Neurobehavioral outcomes of preterm infants: toward a holistic approach.

Children born very preterm (VPT; <32 weeks gestation) are at high risk for adverse developmental outcomes, yet not all children fare poorly. Some children born VPT have few or no neurodevelopmental concerns, while others have significant impairment in one or more domains. Historically, research has taken a variable-centered approach, reporting rates of impairment in single domains or single assessments as if they are independent of one another. More recently, child-centered approaches have been applied to studying outcomes for preterm children. Child-centered analyses allow us to integrate across multiple measures and domains to more holistically describe groups of children who vary in terms of the severity and co-occurrence of neurodevelopmental and behavioral strengths and difficulties. In this review, we will summarize current research that has taken a "whole child" approach to describing neurodevelopmental outcomes following preterm birth while highlighting the implications of this approach for research and clinical practice. We end by describing unanswered questions and areas that are in need of future research. IMPACT: Most research on outcomes for children born very preterm has reported rates of impairment in single domains or on single instruments. Recent findings suggest that a child-centered approach can identify unique phenotypes composed of multiple measures and domains that may be of clinical interest. A better understanding of unique combinations of neurodevelopmental and behavioral strengths and weaknesses could improve post-NICU care by emphasizing a personalized approach to intervention and treatment.

Evidence for neurobehavioral risk phenotypes at birth.

Observations of newborn behavior provide clinicians and researchers with a first description of the neurobehavioral organization of the newborn that is largely independent of the postnatal environment. The Neonatal Network Neurobehavioral Scale (NNNS) was developed in 2004 to evaluate how prenatal exposure to substances such as cocaine is related to neurobehavioral outcomes. There are now 156 empirical articles published using the NNNS, which we review and summarize. Z-scores from published studies using the NNNS were compiled and aggregated supporting the replicability of three newborn neurobehavioral phenotypes: one typical and two that are predictive of later cognitive and behavioral delay; hyper- and hypo-dysregulated newborns. These phenotypes emerged from independent samples and research groups and were identified in a variety of populations, including infants with prenatal substance exposure, preterm infants, and healthy term infants. Our findings show that newborn neurobehavior can be measured in a reliable and valid manner and that certain behavioral phenotypes, identifiable at birth, can predict neurodevelopmental challenges. These findings have important clinical utility. Intervening early with infants exhibiting these risk phenotypes may prevent later neurodevelopmental delay. IMPACT: We reviewed all empirical studies published using the Neonatal Network Neurobehavioral Scale and found evidence for two replicable stress phenotypes that predict later behavioral outcomes. This study highlights the utility of the Neonatal Network Neurobehavioral Scale for early identification of newborn neurodevelopmental risk phenotypes. Early identification of neurodevelopmental risk, when neuroplasticity is high, may ultimately reduce the burden of subsequent neurobehavioral problems through early intervention.

Approaches to protocol standardization and data harmonization in the ECHO-wide cohort study.

The United States (U.S.) National Institutes of Health-funded Environmental influences on Child Health Outcomes (ECHO)-wide Cohort was established to conduct high impact, transdisciplinary science to improve child health and development. The cohort is a collaborative research design in which both extant and new data are contributed by over 57,000 children across 69 cohorts. In this review article, we focus on two key challenging issues in the ECHO-wide Cohort: data collection standardization and data harmonization. Data standardization using a Common Data Model and derived analytical variables based on a team science approach should facilitate timely analyses and reduce errors due to data misuse. However, given the complexity of collaborative research designs, such as the ECHO-wide Cohort, dedicated time is needed for harmonization and derivation of analytic variables. These activities need to be done methodically and with transparency to enhance research reproducibility. IMPACT: Many collaborative research studies require data harmonization either prior to analyses or in the analyses of compiled data. The Environmental influences on Child Health Outcomes (ECHO) Cohort pools extant data with new data collection from over 57,000 children in 69 cohorts to conduct high-impact, transdisciplinary science to improve child health and development, and to provide a national database and biorepository for use by the scientific community at-large. We describe the tools, systems, and approaches we employed to facilitate harmonized data for impactful analyses of child health outcomes.

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.

Associations between neighborhood characteristics and child well-being before and during the COVID-19 pandemic: A repeated cross-sectional study in the Environmental influences on Child Health Outcomes (ECHO) program.

The corona virus disease (COVID-19) pandemic disrupted daily life worldwide, and its impact on child well-being remains a major concern. Neighborhood characteristics affect child well-being, but how these associations were affected by the pandemic is not well understood. We analyzed data from 1039 children enrolled in the Environmental influences on Child Health Outcomes Program whose well-being was assessed using the Patient-Reported Outcomes Measurement Information System Global Health questionnaire and linked these data to American Community Survey (ACS) data to evaluate the impacts of neighborhood characteristics on child well-being before and during the pandemic. We estimated the associations between more than 400 ACS variables and child well-being t-scores stratified by race/ethnicity (non-Hispanic white vs. all other races and ethnicities) and the timing of outcome data assessment (pre-vs. during the pandemic). Network graphs were used to visualize the associations between ACS variables and child well-being t-scores. The number of ACS variables associated with well-being t-scores decreased during the pandemic period. Comparing non-Hispanic white with other racial/ethnic groups during the pandemic, different ACS variables were associated with child well-being. Multiple ACS variables representing census tract-level housing conditions and neighborhood racial composition were associated with lower well-being t-scores among non-Hispanic white children during the pandemic, while higher percentage of Hispanic residents and higher percentage of adults working as essential workers in census tracts were associated with lower well-being t-scores among non-white children during the same study period. Our study provides insights into the associations between neighborhood characteristics and child well-being, and how the COVID-19 pandemic affected this relationship.

The Environmental Influences on Child Health Outcomes (ECHO)-Wide Cohort.

The Environmental Influences on Child Health Outcomes (ECHO)-Wide Cohort Study (EWC), a collaborative research design comprising 69 cohorts in 31 consortia, was funded by the National Institutes of Health (NIH) in 2016 to improve children's health in the United States. The EWC harmonizes extant data and collects new data using a standardized protocol, the ECHO-Wide Cohort Data Collection Protocol (EWCP). EWCP visits occur at least once per life stage, but the frequency and timing of the visits vary across cohorts. As of March 4, 2022, the EWC cohorts contributed data from 60,553 children and consented 29,622 children for new EWCP data and biospecimen collection. The median (interquartile range) age of EWCP-enrolled children was 7.5 years (3.7-11.1). Surveys, interviews, standardized examinations, laboratory analyses, and medical record abstraction are used to obtain information in 5 main outcome areas: pre-, peri-, and postnatal outcomes; neurodevelopment; obesity; airways; and positive health. Exposures include factors at the level of place (e.g., air pollution, neighborhood socioeconomic status), family (e.g., parental mental health), and individuals (e.g., diet, genomics).

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.

Polygenic risk scores and the need for pharmacotherapy in neonatal abstinence syndrome.

BACKGROUND: The aim of this study was to identify genetic variants associated with NAS through a genome-wide association study (GWAS) and estimate a Polygenic Risk Score (PRS) model for NAS. METHODS: A prospective case-control study included 476 in utero opioid-exposed term neonates. A GWAS of 1000 genomes-imputed genotypes was performed to identify variants associated with need for pharmacotherapy for NAS. PRS models for estimating genetic predisposition were generated via a nested cross-validation approach using 382 neonates of European ancestry. PRS predictive ability, discrimination, and calibration were assessed. RESULTS: Cross-ancestry GWAS identified one intergenic locus on chromosome 7 downstream of SNX13 exhibiting genome-wide association with need for pharmacotherapy. PRS models derived from the GWAS for a subset of the European ancestry neonates reliably discriminated between need for pharmacotherapy using cis variant effect sizes within validation sets of European and African American ancestry neonates. PRS were less effective when applying variant effect sizes across datasets and in calibration analyses. CONCLUSIONS: GWAS has the potential to identify genetic loci associated with need for pharmacotherapy for NAS and enable development of clinically predictive PRS models. Larger GWAS with additional ancestries are needed to confirm the observed SNX13 association and the accuracy of PRS in NAS risk prediction models. IMPACT: Genetic associations appear to be important in neonatal abstinence syndrome. This is the first genome-wide association in neonates with neonatal abstinence syndrome. Polygenic risk scores can be developed examining single-nucleotide polymorphisms across the entire genome. Polygenic risk scores were higher in neonates receiving pharmacotherapy for treatment of their neonatal abstinence syndrome. Future studies with larger cohorts are needed to better delineate these genetic associations.

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.

Annual Research Review: Prenatal opioid exposure - a two-generation approach to conceptualizing neurodevelopmental outcomes.

Opioid use during pregnancy impacts the health and well-being of two generations: the pregnant person and the child. The factors that increase risk for opioid use in the adult, as well as those that perpetuate risk for the caregiver and child, oftentimes replicate across generations and may be more likely to affect child neurodevelopment than the opioid exposure itself. In this article, we review the prenatal opioid exposure literature with the perspective that this is not a singular event but an intergenerational cascade of events. We highlight several mechanisms of transmission across generations: biological factors, including genetics and epigenetics and the gut-brain axis; parent-child mechanisms, such as prepregnancy experience of child maltreatment, quality of parenting, infant behaviors, neonatal opioid withdrawal diagnosis, and broader environmental contributors including poverty, violence exposure, stigma, and Child Protective Services involvement. We conclude by describing ways in which intergenerational transmission can be disrupted by early intervention.

Prenatal Substance Exposure: Associations with Neurodevelopment in Middle Childhood.

OBJECTIVE: Single-substance exposure effects on neurodevelopmental outcomes, such as problem behavior and intelligence quotient (IQ), have been studied in children for decades. However, the long-term consequences of polysubstance exposure are poorly understood. STUDY DESIGN: Longitudinal neurodevelopmental data were gathered from cohorts across the United States through the Environmental Influences on Child Health Outcomes Program. Data on prenatal exposure to opioids, nicotine, marijuana, and alcohol were collected from children ages 6 to 11 years (N = 256). Problem behavior was assessed using the Child Behavior Checklist (school-age version), and verbal IQ (VIQ) and performance IQ (PIQ) were assessed using the Weschler Intelligence Scale for Children, Fifth Edition. We first identified latent profiles in the overall sample, then evaluated differences in profile membership for children with and without prenatal substance exposure. RESULTS: Latent profile analysis identified two mutually exclusive categories: average VIQ and PIQ, with typical problem behavior, and below-average VIQ with average PIQ and clinically significant problem behavior. Children with prenatal nicotine and polysubstance exposures were more likely to be classified in the below-average VIQ, elevated problem behavior profile compared with children without prenatal nicotine exposure. CONCLUSION: The presence of clinically significant behavior problems in children with average PIQ, but below-average VIQ, could represent a unique endophenotype related to prenatal nicotine exposure in the context of other prenatal substance exposures. KEY POINTS: · The neurodevelopmental consequences of prenatal polysubstance exposure are poorly understood.. · Children with prenatal polysubstance exposure exhibited reduced IQ and elevated problem behavior.. · We found significant behavior problems in children with average PIQ and below-average VIQ.. · This may represent a unique endophenotype related to prenatal nicotine exposure..

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..

Cardiometabolic Pregnancy Complications in Association With Autism-Related Traits as Measured by the Social Responsiveness Scale in ECHO.

Prior work has examined associations between cardiometabolic pregnancy complications and autism spectrum disorder (ASD) but not how these complications may relate to social communication traits more broadly. We addressed this question within the Environmental Influences on Child Health Outcomes program, with 6,778 participants from 40 cohorts conducted from 1998-2021 with information on ASD-related traits via the Social Responsiveness Scale. Four metabolic pregnancy complications were examined individually, and combined, in association with Social Responsiveness Scale scores, using crude and adjusted linear regression as well as quantile regression analyses. We also examined associations stratified by ASD diagnosis, and potential mediation by preterm birth and low birth weight, and modification by child sex and enriched risk of ASD. Increases in ASD-related traits were associated with obesity (ß = 4.64, 95% confidence interval: 3.27, 6.01) and gestational diabetes (ß = 5.21, 95% confidence interval: 2.41, 8.02), specifically, but not with hypertension or preeclampsia. Results among children without ASD were similar to main analyses, but weaker among ASD cases. There was not strong evidence for mediation or modification. Results suggest that common cardiometabolic pregnancy complications may influence child ASD-related traits, not only above a diagnostic threshold relevant to ASD but also across the population.

Effects of Pharmacologic Treatment for Neonatal Abstinence Syndrome on DNA Methylation and Neurobehavior: A Prospective Cohort Study.

OBJECTIVE: To determine whether pharmacologic treatment for neonatal abstinence syndrome (NAS) is associated with changes in DNA methylation (DNAm) of the mu-opioid receptor gene (OPRM1) and improvements in neonatal neurobehavior. STUDY DESIGN: Buccal swabs were collected from 37 neonates before and after morphine treatment for NAS. Genomic DNA was extracted, and DNAm was examined at 4 cytosine-phosphate-guanine (CpG) sites within the OPRM1 gene. Assessment with the NICU Network Neurobehavioral Scales (NNNS) was also performed before and after NAS treatment. Changes in DNAm (DNAmpost-tx - DNAmpre-tx) and NNNS summary scores (NNNSpost-tx - NNNSpre-tx) were then calculated. Path analysis was used to examine associations among pharmacologic treatment (length of treatment [LOT] and total dose of morphine), changes in DNAm, and changes in NNNS summary scores. RESULTS: DNAm was significantly decreased from pretreatment to post-treatment at 1 of 4 CpG sites within the OPRM1 gene. Neonates also demonstrated decreased excitability, hypertonia, lethargy, signs of stress and abstinence, and increased quality of movement and regulation from pretreatment to post-treatment. Longer LOT and higher morphine dose were associated with greater decreases in DNAm; greater decreases in DNAm were associated with greater decreases in excitability and hypertonia on the NNNS. CONCLUSIONS: Pharmacologic treatment of NAS is associated with decreased DNAm of the OPRM1 gene and improved neonatal neurobehavior. Epigenetic changes may play a role in these changes in neonatal neurobehavior.

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.

Testing the mid-range model: Attachment in a high risk sample.

Infant attachment is a key predictor of later socioemotional functioning, but it is not clear how parental responsivity to infant expressive behavior is associated with attachment outcomes. A mid-range model of responsivity holds that both unresponsive and highly reactive parental behaviors lead to insecure and disorganized attachment. We examined the relationship between maternal (and infant) contingent responsivity and attachment in a high-risk sample. Participants were 625 infant-mother pairs from a longitudinal study of children with and without prenatal drug exposure and variable levels of associated social risks. Infant-mother pairs participated in the Face-to-Face/Still-Face paradigm (FFSF) at 4-months and in the Strange Situation Procedure (SSP) at 18-months. A model incorporating both linear and quadratic responsivity effects indicated that mothers who were either very high (reactive) or very low (unresponsive) in responsivity were more likely to have infants with disorganized attachment outcomes. While maternal responsivity was associated with attachment disorganization, no associations between maternal responsivity, and attachment security/insecurity were detected. Infant responsivity to mother was not associated with attachment outcomes. The findings suggest the importance of mid-range levels of maternal responsivity in the development of organized attachment among infants facing high levels of prenatal and social risk.

Parent-child relationship quality and adolescent health: Testing the differential susceptibility and diathesis-stress hypotheses in African American youths.

This study tested two competing models of differential susceptibility and diathesis-stress in a prospective longitudinal study of African American youths (N = 935). It examined whether individual variations in the functioning of the hypothalamic-pituitary-adrenocortical axis at age 11 interact with middle childhood parent-child relationship quality to predict mental and physical health problems in adolescence (ages 11-15 years old). Adolescent boys with lower levels of cortisol reactivity to laboratory challenges had the highest levels of internalizing problems if they experienced a high conflictual relationship with their parents. Equally low-reactive boys, however, reported the lowest number of physical illnesses if their relationship with their parents was characterized by high levels of intimacy and support.