Anjali Sadhwani

Cognitive Effects of Adenotonsillectomy for Obstructive Sleep Apnea.

OBJECTIVE: Research reveals mixed evidence for the effects of adenotonsillectomy (AT) on cognitive tests in children with obstructive sleep apnea syndrome (OSAS). The primary aim of the study was to investigate effects of AT on cognitive test scores in the randomized Childhood Adenotonsillectomy Trial. METHODS: Children ages 5 to 9 years with OSAS without prolonged oxyhemoglobin desaturation were randomly assigned to watchful waiting with supportive care (n = 227) or early AT (eAT, n = 226). Neuropsychological tests were administered before the intervention and 7 months after the intervention. Mixed model analysis compared the groups on changes in test scores across follow-up, and regression analysis examined associations of these changes in the eAT group with changes in sleep measures. RESULTS: Mean test scores were within the average range for both groups. Scores improved significantly (P < .05) more across follow-up for the eAT group than for the watchful waiting group. These differences were found only on measures of nonverbal reasoning, fine motor skills, and selective attention and had small effects sizes (Cohen’s d, 0.20–0.24). As additional evidence for AT-related effects on scores, gains in test scores for the eAT group were associated with improvements in sleep measures. CONCLUSIONS: Small and selective effects of AT were observed on cognitive tests in children with OSAS without prolonged desaturation. Relative to evidence from Childhood Adenotonsillectomy Trial for larger effects of surgery on sleep, behavior, and quality of life, AT may have limited benefits in reversing any cognitive effects of OSAS, or these benefits may require more extended follow-up to become manifest.

Extremely low gestational age and very low birthweight for gestational age are risk factors for autism spectrum disorder in a large cohort study of 10-year-old children born at 23-27 weeks' gestation.

Background: No prospective cohort study of high‐risk children has used rigorous exposure assessment and optimal diagnostic procedures to examine the perinatal antecedents of autism spectrum disorder separately among those with and without cognitive impairment. Objective: We sought to identify perinatal factors associated with increased risk for autism spectrum disorder with and without intellectual disability (intelligence quotient <70) in children born extremely preterm. Study Design: This prospective multicenter (14 institutions in 5 states) birth cohort study included children born at 23–27 weeks’ gestation in 2002 through 2004 who were evaluated for autism spectrum disorder and intellectual disability at age 10 years. Pregnancy information was obtained from medical records and by structured maternal interview. Cervical‐vaginal “infection” refers to maternal report of bacterial infection (n = 4), bacterial vaginosis (n = 30), yeast infection (n = 62), mixed infection (n = 4), or other/unspecified infection (n = 43; eg, chlamydia, trichomonas, or herpes). We do not know the extent to which infection per se was confirmed by microbial colonization. We use the terms “fetal growth restriction” and “small for gestational age” interchangeably in light of the ongoing challenge to discern pathologically from constitutionally small newborns. Severe fetal growth restriction was defined as a birthweight Z‐score for gestational age at delivery <–2 (ie, ≥2 SD below the median birthweight in a referent sample that excluded pregnancies delivered for preeclampsia or fetal indications). Participants were classified into 4 groups based on whether or not they met rigorous diagnostic criteria for autism spectrum disorder and intellectual disability (autism spectrum disorder+/intellectual disability–, autism spectrum disorder+/intellectual disability+, autism spectrum disorder–/intellectual disability+, and autism spectrum disorder–/intellectual disability–). Temporally ordered multinomial logistic regression models were used to examine the information conveyed by perinatal factors about increased risk for autism spectrum disorder and/or intellectual disability (autism spectrum disorder+/intellectual disability–, autism spectrum disorder+/intellectual disability+, and autism spectrum disorder–/intellectual disability+). Results: In all, 889 of 966 (92%) children recruited were assessed at age 10 years, of whom 857 (96%) were assessed for autism spectrum disorder; of these, 840 (98%) children were assessed for intellectual disability. Autism spectrum disorder+/intellectual disability– was diagnosed in 3.2% (27/840), autism spectrum disorder+/intellectual disability+ in 3.8% (32/840), and autism spectrum disorder–/intellectual disability+ in 8.5% (71/840). Maternal report of presumed cervical‐vaginal infection during pregnancy was associated with increased risk of autism spectrum disorder+/intellectual disability+ (odds ratio, 2.7; 95% confidence interval, 1.2–6.4). The lowest gestational age category (23–24 weeks) was associated with increased risk of autism spectrum disorder+/intellectual disability+ (odds ratio, 2.9; 95% confidence interval, 1.3–6.6) and autism spectrum disorder+/intellectual disability– (odds ratio, 4.4; 95% confidence interval, 1.7–11). Severe fetal growth restriction was strongly associated with increased risk for autism spectrum disorder+/intellectual disability– (odds ratio, 9.9; 95% confidence interval, 3.3–30), whereas peripartum maternal fever was uniquely associated with increased risk of autism spectrum disorder–/intellectual disability+ (odds ratio, 2.9; 95% confidence interval, 1.2–6.7). Conclusion: Our study confirms that low gestational age is associated with increased risk for autism spectrum disorder irrespective of intellectual ability, whereas severe fetal growth restriction is strongly associated with autism spectrum disorder without intellectual disability. Maternal report of cervical‐vaginal infection is associated with increased risk of autism spectrum disorder with intellectual disability, and peripartum maternal fever is associated with increased risk for intellectual disability without autism spectrum disorder.

Neurocognitive Outcomes at 10 Years of Age in Extremely Preterm Newborns with Late-Onset Bacteremia

OBJECTIVE To evaluate the difference in 10-year neurocognitive outcomes between extremely low gestational age newborns without bacteremia and those with suspected or confirmed late-onset bacteremia. STUDY DESIGN Neurocognitive function was evaluated at 10 years of age in 889 children born at <28 weeks of gestation and followed from birth. Definite (culture-positive) late-onset bacteremia during postnatal weeks 2-4 was identified in 223 children, and 129 children had suspected bacteremia. RESULTS Infants with the lowest gestational age and birth weight z-score had the highest prevalence of definite and suspected late-onset bacteremia. Compared with peers with no or suspected bacteremia, infants with definite bacteremia performed worse on tests of general cognitive ability, language, academic achievement, and executive function, even after adjustment for potential confounders. Adjustment for low IQ attenuated the associations between bacteremia and all dysfunctions at age 10 years. Children with suspected bacteremia did not differ appreciably from those with no evidence of bacteremia. The motor domain was unaffected. CONCLUSIONS Extremely low gestational age newborns who had definite late bacteremia during postnatal weeks 2-4 are at heightened risk of neurocognitive limitations at age 10 years.

Neurodevelopmental Outcome in Children after Fetal Cardiac Intervention for Aortic Stenosis with Evolving Hypoplastic Left Heart Syndrome

Objective To characterize neurodevelopmental outcomes after fetal aortic valvuloplasty for evolving hypoplastic left heart syndrome and determine the risk factors for adverse neurodevelopment. Study design Questionnaires were mailed to families of children who underwent fetal aortic valvuloplasty from 2000 to 2012, and medical records were reviewed retrospectively. The primary outcome was the General Adaptive Composite score of the Adaptive Behavior Assessment System Questionnaire‐Second Edition. Other questionnaires included the Behavior Assessment System for Children, Behavior Rating Inventory of Executive Function, Ages and Stages, and Pediatric Quality of Life Inventory. Results Among 69 eligible subjects, 52 (75%) completed questionnaires at median age of 5.5 (range 1.3‐12) years; 30 (58%) had biventricular status circulation. The General Adaptive Composite mean score (92 ± 17) was lower than population norms (P < .001) and similar to published reports in patients with hypoplastic left heart syndrome without fetal intervention; scores in the single ventricular versus biventricular group were 97 ± 19 vs 89 ± 14, respectively (P = .10). On multivariable analysis, independent predictors of a lower General Adaptive Composite score were total hospital duration of stay in the first year of life (P = .001) and, when forced into the model, biventricular status (P = .02). For all other neurodevelopmental questionnaires (Behavior Assessment System for Children, Behavior Rating Inventory of Executive Function, Ages and Stages, Pediatric Quality of Life Inventory), most subscale scores for patients with biventricular and single ventricular status were similar. Conclusion Children who underwent fetal aortic valvuloplasty have neurodevelopmental delay, similar to patients with hypoplastic left heart syndrome without fetal intervention. Achievement of biventricular circulation was not associated with better outcomes. We infer that innate patient factors and morbidity during infancy have the greatest effect on neurodevelopmental outcomes.

Everolimus for treatment of tuberous sclerosis complex-associated neuropsychiatric disorders

To evaluate if short‐term treatment with everolimus was safe and could improve neurocognition and behavior in children with TSC.

Antecedents of Screening Positive for Attention Deficit Hyperactivity Disorder in Ten-Year-Old Children Born Extremely Preterm

BACKGROUND The incidence of attention deficit hyperactivity disorder is higher among children born very preterm than among children who are mature at birth. METHODS We studied 583 ten-year-old children who were born before 28 weeks of gestation whose IQ was above 84 and had a parent-completed Child Symptom Inventory-4, which allowed classification of the child as having or not having symptoms of attention deficit hyperactivity disorder. For 422 children, we also had a teacher report, and for 583 children, we also had a parent report of whether or not a physician made an attention deficit hyperactivity disorder diagnosis. RESULTS The risk profile of screening positive for attention deficit hyperactivity disorder based on a parents report differed from the risk profile based on the teachers report, whereas the risk profile according to a physician and according to any two observers closely resembled the parent-reported profile. Among the statistically significant risk factors were young maternal age (parent, physician, and two observers), maternal obesity (parent, physician, and two observers), maternal smoking (parent, physician, and two observers), magnesium given at delivery for seizure prophylaxis (parent and two observers), recovery of Mycoplasma sp. from the placenta (teacher and two observers), low gestational age (parent and two observers), low birth weight (teacher and physician), singleton (parent, physician, and two observers), male (parent, teacher, physician, and two observers), mechanical ventilation on postnatal day seven (physician), receipt of a sedative (parent and two observers), retinopathy of prematurity (parent), necrotizing enterocolitis (physician), antibiotic receipt (physician and two observers), and ventriculomegaly on brain scan (parent and two observers). CONCLUSIONS The multiplicity of risk factors identified can be subsumed as components of four broad themes: low socioeconomic state, immaturity or vulnerability, inflammation, and epigenetic phenomena.

The Relationship of Maternal Prepregnancy Body Mass Index and Pregnancy Weight Gain to Neurocognitive Function at Age 10 Years among Children Born Extremely Preterm

Objective To assess the association between maternal prepregnancy body mass index and adequacy of pregnancy weight gain in relation to neurocognitive function in school‐aged children born extremely preterm. Study design Study participants were 535 ten‐year‐old children enrolled previously in the prospective multicenter Extremely Low Gestational Age Newborns cohort study who were products of singleton pregnancies. Soon after delivery, mothers provided information about prepregnancy weight. Prepregnancy body mass index and adequacy of weight gain were characterized based on this information. Children underwent a neurocognitive evaluation at 10 years of age. Results Maternal prepregnancy obesity was associated with increased odds of a lower score for Differential Ability Scales‐II Verbal IQ, for Developmental Neuropsychological Assessment‐II measures of processing speed and visual fine motor control, and for Wechsler Individual Achievement Test‐III Spelling. Children born to mothers who gained an excessive amount of weight were at increased odds of a low score on the Oral and Written Language Scales Oral Expression assessment. Conversely, children whose mother did not gain an adequate amount of weight were at increased odds of a lower score on the Oral and Written Language Scales Oral Expression and Wechsler Individual Achievement Test‐III Word Reading assessments. Conclusion In this cohort of infants born extremely preterm, maternal obesity was associated with poorer performance on some assessments of neurocognitive function. Our findings are consistent with the observational and experimental literature and suggest that opportunities may exist to mitigate risk through education and behavioral intervention before pregnancy. (J Pediatr 2017;187:50‐7).

Neurodevelopmental assessment of infants with congenital heart disease in the early postoperative period

OBJECTIVE Mortality rates for children with congenital heart disease (CHD) have significantly declined, resulting in a growing population with associated neurodevelopmental disabilities. American Heart Association guidelines recommend systematic developmental screening for children with CHD. The present study describes results of inpatient newborn neurodevelopmental assessment of infants after open heart surgery. OUTCOME MEASURES We evaluated the neurodevelopment of a convenience sample of high-risk infants following cardiac surgery but before hospital discharge using an adaptation of the Newborn Behavioral Observation. Factor analysis examined relationships among assessment items and consolidated them into domains of development. RESULTS We assessed 237 infants at a median of 11 days (interquartile range [IQR]: 7-19 days) after cardiac surgery and median corrected age of 21 days (IQR: 13-33 days). Autonomic regulation was minimally stressed or well organized in 14% of infants. Upper and lower muscle tone was appropriate in 33% and 35%, respectively. Appropriate response to social stimulation ranged between 7% and 12% depending on task, and state regulation was well organized in 14%. The vast majority (87%) required enhanced examiner facilitation for participation. Factor analyses of assessment items aligned into four domains of development (autonomic, motor, oral motor, and attention organization). CONCLUSION At discharge, postoperative infants with CHD had impairments in autonomic, motor, attention, and state regulation following cardiac surgery. Findings highlight the challenges faced by children with CHD relative to healthy peers, suggesting that neurodevelopmental follow-up and intervention should begin early in infancy.

A randomized controlled trial of levodopa in patients with Angelman syndrome

Treatment for Angelman syndrome (AS) is currently limited to symptomatic interventions. A mouse model of AS has reduced calcium/calmodulin‐dependent kinase II activity due to excessive phosphorylation of specific threonine residues, leading to diminished long‐term potentiation. In a rat model of Parkinson disease, levodopa reduced phosphorylation of various proteins, including calcium/calmodulin‐dependent kinase II. Further studies demonstrated that AS mice treated with levodopa performed better on rotarod testing than untreated AS mice. We conducted a multi‐center double‐blind randomized placebo‐controlled 1‐year trial of levodopa / carbidopa with either 10 or 15 mg/kg/day of levodopa in children with AS. The outcome of this intervention was assessed using either the Bayley Scales of Infant Development or the Mullen Scales of Early Learning, as well as the Vineland Adaptive Behavior Scales, and the Aberrant Behavior Checklist. Of the 78 participants enrolled, 67 participants received study medication (33 on levodopa, 34 on placebo), and 55 participants (29 on levodopa, 26 on placebo) completed the 1‐year study. There were no clinically or statistically significant changes in any of the outcome measures over a 1‐year period comparing the levodopa and placebo groups. The number of adverse events reported, including the more serious adverse events, was similar in both groups, but none were related to treatment with levodopa. Our data demonstrate that levodopa is well‐tolerated by children with AS. However, in the doses used in this study, it failed to improve their neurodevelopment or behavioral outcome.

Among Children Born Extremely Preterm a Higher Level of Circulating Neurotrophins Is Associated with Lower Risk of Cognitive Impairment at School Age

Objectives To test the hypothesis that higher blood levels of neurotrophic proteins (proteins that support neuronal survival and function) in the first 2 weeks of life are associated with a lower risk of cognitive impairment at 10 years. Study design We evaluated 812 10‐year‐old children with neonatal blood specimens enrolled in the multicenter prospective Extremely Low Gestational Age Newborn Study, assessing 22 blood proteins collected on 3 days over the first 2 weeks of life. Using latent profile analysis, we derived a cognitive function level based on standardized cognitive and executive function tests. We defined high exposure as the top quartile neurotrophic protein blood level on ≥2 days either for ≥4 proteins or for a specific cluster of neurotrophic proteins (defined by latent class analysis). Multinomial logistic regression analyzed associations between high exposures and cognitive impairment. Results Controlling for the effects of inflammatory proteins, persistently elevated blood levels of ≥4 neurotrophic proteins were associated with reduced risk of moderate (OR, 0.35; 95% CI, 0.18‐0.67) and severe cognitive impairment (OR, 0.22; 95% CI, 0.09‐0.53). Children with a cluster of elevated proteins including angiopoietin 1, brain‐derived neurotrophic factor, and regulated upon activation, normal T‐cell expressed, and secreted had a reduced risk of adverse cognitive outcomes (OR range, 0.31‐0.6). The risk for moderate to severe cognitive impairment was least with 0‐1 inflammatory and >4 neurotrophic proteins. Conclusions Persisting elevations of circulating neurotrophic proteins during the first 2 weeks of life are associated with lowered risk of impaired cognition at 10 years of age, controlling for increases in inflammatory proteins.