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OBJECTIVES: To examine elevated neonatal inflammatory and neurotrophic proteins from children born extremely preterm in relation to later childhood brain Magnetic Resonance Imaging volumes and cognition. STUDY DESIGN: We measured circulating inflammation-related proteins and neurotrophic proteins on postnatal days 1, 7, and 14 in 166 children at 10 years of age (73 males; 93 females). Top quartile levels on ≥2 days for ≥3 inflammation-related proteins and for ≥4 neurotrophic proteins defined exposure. We examined associations among protein levels, brain Magnetic Resonance Imaging volumes, and cognition with multiple linear and logistic regressions. RESULTS: Analyses were adjusted for gestational age at birth and sex. Children with ≥3 elevated inflammation-related proteins had smaller grey matter, brain stem/cerebellar, and total brain volumes than those without elevated inflammation-related proteins, adjusted for neurotrophic proteins. When adjusted for inflammation-related proteins, children with ≥4 neurotrophic proteins, compared with children with no neurotrophic proteins, had larger grey matter and total brain volumes. Higher grey matter, white matter, and cerebellum and brainstem volumes were significantly correlated with higher IQ. Grey and white matter volumes were correlated with each other (r = −0.18; P = .021), and cerebellum and brainstem was highly correlated with grey matter (r = 0.55; P < .001) and white matter (r = 0.29; P < .001). Adjusting for other brain compartments, cerebellum and brainstem was associated with IQ (P = .016), but the association with white matter was marginally significant (P = .051). Grey matter was not associated with IQ. After adjusting for brain volumes, elevated inflammation-related proteins remained significantly associated with a lower IQ, and elevated neurotrophic proteins remained associated with a higher IQ. CONCLUSIONS: Newborn inflammatory and neurotrophin protein levels are associated with later brain volumes and cognition, but their effects on cognition are not entirely explained by altered brain volumes.

Objective To assess appropriate pantoprazole dosing for obese children, we conducted a prospective pharmacokinetics (PK) investigation of pantoprazole in obese children, a patient population that is traditionally excluded from clinical trials. Study design A total of 41 obese children (6-17 years of age), genotyped for CYP2C19 variants * 2, * 3, * 4, and * 17, received a single oral dose of pantoprazole, ~1.2 mg/kg lean body weight (LBW), with LBW calculated via a validated formula. Ten post-dose pantoprazole plasma concentrations were measured, and PK variables generated via noncompartmental methods (WinNonlin). Linear and nonlinear regression analyses and analyses of variance were used to explore obesity, age, and CYP2C19 genotype contribution to pantoprazole PK. PK variables of interest were compared with historic nonobese peers treated with pantoprazole. Results Independent of genotype, when normalized to dose per kg total body weight, pantoprazole apparent clearance and apparent volume of distribution were significantly lower ( P P Conclusions LBW dosing of pantoprazole led to pantoprazole PK similar to nonobese peers. Additional factors, other than body size (eg, age-related changes in CYP2C19 activity), appear to affect pantoprazole PK in children Trial registration ClinicalTrials.gov : NCT02186652

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 parent's report differed from the risk profile based on the teacher's 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 association of hand preference (left, mixed, and right) with cognitive, academic, motor, and behavioral function was evaluated in 864 extremely preterm children at 10 years of age. Left-handed and right-handed children performed similarly but mixed-handed children had greater odds of functional deficits across domains than right-handed children.

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.Neurocognitive function was evaluated at 10 years of age in 889 children born at28 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.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.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.

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.

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.We sought to identify perinatal factors associated with increased risk for autism spectrum disorder with and without intellectual disability (intelligence quotient70) in children born extremely preterm.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+).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).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.

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.

Placement of peripheral pediatric intravenous (IV) catheters in infants and children is difficult, even in skilled hands. This large, 2-institution prospective study used real-time independent observations to describe the effect of nurse experience and competence on the length of time and the number of attempts to establish a successful IV placement in the hospitalized child. Data from a convenience sample of 592 evaluable patients and 1135 venipunctures showed that successful IV placements required an average of 2 venipunctures over 28 minutes. Although nurse experience and self-rated competence were correlated with attaining a successful IV placement, time of day, predicted difficulty of the venipuncture, and cooperativeness of the child appeared to be better predictors of success.

Objectives To compare the prevalence of cognitive, neurologic, and behavioral outcomes at 10 years of age in 428 girls and 446 boys who were born extremely preterm. Study design A total of 889 of 966 eligible children previously enrolled in the multicenter Extremely Low Gestational Age Newborns Study from 2002-2004 were evaluated at 10 years of age. Children underwent a neuropsychological battery and testing for autism spectrum disorder (ASD), and parents reported on their child's behavior, development, and seizures. Results Of the children, 28% of boys and 21% of girls exhibited moderate to severe impairment on summary measures of cognitive abilities. Boys had a higher prevalence of impairment than girls in nearly all measures of cognition, were more than twice as likely to have microcephaly (15% in boys, 8% in girls), and require more often assistive devices to ambulate (6% in boys, 4% in girls). In contrast, boys and girls had comparable risk for a history of seizure (identified in 10% of the cohort) or epilepsy (identified in 7% of the cohort). The boy-to-girl ratio of ASD (9% in boys, 5% in girls) was lower than expected compared with the overall US autism population. Conclusions In this contemporary cohort of children born extremely premature and evaluated at school age, boys had higher prevalence of cognitive, neurologic, and behavioral deficits than girls. The ratio of boys to girls among those with ASD deserves further study as does the perinatal environmental-genetic interactions that might contribute to male preponderance of deficits in this high-risk sample.