Design, implementation, and inferential issues associated with clinical trials that rely on data in electronic medical records: a narrative review.

Real world evidence is now accepted by authorities charged with assessing the benefits and harms of new therapies. Clinical trials based on real world evidence are much less expensive than randomized clinical trials that do not rely on "real world evidence" such as contained in electronic health records (EHR). Consequently, we can expect an increase in the number of reports of these types of trials, which we identify here as 'EHR-sourced trials.' 'In this selected literature review, we discuss the various designs and the ethical issues they raise. EHR-sourced trials have the potential to improve/increase common data elements and other aspects of the EHR and related systems. Caution is advised, however, in drawing causal inferences about the relationships among EHR variables. Nevertheless, we anticipate that EHR-CTs will play a central role in answering research and regulatory questions.

Self-management education for children with epilepsy and their caregivers. A scoping review.

Self-management education programs have been highly successful in preparing people to manage medical conditions with recurring events. A detailed curriculum for epilepsy patients, and their caretakers, is lacking. Here we assess what is available for patients who have disorders with recurring events and offer an approach to developing a potential self-care curriculum for patients with seizures and their caregivers. Among the anticipated components are a baseline efficacy assessment and training tailored to increasing self-efficacy, medication compliance, and stress management. Those at risk of status epilepticus will also need guidance in preparing a personalized seizure action plan and training in how to decide when rescue medication is appropriate and how to administer the therapy. Peers, as well as professionals, could teach and provide support. To our knowledge, no such programs are currently available in English. We encourage their creation, dissemination, and widespread use.

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.

Histologic chorioamnionitis and risk of neurodevelopmental impairment at age 10 years among extremely preterm infants born before 28 weeks of gestation.

BACKGROUND: 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. OBJECTIVE: We investigated the association between histologic chorioamnionitis and neurodevelopmental impairment at 10 years among children born <28 weeks' gestation (extremely preterm). STUDY DESIGN: 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 quotient >2 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. RESULTS: 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. CONCLUSION: Histologic chorioamnionitis may be associated with some forms of neurodevelopmental impairment at 10 years of life among infants born <28 weeks' gestation.

Early Postnatal IGF-1 and IGFBP-1 Blood Levels in Extremely Preterm Infants: Relationships with Indicators of Placental Insufficiency and with Systemic Inflammation.

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.

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.

The risk of neurodevelopmental disorders at age 10 years associated with blood concentrations of interleukins 4 and 10 during the first postnatal month of children born extremely preterm.

BACKGROUND: Interleukin (IL)-4 and IL-10 are viewed mainly as anti-inflammatory cytokines. Yet, high concentrations have also been associated with inflammation-related diseases in newborns. METHODS: We measured the concentrations of IL-4 and IL-10, as well as IL-8 and ICAM-1 in blood specimens collected on postnatal day 21 (N = 555), day 28 (N = 521), and both days 21 and 28 (N = 449) from children born extremely preterm (EP) (<28 weeks gestation) who at age 10 years had a DAS-II IQ Z-score > -2 (which approximates a score of >70) and the following assessments, CCC-2, and CSI-4, DAS-II, NEPSY-II, OWLS-II, SCQ, and WIAT-III. Selected children also were assessed with the ADI-R and the ADOS-2. We modeled the risk of low scores or dysfunctions associated with top quartile concentrations of IL-4 and IL-10 on each day and on both days. RESULTS: The risks of low scores on the Animal Sorting and Arrows components of the NEPSY-II, both components of the OWLS-II, and the PseudoWord and Spelling components of the WIAT-III were heightened among children who had top quartile concentrations of IL-4 on postnatal days 21 and 28. Children who had high concentrations of IL-10 on days 21 and 28, individually and collectively, were at increased risk of low scores on the WIAT-III Spelling component. High concentrations of IL-4 on day 28 were associated with autism spectrum disorder (ASD). High concentrations of IL-10 on day 28 were also associated with a doubling of ASD risk, but this did not achieve statistical significance. Top quartile concentrations of IL-4 and IL10 on both days were not associated with increased risk of social, language, or behavioral dysfunctions. CONCLUSION: Among children born EP, those who had top quartile concentrations of IL-4 and/or IL-10 on postnatal days 21 and/or 28 were more likely than their peers to have low scores on components of the NEPSY-II, OWLS-II, and WIAT-III assessments, as well as identification as having an ASD. What is known: What is not known: What this study adds.

Elevations of inflammatory proteins in neonatal blood are associated with obesity and overweight among 2-year-old children born extremely premature.

BackgroundChildhood obesity is associated with elevated blood concentrations of inflammation markers. It is not known to what extent inflammation precedes the development of obesity.MethodsIn a cohort of 882 infants born before 28 weeks of gestation, we examined relationships between concentrations of 25 inflammation-related proteins in blood obtained during the first two postnatal weeks and body mass index at 2 years of age.ResultsAmong children delivered for spontaneous indications (n=734), obesity was associated with elevated concentrations of four proteins (IL-1ß, IL-6, TNF-R1, and MCP-1) on the first postnatal day; one protein (IL-6) on postnatal day 7; and two proteins (ICAM-3 and VEGF-R1) on postnatal day 14. Among children delivered for maternal or fetal indications (n=148), obesity was associated with elevated concentrations of seven proteins on the 14th postnatal day. In multivariable models in the spontaneous indications subsample, elevated IL-6 on day 1 predicted obesity (odds ratio: 2.9; 95% confidence limits: 1.2, 6.8), whereas elevated VCAM-1 on day 14 predicted overweight at 2 years of age (odds ratio: 2.3; 95% confidence limits: 1.2, 4.3).ConclusionsIn this cohort, neonatal systemic inflammation preceded the onset of obesity, suggesting that inflammation might contribute to the development of obesity.

Can a collaborative healthcare network improve the care of people with epilepsy?

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.

Caring electronically for young outpatients who have epilepsy.

PURPOSE: The purpose of this study was to review electronic tools that might improve the delivery of epilepsy care, reduce medical care costs, and empower families to improve self-management capability. METHOD: We reviewed the epilepsy-specific literature about self-management, electronic patient-reported or provider-reported outcomes, on-going remote surveillance, and alerting/warning systems. CONCLUSIONS: The improved care delivery system that we envision includes self-management, electronic patient (or provider)-reported outcomes, on-going remote surveillance, and alerting/warning systems. This system and variants have the potential to reduce seizure burden through improved management, keep children out of the emergency department and hospital, and even reduce the number of outpatient visits.

Hypoxia-ischemia is not an antecedent of most preterm brain damage: the illusion of validity.

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.

Behavioural dysfunctions of 10-year-old children born extremely preterm associated with corticotropin-releasing hormone expression in the placenta.

AIM: To evaluate the relationship between corticotropin-releasing hormone (CRH) expression in the placenta and the risk of school-related dysfunctions at the age of 10 years among children born extremely preterm (EP). METHODS: Corticotropin-releasing hormone expression was measured in the placenta of 761 EP children, who had the following assessments at the age of 10 years: Differential Ability Scales, Oral and Written Language Scales, the Wechsler Individual Achievement Test-III, NEPSY-II and the Child Symptom Inventory-4. We evaluated whether lowest and highest quartiles of CRH mRNA were associated with undesirable scores on these assessments. With 272 evaluations, we would expect 14 to be significant at p < 0.05. RESULTS: Only 16 associations were statistically significant. On the other hand, seven of these were social limitations among girls whose placenta CRH mRNA was in the top quartile. Adjusting for delivery indication or restricting the sample to one delivery indication group resulted in few differences. CONCLUSION: Overall, placenta CRH mRNA concentrations in the top or bottom quartiles were not associated with increased risks of dysfunctions 10 years later. Girls whose placenta CRH expression was in the top quartile, however, were at increased risk of seven indicators/correlates of social limitations.

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.

Antecedents and correlates of blood concentrations of neurotrophic growth factors in very preterm newborns.

AIM: To identify the antecedents and very early correlates of low concentrations of neurotrophic growth factors in the blood of extremely preterm newborns during the first postnatal month. METHODS: Using an immunobead assay, we measured the concentrations of neurotrophin 4 (NT4), brain-derived neurotrophic factor (BDNF), and basic fibroblast growth factor (bFGF) 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 correlates of measurements in the top and bottom quartiles for gestational age and day the specimen was collected. RESULTS: The concentrations of 2 neurotrophic proteins, NT4 and BDNF, were low among children delivered for medical (maternal or fetal) indications, and among those who were growth restricted. Children who had top quartile concentrations of NT4, BDNF, and bFGF tended to have elevated concentrations of inflammation-related proteins that day. This pattern persisted for much of the first postnatal month. CONCLUSIONS: Delivery for medical indications and fetal growth restriction are associated with a relative paucity of NT4 and BDNF concentrations during the first 24 h after very preterm birth. Elevated blood concentrations of NT4, BDNF, and bFGF tended to co-occur with indicators of systemic inflammation on the same day.

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.

Cognitive functioning at the age of 10 years among children born extremely preterm: a latent profile approach.

BackgroundSchool-age children born extremely preterm (EP) are more likely than their term peers to have multiple neurocognitive limitations. We identify subgroups of EP children who share similar profiles on measures of intelligence quotient (IQ) and executive function (EF), and describe the nature and prevalence of cognitive impairment in EP children.MethodsOn the basis of measures of IQ and EF, subgroups of EP children with common neurocognitive function are identified using latent profile analysis (LPA). On the basis of these subgroups, we describe the nature and prevalence of impairment in EP children, and examine associations between cognitive function, gestational age, and academic achievement. Classification of neurocognitive function using IQ and EF is compared with a standard classification based on IQ Z-scores.ResultsLPA identified four neurocognitive profiles in EP children, with 34% of EP children classified as normal, 41% low-normal, 17% moderately impaired, and 8% severely impaired. Impaired children exhibited global impairment across cognitive domains, whereas children in the low-normal group tended to have impaired inhibition relative to their reasoning and working memory skills.ConclusionWithin categories of EP children defined in terms of IQ, there is substantial variation in EF; thus, both IQ and EF assessments are needed when describing school-age outcome of EP children.

Both antenatal and postnatal inflammation contribute information about the risk of brain damage in extremely preterm newborns.

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.