Early postnatal illness severity scores predict neurodevelopmental impairments at 10 years of age in children born extremely preterm.

OBJECTIVE: 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. STUDY DESIGN: 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. RESULTS: 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). CONCLUSION: 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.

Systems Epidemiology: What's in a Name?

Systems biology is an interdisciplinary effort to integrate molecular, cellular, tissue, organ, and organism levels of function into computational models that facilitate the identification of general principles. Systems medicine adds a disease focus. Systems epidemiology adds yet another level consisting of antecedents that might contribute to the disease process in populations. In etiologic and prevention research, systems-type thinking about multiple levels of causation will allow epidemiologists to identify contributors to disease at multiple levels as well as their interactions. In public health, systems epidemiology will contribute to the improvement of syndromic surveillance methods. We encourage the creation of computational simulation models that integrate information about disease etiology, pathogenetic data, and the expertise of investigators from different disciplines.

Toward multi-scale computational modeling in developmental disability research.

The field of theoretical neuroscience is gaining increasing recognition. Virtually all areas of neuroscience offer potential linkage points for computational work. In developmental neuroscience, main areas of research are neural development and connectivity, and connectionist modeling of cognitive development. In this paper, we suggest that computational models can be helpful tools for understanding the pathogenesis and consequences of perinatal brain damage and subsequent developmental disability. In particular, designing multi-scale computational models should be considered by developmental neuroscientists interested in helping reduce the risk for developmental disabilities.

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 infant's 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.

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.

Pregnancy disorders that lead to delivery before the 28th week of gestation: an epidemiologic approach to classification.

Epidemiologists have grouped the multiple disorders that lead to preterm delivery before the 28th week of gestation in a variety of ways. The authors sought to identify characteristics that would help guide how to classify disorders that lead to such preterm delivery. They enrolled 1,006 women who delivered a liveborn singleton infant of less than 28 weeks' gestation at 14 centers in the United States between 2002 and 2004. Each delivery was classified by presentation: preterm labor (40%), prelabor premature rupture of membranes (23%), preeclampsia (18%), placental abruption (11%), cervical incompetence (5%), and fetal indication/intrauterine growth restriction (3%). Using factor analysis (eigenvalue = 1.73) to compare characteristics identified by standardized interview, chart review, placental histology, and placental microbiology among the presentation groups, the authors found 2 broad patterns. One pattern, characterized by histologic chorioamnionitis and placental microbe recovery, was associated with preterm labor, prelabor premature rupture of membranes, placental abruption, and cervical insufficiency. The other, characterized by a paucity of organisms and inflammation but the presence of histologic features of dysfunctional placentation, was associated with preeclampsia and fetal indication/intrauterine growth restriction. Disorders leading to preterm delivery may be separated into two groups: those associated with intrauterine inflammation and those associated with aberrations of placentation.

Interleukin-10 high producer allele and ultrasound-defined periventricular white matter abnormalities in preterm infants: a preliminary study.

OBJECTIVES: Inflammation plays a role in prematurity, in neonatal disorders of the brain, lung, eye, bowel, and in developmental disability among preterm infants. We initiated a pilot study in preterm children to determine the prevalence of single nucleotide polymorphisms (SNPs) in the infection/inflammation-associated genes for interleukin (IL)-10 (- 1082 G/A), IL-1beta (+ 3953 C/T), tumor necrosis factor (TNF)-alpha (- 308 G/A) and toll-like receptor 4 (TLR-4) (Asp299Gly) and whether these SNPs affect the risk for neonatal disorders. STUDY DESIGN: We genotyped 73 children >/= 2 years of age whose gestational age at birth was < 32 weeks, and explored the associations between genotypes and neonatal disorders and developmental status at age 2 + years. RESULTS: Infants homozygous for the high IL-10 producer - 1082 G-allele (n = 15) were significantly less likely to develop ultrasound-defined periventricular echodensities. A non-significant, but prominent, risk reduction for bronchopulmonary dysplasia, high-grade retinopathy, cerebral palsy, and developmental delay at age 2 + years was present. Polymorphisms in the IL-1beta, TNF-alpha, and TLR-4 genes were too infrequent in our pilot sample to allow for reasonable analysis. CONCLUSION: Infants homozygous for the IL-10 high producer - 1082 G allele might be at reduced risk for prematurity-associated disorders.

[Intrauterine infection and the preterm brain: dimensions of aetiology research]. / Intrauterine Infektion und das Gehirn Frühgeborener - Dimensionen der Atiologieforschung.

Perinatal brain damage has a diverse and complex aetiology. Over the past decades, much progress has been made in this research field. In this article, I offer a discussion of seven dimensions of aetiological perinatal brain damage research: (1) hypoxia-ischaemia vs. inflammation; (2) "classic" vs. "remote" intrauterine infection; (3) focal vs. diffuse white matter damage; (4) maternal vs. foetal inflammatory response; (5) clinical vs. experimental data; (6) bacterial vs. viral infection; and (7) preterm vs. term delivery. Despite these complexities, it is hoped that obstetricians, neonatologists, and neuropaediatricians will agree on a perinatal neuroprotective strategy in the near future.

Brain lesions in newborns exposed to high-dose magnesium sulfate during preterm labor.

High-dosage, tocolytic magnesium sulfate (MgSO4) administered to pregnant women during preterm labor can be toxic, and sometimes lethal, for their newborns (Cochrane Database of Systematic Reviews (relative mortality risk 2.82, 95% confidence interval 1.2-6.6)). Based on the results of the Magnesium and Neurologic Endpoints Trial and the work of many others, a unifying triangular concept is proposed to account for the increased prevalence of brain lesions, with their likely resultant mortality, in neonates and infants exposed to high-dose MgSO4 in the context of preterm labor. We review the evidence that: (1) elevated circulating levels of serum ionized magnesium occurring in mothers, and therefore in their babies, at the time of delivery are associated with subsequent neonatal intraventricular hemorrhage (IVH); (2) neonatal IVH is strongly associated with lenticulostriate vasculopathy (LSV), an unusual mineralizing lesion involving the thalami and basal ganglia of the neonate; and, (3) exposure to 50 g or more of tocolytic MgSO4 during preterm labor is associated with the development of LSV.

Population based study on the outcome of small for gestational age newborns.

OBJECTIVE: To explore whether and how population based data from a regional quality control programme can be used to investigate the hypothesis that small for gestational age (SGA) very low birthweight infants (VLBW, <1500 g) are at increased risk of death, severe intraventricular haemorrhage (IVH), and periventricular leucomalacia (PVL), but at decreased risk of respiratory distress syndrome (RDS). METHODS: Analyses of population based perinatal/neonatal data (1991-96) from a quality control programme in Lower Saxony, Germany. After assessment of data validity and representativeness, exclusion criteria were defined: birth weight >90th centile, severe malformations, siblings of multiple births, and gestational age (GA) <25 or >29 weeks. Outcomes of interest were death, severe IVH, PVL, and RDS. Multivariable analyses were performed by Cox proportional hazard and logistic regression models. RESULTS: Within the data validation procedure, an increase in proportions of both VLBW (from 0.95% in 1991 to 1.11% in 1996; +17%) and SGA (from 22.7% to 27.4%; +21%) infants became apparent (p<0.05). The study population consisted of 1623 infants (173 SGA). Mortality was 12.1% (n = 196), with an adjusted hazard ratio for SGA infants of 2.54, 95% confidence interval (CI) 1.70 to 3.79. Both groups were at similar risk of severe IVH (adjusted odds ratio 0.93, 95% CI 0.5 to 1.65) and PVL (1.54, 95% CI 0.78 to 2.87), but SGA infants had less RDS (0.57, 95% CI 0.35 to 0.93). Male sex, multiple birth, hypothermia (<35.5 degrees C), and sepsis were associated with IVH and RDS. Infants admitted to hospitals with <36 VLBW admissions/year had increased mortality (adjusted hazard ratio 1.56, 95% CI 1.12 to 2.18). CONCLUSIONS: SGA VLBW infants are at increased risk of death, but not of IVH and PVL, and at decreased risk of RDS. That mortality is higher in smaller hospitals needs further investigation.

Fetal vasculitis in preterm newborns: interrelationships, modifiers, and antecedents.

Histologic expressions of the fetal inflammatory response predict preterm delivery and neonatal disorders. We examined 1146 placentas in the Developmental Epidemiology Network data set for histologic evidence of membrane inflammation (subchorionitis, chorionitis, and chorioamnionitis) and fetal vasculitis (acute umbilical vasculitis or chorionic vasculitis). Our main findings are that (1) in the presence of membrane inflammation, fetal vasculitis is common, (2) duration of membrane rupture and gestational age appear to modify the risk of fetal vasculitis, (3) this risk modification differs for the different components of fetal vasculitis, i.e. umbilical and chorionic vasculitis, and (4) antecedents can be identified that appear to increase or decrease the risk of fetal vasculitis among births with membrane inflammation. We conclude that fetal vasculitis, the morphologic component of the fetal inflammatory response, might not be a homogeneous entity and deserves further study.

Association of morphological characteristics with precocious puberty and/or gelastic seizures in hypothalamic hamartoma.

The pathogenesis of central precocious puberty (PP) and/or gelastic seizures due to a hypothalamic hamartoma (HH) is still under debate. We evaluated the association of clinical symptoms with morphology and localization of the HH in 34 patients. The majority (86.4%) of HHs in patients with isolated PP (n = 22; 68.2% females) revealed a parahypothalamic position without affecting the third ventricle (91%). Half of them were pedunculated, and 40.9% showed a diameter less than 10 mm. In contrast, 11 of 12 patients with seizures, eight of whom were male, presented with a sessile intrahypothalamic hamartoma, 10 of which distorted the third ventricle. Logistic regression analysis revealed an increased relative risk (RR) for epilepsy in males (RR, 4.3; 95% confidence interval, 0.96-19). However, combination of the risk factor gender with intrahypothalamic position (RR, 19; 1.3-285) and distortion of the third ventricle (RR, 10; 0.6-164) reduced the risk associated with male gender to 1.1. The position of a HH and involvement of the third ventricle are likely to be more predictive for clinical characteristics than size and shape. Male gender was associated with an intrahypothalamic HH and epilepsy, suggesting a sexually dimorphic developmental pattern of this heterotopic mass.

Brain damage markers in children. Neurobiological and clinical aspects.

UNLABELLED: The presence in blood of proteins normally confined to the cytoplasm of brain cells is considered peripheral evidence of brain damage. Only recently have these proteins been measured in the blood of children at risk of brain damage. To show the value and limitations of measuring these proteins, we review their biology and the adult literature that has correlated the blood concentrations of these proteins with lesion size and dysfunction. CONCLUSION: We conclude that brain damage markers will increasingly be measured in the blood of newborns and other children at risk of brain damage.

Adult stroke and perinatal brain damage: like grandparent, like grandchild?

Biomarkers of inflammation are found in the circulation of adults who have had a stroke. Although these biomarkers may, in part, be indicators of damage, some appear to contribute to damage. Similar biomarkers are found in newborns with cerebral white matter damage or at risk of cerebral palsy. Can we learn about the pathogenesis of neonatal white matter damage from what has been learned about the inflammatory correlates of adult stroke? We discuss relevant findings about systemic inflammatory markers in adult stroke and relate this information to our current understanding of cerebral white matter damage in newborns, especially those born at an extremely low gestational age. We also describe desirable characteristics of future studies of perinatal brain damage that involve measurements of systemic biomarkers.

Cloning of two thyrotropin-releasing hormone receptor subtypes from a lower vertebrate (Catostomus commersoni): functional expression, gene structure, and evolution.

A PCR approach was used to clone thyrotropin-releasing hormone receptors (TRH-R) from the brain and anterior pituitary of the teleost Catostomus commersoni (cc), the white sucker. Two distinct TRH-R, designated ccTRH-R1 and ccTRH-R2, were identified. ccTRH-R1 was similar to mammalian TRH-R of the subtype 1, whereas ccTRH-R2 exhibited the highest identity (61% at the amino acid level) with the recently discovered rat TRH-R2. It is postulated that ccTRH-R2 and rat TRH-R2 are members of the same TRH-R subfamily 2. Functional expression of ccTRH receptors in human embryonic kidney cells and in Xenopus laevis oocytes demonstrated that both ccTRH receptors were fully functional in both systems. Oocytes expressing either receptor responded to the application of TRH by an induction of membrane chloride currents, indicating that ccTRH-R of both subtypes are coupled to the inositol phosphate/calcium pathway. The analysis of genomic clones revealed, for the first time, both similarities and differences in the structure of TRH-R subtype genes. Both ccTRH-R genes contained an intron within the coding region at the beginning of transmembrane domain (TM) 6. The position of this intron is highly conserved, as it was found at an identical position in the human TRH-R1 gene. The ccTRH-R2 gene contained an additional intron at the end of TM 3 that was not found in any of the TRH-R1 genes identified so far. The analysis of the gene structure of ccTRH-R and the amino acid sequence comparisons of mammalian and teleost TRH-R of both subtypes suggest that TRH receptors have been highly conserved during the course of vertebrate evolution. A common ancestral TRH receptor gene that could be found much earlier in evolution, possibly in invertebrates, might be the origin of ccTRH-R genes.

Symptom-limited stair climbing as a predictor of postoperative cardiopulmonary complications after high-risk surgery.

STUDY OBJECTIVE: Thoracotomy, sternotomy, and upper abdominal laparotomy are associated with high rate of postoperative cardiopulmonary complications (POCs). We hypothesized that symptom-limited stair climbing predicts POCs after high-risk surgery. DESIGN: A prospective evaluation of 83 patients undergoing thoracotomy, sternotomy, and upper abdominal laparotomy surgery. METHODS: The 52 men and 31 women completed symptom-limited stair climbing. A separate investigator, blinded to the number of flights of stairs climbed, assessed 30-day actual outcomes for POCs, including pneumonia, atelectasis, mechanical ventilation for > 48 h, reintubation, myocardial infarction, congestive heart failure, arrhythmia, pulmonary embolus, and death within 30 days of surgery. The operations performed included 31 lobectomies, 6 wedge resections, 3 pneumonectomies, 3 substernal thymectomies, 1 substernal thyroidectomy, 23 colectomies, 3 laparotomies, 7 abdominal aortic aneurysm repairs, 5 esophagogastrectomies, and 1 nephrectomy. RESULTS: POCs occurred in 21 of 83 patients (25%) overall, in 9 of 44 patients undergoing thoracotomy/sternotomy (20%), and in 12 of 39 patients undergoing upper abdominal laparotomy (31%). Of those unable to climb one flight of stairs, 89% developed a POC. No patient able to climb the maximum of seven flights of stairs had a POC. The inability to climb two flights of stairs was associated with a positive predictive value of 82% for the development of a POC. The number of days in the hospital postoperatively decreased with a patient's increased ability to climb stairs. CONCLUSIONS: Symptom-limited stair climbing offers a simple, inexpensive means to predict POCs after high-risk surgery.

Fetal growth restriction is not associated with a reduced risk for bilateral spastic cerebral palsy in very-low-birthweight infants.

OBJECTIVE: To evaluate the influence of confounding and sampling bias on the relationship between fetal growth restriction in a very-low-birthweight-defined cohort (VLBW, < or =1500 g) and bilateral spastic cerebral palsy (BSCP) at early school-age. METHODS: Three hundred twenty-four of 407 long-term survivors of a regional cohort of VLBW newborns were followed until age 6 years. We categorized as small for gestational age (SGA) all infants whose birthweight Z-score was below -2 relative to published reference values. Uni- and multivariable logistic regression models were fit to estimate the risk of BSCP associated with SGA in the total sample, in subsamples defined by gestational age, and in a gestational age-matched case-control sample. RESULTS: In the total sample, no child below 28 weeks was SGA, and no child above 32 weeks had an appropriate birthweight for gestational age (AGA). The prevalence of BSCP was 14% in AGA and 2% in SGA infants. In both uni- and multivariable logistic regression analyses of the total sample, SGA was associated with a prominently reduced risk of BSCP (odds ratios range from 0.1 to 0.2, all 95% confidence limits exclude 1.0). However, analyses performed in samples defined by different gestational age cutoffs (24--31 weeks, 28--31 weeks) and in a sample using three gestational age-matched controls per BSCP-case did not show a protection by growth restriction (odds ratios range from 0.8 to 2.2, all 95% confidence limits include 1.0). CONCLUSIONS: In VLBW-defined samples, the apparent protective effect of SGA for BSCP can be explained, at least in part, by the highly skewed distribution of SGA over the available gestational age range. From this follows that study cohorts should be defined by gestational age and not by birthweight. In distorted samples like this one, even controlling for gestational age does not reduce the illusion of a reduced cerebral palsy risk for growth restricted infants. Only restriction of the sample by gestational age and/or matching for gestational age reveals the absence of this apparent protective effect.