Thomas M. O'Shea

The ELGAN study of the brain and related disorders in extremely low gestational age newborns.

BACKGROUND Extremely low gestational age newborns (ELGANs) are at increased risk for structural and functional brain abnormalities. AIM To identify factors that contribute to brain damage in ELGANs. STUDY DESIGN Multi-center cohort study. SUBJECTS We enrolled 1506 ELGANs born before 28 weeks gestation at 14 sites; 1201 (80%) survived to 2 years corrected age. Information about exposures and characteristics was collected by maternal interview, from chart review, microbiologic and histological examination of placentas, and measurement of proteins in umbilical cord and early postnatal blood spots. OUTCOME MEASURES Indicators of white matter damage, i.e. ventriculomegaly and echolucent lesions, on protocol cranial ultrasound scans; head circumference and developmental outcomes at 24 months adjusted age, i.e., cerebral palsy, mental and motor scales of the Bayley Scales of Infant Development, and a screen for autism spectrum disorders. RESULTS ELGAN Study publications thus far provide evidence that the following are associated with ultrasongraphically detected white matter damage, cerebral palsy, or both: preterm delivery attributed to preterm labor, prelabor premature rupture of membranes, or cervical insufficiency; recovery of microorganisms in the placenta parenchyma, including species categorized as human skin microflora; histological evidence of placental inflammation; lower gestational age at delivery; greater neonatal illness severity; severe chronic lung disease; neonatal bacteremia; and necrotizing enterocolitis. CONCLUSIONS In addition to supporting a potential role for many previously identified antecedents of brain damage in ELGANs, our study is the first to provide strong evidence that brain damage in extremely preterm infants is associated with microorganisms in placenta parenchyma.

Antenatal Antecedents of Cognitive Impairment at 24 Months In Extremely Low Gestational Age Newborns

BACKGROUND AND OBJECTIVES: Extremely low gestational age neonates are more likely than term infants to develop cognitive impairment. Few studies have addressed antenatal risk factors of this condition. We identified antenatal antecedents of cognitive impairment determined by the Mental Development Index (MDI) portion of the Bayley Scales of Infant Development, Second Edition (BSID-II), at 24 months corrected age. METHODS: We studied a multicenter cohort of 921 infants born before 28 weeks of gestation during 2002 to 2004 and assessed their placentas for histologic characteristics and microorganisms. The mother was interviewed and her medical record was reviewed. At 24 months adjusted age, children were assessed with BSID-II. Multinomial logistic models were used to estimate odds ratios. RESULTS: A total of 103 infants (11%) had an MDI <55, and 99 infants (11%) had an MDI between 55 and 69. No associations were identified between organisms recovered from the placenta and developmental delay. Factors most strongly associated with MDI <55 were thrombosis of fetal vessels (OR 3.1; 95% confidence interval [CI] 1.2, 7.7), maternal BMI >30 (OR 2.0; 95% CI 1.1, 3.5), maternal education ≤12 years (OR 3.4; 95% CI 1.9, 6.2), nonwhite race (OR 2.2; 95% CI 1.3, 3.8), birth weight z score < −2 (OR 2.8; 95% CI 1.1, 6.9), and male gender (OR 2.7; 95% CI 1.6, 4.5). CONCLUSIONS: Antenatal factors, including thrombosis of fetal vessels in the placenta, severe fetal growth restriction, and maternal obesity, convey information about the risk of cognitive impairment among extremely premature newborns.

Neurodevelopmental Outcome of Infants With Unilateral or Bilateral Periventricular Hemorrhagic Infarction

OBJECTIVE: Periventricular hemorrhagic infarction (PVHI) is a major contributing factor to poor neurodevelopmental outcomes in preterm infants. We hypothesized that surviving infants with unilateral PVHI would have more favorable outcomes than those with bilateral PVHI. METHODS: This was a multicenter, retrospective study of infants who were admitted to 3 NICUs in North Carolina from 1998 to 2004. The clinical course and late neuroimaging studies and neurodevelopmental outcomes of 69 infants who weighed <1500 g and had confirmed PVHI on early cranial ultrasonography were reviewed. A predictive model for Bayley Scales of Infant Development, Second Edition, Mental Developmental Index (MDI) <70 was constructed by using radiologic and clinical variables. RESULTS: Infants with unilateral PVHI had higher median MDI (82 vs 49) and Psychomotor Developmental Index (53 vs 49) than infants with bilateral PVHI. Infants with unilateral PVHI were less likely to have severe cerebral palsy (adjusted odds ratio: 0.15 [95% confidence interval (CI): 0.05–0.45]) than infants with bilateral PVHI. Infants who had unilateral PVHI and developed periventricular leukomalacia and retinopathy of prematurity that required surgery had an increased probability of having MDI <70 compared with those without these complications (probability of MDI <70: 89% [95% CI: 0.64–1.00] vs 11% [95% CI: 0.01–0.28]). CONCLUSIONS: Infants with unilateral PVHI had better motor and cognitive outcomes than infants with bilateral PVHI. By combining laterality of PVHI, periventricular leukomalacia, and retinopathy of prematurity it is possible to estimate the probability of having an MDI <70, which will assist clinicians when counseling families.

Neurocognitive and academic outcomes at age 10 years of extremely preterm newborns

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. METHODS: The families of 889 of 966 (92%) children enrolled from 2002 to 2004 at 14 sites in 5 states returned at age 10 years for a comprehensive assessment of IQ, language, attention, executive function, processing speed, visual perception, visual-motor function, and academic achievement. RESULTS: A total of 873 children were assessed with well-validated tests of cognitive and academic function. Distributions of test scores were consistently and markedly shifted below normative expectation, with one-third to two-thirds of children performing >1 SD below age expectation. The most extreme downward shifts were on measures of executive control and processing speed. Multivariate analyses, adjusted for socioeconomic status, growth restriction, and other potential confounders, revealed that the risk of poor outcome was highest at the lowest gestational age across all 18 measures. CONCLUSIONS: More than half of our extremely preterm cohort exhibited moderate or severe neurocognitive deficits at age 10 years, with the most extensive impairments found among those born at the lowest gestational age. Children born extremely preterm continue to be at significant risk of persistent impairments in neurocognitive function and academic achievement, underscoring the need for monitoring and remediating such outcomes beginning in early childhood.

Prevalence and associated features of autism spectrum disorder in extremely low gestational age newborns at age 10 years

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.

Survival and major neurodevelopmental impairment in extremely low gestational age newborns born 1990–2000: a retrospective cohort study

BackgroundIt is important to determine if rates of survival and major neurodevelopmental impairment in extremely low gestational age newborns (ELGANs; infants born at 23–27 weeks gestation) are changing over time.MethodsStudy infants were born at 23 to 27 weeks of gestation without congenital anomalies at a tertiary medical center between July 1, 1990 and June 30, 2000, to mothers residing in a thirteen-county region in North Carolina. Outcomes at one year adjusted age were compared for two epochs of birth: epoch 1, July 1, 1990 to June 30, 1995; epoch 2, July 1, 1995 to June 30, 2000. Major neurodevelopmental impairment was defined as cerebral palsy, Bayley Scales of Infant Development Mental Developmental Index more than two standard deviations below the mean, or blindness.ResultsSurvival of ELGANs, as a percentage of live births, was 67% [95% confidence interval: (61, 72)] in epoch 1 and 71% (65, 75) in epoch 2. Major neurodevelopmental impairment was present in 20% (15, 27) of survivors in epoch 1 and 14% (10, 20) in epoch 2. When adjusted for gestational age, survival increased [odds ratio 1.5 (1.0, 2.2), p = .03] and major neurodevelopmental impairment decreased [odds ratio 0.54 (0.31, 0.93), p = .02] from epoch 1 to epoch 2.ConclusionThe probability of survival increased while that of major neurodevelopmental impairment decreased during the 1990s in this regionally based sample of ELGANs.

Early postnatal hypotension is not associated with indicators of white matter damage or cerebral palsy in extremely low gestational age newborns

Objective:To evaluate, in extremely low gestational age newborns (ELGANs), relationships between indicators of early postnatal hypotension and cranial ultrasound indicators of cerebral white matter damage imaged in the nursery and cerebral palsy diagnoses at 24 months follow-up.Study Design:The 1041 infants in this prospective study were born at <28 weeks gestation, were assessed for three indicators of hypotension in the first 24 postnatal hours, had at least one set of protocol cranial ultrasound scans and were evaluated with a structured neurological exam at 24 months corrected age. Indicators of hypotension included: (1) lowest mean arterial pressure (MAP) in the lowest quartile for gestational age; (2) treatment with a vasopressor; and (3) blood pressure lability, defined as the upper quartile of the difference between each infants lowest and highest MAP. Outcomes included indicators of cerebral white matter damage, that is, moderate/severe ventriculomegaly or an echolucent lesion on cranial ultrasound and cerebral palsy diagnoses at 24 months gestation. Logistic regression was used to evaluate relationships among hypotension indicators and outcomes, adjusting for potential confounders.Result:Twenty-one percent of surviving infants had a lowest blood pressure in the lowest quartile for gestational age, 24% were treated with vasopressors and 24% had labile blood pressure. Among infants with these hypotension indicators, 10% percent developed ventriculomegaly and 7% developed an echolucent lesion. At 24 months follow-up, 6% had developed quadriparesis, 4% diparesis and 2% hemiparesis. After adjusting for confounders, we found no association between indicators of hypotension, and indicators of cerebral white matter damage or a cerebral palsy diagnosis.Conclusion:The absence of an association between indicators of hypotension and cerebral white matter damage and or cerebral palsy suggests that early hypotension may not be important in the pathogenesis of brain injury in ELGANs.

Predictive Validity of the Modified Checklist for Autism in Toddlers (M-CHAT) Born Very Preterm

OBJECTIVE To examine the predictive validity of the Modified Checklist for Autism in Toddlers (M-CHAT) administered at age 24 months for autism spectrum disorder (ASD) diagnosed at 10 years of age in a US cohort of 827 extremely low gestational age newborns (ELGANs) followed from birth. STUDY DESIGN We examined the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the M-CHAT in predicting an ASD diagnosis at age 10 years based on gold standard diagnostic instruments. We then assessed how these predictive parameters were affected by sensorimotor and cognitive impairments, socioeconomic status (SES), and emotional/behavioral dysregulation at age 2 years. RESULTS Using standard criteria, the M-CHAT had a sensitivity of 52%, a specificity of 84%, a PPV of 20%, and an NPV of 96%. False-positive and false-negative rates were high among children with hearing and vision impairments. High false-positive rates also were associated with lower SES, motor and cognitive impairments, and emotional/behavioral dysregulation at age 2 years. CONCLUSIONS Among extremely preterm children with ASD, almost one-half were not correctly screened by the M-CHAT at age 2 years. Sensorimotor and cognitive impairments, SES, and emotional/behavioral dysregulation contributed significantly to M-CHAT misclassifications. Clinicians are advised to consider these factors when screening very preterm toddlers for ASD.

Circulating Inflammatory-Associated Proteins in the First Month of Life and Cognitive Impairment at Age 10 Years in Children Born Extremely Preterm

Objectives To evaluate whether in children born extremely preterm, indicators of sustained systemic inflammation in the first month of life are associated with cognitive impairment at school age. Study design A total of 873 of 966 eligible children previously enrolled in the multicenter Extremely Low Gestational Age Newborn Study from 2002 to 2004 were evaluated at age 10 years. We analyzed the relationship between elevated blood concentrations of inflammation‐associated proteins in the first 2 weeks (“early elevations”; n = 812) and the third and fourth week (“late elevations”; n = 532) of life with neurocognition. Results Early elevations of C‐reactive protein, tumor necrosis factor‐&agr;, interleukin (IL)‐8, intercellular adhesion molecule (ICAM)‐1, and erythropoietin were associated with IQ values >2 SD below the expected mean (ORs: 2.0‐2.3) and with moderate to severe cognitive impairment on a composite measure of IQ and executive function (ORs: 2.1‐3.6). Additionally, severe cognitive impairment was associated with late protein elevations of C‐reactive protein (OR: 4.0; 95% CI 1.5, 10), IL‐8 (OR: 5.0; 1.9, 13), ICAM‐1 (OR: 6.5; 2.6, 16), vascular endothelial growth factor‐receptor 2 (OR: 3.2; 1.2, 8.3), and thyroid‐stimulating hormone (OR: 3.1; 1.3, 7.3). Moderate cognitive impairment was most strongly associated with elevations of IL‐8, ICAM‐1, and vascular endothelial growth factor‐receptor 2. When 4 or more inflammatory proteins were elevated early, the risk of having an IQ <70 and having overall impaired cognitive ability was more than doubled (ORs: 2.1‐2.4); the presence of 4 or more inflammatory protein elevated late was strongly linked to adverse cognitive outcomes (ORs: 2.9‐4.8). Conclusions Extremely preterm children who had sustained elevations of inflammation‐related proteins in the first postnatal month are more likely than extremely preterm peers without such elevations to have cognitive impairment at 10 years.

Are preterm newborns who have relative hyperthyrotropinemia at increased risk of brain damage

Abstract Background: We sought to disentangle the contributions of hyperthyrotropinemia (an indicator of thyroid dysfunction) (HTT) and intermittent or sustained systemic inflammation (ISSI) to structural and functional indicators of brain damage. Methods: We measured the concentrations of thyroid-stimulating hormone (TSH) on day 14 and of 25 inflammation-related proteins in blood collected during the first 2 postnatal weeks from 786 infants born before the 28th week of gestation who were not considered to have hypothyroidism. We defined hyperthyrotropinemia (HTT) as a TSH concentration in the highest quartile for gestational age on postnatal day 14 and ISSI was defined as a concentration in the top quartile for gestational age of a specific inflammation-related protein on 2 separate days a week apart during the first 2 postnatal weeks. We first assessed the risk of brain damage indicators by comparing 1) neonates who had HTT to those without (regardless of ISSI) and 2) neonates with HTT only, ISSI only, or HTT+ISSI to those who were exposed to neither HTT nor ISSI. Results: In univariable models that compared those with HTT to those without, HTT was not significantly associated with any indicator of brain damage. In models that compared HTT only, ISSI only, and HTT+ISSI to those with neither, children with ISSI only or with HTT+ISSI were at significantly higher risk of ventriculomegaly [odds ratios (ORs) 2–6], whereas those with HTT only were at significantly reduced risk of a hypoechoic lesion (ORs 0.2–0.4). Children with HTT only had a higher risk of quadriparesis and those with ISSI alone had a higher risk of hemiparesis (ORs 1.6–2.4). Elevated risk of a very low mental development score was associated with both ISSI only and HTT+ISSI, whereas a very low motor development score and microcephaly were associated with HTT+ISSI. Conclusions: The association of HTT with increased or decreased risk of indicators of brain damage depends on the presence or absence of ISSI.