Neonatal Cranial Ultrasound Findings among Infants Born Extremely Preterm: Associations with Neurodevelopmental Outcomes at 10 Years of Age.

OBJECTIVE: To examine the association between neonatal cranial ultrasound (CUS) abnormalities among infants born extremely preterm and neurodevelopmental outcomes at 10 years of age. STUDY DESIGN: In a multicenter birth cohort of infants born at <28 weeks of gestation, 889 of 1198 survivors were evaluated for neurologic, cognitive, and behavioral outcomes at 10 years of age. Sonographic markers of white matter damage (WMD) included echolucencies in the brain parenchyma and moderate to severe ventricular enlargement. Neonatal CUS findings were classified as intraventricular hemorrhage (IVH) without WMD, IVH with WMD, WMD without IVH, and neither IVH nor WMD. RESULTS: WMD without IVH was associated with an increased risk of cognitive impairment (OR 3.5, 95% CI 1.7, 7.4), cerebral palsy (OR 14.3, 95% CI 6.5, 31.5), and epilepsy (OR 6.9; 95% CI 2.9, 16.8). Similar associations were found for WMD accompanied by IVH. Isolated IVH was not significantly associated these outcomes. CONCLUSIONS: Among children born extremely preterm, CUS abnormalities, particularly those indicative of WMD, are predictive of neurodevelopmental impairments at 10 years of age. The strongest associations were found with cerebral palsy.

Neurocognitive and Health Correlates of Overweight and Obesity among Ten-Year-Old Children Born Extremely Preterm.

OBJECTIVE: To assess the relationship between overweight (body mass index [BMI] percentile ≥85 and <95) and obesity (BMI ≥95 percentile) and developmental and health outcomes at 10 years of age in a cohort of individuals born extremely preterm. STUDY DESIGN: This was an observational cohort study of children born extremely preterm and then assessed at age 10 years for neurocognitive function and parent-reported behavior and health outcomes. Participants included 871 children aged 10 years. To describe the strength of association between overweight or obesity and outcomes, we used logistic regression models adjusting for confounders. Neurocognitive function, academic achievement, parent-reported health outcome surveys, and height and weight were measured. RESULTS: BMI category at 10 years of age was not associated with differences in intelligence, language, or academic achievement. Parents of children with obesity were more likely to report their child had asthma (OR 2.2; 95% CI 1.4-3.5), fair/poor general health (OR 3.2; 95% CI 1.4-7.5), and decreased physical function (OR 1.7; 95% CI 1.1-2.9) but less likely to have physician diagnosed attention-deficit/hyperactivity disorder (OR 0.5; 95% CI 0.3-0.97) or an individualized education plan (OR 0.6; 95% CI 0.4-0.99). CONCLUSION: Among children born extremely preterm, an elevated BMI, compared with normal or low BMI, is not associated with a difference in neurocognitive function. However, asthma, fair/poor general health, and decreased physical function were more prevalent among study participants with obesity, and attention-deficit/hyperactivity disorder and individualized education plan were less prevalent.

Hand Preference and Cognitive, Motor, and Behavioral Functioning in 10-Year-Old Extremely Preterm Children.

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.

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.

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.

Predictive Validity of the Modified Checklist for Autism in Toddlers (M-CHAT) Born Very Preterm.

OBJECTIVE: To examine the predictive validity of the Modified Checklist for Autism in Toddlers (M-CHAT) administered at age 24 months for autism spectrum disorder (ASD) diagnosed at 10 years of age in a US cohort of 827 extremely low gestational age newborns (ELGANs) followed from birth. STUDY DESIGN: We examined the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the M-CHAT in predicting an ASD diagnosis at age 10 years based on gold standard diagnostic instruments. We then assessed how these predictive parameters were affected by sensorimotor and cognitive impairments, socioeconomic status (SES), and emotional/behavioral dysregulation at age 2 years. RESULTS: Using standard criteria, the M-CHAT had a sensitivity of 52%, a specificity of 84%, a PPV of 20%, and an NPV of 96%. False-positive and false-negative rates were high among children with hearing and vision impairments. High false-positive rates also were associated with lower SES, motor and cognitive impairments, and emotional/behavioral dysregulation at age 2 years. CONCLUSIONS: Among extremely preterm children with ASD, almost one-half were not correctly screened by the M-CHAT at age 2 years. Sensorimotor and cognitive impairments, SES, and emotional/behavioral dysregulation contributed significantly to M-CHAT misclassifications. Clinicians are advised to consider these factors when screening very preterm toddlers for ASD.

Girls and Boys Born before 28 Weeks Gestation: Risks of Cognitive, Behavioral, and Neurologic Outcomes at Age 10 Years.

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.

Weight Status in the First 2 Years of Life and Neurodevelopmental Impairment in Extremely Low Gestational Age Newborns.

OBJECTIVE: To examine the extent to which weight gain and weight status in the first 2 years of life relate to the risk of neurodevelopmental impairment in extremely preterm infants. STUDY DESIGN: In a cohort of 1070 infants born between 23 and 27 weeks' gestation, we examined weight gain from 7-28 days of life (in quartiles) and weight z-score at 12 and 24 months corrected age (in 4 categories: <-2; ≥-2, <-1; ≥1, <1; and ≥1) in relation to these adverse neurodevelopmental outcomes: Bayley-II mental development index <55, Bayley-II psychomotor development index <55, cerebral palsy, Gross Motor Function Classification System ≥1 (cannot walk without assistance), microcephaly. We adjusted for confounders in logistic regression, stratified by sex, and performed separate analyses including the entire sample, and excluding children unable to walk without assistance (motor impairment). RESULTS: Weight gain in the lowest quartile from 7-28 days was not associated with higher risk of adverse outcomes. Children with a 12-month weight z-score <-2 were at increased risk for all adverse outcomes in girls, and for microcephaly and Gross Motor Function Classification System ≥1 in boys. However, excluding children with motor impairment attenuated all associations except that of weight z-score <-2 with microcephaly in girls. Similarly, most associations of low weight z-score at 24 months with adverse outcomes were attenuated with exclusion of children with motor impairment. CONCLUSION: Excluding children who have gross motor impairment appears to eliminate the association of low weight status with neurodevelopmental impairments at 2 years in extremely preterm infants.

Antenatal and early postnatal antecedents of parent-reported attention problems at 2 years of age.

OBJECTIVES: To assess antenatal and early postnatal antecedents of attention problems identified by the Child Behavior Checklist in extremely preterm children. STUDY DESIGN: In a cohort of 826 children born between 23 and 27 weeks' gestation, we collected demographic, birth, and postnatal information. We then identified behavior problems by using parent ratings from the Child Behavior Checklist at 2 years' adjusted age. We created time-oriented logistic regression risk models to identify significant risk factors for attention problems and Diagnostic and Statistical Manual of Mental Disorders-compatible attention deficit/hyperactivity problems (ADHP(DSM)). RESULTS: Children were at increased risk of both attention problems if they were born to a woman who had no formal education beyond high school and/or a woman who was exposed to secondhand smoke. Recovery of a single organism from the placenta was associated with increased risk of an attention problem, and fetal stem vessel thrombosis and recovery of Mycoplasma species were associated with increased risk of ADHP(DSM). Infants of multifetal gestations were at reduced risk of both attention problems. The only postnatal risk factor for an attention problem was recovery of bacteria from a tracheal aspirate. CONCLUSION: Among extremely preterm infants, several potentially modifiable antenatal and perinatal antecedents are associated with increased risk for attention problems and ADHP(DSM) at 2 years adjusted age.

Comparison of frozen and unfrozen blood spots for gene expression studies.

We studied gene expression in 9 sets of paired newborn blood spots stored for 8-10 years in either the frozen state or the unfrozen state. Fewer genes were expressed in unfrozen spots, but the average correlation coefficient for overall gene expression comparing the frozen and unfrozen state was 0.771 (95% CI, 0.700-0.828).

Candidate gene analysis: severe intraventricular hemorrhage in inborn preterm neonates.

Intraventricular hemorrhage (IVH) is a disorder of complex etiology. We analyzed genotypes for 7 genes from 224 inborn preterm neonates treated with antenatal steroids and grade 3-4 IVH and 389 matched controls. Only methylenetetrahydrofolate reductase was more prevalent in cases of IVH, emphasizing the need for more comprehensive genetic strategies.

Elevated concentrations of inflammation-related proteins in postnatal blood predict severe developmental delay at 2 years of age in extremely preterm infants.

OBJECTIVE: To evaluate the hypothesis that elevated levels of inflammation-related proteins in early postnatal blood predict impaired mental and motor development in extremely preterm infants. STUDY DESIGN: We measured concentrations of 25 inflammation-related proteins in blood collected on postnatal days 1, 7, and 14 from 939 infants born before 28 weeks gestation. An elevated level was defined as a concentration in the highest quartile for gestational age and day of blood collection. We identified impaired development at age 24 months using the Bayley Scales of Infant Development, Second Edition. The primary outcomes were scores on the Mental Scale or the Motor Scale of <55 (more than 3 SDs below the mean). RESULTS: For 17 of the 25 inflammation-related proteins, 1 or more statistically significant associations (P<.01) was found between an elevated blood level of the protein and a developmental impairment. Elevations on multiple days were more often associated with developmental impairment than were elevations present for only 1 day. The highest number of predictive elevations was found in day-14 blood. CONCLUSION: In extremely preterm infants, elevated levels of inflammation-related proteins in blood collected on postnatal days 7 and 14, especially when sustained, are associated with impaired mental and motor development at age 2 years.

The relationship between early concentrations of 25 blood proteins and cerebral white matter injury in preterm newborns: the ELGAN study.

OBJECTIVE: To evaluate whether concentrations of inflammation-related proteins are elevated in the blood of preterm newborns who develop cerebral white matter damage. STUDY DESIGN: We measured 25 proteins in blood collected on days 1, 7, and 14 from 939 infants born before the 28th week of gestation. Brain ultrasound scans were read by at least two sonologists, who agreed on the presence or absence of lesions. A protein concentration was considered elevated if it was in the highest quartile for gestational age and the day on which the specimen was collected. RESULTS: In time-oriented models, elevated concentrations of vascular endothelial growth factor receptor 1, serum amyloid A, and macrophage inflammatory protein 1ß on day 1 and interleukin-8 on day 7 were associated with increased risk of ventriculomegaly. Elevated concentrations of macrophage inflammatory protein 1ß on day 1 and intercellular adhesion molecule 1 on day 7 were associated with increased risk of an echolucent lesion. Infants with elevated concentrations of inflammation-related proteins on two separate days were at significantly increased risk for ventriculomegaly, but at only modestly increased risk for an echolucent lesion. CONCLUSIONS: Concentrations of inflammation-related proteins in the circulation in the first days after preterm birth provide information about the risk of sonographic white matter damage. The inflammatory process might begin in utero.

Neurodevelopment of extremely preterm infants who had necrotizing enterocolitis with or without late bacteremia.

OBJECTIVE: To evaluate neurodevelopment after necrotizing enterocolitis (NEC) and late bacteremia, alone and together. STUDY DESIGN: Sample included 1155 infants born at 23 to 27 weeks' gestation. NEC was classified by the modified Bell's staging criteria and grouped as medical NEC or surgical NEC. Late bacteremia was defined as a positive blood culture result after the first postnatal week. Neurodevelopment was assessed at 24 months corrected age. Multivariable models estimated the risk of developmental dysfunction and microcephaly associated with medical or surgical NEC with and without late bacteremia. RESULTS: Children who had surgical NEC unaccompanied by late bacteremia were at increased risk of psychomotor developmental indexes <70 (OR = 2.7 [1.2, 6.4]), and children who had both surgical NEC and late bacteremia were at increased risk of diparetic cerebral palsy (OR = 8.4 [1.9, 39]) and microcephaly (OR = 9.3 [2.2, 40]). In contrast, children who had medical NEC with or without late bacteremia were not at increased risk of any developmental dysfunction. CONCLUSION: The risk of neurodevelopmental dysfunction and microcephaly is increased in children who had surgical NEC, especially if they also had late bacteremia. These observations support the hypothesis that bowel injury might initiate systemic inflammation potentially affecting the developing brain.

Developmental correlates of head circumference at birth and two years in a cohort of extremely low gestational age newborns.

OBJECTIVES: To evaluate the developmental correlates of microcephaly evident at birth and at 2 years in a cohort born at extremely low gestational age. METHODS: We assessed development and motor function at 2 years of 958 children born before the 28th week of gestation, comparing those who had microcephaly at birth or 2 years with children with normal head circumference while considering the contribution of neonatal cranial ultrasound lesions. RESULTS: A total of 11% of infants in our sample had microcephaly at 2 years. Microcephaly at 2 years, but not at birth, predicts severe motor and cognitive impairments at 2 years. A total of 71% of children with congenital microcephaly had a normal head circumference at 2 years and had neurodevelopmental outcomes comparable with those with normal head circumference at birth and 2 years. Among children with microcephaly at 2 years, more than half had a Mental Developmental Index <70, and nearly a third had cerebral palsy. The risks were increased if the child also had cerebral white matter damage on a cranial ultrasound scan obtained 2 years previously. CONCLUSION: Among extremely low gestational age newborns, microcephaly at 2 years, but not at birth, is associated with motor and cognitive impairment at age 2.

Positive screening on the Modified Checklist for Autism in Toddlers (M-CHAT) in extremely low gestational age newborns.

OBJECTIVE: To test the hypothesis that children born preterm are more likely to screen positive on the M-CHAT for an autism spectrum disorder. STUDY DESIGN: We compared the M-CHAT positive rate of those with cerebral palsy, cognitive impairment, and vision and hearing impairments to those without such deficits. RESULTS: Relative to children who could walk, the odds for screening positive on the M-CHAT were increased 23-fold for those unable to sit or stand independently and more than 7-fold for those requiring assistance to walk. Compared with children without a diagnosis of cerebral palsy, those with quadriparesis were 13 times more likely to screen positive, and those with hemiparesis were 4 times more likely to screen positive. Children with major vision or hearing impairments were 8 times more likely to screen positive than those without such impairments. Relative to those with a Mental Development Index (MDI) of >70, the odds for screening positive were increased 13-fold for those with an MDI of <55 and more than 4-fold for those with an MDI of 55 to 69. CONCLUSIONS: Major motor, cognitive, visual, and hearing impairments appear to account for more than half of the positive M-CHAT screens in extremely low gestational age newborns. Even after those with such impairments were eliminated, 10% of children--nearly double the expected rate--screened positive.

An algorithm for identifying and classifying cerebral palsy in young children.

OBJECTIVE: To develop an algorithm on the basis of data obtained with a reliable, standardized neurological examination and report the prevalence of cerebral palsy (CP) subtypes (diparesis, hemiparesis, and quadriparesis) in a cohort of 2-year-old children born before 28 weeks gestation. STUDY DESIGN: We compared children with CP subtypes on extent of handicap and frequency of microcephaly, cognitive impairment, and screening positive for autism. RESULTS: Of the 1056 children examined, 11.4% (120) were given an algorithm-based classification of CP. Of these children, 31% had diparesis, 17% had hemiparesis, and 52% had quadriparesis. Children with quadriparesis were 9 times more likely than children with diparesis (76% versus 8%) to be more highly impaired and 5 times more likely than children with diparesis to be microcephalic (43% versus 8%). They were more than twice as likely as children with diparesis to have a score <70 on the mental scale of the BSID-II (75% versus 34%) and had the highest rate of the Modified Checklist for Autism in Toddlers positivity (76%) compared with children with diparesis (30%) and children without CP (18%). CONCLUSION: We developed an algorithm that classifies CP subtypes, which should permit comparison among studies. Extent of gross motor dysfunction and rates of co-morbidities are highest in children with quadriparesis and lowest in children with diparesis.

Chorioamnionitis, mechanical ventilation, and postnatal sepsis as modulators of chronic lung disease in preterm infants.

OBJECTIVE: This case-control study of chronic lung disease (CLD) evaluated the hypothesis that chorioamnionitis promotes CLD and interacts with other risk factors for CLD, including mechanical ventilation and postnatal infection. STUDY DESIGN: We identified a population of 193 infants who met our case criteria for CLD whose birth weights were 7 days and culture-documented sepsis. In multivariable analyses, infants were at greatest risk for CLD when they had exposure to both chorioamnionitis and either mechanical ventilation >7 days (odds ratio, 3.2; 95% confidence interval, 0.9-11) or postnatal infection (odds ratio, 2.9; 95% confidence interval, 1.1-7.4). CONCLUSIONS: We conclude that prolonged mechanical ventilation or postnatal infection increases the risk of CLD among surviving preterm infants and that these 2 factors interact with antenatal infection to further increase the risk of CLD.