Development of a Self-Report Measure of Prediction in Daily Life: The Prediction-Related Experiences Questionnaire.

PURPOSE: Predictions are complex, multisensory, and dynamic processes involving real-time adjustments based on environmental inputs. Disruptions to prediction abilities have been proposed to underlie characteristics associated with autism. While there is substantial empirical literature related to prediction, the field lacks a self-assessment measure of prediction skills related to daily tasks. Such a measure would be useful to better understand the nature of day-to-day prediction-related activities and characterize these abilities in individuals who struggle with prediction. METHODS: An interdisciplinary mixed-methods approach was utilized to develop and validate a self-report questionnaire of prediction skills for adults, the Prediction-Related Experiences Questionnaire (PRE-Q). Two rounds of online field testing were completed in samples of autistic and neurotypical (NT) adults. Qualitative feedback from a subset of these participants regarding question content and quality was integrated and Rasch modeling of the item responses was applied. RESULTS: The final PRE-Q includes 19 items across 3 domains (Sensory, Motor, Social), with evidence supporting the validity of the measure's 4-point response categories, internal structure, and relationship to other outcome measures associated with prediction. Consistent with models of prediction challenges in autism, autistic participants indicated more prediction-related difficulties than the NT group. CONCLUSIONS: This study provides evidence for the validity of a novel self-report questionnaire designed to measure the day-to-day prediction skills of autistic and non-autistic adults. Future research should focus on characterizing the relationship between the PRE-Q and lab-based measures of prediction, and understanding how the PRE-Q may be used to identify potential areas for clinical supports for individuals with prediction-related challenges.

Association of Growth During Infancy with Neurodevelopment and Obesity in Children Born Very Preterm: The Environmental Influences on Child Health Outcomes Cohort.

OBJECTIVE: To evaluate associations between change in weight z score after neonatal intensive care unit (NICU) discharge and neurodevelopmental outcomes and obesity at 12-48 months of age among individuals born very preterm. STUDY DESIGN: This secondary analysis used data from infants born very preterm participating in the Environmental influences on Child Health Outcomes cohort (n = 1400). Growth during infancy was calculated as change in weight z score between NICU discharge and follow-up at a mean of 27 months of age. Very low weight gain was defined as a change in weight z score <-1.67; very high weight gain was a change in weight z score >1.67. Neurodevelopmental outcomes included the Bayley Scales of Infant and Toddler Development, Child Behavior Checklist 1.5-5 years, and Modified Checklist for Autism in Toddlers. Multivariable linear regression was used to estimate associations between increase in weight z score and neurodevelopmental outcomes. RESULTS: Very low weight gain between NICU discharge and follow-up (experienced by 6.4% of participants) was associated with lower scores on cognitive (adjusted mean difference: -4.26; 95% CI: -8.55, -0.04) and language (adjusted mean difference: -4.80; 95% CI: -9.70, -0.11) assessments. Very high weight gain (experienced by 13.6% of participants) was associated with an increased obesity risk (adjusted relative risk: 6.20; 95% CI: 3.99, 9.66) but not with neurodevelopmental outcomes. CONCLUSIONS: Very high weight gain in the first 12-48 months after NICU discharge was associated with a higher risk of obesity at follow-up; very low weight gain was associated with lower scores on cognitive and language assessments.

Cerebral Palsy and Motor Impairment After Extreme Prematurity: Prediction of Diagnoses at Ages 2 and 10 Years.

OBJECTIVE: To identify perinatal factors in children born extremely preterm (EP) that were associated with motor impairment (MI) at 2 and 10 years of age and develop a predictive algorithm to estimate the risk of MI during childhood. STUDY DESIGN: Participants of the Extremely Low Gestational Age Newborns Study (ELGANS) were classified as: no MI, MI only at 2 years, MI only at 10 years, and MI at both 2 and 10 years, based on a standardized neurological examination at 2 and the Gross Motor Function Classification System (GMFCS) at 10 years of age. Least Absolute Shrinkage and Selection Operator (LASSO) regression was used to develop the final predictive model. RESULTS: Of the 849 study participants, 64 (7.5%) had a diagnosis of MI at both 2 and 10 years and 63 (7.4%) had a diagnosis of MI at 1 visit but not the other. Of 22 total risk factors queried, 4 variables most reliably and accurately predicted MI: gestational age, weight z-score growth trajectory during neonatal intensive care unit (NICU) stay, ventriculomegaly, and cerebral echolucency on head ultrasound. By selecting probability thresholds of 3.5% and 7.0% at ages 2 and 10, respectively, likelihood of developing MI can be predicted with a sensitivity and specificity of 71.2%/72.1% at age 2 and 70.7%/70.7% at age 10. CONCLUSION: In our cohort, the diagnosis of MI at 2 years did not always predict a diagnosis of MI at 10 years. Specific risk factors are predictive of MI and can estimate an individual infant's risk at NICU discharge of MI at age 10 years.

Developmental characteristics and accuracy of autism screening among two-year-old toddlers in the ECHO program.

BACKGROUND: The Modified Checklist for Autism in Toddlers (M-CHAT) is a common pediatric screening tool with mixed accuracy findings. Prior evidence supports M-CHAT screening for developmental concerns, especially in toddlers born preterm. This study examined M-CHAT accuracy in a large, nationwide sample. METHODS: 3393 participants from the Environmental influences on Child Health Outcomes (ECHO) program were included. Harmonized M-CHAT (M-CHAT-H) results were compared with parent-reported autism diagnosis and autism-related characteristics to assess accuracy for term and preterm children, together and separately. Generalized estimating equations, clustering for ECHO cohort and controlling for demographic covariates, were used to examine associations between developmental and behavioral characteristics with M-CHAT-H accuracy. RESULTS: Sensitivity of the M-CHAT-H ranged from 36 to 60%; specificity ranged from 88 to 99%. Positive M-CHAT-H was associated with more developmental delays and behavior problems. Children with severe motor delays and more autism-related problems were more likely to have a false-negative M-CHAT-H. Children with fewer behavior problems and fewer autism-related concerns were more likely to have a false-positive screen. CONCLUSION: The M-CHAT-H accurately detects children at low risk for autism and children at increased risk with moderate accuracy. These findings support use of the M-CHAT-H in assessing autism risk and developmental and behavioral concerns in children. IMPACT: Previous literature regarding accuracy of the Modified Checklist for Autism in Toddlers (M-CHAT) is mixed but this study provides evidence that the M-CHAT performs well in detecting children at low risk for autism and consistently detects children with developmental delays and behavioral problems. The M-CHAT moderately detects children at increased risk for autism and remains a useful screening tool. This study examines M-CHAT accuracy in a large-scale, nationwide sample, examining associations between screening accuracy and developmental outcomes. These findings impact pediatric screening for autism, supporting continued use of the M-CHAT while further elucidating the factors associated with inaccurate screens.

Sex Differences in Autistic Youth Born Extremely Preterm.

PURPOSE: To evaluate sex differences in autistic traits in youth born extremely preterm (EP; 23-27 weeks) who were later diagnosed with autism spectrum disorder (ASD) at 10-years. METHOD: A longitudinal cohort design from the Extremely Low Gestational Age Newborn Study (ELGAN) followed N = 857 EP infants from birth through 10-years. EP infants later diagnosed with ASD (N = 61, 20 females) participated in the study. Group differences were evaluated via inferential and Bayesian statistics (values > 1 suggest evidence for alternate hypothesis) on ASD screeners (M-CHAT at 2-years, SCQ and SRS-2 at 10-years), and gold-standard diagnostic measures (ADOS-2, ADI-R) at 10-years. RESULTS: Males scored significantly higher than females on measures of Social Affect from the ADOS-2, t(34.27)=-2.20, BF10 = 2.33, and measures of Repetitive and Restricted Behaviors from the ADI-R, t(40.52)=-2.85, BF10 = 5.26. Bayesian estimates suggested marginal evidence for sex differences in Nonverbal Communication, t(30.66)=-1.81, BF10 = 1.25, and Verbal Communication, t(24.64)=-1.89, BF10 = 1.39, from the ADI-R, wherein males scored higher than females. No statistically significant sex differences were identified on any of the ASD screeners at 2 (M-CHAT) or 10 years (SCQ). No significant sex differences were observed on any subscales of the SRS at 10 years. CONCLUSIONS: EP autistic males present with more autistic traits than EP autistic females on gold-standard diagnostic measures of autism at 10-years of age, despite not presenting with higher autistic traits on screeners at either age. These results align with sex differences observed in full-term, autistic youth. These results suggest ASD screeners may under identify autism in EP youth, particularly females.

Neurodevelopmental and behavioral outcomes of very preterm infants: latent profile analysis in the Environmental influences on Child Health Outcomes (ECHO) Program.

BACKGROUND: Very preterm infants are at high risk for neurodevelopmental impairments. We used a child-centered approach (latent profile analysis [LPA]) to describe 2-year neurobehavioral profiles for very preterm infants based on cognitive, motor, and behavioral outcomes. We hypothesized that distinct outcome profiles would differ in the severity and co-occurrence of neurodevelopmental and behavioral impairment. METHODS: We studied children born <33 weeks' gestation from the Environmental influences on Child Health Outcomes Program with at least one neurobehavioral assessment at age 2 (Bayley Scales of Infant and Toddler Development, Child Behavior Checklist, Modified Checklist for Autism in Toddlers, cerebral palsy diagnosis). We applied LPA to identify subgroups of children with different patterns of outcomes. RESULTS: In 2036 children (52% male; 48% female), we found four distinct neurobehavioral profiles. Most children (~85%) were categorized into one of two profiles characterized by no/mild neurodevelopmental delay and a low prevalence of behavioral problems. Fewer children (~15%) fell into one of two profiles characterized by severe neurodevelopmental impairments. One profile consisted of children (5%) with co-occurring neurodevelopmental impairment and behavioral problems. CONCLUSION: Child-centered approaches provide a comprehensive, parsimonious description of neurodevelopment following preterm birth and can be useful for clinical and research purposes. IMPACT: Most research on outcomes for children born very preterm have reported rates of impairment in single domains. Child-centered approaches describe profiles of children with unique combinations of cognitive, motor, and behavioral strengths and weaknesses. We capitalized on data from the nationwide Environmental influences on Child Health Outcomes Program to examine these profiles in a large sample of children born <33 weeks gestational age. We found four distinct neurobehavioral profiles consisting of different combinations of cognitive, motor, and behavioral characteristics. This information could aid in the development of clinical interventions that target different profiles of children with unique developmental needs.

Both stronger and weaker cerebro-cerebellar functional connectivity patterns during processing of spoken sentences in autism spectrum disorder.

Cerebellar differences have long been documented in autism spectrum disorder (ASD), yet the extent to which such differences might impact language processing in ASD remains unknown. To investigate this, we recorded brain activity with magnetoencephalography (MEG) while ASD and age-matched typically developing (TD) children passively processed spoken meaningful English and meaningless Jabberwocky sentences. Using a novel source localization approach that allows higher resolution MEG source localization of cerebellar activity, we found that, unlike TD children, ASD children showed no difference between evoked responses to meaningful versus meaningless sentences in right cerebellar lobule VI. ASD children also had atypically weak functional connectivity in the meaningful versus meaningless speech condition between right cerebellar lobule VI and several left-hemisphere sensorimotor and language regions in later time windows. In contrast, ASD children had atypically strong functional connectivity for in the meaningful versus meaningless speech condition between right cerebellar lobule VI and primary auditory cortical areas in an earlier time window. The atypical functional connectivity patterns in ASD correlated with ASD severity and the ability to inhibit involuntary attention. These findings align with a model where cerebro-cerebellar speech processing mechanisms in ASD are impacted by aberrant stimulus-driven attention, which could result from atypical temporal information and predictions of auditory sensory events by right cerebellar lobule VI.

A Comparative Analysis of the Full and Short Versions of the Social Responsiveness Scale in Estimating an Established Autism Risk Factor Association in ECHO: Do we Get the Same Estimates?

PURPOSE: Prior work developed a shortened 16-item version of the Social Responsiveness Scale (SRS), a quantitative measure of social communication and autism spectrum disorder (ASD)-related traits. However, its properties for use in risk factor estimation have not been fully tested compared to the full SRS. We compared the associations between gestational age (previously established risk factor for ASD) and the 65-item "full" and 16-item "short" versions of the SRS to test the shortened version's ability to capture associations in epidemiologic analyses of ASD risk factors. METHODS: We used data from participants in the Environmental influences on Child Health Outcomes (ECHO) Program (n = 2,760). SRS scores were collected via maternal/caregiver report when children were aged 2.5-18 years. We compared estimates of associations between gestational age and preterm birth between the full and short SRS using multivariable linear regression, quantile regression, and prediction methods. RESULTS: Overall, associations based on full and short SRS scores were highly comparable. For example, we observed positive associations between preterm birth with both full ([Formula: see text]=2.8; 95% CI [1.7, 4.0]) and short ([Formula: see text]=2.9; 95% CI [1.6, 4.3]) SRS scores. Quantile regression analyses indicated similar direction and magnitude of associations across the distribution of SRS scores between gestational age with both short and full SRS scores. CONCLUSION: The comparability in estimates obtained for full and short SRS scores with an "established" ASD risk factor suggests ability of the shortened SRS in assessing associations with potential ASD-related risk factors and has implications for large-scale research studies seeking to reduce participant burden.

Perinatal Factors and Emotional, Cognitive, and Behavioral Dysregulation in Childhood and Adolescence.

OBJECTIVE: This cohort study assessed perinatal factors known to be related to maternal and neonatal inflammation and hypothesized that several would be associated with emotional, cognitive, and behavioral dysregulation in youth. METHOD: The Environmental influences on Child Health Outcomes (ECHO) is a research consortium of 69 pediatric longitudinal cohorts. A subset of 18 cohorts that had both Child Behavior Checklist (CBCL) data on children (6-18 years) and information on perinatal exposures including maternal prenatal infections was used. Children were classified as having the CBCL-Dysregulation Profile (CBCL-DP) if the sum of their T scores for 3 CBCL subscales (attention, anxious/depressed, and aggression) was ≥180. Primary exposures were perinatal factors associated with maternal and/or neonatal inflammation, and associations between these and outcome were assessed. RESULTS: Approximately 13.4% of 4,595 youth met criteria for CBCL-DP. Boys were affected more than girls (15.1% vs 11.5%). More youth with CBCL-DP (35%) were born to mothers with prenatal infections compared with 28% of youth without CBCL-DP. Adjusted odds ratios indicated the following were significantly associated with dysregulation: having a first-degree relative with a psychiatric disorder; being born to a mother with lower educational attainment, who was obese, had any prenatal infection, and/or who smoked tobacco during pregnancy. CONCLUSION: In this large study, a few modifiable maternal risk factors with established roles in inflammation (maternal lower education, obesity, prenatal infections, and smoking) were strongly associated with CBCL-DP and could be targets for interventions to improve behavioral outcomes of offspring. DIVERSITY & INCLUSION STATEMENT: We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. We actively worked to promote sex and gender balance in our author group. The author list of this paper includes contributors from the location and/or community where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work.

A multi-omic approach identifies an autism spectrum disorder (ASD) regulatory complex of functional epimutations in placentas from children born preterm.

Children born preterm are at heightened risk of neurodevelopmental impairments, including Autism Spectrum Disorder (ASD). The placenta is a key regulator of neurodevelopmental processes, though the precise underlying molecular mechanisms remain unclear. Here, we employed a multi-omic approach to identify placental transcriptomic and epigenetic modifications related to ASD diagnosis at age 10, among children born preterm. Working with the extremely low gestational age (ELGAN) cohort, we hypothesized that a pro-inflammatory placental environment would be predictive of ASD diagnosis at age 10. Placental messenger RNA (mRNA) expression, CpG methylation, and microRNA (miRNA) expression were compared among 368 ELGANs (28 children diagnosed with ASD and 340 children without ASD). A total of 111 genes displayed expression levels in the placenta that were associated with ASD. Within these ASD-associated genes is an ASD regulatory complex comprising key genes that predicted ASD case status. Genes with expression that predicted ASD case status included Ewing Sarcoma Breakpoint Region 1 (EWSR1) (OR: 6.57 (95% CI: 2.34, 23.58)) and Bromodomain Adjacent To Zinc Finger Domain 2A (BAZ2A) (OR: 0.12 (95% CI: 0.03, 0.35)). Moreover, of the 111 ASD-associated genes, nine (8.1%) displayed associations with CpG methylation levels, while 14 (12.6%) displayed associations with miRNA expression levels. Among these, LRR Binding FLII Interacting Protein 1 (LRRFIP1) was identified as being under the control of both CpG methylation and miRNAs, displaying an OR of 0.42 (95% CI: 0.17, 0.95). This gene, as well as others identified as having functional epimutations, plays a critical role in immune system regulation and inflammatory response. In summary, a multi-omic approach was used to identify functional epimutations in the placenta that are associated with the development of ASD in children born preterm, highlighting future avenues for intervention.

No Differences in Auditory Steady-State Responses in Children with Autism Spectrum Disorder and Typically Developing Children.

Auditory steady-state response (ASSR) has been studied as a potential biomarker for abnormal auditory sensory processing in autism spectrum disorder (ASD), with mixed results. Motivated by prior somatosensory findings of group differences in inter-trial coherence (ITC) between ASD and typically developing (TD) individuals at twice the steady-state stimulation frequency, we examined ASSR at 25 and 50 as well as 43 and 86 Hz in response to 25-Hz and 43-Hz auditory stimuli, respectively, using magnetoencephalography. Data were recorded from 22 ASD and 31 TD children, ages 6-17 years. ITC measures showed prominent ASSRs at the stimulation and double frequencies, without significant group differences. These results do not support ASSR as a robust ASD biomarker of abnormal auditory processing in ASD. Furthermore, the previously observed atypical double-frequency somatosensory response in ASD did not generalize to the auditory modality. Thus, the hypothesis about modality-independent abnormal local connectivity in ASD was not supported.

Atypical cortical processing of bottom-up speech binding cues in children with autism spectrum disorders.

Individuals with autism spectrum disorder (ASD) commonly display speech processing abnormalities. Binding of acoustic features of speech distributed across different frequencies into coherent speech objects is fundamental in speech perception. Here, we tested the hypothesis that the cortical processing of bottom-up acoustic cues for speech binding may be anomalous in ASD. We recorded magnetoencephalography while ASD children (ages 7-17) and typically developing peers heard sentences of sine-wave speech (SWS) and modulated SWS (MSS) where binding cues were restored through increased temporal coherence of the acoustic components and the introduction of harmonicity. The ASD group showed increased long-range feedforward functional connectivity from left auditory to parietal cortex with concurrent decreased local functional connectivity within the parietal region during MSS relative to SWS. As the parietal region has been implicated in auditory object binding, our findings support our hypothesis of atypical bottom-up speech binding in ASD. Furthermore, the long-range functional connectivity correlated with behaviorally measured auditory processing abnormalities, confirming the relevance of these atypical cortical signatures to the ASD phenotype. Lastly, the group difference in the local functional connectivity was driven by the youngest participants, suggesting that impaired speech binding in ASD might be ameliorated upon entering adolescence.

Child and family factors associated with positive outcomes among youth born extremely preterm.

BACKGROUND: To analyze the relationship of child behavioral and communication disorders, and adverse family events, to later-in-life child health and cognitive function among youth born extremely preterm. METHODS: The study participants were 694 children enrolled in the Extremely Low Gestational Age Newborn Study. At ages 2 and 10, we assessed internalizing and externalizing behaviors, and at age 10, we assessed adverse life events within the family. Associations were evaluated between these child and family factors and positive child health at age 10 years, and global health and cognitive function at age 15 years. RESULTS: Lower T-scores for internalizing or externalizing behaviors at age 2 were associated with more positive health at age 10. The absence of internalizing behaviors at age 10 was associated with better global child health and better cognitive function at age 15. The absence of communication deficits at age 10 was associated with better cognitive function at age 15. The absence of parent job loss was associated with better global child health at age 15. CONCLUSION: Among individuals born extremely preterm, child health and cognitive outcomes might be improved by timely interventions to address child behavioral symptoms and the impact of adverse life events in the family. IMPACT: The absence of child behavioral and communication disorders, and adverse family events, were associated with more positive health, higher global health, and better cognitive function among youth born extremely preterm. Interventions to address behavioral disorders in early childhood, and to reduce the impact of adverse life events on the family, might promote improved health and developmental outcomes for adolescents born extremely preterm.

Comparing autism phenotypes in children born extremely preterm and born at term.

Children born preterm are at increased risk for autism spectrum disorder (ASD). There is limited knowledge about whether ASD phenotypes in children born preterm differ from children born at term. The objective of this study was to compare ASD core symptoms and associated characteristics among extremely preterm (EP) and term-born children with ASD. EP participants (n = 59) from the Extremely Low Gestational Age Newborn Study who met diagnostic criteria for ASD at approximately 10 years of age were matched with term-born participants from the Simons Simplex Collection on age, sex, spoken language level, and nonverbal IQ. Core ASD symptomatology was evaluated with the Autism Diagnostic Interview-Revised (ADI-R) and the Autism Diagnostic Observation Schedule (ADOS). Developmental milestones, anthropometrics, seizure disorder, and psychiatric symptoms were also investigated. The EP group had lower parent-reported symptom scores on ADI-R verbal communication, specifically stereotyped language, and restricted, repetitive behaviors. There were no between-group differences on ADI-R nonverbal communication and ADI-R reciprocal social interaction or with direct observation on the ADOS-2. The EP group was more likely to have delayed speech milestones and lower physical growth parameters. Results from female-only analyses were similar to those from whole-group analyses. In sum, behavioral presentation was similar between EP and IQ- and sex-matched term-born children assessed at age 10 years, with the exception of less severe retrospectively reported stereotyped behaviors, lower physical growth parameters, and increased delays in language milestones among EP-born children with ASD.

CpG methylation patterns in placenta and neonatal blood are differentially associated with neonatal inflammation.

BACKGROUND: Infants born extremely premature are at increased risk for health complications later in life for which neonatal inflammation may be a contributing biological driver. Placental CpG methylation provides mechanistic information regarding the relationship between prenatal epigenetic programming, prematurity, neonatal inflammation, and later-in-life health. METHODS: We contrasted CpG methylation in the placenta and neonatal blood spots in relation to neonatal inflammation in the Extremely Low Gestational Age Newborn (ELGAN) cohort. Neonatal inflammation status was based on the expression of six inflammation-related proteins, assessed as (1) day-one inflammation (DOI) or (2) intermittent or sustained systemic inflammation (ISSI, inflammation on ≥2 days in the first 2 postnatal weeks). Epigenome-wide CpG methylation was assessed in 354 placental samples and 318 neonatal blood samples. RESULTS: Placental CpG methylation displayed the strongest association with ISSI (48 CpG sites) but was not associated with DOI. This was in contrast to CpG methylation in blood spots, which was associated with DOI (111 CpG sites) and not with ISSI (one CpG site). CONCLUSIONS: Placental CpG methylation was strongly associated with ISSI, a measure of inflammation previously linked to later-in-life cognitive impairment, while day-one neonatal blood methylation was associated with DOI. IMPACT: Neonatal inflammation increases the risk of adverse later-life outcomes, especially in infants born extremely preterm. CpG methylation in the placenta and neonatal blood spots were evaluated in relation to neonatal inflammation assessed via circulating proteins as either (i) day-one inflammation (DOI) or (ii) intermittent or sustained systemic inflammation (ISSI, inflammation on ≥2 days in the first 2 weeks). Tissue specificity was observed in epigenetic-inflammatory relationships: placental CpG methylation was associated with ISSI, neonatal blood CpG methylation was associated with DOI. Supporting the placental origins of disease framework, placental epigenetic patterns are associated with a propensity for ISSI in neonates.

Growth During Infancy After Extremely Preterm Birth: Associations with Later Neurodevelopmental and Health Outcomes.

OBJECTIVE: To evaluate associations between changes in weight, length, and weight/length ratio during infancy and outcomes later in life among individuals born extremely preterm. STUDY DESIGN: Among participants in the Extremely Low Gestational Age Newborn (ELGAN) study, we measured weight and length at discharge from the neonatal intensive care unit (NICU) and at age 2 years and evaluated neurocognitive, psychiatric, and health outcomes at age 10 years and 15 years. Using multivariable logistic regression, we estimated associations between gains in weight, length, and weight/length ratio z-scores between discharge and 2 years and outcomes at 10 and 15 years. High gain was defined as the top quintile of change; low gain, as the bottom quintile of change. RESULTS: High gains in weight and weight/length were associated with greater odds of obesity at 10 years, but not at 15 years. These associations were found only for females. High gain in length z-score was associated with lower odds of obesity at 15 years. The only association found between high gains in growth measures and more favorable neurocognitive or psychiatric outcomes was between high gain in weight/length and lower odds of cognitive impairment at age 10 years. CONCLUSIONS: During the 2 years after NICU discharge, females born extremely preterm with high gains in weight/length or weight have greater odds of obesity at 10 years, but not at 15 years. Infants with high growth gains in the 2 years after NICU discharge have neurocognitive and psychiatric outcomes in middle childhood and adolescence similar to those of infants with lower gains in weight and weight/length.

Maternal Social Risk, Gestational Age at Delivery, and Cognitive Outcomes among Adolescents Born Extremely Preterm.

Background: Children born extremely preterm (EP) are at increased risk of cognitive deficits that persist into adulthood. Few large cohort studies have examined differential impairment of cognitive function in EP-born adolescents in relation to early life risk factors, including maternal social disadvantage, gestational age at delivery, and neonatal morbidities prevalent among EP neonates. Objectives: To assess cognitive abilities in relation to early life risk factors in an EP-born cohort at 15 years of age. Methods: 681 of 1198 surviving participants (57%) enrolled from 2002 to 2004 in the Extremely Low Gestational Age Newborn Study returned at age 15 years for an assessment of cognitive abilities with the Wechsler Abbreviated Scale of Intelligence-II and the NIH Toolbox Cognition Battery (NTCB) verbal cognition and fluid processing composites, the latter of which measured executive functions and processing speed. Three cognitive outcomes, WASI-II IQ, NTCB verbal cognition, and NTCB fluid processing, were analyzed for associations with maternal social disadvantage and gestational age. Mediation of maternal social disadvantage by gestational age and mediation of gestational age by neonatal morbidities were also examined. Results: Test scores were lower for NTCB fluid processing relative to IQ and NTCB verbal abilities. Social disadvantage and gestational age were associated with all three cognitive outcomes. Mediation analyses indicated partial mediation of gestational age associations with all three outcomes by neonatal morbidities but did not support mediation by gestational age of social risk associations with cognitive outcomes. Conclusions: Greater maternal social disadvantage and lower gestational age are associated with less favorable cognitive outcomes among EP-born adolescents at 15 years of age. Neonatal morbidities partially mediate associations between lower gestational age and cognitive outcomes. These findings highlight the need for improved medical and remedial interventions to mitigate risk of poor cognitive outcomes among EP-born adolescents.

Analysis of Neurodevelopment in Children Born Extremely Preterm Treated With Acid Suppressants Before Age 2 Years.

Importance: Children born preterm are at increased risk of adverse neurodevelopmental outcomes and may be particularly vulnerable to the effects of gastric acid suppression during infancy. Objective: To assess whether early acid suppressant use in infants born extremely preterm is associated with poorer neurodevelopmental outcomes. Design, Setting, and Participants: The Extremely Low Gestational Age Newborn study was a multicenter, longitudinal cohort study of infants born before 28 weeks' gestational age between March 22, 2002, and August 31, 2004. The current analyses were performed from September 12, 2020, through September 22, 2022. Of the 1506 infants enrolled, 284 died before discharge and 22 died before 24 months of age. An additional 2 died before age 10 years, leaving 1198 (79.5%) eligible for a visit. Of these, 889 (74%) participated in the visit at age 10. At age 10 years, the association of early-life acid suppressant use with neurocognitive, neurodevelopmental, and psychiatric symptomatology was assessed. Exposures: Acid suppressant use before 24 months of age was determined from medical records and from questionnaires administered to mothers. Main Outcomes and Measures: Neurodevelopmental assessments at age 10 years included the School-Age Differential Ability Scales-II, the Developmental Neuropsychological Assessment-II, the Autism Diagnostic Observation Schedule-2, the Social Responsiveness Scale-2, and the Child Symptom Inventory-4 for attention-deficit/hyperactivity disorder (ADHD), depression, and anxiety. Results: Of the 889 participants assessed at age 10 years (mean [SD] age, 9.97 [0.67] years; mean [SD] gestational age at birth, 26.1 [1.3] weeks; 455 [51.2%] male), 368 (41.4%) had received acid suppressants by 24 months of age. Associations were observed between acid suppressant use and decreased full-scale IQ z score (adjusted ß, -0.29; 95% CI, -0.45 to -0.12), verbal IQ z score (adjusted ß, -0.34; 95% CI, -0.52 to -0.15), nonverbal IQ z score (adjusted ß, -0.22; 95% CI to -0.39 to -0.05), working memory z score (adjusted ß, -0.26; 95% CI to -0.45, -0.08), autism spectrum disorder (adjusted relative risk, 1.84; 95% CI, 1.15-2.95), and epilepsy (adjusted relative risk, 2.07; 95% CI, 1.31 to 3.35). Results were robust to multiple sensitivity analyses. Use of acid suppressants was not associated with inhibitory control, ADHD, anxiety, or depression. Conclusions and Relevance: The results of this cohort study suggest that early-life use of acid suppressants in extremely preterm infants may be associated with poorer neurodevelopmental outcomes and add to evidence indicating caution in use of these agents.

Association of prenatal modifiable risk factors with attention-deficit hyperactivity disorder outcomes at age 10 and 15 in an extremely low gestational age cohort.

Background: The increased risk of developing attention-deficit hyperactivity disorder (ADHD) in extremely preterm infants is well-documented. Better understanding of perinatal risk factors, particularly those that are modifiable, can inform prevention efforts. Methods: We examined data from the Extremely Low Gestational Age Newborns (ELGAN) Study. Participants were screened for ADHD at age 10 with the Child Symptom Inventory-4 (N = 734) and assessed at age 15 with a structured diagnostic interview (MINI-KID) to evaluate for the diagnosis of ADHD (N = 575). We studied associations of pre-pregnancy maternal body mass index (BMI), pregestational and/or gestational diabetes, maternal smoking during pregnancy (MSDP), and hypertensive disorders of pregnancy (HDP) with 10-year and 15-year ADHD outcomes. Relative risks were calculated using Poisson regression models with robust error variance, adjusted for maternal age, maternal educational status, use of food stamps, public insurance status, marital status at birth, and family history of ADHD. We defined ADHD as a positive screen on the CSI-4 at age 10 and/or meeting DSM-5 criteria at age 15 on the MINI-KID. We evaluated the robustness of the associations to broadening or restricting the definition of ADHD. We limited the analysis to individuals with IQ ≥ 70 to decrease confounding by cognitive functioning. We evaluated interactions between maternal BMI and diabetes status. We assessed for mediation of risk increase by alterations in inflammatory or neurotrophic protein levels in the first week of life. Results: Elevated maternal BMI and maternal diabetes were each associated with a 55-65% increase in risk of ADHD, with evidence of both additive and multiplicative interactions between the two exposures. MSDP and HDP were not associated with the risk of ADHD outcomes. There was some evidence for association of ADHD outcomes with high levels of inflammatory proteins or moderate levels of neurotrophic proteins, but there was no evidence that these mediated the risk associated with maternal BMI or diabetes. Conclusion: Contrary to previous population-based studies, MSDP and HDP did not predict ADHD outcomes in this extremely preterm cohort, but elevated maternal pre-pregnancy BMI, maternal diabetes, and perinatal inflammatory markers were associated with increased risk of ADHD at age 10 and/or 15, with positive interaction between pre-pregnancy BMI and maternal diabetes.

Long-Term Outcome of Necrotizing Enterocolitis and Spontaneous Intestinal Perforation.

OBJECTIVES: Necrotizing enterocolitis (NEC) and spontaneous intestinal perforation (SIP) are complications in preterm infants associated with high morbidity, mortality, impaired growth, and neurodevelopmental (ND) outcomes. Few studies have reported growth or ND outcomes of infants born extremely preterm with NEC/SIP beyond early childhood. Here, we compared anthropometric and ND outcomes, at 10 and 15 years, for children with medical NEC, surgical NEC, SIP, and neither NEC nor SIP. METHODS: Participants from the prospective longitudinal extremely low gestational age newborns study were evaluated at ages 10 and 15 years for anthropometrics, neurocognition, attention-deficit/hyperactivity disorder, epilepsy, and gross motor function. RESULTS: At age 10 years, 889 children were followed-up (medical NEC = 138, surgical NEC = 33, SIP = 29, no NEC/SIP = 689), and 694 children were followed up-at 15 years. Children with medical NEC had similar weight, BMI, height, and head circumference compared with controls at both 10 and 15 years. At 15 years, children with surgical NEC had lower weight z-score (adjusted ß: -0.75, 95% confidence interval [CI]: -1.25 to -0.25), lower BMI z-score (adjusted ß: -0.55, 95% CI: -1.09 to -0.01), and lower height z-score (adjusted ß: -0.65, 95% CI: -1.16 to -0.14). Children with SIP had lower weight and height z-scores at age 10 years when adjusted for sample attrition, but these differences were not significant when adjusted for confounders. We observed no differences in long-term ND outcomes. CONCLUSIONS: Surgical NEC- and SIP-associated growth impairment may persist through late childhood. ND outcomes among school-aged children born extremely preterm with any NEC or SIP are no different from children without NEC/SIP.