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.

Effect of Depth and Duration of Cooling on Death or Disability at Age 18 Months Among Neonates With Hypoxic-Ischemic Encephalopathy: A Randomized Clinical Trial.

IMPORTANCE: Hypothermia for 72 hours at 33.5°C for neonatal hypoxic-ischemic encephalopathy reduces death or disability, but rates continue to be high. OBJECTIVE: To determine if cooling for 120 hours or to a temperature of 32.0°C reduces death or disability at age 18 months in infants with hypoxic-ischemic encephalopathy. DESIGN, SETTING, AND PARTICIPANTS: Randomized 2 × 2 factorial clinical trial in neonates (≥36 weeks' gestation) with hypoxic-ischemic encephalopathy at 18 US centers in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network between October 2010 and January 2016. INTERVENTIONS: A total of 364 neonates were randomly assigned to 4 hypothermia groups: 33.5°C for 72 hours (n = 95), 32.0°C for 72 hours (n = 90), 33.5°C for 120 hours (n = 96), or 32.0°C for 120 hours (n = 83). MAIN OUTCOMES AND MEASURES: The primary outcome was death or moderate or severe disability at 18 to 22 months of age adjusted for center and level of encephalopathy. Severe disability included any of Bayley Scales of Infant Development III cognitive score less than 70, Gross Motor Function Classification System (GMFCS) level of 3 to 5, or blindness or hearing loss despite amplification. Moderate disability was defined as a cognitive score of 70 to 84 and either GMFCS level 2, active seizures, or hearing with amplification. RESULTS: The trial was stopped for safety and futility in November 2013 after 364 of the planned 726 infants were enrolled. Among 347 infants (95%) with primary outcome data (mean age at follow-up, 20.7 [SD, 3.5] months; 42% female), death or disability occurred in 56 of 176 (31.8%) cooled for 72 hours and 54 of 171 (31.6%) cooled for 120 hours (adjusted risk ratio, 0.92 [95% CI, 0.68-1.25]; adjusted absolute risk difference, -1.0% [95% CI, -10.2% to 8.1%]) and in 59 of 185 (31.9%) cooled to 33.5°C and 51 of 162 (31.5%) cooled to 32.0°C (adjusted risk ratio, 0.92 [95% CI, 0.68-1.26]; adjusted absolute risk difference, -3.1% [95% CI, -12.3% to 6.1%]). A significant interaction between longer and deeper cooling was observed (P = .048), with primary outcome rates of 29.3% at 33.5°C for 72 hours, 34.5% at 32.0°C for 72 hours, 34.4% at 33.5°C for 120 hours, and 28.2% at 32.0°C for 120 hours. CONCLUSIONS AND RELEVANCE: Among term neonates with moderate or severe hypoxic-ischemic encephalopathy, cooling for longer than 72 hours, cooling to lower than 33.5°C, or both did not reduce death or moderate or severe disability at 18 months of age. However, the trial may be underpowered, and an interaction was found between longer and deeper cooling. These results support the current regimen of cooling for 72 hours at 33.5°C. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01192776.

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.

Rates of Autism Spectrum Disorder Diagnosis Under the DSM-5 Criteria Compared to DSM-IV-TR Criteria in a Hospital-Based Clinic.

BACKGROUND: We aimed to determine whether there was a decrease in the number of children diagnosed on the autism spectrum after the implementation of the new diagnostic criteria as outlined in the Diagnostic and Statistical Manual of Mental Health Disorders Fifth Edition published in May 2013. METHOD: We reviewed 1552 charts of children evaluated at the Women and Children's Hospital of Buffalo, Autism Spectrum Disorders Clinic. A comparison was made of children diagnosed with autism spectrum disorder (autism, Asperger disorder, pervasive developmental disorder-not otherwise specified) from 2010 to May 2013 using the Diagnostic and Statistical Manual of Mental Health Disorders Fourth Edition, Text Revision criteria with children diagnosed from June 2013 through June 2015 under the Diagnostic and Statistical Manual of Mental Health Disorders Fifth Edition. RESULTS: Using χ(2) analysis, the 2013-2015 rate of autism spectrum disorder diagnosis (39%) was significantly lower (P < 0.01) than the 2010 to May 2013 sample years rate (50%). CONCLUSION: The rate of autism spectrum disorder diagnosis was significantly lower under the recently implemented Diagnostic and Statistical Manual of Mental Health Disorders Fifth Edition criteria.

Central nervous system herpes simplex virus infection in afebrile children with seizures.

Central nervous system herpes simplex virus infection is suspected in patients presenting with acute-onset seizures and lethargy. The potential neurologic sequelae from untreated herpes infection can prompt empirical acyclovir therapy, even in afebrile subjects. The objectives of this study were to determine the frequency of central nervous system herpes simplex virus infection in children presenting with afebrile seizures and to assess the need for empirical acyclovir therapy. Clinical and laboratory data of children with acute-onset afebrile seizures and children with central nervous system herpes simplex virus infection were compared. Polymerase chain reaction and viral cultures of the cerebrospinal fluid for herpes simplex virus infection were negative in all subjects with afebrile seizures; 32.7% of these subjects were empirically treated with acyclovir. In conclusion, central nervous system herpes simplex virus infection is uncommon in children presenting with afebrile seizures, and acyclovir therapy is rarely necessary in subjects with normal neurologic examination and cerebrospinal fluid analysis.

Managing behavior for a child with autism in a body cast.

CASE: : Elisa is a 6 ½-year-old white female who has a follow-up appointment in the Developmental Clinic where she is seen for autism, developmental delay, and significant behavioral problems. Her grandparents, who are her legal guardians, request an opinion on a proposed surgery for developmental dysplasia of the hip that will require several months in a whole body cast. Reconstruction of the hip was recommended by 2 pediatric orthopedic surgeons to prevent later disability and pain.Elisa was born following a 41-week gestation. She sat without support at 7 months, but she did not walk until 23 months of age. An evaluation at the Developmental Clinic at 28 months of age documented gross and fine motor delays, cognitive impairment, and autism. A karyotype, fragile X, and microarray were normal. Elisa has a brother with autism and a maternal cousin with mental retardation. After her mother's death from meningitis 2 years ago, her maternal grandparents became her legal guardian.Behavior problems include significant hyperactivity, impulsivity, and aggressive behaviors. She seldom sits still. She also has frequent stereotypies, such as jumping and arm flapping when she is excited or upset. Methylphenidate was associated with increased hyperactivity and irritability.Physical examination demonstrates that she can walk with a very wide gait and swings her right foot out. A magnetic resonance imaging of her brain, acoustic brain response audiometry, and metabolic studies are normal. Other medical issues include gastroesophageal reflux, recurrent pneumonia, and ear infections. Radiographs of the hip reveal a steep acetabulum and a hip that easily dislocates. A magnetic resonance imaging of the hip shows early formation of a pseudoarthrosis. Her grandparents and pediatrician are concerned about managing her behavior after the surgery when she will be in a body cast.

Autism Spectrum Disorder: Correlation between aberrant behaviors, EEG abnormalities and seizures.

The relationship between epilepsy, epileptiform discharges, cognitive, language and behavioral symptoms is not clearly understood. Since difficulties with socialization and maladaptive behaviors are found in children with Autism Spectrum Disorder (ASD), we inquired whether epileptiform activity and seizures are associated with adverse behavioral manifestations in this population. We reviewed our EEG database between 1999-2006, and identified 123 children with ASD. EEG abnormalities were found in 39 children (31%). A control group of age and gender matched ASD children with normal EEG's was obtained. Packets of questionnaires including the Vineland Adaptive Behavior Scale II (VABS), Aberrant Behavior Checklist (ABC) and the Childhood Autism Rating Scale (CARS) were sent by mail. Out of 21 packets received, 11 had normal and 10 had abnormal EEG's. There were no statistically significant differences in behavior between the two groups. Statistical analysis of discharge location and frequency did not reveal a significant trend. However, children with ASD and seizures had statistically significant lower scores in VABS daily living (P=0.009) and socialization (P=0.007) as compared to those without seizures. ASD children with seizures had higher ABC levels of hyperactivity and irritability. Differences in irritability scores nearly reached statistical significance (P=0.058). There was no significant difference in the degree of CARS autism rating between the groups. Our study did not reveal statistically significant differences in behaviors between ASD children with and without EEG abnormalities. However, ASD children with seizures revealed significantly worse behaviors as compared to counterparts without seizures.