BACKGROUND:To evaluate the feasibility of a protocol using combined magnetic resonance imaging (MRI), clinical data, and electroencephalogram (EEG) to identify neonates with mild neonatal encephalopathy (NE) treated with therapeutic hypothermia (TH) who are eligible for "early exit".METHODS:Retrospective chart review of TH cases at a single Level III NICU over a 5-year period was used to describe the demographic, clinical, and outcome data in neonates that received early exit in contrast to 72 hour TH treatment.RESULTS:Two hundred and eight TH cases, including 18 early exit cases (9%) and 9 cases (4%) evaluated for early exit with MRI but continued on 72 hours of TH, were identified. Early exit and 72 hour treatment groups did not differ in demographics or cord gas measures, although early exit neonates had a shorter length of stay (p < 0.05). Consistent with the early exit protocol, no early exit infants had evidence of moderate or severe encephalopathy on EEG or evidence of hypoxic ischemic injury on MRI at 24 hours of life. Neurology follow up between age 1 and 18 months was available for 10 early exit infants, 8 of whom had a normal examination.CONCLUSIONS:Early MRI at 24 hours of age, alongside clinical and EEG criteria, is feasible as part of a protocol to identify neonates eligible for early exit from therapeutic hypothermia.

Investigating the cerebral physiology of healthy term newborns' brains is important for better understanding perinatal brain injuries, of which the most common etiologies are hypoxia and ischemia. Hence, cerebral blood flow and cerebral oxygenation are important biomarkers of brain health. In this study, we employed a hybrid diffuse optical system consisting of diffuse correlation spectroscopy (DCS) and frequency-domain near infrared spectroscopy (FDNIRS) to measure hemoglobin concentration, oxygen saturation, and indices of cerebral blood flow and metabolism. We measured 30 term infants to assess the optical and physiological characteristics of the healthy neonatal brain in the frontal, temporal, and parietal lobes. We observed higher metabolism in the right hemisphere compared to the left and a positive correlation between gestational age and the level of cerebral hemoglobin concentration, blood volume, and oxygen saturation. Moreover, we observed higher cerebral blood flow and lower oxygen saturation in females compared to males. The delayed maturation in males and the sexual dimorphism in cerebral hemodynamics may explain why males are more vulnerable to perinatal brain injuries than females.

To investigate the effects of parental presence and infant holding in the neonatal intensive care unit (NICU) on neurobehavior at term equivalent. Prospective cohort enrolled 81 infants born ⩽30 weeks gestation. Nurses tracked parent visitation, holding and skin-to-skin care throughout the NICU hospitalization. At term, the NICU Network Neurobehavioral Scale was administered. Associations between visitation, holding and early neurobehavior were determined using linear and logistic regression. The mean hours per week of parent visitation was 21.33±20.88 (median=13.90; interquartile range 10.10 to 23.60). Infants were held an average of 2.29±1.47 days per week (median=2.00; interquartile range 1.20 to 3.10). Over the hospital stay, visitation hours decreased (P=0.01), while holding frequencies increased (P<0.001). More visitation was associated with better quality of movement (P=0.02), less arousal (P=0.01), less excitability (P=0.03), more lethargy (P=0.01) and more hypotonia (P<0.01). More holding was associated with improved quality of movement (P<0.01), less stress (P<0.01), less arousal (P=0.04) and less excitability (P<0.01). Infants of caregivers who were visited and held more often in the NICU had differences in early neurobehavior by term equivalent, which supports the need for and importance of early parenting in the NICU.

Gradient Echo Plural Contrast Imaging in Studying Neonatal Brain Development: Preliminary Results Jie Wen, Jeffrey J. Neil, Joseph Ackerman Jr. , Jie Luo, Terri E. Inder, and Dmitriy A. Yablonskiy Mallinckrodt Institute of Radiology, Washington University in St. Louis, St. Louis, MO, United States, Department of Pediatrics Newborn Medicine, Washington University in St. Louis, St. Louis, MO, United States, Massachusetts Institute of Technology, MA, United States

Background: Experimental studies suggest that hypothermia following peripartum hypoxia-ischaemia in newborn infants may reduce neurological sequelae. Aims: To determine whether therapeutic hypothermia in encephalopathic asphyxiated newborn infants reduces mortality and neurodevelopmental disability, without clinically important side effects. Methods: Randomised controlled trials (RCTs) evaluating therapeutic hypothermia in newborns with hypoxic ischaemic encephalopathy (HIE) were identified using the standard search strategy of the Neonatal Review Group of the Cochrane Library. The primary outcome was death or long-term major neurodevelopmental disability. Other outcomes included adverse effects of cooling. Three reviewers independently selected, assessed the quality of and extracted data. Meta-analyses were performed using relative risk and risk difference for dichotomous data, and weighted mean difference for continuous data with 95% confidence intervals. Results: Four RCTs were included in this review, comprising 349 term infants with HIE. Two studies (Gunn 1998, Gluckman 2005) achieved excellent follow-up rates at 18 months of age; one (Eicher 2005) had incomplete follow-up at 12 months (81.5%) and one (Shankaran 2002) has not reported long-term outcomes. The pooled analysis of the 2 higher quality studies showed no significant effect of therapeutic hypothermia on the combined outcome of death or major neurodevelopmental disability in survivors followed (RR 0.89 [95% CI 0.69, 1.05]). Inclusion of the poorer quality study (Eicher 2005) resulted in a significant reduction in death or major disability in infants allocated to therapeutic hypothermia (RR 0.80 [95% CI 0.66, 0.96]). No adverse effects of hypothermia on short term outcomes were detected. Conclusions: Four RCTs showed no evidence of harm from therapeutic hypothermia. Evidence of efficacy remains inconclusive. Therapeutic hypothermia for infants with HIE should continue to be evaluated in well designed RCTs. This abstract is a preliminary version of the update to be included in the Cochrane Library Issue 4 2005.

Objective: The objective of this work was to determine the impact of therapeutic hypothermia (TH) on the magnitude and time course of mean diffusivity (MD) changes following hypoxic-ischemic encephalopathy (HIE) in newborns. Methods: Cerebral MRI scans of infants undergoing whole body TH for HIE from 2007 to 2010 were retrospectively reviewed. The data were analyzed identically to a control group of newborns with HIE previously published, prior to the development of TH. Anatomic injury was defined on T1- and T2-weighted (“late”) MRI obtained after the fifth day of life. Since MD values vary regionally, the ratios of MD values for injured and normal tissue were calculated for areas of injury. Normal values were obtained from corresponding brain regions of 12 infants undergoing TH who had no injury on MRI studies. Results: Twenty-three of 59 infants who underwent TH and MRI displayed cerebral injury on late MRI and were included in the study. MD ratios were decreased in all injured infants within the first 7 days of life. The return of MD to normal (pseudonormalization) occurred after the tenth day as compared to 6–8 days in the control group. Infants with severest injury demonstrated greater reduction in MD, but no difference in time to pseudonormalization. Conclusion: TH slows the evolution of diffusion abnormalities on MRI following HIE in term infants.

In the context of amplitude-integrated electroencephalography (aEEG), the term ‘sleep–wake cycling’ (SWC), which is frequently used by clinicians and researchers, should be changed to ‘cyclicity’. SWC is a technical term that refers to the biological pattern of alternating sleeping and waking states, which is difficult to define with only aEEG and no physical parameters. Additionally, the absence of cyclicity on aEEG is a more robust reflection of the sequence of the suppressed background patterns of an aEEG following cerebral injury or dysfunction than are sleep/wake states.

Objective: To explore differences in maternal factors, including visitation and holding, among premature infants cared for in single-patient rooms (SPR) compared with open-bay in the neonatal intensive care unit (NICU). Study Design: A total of 81 premature infants were assigned to a bed space in either the open-bay area or in a SPR upon NICU admission, based on bed space and staffing availability in each area. Parent visitation and holding were tracked through term equivalent, and parents completed a comprehensive questionnaire at discharge to describe maternal health. Additional maternal and medical factors were collected from the medical record. Differences in outcome variables were investigated using linear regression. Result: No significant differences in gestational age at birth, initial medical severity, hours of intubation or other factors that could affect the outcome were observed across room type. Significantly more hours of visitation were observed in the first 2 weeks of life ( P =0.02) and in weeks 3 and 4 ( P =0.02) among infants in the SPR. More NICU stress was reported by mothers in the SPR after controlling for social support ( P =0.04). Conclusion: Increased parent visitation is an important benefit of the SPR, however, mothers with infants in the SPR reported more stress.

Introduction Studying cerebral cortical folding in normal development or in association with disease of injury requires assessing how folded cortex is. Recently, a series of surface-area independent measures of global curvature were proposed to study cortical folding in infants (1). We have systematically evaluated slightly modified versions of these measures using cortical surfaces derived from premature infants of differing postmenstrual age (PMA). Our analysis provides an indication of the sensitivity of different measures to the changes in cortical folding associated with development. Materials and Methods Patient population: Infants were recruited from the Neonatal Intensive Care Unit. If clinically stable underwent MRI studies as soon as practical after birth, at 30 wks PMA, 34 wks PMA, and term equivalent PMA. The MR studies included a T1-weighted, 3D MPRAGE acquisition of 1-mm isotropic spatial resolution, TI = 1100 ms, TR = 2100 ms, TE = 2.93 ms. Global folding measures were computed for 4 infants at each of the following PMAs: <27, 30-31, 34-35, and 38-39 wks. Calculation of folding indices: Data were analyzed using mesh surfaces generated using Caret software (2). The measures of global curvature tested (1) fall into several broad categories according to the curvature values on which they are based. The intrinsic curvature index (ICI), negative intrinsic curvature index (NICI), Gaussian L2 norm (GLN), and absolute intrinsic curvature index (AICI) are based on the Gaussian curvature; the mean curvature index (MCI), negative mean curvature index (NMCI), mean L2 norm (MLN), and absolute mean curvature index (AMCI), are based on the mean curvature; the folding index (FI), curvedness index (CI), and shape index (SI), are based on a individual indices; the area area fraction of intrinsic curvature index (FICI), area fraction of negative intrinsic curvature index (FnICI), area fraction of mean curvature index (FMCI), and area fraction of negative mean curvature index (FNMCI) are calculate the proportion of total surface area where the Gaussian or mean curvature is either positive or negative; the last two measures (SH2SH and SK2SK) are ratios of other global curvature measures. Results and Discussions The figure shows fiducial surface reconstructions in lateral (top) and medial (bottom) views at the indicated PMA’s. Note the increase in cortical folding complexity with increasing PMA. The 17 measures tested can be organized into 5 groups that behave similarly on several evaluations of cortical folding (Table). In general, measures in groups 1 and 2 perform better (i.e., increase monotonically with increased complexity of folding associated with development) than the other groups. These measures appropriately track the large complexity changes that occur with increasing PMA, maintain sensitivity to changes at several levels of cortical complexity. In contrast, the measures in groups 3 and 4 tend to become less sensitive to differences in cortical complexity as complexity increases. The measures in group 5 do not behave in a manner that is consistent with visual inspection.

OBJECTIVE:To evaluate an electroencephalography (EEG)-based index, the Cerebral Health Index in babies (CHI/b), for identification of neonates with high Sarnat scores and abnormal EEG as markers of hypoxic ischemic encephalopathy (HIE) after perinatal asphyxia.STUDY DESIGN:This is a retrospective study using 30 min of EEG data collected from 20 term neonates with HIE and 20 neurologically normal neonates. The HIE diagnosis was made on clinical grounds based on history and examination findings. The maximum-modified clinical Sarnat score was used to grade HIE severity within 72 h of life. All neonates underwent 2-channel bedside EEG monitoring. A trained electroencephalographer blinded to clinical data visually classified each EEG as normal, mild or severely abnormal. The CHI/b was trained using data from Channel 1 and tested on Channel 2.RESULT:The CHI/b distinguished among HIE and controls (P<0.02) and among the three visually interpreted EEG categories (P<0.0002). It showed a sensitivity of 82.4% and specificity of 100% in detecting high grades of neonatal encephalopathy (Sarnat 2 and 3), with an area under the receiver operator characteristic (ROC) curve of 0.912. CHI/b also identified differences between normal vs mildly abnormal (P<0.005), mild vs severely abnormal (P<0.01) and normal vs severe (P<0.002) EEG groups. An ROC curve analysis showed that the optimal ability of CHI/b to discriminate poor outcome was 89.7% (sensitivity: 87.5%; specificity: 82.4%).CONCLUSION:The CHI/b identified neonates with high Sarnat scores and abnormal EEG. These results support its potential as an objective indicator of neurological injury in infants with HIE.

BACKGROUND A potential therapeutic effect of sex steroids on premature infants has been proposed from animal data and observational studies in humans. Purported benefits include reduction in chronic lung disease, improved bone density and improved neurodevelopmental outcome. OBJECTIVES To determine if estrogens or progestins, either alone or in combination, when compared to placebo or no treatment, reduce morbidity and/or mortality in preterm infants. SEARCH STRATEGY The standard search strategy of the Cochrane Neonatal Review Group as outlined in the Cochrane Library (Issue 2, 2004) was used. This included searches of the Oxford Database of Perinatal Trials, Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2004), MEDLINE 1966 to July 2004 inclusive, previous reviews including cross references, abstracts, conferences and symposia proceedings (Perinatal Society of Australia and New Zealand 1998-2004 and Pediatric Academic Societies meetings 1998-2004). SELECTION CRITERIA Randomised controlled trials comparing the use of estrogens and/or progestins with placebo or no treatment in preterm infants born less than 30 weeks gestation were included in this review. The primary outcome measures were neonatal mortality and medium-term neurodevelopmental outcome. Other outcomes included length of hospital stay, incidence of chronic lung disease, osteopaenia causing fractures and adverse effects of sex steroid administration. DATA COLLECTION AND ANALYSIS Two reviewers independently selected, assessed the quality of and extracted data from the included studies. Meta-analyses were performed using relative risk and risk difference for dichotomous data, and weighted mean difference for continuous data with 95% confidence intervals. MAIN RESULTS Two randomised controlled trials were identified by the search strategy and one was included in this review, comprising 30 preterm infants. There was no significant effect of replacement of estradiol and progesterone on the outcomes of mortality or neurodevelopmental disability in survivors followed. No adverse effects of sex steroid replacement on short or longer term outcomes were detected. REVIEWERS' CONCLUSIONS The one small randomised controlled trial demonstrated neither evidence of benefit or harm related to the replacement of estradiol and progesterone in preterm infants less than 30 weeks gestation. A properly powered randomised controlled trial is required to determine whether or not administration of estradiol or progesterone, either alone or in combination, and at varying doses, confers any clinically significant benefits, or poses any risk, to the preterm infant.

Periventricular leukomalacia (PVL), the principal form of brain injury in the premature infant, is characterized by overt focal necrotic lesions in periventricular white matter and less prominent, more diffuse cerebral white matter injury. The early detection of the latter, diffuse component of PVL is not consistently possible with conventional brain imaging techniques. We demonstrate the early detection of the diffuse component of PVL by diffusion-weighted magnetic resonance imaging (DWI). In a premature infant with no definite cerebral abnormality detectable by cranial ultrasonography or conventional magnetic resonance imaging, DWI showed a striking bilateral decrease in water diffusion in cerebral white matter. The DWI abnormality (ie, decreased apparent diffusion coefficient) was similar to that observed with acute cerebral ischemic lesions in adults. At 10 weeks of age, conventional magnetic resonance imaging and ultrasonography showed striking changes consistent with PVL, including the presence of small cysts. The observations indicate the importance of DWI in the early identification of the diffuse component of PVL and also perhaps the role of ischemia in the pathogenesis of the lesion. (J Pediatr 1999;134:631-4)