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.

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.

Epigenetic associations in HPA axis genes related to bronchopulmonary dysplasia and antenatal steroids.

BACKGROUND: Bronchopulmonary dysplasia (BPD), a common morbidity among very preterm infants, is associated with chronic disease and neurodevelopmental impairments. A hypothesized mechanism for these outcomes lies in altered glucocorticoid (GC) activity. We hypothesized that BPD and its treatments may result in epigenetic differences in the hypothalamic-pituitary-adrenal (HPA) axis, which is modulated by GC, and could be ascertained using an established GC risk score and DNA methylation (DNAm) of HPA axis genes. METHODS: DNAm was quantified from buccal tissue (ECHO-NOVI) and from neonatal blood spots (ELGAN ECHO) via the EPIC microarray. Prenatal maternal characteristics, pregnancy complication, and neonatal medical complication data were collected from medical record review and maternal interviews. RESULTS: The GC score was not associated with steroid exposure or BPD. However, six HPA genes involved in stress response regulation demonstrated differential methylation with antenatal steroid exposure; two CpGs within FKBP5 and POMC were differentially methylated with BPD severity. These findings were sex-specific in both cohorts; males had greater magnitude of differential methylation within these genes. CONCLUSIONS: These findings suggest that BPD severity and antenatal steroids are associated with DNAm at some HPA genes in very preterm infants and the effects appear to be sex-, tissue-, and age-specific. IMPACT: This study addresses bronchopulmonary dysplasia (BPD), an important health outcome among preterm neonates, and interrogates a commonly studied pathway, the hypothalamic-pituitary-adrenal (HPA) axis. The combination of BPD, the HPA axis, and epigenetic markers has not been previously reported. In this study, we found that BPD itself was not associated with epigenetic responses in the HPA axis in infants born very preterm; however, antenatal treatment with steroids was associated with epigenetic responses.

Maternal Prenatal Risk Phenotypes and Neurobehavioral Outcomes among Infants Born Very Preterm.

OBJECTIVE: To assess whether prenatal risk phenotypes are associated with neurobehavioral impairment for children born <30 weeks of gestation at discharge from the neonatal intensive care unit (NICU) and at 24-month follow-up. STUDY DESIGN: We studied infants from the Neonatal Neurobehavior and Outcomes in Very Preterm Infants (NOVI) study, a multisite investigation of infants born <30 weeks of gestation. There were 704 newborns enrolled in the NOVI study; of these, 679 (96%) had neonatal neurobehavioral data and 556 (79%) had 24-month follow-up data. Maternal prenatal phenotypes (physical and psychological risk groups) were characterized from 24 physical and psychological health risk factors. Neurobehavior was assessed at NICU discharge using the NICU Network Neurobehavioral Scales and at 2-year follow-up using the Bayley Scales of Infant and Toddler Development and the Child Behavior Checklist. RESULTS: Children born to mothers in the psychological risk group were at increased risk for dysregulated neonatal neurobehavior (OR, 2.04; 95% CI, 1.08-3.87) at NICU discharge, and for severe motor delay (OR, 3.80; 95% CI, 1.48-9.75), and clinically significant externalizing problems (OR, 2.54; 95% CI, 1.15-5.56) at age 24 months, compared with children born to mothers in the low-risk group. Children born to mothers in the physical risk group were more likely to have severe motor delay (OR, 2.70; 95% CI, 1.07-6.85) compared with the low-risk group. CONCLUSIONS: High-risk maternal prenatal phenotypes were associated with neurobehavioral impairment for children born very preterm. This information could identify newborns at risk for adverse neurodevelopmental outcomes.

Neurobehavioral and Medical Correlates of Autism Screening: 2-Year Outcomes for Infants Born Very Preterm.

OBJECTIVE: To identify neonatal characteristics and 2-year neurodevelopmental outcomes associated with positive screening for risk of autism. STUDY DESIGN: Nine university-affiliated neonatal intensive care units (NICUs) enrolled infants born at <30 weeks of gestation. Infants underwent the NICU Network Neurobehavioral Scale examination before discharge and the Bayley Scales of Infant and Toddler Development, Third Edition, the Child Behavior Checklist, and the Modified Checklist for Autism in Toddlers, revised with follow-up (M-CHAT-R/F) at 2 years of corrected age. Generalized estimating equations examined associations between M-CHAT-R/F, neurobehavioral test results, and neonatal medical morbidities. RESULTS: At 2 years of corrected age, data were available for 466 of 744 enrolled infants without cerebral palsy. Infants with hypoaroused NICU Network Neurobehavioral Scale profiles were more likely to screen M-CHAT-R/F-positive (OR 2.76, 95% CI 1.38-5.54). Infants with ≥2 medical morbidities also were more likely to screen positive (OR 2.65, 95% CI 1.27-5.54). Children with positive M-CHAT-R/F scores had lower Bayley Scales of Infant and Toddler Development, Third Edition, Cognitive (t [451] = 5.43, P < .001, d = 0.82), Language (t [53.49] = 7.82, P < .001, d = 1.18), and Motor (t [451] = 7.98, P < .001, d = 1.21) composite scores and significantly greater Child Behavior Checklist Internalizing (t [457] -6.19, P < .001, d = -0.93) and Externalizing (t [57.87] = -5.62, P < .001, d = -0.84) scores. CONCLUSIONS: Positive M-CHAT-R/F screens at 2 years of corrected age were associated with neonatal medical morbidities and neurobehavioral examinations as well as toddler developmental and behavioral outcomes. These findings demonstrate the potential utility of the M-CHAT-R/F as a global developmental screener in infants born very preterm, regardless of whether there is a later autism diagnosis.

Prenatal and perinatal factors associated with neonatal neurobehavioral profiles in the ECHO Program.

BACKGROUND: Single-cohort studies have identified distinct neurobehavioral profiles that are associated with prenatal and neonatal factors based on the NICU Network Neurobehavioral Scale (NNNS). We examined socioeconomic, medical, and substance use variables as predictors of NNNS profiles in a multi-cohort study of preterm and term-born infants with different perinatal exposures. METHODS: We studied 1112 infants with a neonatal NNNS exam from the Environmental influences on Child Health Outcomes (ECHO) consortium. We used latent profile analysis to characterize infant neurobehavioral profiles and generalized estimating equations to determine predictors of NNNS profiles. RESULTS: Six distinct neonatal neurobehavioral profiles were identified, including two dysregulated profiles: a hypo-aroused profile (16%) characterized by lethargy, hypotonicity, and nonoptimal reflexes; and a hyper-aroused profile (6%) characterized by high arousal, excitability, and stress, with low regulation and poor movement quality. Infants in the hypo-aroused profile were more likely to be male, have younger mothers, and have mothers who were depressed prenatally. Infants in the hyper-aroused profile were more likely to be Hispanic/Latino and have mothers who were depressed or used tobacco prenatally. CONCLUSIONS: We identified two dysregulated neurobehavioral profiles with distinct perinatal antecedents. Further understanding of their etiology could inform targeted interventions to promote positive developmental outcomes. IMPACT: Prior research on predictors of neonatal neurobehavior have included single-cohort studies, which limits generalizability of findings. In a multi-cohort study of preterm and term-born infants, we found six distinct neonatal neurobehavioral profiles, with two profiles being identified as dysregulated. Hypo- and hyper-aroused neurobehavioral profiles had distinct perinatal antecedents. Understanding perinatal factors associated with dysregulated neurobehavior could help promote positive developmental outcomes.

Risk Factors for Postpartum Depression and Severe Distress among Mothers of Very Preterm Infants at NICU Discharge.

OBJECTIVE: To identify psychological, medical, and socioenvironmental risk factors for maternal postpartum depression (PPD) and severe psychological distress (SPD) at intensive care nursery discharge among mothers of very preterm infants. STUDY DESIGN: We studied 562 self-identified mothers of 641 infants born <30 weeks who were enrolled in the Neonatal Neurobehavior and Outcomes in Very Preterm Infants Study (NOVI) conducted in nine university-affiliated intensive care nurseries. Enrollment interviews collected socioenvironmental data, depression, and anxiety diagnoses prior to and during the study pregnancy. Standardized medical record reviews ascertained prenatal substance use, maternal and neonatal medical complications. The Edinburgh Postnatal Depression Scale and Brief Symptom Inventory were administered at nursery discharge to screen for PPD and SPD symptoms, respectively. RESULTS: Unadjusted analyses indicated mothers with positive screens for depression (n = 76, 13.5%) or severe distress (n = 102, 18.1%) had more prevalent prepregnancy/prenatal depression/anxiety, and their infants were born at younger gestational ages, with more prevalent bronchopulmonary dysplasia, and discharge after 40 weeks postmenstrual age. In multivariable analyses, prior depression or anxiety was associated with positive screens for PPD (risk ratio [RR]: 1.6, 95% confidence interval [CI]: 1.1-2.2) and severe distress (RR: 1.6, 95% CI: 1.1-2.2). Mothers of male infants had more prevalent depression risk (RR: 1.7, 95% CI: 1.1-2.4), and prenatal marijuana use was associated with severe distress risk (RR: 1.9, 95% CI: 1.1-2.9). Socioenvironmental and obstetric adversities were not significant after accounting for prior depression/anxiety, marijuana use, and infant medical complications. CONCLUSION: Among mothers of very preterm newborns, these multicenter findings extend others' previous work by identifying additional indicators of risk for PPD and SPD associated with a history of depression, anxiety, prenatal marijuana use, and severe neonatal illness. Findings could inform designs for continuous screening and targeted interventions for PPD and distress risk indicators from the preconception period onward. KEY POINTS: · Preconceptional and prenatal screening for postpartum depression and severe distress may inform care.. · Prior depression, anxiety, and neonatal complications predicted severe distress and depression symptoms at NICU discharge.. · Readily identifiable risk factors warrant continuous NICU screening and targeted interventions to improve outcomes..

Neurodevelopmental profiles of infants born <30 weeks gestation at 2 years of age.

BACKGROUND: Infants born <30 weeks postmenstrual age (PMA) are at increased risk for neurodevelopmental impairment by age 2. Prior studies report rates of impairment for individual outcomes separately. Our objective was to describe neurodevelopmental profiles of children born <30 weeks PMA, using cognitive, language, motor, and behavioral characteristics. METHODS: We studied 587 children from a multi-center study of infants born <30 weeks PMA. Age 2 outcomes included Bayley-III subscale scores, Child Behavior Checklist syndrome scores, diagnosis of cerebral palsy (CP), and positive screen for autism spectrum disorder (ASD) risk. We used latent profile analysis (LPA) to group children into mutually exclusive profiles. RESULTS: We found four discrete neurodevelopmental profiles indicating distinct combinations of developmental and behavioral outcomes. Two of the profiles included 72.7% of the sample with most having Bayley scores within the normal range. The other two profiles included the remaining 27.3% of the sample with most having Bayley scores outside of the normal range. Only one profile (11% of sample) was comprised of children with elevated behavioral problems. CONCLUSION: Child-centered analysis techniques could facilitate the development of targeted intervention strategies and provide caregivers and practitioners with an integrative understanding of child behavior. IMPACT: Most studies examining neurodevelopmental outcomes in very preterm children report rates of impairment for individual outcomes separately. Comprehensive, "child-centered" approaches that integrate across multiple domains can be used to identify subgroups of children who experience different types of neurodevelopmental impairments. We identified four discrete neurodevelopmental profiles indicating distinct combinations of developmental and behavioral outcomes in very preterm children at 24 months. "Child-centered" analysis techniques may provide clinically useful information and could facilitate the development of targeted intervention strategies for high-risk children.

Epigenome-wide analysis identifies genes and pathways linked to acoustic cry variation in preterm infants.

BACKGROUND: Preterm birth places infants at higher risk of adverse long-term behavioral and cognitive outcomes. Combining biobehavioral measures and molecular biomarkers may improve tools to predict the risk of long-term developmental delays. METHODS: The Neonatal Neurobehavior and Outcomes in Very Preterm Infants study was conducted at nine neonatal intensive care units between April 2014 and June 2016. Cries were recorded and buccal swabs collected during the neurobehavioral exam. Cry episodes were extracted and analyzed using a computer system and the data were summarized using factor analysis. Genomic DNA was extracted from buccal swabs, quantified using the Qubit Fluorometer, and aliquoted into standardized concentrations. DNA methylation was measured with the Illumina MethylationEPIC BeadArray, and an epigenome-wide association study was performed using cry factors (n = 335). RESULTS: Eighteen CpGs were associated with the cry factors at genome-wide significance (α = 7.08E - 09). Two CpG sites, one intergenic and one linked to gene TCF3 (important for B and T lymphocyte development), were associated with acoustic measures of cry energy. Increased methylation of TCF3 was associated with a lower energy-related cry factor. We also found that pitch (F0) and hyperpitch (F0 > 1 kHz) were associated with DNA methylation variability at 16 CpG sites. CONCLUSIONS: Acoustic cry characteristics are related to variation in DNA methylation in preterm infants. IMPACT: Preterm birth is a major public health problem and its long-term impact on health is not well understood. Cry acoustics, related to prematurity, has been linked to a variety of medical conditions. Biobehavioral measures and molecular biomarkers can improve prediction tools for long-term developmental risks of preterm birth. Variation in epigenetic modulation in preterm infants provides a potential link between preterm birth and unfavorable developmental outcomes.

Mortality and Neurodevelopmental Outcomes in the Heart Rate Characteristics Monitoring Randomized Controlled Trial.

OBJECTIVE: To test whether the composite outcome of death or neurodevelopmental impairment (NDI) at 18-22 months corrected age for infants ≤1000 g at birth is decreased by continuous monitoring of heart rate characteristics during neonatal intensive care. STUDY DESIGN: We studied a subset of participants enrolled in a multicenter randomized trial of heart rate characteristics monitoring. Survivors were evaluated at 18-22 months corrected age with a standardized neurologic examination and the Bayley Scales of Infant Development-III (BSID-III). NDI was defined as Gross Motor Function Classification System of >2 (moderate or severe cerebral palsy), BSID-III language or cognitive scores of <70, severe bilateral hearing impairment, and/or bilateral blindness. RESULTS: The composite outcome, death or NDI, was obtained for 628 of 884 study infants (72%). The prevalence of this outcome was 44.4% (136/306) among controls (infants randomized to heart rate characteristics monitored but not displayed) and 38.9% (125/322) among infants randomized to heart rate characteristics monitoring displayed (relative risk, 0.87; 95% CI, 0.73-1.05; P = .17). Mortality was reduced from 32.0% (99/307) among controls to 24.8% (81/326) among monitoring displayed infants (relative risk, 0.75; 95% CI, 0.59 to 0.97; P = .028). The composite outcomes of death or severe CP and death or mildly low Bayley cognitive score occurred less frequently in the displayed group (P < .05). CONCLUSIONS: We found no difference in the composite outcome of death or NDI for extremely preterm infants whose heart rate characteristics were and were not displayed during neonatal intensive care. Two outcomes that included mortality or a specific NDI were less frequent in the displayed group.

Psychosocial and medical adversity associated with neonatal neurobehavior in infants born before 30 weeks gestation.

BACKGROUND: Psychosocial adversity escalates medical risk for poor outcomes in infants born <30 weeks gestation. Neonatal neurobehavior and maternal psychological and socioenvironmental assessments may identify the earliest specific intervention needs. We hypothesized that maternal prenatal anxiety, depression, and adverse medical and socioenvironmental conditions would be associated with less optimal neonatal neurobehavior at neonatal intensive care unit (NICU) discharge. METHODS: We studied 665 infants at 9 university NICUs. Risk indices of socioenvironmental, maternal, and neonatal medical factors were obtained from standardized, structured maternal interviews and medical record reviews. Brain injuries were classified by consensus ultrasonogram readings. NICU Network Neurobehavioral Scale (NNNS) exams were conducted at NICU discharge. RESULTS: On the NNNS, generalized estimating equations indicated infants of mothers with prenatal anxiety had less optimal attention, and those born to mothers with prenatal depression had increased lethargy. Maternal medical complications predicted suboptimal reflexes. Socioenvironmental risk predicted lower self-regulation and movement quality. Infants with more severe neonatal medical complications had lower attention, increased lethargy, and suboptimal reflexes. CONCLUSIONS: Combined information from the observed associations among adverse prenatal maternal medical and psychosocial conditions, and neonatal complications may assist in the early identification of infants at elevated neurobehavioral risk.

The Randomized, Controlled Trial of Late Surfactant: Effects on Respiratory Outcomes at 1-Year Corrected Age.

OBJECTIVE: To determine the effects of late surfactant on respiratory outcomes determined at 1-year corrected age in the Trial of Late Surfactant (TOLSURF), which randomized newborns of extremely low gestational age (≤28 weeks' gestational age) ventilated at 7-14 days to late surfactant and inhaled nitric oxide vs inhaled nitric oxide-alone (control). STUDY DESIGN: Caregivers were surveyed in a double-blinded manner at 3, 6, 9, and 12 months' corrected age to collect information on respiratory resource use (infant medication use, home support, and hospitalization). Infants were classified for composite outcomes of pulmonary morbidity (no PM, determined in infants with no reported respiratory resource use) and persistent PM (determined in infants with any resource use in ≥3 surveys). RESULTS: Infants (n = 450, late surfactant n = 217, control n = 233) were 25.3 ± 1.2 weeks' gestation and 713 ± 164 g at birth. In the late surfactant group, fewer infants received home respiratory support than in the control group (35.8% vs 52.9%, relative benefit [RB] 1.28 [95% CI 1.07-1.55]). There was no benefit of late surfactant for No PM vs PM (RB 1.27; 95% CI 0.89-1.81) or no persistent PM vs persistent PM (RB 1.01; 95% CI 0.87-1.17). After adjustment for imbalances in baseline characteristics, relative benefit of late surfactant treatment increased: RB 1.40 (95% CI 0.89-1.80) for no PM and RB 1.24 (95% CI 1.08-1.42) for no persistent PM. CONCLUSION: Treatment of newborns of extremely low gestational age with late surfactant in combination with inhaled nitric oxide decreased use of home respiratory support and may decrease persistent pulmonary morbidity. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01022580.

Neonatal neurobehavior associated with developmental changes from age 2 to 3 in very preterm infants.

OBJECTIVE: Understand how high-risk infants' development changes over time. Examine whether NICU Network Neurobehavioral Scale (NNNS) profiles are associated with decrements in developmental outcomes between ages 2 and 3 years in infants born very preterm. STUDY DESIGN: The Neonatal Outcomes for Very preterm Infants (NOVI) cohort is a multisite prospective study of 704 preterm infants born <30 weeks' gestation across nine university and VON affiliated NICUs. Data included infant neurobehavior measured by NNNS profiles at NICU discharge and the Bayley Scales of Infant and Toddler Development (BSID-III) at ages 2 and 3 years. Generalized estimating equations tested associations between NNNS profiles and BSID-III composite score changes between ages 2 and 3 years. RESULTS: The final study sample included 433 infants with mean gestational age of 27 weeks at birth. Infants with dysregulated NNNS profiles were more likely to have decreases in BSID-III Cognitive (OR = 2.66) and Language scores (OR = 2.53) from age 2 to 3 years compared to infants with more well-regulated neurobehavioral NNNS profiles. Further, infants with more well-regulated NNNS profiles were more likely to have increases in BSID-III Cognitive scores (OR = 2.03), rather than no change, compared to infants with dysregulated NNNS profiles. CONCLUSIONS AND RELEVANCE: Prior to NICU discharge, NNNS neurobehavioral profiles identified infants at increased risk for developing later language and cognitive challenges. Findings suggests that neonatal neurobehavior provides a unique, clinically significant contribution to the evaluation of very preterm infants to inform treatment planning for the most vulnerable.

Agreement Between Two Behavioral Rating Scales in Preschoolers Born Very Preterm.

OBJECTIVE: Broadband parent rating scales are commonly used to assess behavioral problems in children. Multiple rating scales are available, yet agreement between them is not well-understood. The objective of this study was to evaluate agreement between the Behavior Assessment System for Children, Third Edition (BASC-3), and Child Behavior Checklist 1.5 to 5 years (CBCL) in a sample of children born very preterm. METHOD: We assessed 73 children born < 30 weeks' gestational age whose caregivers completed the BASC-3 and CBCL at age 4. We examined correlations, within-person differences, and agreement in clinical categorization for all corresponding subscales and composites. RESULTS: Comparable subscales on the BASC-3 and CBCL were significantly correlated, albeit to differing magnitudes. Subscales indexing hyperactivity and attention problems were the most comparable across the 2 measures, evidenced by strong correlations and few to no differences in mean T-scores. Composite scores indexing internalizing, externalizing, and total problems were also strongly correlated, and there were no differences in the mean T-scores for externalizing or total problems across measures. Agreement in clinical classifications were weak to moderate, though again, the highest agreement was found for hyperactivity, attention, externalizing, and total problems. CONCLUSION: Agreement between BASC-3 and CBCL subscales was weak to moderate, with the exception of subscales related to attention and hyperactivity, as well as composite scores indicating overall behavior problems. Researchers and clinicians should consider these discrepancies when interpreting the results of behavior rating scales with preschool children because conclusions could differ based on the assessment that is used.

Preeclampsia, Fetal Growth Restriction, and 24-Month Neurodevelopment in Very Preterm Infants.

Importance: Preeclampsia has direct influences on a developing fetus and may impact postnatal health, and fetal growth restriction (FGR) is often seen co-occurring with preeclampsia. The development of children born very preterm after preeclampsia diagnosis with and without FGR is not well characterized. Objective: To examine the associations of preeclampsia and FGR with developmental and/or behavioral outcomes in a cohort of very preterm infants. Design, Setting, and Participants: In this cohort study, infants in the prospective Neonatal Neurobehavior and Outcomes in Very Preterm Infants study were enrolled between April 2014 and June 2016 from 9 US university-affiliated neonatal intensive care units (NICUs). Eligible infants were born before 30 weeks' gestation. Infants were excluded for any major congenital anomalies and for maternal age younger than 18 years or cognitive impairment impacting the ability to provide informed consent. Data analysis was performed from November 2023 to January 2024. Exposure: Maternal preeclampsia and FGR in very preterm infants. Main Outcomes and Measures: The Bayley-III cognition, motor, and language scores less than 85 (-1 SD) indicated developmental delay. Child Behavior Checklist/Preschool 1.5-5 T-scores greater than or equal to 64 for internalizing, externalizing, or total problems indicated clinical importance. Results: Of 704 infants enrolled, 529 (mean [SD] gestational age, 27.0 [1.9] weeks; 287 male [54.3%]) were studied at 24-month follow-up. A total of 94 infants' mothers had preeclampsia (23.2%), and 46 infants (8.7%) had FGR. In adjusted models, preeclampsia was not associated with Bayley-III (cognitive, B = 3.43 [95% CI, -0.19 to 6.66]; language, B = 3.92 [95% CI, 0.44 to 7.39]; motor, B = 1.86 [95% CI, -1.74 to 5.47]) or Child Behavior Checklist/Preschool 1.5-5 (internalizing, B = -0.08 [95% CI, -2.58 to 2.73]; externalizing, B = 0.69 [95% CI, -1.76 to 3.15]; total, B = 0.21 [95% CI, -2.48 to 2.91]) outcomes. FGR was associated with significantly lower Bayley-III scores (cognitive, B = -8.61 [95% CI, -13.33 to -3.89]; language, B = -8.29 [95% CI, -12.95 to -3.63]; motor, B = -7.60 [95% CI, -12.40 to -2.66]), regardless of preeclampsia status. Conclusions and Relevance: In this cohort study of preterm infants, preeclampsia was not associated with developmental and/or behavioral outcomes, but infants with FGR may be prone to developmental delays. These findings suggest future areas of research for understanding the roles of preeclampsia and FGR separately and together in early child development for preterm infants.

Epigenome-wide association study identifies neonatal DNA methylation associated with two-year attention problems in children born very preterm.

Prior research has identified epigenetic predictors of attention problems in school-aged children but has not yet investigated these in young children, or children at elevated risk of attention problems due to preterm birth. The current study evaluated epigenome-wide associations between neonatal DNA methylation and attention problems at age 2 years in children born very preterm. Participants included 441 children from the Neonatal Neurobehavior and Outcomes in Very Preterm Infants (NOVI) Study, a multi-site study of infants born < 30 weeks gestational age. DNA methylation was measured from buccal swabs collected at NICU discharge using the Illumina MethylationEPIC Bead Array. Attention problems were assessed at 2 years of adjusted age using the attention problems subscale of the Child Behavior Checklist (CBCL). After adjustment for multiple testing, DNA methylation at 33 CpG sites was associated with child attention problems. Differentially methylated CpG sites were located in genes previously linked to physical and mental health, including several genes associated with ADHD in prior epigenome-wide and genome-wide association studies. Several CpG sites were located in genes previously linked to exposure to prenatal risk factors in the NOVI sample. Neonatal epigenetics measured at NICU discharge could be useful in identifying preterm children at risk for long-term attention problems and related psychiatric disorders, who could benefit from early prevention and intervention efforts.

Contributions of prenatal risk factors and neonatal epigenetics to cognitive outcome in children born very preterm.

Children born less than 30 weeks gestational age (GA) are at high risk for neurodevelopmental delay compared to term peers. Prenatal risk factors and neonatal epigenetics could help identify preterm children at highest risk for poor cognitive outcomes. We aimed to understand the associations among cumulative prenatal risk, neonatal DNA methylation, and child cognitive ability at age 3 years, including whether DNA methylation mediates the association between prenatal risk and cognitive ability. We studied 379 neonates (54% male) born less than 30 weeks GA who had DNA methylation measured at neonatal intensive care unit discharge along with 3-year follow-up data. Cumulative prenatal risk was calculated from 24 risk factors obtained from maternal report and medical record and epigenome-wide neonatal DNA methylation was assayed from buccal swabs. At 3-year follow-up, child cognitive ability was assessed using the Bayley Scales of Infant and Toddler Development (third edition). Cumulative prenatal risk and DNA methylation at two cytosine-phosphate-guanines (CpGs) were uniquely associated with child cognitive ability. Using high-dimensional mediation analysis, we also identified differential methylation of 309 CpGs that mediated the association between cumulative prenatal risk and child cognitive ability. Many of the associated CpGs were located in genes (TNS3, TRAPPC4, MAD1L1, APBB2, DIP2C, TRAPPC9, DRD2) that have previously been associated with prenatal exposures and/or neurodevelopmental phenotypes. Our findings suggest a role for both prenatal risk factors and DNA methylation in explaining outcomes for children born preterm and suggest we should further study DNA methylation as a potential mechanism underlying the association between prenatal risk and child neurodevelopment. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Two-Year Autism Risk Screening and 3-Year Developmental Outcomes in Very Preterm Infants.

Importance: Use of the Modified Checklist for Autism in Toddlers, Revised With Follow-Up, a 2-stage parent-report autism risk screening tool, has been questioned due to reports of poor sensitivity and specificity. How this measure captures developmental delays for very preterm infants may provide support for continued use in pediatric care settings. Objective: To determine whether autism risk screening with the 2-stage parent-report autism risk screening tool at age 2 years is associated with behavioral and developmental outcomes at age 3 in very preterm infants. Design, Setting, and Participants: Neonatal Neurobehavior and Outcomes for Very Preterm Infants was a longitudinal, multisite cohort study. Enrollment occurred April 2014 to June 2016, and analyses were conducted from November 2022 to May 2023. Data were collected across 9 university-affiliated neonatal intensive care units (NICUs). Inclusion criteria were infants born less than 30 weeks' gestational age, a parent who could read and speak English and/or Spanish, and residence within 3 hours of the NICU and follow-up clinic. Exposures: Prematurity and use of the 2-stage parent-report autism risk screening tool at age 2 years. Main Outcomes and Measures: Outcomes include cognitive, language, motor composites on Bayley Scales for Infant and Toddler Development, third edition (Bayley-III) and internalizing, externalizing, total problems, and pervasive developmental disorder (PDD) subscale on the Child Behavior Checklist (CBCL) at age 3 years. Generalized estimating equations tested associations between the 2-stage parent-report autism risk screening tool and outcomes, adjusting for covariates. Results: A total of 467 children (mean [SD] gestational age, 27.1 [1.8] weeks; 243 male [52%]) were screened with the 2-stage parent-report autism risk screening tool at age 2 years, and outcome data at age 3 years were included in analyses. Mean (SD) maternal age at birth was 29 (6) years. A total of 51 children (10.9%) screened positive on the 2-stage parent-report autism risk screening tool at age 2 years. Children with positive screening results were more likely to have Bayley-III composites of 84 or less on cognitive (adjusted odds ratio [aOR], 4.03; 95% CI, 1.65-9.81), language (aOR, 5.38; 95% CI, 2.43-11.93), and motor (aOR, 4.74; 95% CI, 2.19-10.25) composites and more likely to have CBCL scores of 64 or higher on internalizing (aOR, 4.83; 95% CI, 1.88-12.44), externalizing (aOR, 2.69; 95% CI, 1.09-6.61), and PDD (aOR, 3.77; 95% CI, 1.72-8.28) scales. Conclusions and Relevance: Results suggest that the 2-stage parent-report autism risk screening tool administered at age 2 years was a meaningful screen for developmental delays in very preterm infants, with serious delays detected at age 3 years.

Epigenetic associations with neonatal age in infants born very preterm, particularly among genes involved in neurodevelopment.

The time from conception through the first year of life is the most dynamic period in human development. This time period is particularly important for infants born very preterm (< 30 weeks gestation; VPT), as they experience a significant disruption in the normal developmental trajectories and are at heightened risk of experiencing developmental impairments and delays. Variations in the epigenetic landscape during this period may reflect this disruption and shed light on the interrelationships between aging, maturation, and the epigenome. We evaluated how gestational age (GA) and age since conception in neonates [post-menstrual age (PMA)], were related to DNA methylation in buccal cells collected at NICU discharge from VPT infants (n = 538). After adjusting for confounders and applying Bonferroni correction, we identified 2,366 individual CpGs associated with GA and 14,979 individual CpGs associated with PMA, as well as multiple differentially methylated regions. Pathway enrichment analysis identified pathways involved in axonogenesis and regulation of neuron projection development, among many other growth and developmental pathways (FDR q < 0.001). Our findings align with prior work, and also identify numerous novel associations, suggesting that genes important in growth and development, particularly neurodevelopment, are subject to substantial epigenetic changes during early development among children born VPT.

Early enteral fat supplement and fish oil increases fat absorption in the premature infant with an enterostomy.

OBJECTIVE: To test the hypothesis that in the premature infant with an enterostomy, early enteral supplementation with Microlipid (fat supplement) and fish oil increases enteral fat absorption and decreases the requirement for Intralipid (intravenous fat emulsion). STUDY DESIGN: Premature infants (<2 months old) with an enterostomy after surgical treatment for necrotizing enterocolitis or spontaneous intestinal perforation and tolerating enteral feeding at 20 mL/kg/day were randomized to usual care (control 18 infants) or early supplementing enteral fat and fish oil (treatment 18 infants). Intravenous fat emulsion was decreased as enteral fat intake was increased. Daily weight, ostomy output, and nutrition data were recorded. Weekly 24-hour ostomy effluent was collected until bowel reanastomosis, and fecal fat, fecal liquid, and dry feces were measured. Fat absorption (g/kg/d) was calculated by subtracting fecal fat from dietary fat. The fecal liquid and dry feces were reported as mg/g wet stool. Date were analyzed by using ANOVA and mixed-effects model. RESULTS: The interval from initial postoperative feeding to bowel reanastomosis varied from 2 to 10 weeks. The treatment group received more dietary fat and less intravenous fat emulsion and had higher enteral fat absorption, less fecal liquid, and drier feces than the control group. These effects were greater among infants with a high ostomy compared with those with a low ostomy. Enteral fat intake was significantly correlated with fat absorption. CONCLUSION: Early enteral fat supplement and fish oil increases fat absorption and decreases the requirement for intravenous fat emulsion. This approach could be used to promote bowel adaptation and reduce the use of intravenous fat emulsion in the premature infant with an enterostomy.