Antecedents of epilepsy and seizures among children born at extremely low gestational age.

OBJECTIVE: To identify specific risk factors for epilepsy for individuals born extremely preterm. STUDY DESIGN: In a prospective cohort study, at 10-year follow-up, children were classified as having epilepsy or seizures not associated with epilepsy. We evaluated for association of perinatal factors using time-oriented, multinomial logistic regression models. RESULTS: Of the 888 children included in the study, 66 had epilepsy and 39 had seizures not associated with epilepsy. Epilepsy was associated with an indicator of low socioeconomic status, maternal gestational fever, early physiologic instability, postnatal exposure to hydrocortisone, cerebral white matter disease and severe bronchopulmonary dysplasia. Seizure without epilepsy was associated with indicators of placental infection and inflammation, and hypoxemia during the first 24 postnatal hours. CONCLUSIONS: In children born extremely preterm, epilepsy and seizures not associated with epilepsy have different risk profiles. Though both profiles included indicators of infection and inflammation, the profile of risk factors for epilepsy included multiple indicators of endogenous vulnerability.

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.

Elevated endogenous erythropoietin concentrations are associated with increased risk of brain damage in extremely preterm neonates.

BACKGROUND: We sought to determine, in very preterm infants, whether elevated perinatal erythropoietin (EPO) concentrations are associated with increased risks of indicators of brain damage, and whether this risk differs by the co-occurrence or absence of intermittent or sustained systemic inflammation (ISSI). METHODS: Protein concentrations were measured in blood collected from 786 infants born before the 28th week of gestation. EPO was measured on postnatal day 14, and 25 inflammation-related proteins were measured weekly during the first 2 postnatal weeks. We defined ISSI as a concentration in the top quartile of each of 25 inflammation-related proteins on two separate days a week apart. Hypererythropoietinemia (hyperEPO) was defined as the highest quartile for gestational age on postnatal day 14. Using logistic regression and multinomial logistic regression models, we compared risks of brain damage among neonates with hyperEPO only, ISSI only, and hyperEPO+ISSI, to those who had neither hyperEPO nor ISSI, adjusting for gestational age. RESULTS: Newborns with hyperEPO, regardless of ISSI, were more than twice as likely as those without to have very low (< 55) Mental (OR 2.3; 95% CI 1.5-3.5) and/or Psychomotor (OR 2.4; 95% CI 1.6-3.7) Development Indices (MDI, PDI), and microcephaly at age two years (OR 2.4; 95%CI 1.5-3.8). Newborns with both hyperEPO and ISSI had significantly increased risks of ventriculomegaly, hemiparetic cerebral palsy, microcephaly, and MDI and PDI < 55 (ORs ranged from 2.2-6.3), but not hypoechoic lesions or other forms of cerebral palsy, relative to newborns with neither hyperEPO nor ISSI. CONCLUSION: hyperEPO, regardless of ISSI, is associated with elevated risks of very low MDI and PDI, and microcephaly, but not with any form of cerebral palsy. Children with both hyperEPO and ISSI are at higher risk than others of very low MDI and PDI, ventriculomegaly, hemiparetic cerebral palsy, and microcephaly.

Endogenous erythropoietin varies significantly with inflammation-related proteins in extremely premature newborns.

INTRODUCTION: Erythropoietin, a pluripotent glycoprotein essential for erythropoiesis, fetal growth, and development, has recently been implicated in innate immune regulation. Data from the ELGAN Study allowed us to evaluate relationships between endogenous erythropoietin and 25 inflammation-related proteins in extremely premature newborns. METHODS: We measured the concentrations of 25 inflammation-related proteins and of erythropoietin in blood spots collected on postnatal days 1, 7, and 14 from 936 infants born before 28 weeks gestation. We calculated the odds that infants with an inflammation-related protein in the highest quartile for gestational age and collection day had an erythropoietin concentration in the highest or lowest quartile. RESULTS: The proportion of children with inflammation-associated protein concentrations in the top quartile tended to increase monotonically with increasing quartile of EPO concentrations on 2 of the 3 days assessed. To a large extent, on each of the 3 days assessed, the odds ratios for an erythropoietin concentration in the top quartile were significantly elevated among those with an inflammation-related protein concentration in the top quartile. CONCLUSIONS: Our findings suggest that in very preterm newborns, circulating levels of endogenous erythropoietin vary significantly with circulating levels of inflammation-related proteins. Elevation of endogenous erythropoietin might not be an epiphenomenon, but instead might contribute to subsequent events, by either promoting or reducing inflammation, or by promoting an anti-injury or repair capability.

Systemic inflammation, intraventricular hemorrhage, and white matter injury.

To see if the systemic inflammation profile of 123 infants born before the 28th week of gestation who had intraventricular hemorrhage without white matter injury differed from that of 68 peers who had both lesions, we compared both groups to 677 peers who had neither. Cranial ultrasound scans were read independently by multiple readers until concordance. The concentrations of 25 proteins were measured with multiplex arrays using an electrochemiluminescence system. Infants who had both hemorrhage and white matter injury were more likely than others to have elevated concentrations of C-reactive protein and interleukin 8 on days 1, 7, and 14, and elevated concentrations of serum amyloid A and tumor necrosis factor-α on 2 of these days. Intraventricular hemorrhage should probably be viewed as 2 entities: hemorrhage alone and hemorrhage with white matter injury. Each entity is associated with inflammation, but the combination has a stronger inflammatory signal than hemorrhage alone.

Exploring modifiable risk factors for wheezing in African American premature infants.

OBJECTIVE: To examine the degree to which obesity during infancy, consistent exposure to secondhand smoke, and parenting (positive attention, maternal involvement, and negative control) were related to early development of wheezing in a cohort of African American premature infants at 2, 6, 12, 18, and 24 months corrected age. DESIGN: Secondary analysis of a subset of variables from a larger nursing support intervention study. SETTING: Two regional perinatal centers in the southeastern United States. PARTICIPANTS: One hundred and sixty-eight African American premature infants (70 boys, 98 girls) who weighed less than 1,750 g or required mechanical ventilation and their mothers. METHODS: The presence of wheezing was obtained from maternal report at 2, 6, 12, 18, and 24 months. Infants were considered to have medically significant wheezing if they were using bronchodilators or pulmonary anti-inflammatory medications. RESULTS: The percentage of infants who had medically significant wheezing increased from 12% at 2 months to 24% at 24 months corrected age. Infants who received more positive attention from their mothers had a slightly higher increase in the probability of developing wheezing over time. Infants of mothers who received public assistance had an increased probability of wheezing. Consistent exposure to secondhand smoke, obesity during infancy, maternal negative control, and maternal involvement were not related to the development of wheezing. CONCLUSION: These findings suggest that the likelihood of developing wheezing in African American premature infants is associated with receiving more positive attention from their mothers and having mothers who receive public assistance. Because modifiable risk factors were not highly related to wheezing, intervention efforts need to focus on early identification and treatment of wheezing and asthma-related symptoms.

Early postnatal hypotension and developmental delay at 24 months of age among extremely low gestational age newborns.

OBJECTIVES: To evaluate in extremely low gestational age newborns, relationships between indicators of hypotension during the first 24 postnatal hours and developmental delay at 24 months of age. METHODS: The 945 infants in this prospective study were born at <28 weeks, were assessed for three indicators of hypotension in the first 24 postnatal hours, and were evaluated with the Bayley Mental Development Index (MDI) and Psychomotor Development Index (PDI) at 24 months corrected age. Indicators of hypotension included: (1) mean arterial pressure in the lowest quartile for gestational age; (2) treatment with a vasopressor; and (3) blood pressure lability, defined as the upper quartile for the difference between the lowest and highest mean arterial pressure. Logistic regression was used to evaluate relationships between hypotension and developmental outcomes, adjusting for potential confounders. RESULTS: 78% of infants in this cohort received volume expansion or vasopressor; all who received a vasopressor were treated with volume expansion. 26% had an MDI <70 and 32% had a PDI <70. Low MDI and PDI were associated with low gestational age, which in turn, was associated with receipt of vasopressor treatment. Blood pressure in the lowest quartile for gestational age was associated with vasopressor treatment and labile blood pressure. After adjusting for potential confounders, none of the indicators of hypotension were associated with MDI <70 or PDI <70. CONCLUSIONS: In this large cohort of extremely low gestational age newborns, we found little evidence that early postnatal hypotension indicators are associated with developmental delay at 24 months corrected gestational age.

Effects of secondhand smoke exposure on the health and development of african american premature infants.

Objective. To explore the effects of secondhand smoke exposure on growth, health-related illness, and child development in rural African American premature infants through 24 months corrected age. Method. 171 premature infants (72 boys, 99 girls) of African American mothers with a mean birthweight of 1114 grams. Mothers reported on household smoking and infant health at 2, 6, 12, 18, and 24 months corrected age. Infant growth was measured at 6, 12, 18, and 24 months, and developmental assessments were conducted at 12 and 24 months. Results. Thirty percent of infants were exposed to secondhand smoke within their first 2 years of life. Secondhand smoke exposure was associated with poorer growth of head circumference and the development of otitis media at 2 months corrected age. Height, weight, wheezing, and child development were not related to secondhand smoke exposure. Conclusion. Exposure to secondhand smoke may negatively impact health of rural African American premature infants. Interventions targeted at reducing exposure could potentially improve infant outcomes.

The clustering of disorders in infants born before the 28th week of gestation.

AIM: To see whether disorders prevalent in infants born extremely preterm cluster. DESIGN: Observational cohort study. SETTING: University-affiliated newborn intensive care nurseries. SUBJECTS: One thousand two hundred and twenty-three infants born before the 28th week of gestation who survived until 36 weeks postmenstrual age when the diagnosis of bronchopulmonary dysplasia (BPD) could be made. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Cerebral white matter damage (an echolucent lesion, or moderate or severe ventriculomegaly on a protocol cranial ultrasound scan), BPD, retinopathy of prematurity (ROP), necrotizing enterocolitis (NEC) and early and late bacteremia. RESULTS: After adjustment for gestational age, children who had severe NEC (Bell stage IIIb) were at increased risk of cerebral white matter damage, severe ROP (stage 3+), and severe BPD (defined as both oxygen and ventilator dependent). Children who had early bacteremia were at increased risk of late bacteremia and severe ROP. Those who had severe ROP were at increased risk of severe BPD and both early and late bacteremia. CONCLUSIONS: Necrotizing enterocolitis is the disorder common to most of the clusters, but we do not know if its onset occurred before the others. Organ-damage-promoting substances, however, have been found in the circulation of newborn animals with bowel inflammation, supporting the view that NEC contributes to the damage of other organs.

Patterns of distress in African-American mothers of preterm infants.

OBJECTIVE: To examine inter-relationships among stress due to infant appearance and behavior in the neonatal intensive care unit (NICU), parental role alteration stress in the NICU, depressive symptoms, state anxiety, posttraumatic stress symptoms, and daily hassles exhibited by African-American mothers of preterm infants and to determine whether there were subgroups of mothers based on patterns of psychological distress. METHOD: One hundred seventy-seven African-American mothers completed questionnaires on their psychological distress at enrollment during infant hospitalization and 2, 6, 12, 18, and 24 months after term. RESULTS: Psychological distress measures were intercorrelated. There were four latent classes of mothers: the low distress class with low scores on all measures; the high NICU-related stress class with high infant appearance and parental role stress and moderate scores on other measures; the high depressive symptoms class with high depressive symptoms and state anxiety and moderately elevated scores on NICU-related stress and posttraumatic stress symptoms; the extreme distress class with the highest means on all measures. Infants in the high stress class were sicker than infants in the other classes. The extreme distress class mothers averaged the lowest educational level. The classes differed on distress measures, worry about the child, and parenting stress through 24 months with the extreme distress class having the highest values. CONCLUSION: Although different types of maternal psychological distress were substantially related, there were distinct subgroups of mothers that were identifiable in the NICU. Moreover, these subgroups continued to differ on trajectories of distress and on their perceptions of the infants and parenting through 24 months after term.