Stephen C. Engelke

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.

Cranial Ultrasound Lesions in the NICU Predict Cerebral Palsy at Age 2 Years in Children Born at Extremely Low Gestational Age

Our prospective cohort study of extremely low gestational age newborns evaluated the association of neonatal head ultrasound abnormalities with cerebral palsy at age 2 years. Cranial ultrasounds in 1053 infants were read with respect to intraventricular hemorrhage, ventriculomegaly, and echolucency, by multiple sonologists. Standardized neurological examinations classified cerebral palsy, and functional impairment was assessed. Forty-four percent with ventriculomegaly and 52% with echolucency developed cerebral palsy. Compared with no ultrasound abnormalities, children with echolucency were 24 times more likely to have quadriparesis and 29 times more likely to have hemiparesis. Children with ventriculomegaly were 17 times more likely to have quadriparesis or hemiparesis. Forty-three percent of children with cerebral palsy had normal head ultrasound. Focal white matter damage (echolucency) and diffuse damage (late ventriculomegaly) are associated with a high probability of cerebral palsy, especially quadriparesis. Nearly half the cerebral palsy identified at 2 years is not preceded by a neonatal brain ultrasound abnormality.

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.

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.

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.

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.

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.

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.

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.

Cerebrospinal Fluid Lactate Dehydrogenase in Neonatal Intracranial Hemorrhage

Cerebrospinal fluid (CSF) lactate dehydrogenase (LDH) was measured in 54 neonates with intracranial hemorrhage and compared with 82 control, 27 traumatic lumbar puncture, seven meningitis, and 30 asphyxiated newborns. Hospital data, neonatal outcomes, and long-term neurodevelopmental follow-up results were reviewed. CSF LDH was not significantly affected by traumatic lumbar puncture but was elevated in proportion to the severity of CNS hemorrhage as scored by computerized to mography. LDH was also significantly associated with subsequent seizures and hydrocephalus and abnormal long-term developmental outcome.