Serum ferritin values in neonates <29 weeks' gestation are highly variable and do not correlate with reticulocyte hemoglobin content.

OBJECTIVES: To compare serum ferritin and RET-He values among extremely low gestational age neonates ELGANs with other markers of iron-deficient erythropoiesis. STUDY DESIGN: This is a secondary analysis of the NICHD Darbepoetin Trial. Study data from placebo recipients who had a serum ferritin, a RET-He, and a mean corpuscular volume (MCV) measurement within a 24-hour period were analyzed for correlation. RESULTS: Mixed linear regression models showed no association between ferritin and RET-He at both early (ß = 0.0016, p = 0.40) and late (ß = -0.0001, p = 0.96) time points. Positive associations were observed between RET-He and MCV at baseline, early, and late time points (p < 0.01, =0.01, <0.001, respectively), while ferritin was not associated with MCV at any time point. CONCLUSIONS: Our study shows that RET-He is better correlated with MCV as a marker of iron-limited erythropoiesis than ferritin. The results suggest that ferritin is limited as a marker of iron sufficiency in premature infants. STUDY IDENTIFICATION: FDA IND Number 100138; ClinicalTrials.gov number NCT03169881; NRN ID number NICHD-NRN-0058 (Darbe).

Relationships between retinopathy of prematurity without ophthalmologic intervention and neurodevelopment and vision at 2 years.

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.

Early developmental trajectory of children with prenatal alcohol and opioid exposure.

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.

Trial of Erythropoietin for Hypoxic-Ischemic Encephalopathy in Newborns.

BACKGROUND: Neonatal hypoxic-ischemic encephalopathy is an important cause of death as well as long-term disability in survivors. Erythropoietin has been hypothesized to have neuroprotective effects in infants with hypoxic-ischemic encephalopathy, but its effects on neurodevelopmental outcomes when given in conjunction with therapeutic hypothermia are unknown. METHODS: In a multicenter, double-blind, randomized, placebo-controlled trial, we assigned 501 infants born at 36 weeks or more of gestation with moderate or severe hypoxic-ischemic encephalopathy to receive erythropoietin or placebo, in conjunction with standard therapeutic hypothermia. Erythropoietin (1000 U per kilogram of body weight) or saline placebo was administered intravenously within 26 hours after birth, as well as at 2, 3, 4, and 7 days of age. The primary outcome was death or neurodevelopmental impairment at 22 to 36 months of age. Neurodevelopmental impairment was defined as cerebral palsy, a Gross Motor Function Classification System level of at least 1 (on a scale of 0 [normal] to 5 [most impaired]), or a cognitive score of less than 90 (which corresponds to 0.67 SD below the mean, with higher scores indicating better performance) on the Bayley Scales of Infant and Toddler Development, third edition. RESULTS: Of 500 infants in the modified intention-to-treat analysis, 257 received erythropoietin and 243 received placebo. The incidence of death or neurodevelopmental impairment was 52.5% in the erythropoietin group and 49.5% in the placebo group (relative risk, 1.03; 95% confidence interval [CI], 0.86 to 1.24; P = 0.74). The mean number of serious adverse events per child was higher in the erythropoietin group than in the placebo group (0.86 vs. 0.67; relative risk, 1.26; 95% CI, 1.01 to 1.57). CONCLUSIONS: 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 than placebo and was associated with a higher rate of serious adverse events. (Funded by the National Institute of Neurological Disorders and Stroke; ClinicalTrials.gov number, NCT02811263.).

Preliminary longitudinal evidence for stability of maternal behavior and infant stress regulation among infants born preterm at 4 and 9 months during the Still Face paradigm.

Stress regulation begins to develop in the first year of life through interactions with caregivers, particularly in the presence of stressors. High quality caregiving, characterized by maternal sensitivity and responsiveness to the infant's emotional cues, is particularly important in the development of infant stress regulation. The purpose of this study was to assess the longitudinal stability of, and associations between, maternal interactive behavior and infant stress regulation (indexed by positive infant affect and cortisol reactivity) in response to the Still Face paradigm (SF) in a cohort of infants born preterm (< 32 weeks gestation, N = 22) at four months and nine months (adjusted age). The percent of time mothers spent using specific interaction styles (contingent maternal interaction (CMI), attention seeking, and watching) during Play/baseline, Reunion#1, and Reunion#2 SF episodes was calculated To assess infant stress regulation, two indices were obtained at both 4 and 9 months during the SF paradigm: the percent of positive affect displayed over each SF episode (0-100%) and a neuroendocrine stress response score based on salivary cortisol reactivity. We found three non-significant but medium-large effect size differences between 4 and 9 month variables, with more positive findings at 9 months. Regarding stability within the 4 month and 9 month episodes, maternal behavior and positive infant affect were non-significantly but moderately stable, with maternal watching behavior being particularly stable. Positive infant affect stability between Reunion#1 and Reunion#2 at 4 months was significantly greater than positive infant affect stability across these two episodes at 9 months. Regarding stability across 4 and 9 month (same) episodes, CMI and positive infant affect showed modest but non-significant stability across (same) 4 and 9 month episodes. Finally, with positive infant affect at Reunion#2 as the "outcome" of the Still Face, CMI at both 4 month Play and Reunion#1 episodes were significantly correlated with this "outcome." Further, positive infant affect at Reunion#2 was more strongly correlated with CMI at both Play and Reunion#1 for 4 month old compared with 9 month old infants. Thus, sensitive care appears particularly important for younger infants born preterm, and mothers' behavior early in a repeated stress exposure paradigm may be particularly important in maintaining positive infant affect and in the development of infants' stress regulation more generally. Identifying the longer-term effects of early stress on infant stress regulation, and its relationship with maternal interaction, has important implications for understanding trajectories of regulatory patterns and deficits. A greater understanding of these relationships is particularly important given that greater emotion and neuroendocrine stress regulation in infancy have been directly associated with numerous positive outcomes throughout childhood.

Hydrocortisone to Improve Survival without Bronchopulmonary Dysplasia.

BACKGROUND: Bronchopulmonary dysplasia is a prevalent complication after extremely preterm birth. Inflammation with mechanical ventilation may contribute to its development. Whether hydrocortisone treatment after the second postnatal week can improve survival without bronchopulmonary dysplasia and without adverse neurodevelopmental effects is unknown. METHODS: We conducted a trial involving infants who had a gestational age of less than 30 weeks and who had been intubated for at least 7 days at 14 to 28 days. Infants were randomly assigned to receive either hydrocortisone (4 mg per kilogram of body weight per day tapered over a period of 10 days) or placebo. Mandatory extubation thresholds were specified. The primary efficacy outcome was survival without moderate or severe bronchopulmonary dysplasia at 36 weeks of postmenstrual age, and the primary safety outcome was survival without moderate or severe neurodevelopmental impairment at 22 to 26 months of corrected age. RESULTS: We enrolled 800 infants (mean [±SD] birth weight, 715±167 g; mean gestational age, 24.9±1.5 weeks). Survival without moderate or severe bronchopulmonary dysplasia at 36 weeks occurred in 66 of 398 infants (16.6%) in the hydrocortisone group and in 53 of 402 (13.2%) in the placebo group (adjusted rate ratio, 1.27; 95% confidence interval [CI], 0.93 to 1.74). Two-year outcomes were known for 91.0% of the infants. Survival without moderate or severe neurodevelopmental impairment occurred in 132 of 358 infants (36.9%) in the hydrocortisone group and in 134 of 359 (37.3%) in the placebo group (adjusted rate ratio, 0.98; 95% CI, 0.81 to 1.18). Hypertension that was treated with medication occurred more frequently with hydrocortisone than with placebo (4.3% vs. 1.0%). Other adverse events were similar in the two groups. CONCLUSIONS: In this trial involving preterm infants, hydrocortisone treatment starting on postnatal day 14 to 28 did not result in substantially higher survival without moderate or severe bronchopulmonary dysplasia than placebo. Survival without moderate or severe neurodevelopmental impairment did not differ substantially between the two groups. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01353313.).

The role of maternal interactive behavior and gestational age in predicting infant affect during the Still-Face Paradigm.

BACKGROUND: Emotion regulation develops through bidirectional affective communication. AIM: To investigate the role of maternal interactive behavior in predicting infant affect among preterm versus full-term infants. STUDY DESIGN: The association between maternal interactive behavior (contingent, attention seeking, watching) and infant affect during a modified Still Face (SF) paradigm in a sample of 22 preterm and 28 full term infants (3 ½ - 4 ½ months old) was investigated. METHODS: Maternal behavior and infant affect were coded in one second intervals. RESULTS: Maternal contingent interaction was positively correlated with positive infant affect (p < 0.001 for Play; p < 0.001 for Reunion#1; p < 0.01 for Reunion#2, respectively), with a stronger association during the second reunion for preterm infants (p < 0.001). In the preterm sample but not in the full-term sample, attention seeking maternal interaction at Play (baseline), Reunion#1, and Reunion#2 were all positively correlated with negative infant affect at Still Face#2. Maternal watching was negatively associated with positive infant affect for the full sample for both Reunion episodes (p < 0.05). Full term infants' negative affect increased from baseline to the first SF episode and then plateaued, whereas preterm infants demonstrated greater negative affect and less recovery throughout. Mothers of full-term infants showed increased contingent responding after the first SF stressor, while mothers of preterm infants did not (p < 0.05). CONCLUSIONS: Preterm infants may be more susceptible to both positive and negative maternal behaviors and mothers of full-term infants may be more responsive to infants' increased distress. Relationship-focused interventions addressing maternal behaviors may enhance positive emotionality and improve self-regulation in medically at-risk infants.

Maternal verbal scaffolding: association with higher language skills for 20-month-old children with prenatal polysubstance exposure.

BACKGROUND: The number of children with prenatal polysubstance exposure is increasing. Supportive mother-child interaction is a protective factor, which can ameliorate adverse effects of prenatal polysubstance exposure on developmental outcomes. AIM: To examine the role of maternal verbal scaffolding on cognitive and language development in children with prenatal polysubstance exposure. STUDY DESIGN: Pregnant women were recruited, and we prospectively followed mother-child dyads to 20 months of age. This analysis included 66 dyads (33 healthy controls and 33 with prenatal polysubstance exposure). Multivariable linear regression modelling was used to examine the cross-sectional association between maternal scaffolding and Bayley Scales of Infant and Toddler Development (BSID-III) score, as well as an interaction between the study group and scaffolding score. OUTCOME MEASURES: The BSID-III cognitive and language score was used. Videotaped mother-child play was coded to obtain a maternal verbal scaffolding score. Effect sizes were measured using average differences in scores between groups. RESULTS: There was no evidence of an association between study group and maternal scaffolding scores. Children in the polysubstance exposure group had lower cognitive and language scores compared to controls, but this association was not statistically significant after controlling for maternal education. Maternal scaffolding was predictive of language scores, with scores increasing by 1.24 points on average (95% CI: 0.42, 2.06) for every 1-point increase in scaffolding score after adjustment for covariates. There was no evidence of a study group-by-scaffolding interaction with respect to the language or cognitive scores. CONCLUSIONS: Maternal scaffolding during play was associated with language development in children with and without prenatal polysubstance exposure.

The association of infant temperament and maternal sensitivity in preterm and full-term infants.

Infants who experience sensitive caregiving are at lower risk for numerous adverse outcomes. This is especially true for infants born preterm, leading them to be more susceptible to risks associated with poorer quality caregiving. Some research suggests that preterm and full-term infants differ on temperament, which may contribute to these findings. This study aimed to investigate associations between infant temperament (negative emotionality, positive affectivity/surgency, and orienting/regulatory capacity) and maternal sensitivity among infants born preterm (M = 30.2 weeks) and full term. It was hypothesized that mothers of infants born preterm and mothers of infants with more difficult temperaments would display lower sensitivity, indicated by lower responsiveness to nondistress, lower positive regard, and higher intrusiveness. Videotaped play interactions and a measure of temperament (Infant Behavior Questionnaire) were coded for 18 preterm and 44 full-term infants at 9 months (corrected) age. Results suggest that mothers of preterm and full-term infants differed significantly in responding to their infants, but these results cannot be explained by infant temperament. Preterm status and sociodemographic risk emerged as correlates of maternal behavior, such that mothers of infants born preterm and mothers with greater sociodemographic risk displayed lower levels of maternal sensitivity.

Los infantes que experimentan un cuidado sensible se encuentran bajo un riesgo más bajo en cuanto a numerosos resultados adversos. Esto es especialmente cierto para infantes nacidos prematuramente, lo cual conlleva que ellos sean más susceptibles a los riesgos asociados con una más pobre calidad de cuidado. Alguna investigación sugiere que los infantes prematuros y aquellos de completa gestación difieren en el temperamento, lo cual pudiera contribuir a estos resultados. Este estudio se propuso investigar las asociaciones entre el temperamento del infante (sentido negativo de la emoción, afectividad/resurgencia positiva y capacidad de orientación/regulatoria) y la sensibilidad materna entre infantes nacidos prematuramente (M = 30.2 semanas) y los nacidos dentro de la gestación completa. La hipótesis fue que las madres de infantes nacidos prematuramente y las madres de infantes con temperamentos más difíciles mostrarían una más baja sensibilidad, indicado por una más baja reacción sensible a la falta de angustia, más baja consideración positiva y más alta intrusión. Se codificaron las interacciones de juego grabadas en video y una medida de temperamento (Cuestionario de Conducta del Infante) para 18 prematuros y 44 infantes de gestación completa a los nueves meses (corregidos) de edad. Los resultados sugieren que las madres de infantes prematuros y de gestación completa difirieron significativamente al responder a sus infantes, pero estos resultados no pueden ser explicados con base en el temperamento del infante. La condición de prematuro y el riesgo sociodemográfico surgieron como una correlación del comportamiento materno, al punto que las madres de infantes nacidos prematuramente y las madres con mayores riesgos sociodemográficos mostraron niveles más bajos de sensibilidad materna.

Les nourrissons qui font l'expérience de soins sensibles sont à moindre risque pour bien des résultats adverses. Cela est particulièrement vrai des nourrissons nés prématurés, ce qui les amène à être plus susceptibles aux risques liés à une plus mauvaise qualité de soins de la personne qui prend soin d'eux. Certaines recherches suggèrent que les nourrissons prématurés et les nourrissons à terme diffèrent quant au tempérament, ce qui peut contribuer à ces résultats. Cette étude s'est donné pour but de rechercher les liens entre le tempérament du nourrisson (émotionalité négative, affectivité/dynamisme positif, et capacité d'orientation/régulatoire) et la sensibilité maternelle chez les nourrissons nés prématurés (M = 30,2 semaines) et ceux à plein terme. Nous avons pris pour hypothèse que les mères des nourrissons nés prématurés et les mères de nourrissons ayant des tempéraments plus difficiles feraient preuve d'une sensibilité plus basse, indiquée par une réaction moindre à la non-détresse, un égard positif plus bas et une intrusion plus élevée. Des interactions de jeu filmées et une mesure de tempérament (Questionnaire du Comportement du Nourrisson) ont été codées pour 18 prématurés et 44 nourrissons à termes à neuf mois (âge corrigé). Les résultats suggèrent que les mères de prématurés et de nourrissons à terme ont différé de manière importante dans leur réaction à leurs nourrissons, mais ces résultats ne peuvent pas être expliqués par le tempérament du nourrisson. Le statut de prématuré et le risque sociodémographique ont émergé comme corrélat du comportement maternel, de telle manière que les nourrissons nés prématurés et les mères avec un risque sociodémographique plus élevé ont fait état de niveaux plus bas de sensibilité maternelle.

Effect of blood transfusions on cognitive development in very low birth weight infants.

OBJECTIVE: Preterm 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 DESIGN: Preterm 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). RESULTS: Cognitive 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. CONCLUSIONS: In 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.

Neural and visceral manipulation in infants with congenital muscular torticollis: a feasibility study.

[Purpose] As an alternative to manual stretching, the aim of this study was to investigate the feasibility of using neural/visceral manipulation as a safe and effective intervention to increase neck range of motion of infants with congenital muscular torticollis. [Participants and Methods] Ten 4-month old infants with congenital muscular torticollis received eight sessions of neural/visceral manipulation administered for 30-50 minutes without observed pain. Specific palpation techniques addressed restricted tissue areas of neck, head, trunk and extremities. Neck rotation and lateral flexion were assessed by still photography and a computer program calculating ROM angles before, immediately following, and 4 months post intervention. Motor development and social competence were monitored over time using the Alberta Infant Motor Scale and Bayley-III Social Emotional Scale. [Results] Results of analysis of variances revealed significant improvements in passive and active neck rotation and lateral flexion. Significant increases were also found on the Alberta Infant Motor Scale and Bayley-III Social-Emotional scale. [Conclusion] Neural/visceral manipulation can be used safely in infants with congenital muscular torticollis to improve neck range of motion.

The association between maternal interaction and infant cortisol stress reactivity among preterm and full term infants at 4 months adjusted age.

The purpose of this study was to assess the association between maternal interactive behavior and infant cortisol stress reactivity in response to the Still Face paradigm (SF) in a cohort of four-month old infants (adjusted age) born preterm (<32 weeks gestation, N = 22) compared with infants born full term (>37 weeks gestation, N = 28). Infant cortisol reactivity was calculated as area under the curve (AUC) from baseline to the third cortisol sample (30 min post-SF) using the trapezoidal rule, while the percent of time mothers spent using a contingent interaction style was measured (0-100%) during episodes 1 (Play; baseline), 3 (Reunion#1), and 5 (Reunion#2) while mother-infant dyads participated in the SF paradigm. We hypothesized that because infants born preterm are at increased risk for dysregulation, they would show, compared to full-term infants, a blunted stress response, involving under-responsiveness. We found blunted cortisol stress reactivity among the preterm infants. We also found that mothers of preterm infants demonstrated less contingent maternal interaction during Renion#1 of the SF; and that contingent maternal interaction at Reunion#2 of the SF was protective against cortisol stress reactivity in response to the SF. However, we did not find that the influence of maternal interaction on cortisol reactivity was moderated by gestational age group (full term vs preterm): the association between contingent maternal interaction and stress reactivity was similar for both gestational groups across episodes. In order to improve self-regulation and longer term social and cognitive developmental outcomes in medically at-risk infants, future research is warranted to determine how these findings relate to infants' stress reactions in naturalistic settings, and the directionality and temporal relationship between cortisol stress responses and maternal interactive behavior.

Behavioral problems are associated with cognitive and language scores in toddlers born extremely preterm.

OBJECTIVE: To evaluate the relationship of parent-reported child behaviors on the Child Behavior Checklist (CBCL) to cognition, language, and motor skills on the Bayley Scales of Infant and Toddler Development - III (Bayley-III) in toddlers born extremely preterm. STUDY DESIGN: Toddlers born extremely preterm (gestational ages 22 0/7 to 26 6/7 weeks) were tested at 22-26 months corrected age with Bayley-III while parents completed the CBCL. Socio-demographic variables and medical history were recorded. Linear regression models were used to assess the relationship of Bayley-III cognitive, motor, and language scores with CBCL scores, adjusting for medical and socio-demographic factors. RESULTS: Internalizing, affective, and pervasive development problem behavior scores on the CBCL correlated significantly with lower Bayley-III cognitive, language, and motor scores on unadjusted and adjusted analyses. Although externalizing and anxiety problems were significantly associated with cognitive and language scores on unadjusted analysis, the relationships were not significant after adjusting for socio-economic factors. CBCL scores were similar for boys and girls, with the exception of the pervasive developmental problem scale; boys had significantly more problems than girls (p = 0.02). CONCLUSIONS: This study showed that parent reported behavior problems were related to lower cognitive, language, and motor development in toddlers born extremely preterm. Early findings of behavioral problems in toddlers born extremely premature may help identify children at greater risk for later learning difficulties. Adding a measure of behavior to the evaluation of these children may help better understand factors that can contribute to delays, especially in cognition and language.

The long-term effect of erythropoiesis stimulating agents given to preterm infants: a proton magnetic resonance spectroscopy study on neurometabolites in early childhood.

BACKGROUND: Erythropoiesis 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). OBJECTIVE: We hypothesized that ESA treatment in premature infants would tend to normalize neurometabolites by 4-6 years of age. MATERIALS AND METHODS: Children 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. RESULTS: No 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. CONCLUSION: Neither 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.

Cognitive development in preterm infants: multifaceted deficits reflect vulnerability of rigorous neurodevelopmental pathways.

Prematurity remains the major cause of neonatal morbidity and mortality, with 15 million preterm births occurring worldwide in 2010. Infants born less than 37 weeks gestation are at high risk of abnormal neurodevelopmental outcomes, given that the central nervous system is extremely sensitive to an abnormal intra- and extra-uterine environment. Children born preterm have multiple neurodevelopmental sequelae involving dynamic and complex cognitive deficits. Former preterm infants have difficulty with each domain of cognition, including executive function, language, learning and memory, complex attention, perceptual-motor function and social cognition when compared to children born at term. Although deficits are not always severe, even mild delays can be impactful, resulting in a spectrum of outcomes from difficulties in school to an inability to lead an independent adult life. Here, we review current literature on the cognitive outcomes of infants born preterm with a focus on how specific disruption in crucial neurodevelopmental pathways render these children vulnerable to dynamic deficits in cognition as they mature. Further, we highlight promising therapies and intervention strategies aimed at mitigating these deficits, including the use of erythropoietin. With an increasing number of preterm infants surviving, understanding developmental deficits will allow therapies to be developed and optimized, in order to ensure the best outcome for this vulnerable patient population.

Impact of Erythropoiesis-Stimulating Agents on Behavioral Measures in Children Born Preterm.

OBJECTIVE: To evaluate the impact of erythropoiesis-stimulating agents (ESAs) administered during initial hospitalization and family demographic factors on behavior at 3.5-4 years of age. STUDY DESIGN: Children were enrolled who had previously participated in a randomized study of ESAs (n = 35) or placebo (n = 14) in infants born preterm with birth weights of 500-1250 g. A term healthy control group (n = 22) also was recruited. Behavior was evaluated by parent report with the Behavioral Assessment System of Children-2. Principal component analyses identified 2 demographic factors, a Socioeconomic Composite (SEC) and a Family Stress Composite. A multivariate general linear model evaluated the impact of study group and sex on the 4 composite scales of the Behavioral Assessment System of Children-2. Demographic factors were treated as covariates and interactions with study group (ESA, placebo, and term) were examined. RESULTS: The ESA group had significantly better scores than the placebo group on behavioral symptoms (P = .04) and externalizing scales (P = .04). An interaction was observed between study group and SEC (P = .001). A beneficial effect of ESAs was maximal in the children with lower SEC scores. CONCLUSIONS: The beneficial effects of ESAs on childhood behavior were maximal in children with lower SEC scores. ESAs seemed to ameliorate the adverse impact of lower SEC on behavioral domains seen in the placebo group. This effect was independent of the beneficial effect of ESAs on global cognition we reported previously. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01207778 and NCT00334737.

Assessment of Maternal-Infant Interaction: Application of the Still Face Paradigm in a Rural Population of Working Women in Ecuador.

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 (F1,118 = 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.

Maternal touch and infant affect in the Still Face Paradigm: A cross-cultural examination.

Touch between mother and infant plays an important role in development starting from birth. Cross-cultural differences surrounding rearing practices have an influence on parent-infant interaction, including types of touch used and the development of emotional regulation. This study was designed to investigate maternal touch and infant emotional regulation in infant-mother dyads from Ecuador (n=25) and Hispanic dyads from the United States (US) (n=26). Mothers and their 4-month-old full-term infants participated in the Still Face Paradigm. Second-by-second coding of maternal touch and infant affect was completed. Overall the analyses showed that Ecuadorian mothers used more nurturing and accompaniment touch and less attention seeking touch than US Hispanic mothers during the pre-stressor (baseline) episode. Lagged multilevel models were used to investigate the effect of the different types of touch on infant emotional regulation in the groups for the episodes. The data suggest that playful touch had a significant increase in infant affect, whereas accompaniment and attention-seeking touch had a significant decrease in infant affect. Overall, this study provides support for the role of touch in mother-infant synchronicity in relation to infant's emotional regulation. Identifying touch that is more calming is important to foster emotional regulation in infancy, which can have important implications for development.

Ethanol, Neurodevelopment, Infant and Child Health (ENRICH) prospective cohort: Study design considerations.

BACKGROUND: While intervention is the leading factor in reducing long-term disabilities in children with fetal alcohol spectrum disorder (FASD), early identification of children affected by prenatal alcohol exposure (PAE) remains challenging. Deficits in higher-order cognitive domains (e.g. executive function) might be more specific to FASD than global neurodevelopmental tests, yet these functions are not developed in very young children. Measures of early sensorimotor development may provide early indications of atypical brain development during the first two years of life. METHODS: This paper describes the novel methodology of the Ethanol, Neurodevelopment, Infant and Child Health (ENRICH) prospective cohort study of 120 maternal-infant pairs with a goal to identify early indices of functional brain impairment associated with PAE. The cohort is established by recruiting women early in pregnancy and classifying them into one of three study groups: patients on opioid-maintenance therapy who consume alcohol during pregnancy (Group 1), patients on opioid-maintenance therapy who abstain from alcohol during pregnancy (Group 2), and healthy controls (Group 3). After the initial prenatal assessment (Visit 1), patients are followed to Visit 2 occurring at delivery, and two comprehensive assessments of children at six (Visit 3) and 20 months (Visit 4) of age. ENRICH recruitment started in November 2013 and 87 women were recruited during the first year. During Year 1, the biospecimen (maternal whole blood, serum, urine, dry blood spots of a newborn) collection rate was 100% at Visit 1, and 97.6% for those who completed Visit 2. DISCUSSION: The tiered screening approach, evaluation of confounders, neurocognitive and magneto-/electro-encephalography (MEG/EEG) outcomes, and ethical considerations are discussed.