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People with diabetes can wear a device that measures blood glucose and delivers just the amount of insulin needed to return the glucose level to within bounds. Currently, people with epilepsy do not have access to an equivalent wearable device that measures a systemic indicator of an impending seizure and delivers a rapidly acting medication or other intervention (e.g., an electrical stimulus) to terminate or prevent a seizure. Given that seizure susceptibility is reliably increased in systemic inflammatory states, we propose a novel closed-loop device where release of a fast-acting therapy is governed by sensors that quantify the magnitude of systemic inflammation. Here, we review the evidence that patients with epilepsy have raised levels of systemic indicators of inflammation than controls, and that some anti-inflammatory drugs have reduced seizure occurrence in animals and humans. We then consider the options of what might be incorporated into a responsive anti-seizure system.

OBJECTIVE To determine the association between prenatal tobacco smoke exposure and neurological impairment at 10 years of age among children born extremely preterm (

OBJECTIVE: To examine the association between neonatal cranial ultrasound abnormalities among infants born extremely preterm and neurodevelopmental outcomes at ten years of age. STUDY DESIGN: In a multi-center birth cohort of infants born at < 28 weeks’ gestation, 889 of 1198 survivors were evaluated for neurological, 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 cranial ultrasound 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, cranial ultrasound abnormalities, particularly those indicative of WMD, are predictive of neurodevelopmental impairments at 10 years of age. The strongest associations were found with cerebral palsy.

Objective Infection of the placenta has been associated with preterm birth as well as neurocognitive impairment. This study aimed to determine whether specific bacterial species in the placenta of extremely preterm pregnancies are associated with neurological deficits later in life. Study Design Using data from 807 children in the ELGAN study the risks of a low score on six neurological assessments in relation to 15 different microbes were quantified with odds ratios. Results The presence of certain microbial species in the placenta was associated with lower scores on numerical and oral language assessments. Lactobacillus sp. was associated with decreased risk of a low oral language score and a composite measure of IQ and executive function. Conclusion Placental microorganisms were associated with neurocognitive, but not social-communicative, outcomes at age 10. In contrast, the presence of the anti-inflammatory Lactobacillus sp. in the placenta was associated with a lower risk of impaired neurocognitive functions.

Objective To evaluate to what extent indicators of placenta insufficiency are associated with low concentrations of insulin-like growth factor 1 (IGF-1) and IGF-1–binding protein-1 (IGFBP-1) in neonatal blood, and to what extent the concentrations of these growth factors are associated with concentrations of proteins with inflammatory, neurotrophic, or angiogenic properties. Study Design Using multiplex immunoassays, we measured the concentrations of IGF-1 and IGFBP-1, as well as 25 other proteins in blood spots collected weekly from ≥ 880 infants born before the 28th week of gestation, and sought correlates of concentrations in the top and bottom quartiles for gestational age and day the specimen was collected. Results Medically indicated delivery and severe fetal growth restriction (sFGR) were associated with low concentrations of IGF-1 on the first postnatal day and with high concentrations of IGFBP-1 on almost all days. Elevated concentrations of IGF-1 and IGFBP-1 were accompanied by elevated concentrations of many other proteins with inflammatory, neurotrophic, or angiogenic properties. Conclusion Disorders associated with impaired placenta implantation and sFGR appear to account for a relative paucity of IGF-1 on the first postnatal day. Elevated concentrations of IGF-1 and especially IGFBP-1 were associated with same-day elevated concentrations of inflammatory, neurotrophic, and angiogenic proteins.

INTRODUCTION: Few studies have examined the relationship between birth plurality and neurocognitive function among children born extremely preterm. STUDY DESIGN: We compared rates of Z-scores ≤ −2 on 18 tests of neurocognitive function and academic achievement at age 10 years in 245 children arising from twin pregnancies, 55 from triplet pregnancies, and 6 from a septuplet pregnancy to that of 568 singletons, all of whom were born before the 28th week of gestation. RESULTS: 874 children were evaluated at age 10-years. After adjusting for confounders, children of multifetal pregnancies performed significantly better on one of 6 subtests of executive function than their singleton peers. Performance was similar on all other assessments of intelligence, language, academic achievement, processing speed, visual perception, and fine motor skills. CONCLUSION: We found no evidence that children born of multifetal pregnancies had worse scores than their singleton peers on assessments of neurocognitive and academic function.

In 1962 a long-recognized pathologic abnormality in neonatal brains characterized by multiple telencephalic focal white matter necroses was renamed periventricular leukomalacia (PVL) and the authors inappropriately asserted that their entity was caused by anoxia. They also failed to include three other white matter histologic abnormalities. In this essay, we identify the breadth of white matter pathology, especially in very preterm newborns, and show that none of the four histologic expressions of white matter damage, including focal necrosis, are associated with hypoxemia or correlates as hypotension, but are instead associated with markers of fetal or perinatal inflammation, particularly in preterm babies. We begin with the background needed to evaluate the evidence.

OBJECTIVE: To see to what extent executive function limitations at age 10 years among children born extremely preterm (EP) are associated with blood levels of inflammatory and neurotrophic proteins during the first postnatal month. DESIGN: Longitudinal cohort SETTING: Children were enrolled shortly before or after birth. SUBJECTS: 692 children born before the 28(th) week of gestation who had an IQ ≥ 70 at age 10 years. EXPOSURES: Blood concentrations during the first four weeks of proteins with inflammatory and neurotrophic properties. MAIN OUTCOME MEASURES: Z-scores ≤ −1 on the Differential Ability Scales–II working memory (WM) assessment) (N=164), the NEPSY-II (A Developmental NEuroPSYchological Assessment-II) Inhibition-Inhibition assessment) (N=350), the NEPSY-II Inhibition-Switching assessment) (N=345), as well as a Zscore ≤ −1 on all three assessments (identified as the executive dysfunction composite (EDC) (N=104). RESULTS: Increased risks of the EDC associated with high concentrations of inflammatory proteins (IL-8, TNF-α, and ICAM-1) were modulated by high concentrations of neurotrophic proteins. This pattern was also seen for the working memory limitation, but only with high concentrations of IL-8 and TNF-α, and the switching limitation, but only with high concentrations of ICAM-1. CONCLUSIONS: Among children born EP, risks of executive function limitations might be explained by perinatal systemic inflammation in the absence of adequate neurotrophic capability.

Extremely preterm infants whose placenta had histologic evidence of chorioamnionitis have early brain dysfunction, but little is known about neurologic development at 10 years of age.We investigated the association between histologic chorioamnionitis and neurodevelopmental impairment at 10 years among children born28 weeks' gestation (extremely preterm).The multicenter Extremely Low Gestational Age Newborns study enrolled extremely preterm newborns from 2002 to 2004 at 14 hospitals in the United States. Chorioamnionitis was defined by histologic stage (early, moderate, and advanced) and grade (mild/moderate and severe) of chorionic plate and umbilical cord inflammation. The children were examined for cerebral palsy at 2 years and for autism spectrum disorder, cognitive impairment (intelligence quotient2 standard deviations below the mean), and epilepsy at the age of 10 years by blinded evaluators using validated measures. Multivariable logistic regression with generalized estimating equations was used.Among 805 placentas, 43% (347/805) had histologic chorioamnionitis by moderate or advanced maternal stage, 36% (286/805) by severe maternal grade, 18% (132/737) by moderate or advanced fetal stage, and 1% (10/737) by severe fetal grade. The frequencies of impairments were 11% (88/767) for cerebral palsy, 7% (56/773) for autism spectrum disorder, 15% (120/788) for cognitive impairment, and 7% (52/763) for epilepsy. After adjustment for maternal age, body mass index, race, insurance status, maternal education, tobacco use, infant sex, and multiple gestations, the adjusted odds ratio for the association between histologic chorioamnionitis and cerebral palsy years was increased with advanced maternal stage (adjusted odds ratio, 2.5; 95% confidence interval, 1.6-3.9), severe maternal grade (adjusted odds ratio, 2.0; 95% confidence interval, 1.2-3.4), moderate fetal stage (adjusted odds ratio, 2.20; 95% confidence interval, 2.1-2.2), and mild or moderate fetal grade (adjusted odds ratio, 1.5; 95% confidence interval, 1.0-2.2). Similarly, the adjusted odds ratio for the association between histologic chorioamnionitis and epilepsy was increased with advanced maternal stage (adjusted odds ratio, 1.5; 95% confidence interval, 1.3-1.6) and severe fetal grade (adjusted odds ratio, 5.9; 95% confidence interval, 1.9-17.8). In addition, the adjusted odds ratio for the association between histologic chorioamnionitis and autism spectrum disorder was increased with mild or moderate fetal grade (adjusted odds ratio, 1.7; 95% confidence interval, 1.0-2.9). Histologic chorioamnionitis was not associated with cognitive impairment. These findings held after adjustment for gestational age at delivery. In contrast to histologic chorioamnionitis, a clinical diagnosis of chorioamnionitis was not associated with neurodevelopmental impairment.Histologic chorioamnionitis may be associated with some forms of neurodevelopmental impairment at 10 years of life among infants born28 weeks' gestation.

OBJECTIVES To evaluate the hypothesis that chronic lung disease of prematurity (CLD) is a risk factor for asthma in children born extremely preterm, and the hypothesis that the risk factors for CLD are similar to those for asthma. METHODS A retrospective analysis was performed using data collected prospectively from 882 children born before the 28th week of gestation between 2002 and 2004 who returned for follow-up at ages 12 and 24 months and 10 years. We created time-oriented logistic regression models to compare risk factors for CLD, defined as need for supplemental oxygen at 36 weeks postmenstrual age, and parent-reported asthma at 10 years of age. RESULTS CLD diagnosed during neonatal admission was associated with bronchodilator use at 12 months and 24 months (P

New opportunities are now available to improve care in ways not possible previously. Information contained in electronic medical records can now be shared without identifying patients. With network collaboration, large numbers of medical records can be searched to identify patients most like the one whose complex medical situation challenges the physician. The clinical effectiveness of different treatment strategies can be assessed rapidly to help the clinician decide on the best treatment for this patient. Other capabilities from different components of the network can prompt the recognition of what is the best available option and encourage the sharing of information about programs and electronic tools. Difficulties related to privacy, harmonization, integration, and costs are expected, but these are currently being addressed successfully by groups of organizations led by those who recognize the benefits.

Aim To assess to what extent the blood concentrations of proteins with neurotrophic and angiogenic properties measured during the first postnatal month convey information about the risk of sonographically-identified brain damage among very preterm newborns. Methods Study participants were 1219 children who had a cranial ultrasound scan during their stay in the intensive care nursery and blood specimens collected on 2 separate days at least a week apart during the first postnatal month. Concentrations of selected proteins in blood spots were measured with electrochemiluminescence or with a multiplex immunobead assay and the risks of cranial ultrasound images associated with top-quartile concentrations were assessed. Results High concentrations of multiple inflammation-related proteins during the first 2 postnatal weeks were associated with increased risk of ventriculomegaly, while high concentrations of just 3 inflammation-related proteins were associated with increased risk of an echolucent/hypoechoic lesion (IL-6, IL-8, ICAM-1), especially on day 7. Concomitant high concentrations of IL6R and bFGF appeared to modulate the increased risks of ventriculomegaly and an echolucent lesion associated with inflammation. More commonly high concentrations of putative protectors/repair-enhancers did not appear to diminish these increased risks. Conclusion Our findings provide support for the hypothesis that endogenous proteins are capable of either protecting the brain against damage and/or enhancing repair of damage.

We describe a new species of coralsnake from northern Dinagat Island, southeastern Philippines. The discovery of this new species comes as a surprise because it is phenotypically distinct from all other Philippine coralsnakes and has a close phylogenetic affinity to the blue coralsnakes of the Sunda Shelf. The new species is distinguished from all Philippine and other Southeast Asian taxa by its large body size and ventral scale counts; its black head and neck; an alternating, broadly banded color pattern of black and off-white; and a bright orange tail. We use DNA sequence data to investigate the phylogenetic placement of the new species and that of several other populations of Philippine coralsnakes with respect to other Southeast Asian and Australasian elapids. Our results corroborate the uniqueness of the new species with respect to all other Philippine and Sundaic taxa, including the species most closely related to it: Calliophis bivirgatus, C. bilineatus, C. philippinus, and C. suluensis. W...

Background Difficulties with reading and math occur more commonly among children born extremely preterm than among children born at term. Reasons for this are unclear. Methods We measured the concentrations of 27 inflammatory-related and neurotrophic/angiogenic proteins (angio-neurotrophic proteins) in multiple blood specimens collected a week apart during the first postnatal month from 660 children born before the 28th week of gestation who at age 10 years had an IQ ≥ 70 and a Wechsler Individual Achievement Test 3rd edition (WIAT-III) assessment. We identified four groups of children, those who had a Z-score ≤ −1 on the Word Reading assessment only, on the Numerical Operations assessment only, on both of these assessments, and on neither, which served as the referent group. We then modeled the risk of each learning limitation associated with a top quartile concentration of each protein, and with high and lower concentrations of multiple proteins. Results The protein profile of low reading scores was confined to the third and fourth postnatal weeks when increased risks were associated with high concentrations of IL-8 and ICAM-1 in the presence of low concentrations of angio-neurotrophic proteins. The profile of low math scores was very similar, except it did not include ICAM-1. In contrast, the profile of low scores on both assessments was present in each of the first four postnatal weeks. The increased risks associated with high concentrations of TNF-α in the first two weeks and of IL-8 and ICAM-1 in the next two weeks were modulated down by high concentrations of angio-neurotrophic proteins. Conclusions High concentrations of angio-neurotrophic proteins appear to reduce/moderate the risk of each learning limitation associated with systemic inflammation. The three categories of limitations have protein profiles with some similarities, and yet some differences, too.

To find out why children born extremely preterm are at heightened risk of executive dysfunctions, the authors assessed 716 children who were 10 years old born extremely preterm whose IQ was ≥ 70. A working memory dysfunction (n = 169), an inhibition dysfunction (n = 360), a switching dysfunction (355), and all 3 (executive dysfunction; n = 107) were defined on the basis of Z-scores ≤ –1 on the Differential Ability Scales–II Working Memory composite, and/or on the NEPSY-II Inhibition-Inhibition and Inhibition-Switching subtests. All risk profiles include an indicator of socioeconomic disadvantage. The risk profile of each of the 3 individual dysfunctions includes an indicator of the newborn’s immaturity, and the risk profiles of the inhibition dysfunction and switching dysfunction also include an indicator of inflammation. Only the switching dysfunction was associated with fetal growth restriction. The risk factors for executive dysfunction can be subsumed under the 4 themes of socioeconomic disadvantage, immaturity/vulnerability, inflammation, and fetal growth restriction.

BACKGROUND: Maternal pre-pregnancy obesity, in term-born children, is associated with an increased risk of attention problems, however this relationship has not been explored among children born extremely preterm.AIM: To estimate the risk of attention problems at age 10years in children born very preterm to overweight (i.e., body mass index (BMI) 25-29kg/m2) and obese (i.e., BMI≥30kg/m2) women relative to the risk among children born to women who were neither overweight nor obese (i.e. BMISTUDY DESIGN: Multi-center prospective cohort study.METHODS: A total of 764 children born before the 28th week of gestation and whose mother's pre-pregnancy height and pre-pregnancy weight were obtained at birth had an IQ≥70 at age 10years when parents and teachers completed Child Symptom Inventory-4 questionnaires that included items about the presence of ADHD.RESULTS: Compared to children whose mother's pre-pregnancy weight was in the normal range (BMICONCLUSION: Maternal overweight and obesity are associated with increased risk of parent-identified ADHD characteristics at 10years of age in children born extremely preterm.

Background To identify the antecedents and very early correlates of low concentrations of angiogenic proteins in the blood of extremely preterm newborns during the first postnatal month. Methods Using multiplex immunoassays we measured the concentrations of vascular endothelial growth factor A (VEGF), VEGF receptor-1 (VEGFR-1), VEGF receptor-2 (VEGFR-2), placenta growth factor (PIGF), and angiopoietins 1 and 2 (Ang-1, Ang-2), as well as 21 other proteins in blood spots collected on postnatal days 1 ( N = 1062), 7 ( N = 1087), 14 ( N = 989), 21 ( N = 940) and 28 ( N = 880) from infants born before the 28th week of gestation. We then sought the protein-concentration correlates of concentrations in the top and bottom quartile for gestational age and day the specimen was collected. Results Children who were delivered for medical indications and those who were severely growth restricted were more likely than others to have low day-1 blood concentrations of VEGF, VEGF-R2, Ang-1, and PIGF. Systemic inflammation accompanied top quartile concentrations of every one of the 6 angiogenic proteins. Conclusions Low day-1 concentrations of most angiogenic proteins are associated with disorders linked to placenta insufficiency/dysfunction. High concentrations, on the other hand, are associated with systemic inflammation throughout the first postnatal month.

BackgroundPreterm newborns exposed to intrauterine inflammation are at an increased risk of neurodevelopmental disorders. We hypothesized that adverse outcomes are more strongly associated with a combination of antenatal and postnatal inflammation than with either of them alone.MethodsWe defined antenatal inflammation as histologic inflammation in the placenta. We measured the concentrations of seven inflammation-related proteins in blood obtained on postnatal days 1, 7, and 14 from 763 infants born before 28 weeks of gestation. We defined postnatal inflammation as a protein concentration in the highest quartile on at least 2 days. We used logistic regression models to evaluate the contribution of antenatal and postnatal inflammation to the risk of neurodevelopmental disorders.ResultsThe risk of white matter damage was increased when placental inflammation was followed by sustained elevation of C-reactive protein or ICAM-1. We found the same for spastic cerebral palsy when placental inflammation was followed by elevation of TNF-α or IL-8. The presence of both placental inflammation and elevated levels of IL-6, TNF-α, or ICAM-1 was associated with an increased risk for microcephaly.ConclusionCompared with a single hit, two inflammatory hits are associated with stronger risk for abnormal cranial ultrasound, spastic cerebral palsy, and microcephaly at 2 years.

Brain injury in preterm newborn infants is often attributed to hypoxia–ischemia even when neither hypoxia nor ischemia is documented, and many causative speculations are based on the same assumption. We review human and animal study contributions with their strengths and limitations, and conclude that – despite all the work done in human fetal neuropathology and developmental models in animals – the evidence remains unconvincing that hypoxemia, in the fetus or newborn infant, contributes appreciably to any encephalopathy of prematurity. Giving an inappropriate causal name to a disorder potentially limits the options for change, should our understanding of the etiologies advance. The only observationally‐based title we think appropriate is ‘encephalopathy of prematurity’. Future pathophysiological research should probably include appropriately designed epidemiology studies, highly active developmental processes, infection and other inflammatory stimuli, the immature immune system, long chain fatty acids and their transporters, and growth (neurotrophic) factors. What this paper adds Fetal hypoxemia is rarely documented in brain injury studies.Animal studies fail to consider human–animal fetal anatomical differences.Putative treatments from animal models have not found clinical use.Observational studies constitute the only approach to etiological understanding.No convincing evidence yet that hypoxemia injures preterm brain. Encephalopathy of prematurity is preferable to hypoxia‐ischemia as a term for this disorder.Encephalopathy of prematurity is preferable to hypoxia‐ischemia as a term for this disorder., What this paper adds Fetal hypoxemia is rarely documented in brain injury studies.Animal studies fail to consider human–animal fetal anatomical differences.Putative treatments from animal models have not found clinical use.Observational studies constitute the only approach to etiological understanding.No convincing evidence yet that hypoxemia injures preterm brain. Encephalopathy of prematurity is preferable to hypoxia‐ischemia as a term for this disorder.Encephalopathy of prematurity is preferable to hypoxia‐ischemia as a term for this disorder. This article is commented on by Paneth on page 115 of this issue. This article's abstract has been translated into Spanish and Portuguese. Follow the links from the abstract to view the translations.

AIM Compared to infants born at term, children born very preterm are at increased risk of visual dysfunctions and neonatal systemic inflammation. Here, we explore whether these two propensities are related. METHODS As part of the ELGAN study, the concentrations of 16 mediators of inflammation were measured in blood obtained on postnatal days 1, 7, 14, 21 and 28 from 1062 children born before the 28th week of gestation. Presence of visual field deficit, strabismus and/or impaired visual fixation was recorded at age two. The concentrations of each protein were divided into quartiles within gestational week categories. We calculated odds ratios with 99% confidence intervals for having each disorder comparing children with concentration in the top quartile of each protein to children whose concentration was in the lower quartiles on the corresponding day. Analyses were adjusted for gestational age and birth weight Z-score. RESULTS Only one of 80 assessments (16 proteins on five different days) was significant for visual field deficit, and one for impaired fixation. No association was found between strabismus and any inflammatory mediator. CONCLUSION None of the three neuro-ophthalmologic dysfunctions assessed at two years appears to be associated with systemic inflammation measured the first four postnatal weeks.

A neonatal illness severity score, The Score for Neonatal Acute Physiology-II (SNAP-II), predicts neurodevelopmental impairments at two years of age among children born extremely preterm. We sought to evaluate to what extent SNAP-II is predictive of cognitive and other neurodevelopmental impairments at 10 years of age.In a cohort of 874 children born before 28 weeks of gestation, we prospectively collected clinical, physiologic and laboratory data to calculate SNAP-II for each infant. When the children were 10 years old, examiners who were unaware of the child's medical history assessed neurodevelopmental outcomes, including neurocognitive, gross motor, social and communication functions, diagnosis and treatment of seizures or attention deficit hyperactivity disorder (ADHD), academic achievement, and quality of life. We used logistic regression to adjust for potential confounders.An undesirably high SNAP-II (⩾30), present in 23% of participants, was associated with an increased risk of cognitive impairment (IQ, executive function, language ability), adverse neurological outcomes (epilepsy, impaired gross motor function), behavioral abnormalities (attention deficit disorder and hyperactivity), social dysfunction (autistic spectrum disorder) and education-related adversities (school achievement and need for educational supports. In analyses that adjusted for potential confounders, Z-scores ⩽-1 on 11 of 18 cognitive outcomes were associated with SNAP-II in the highest category, and 6 of 18 were associated with SNAP-II in the intermediate category. Odds ratios and 95% confidence intervals ranged from 1.4 (1.01, 2.1) to 2.1 (1.4, 3.1). Similarly, 2 of the 8 social dysfunctions were associated with SNAP-II in the highest category, and 3 of 8 were associated with SNAP-II in the intermediate category. Odds ratios and 95% confidence intervals were slightly higher for these assessments, ranging from 1.6 (1.1, 2.4) to 2.3 (1.2, 4.6).Among very preterm newborns, physiologic derangements present in the first 12 postnatal hours are associated with dysfunctions in several neurodevelopmental domains at 10 years of age. We are unable to make inferences about causality.

Background To date, studies of the relationship between antenatal glucocorticoids (AGC) and neonatal inflammation in preterm newborns have been largely limited to umbilical cord blood specimens. Aim To explore the association between exposure to antenatal glucocorticoids and concentrations of inflammation-related proteins in whole blood collected from very preterm newborns at multiple times during the first postnatal month. Methods We measured the protein concentrations on postnatal day 1 (N = 1118), day 7 (N = 1138), day 14 (N = 1030), day 21 (N = 936) and day 28 (N = 877) from infants born before the 28th week of gestation and explored the relationship between antenatal steroid receipt and protein concentrations in the highest and lowest quartiles. The creation of multinomial logistic regression models (adjusted for potential confounders) allowed us calculate odds ratios and 95% confidence intervals. Results Twenty of 420 assessments [21 (proteins) × 2 (exposure levels: partial and full) × 2 (quartile levels: top and bottom) × 5 (days)] were statistically significant without any cohesive pattern. Conclusion Among infants born before 28 weeks of gestational age, neither full, nor partial courses of antenatal glucocorticoids have a sustained anti-inflammatory effect.

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.

BACKGROUND: Childhood obesity is a pervasive public health problem with risk factors such as maternal prepregnancy BMI and rapid infant weight gain. Although catch-up weight gain promotes more favorable neurodevelopment among infants born preterm, it is not clear whether faster weight gain early in life, or other correlates of preterm birth, are associated with later obesity in this population. METHODS: We used prospective data from the multicenter, observational Extremely Low Gestational Age Newborn Study. Among 1506 eligible individuals in the initial cohort, 1198 were eligible for follow-up at 10 years of age. We examined BMI in 871 children (58% of the cohort; 74% of survivors) and analyzed relationships between antecedents and overweight or obesity at 10 years of age. A time-oriented approach to multinomial multivariable regression enabled us to calculate odds of overweight and obesity associated with pre- and postnatal antecedents. RESULTS: Prepregnancy maternal BMI ≥25 and top quartile infant weight gain in the first year were associated with increased risk of both overweight and obesity at 10 years of age. Single marital status was a risk factor for later child obesity and exposure to tobacco smoke was a risk factor for later child overweight. CONCLUSIONS: The risk profiles for overweight and obesity at 10 years of age among children born extremely preterm appear to be similar to the risk profiles of overweight and obesity among children born at term.

Numerous studies have examined the association between maternal caffeine consumption and infant and childhood health outcomes and the results have been inconsistent. The study of maternal caffeine intake and infant and childhood health outcomes is prone to methodologic challenges. In this review, we examine the existing evidence juxtaposed with the epidemiologic design challenges that color the interpretation of the study results presented. In light of methodologic/interpretation challenges, it seems reasonable to infer that exposure to low levels of caffeine is probably not associated with substantial infant and childhood adversities. However, more research is needed using well designed studies that address methodologic challenges.

We sought to estimate the prevalence of autism spectrum disorder (ASD) in children born extremely preterm relative to the U.S. population risk of 1.5% [CDC, 2014] using the best-available diagnostic procedures and minimizing confounding with other neurodevelopmental impairments. Eight hundred and eighty nine 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. Children meeting ASD screening criteria on the Social Communication Questionnaire were evaluated with the Autism Diagnostic Interview-Revised (ADI-R). Those meeting ADI-R criteria were assessed with the Autism Diagnostic Observation Schedule-2 (ADOS-2). A positive ADOS-2 score was the criterion for ASD. Twenty-six participants were not assessed for ASD because of severe sensory or motor impairment. In the remaining sample, 61 children met criteria for ASD, resulting in a prevalence of 7.1% (95% CI = 5.5-9.0). ASD risk decreased with increasing gestational age, from 15.0% (95% CI = 10.0-21.2) for 23-24 weeks, 6.5% (95% CI = 4.2-9.4) for 25-26 weeks, to 3.4% (95% CI = 1.6-6.1) for 27 weeks gestational age, and this association was independent of IQ. Among children with ASD, 40% had intellectual disability. The male-to-female ratio of children with ASD was 2.1:1 (95% CI = 1.2:1-3.5:1), lower than in the general population (4:1). ASD prevalence in the ELGAN cohort was four 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 role in the etiology of autism. Autism Res 2017, 10: 224-232. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

Objective To explore the association between concentrations of endogenous erythropoietin (EPO) in blood the first 2 weeks of life and neonatal disorders in extremely low gestational age newborns (ELGANs). Design Prospective cohort study. Setting Neonatal care units at 14 participating hospitals in the USA. Patients 867 children born before the 28th week of gestation from the ELGAN study cohort. Main outcome measures EPO blood concentrations were measured on postnatal days 1, 7 and 14. The following neonatal characteristics and disorders were registered: blood gases, early and late respiratory dysfunction, pulmonary deterioration, retinopathy of prematurity (ROP), necrotising enterocolitis (NEC) and bronchopulmonary dysplasia (BPD). We calculated the gestational age-adjusted ORs for having each disorder associated with an EPO blood concentration in the highest or lowest quartile, compared with infants whose EPO concentration was in the middle two quartiles on the corresponding day. Results Newborns whose day-1 EPO was in the highest quartile were at increased risk for early and persistent respiratory dysfunction during the first 2 weeks of life, and NEC requiring surgery. The lowest EPO quartile on day 1 was associated with a decreased risk of moderate BPD. The association between low EPO and decreased risk of respiratory complications persisted on day 7. On day 14, being in the highest EPO quartile was associated with increased risk of ROP, and BPD not requiring ventilation assistance. Conclusions EPO blood concentrations in extremely preterm newborns during the first 2 weeks of life convey information about increased risks of bowel, lung and retinal diseases.

Systemic inflammation during the first two postnatal weeks in extremely preterm newborns (28weeks gestation) has been associated with an increased risk of neurodevelopmental dysfunctions. Little is known, however, about the relationship between systemic inflammation during the third and fourth postnatal weeks and subsequent development.We measured the concentrations of 16 inflammation-related proteins in blood spots collected on postnatal days 21 (N=749) and 28 (N=697) from infants born before the 28th week of gestation and assessed at age 2years. We then sought the developmental correlates of top quartile concentrations for gestational age and day the specimen was collected. Odds ratios and 95% confidence intervals were calculated from regular or multinomial logistic regression models (as appropriate).Top quartile concentrations of CRP, IL-1β, IL-6, IL-6R, TNF-R2, IL-8, ICAM-1, and TSH on both days 21 and 28 were associated with ventriculomegaly (when in the NICU) and microcephaly at age 2years. Top quartile concentrations of CRP, SAA, IL-6, TNF-R2, IL-8, and ICAM-1 were associated with mental development index (MDI) of the Bayley-II55, while top quartile concentrations of CRP, TNF-α (inversely), IL-8, and ICAM-1 were associated with psychomotor development index (PDI)55 CONCLUSION: Extremely preterm newborns who had systemic inflammation during the third and fourth postnatal weeks were at increased risk of ventriculomegaly during the months after birth, and of microcephaly, and low Bayley Scale scores at 2years old.