BACKGROUND-High-dose erythropoietin has been shown to have a neuroprotective effect in preclinical models of neonatal brain injury, and phase 2 trials have suggested possible efficacy; however, the benefits and safety of this therapy in extremely preterm infants have not been established. METHODS-In this multicenter, randomized, double-blind trial of high-dose erythropoietin, we assigned 941 infants who were born at 24 weeks 0 days to 27 weeks 6 days of gestation to receive erythropoietin or placebo within 24 hours after birth.

We sought to estimate the prevalence of autism spectrum disorder (ASD) in children born extremely preterm relative to the 1.5% risk of ASD in the general U.S. population. 889 of 966 (92%) 10-year-old children from the Extremely Low Gestational Age Newborn birth cohort, delivered at 23–27 weeks gestation in 2002–2004, participated. 26 participants were not assessed for ASD because their severe sensory or motor impairment prevented a valid assessment of ASD. In the remaining sample, 61 children met criteria for ASD, resulting in a prevalence of 7.1% (approximately 7 in 100 children). ASD risk decreased with increasing gestational age, from 15.0% for 23–24 weeks, 6.5% for 25–26 weeks, to 3.4% for 27 weeks gestational age. The association we found between children's ASD risk and lower gestational age was independent of IQ. Among children diagnosed with ASD, 40% had intellectual disability. The male-to-female ratio of children with ASD was approximately 2 to 1, lower than in the general population in which ASD is estimated to be 3 to 4 times more common in males. ASD prevalence in the ELGAN cohort was 4 times higher than in the general population, and was strongly associated with gestational age, underscoring the need for enhanced ASD screening of children born preterm, and suggesting that some risk factors associated with preterm birth may also play a causal role in ASD.

Background Extremely preterm birth is associated with subsequent behavioral problems. We hypothesized that perinatal systemic inflammation, a risk factor for cerebral white matter injury and cognitive impairment, is associated with behavior problems observed at 2 years. Methods In a cohort of 600 children born before 28 weeks gestation, we measured 25 inflammation-related proteins in blood collected on postnatal days 1, 7, and 14, and identified behavior problems using parent responses to the Child Behavior Checklist for Ages 1.5–5 (CBCL/1.5-5) at two years of age. A persistent or recurrent protein elevation was defined as a concentration in the highest quartile (for gestational age and postnatal age) on at least two days approximately one week apart. Behavior problems were defined by CBCL/1.5-5 subscale scores at or above the 93rd percentile. Results A single-day elevation of ICAM-3 was associated with an increased risk of an attention problem, as were persistent or recurrent elevations of MPO, IL-6, TNF-RI, IL-8, ICAM-3, VEGF-R1, and VEGF-R2. These associations persisted among infants without white matter injury and cognitive impairment. Conclusion Among children born extremely prematurely, recurrent or persistent elevations of inflammation-related proteins in blood during in the first two postnatal weeks are associated with an attention problem at age 2 years.

for the ELGAN Study Investigators abstract BACKGROUND AND OBJECTIVE: Despite reductions in mortality and morbidity among children born extremely preterm, they remain at high risk of neurocognitive deficits, with up to 40% having significant cognitive deficits at school age. We assessed the rate of neurocognitive impairment in a contemporary US cohort of 873 children aged 10 years who were born <28 weeks' gestation.

Aim: Sex-based differences in response to adverse prenatal environments and infant outcomes have been observed, yet the underlying mechanisms for this are unclear. The placental epigenome may be a driver of these differences. Methods: Placental DNA methylation was assessed at more than 480,000 CpG sites from male and female infants enrolled in the extremely low gestational age newborns cohort (ELGAN) and validated in a separate US-based cohort. The impact of gestational age on placental DNA methylation was further examined using the New Hampshire Birth Cohort Study for a total of n = 467 placentas. Results: A total of n = 2745 CpG sites, representing n = 587 genes, were identified as differentially methylated (p < 1 × 10 -7 ). The majority (n = 582 or 99%) of these were conserved among the New Hampshire Birth Cohort. The identified genes encode proteins related to immune function, growth/transcription factor signaling and transport across cell membranes. Conclusion: These data highlight sex-dependent epigenetic patterning in the placenta and provide insight into differences in infant outcomes and responses to the perinatal environment.

We hypothesized that the risk of brain damage in extremely preterm neonates increases with the breadth and type of systemic inflammation, indexed by the number of elevated inflammation-related proteins and the number of functional categories of inflammation-related proteins exhibiting an elevated concentration. Methods In blood from 881 infants born before 28 weeks gestation, we measured the concentrations of 25 inflammation-related proteins, representing 6 functional categories (cytokines, chemokines, growth factors, adhesion molecules, metalloproteinases, and liver-produced acute phase reactant proteins) on postnatal days 1, 7, and 14 and evaluated associations between the number and type of proteins whose concentrations were elevated on two separate occasions a week apart and the diagnoses of ventriculomegaly as a neonate, and, at 2 years, microcephaly, impaired early cognitive functioning, cerebral palsy, and autism risk as assessed with the Modified Checklist for Autism in Toddlers (M-CHAT) screen, and, in a subset of these children from 12 of 14 sites (n= 826), an attention problem identified with the Child Behavior Checklist (CBCL). Results The risk of abnormal brain structure and function overall was increased among children who had recurrent/persistent elevations of the 25 protein. The risk for most outcomes did not rise until at least four proteins in at least two functional categories were elevated. When we focused our analysis on 10 proteins previously found to be associated consistently with neurological outcomes, we found the risk of low Mental Development Index (MDI) on the Bayley Scales of Infant Development-II, microcephaly, and a CBCL-defined attention problem increased with higher numbers of these recurrently/persistently elevated proteins. Interpretation Increasing breadth of early neonatal inflammation, indexed by the number of protein elevations or the number of protein functional classes elevated, is associated with increasing risk of disorders of brain structure and function among infants born extremely premature.

Among children born extremely preterm, those with severe FGR appear to be at increased risk of multiple cognitive and behavioral dysfunctions at age 10 years, raising the possibility that whatever adversely affected their intrauterine growth also adversely affected multiple domains of cognitive and neurobehavioral development.

We hypothesized that among extremely preterm infants, elevated concentrations of inflammation-related proteins in neonatal blood are associated with cerebral palsy (CP) at 24 months. Methods In 939 infants born before 28 weeks gestation, we measured blood concentrations of 25 proteins on postnatal days 1, 7, and 14 and evaluated associations between elevated protein concentrations and CP diagnosis. Results Protein elevations within three days of birth were not associated with CP. Elevations of TNF-α, TNF-R1, IL-8, ICAM-1, on at least two days were associated with diparesis. Recurrent-persistent elevations of IL-6, E-SEL, or IGFBP-1 were associated with hemiparesis. Diparesis and hemiparesis were more likely among infants who had at least four of nine proteins elevations that previously have been associated with cognitive impairment and microcephaly. Interpretation Repeated elevations of inflammation-related proteins during the first two postnatal weeks are associated with increased risk of CP.