95% CI = 0.4, 13). [ABSTRACT FROM AUTHOR]

Aim: Compared to infants born at term, children born very preterm are at increased risk of visual dysfunctions and neonatal systemic inflammation. Here, we explore whether these two propensities are related.Methods: As part of the ELGAN study, the concentrations of 16 mediators of inflammation were measured in blood obtained on postnatal days 1, 7, 14, 21 and 28 from 1062 children born before the 28th week of gestation. Presence of visual field deficit, strabismus and/or impaired visual fixation was recorded at age two. The concentrations of each protein were divided into quartiles within gestational week categories. We calculated odds ratios with 99% confidence intervals for having each disorder comparing children with concentration in the top quartile of each protein to children whose concentration was in the lower quartiles on the corresponding day. Analyses were adjusted for gestational age and birth weight Z-score.Results: Only one of 80 assessments (16 proteins on five different days) was significant for visual field deficit, and one for impaired fixation. No association was found between strabismus and any inflammatory mediator.Conclusion: None of the three neuro-ophthalmologic dysfunctions assessed at two years appears to be associated with systemic inflammation measured the first four postnatal weeks. [ABSTRACT FROM AUTHOR]

Extremely low gestational age newborns (ELGANs, <28 completed weeks of gestation) that exhibit fetal and neonatal systemic inflammatory responses are at increased risk for developmental adversity, especially if the inflammatory process is sustained. We evaluated pro-inflammatory cytokine patterns in whole blood of 1220 ELGANs on one or more of postnatal days 1, 7, 14, 21, and 28. Protein concentrations were divided into quartiles within gestational week categories. We calculated odds ratios (OR) with 99 % confidence intervals (CI) for having a concentration in the top quartile for each protein given that the infant had a protein concentration in the top quartile 1 week or more earlier compared to infants who did not. ELGANs who have elevated systemic levels of IL-6R, TNF- α, or RANTES on their first postnatal day are approximately twice as likely to have elevated levels of these cytokines at the end of each of the first postnatal month. In some, this twofold risk increase persisted for the entire first postnatal month. In extremely preterm newborns, inflammatory processes can be sustained over weeks. [ABSTRACT FROM AUTHOR]

Aim To evaluate to what extent extremely preterm children (<28 weeks' gestational age) of overweight ( BMI 25-29) or obese ( BMI ≥30) women are at increased risk of adverse development at 2 years measured with the Bayley Scales of Infant Development II in a multicenter prospective cohort study. Methods Heights and prepregnancy weights of the mothers of 852 preterm born children were collected and included in multinomial logistic regression models. Results Compared to newborns born to mothers with normal BMIs, newborns of obese mothers, but not those of overweight mothers, were more likely to have Bayley Scales indices more than 3 standard deviations below the reference mean (mental: OR = 2.1; 95% CI: 1.3, 3.5) (motor: OR = 1.7; 95% CI: 1.1, 2.7). These associations were even more prominent in children who did not have the intermittent or sustained systemic inflammation profile previously shown to be associated with severely impaired development (mental: OR = 4.6; 95% CI: 1.6, 14) (motor: OR = 3.7; 95% CI: 1.5, 8.9). Conclusion Maternal obesity is associated with an increased risk of impaired offspring development. Some of this impaired development cannot be attributed to confounding due to immaturity, socio-economic correlates or neonatal systemic inflammation. [ABSTRACT FROM AUTHOR]

Whether intraventricular hemorrhage increases the risk of adverse developmental outcome among premature infants is controversial. Using brain ultrasound, we identified intraventricular hemorrhage and white matter abnormalities among 1064 infants born before 28 weeks’ gestation. We identified adverse developmental outcomes at 24 months of age using a standardized neurologic examination and the Bayley Scales of Infant Development Mental and Motor Scales. In logistic regression models that adjusted for gestational age, sex, and public insurance, isolated intraventricular hemorrhage was associated with visual fixation difficulty but no other adverse outcome. Infants who had a white matter lesion unaccompanied by intraventricular hemorrhage were at increased risk of cerebral palsy, low Mental and Motor Scores, and visual and hearing impairments. Except when accompanied or followed by a white matter lesion, intraventricular hemorrhage is associated with no more than a modest increase (and possibly no increase) in the risk of adverse developmental outcome during infancy. [ABSTRACT FROM PUBLISHER]

The authors explored associations between blood gas abnormalities in more than 1,000 preterm infants during the first postnatal days and indicators of neonatal brain damage. During 2002–2004, women delivering infants before 28 weeks’ gestation at one of 14 participating institutions in 5 US states were asked to enroll in the study. The authors compared infants with blood gas values in the highest or lowest quintile for gestational age and postnatal day (extreme value) on at least 1 of the first 3 postnatal days with the remainder of the subjects, with separate analyses for blood gas abnormalities on multiple days and for partial pressure of oxygen in the alveolar gas of <35. Outcomes analyzed were ventriculomegaly and an echolucent lesion on an ultrasound scan in the neonatal intensive care unit, and cerebral palsy, microcephaly, and a low score on a Bayley Scale of Infant Development at 24 months. Every blood gas derangement (hypoxemia, hyperoxemia, hypocapnia, hypercapnia, and acidosis) was associated with multiple indicators of brain damage. However, for some, the associations were seen with only 1 day of exposure; others were evident with 2 or more days’ exposure. Findings suggest that individual blood gas derangements do not increase brain damage risk. Rather, the multiple derangements associated with indicators of brain damage might be indicators of immaturity/vulnerability and illness severity. [ABSTRACT FROM PUBLISHER]

Abstract: Background: Little is known about the antecedents of microcephaly in early childhood among children born at extremely low gestational age. Aim: To identify some of the antecedents of microcephaly at age two years among children born before the 28th week of gestation. Study design: Observational cohort study. Subjects: 1004 infants born before the 28th week of gestation. Outcome measures: Head circumference Z-scores of <−2 and ≥−2, <−1. Results: Risk of microcephaly and a less severely restricted head circumference decreased monotonically with increasing gestational age. After adjusting for gestational age and other potential confounders, the risk of microcephaly at age 2years was increased if microcephaly was present at birth [odds ratio: 8.8 ((95% confidence interval: 3.7, 21)], alpha hemolytic Streptococci were recovered from the placenta parenchyma [2.9 (1.2, 6.9)], the child was a boy [2.8 (1.6, 4.9)], and the child''s mother was not married [2.5 (1.5, 4.3)]. Antecedents associated not with microcephaly, but with a less extreme reduction in head circumference were recovery of Propionibacterium sp from the placenta parenchyma [2.9 (1.5, 5.5)], tobacco exposure [2.0 (1.4, 3.0)], and increased syncytial knots in the placenta [2.0 (1.2, 3.2)]. Conclusions: Although microcephaly at birth predicts a small head circumference at 2years among children born much before term, pregnancy and maternal characteristics provide supplemental information about the risk of a small head circumference years later. Two findings appear to be novel. Tobacco exposure during pregnancy, and organisms recovered from the placenta predict reduced head circumference at age two years. [Copyright &y& Elsevier]

The neonatal predictors of microcephaly, defined as a head circumference <5th centile in children born preterm, has not been systematically assessed. Children were drawn from the Developmental Epidemiology Network (DEN) cohort of very low-birthweight children (VLBW: 500-1500g) born from 1991 to 1993 at three sites in the USA. Neurological assessments were carried out among 198 singleton children (mean age 6 years 8 months, SD 0.5 years). Ninety-six children (48.5%) were male. Microcephaly was observed in 30 children (15%) and, using multivariate analysis, it was found to be associated with gestational age <26 weeks and bronchopulmonary dysplasia (BPD). Sonography-defined white-matter damage (WMD, i.e. echolucency or echodensities) was not associated with increased odds of microcephaly, while occurrence of intraventricular hemorrhage (IVH) was in univariate but not multivariate analysis. In analyses that excluded children with IVH/WMD, odds of microcephaly increased in dose-related fashion according to number of days on ventilator: >5 days, OR=4.5; 95%CI=1.4 to 15; >10 days, OR=5.7; 95%CI=1.7 to 19; >15 days OR=8.3; 95% CI=2.3 to 29.2. Among children without BPD, microcephaly was not associated with differences in IQ, while IQ scores among children with BPD or any ventilation were disproportionately lower among those with microcephaly. In multivariate analyses predicting IQ at age 7 years, microcephaly was found to modify the association between neonatal lung disease and IQ. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Evidence-based care of extremely preterm infants (<28 weeks' gestation) depends heavily on research in which a primary outcome is infant neurodevelopmental impairment (NDI), yet it is unclear how well NDI in infancy predicts long-term NDI. In this study, we aim to assess the relationship between 2- and 10-year neurodevelopment using a well-known 2-year definition and a 10-year definition developed by an expert panel. METHODS: Using data from the Extremely Low Gestational Age Newborn Study cohort, we classified 2-year NDI using definitions developed by the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. We classified 10-year NDI using definitions developed by an expert panel, which added epilepsy and ASD at 10 years. RESULTS: Of 1506 infants, 80% survived. Data sufficient to classify severity of NDI at both 2 and 10 years were available for 67% of survivors (n = 802). Among children classified as having moderate to severe NDI at 2 years, 63% had none to mild NDI at 10 years; among children classified as having profound NDI at 2 years, 36% had none to mild NDI at 10 years. Cohen's κ statistic indicated minimal to fair agreement between NDI at 2 and 10 years (0.34, P < .001). CONCLUSIONS: NDI in infancy, as defined in this study, only weakly predicts NDI in middle childhood. For the parents at risk for delivery of an extremely preterm infant, a hopeful message can be taken from our findings that one-third of surviving children classified as having profound NDI and nearly two-thirds of those classified as having moderate to severe NDI at 2 years had none to mild NDI at 10 years. [ABSTRACT FROM AUTHOR]

Background: No prospective cohort study of high-risk children has used rigorous exposure assessment and optimal diagnostic procedures to examine the perinatal antecedents of autism spectrum disorder separately among those with and without cognitive impairment.Objective: We sought to identify perinatal factors associated with increased risk for autism spectrum disorder with and without intellectual disability (intelligence quotient <70) in children born extremely preterm.Study Design: This prospective multicenter (14 institutions in 5 states) birth cohort study included children born at 23-27 weeks' gestation in 2002 through 2004 who were evaluated for autism spectrum disorder and intellectual disability at age 10 years. Pregnancy information was obtained from medical records and by structured maternal interview. Cervical-vaginal "infection" refers to maternal report of bacterial infection (n = 4), bacterial vaginosis (n = 30), yeast infection (n = 62), mixed infection (n = 4), or other/unspecified infection (n = 43; eg, chlamydia, trichomonas, or herpes). We do not know the extent to which infection per se was confirmed by microbial colonization. We use the terms "fetal growth restriction" and "small for gestational age" interchangeably in light of the ongoing challenge to discern pathologically from constitutionally small newborns. Severe fetal growth restriction was defined as a birthweight Z-score for gestational age at delivery <-2 (ie, ≥2 SD below the median birthweight in a referent sample that excluded pregnancies delivered for preeclampsia or fetal indications). Participants were classified into 4 groups based on whether or not they met rigorous diagnostic criteria for autism spectrum disorder and intellectual disability (autism spectrum disorder+/intellectual disability-, autism spectrum disorder+/intellectual disability+, autism spectrum disorder-/intellectual disability+, and autism spectrum disorder-/intellectual disability-). Temporally ordered multinomial logistic regression models were used to examine the information conveyed by perinatal factors about increased risk for autism spectrum disorder and/or intellectual disability (autism spectrum disorder+/intellectual disability-, autism spectrum disorder+/intellectual disability+, and autism spectrum disorder-/intellectual disability+).Results: In all, 889 of 966 (92%) children recruited were assessed at age 10 years, of whom 857 (96%) were assessed for autism spectrum disorder; of these, 840 (98%) children were assessed for intellectual disability. Autism spectrum disorder+/intellectual disability- was diagnosed in 3.2% (27/840), autism spectrum disorder+/intellectual disability+ in 3.8% (32/840), and autism spectrum disorder-/intellectual disability+ in 8.5% (71/840). Maternal report of presumed cervical-vaginal infection during pregnancy was associated with increased risk of autism spectrum disorder+/intellectual disability+ (odds ratio, 2.7; 95% confidence interval, 1.2-6.4). The lowest gestational age category (23-24 weeks) was associated with increased risk of autism spectrum disorder+/intellectual disability+ (odds ratio, 2.9; 95% confidence interval, 1.3-6.6) and autism spectrum disorder+/intellectual disability- (odds ratio, 4.4; 95% confidence interval, 1.7-11). Severe fetal growth restriction was strongly associated with increased risk for autism spectrum disorder+/intellectual disability- (odds ratio, 9.9; 95% confidence interval, 3.3-30), whereas peripartum maternal fever was uniquely associated with increased risk of autism spectrum disorder-/intellectual disability+ (odds ratio, 2.9; 95% confidence interval, 1.2-6.7).Conclusion: Our study confirms that low gestational age is associated with increased risk for autism spectrum disorder irrespective of intellectual ability, whereas severe fetal growth restriction is strongly associated with autism spectrum disorder without intellectual disability. Maternal report of cervical-vaginal infection is associated with increased risk of autism spectrum disorder with intellectual disability, and peripartum maternal fever is associated with increased risk for intellectual disability without autism spectrum disorder. [ABSTRACT FROM AUTHOR]

BACKGROUND AND OBJECTIVES: Extremely low gestational age neo- nates are more likely than term infants to develop cognitive impairment. Few studies have addressed antenatal risk factors of this condition. We identified antenatal antecedents of cognitive impairment determined by the Mental Development Index (MDI) portion of the Bayley Scales of Infant Development, Second Edition (BSID-II), at 24 months corrected age. METHODS: We studied a multicenter cohort of 921 infants born before 28 weeks of gestation during 2002 to 2004 and assessed their placentas for histologie characteristics and microorganisms. The mother was interviewed and her medical record was reviewed. At 24 months adjusted age, children were assessed with BSID-II. Multinomial logistic models were used to estimate odds ratios. RESULTS: A total of 103 infants (11%) had an MDI <55, and 99 infants (11%) had an MDI between 55 and 69. No associations were identified between organisms recovered from the placenta and developmental delay. Factors most strongly associated with MDI <55 were thrombosis of fetal vessels (OR 3.1; 95% confidence interval [CI] 1.2, 7.7), maternal BMI >30 (OR 2.0; 95% CI 1.1, 3.5), maternal education <12 years (OR 3.4; 95% C11.9, 6.2), nonwhite race (OR 2.2,95% CI 1.3, 3.8), birth weight /score < -2 (OR 2.8; 95% CI 1.1, 6.9), and male gender (OR 2.7; 95% CI 1.6, 4.5). CONCLUSIONS: Antenatal factors, including thrombosis of fetal vessels in the placenta, severe fetal growth restriction, and maternal obesity, convey information about the risk of cognitive impairment among extremely premature newborns. [ABSTRACT FROM AUTHOR]

BACKGROUND: Childhood obesity is a pervasive public health problem with risk factors such as maternal prepregnancy BMI and rapid infant weight gain. Although catch-up weight gain promotes more favorable neurodevelopment among infants born preterm, it is not clear whether faster weight gain early in life, or other correlates of preterm birth, are associated with later obesity in this population. METHODS: We used prospective data from the multicenter, observational Extremely Low Gestational Age Newborn Study. Among 1506 eligible individuals in the initial cohort, 1198 were eligible for follow-up at 10 years of age. We examined BMI in 871 children (58% of the cohort; 74% of survivors) and analyzed relationships between antecedents and overweight or obesity at 10 years of age. A time-oriented approach to multinomial multivariable regression enabled us to calculate odds of overweight and obesity associated with pre- and postnatal antecedents. RESULTS: Prepregnancy maternal BMI -25 and top quartile infant weight gain in the first year were associated with increased risk of both overweight and obesity at 10 years of age. Single marital status was a risk factor for later child obesity and exposure to tobacco smoke was a risk factor for later child overweight. CONCLUSIONS: The risk profiles for overweight and obesity at 10 years of age among children born extremely preterm appear to be similar to the risk profiles of overweight and obesity among children born at term. [ABSTRACT FROM AUTHOR]

Objective: We evaluated the incidence of seizures and epilepsy in the first decade of life among children born extremely premature (less than 28 weeks' gestation).Method: In a prospective, multicenter, observational study, 889 of 966 eligible children born in 2002 to 2004 were evaluated at two and ten years for neurological morbidity. Complementing questionnaire data to determine a history of seizures, all caregivers were interviewed retrospectively for postneonatal seizures using a validated seizure screen followed by a structured clinical interview by a pediatric epileptologist. A second pediatric epileptologist established an independent diagnosis based on recorded responses of the interview. A third epileptologist determined the final diagnosis when evaluators disagreed (3%). Life table survival methods were used to estimate seizure incidence through ten years.Results: By age ten years, 12.2% (95% confidence interval: 9.8, 14.5) of children had experienced one or more seizures, 7.6% (95% confidence interval: 5.7, 9.5) had epilepsy, 3.2% had seizure with fever, and 1.3% had a single, unprovoked seizure. The seizure incidence increased with decreasing gestational age. In more than 75% of children with seizures, onset was after one year of age. Seizure incidence was comparable in both sexes. Two-thirds of those with epilepsy had other neurological disorders. One third of children with epilepsy were not recorded on the medical history questionnaire.Significance: The incidence of epilepsy through age ten years among children born extremely premature is approximately 7- to 14-fold higher than the 0.5% to 1% lifetime incidence reported in the general pediatric population. Seizures in this population are under-recognized, and possibly underdiagnosed, by parents and providers. [ABSTRACT FROM AUTHOR]

Aim To identify the antecedents and very early correlates of low concentrations of neurotrophic growth factors in the blood of extremely preterm newborns during the first postnatal month. Methods Using an immunobead assay, we measured the concentrations of neurotrophin 4 (NT4), brain-derived neurotrophic factor (BDNF), and basic fibroblast growth factor (bFGF) in blood spots collected on postnatal days 1 (N = 1062), 7 (N = 1087), 14 (N = 989), 21 (N = 940) and 28 (N = 880) from infants born before the 28th week of gestation. We then sought the correlates of measurements in the top and bottom quartiles for gestational age and day the specimen was collected. Results The concentrations of 2 neurotrophic proteins, NT4 and BDNF, were low among children delivered for medical (maternal or fetal) indications, and among those who were growth restricted. Children who had top quartile concentrations of NT4, BDNF, and bFGF tended to have elevated concentrations of inflammation-related proteins that day. This pattern persisted for much of the first postnatal month. Conclusions Delivery for medical indications and fetal growth restriction are associated with a relative paucity of NT4 and BDNF concentrations during the first 24 h after very preterm birth. Elevated blood concentrations of NT4, BDNF, and bFGF tended to co-occur with indicators of systemic inflammation on the same day. [ABSTRACT FROM AUTHOR]

Objective: Extremely preterm newborns are at heightened risk for emotional and behavioral dysregulation later in childhood. Our goal was to systematically evaluate the antenatal and early postnatal antecedents that might mediate the association between extreme preterm birth and emotional and behavioral dysregulation at age 2 years (corrected age).Method: In a multi-site prospective study, the parents of 826 infants born before 28 weeks gestation completed a Child Behavior Checklist (CBCL) when the child was 2 years corrected age. We compared the maternal, pregnancy, placenta, delivery, and newborn characteristics, as well as early postnatal characteristics and exposures of those who satisfied criteria for the CBCL-Dysregulation Profile (CBCL-DP) to those of their peers. We then used time-oriented logistic regression models, starting first with antenatal variables that distinguished children with the CBCL-DP profile from their peers, and then added the distinguishing postnatal variables.Results: Approximately 9% of the children had a CBCL-DP. In the time-oriented logistic regression model with antenatal variables only, low maternal education achievement, passive smoking, and recovery of Mycoplasma from the placenta were associated with increased risk, whereas histologic chorioamnionitis was associated with reduced risk. None of the postnatal variables added statistically significant discriminating information.Conclusion: Very preterm newborns who later manifest the CBCL-DP at age 2 years differ in multiple ways from their preterm peers who do not develop the CBCL-DP, raising the possibility that potentially modifiable antenatal and early postnatal phenomena contribute to the risk of developing emotional and behavioral dysregulation. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the prevalence, co-occurrence, sex differences, and functional correlates of DSM-5 psychiatric disorders in 15-year-old adolescents born extremely preterm.Method: The Extremely Low Gestational Age Newborns (ELGAN) Study is a longitudinal study of children born <28 weeks gestation. At age 15, 670 adolescents completed the Mini-International Neuropsychiatric Interview for Children and Adolescents (MINI-KID), the Youth Self-Report, a disability scale of participation in social roles, and cognitive testing. Parents completed a family psychiatric history questionnaire.Results: The most prevalent psychiatric disorders were anxiety, attention-deficit/hyperactivity disorder, and major depression. More girls met criteria for anxiety than boys. Though 66% of participants did not meet criteria for a psychiatric disorder, 15% met criteria for 1, 9% for 2, and 8% for ≥3 psychiatric disorders. Participants with ≥2 psychiatric disorders were more likely to have repeated a grade, to have an individualized educational program, and to have a lower nonverbal IQ than those with no psychiatric disorders. Participants with any psychiatric disorder were more likely to use psychotropic medications; to have greater cognitive and functional impairment; and to have mothers who were single, were on public health insurance, and had less than a high school education. Finally, a positive family psychiatric history was identified more frequently among adolescents with ≥3 psychiatric disorders.Conclusion: Among adolescents born extremely preterm, anxiety, major depression, and attention-deficit/hyperactivity disorder were the most prevalent psychiatric disorders at age 15. Adolescents with >1 psychiatric disorder were at increased risk for multiple functional and participatory challenges. [ABSTRACT FROM AUTHOR]

Abstract: Background: The offspring of obese women are at increased risk for systemic inflammation. Blood concentrations of inflammatory proteins in preterm newborns of obese women have not been reported. Aim: To compare blood concentrations in the highest quartile for gestational age of inflammatory proteins and day of blood specimen collection on two days at least one week apart of newborns of overweight (i.e., BMI 25–29) and obese women (i.e., BMI≥30) with newborns of women with lower BMIs. Because deliveries for spontaneous indications are more likely than those for other indications to be associated with inflammation, we evaluated spontaneous indication deliveries separately from maternal or fetal indications. Study design: Prospective cohort study. Subjects and outcome measures: We measured from 939 children born before the 28th week of gestation 25 inflammation-related proteins in blood obtained on postnatal day 1 (range 1–3), day 7 (range 5–8) and day 14 (range 12–15). Results: Among infants delivered for spontaneous indications, maternal BMI was not related to elevated concentrations of any protein. Among infants delivered for maternal (i.e., preeclampsia) or fetal indications, those whose mother was overweight or obese were more likely than others to have elevated concentrations of inflammation proteins. Conclusions: Maternal pre-pregnancy overweight and obesity appear to contribute to a pro-inflammatory state in very preterm newborns delivered for maternal or fetal indications. Our failure to see a similar pattern among newborns delivered for spontaneous indications, which often have inflammatory characteristics, might reflect competing risks. [Copyright &y& Elsevier]

Abstract: Background: The newborn classified as growth-restricted on fetal weight curves, but not on birth weight curves, is classified prenatally as small for gestational age (SGA), but postnatally as appropriate for gestational age (AGA). Aims: To see (1) to what extent the neurodevelopmental outcomes at 24months corrected age differed among three groups of infants (those identified as SGA based on birth weight curves (B-SGA), those identified as SGA based on fetal weight curves only (F-SGA), and the referent group of infants considered AGA, (2) if girls and boys were equally affected by growth restriction, and (3) to what extent neurosensory limitations influenced what we found. Study design: Observational cohort of births before the 28th week of gestation. Outcome measures: Mental Development Index (MDI) and Psychomotor Development Index (PDI) of the Bayley Scales of Infant Development II. Results: B-SGA, but not F-SGA girls were at an increased risk of a PDI<70 (OR=2.8; 95% CI: 1.5, 5.3) compared to AGA girls. B-SGA and F-SGA boys were not at greater risk of low developmental indices than AGA boys. Neurosensory limitations diminished associations among girls of B-SGA with low MDI, and among boys B-SGA and F-SGA with PDI<70. Conclusions: Only girls with the most severe growth restriction were at increased risk of neurodevelopmental impairment at 24months corrected age in the total sample. Neurosensory limitations appear to interfere with assessing growth restriction effects in both girls and boys born preterm. [Copyright &y& Elsevier]

INTRODUCTION: Extremely low gestational age newborns (ELGANs) are at increased risk of chronic lung disease (CLD) and of developmental delay. Some studies have suggested that CLD contributes to developmental delay. PATIENTS AND METHODS: We examined data collected prospectively on 915 infants born before the 28th week of gestation in 2002-2004 who were assessed at 24 months of age with the Bayley Scales of Infant Development 2nd Edition or the Vineland Adaptive Behavior Scales. We excluded infants who were not able to walk independently (Gross Motor Function Classification System score < 1) and, therefore, more likely to have functionally important fine motor impairments. We defined CLD as receipt of oxygen at 36 weeks' postmenstrual age and classified infants as either not receiving mechanical ventilation (MV) (CLD without MV) or receiving MV (CLD with MV). RESULTS: Forty-nine percent of ELGANs had CLD; of these, 14% were receiving MV at 36 weeks' postmenstrual age. ELGANs without CLD had the lowest risk of a Mental Developmental Index (MDI) or a Psychomotor Developmental Index (PDI) of <55, followed by ELGAN5 with CLD not receiving MV, and ELGANs with CLD receiving MV (9%, 12%, and 18% for the MDI and 7%, 10%, and 20% for the PDI, respectively). In time-oriented multivariate models, the risk of an MDI of <55 was associated with the following variables: gestational age of <25 weeks; single mother; late bacteremia; pneumothorax; and necrotizing enterocolitis. The risk of a PDI of <55 was associated with variables such as single mother, a complete course of antenatal corticosteroids, early and persistent pulmonary dysfunction, pulmonary deterioration during the second postnatal week, pneumothorax, and pulmonary interstitial emphysema. CLD, without or with MV, was not associated with the risk of either a low MDI or a low PDI. However, CLD with MV approached, but did not achieve, nominal statistical significance (odds ratio: 1.9 [95% confidence interval: 0.97-3.9]) for the association with a PD1 of <55. CONCLUSIONS: Among children without severe gross motor delays, risk factors for CLD account for the association between CLD and developmental delay. Once those factors are considered in time-oriented risk models, CLD does not seem to increase the risk of either a low MDI or a low PD1. However, severe CLD might increase the risk of a low PDI. [ABSTRACT FROM AUTHOR]