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.).

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.).

Relationship of Neonatal Seizure Burden Before Treatment and Response to Initial Antiseizure Medication.

OBJECTIVE: To assess among a cohort of neonates with hypoxic-ischemic encephalopathy (HIE) the association of pretreatment maximal hourly seizure burden and total seizure duration with successful response to initial antiseizure medication (ASM). STUDY DESIGN: This was a retrospective review of data collected from infants enrolled in the HEAL Trial (NCT02811263) between January 25, 2017, and October 9, 2019. We evaluated a cohort of neonates born at ≥36 weeks of gestation with moderate-to-severe HIE who underwent continuous electroencephalogram monitoring and had acute symptomatic seizures. Poisson regression analyzed associations between (1) pretreatment maximal hourly seizure burden, (2) pretreatment total seizure duration, (3) time from first seizure to initial ASM, and (4) successful response to initial ASM. RESULTS: Among 39 neonates meeting inclusion criteria, greater pretreatment maximal hourly seizure burden was associated with lower chance of successful response to initial ASM (adjusted relative risk for each 5-minute increase in seizure burden 0.83, 95% CI 0.69-0.99). There was no association between pretreatment total seizure duration and chance of successful response. Shorter time-to-treatment was paradoxically associated with lower chance of successful response to treatment, although this difference was small in magnitude (relative risk 1.007, 95% CI 1.003-1.010). CONCLUSIONS: Maximal seizure burden may be more important than other, more commonly used measures in predicting response to acute seizure treatments.

Neurodevelopmental Outcomes of Extremely Preterm Infants Fed Donor Milk or Preterm Infant Formula: A Randomized Clinical Trial.

Importance: Maternal milk feeding of extremely preterm infants during the birth hospitalization has been associated with better neurodevelopmental outcomes compared with preterm formula. For infants receiving no or minimal maternal milk, it is unknown whether donor human milk conveys similar neurodevelopmental advantages vs preterm formula. Objective: To determine if nutrient-fortified, pasteurized donor human milk improves neurodevelopmental outcomes at 22 to 26 months' corrected age compared with preterm infant formula among extremely preterm infants who received minimal maternal milk. Design, Setting, and Participants: Double-blind, randomized clinical trial conducted at 15 US academic medical centers within the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Infants younger than 29 weeks 0 days' gestation or with a birth weight of less than 1000 g were enrolled between September 2012 and March 2019. Intervention: Preterm formula or donor human milk feeding from randomization to 120 days of age, death, or hospital discharge. Main Outcomes and Measures: The primary outcome was the Bayley Scales of Infant and Toddler Development (BSID) cognitive score measured at 22 to 26 months' corrected age; a score of 54 (score range, 54-155; a score of ≥85 indicates no neurodevelopmental delay) was assigned to infants who died between randomization and 22 to 26 months' corrected age. The 24 secondary outcomes included BSID language and motor scores, in-hospital growth, necrotizing enterocolitis, and death. Results: Of 1965 eligible infants, 483 were randomized (239 in the donor milk group and 244 in the preterm formula group); the median gestational age was 26 weeks (IQR, 25-27 weeks), the median birth weight was 840 g (IQR, 676-986 g), and 52% were female. The birthing parent's race was self-reported as Black for 52% (247/478), White for 43% (206/478), and other for 5% (25/478). There were 54 infants who died prior to follow-up; 88% (376/429) of survivors were assessed at 22 to 26 months' corrected age. The adjusted mean BSID cognitive score was 80.7 (SD, 17.4) for the donor milk group vs 81.1 (SD, 16.7) for the preterm formula group (adjusted mean difference, -0.77 [95% CI, -3.93 to 2.39], which was not significant); the adjusted mean BSID language and motor scores also did not differ. Mortality (death prior to follow-up) was 13% (29/231) in the donor milk group vs 11% (25/233) in the preterm formula group (adjusted risk difference, -1% [95% CI, -4% to 2%]). Necrotizing enterocolitis occurred in 4.2% of infants (10/239) in the donor milk group vs 9.0% of infants (22/244) in the preterm formula group (adjusted risk difference, -5% [95% CI, -9% to -2%]). Weight gain was slower in the donor milk group (22.3 g/kg/d [95% CI, 21.3 to 23.3 g/kg/d]) compared with the preterm formula group (24.6 g/kg/d [95% CI, 23.6 to 25.6 g/kg/d]). Conclusions and Relevance: Among extremely preterm neonates fed minimal maternal milk, neurodevelopmental outcomes at 22 to 26 months' corrected age did not differ between infants fed donor milk or preterm formula. Trial Registration: ClinicalTrials.gov Identifier: NCT01534481.

Bayley trajectories predict school readiness better than single assessments in formerly very preterm preschoolers.

BACKGROUND: Development of children born very preterm (VPT) is evaluated using the Bayley Scales of Infant Development. Early Bayley scores may not predict later outcomes. We studied whether VPT Bayley trajectories in the early years predicted school readiness better than single assessments. METHODS: We prospectively evaluated 53 VPT at 4-5 years using standardized measures of school readiness, including the domains of cognition, early mathematical and literacy abilities, and motor skills. Predictors were Bayley-III scores obtained 1-5 times/child between 6 and 35 months. Linear mixed models (LMM) with random effects extracted estimated random effect for slope (change in Bayley score/1 year) and fixed+random effect sum for the intercept (initial Bayley score) for each participant, to then evaluate 4-5-year outcomes prediction. RESULTS: Variability of individual trajectories prevailed across developmental domains. For the initial LMM, adding Bayley change to models with only initial score improved model fits for several Bayley-III domains. Models containing estimates for initial Bayley scores and Bayley change explained significantly more variability in school readiness scores (21-63%) than either variable alone. CONCLUSION: Neurodevelopmental follow-up of VPT is more relevant to school readiness when children are assessed multiple times in the first 3 years. Neonatal intervention research could use early trajectories rather than single timepoints as outcomes. IMPACT: This study is the first to examine individual Bayley scores and trajectories to predict school readiness of formerly preterm children at 4-5 years. Modeling demonstrated extreme variability of individual trajectories compared to the group's average trajectories. Models containing initial Bayley scores and Bayley change over time explained more variability in preschool readiness than either variable alone. Using the Bayley to predict future school readiness is enhanced by administration across multiple follow-up visits and inclusion of change across the first 3 years. Follow-up care models and clinical trial design for neonatal interventions may benefit from a trajectory-based approach to outcomes evaluation.

Risk of seizures in neonates with hypoxic-ischemic encephalopathy receiving hypothermia plus erythropoietin or placebo.

BACKGROUND: An ancillary study of the High-Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) trial for neonates with hypoxic-ischemic encephalopathy (HIE) and treated with therapeutic hypothermia examined the hypothesis that neonates randomized to receive erythropoietin (Epo) would have a lower seizure risk and burden compared with neonates who received placebo. METHODS: Electroencephalograms (EEGs) from 7/17 HEAL trial centers were reviewed. Seizure presence was compared across treatment groups using a logistic regression model adjusting for treatment, HIE severity, center, and seizure burden prior to the first dose. Among neonates with seizures, differences across treatment groups in median maximal hourly seizure burden were assessed using adjusted quantile regression models. RESULTS: Forty-six of 150 (31%) neonates had EEG seizures (31% in Epo vs 30% in placebo, p = 0.96). Maximal hourly seizure burden after the study drug was not significantly different between groups (median 11.4 for Epo, IQR: 5.6, 18.1 vs median 9.7, IQR: 4.9, 21.0 min/h for placebo). CONCLUSION: In neonates with HIE treated with hypothermia who were randomized to Epo or placebo, we found no meaningful between-group difference in seizure risk or burden. These findings are consistent with overall trial results, which do not support Epo use for neonates with HIE undergoing therapeutic hypothermia. IMPACT: In the HEAL trial of erythropoietin (Epo) vs placebo for neonates with encephalopathy presumed due to hypoxic-ischemic encephalopathy (HIE) who were also treated with therapeutic hypothermia, electrographic seizures were detected in 31%, which is lower than most prior studies. Epo did not reduce the proportion of neonates with acute provoked seizures (31% in Epo vs 30% in placebo) or maximal hourly seizure burden after the study drug (median 11.4, IQR 5.6, 18.1 for Epo vs median 9.7, IQR 4.9, 21.0 min/h for placebo). There was no anti- or pro-convulsant effect of Epo when combined with therapeutic hypothermia for HIE.

Associations of Parental Distress and Behavior with School Readiness in Children Born Very Preterm.

OBJECTIVE: Children born very preterm (VPT; gestational age [GA] <31 weeks) have robust school readiness difficulties relative to children born full-term (FT; GA ≥37 weeks). This study examined whether four aspects of parental well-being and behavior-distress, harshness, responsiveness and positive control, and cognitive stimulation-were linked to school readiness in a sample of children born VPT <31 weeks GA and whether these characteristics similarly impact VPT and FT children. METHODS: Parents of 4-year-olds born VPT (n = 55) and FT (n = 38) reported on parental distress, behavior, and cognitive stimulation. Children's cognition, executive function, motor skills, preacademic abilities, and behavior were assessed via neuropsychological tests and parent-report questionnaires. RESULTS: For both groups of children, higher psychological distress and harshness were associated with more behavior problems, and more cognitive stimulation was associated with higher scores on tests of cognitive, motor, and preacademic abilities. More parental distress was associated with lower cognitive ability only for children born VPT and more harshness was associated with lower preacademic skills only for children born FT. CONCLUSIONS: Identifying modifiable family factors associated with school readiness in children born VPT is essential for informing family-based interventions to improve school readiness in this population. Findings suggest that distress, harshness, and cognitive stimulation may be reasonable targets for interventions to improve school readiness in children born VPT.

Implementing Parent Coaching in Hospital-Based Pediatric Occupational Therapy: A Multisite Quality Improvement Project.

IMPORTANCE: Parent coaching (PC) is a best practice for young children with, or at high risk for, cerebral palsy (CP). Occupational therapy practitioners in outpatient settings encounter barriers to implementing PC. OBJECTIVE: To increase the documented use of PC in outpatient occupational therapy visits for children younger than age 2 yr with, or at high risk for, CP from 0% to 80%. DESIGN: Multicenter quality improvement (QI) initiative with a time-series design. SETTING: Three pediatric tertiary-care institutions, each with multiple outpatient occupational therapy clinics. PARTICIPANTS: Practitioners in the outpatient clinics and patients <2 yr old with, or at high risk for, cerebral palsy. INTERVENTION: Plan-do-study-act cycles included interventions packaged as a toolkit: education sessions, quick references, electronic medical record (EMR) supports, and site-specific strategies. OUTCOMES AND MEASURES: The primary outcome measure was the use of PC in outpatient sessions. Process measures included pre- and posteducation practitioner knowledge scores and an EMR checklist. Balancing measures (ensuring that changes do not cause problems in other areas) of parent satisfaction/experience and practitioner productivity were measured pre- and postintervention. RESULTS: The primary outcome measure goal (80% documented use of PC in sessions) was attained in the seventh month of the study, sustained for 4 mo, and settled at 79.1% for the remaining 6 mo. Practitioner knowledge scores increased from 83.1% to 87.9% after initial education sessions, t[56] = 3.289, p = .001. Parent satisfaction/experience and practitioner productivity scores did not change. CONCLUSIONS AND RELEVANCE: QI methodology can support PC implementation in pediatric outpatient practice. What This Article Adds: This multisite QI initiative shows that outpatient occupational therapy practitioners can implement PC as a best practice with the use of a toolkit. Results suggest that education alone does not result in changes to practitioner behavior and that QI methods can help when implementing best practices in a clinical setting.

Randomized Trial to Increase Speech Sound Differentiation in Infants Born Preterm.

OBJECTIVE: To test whether infant-directed foreign language active learning would specifically increase speech sound differentiation to the intervention language while not decreasing differentiation in response to English. STUDY DESIGN: Pilot randomized controlled trial of stable infants born preterm in the newborn intensive care unit with normal auditory brainstem responses, whose parents spoke only English and had no musical training or familial hearing abnormality. Assignment was to 1 of 3 groups: passive exposure to English infant-directed lullabies and readings (English-enrichment, control group) and contingent exposure by active sucking on a sensor-equipped pacifier to either infant-directed French lullabies and readings (English environment, French-contingent learning group) or infant-directed Mandarin lullabies and readings (English environment, Chinese-contingent learning group). The main outcome measures were preintervention and postintervention event-related potentials (ERPs) in response to standardized speech syllables in each language. RESULTS: Forty-one subjects completed the study, including 15 in the English-enrichment control group and 13 each in the French-contingent and Chinese-contingent groups. The median gestational age at birth was 34 weeks (IQR, 8.75 weeks); postmenstrual age at intervention ranged from 36 to 46 weeks and was similar across the 3 groups. Postintervention mean ERP amplitude to pairs of English speech sounds did not differ across the 3 groups; however, ERP amplitude in French sound differentiation was greater in the French-contingent group than in the Chinese-contingent or English-enrichment groups, and ERP amplitude greater in Chinese sound differentiation was greater in the Chinese-contingent group compared with the other 2 groups. CONCLUSION: Contingent infant-directed foreign language exposure increased speech sound differentiation specific to the intervention language and did not decrease differentiation in response to English. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03232931.

Intrauterine drug exposure as a risk factor for cerebral palsy.

AIM: To determine whether infants with intrauterine drug exposure (IUDE) are similarly at risk for cerebral palsy (CP) as other high-risk populations, whether CP classification differs based on IUDE status, and describe the association of CP with specific substances among exposed infants. METHOD: This was a retrospective analysis of infants in a high-risk follow-up program (n=5578) between January 2014 and February 2018 with a history of IUDE or who received a CP diagnosis. CP rates were compared using two-sample z-tests. CP classification was assessed using Fisher's exact, Cochran-Armitage, and Wilcoxon rank-sum tests. Models for CP risk were assessed using multivariable logistic regression. RESULTS: Among all infants with IUDE (n=1086), 53.8% were male with a mean (SD) birth gestational age of 36.8 (3.6) weeks. Among unexposed infants with CP (n=259), 54.4% were male with a mean (SD) birth gestational age of 29.9 (5.7) weeks. Opioids were the most common exposure (93.7%) of all infants with IUDE. The CP rate in the IUDE (5.2%) and unexposed (5.7%) high-risk populations were not significantly different (p=0.168), nor were there differences in CP typology, topography, or severity between exposed (n=57) and unexposed (n=259) infants (all p>0.05). In patients with IUDE and after controlling for established CP risk factors, the observed odds of CP varied among substances. INTERPRETATION: We suggest that IUDE should be considered a 'newborn-detectable risk' in the guidelines for the early detection of CP.

Acute and Chronic Placental Abnormalities in a Multicenter Cohort of Newborn Infants with Hypoxic-Ischemic Encephalopathy.

OBJECTIVE: To examine the frequency of placental abnormalities in a multicenter cohort of newborn infants with hypoxic-ischemic encephalopathy (HIE) and to determine the association between acuity of placental abnormalities and clinical characteristics of HIE. STUDY DESIGN: Infants born at ≥36 weeks of gestation (n = 500) with moderate or severe HIE were enrolled in the High-dose Erythropoietin for Asphyxia and Encephalopathy Trial. A placental pathologist blinded to clinical information reviewed clinical pathology reports to determine the presence of acute and chronic placental abnormalities using a standard classification system. RESULTS: Complete placental pathologic examination was available for 321 of 500 (64%) trial participants. Placental abnormalities were identified in 273 of 321 (85%) and were more common in infants ≥40 weeks of gestation (93% vs 81%, P = .01). A combination of acute and chronic placental abnormalities (43%) was more common than either acute (20%) or chronic (21%) abnormalities alone. Acute abnormalities included meconium staining of the placenta (41%) and histologic chorioamnionitis (39%). Chronic abnormalities included maternal vascular malperfusion (25%), villitis of unknown etiology (8%), and fetal vascular malperfusion (6%). Infants with chronic placental abnormalities exhibited a greater mean base deficit at birth (-15.9 vs -14.3, P = .049) than those without such abnormalities. Patients with HIE and acute placental lesions had older mean gestational ages (39.1 vs 38.0, P < .001) and greater rates of clinically diagnosed chorioamnionitis (25% vs 2%, P < .001) than those without acute abnormalities. CONCLUSIONS: Combined acute and chronic placental abnormalities were common in this cohort of infants with HIE, underscoring the complex causal pathways of HIE. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02811263.

Perspectives from the Society for Pediatric Research. Neonatal encephalopathy clinical trials: developing the future.

The next phase of clinical trials in neonatal encephalopathy (NE) focuses on hypothermia adjuvant therapies targeting alternative recovery mechanisms during the process of hypoxic brain injury. Identifying infants eligible for neuroprotective therapies begins with the clinical detection of brain injury and classification of severity. Combining a variety of biomarkers (serum, clinical exam, EEG, movement patterns) with innovative clinical trial design and analyses will help target infants with the most appropriate and timely treatments. The timing of magnetic resonance imaging (MRI) and MR spectroscopy after NE both assists in identifying the acute perinatal nature of the injury (days 3-7) and evaluates the full extent and evolution of the injury (days 10-21). Early, intermediate outcome of neuroprotective interventions may be best defined by the 21-day neuroimaging, with recognition that the full neurodevelopmental trajectory is not yet defined. An initial evaluation of each new therapy at this time point may allow higher-throughput selection of promising therapies for more extensive investigation. Functional recovery can be assessed using a trajectory of neurodevelopmental evaluations targeted to a prespecified and mechanistically derived hypothesis of drug action. As precision medicine revolutionizes healthcare, it should also include the redesign of NE clinical trials to allow safe, efficient, and targeted therapeutics. IMPACT: As precision medicine revolutionizes healthcare, it should also include the redesign of NE clinical trials to allow faster development of safe, effective, and targeted therapeutics. This article provides a multidisciplinary perspective on the future of clinical trials in NE; novel trial design; study management and oversight; biostatistical methods; and a combination of serum, imaging, and neurodevelopmental biomarkers can advance the field and improve outcomes for infants affected by NE. Innovative clinical trial designs, new intermediate trial end points, and a trajectory of neurodevelopmental evaluations targeted to a prespecified and mechanistically derived hypothesis of drug action can help address common challenges in NE clinical trials and allow for faster selection and validation of promising therapies for more extensive investigation.

Regional anesthesia in neonates and infants outside the immediate perioperative period: A systematic review of studies with efficacy and safety considerations.

This review examines the quality and quantity of literature regarding methods that measure efficacy in the context of reported safety of regional anesthesia techniques in preterm and term infants <1 year of age. Because the role of anesthesiologists continues to expand outside the operating room, we focused on all relevant settings with assessments that extend beyond 24 hours from the intraoperative period. All study designs were included from a search of MEDLINE, EMBASE, CINAHL, Scopus, and Cochrane databases from 1946 to the end of 2019. A total of 31 studies were included (n = 1038 participants), consisting of five randomized controlled trials and 26 observational studies. Twenty-three studies examined neuraxial procedures, seven studies examined peripheral procedures, and one study examined both. Efficacy measures included pain assessment tools, analgesic use, and factors pertaining to the recovery of patients. Safety was assessed in multiple systems (neurological, cardiovascular, respiratory, pathological) and with vital signs and/or measures of systemic toxicity. Evidence in this review establishes that neuraxial and peripheral anesthesia treatments may be applied to neonates and infants with a high degree of safety. However, large gaps in the consistency of methods used to assess pain in these studies underline the need for rigorous prospective efficacy studies of these techniques in this population. This systematic review was registered on PROSPERO (CRD42018114466).

Hammersmith Infant Neurological Examination Clinical Use to Recommend Therapist Assessment of Functional Hand Asymmetries.

PURPOSE: To determine whether asymmetry scores derived from the Hammersmith Infant Neurological Examination (HINE) can provide cutoff scores for recommending in-depth assessment of upper extremity functional deficits by therapists using the Hand Assessment for Infants (HAI). METHODS: Observational study in a clinical laboratory with the HINE and the HAI administered concurrently to 101 infants 3 to 12 months corrected age developing typically or atypically. Predictive value of HINE asymmetry scores for atypical HAI was determined. RESULTS: Total HINE asymmetry scores of 4 or greater had 100% sensitivity and 88% or greater specificity for identifying infants with an asymmetric HAI score of 3 or greater point difference between hands. CONCLUSIONS: For infants receiving a total HINE asymmetry score of 4 or greater, referral to therapists for HAI assessment may be beneficial to precisely evaluate function and determine the need for targeted upper extremity interventions.

Hand Function at 18-22 Months Is Associated with School-Age Manual Dexterity and Motor Performance in Children Born Extremely Preterm.

OBJECTIVES: To determine associations between hand function at age 18-22 months (early) and scores on the Movement Assessment Battery for Children, 2nd edition (MABC) at 6-7 years of age (school age) in extremely preterm children. STUDY DESIGN: Prospective multicenter cohort of 313 extremely preterm children with early hand function assessment and school-age MABC testing. Early hand function was compared with "definite deficits" (MABC <5th percentile) and MABC standard scores. Early hand function was categorized as "no deficit" vs "any deficit." Mixed-effects regression models were used to evaluate the association of early hand function with MABC deficits, controlling for multiple demographic, neonatal, and childhood factors. RESULTS: Children with early hand function deficits were more likely to have definite school-age deficits in all MABC subtests (Manual Dexterity, Aiming and Catching, and Balance) and to have received physical or occupational therapy (45% vs 26%; P < .001). Children with early hand function deficits had lower Manual Dexterity (P = .006), Balance (P = .035), and Total Test (P = .039) scores. Controlling for confounders, children with early hand function deficits had higher odds of definite school-age deficits in Manual Dexterity (aOR, 2.78; 95% CI, 1.36-5.68; P = .005) and lower Manual Dexterity (P = .031) and Balance (P = .027) scores. When excluding children with cerebral palsy and those with an IQ <70, hand function deficits remained significantly associated with manual dexterity. CONCLUSION: Hand function deficits at age 18-22 months are associated with manual dexterity deficits and motor difficulties at school age, independent of perinatal-neonatal factors and the use of occupational or physical therapy. This has significant implications for school success, intervention, and rehabilitative therapy development.

Kinematic and Somatosensory Gains in Infants with Cerebral Palsy After a Multi-Component Upper-Extremity Intervention: A Randomized Controlled Trial.

Upper extremity (UE) impairments in infants with cerebral palsy (CP) result from reduced quality of motor experiences and "noisy" sensory inputs. We hypothesized that a neuroscience-based multi-component intervention would improve somatosensory processing and motor measures of more-affected (UEs) in infants with CP and asymmetric UE neurologic impairments, while remaining safe for less-affected UEs. Our randomized controlled trial compared infants (6-24 months) with CP receiving intervention (N = 37) versus a waitlisted group (N = 36). Treatment effects tested a direct measurement of reach smoothness (3D-kinematics), a measure of unimanual fine motor function (Bayley unimanual fine motor raw scores), and EEG measures of cortical somatosensory processing. The four-week therapist-directed, parent-administered intervention included daily (1) bimanual play; (2) less-affected UE wearing soft-constraint (6 h/day, electronically-monitored); (3) reach training on more-affected UE; (4) graduated motor-sensory training; and (5) parent education. Waitlist infants received only bimanual play. Effectiveness and safety were tested; z-scores from 54 posttest-matched typically-developing infants provided benchmarks for treatment effects. Intervention and waitlist infants had no pretest differences. Median weekly constraint wear was 38 h; parent-treatment fidelity averaged > 92%. On the more affected side, the intervention significantly increased smoothness of reach (Cohen's d = - 0.90; p < .001) and unimanual fine motor skill (d = 0.35; p = .004). Using unadjusted p values, intervention improved somatosensory processing (d = 0.53; p = .04). All intervention effects referenced well to typically developing children. Safety of the intervention was demonstrated through positive- or non-effects on measurements involving the constrained, less-affected UE and gross motor function; unexpected treatment effects on reach smoothness occurred in less-affected UEs (d = - 0.85; p = .01). This large clinical trial demonstrated intervention effectiveness and safety for developing sensory and motor systems with improvements in reach smoothness, and developmental abilities.Clinical Trail Registration: ClinicalTrials.gov NCT02567630, registered October 5, 2015.

Neonatal Multisensory Processing in Preterm and Term Infants Predicts Sensory Reactivity and Internalizing Tendencies in Early Childhood.

Multisensory processes include the capacity to combine information from the different senses, often improving stimulus representations and behavior. The extent to which multisensory processes are an innate capacity or instead require experience with environmental stimuli remains debated. We addressed this knowledge gap by studying multisensory processes in prematurely born and full-term infants. We recorded 128-channel event-related potentials (ERPs) from a cohort of 55 full-term and 61 preterm neonates (at an equivalent gestational age) in response to auditory, somatosensory, and combined auditory-somatosensory multisensory stimuli. Data were analyzed within an electrical neuroimaging framework, involving unsupervised topographic clustering of the ERP data. Multisensory processing in full-term infants was characterized by a simple linear summation of responses to auditory and somatosensory stimuli alone, which furthermore shared common ERP topographic features. We refer to the ERP topography observed in full-term infants as "typical infantile processing" (TIP). In stark contrast, preterm infants exhibited non-linear responses and topographies less-often characterized by TIP; there were distinct patterns of ERP topographies to multisensory and summed unisensory conditions. We further observed that the better TIP characterized an infant's ERPs, independently of prematurity, the more typical was the score on the Infant/Toddler Sensory Profile (ITSP) at 12 months of age and the less likely was the child to the show internalizing tendencies at 24 months of age. Collectively, these results highlight striking differences in the brain's responses to multisensory stimuli in children born prematurely; differences that relate to later sensory and internalizing functions.

Caregiver perception of hand function in infants with cerebral palsy: psychometric properties of the Infant Motor Activity Log.

AIM: To evaluate the properties of the Infant Motor Activity Log (IMAL), a caregiver-report for frequency and quality of use of more affected upper extremity in infants with neurological and functional impairments. METHOD: This was a prospective cohort study of 66 children (34 females, 32 males) aged 6 to 24 months (mean age [SD] 13.7mo [5.3]) with neurological and functional impairments and a confirmed cerebral palsy diagnoses after 2 years, and 51 age-matched typically developing children. The IMAL was administered at baseline and 4 weeks later. Typically developing infants were tested with randomly assigned 'more affected' upper extremity. Psychometric properties were evaluated using Spearman's correlation coefficient, Cronbach's alpha, and Jonckheere-Terpstra tests. RESULTS: In the children with impairments, the IMAL showed internal consistency (alpha≥0.88) for the How Well Scale (HWS) and How Often Scale (HOS). Test-retest reliability was 0.64 (HOS) and 0.70 (HWS), demonstrating stability over time. Correlation with Bayley Scales of Infant and Toddler Development, Third Edition more affected arm raw scores were 0.70 (HOS) and 0.72 (HWS) (p<0.001) demonstrating construct validity. Both scale scores decreased with increasing Gross Motor Function Classification System and Mini-Manual Ability Classification System (p<0.001) levels, supporting discriminative validity. Discrimination between typically developing infants and infants with impairments was high (HWS: area under the receiver operating characteristic curve [AUC] 0.96, 95% confidence interval [CI] 0.94-0.99 and HOS AUC=0.95, CI 0.92-0.99). INTERPRETATION: The IMAL is a valid and reliable discriminative caregiver measure of upper limb performance and may complement measures of capacity in infants with neurological and functional impairments. WHAT THIS PAPER ADDS: The Infant Motor Activity Log (IMAL) is a valid and reliable measure of caregiver perception of upper limb function. The IMAL fills a measurement gap for infant motor performance in children with impairments. The IMAL discriminates among motor function levels.