An Individualized Approach to Kidney Disease Screening in Children With a History of Preterm Birth

Sanderson K, O'Shea TM, Kistler CE.

Clin Pediatr (Phila). 2023 Jun;62(5):385-388. doi: 10.1177/00099228221132126. Epub 2022 Oct 21. PMID: 36271655; PMCID: PMC10119330.

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Well-child Bright Futures screenings provide considerable benefits for child health and disease prevention; however, the benchmarks and screening for the many children with medical comorbidities are less well defined. With advancements in pediatric medicine, more children are living well with chronic diseases such as asthma, obesity, and hypertension. For these children, a more individualized approach to screening for comorbidities is needed. Many studies indicate that biological aging is accelerated among childhood survivors of critical illness and disease. We suggest that a risk-stratification framework for chronic disease, based on early life and childhood exposures, will enhance early chronic disease recognition and improve long-term health outcomes in children. One of the most prevalent risk factors for long-term morbidity in children that pediatricians encounter is preterm birth. While an individualized approach to screening for comorbidities would benefit all children with a chronic diagnosis or a history of prolonged hospital course, the specific example on which we focus on in this commentary is the relationship between preterm birth and chronic kidney disease (CKD).

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

Frazier JA, Li X, Kong X, Hooper SR, Joseph RM, Cochran DM, Kim S, Fry RC, Brennan PA, Msall ME, Fichorova RN, Hertz-Picciotto I, Daniels JL, Lai JS, Boles RE, Zvara BJ, Jalnapurkar I, Schweitzer JB, Singh R, Posner J, Bennett DH, Kuban KCK, O'Shea TM; program collaborators for Environmental influences on Child Health Outcomes.

J Am Acad Child Adolesc Psychiatry. 2023 May 15:S0890-8567(23)00248-4. doi: 10.1016/j.jaac.2023.05.010. Epub ahead of print. PMID: 37207889.

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Objective: In this cohort study, we assessed perinatal factors known to be related to maternal and neonatal inflammation and hypothesized several would be associated with emotional, cognitive, and behavioral dysregulation in youth.

Method: The Environmental Influences on Child Health Outcomes is a research consortium of 69 pediatric longitudinal cohorts. We used 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. Children were classified as having the CBCL dysregulation profile (CBCL-DP) if the sum of their T-Scores for three CBCL subscales (attention, anxious/depressed, and aggression) was ≥ 180. Perinatal factors associated with maternal and/or neonatal inflammation were our primary exposures and we assessed associations between these and our outcome.

Results: Approximately 13.4 % of 4,595 youth met criteria for the CBCL-DP. Boys were affected more than girls (15.1% vs 11.5%). More youth with the CBCL-DP (35%) were born to mothers with prenatal infection(s), compared to 28% of youth without the 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 the CBCL-DP and could be targets for interventions to improve offspring’s behavioral outcomes.

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

Freedman AN, Clark J, Eaves LA, Roell K, Oran A, Koval L, Rager J, Santos HP Jr, Kuban K, Joseph RM, Frazier J, Marsit CJ, Burt AA, O'Shea TM, Fry RC.

Autism Res. 2023 May;16(5):918-934. doi: 10.1002/aur.2915. Epub 2023 Mar 20. PMID: 36938998; PMCID: PMC10192070.

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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.

Healthcare utilization during the COVID-19 pandemic among children born preterm in the ECHO Program

McGowan EC, McGrath M, Law A, O'Shea TM, Aschner JL, Blackwell CK, Fry RC, Ganiban JM, Higgins R, Margolis A, Sathyanarayana S, Taylor G, Alshawabkeh AN, Cordero JF, Spillane NT, Hudak ML, Camargo CA Jr, Dabelea D, Dunlop AL, Elliott AJ, Ferrara AM, Talavera-Barber M, Singh AM, Karagas MR, Karr C, O'Connor TG, Paneth N, Wright RJ, Wright RO, Cowell W, Stanford JB, Bendixsen C, Lester BM; program collaborators for Environmental Influences on Child Health Outcomes (ECHO).

JAMA Netw Open. 2023 Apr 3;6(4):e2310696. doi: 10.1001/jamanetworkopen.2023.10696. PMID: 37115545; PMCID: PMC10148204.

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Importance: Limited data exist on pediatric health care utilization during the COVID-19 pandemic among children and young adults born preterm.

Objective: To investigate differences in health care use related to COVID-19 concerns during the pandemic among children and young adults born preterm vs those born at term.

Design, setting, and participants: In this cohort study, questionnaires regarding COVID-19 and health care utilization were completed by 1691 mother-offspring pairs from 42 pediatric cohorts in the National Institutes of Health Environmental Influences on Child Health Outcomes Program. Children and young adults (ages 1-18 years) in these analyses were born between 2003 and 2021. Data were recorded by the August 31, 2021, data-lock date and were analyzed between October 2021 and October 2022.

Exposures: Premature birth (<37 weeks’ gestation).

Main outcomes and measures: The main outcome was health care utilization related to COVID-19 concerns (hospitalization, in-person clinic or emergency department visit, phone or telehealth evaluations). Individuals born preterm vs term (≥37 weeks’ gestation) and differences among preterm subgroups of individuals (<28 weeks’, 28-36 weeks’ vs ≥37 weeks’ gestation) were assessed. Generalized estimating equations assessed population odds for health care used and related symptoms, controlling for maternal age, education, and psychiatric disorder; offspring history of bronchopulmonary dysplasia (BPD) or asthma; and timing and age at COVID-19 questionnaire completion.

Results: Data from 1691 children and young adults were analyzed; among 270 individuals born preterm, the mean (SD) age at survey completion was 8.8 (4.4) years, 151 (55.9%) were male, and 193 (71.5%) had a history of BPD or asthma diagnosis. Among 1421 comparison individuals with term birth, the mean (SD) age at survey completion was 8.4 (2.4) years, 749 (52.7%) were male, and 233 (16.4%) had a history of BPD or asthma. Preterm subgroups included 159 individuals (58.5%) born at less than 28 weeks’ gestation. In adjusted analyses, individuals born preterm had a significantly higher odds of health care utilization related to COVID-19 concerns (adjusted odds ratio [aOR], 1.70; 95% CI, 1.21-2.38) compared with term-born individuals; similar differences were also seen for the subgroup of individuals born at less than 28 weeks’ gestation (aOR, 2.15; 95% CI, 1.40-3.29). Maternal history of a psychiatric disorder was a significant covariate associated with health care utilization for all individuals (aOR, 1.44; 95% CI, 1.17-1.78).

Conclusions and relevance: These findings suggest that during the COVID-19 pandemic, children and young adults born preterm were more likely to have used health care related to COVID-19 concerns compared with their term-born peers, independent of a history of BPD or asthma. Further exploration of factors associated with COVID-19-related health care use may facilitate refinement of care models.

Assessment of Psychosocial and Neonatal Risk Factors for Trajectories of Behavioral Dysregulation Among Young Children From 18 to 72 Months of Age

Hofheimer JA, McGrath M, Musci R, Wu G, Polk S, Blackwell CK, Stroustrup A, Annett RD, Aschner J, Carter BS, Check J, Conradt E, Croen LA, Dunlop AL, Elliott AJ, Law A, Leve LD, Neiderhiser JM, O'Shea TM, Salisbury AL, Sathyanarayana S, Singh R, Smith LM, Aguiar A, Angal J, Carliner H, McEvoy C, Ondersma SJ, Lester B; Program Collaborators for Environmental influences on Child Health Outcomes.

JAMA Netw Open. 2023 Apr 3;6(4):e2310059. doi: 10.1001/jamanetworkopen.2023.10059. PMID: 37099294; PMCID: PMC10134008.

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Importance: Emotional and behavioral dysregulation during early childhood are associated with severe psychiatric, behavioral, and cognitive disorders through adulthood. Identifying the earliest antecedents of persisting emotional and behavioral dysregulation can inform risk detection practices and targeted interventions to promote adaptive developmental trajectories among at-risk children.

Objective: To characterize children’s emotional and behavioral regulation trajectories and examine risk factors associated with persisting dysregulation across early childhood.

Design, setting, and participants: This cohort study examined data from 20 United States cohorts participating in Environmental influences on Child Health Outcomes, which included 3934 mother-child pairs (singleton births) from 1990 to 2019. Statistical analysis was performed from January to August 2022.

Exposures: Standardized self-reports and medical data ascertained maternal, child, and environmental characteristics, including prenatal substance exposures, preterm birth, and multiple psychosocial adversities.

Main outcomes and measures: Child Behavior Checklist caregiver reports at 18 to 72 months of age, with Dysregulation Profile (CBCL-DP = sum of anxiety/depression, attention, and aggression).

Results: The sample included 3934 mother-child pairs studied at 18 to 72 months. Among the mothers, 718 (18.7%) were Hispanic, 275 (7.2%) were non-Hispanic Asian, 1220 (31.8%) were non-Hispanic Black, 1412 (36.9%) were non-Hispanic White; 3501 (89.7%) were at least 21 years of age at delivery. Among the children, 2093 (53.2%) were male, 1178 of 2143 with Psychosocial Adversity Index [PAI] data (55.0%) experienced multiple psychosocial adversities, 1148 (29.2%) were exposed prenatally to at least 1 psychoactive substance, and 3066 (80.2%) were term-born (≥37 weeks’ gestation). Growth mixture modeling characterized a 3-class CBCL-DP trajectory model: high and increasing (2.3% [n = 89]), borderline and stable (12.3% [n = 479]), and low and decreasing (85.6% [n = 3366]). Children in high and borderline dysregulation trajectories had more prevalent maternal psychological challenges (29.4%-50.0%). Multinomial logistic regression analyses indicated that children born preterm were more likely to be in the high dysregulation trajectory (adjusted odds ratio [aOR], 2.76; 95% CI, 2.08-3.65; P < .001) or borderline dysregulation trajectory (aOR, 1.36; 95% CI, 1.06-1.76; P = .02) vs low dysregulation trajectory. High vs low dysregulation trajectories were less prevalent for girls compared with boys (aOR, 0.60; 95% CI, 0.36-1.01; P = .05) and children with lower PAI (aOR, 1.94; 95% CI, 1.51-2.49; P < .001). Combined increases in PAI and prenatal substance exposures were associated with increased odds of high vs borderline dysregulation (aOR, 1.28; 95% CI, 1.08-1.53; P = .006) and decreased odds of low vs high dysregulation (aOR, 0.77; 95% CI, 0.64-0.92; P = .005).

Conclusions and relevance: In this cohort study of behavioral dysregulation trajectories, associations were found with early risk factors. These findings may inform screening and diagnostic practices for addressing observed precursors of persisting dysregulation as they emerge among at-risk children.

When a birth cohort grows up: challenges and opportunities in longitudinal developmental origins of health and disease (DOHaD) research

Oken E, Bastain TM, Bornkamp N, Breton CV, Fry RC, Gold DR, Hivert MF, Howland S, Jackson DJ, Johnson CC, Jones K, Killingbeck M, O'Shea TM, Ortega M, Ownby D, Perera F, Rollins JV, Herbstman JB; program collaborators for Environmental influences on Child Health Outcomes.

J Dev Orig Health Dis. 2023 Apr;14(2):175-181. doi: 10.1017/S2040174422000629. Epub 2022 Nov 21. PMID: 36408681; PMCID: PMC9998333.

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High-quality evidence from prospective longitudinal studies in humans is essential to testing hypotheses related to the developmental origins of health and disease. In this paper, the authors draw upon their own experiences leading birth cohorts with longitudinal follow-up into adulthood to describe specific challenges and lessons learned. Challenges are substantial and grow over time. Long-term funding is essential for study operations and critical to retaining study staff, who develop relationships with participants and hold important institutional knowledge and technical skill sets. To maintain contact, we recommend that cohorts apply multiple strategies for tracking and obtain as much high-quality contact information as possible before the child’s 18th birthday. To maximize engagement, we suggest that cohorts offer flexibility in visit timing, length, location, frequency, and type. Data collection may entail multiple modalities, even at a single collection timepoint, including measures that are self-reported, research-measured, and administrative with a mix of remote and in-person collection. Many topics highly relevant for adolescent and young adult health and well-being are considered to be private in nature, and their assessment requires sensitivity. To motivate ongoing participation, cohorts must work to understand participant barriers and motivators, share scientific findings, and provide appropriate compensation for participation. It is essential for cohorts to strive for broad representation including individuals from higher risk populations, not only among the participants but also the staff. Successful longitudinal follow-up of a study population ultimately requires flexibility, adaptability, appropriate incentives, and opportunities for feedback from participants.

The Environmental influences on Child Health Outcomes (ECHO)-wide Cohort

Knapp EA, Kress AM, Parker CB, Page GP, McArthur K, Gachigi KK, Alshawabkeh AN, Aschner JL, Bastain TM, Breton CV, Bendixsen CG, Brennan PA, Bush NR, Buss C, Camargo CA Jr, Catellier D, Cordero JF, Croen L, Dabelea D, Deoni S, D'Sa V, Duarte CS, Dunlop AL, Elliott AJ, Farzan SF, Ferrara A, Ganiban JM, Gern JE, Giardino AP, Towe-Goodman NR, Gold DR, Habre R, Hamra GB, Hartert T, Herbstman JB, Hertz-Picciotto I, Hipwell AE, Karagas MR, Karr CJ, Keenan K, Kerver JM, Koinis-Mitchell D, Lau B, Lester BM, Leve LD, Leventhal B, LeWinn KZ, Lewis J, Litonjua AA, Lyall K, Madan JC, McEvoy CT, McGrath M, Meeker JD, Miller RL, Morello-Frosch R, Neiderhiser JM, O'Connor TG, Oken E, O'Shea M, Paneth N, Porucznik CA, Sathyanarayana S, Schantz SL, Spindel ER, Stanford JB, Stroustrup A, Teitelbaum SL, Trasande L, Volk H, Wadhwa PD, Weiss ST, Woodruff TJ, Wright RJ, Zhao Q, Jacobson LP, Environmental Influences On Child Health Outcomes OBOPCF.

Am J Epidemiol. 2023 Mar 24:kwad071. doi: 10.1093/aje/kwad071. Epub ahead of print. PMID: 36963379.

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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 five main outcome areas: pre-, peri-, and post-natal outcomes; neurodevelopment; obesity; airways; and positive health. Exposures include place- (e.g., air pollution, neighborhood socioeconomic status), family- (e.g., parental mental health), and individual-level (e.g., diet, genomics) factors.

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

Joseph RM, Lai ER, Bishop S, Yi J, Bauman ML, Frazier JA, Santos HP Jr, Douglas LM, Kuban KKC, Fry RC, O'Shea TM.

Autism Res. 2023 Mar;16(3):653-666. doi: 10.1002/aur.2885. Epub 2023 Jan 3. PMID: 36595641.

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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.

Bronchopulmonary dysplasia and neurobehavioural outcomes at birth and 2 years in infants born before 30 weeks

Martin M, Smith L, Hofheimer JA, McGowan EC, O'Shea TM, Pastyrnak S, Carter BS, Helderman J, Check J, Neal C, Roberts MB, Dansereau LM, Della Grotta SA, Lester BM.

Arch Dis Child Fetal Neonatal Ed. 2023 Mar;108(2):142-148. doi: 10.1136/archdischild-2021-323405. Epub 2022 Aug 23. PMID: 35999044; PMCID: PMC9947192.

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Objective: To identify neurobehavioural risks in preterm infants with bronchopulmonary dysplasia (BPD) prior to hospital discharge.

Design and patients: Longitudinal study of 676 newborns born before 30 weeks of gestation.

Setting: Nine university NICUs affiliated with six universities. All were Vermont Oxford Network (VON) participants.

Patients and interventions: Infants were enrolled in the Neonatal Neurobehavior and Outcomes in Very Preterm Infants Study from April 2014 to June 2016. Prospective medical record reviews, VON definitions and criteria, and maternal interviews were used to collect maternal and neonatal medical variables and socioenvironmental data.

Main outcome measures: NICU Network Neurobehavioral Scale (NNNS) at the time of hospital discharge; Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) and Gross Motor Function Classification System at 2 years’ corrected age.

Results: Infants with moderate/severe BPD were less attentive (Wald χ2 9.68, p=0.008), more lethargic (Wald χ2 9.91, p=0.007), with increased non-optimal reflexes (Wald χ2 7.37, p=0.025). Infants with moderate/severe BPD were more likely to have Bayley-III language and motor scores <85 (adjusted OR (aOR) 1.74, 95% CI 1.06 to 2.85, and aOR 2.06, 95% CI 1.10 to 3.85). Infants with both moderate/severe and mild BPD were more likely to have a cerebral palsy diagnosis (aOR 2.96, 95% CI 1.34 to 6.54, and aOR 2.81, 95% CI 1.32 to 5.99).

Conclusions: BPD severity presents risks for poor neurodevelopment at NICU discharge and at age 2 years. Early identification of poorly regulated behaviour can provide critical information for early preventive and targeted interventions with potential to improve long-term outcomes.

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

Camerota M, McGowan EC, Aschner J, Stroustrup A, Karagas MR, Conradt E, Crowell SE, Brennan PA, Carter BS, Check J, Dansereau LM, DellaGrotta SA, Everson TM, Helderman JB, Hofheimer JA, Kuiper JR, Loncar CM, Marsit CJ, Neal CR, O'Shea TM, Pastyrnak SL, Sheinkopf SJ, Smith LM, Zhang X, Lester BM.

Pediatr Res. 2023 Feb 25. doi: 10.1038/s41390-023-02540-2. Epub ahead of print. PMID: 36841884.

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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.