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.

Vibration-based mitigation of noxious-evoked responses to skin puncture in neonates and infants: a randomised controlled trial.

OBJECTIVE: To assess the effect of a non-noxious vibratory stimulus on noxious-evoked cortical responses to skin puncture and to determine whether the presence of certain behavioural components may be used to predict such cortical responses. DESIGN: Randomised controlled trial. SETTING: Level IV neonatal intensive care unit at a stand-alone children's hospital. PATIENTS: 134 hospitalised infants between 36 and 52 weeks' postmenstrual age and ordered to receive a clinically required laboratory draw. INTERVENTIONS: Infants randomised to receive the intervention, a vibratory stimulus at the site of skin puncture beginning 10 s prior to a heel stick, or the control, no vibration. MAIN OUTCOME MEASURES: Electroencephalography and video recording time-locked to the deployment of the lancet for the skin puncture. Noxious-evoked cortical responses were measured by the area under the curve in the somatosensory region contralateral to the skin puncture. Behavioural responses were coded through video analysis. RESULTS: Noxious-evoked cortical responses were significantly reduced in participants receiving the vibratory stimulus compared with the control (frontal, p<0.0001; central, p=0.0088; central-parietal, p=0.0111). There were no significant differences in behavioural responses between groups (all p>0.05). CONCLUSIONS: A non-noxious vibratory stimulus presented prior to and continuing simultaneously with skin puncture significantly mitigates nociception in hospitalised infants. The presence or absence of facial expression components is inadequate to reliably predict pain signalling in the brain. TRIAL REGISTRATION NUMBER: NCT04050384.

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.

A Call for Early Detection of Cerebral Palsy.

Cerebral palsy (CP) is the most common physical disability across the lifespan, but historically, CP has not been diagnosed before the age of 2 years. Barriers to early diagnosis ranged from lack of available biomarkers, absence of curative treatments, perceived stigma associated with a lifelong diagnosis, and a desire to rule out other diagnoses first. Most importantly, the fundamental question that remained was whether children would benefit from earlier detection and intervention given the paucity of research. However, evidence-based guidelines published in 2017 demonstrated that the General Movements Assessment, the Hammersmith Infant Neurological Examination, and neuroimaging can be combined with other elements such as a clinical history and standardized motor assessments to provide the highest predictive value for diagnosing CP as early as age 3 months in high-risk newborns. Implementation of these guidelines has been successful in decreasing the age at CP diagnosis, particularly in high-risk infant follow-up clinics with expertise in performing these assessments. Early detection of CP allows for clinical and research opportunities investigating earlier interventions during a critical period of neuroplasticity, with the goal of improving developmental trajectories for children and their families. New guidelines and research are now being developed with a focus on early, targeted interventions that continue to be studied, along with global detection initiatives.

Association of EEG Background and Neurodevelopmental Outcome in Neonates With Hypoxic-Ischemic Encephalopathy Receiving Hypothermia.

BACKGROUND AND OBJECTIVES: Predicting neurodevelopmental outcome for neonates with hypoxic-ischemic encephalopathy (HIE) is important for clinical decision-making, care planning, and parent communication. We examined the relationship between EEG background and neurodevelopmental outcome among children enrolled in a trial of erythropoietin or placebo for neonates with HIE treated with therapeutic hypothermia. METHODS: Participants had EEG recorded throughout hypothermia. EEG background was classified as normal, discontinuous, or severely abnormal (defined as burst suppression, low voltage suppressed, or status epilepticus) at 5 1-hour epochs: onset of recording, 24, 36, 48, and 72 hours after birth. The predominant background pattern during the entire continuous video EEG monitoring recording was calculated using the arithmetic mean of the 5 EEG background ratings (normal = 0; discontinuous = 1; severely abnormal = 2) as follows: "predominantly normal" (mean = 0), "normal/discontinuous" (0 < mean<1), "predominantly discontinuous" (mean = 1), "discontinuous/severely abnormal" (1 < mean<2), or "predominantly severely abnormal" (mean = 2). Primary outcome was death or neurodevelopmental impairment (NDI) defined as cerebral palsy, Gross Motor Function Classification Score ≥1, or cognitive score <90 on Bayley Scales of Infant Toddler Development, third edition at age 2 years. Neurodevelopment was also categorized into a 5-level ordinal measure: no, mild, moderate, severe NDI, or death for secondary analysis. We used generalized linear regression models with robust standard errors to assess the relative risk of death or NDI by EEG background in both unadjusted and adjusted analyses controlling for the effects of treatment group, sex, HIE severity, and study recruitment site. RESULTS: Among 142 neonates, the predominant background EEG pattern was predominantly normal in 35 (25%), normal/discontinuous in 68 (48%), predominantly discontinuous in 11 (7.7%), discontinuous/severely abnormal in 16 (11%), and predominantly severely abnormal in 12 (8.5%). Increasing severity of background across monitoring epochs was associated with increasingly worse clinical outcomes. Children with severe EEG background abnormality at any time point (n = 36, 25%) were significantly more likely to die or have severe NDI at 2 years (adjusted relative risk: 7.95, 95% CI 3.49-18.12). DISCUSSION: EEG background is strongly associated with NDI at age 2 years. These results can be used to assist health care providers to plan follow-up care and counsel families for decision-making related to goals of care.

Behavioral and neural measures of infant responsivity increase with maternal multisensory input in non-irritable infants.

INTRODUCTION: Parents often use sensory stimulation during early-life interactions with infants. These interactions, including gazing, rocking, or singing, scaffold child development. Previous studies have examined infant neural processing during highly controlled sensory stimulus presentation paradigms. OBJECTIVE: In this study, we investigated infant behavioral and neural responsiveness during a mother-child social interaction during which the mother provided infant stimulation with a progressive increase in the number of sensory modalities. METHODS: We prospectively collected and analyzed video-coded behavioral interactions and electroencephalogram (EEG) frontal asymmetry (FAS) from infants (n = 60) at 2-4 months born at ≥ 34 weeks gestation. As the number of sensory modalities progressively increased during the interaction, infant behaviors of emotional connection in facial expressiveness, sensitivity to mother, and vocal communication increased significantly. Conversely, infant FAS for the entire cohort did not change significantly. However, when we accounted for infant irritability, both video-coded behaviors and EEG FAS markers of infant responsiveness increased across the interaction in the non-irritable infants. The non-irritable infants (49%) demonstrated positive FAS, indicating readiness to engage with, rather than to withdraw from, multisensory but not unisensory interactions with their mothers. RESULTS: These results suggest that multisensory input from mothers is associated with greater infant neural approach state and highlight the importance of infant behavioral state during neural measures of infant responsiveness.

Contingent Mother's Voice Intervention Targeting Feeding in Hospitalized Infants with Critical Congenital Heart Defects.

Infants with critical congenital heart defects (CCHD) are at high risk for feeding challenges and neurodevelopmental delays; however, few interventions promoting the neurodevelopmental progression of feeding have been studied with this population. Contingent mother's voice has been successfully used as positive reinforcement for non-nutritive suck (NNS) in studies with preterm infants, leading to improved weight gain and more rapid cessation of tube feedings; however, this type of intervention has not been studied in infants with CCHD. This study aimed to determine whether an NNS-training protocol using the mother's voice as positive reinforcement and validated in preterm infants could improve oral feeding outcomes in hospitalized infants with CCHD undergoing cardiac surgical procedures. Infants were randomized to receive the contingent mother's voice intervention before or after cardiac surgery, with a control comparison group receiving passive exposure to the mother's voice after surgery. There were no significant differences in discharge weight, PO intake, length of stay, time to full feeds, or feeding status at 1-month post-discharge between infants who received contingent mother's voice compared to those who did not. There were significant differences in PO intake and time to full feeds following surgery based on infants' pre-enrollment PO status and severity of illness. At 1-month post-discharge, parents of infants in the intervention group expressed a higher rate of positive feelings and fewer concerns regarding their infant's feeding compared to parents of infants in the control group. While the current protocol of 5 sessions was not associated with improved feeding outcomes in infants with CCHD, it empowered parents to contribute to their infant's care and demonstrated the feasibility of using the mother's voice as positive reinforcement for infants with CCHD. Further study of timing, intensity, and duration of interventions leveraging the mother's voice in this population is needed. ClinicalTrials.gov Identifier: NCT03035552.

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.

Use of term reference infants in assessing the developmental outcome of extremely preterm infants: lessons learned in a multicenter study.

OBJECTIVE: Extremely preterm (EP) impairment rates are likely underestimated using the Bayley III norm-based thresholds scores and may be better assessed relative to concurrent healthy term reference (TR) infants born in the same hospital. STUDY DESIGN: Blinded, certified examiners in the Neonatal Research Network (NRN) evaluated EP survivors and a sample of healthy TR infants recruited near the 2-year assessment age. RESULTS: We assessed 1452 EP infants and 183 TR infants. TR-based thresholds showed higher overall EP impairment than Bayley norm-based thresholds (O.R. = 1.86; [95% CI 1.56-2.23], especially for severe impairment (36% vs. 24%; p ≤ 0.001). Difficulty recruiting TR patients at 2 years extended the study by 14 months and affected their demographics. CONCLUSION: Impairment rates among EP infants appear to be substantially underestimated from Bayley III norms. These rates may be best assessed by comparison with healthy term infants followed with minimal attrition from birth in the same centers. GOV ID: Term Reference (under the Generic Database Study): NCT00063063.

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.

Implementation of Early Detection and Intervention for Cerebral Palsy in High-Risk Infant Follow-Up Programs: U.S. and Global Considerations.

Early detection and intervention for cerebral palsy is best practice for all high-risk infants according to international guidelines, consensus statements and research-supported evidence. It allows support for families and optimization of developmental trajectories into adulthood. All phases of implementation of CP early detection can be found across the world in high-risk infant follow-up programs, demonstrating feasibility and acceptability through standardized implementation science. The largest clinical network for CP early detection and intervention in the world has now sustained an average age at detection less than 12 months corrected age for more than 5 years. Targeted referrals and interventions for CP can now be offered to patients in optimal periods of neuroplasticity, and new therapies researched as the age of detection decreases. Implementation of guidelines and incorporation of rigorous CP research studies both allow high-risk infant follow-up programs to fulfill their mission of improving outcomes of those with the most vulnerable developmental trajectories from birth.

The Future of High-Risk Infant Follow-Up.

As this issue of Clinics in Perinatology illustrates, a profound shift has occurred in the driving purpose of high-risk infant follow-up (HRIF) over the past 5 years. As a result, HRIF has evolved from primarily providing an ethical compass, concerned surveillance and documentation of outcomes, to developing novel models of care, considering new high-risk populations, settings, and psychosocial factors, and incorporating active, targeted interventions to improve outcomes.

A Comparison of the Clinical Presentation of Preterm Birth and Autism Spectrum Disorder: Commonalities and Distinctions in Children Under 3.

Premature infants and infants later diagnosed with autism spectrum disorder (ASD) share many commonalities in clinical presentations. However, prematurity and ASD also have differences in clinical presentation. These overlapping phenotypes can lead to misdiagnoses of ASD or missing a diagnosis of ASD in preterm infants. We document these commonalities and differences in various developmental domains with the hope of aiding in the accurate early detection of ASD and timely intervention implementation in children born premature. Given the degree of similarities in presentation, evidence-based interventions designed specifically for preterm toddlers or toddlers with ASD may ultimately aid both populations.