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Background With significant increases in opioid use/misuse and persistent high prevalence of prenatal alcohol exposure (PAE), identifying infants at risk for long-term developmental sequelae due to these exposures remains an urgent need. This study reports on developmental outcomes in young children from a prospective cohort, ENRICH-1, which recruited pregnant women and followed up maternal–infant pairs. Methods Subjects were assigned to four study groups based on prenatal use of medications for opioid use disorder (MOUD), PAE, MOUD+PAE, and unexposed controls (UC). Mixed effects modeling was used to evaluate changes in the Bayley Scales of Infant Development-III (BSID-III) Cognitive, Language, and Motor scores between 6 and 20 months. Results There was a significant three-way interaction (MOUD-by-PAE-by-Time) with respect to the BSID-III Cognitive ( p  = 0.045) and Motor ( p  = 0.033) scales. Significant changes between the two evaluations were observed for MOUD group in Cognitive and Language scores; for PAE group in Cognitive, Language, and Motor scores, and for MOUD+PAE group in Language scores after adjusting for child sex and family socio-economic status. The developmental scores for the UC remained stable. Conclusion Observed decline in neurodevelopmental scores during the first 2 years of life emphasizes the importance of a longitudinal approach when evaluating children with prenatal polysubstance exposure. Impact BSID-III scores were stable during the first 2 years of life for unexposed children. BSID-III scores declined for children with prenatal exposures to alcohol and/or opioids. Standard developmental tests may not be sensitive enough during the first year of life. Findings emphasize the need for repeated evaluations of children who are at high risk.

Background Severe retinopathy of prematurity (ROP) is associated with adverse outcomes. Relationships between milder ROP and outcomes have not been defined. We hypothesized that children with ROP stage ≤3 who did not receive ophthalmologic intervention would have worse motor, cognitive, and language skills and more vision abnormalities than children without ROP. Methods This was a secondary analysis of a randomized trial evaluating the effects of myo -inositol on ROP in the NICHD Neonatal Research Network. Primary outcomes were Bayley Scales of Infant Development composite scores; secondary outcomes included behavioral difficulties and ophthalmologic measures. Outcomes were compared using adjusted linear or modified Poisson models. Results Of 506 children, 173 (34%) had no ROP, 262 (52%) had ROP stage ≤3 without intervention, and 71 (14%) had ROP with intervention. There was no difference in motor, cognitive, or language scores between children with ROP stage ≤3 without intervention and children without ROP. Children with ROP stage ≤3 without intervention had a higher rate of strabismus compared to children without ROP ( p  = 0.040). Conclusion Children with ROP stage ≤3 without intervention did not have adverse neurodevelopmental outcomes at 2 years’ corrected age compared to children without ROP but did have an increased incidence of strabismus. Impact This study addresses a gap in the literature regarding the relationship between milder forms of retinopathy of prematurity (ROP) that regress without intervention and neurodevelopment and vision outcomes. Children with a history of ROP stage ≤3 without intervention have similar neurodevelopmental outcomes at 2 years’ corrected age as children born extremely preterm without a history of ROP and better outcomes than children with a history of ROP with ophthalmologic intervention. Counseling about likely neurodevelopment and vision outcomes for children born extremely preterm with a history of ROP may be tailored based on the severity of ROP. Clinical trial registration ClinicalTrials.gov ID: Inositol to Reduce Retinopathy of Prematurity Trial: NCT01954082.

ObjectivePreterm infants frequently receive red cell transfusions; however, the effect of transfusions on cognition is unclear. We evaluated the relationship between transfusions and cognitive outcomes in preterm infants enrolled in a randomized trial of erythropoiesis stimulating agents (ESAs).Study designPreterm infants were randomized to ESAs or placebo during initial hospitalization, and transfusions recorded. Children were evaluated using standard developmental tests of cognition at 18–22 months (56 ESA, 24 placebo) and 3.5–4 years (39 ESA, 14 placebo).ResultsCognitive scores at 18–22 months were inversely correlated with transfusion volume (p = 0.02). Among those receiving ≥1 transfusion, cognitive scores were significantly higher in the ESA-treated group (p = 0.003). At 3.5–4 years, transfusions were not correlated with cognitive scores.ConclusionsIn the placebo group, transfused children had lower cognitive scores than did non-transfused children at 18–22 months. In the ESA group, cognitive scores did not differ by transfusion status, suggesting ESAs might provide neuroprotection.

Background Bronchopulmonary dysplasia (BPD) affects up to half of extremely preterm infants, and is associated with adverse long-term respiratory, neurodevelopmental, and educational sequelae and costly health service and family economic outcomes. The NICHD Neonatal Research Network Hydrocortisone for Bronchopulmonary Dysplasia (BPD) Trial evaluated the efficacy and safety of hydrocortisone treatment to prevent BPD in high-risk infants. The trial enrolled 800 very preterm infants with respiratory failure and followed the participants until 2 years corrected age to assess safety of the trial intervention. Longer-term impacts of hydrocortisone exposure and severity of BPD on functional outcomes of high-risk infants remain unknown. The HYdrocortisone for BPD Respiratory and Developmental (HYBRiD) Outcomes Study extends follow-up of all surviving children enrolled in the Hydrocortisone for BPD Trial until early school age. It aims to characterize the childhood functional motor, cognitive, academic, and pulmonary outcomes of this large, well-phenotyped trial cohort. Methods Parents of surviving trial participants complete telephone questionnaires when their children are 3 and 4 years corrected age. A single in-person study visit takes place at early school age (5 years, 0 months to 7 years, 11 months corrected age). Children undergo a multidimensional assessment of functional outcomes and parents complete a battery of questionnaires. In 5 of 19 participating centers, respiratory mechanics are evaluated with impulse oscillometry. Discussion The HYBRiD Outcomes Study will be the largest and most comprehensive evaluation to date of the functional early school age outcomes of children with a history of severe neonatal lung disease and of children exposed to HC during infancy. This will substantially improve understanding of the longer-term implications of severe neonatal lung disease; provide data to facilitate the development of future randomized intervention trials in this population; and inform public policy by enhancing knowledge about school age resource requirements in children with a history of prematurity and lung disease. Trial registration clinicaltrials.gov ID NCT01353313. Primary trial registration 5/11/11 modified to include followup through school age 12/13/17. This manuscript reflects version 3 of the trial manuscript, dated 10/12/2020.

The purpose of this study was to examine the associations between child-mother interactive behaviors and cognition in preschoolers born preterm (<32 weeks gestation; n = 82) and full term (>37 weeks gestation; n = 53). Child-mother interactive behaviors were assessed during a videotaped free play session. Maternal education and neonatal medical factors were included as covariates. Although the preterm and full term groups showed some differences in child and mother interactive behaviors, we found that the child and mother behaviors associated with Verbal IQ (VIQ) and Performance IQ (PIQ) were the same for both children born preterm and full term and for both sexes. Child positive affect and quality of communication; and maternal responsiveness to verbal cues remained significantly associated with VIQ after controlling for sociodemographic variables. Children born preterm showed significantly less responsiveness to their mother and lower levels of play sophistication compared with children born full term. Mothers of children born preterm showed less emotional attunement, lower responsiveness to nonverbal cues, and lower quality of communication compared with mothers of children born full term. Models predicting VIQ and PIQ included maternal education, gestational age, maternal and child interactive behaviors, and one uniquely significant combined mother-child (interaction) term in each model. Child-mother interactive behaviors associated with VIQ and PIQ are the same for both children born preterm and full term and for both sexes, suggesting that similar interactive behaviors may be important in facilitating cognitive development.

BackgroundErythropoiesis stimulating agents (ESAs) are neuroprotective in cell and animal models of preterm birth. Prematurity has been shown to alter neurometabolite levels in children in studies using proton magnetic resonance spectroscopy (1H-MRS).ObjectiveWe hypothesized that ESA treatment in premature infants would tend to normalize neurometabolites by 4–6 years of age.Materials and methodsChildren in a longitudinal study of neurodevelopment underwent MRI and 1H-MRS at approximately 4 years and 6 years of age. Prematurely born children (500–1,250 g birth weight) received ESAs (erythropoietin or darbepoetin) or placebo during their neonatal hospitalization, and these groups were compared to healthy term controls. 1H-MRS spectra were obtained from the anterior cingulate (gray matter) and frontal lobe white matter, assessing combined N-acetylaspartate and N-acetylaspartylglutamate (tNAA), myo-inositol, choline compounds (Cho), combined creatine and phosphocreatine, and combined glutamate and glutamine.ResultsNo significant (P≤0.5) group differences were observed for any metabolite level. Significant age-related increases in white-matter tNAA and Cho were observed, as well as a trend for increased gray-matter tNAA.ConclusionNeither prematurity nor neonatal ESA treatment was associated with differences in brain metabolite levels in the children of this study at a significance level of 0.05. These findings suggest that earlier differences that might have existed had normalized by 4–6 years of age or were too small to be statistically significant in the current sample.

Objectives The importance of mother-child interaction in early infancy on child development has been well documented. The purpose of this study was to assess the feasibility of using the Still Face Paradigm to measure mother interactive style, infant affect and emotional regulation in a rural Ecuador setting. Methods Infant’s emotional regulation and the quality of mother’s interaction were measured with the Still Face Paradigm at 4 months of age (±15 days). Twenty-four infants and their mothers were assessed in their home. Mother interactive style was coded for attention seeking and contingent responding. Emotional regulation was described by change in infant affect between Still Face episodes. Results A significant difference was found for infant affect between the five Still Face episodes (F 1,118  = 9.185, p  = 0.003). A significant negative correlation was found for infant affect between episode 3 and 2 with attention seeking mother interactive style during episode 3 (rho = −0.44, p  = 0.03), indicating that mothers using more contingent-responding interactions had infants with more positive affect. Conversely, a significant positive association was found for infant affect between episode 3 and 2 and contingent responding mother interactive style during episode 3 (rho = 0.46, p  = 0.02), indicating that mothers who used more attention seeking play had infants who showed less positive affect. Conclusion for Practice Study results demonstrate feasibility in using the Still Face Paradigm in working populations residing in a rural region in Ecuadorian highlands and may be feasible in other similar populations in Latin America, and as a successful approach to measuring maternal-child interactions within a field-based epidemiological study design.

In this multicenter, randomized trial, the administration of erythropoietin to newborns undergoing therapeutic hypothermia for hypoxic–ischemic encephalopathy did not result in a lower risk of death or neurodevelopmental impairment at 22 to 36 months of age than placebo and was associated with a higher rate of serious adverse events.

Glucocorticoids might prevent bronchopulmonary dysplasia in extremely preterm infants but have adverse neurodevelopmental effects. In this trial involving preterm infants, there was little difference in survival without bronchopulmonary dysplasia or in the occurrence of neurodevelopmental impairment with hydrocortisone as compared with placebo.

The aim of this study was to compare executive function (EF) in preschoolers born very low birth weight (VLBW ≤ 1500 g) and full term (FT) using performance measures of EF, parent report of EF, and naturalistic child behaviors. Examining the relationship between multimodal measures of EF may elucidate the interrelations between EF measurement methods. Participants included 61 preschoolers born VLBW and 40 born FT between the ages of 3 and 4.5 years. Performance measures of EF (Bear Dragon, Dimensional Change Card Sort-Separated Dimensions (DCCSS), Gift Peek, and Gift Touch), parent report of EF (BRIEF-P), and naturalistic child behaviors (NICHD Cleanup Child Defiant Noncompliance) were utilized. FT preschoolers showed superior EF over VLBW preschoolers across all types of EF measures. These differences remained after correcting for age, maternal education, and WPPSI-III FSIQ. While performance measures of EF correlated highly in both FT and VLBW groups, different patterns by birth weight group emerged with parent report and naturalistic behavioral coding. In the VLBW group, BRIEF-P GEC correlated with working memory, switching, and inhibition-based tasks, while better compliance during a cleanup task was associated with better performance in the inhibition-based tasks. In contrast, in the FT sample, parent report and naturalistic behavioral coding scores were not correlated with any other EF measures. Children born VLBW had poorer EF outcomes than the FT group, regardless of measurement method. Correlations among multi-method measures of EF demonstrated different patterns of association in the VLBW and FT groups; BRIEF-P and compliance scores were only associated with other EF measures in the VLBW group.