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

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

Quantitative MRI Characterization of the Extremely Preterm Brain at Adolescence: Atypical versus Neurotypical Developmental Pathways.

Background Extremely preterm (EP) birth is associated with higher risks of perinatal white matter (WM) injury, potentially causing abnormal neurologic and neurocognitive outcomes. MRI biomarkers distinguishing individuals with and without neurologic disorder guide research on EP birth antecedents, clinical correlates, and prognoses. Purpose To compare multiparametric quantitative MRI (qMRI) parameters of EP-born adolescents with autism spectrum disorder, cerebral palsy, epilepsy, or cognitive impairment (ie, atypically developing) with those without (ie, neurotypically developing), characterizing sex-stratified brain development. Materials and Methods This prospective multicenter study included individuals aged 14-16 years born EP (Extremely Low Gestational Age Newborns-Environmental Influences on Child Health Outcomes Study, or ELGAN-ECHO). Participants underwent 3.0-T MRI evaluation from 2017 to 2019. qMRI outcomes were compared for atypically versus neurotypically developing adolescents and for girls versus boys. Sex-stratified multiple regression models were used to examine associations between spatial entropy density (SEd) and T1, T2, and cerebrospinal fluid (CSF)-normalized proton density (nPD), and between CSF volume and T2. Interaction terms modeled differences in slopes between atypically versus neurotypically developing adolescents. Results A total of 368 adolescents were classified as 116 atypically (66 boys) and 252 neurotypically developing (125 boys) participants. Atypically versus neurotypically developing girls had lower nPD (mean, 557 10 × percent unit [pu] ± 46 [SD] vs 573 10 × pu ± 43; P = .04), while atypically versus neurotypically developing boys had longer T1 (814 msec ± 57 vs 789 msec ± 82; P = .01). Atypically developing girls versus boys had lower nPD and shorter T2 (eg, in WM, 557 10 × pu ± 46 vs 580 10 × pu ± 39 for nPD [P = .006] and 86 msec ± 3 vs 88 msec ± 4 for T2 [P = .003]). Atypically versus neurotypically developing boys had a more moderate negative association between T1 and SEd (slope, -32.0 msec per kB/cm3 [95% CI: -49.8, -14.2] vs -62.3 msec per kB/cm3 [95% CI: -79.7, -45.0]; P = .03). Conclusion Atypically developing participants showed sexual dimorphisms in the cerebrospinal fluid-normalized proton density (nPD) and T2 of both white matter (WM) and gray matter. Atypically versus neurotypically developing girls had lower WM nPD, while atypically versus neurotypically developing boys had longer WM T1 and more moderate T1 associations with microstructural organization in WM. © RSNA, 2022 Online supplemental material is available for this article.

The risk of neurodevelopmental disorders at age 10 years associated with blood concentrations of interleukins 4 and 10 during the first postnatal month of children born extremely preterm.

BACKGROUND: Interleukin (IL)-4 and IL-10 are viewed mainly as anti-inflammatory cytokines. Yet, high concentrations have also been associated with inflammation-related diseases in newborns. METHODS: We measured the concentrations of IL-4 and IL-10, as well as IL-8 and ICAM-1 in blood specimens collected on postnatal day 21 (N = 555), day 28 (N = 521), and both days 21 and 28 (N = 449) from children born extremely preterm (EP) (<28 weeks gestation) who at age 10 years had a DAS-II IQ Z-score > -2 (which approximates a score of >70) and the following assessments, CCC-2, and CSI-4, DAS-II, NEPSY-II, OWLS-II, SCQ, and WIAT-III. Selected children also were assessed with the ADI-R and the ADOS-2. We modeled the risk of low scores or dysfunctions associated with top quartile concentrations of IL-4 and IL-10 on each day and on both days. RESULTS: The risks of low scores on the Animal Sorting and Arrows components of the NEPSY-II, both components of the OWLS-II, and the PseudoWord and Spelling components of the WIAT-III were heightened among children who had top quartile concentrations of IL-4 on postnatal days 21 and 28. Children who had high concentrations of IL-10 on days 21 and 28, individually and collectively, were at increased risk of low scores on the WIAT-III Spelling component. High concentrations of IL-4 on day 28 were associated with autism spectrum disorder (ASD). High concentrations of IL-10 on day 28 were also associated with a doubling of ASD risk, but this did not achieve statistical significance. Top quartile concentrations of IL-4 and IL10 on both days were not associated with increased risk of social, language, or behavioral dysfunctions. CONCLUSION: Among children born EP, those who had top quartile concentrations of IL-4 and/or IL-10 on postnatal days 21 and/or 28 were more likely than their peers to have low scores on components of the NEPSY-II, OWLS-II, and WIAT-III assessments, as well as identification as having an ASD. What is known: What is not known: What this study adds.

Maternal educational status at birth, maternal educational advancement, and neurocognitive outcomes at age 10 years among children born extremely preterm.

BackgroundTo determine if a key marker of socioeconomic status, maternal education, is associated with later neurocognitive and academic outcomes among children born extremely preterm (EP).MethodEight hundred and seventy-three children born at 23 to 27 weeks of gestation were assessed for cognitive and academic ability at age 10 years. With adjustments for gestational age (GA) and potential confounders, outcomes of children whose mothers had fewer years of education at the time of delivery and children whose mother advanced in education between birth and 10 years were examined.ResultsChildren of mothers in the lowest education stratum at birth were significantly more likely to score ≥2 SDs below normative expectation on 17 of 18 tests administered. Children of mothers who advanced in education (n=199) were at reduced risk for scoring ≥2 SDs on 15 of 18 measures, but this reduction was statistically significant on only 2 of 18 measures.ConclusionAmong EP children, socioeconomic disadvantage at birth, indexed by maternal education, is associated with significantly poorer neurocognitive and academic outcomes at 10 years of age, independently of GA. Maternal educational advancement during the child's first 10 years of life is associated with modestly improved neurocognitive outcomes.

Predictive Validity of the Modified Checklist for Autism in Toddlers (M-CHAT) Born Very Preterm.

OBJECTIVE: To examine the predictive validity of the Modified Checklist for Autism in Toddlers (M-CHAT) administered at age 24 months for autism spectrum disorder (ASD) diagnosed at 10 years of age in a US cohort of 827 extremely low gestational age newborns (ELGANs) followed from birth. STUDY DESIGN: We examined the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the M-CHAT in predicting an ASD diagnosis at age 10 years based on gold standard diagnostic instruments. We then assessed how these predictive parameters were affected by sensorimotor and cognitive impairments, socioeconomic status (SES), and emotional/behavioral dysregulation at age 2 years. RESULTS: Using standard criteria, the M-CHAT had a sensitivity of 52%, a specificity of 84%, a PPV of 20%, and an NPV of 96%. False-positive and false-negative rates were high among children with hearing and vision impairments. High false-positive rates also were associated with lower SES, motor and cognitive impairments, and emotional/behavioral dysregulation at age 2 years. CONCLUSIONS: Among extremely preterm children with ASD, almost one-half were not correctly screened by the M-CHAT at age 2 years. Sensorimotor and cognitive impairments, SES, and emotional/behavioral dysregulation contributed significantly to M-CHAT misclassifications. Clinicians are advised to consider these factors when screening very preterm toddlers for ASD.

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

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

Antenatal and neonatal antecedents of learning limitations in 10-year old children born extremely preterm.

BACKGROUND: Children born extremely preterm are at increased risk of learning limitations. AIM: To identify the antecedents of learning limitations of children born extremely preterm. STUDY DESIGN: Prospective observational study from birth to age 10 years. Variables entered into the multinomial logistic regression analyses were ordered temporally, with the earliest occurring predictors/covariates of each learning limitation risk entered first and not displaced by later occurring covariates. SUBJECTS: 874 children who were born before the 28th week of gestation. OUTCOME MEASURES: A reading limitation was defined as a score one or more standard deviations below the expected mean on the WIAT-III Word Reading and a mathematics limitation was defined as a similarly low score on the Numerical Operations component. RESULTS: 56 children had a "reading ONLY" limitation, 132 children had a "math ONLY" limitation and 89 children had "reading AND math" limitations. All risk profiles included an indicator of socioeconomic disadvantage (e.g., mother's "racial" identity and eligibility for government-provided health care insurance), an indicator of newborn's immaturity/vulnerability (e.g., high illness severity score, receipt of hydrocortisone, and/or ventilator-dependence at 36 weeks post-menstruation), and all but the math only limitation included an indicator of fetal growth restriction and inflammation (i.e., pregnancy urinary tract infection or late ventilator-dependence). CONCLUSIONS: The themes of socioeconomic disadvantage and immaturity/vulnerability characterize all three risk profiles, while the themes of fetal growth restriction and inflammation are characteristic of a reading limitation only, and the reading and math limitations entity.

Antenatal and Neonatal Antecedents of Executive Dysfunctions in Extremely Preterm Children.

To find out why children born extremely preterm are at heightened risk of executive dysfunctions, the authors assessed 716 children who were 10 years old born extremely preterm whose IQ was ≥ 70. A working memory dysfunction (n = 169), an inhibition dysfunction (n = 360), a switching dysfunction (355), and all 3 (executive dysfunction; n = 107) were defined on the basis of Z-scores ≤ -1 on the Differential Ability Scales-II Working Memory composite, and/or on the NEPSY-II Inhibition-Inhibition and Inhibition-Switching subtests. All risk profiles include an indicator of socioeconomic disadvantage. The risk profile of each of the 3 individual dysfunctions includes an indicator of the newborn's immaturity, and the risk profiles of the inhibition dysfunction and switching dysfunction also include an indicator of inflammation. Only the switching dysfunction was associated with fetal growth restriction. The risk factors for executive dysfunction can be subsumed under the 4 themes of socioeconomic disadvantage, immaturity/vulnerability, inflammation, and fetal growth restriction.

Circulating biomarkers in extremely preterm infants associated with ultrasound indicators of brain damage.

AIM: To assess to what extent the blood concentrations of proteins with neurotrophic and angiogenic properties measured during the first postnatal month convey information about the risk of sonographically-identified brain damage among very preterm newborns. METHODS: Study participants were 1219 children who had a cranial ultrasound scan during their stay in the intensive care nursery and blood specimens collected on 2 separate days at least a week apart during the first postnatal month. Concentrations of selected proteins in blood spots were measured with electrochemiluminescence or with a multiplex immunobead assay and the risks of cranial ultrasound images associated with top-quartile concentrations were assessed. RESULTS: High concentrations of multiple inflammation-related proteins during the first 2 postnatal weeks were associated with increased risk of ventriculomegaly, while high concentrations of just 3 inflammation-related proteins were associated with increased risk of an echolucent/hypoechoic lesion (IL-6, IL-8, ICAM-1), especially on day 7. Concomitant high concentrations of IL6R and bFGF appeared to modulate the increased risks of ventriculomegaly and an echolucent lesion associated with inflammation. More commonly high concentrations of putative protectors/repair-enhancers did not appear to diminish these increased risks. CONCLUSION: Our findings provide support for the hypothesis that endogenous proteins are capable of either protecting the brain against damage and/or enhancing repair of damage.