Development of a neonatal adverse event severity scale through a Delphi consensus approach.

BACKGROUND: Assessment of the seriousness, expectedness and causality are necessary for any adverse event (AE) in a clinical trial. In addition, assessing AE severity helps determine the importance of the AE in the clinical setting. Standardisation of AE severity criteria could make safety information more reliable and comparable across trials. Although standardised AE severity scales have been developed in other research fields, they are not suitable for use in neonates. The development of an AE severity scale to facilitate the conduct and interpretation of neonatal clinical trials is therefore urgently needed. METHODS: A stepwise consensus process was undertaken within the International Neonatal Consortium (INC) with input from all relevant stakeholders. The consensus process included several rounds of surveys (based on a Delphi approach), face-to-face meetings and a pilot validation. RESULTS: Neonatal AE severity was classified by five grades (mild, moderate, severe, life threatening or death). AE severity in neonates was defined by the effect of the AE on age appropriate behaviour, basal physiological functions and care changes in response to the AE. Pilot validation of the generic criteria revealed κ=0.23 and guided further refinement. This generic scale was applied to 35 typical and common neonatal AEs resulting in the INC neonatal AE severity scale (NAESS) V.1.0, which is now publicly available. DISCUSSION: The INC NAESS is an ongoing effort that will be continuously updated. Future perspectives include further validation and the development of a training module for users.

A directory for neonatal intensive care: potential for facilitating network-based research in neonatology.

Directories of contact information have evolved over time from thick paperback times such as the "Yellow Pages" to electronic forms that are searchable and have other functionalities. In our clinical specialty, the development of a professional directory helped to promote collaboration in clinical care, education, and quality improvement. However, there are opportunities for increasing the utility of the directory by taking advantage of modern web-based tools, and expanding the use of the directory to fill a gap in the area of collaborative research.

The late preterm infant and the control of breathing, sleep, and brainstem development: a review.

The brainstem development of infants born between 33 and 38 weeks' gestation is less mature than that of a full-term infant. During late gestation, there are dramatic and nonlinear developmental changes in the brainstem. This translates into immaturity of upper airway and lung volume control, laryngeal reflexes, chemical control of breathing, and sleep mechanisms. Ten percent of late preterm infants have significant apnea of prematurity and they frequently have delays in establishing coordination of feeding and breathing. Unfortunately, there is a paucity of clinical, physiologic, neuroanatomic, and neurochemical data in this specific group of infants. Research focused on this group of infants will not only further our understanding of brainstem maturation during this high risk period, but will help develop focused plans for their management.

The Role of Biomarkers and Surrogate End Points in Drug Development for Neonatal Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a rare disease in newborns, infants, and children. It is associated with significant morbidity and mortality, but has limited treatment options. Except for inhaled nitric oxide, which is approved for persistent pulmonary hypertension of the newborn (PPHN), no drug is approved for the treatment of newborns, infants, and children with PAH. The lack of developmentally appropriate pediatric efficacy end points and pediatric clinical trials contribute to this unmet medical need. The noninvasive biomarkers reported in the literature that can be used as potential surrogate end points to assess disease severity and treatment response in neonates, infants, and children with PAH are reviewed herein. In addition, the role of the US Food and Drug Administration in developing potential biomarkers as surrogate end points to facilitate drug development for the treatment of children with PPHN and PAH in children is reviewed herein.

Neurobehavioral assessment predicts differential outcome between VLBW and ELBW preterm infants.

OBJECTIVE: To evaluate the impact of birth weight on development of very low birth weight (VLBW) infants using the Neurobehavioral Assessment of the Preterm Infant (NAPI) before hospital discharge, and to show the relation to follow-up outcomes at 12, 18 and 30 months of age. STUDY DESIGN: In total, 113 preterm infants were assessed with the NAPI at 36 weeks postmenstrual age. Later, neurodevelopment was examined using the Bayley Infant Neurodevelopmental Screener (BINS) at 12 months and the Bayley Scales of Infant Development, at 18 and 30 months. The cohort was divided into two groups, based on birth weight, extremely low birth weight (ELBW) (<1000 g) and VLBW (1000 to 1500 g). RESULTS: ELBW infants showed significantly lower NAPI scores compared with VLBW infants at 36 weeks. The predischarge NAPI scores correlated with the 12, 18 and 30 months scores when the ELBW infants continue to have lower performance than the VLBW infants. In all, 14 infants developed cerebral palsy. These infants had significantly lower NAPI, BINS and Bayley scores compared with all other preterm infants. CONCLUSION: NAPI before discharge provides clinically meaningful information related to later neurodevelopmental outcome.

Development of fetal and neonatal sleep and circadian rhythms.

The origin of sleep and circadian rhythms development is found during the fetal period. Both quiet (NREM) and active (REM) sleep are distinguishable during the last 10 weeks of gestation. Comparable to fetuses, low risk preterm infants recorded at 30-40 weeks postconceptional age, had a similar development of sleep i.e. an increase in quiet sleep and a decrease in indeterminate sleep. A further development in sleep organization characterized by increased slow wave and spindle activity during quiet sleep and coupling with circadian rhythm takes place during the first 6 months of life in both term and preterm infants.Circadian rhythm of fetal heart rate synchronized with maternal rest-activity, heart rate, cortisol, melatonin, and body temperature rhythms is present during the last 10 weeks of gestation. Although maternally influenced, circadian rhythm antenatally becomes ultradian at birth. Both preterm and term infants show a significant increase in circadian body temperature rhythm amplitude during the first 3 months of life.

Research in neonatology for the 21st century: executive summary of the National Institute of Child Health and Human Development-American Academy of Pediatrics workshop. Part I: academic issues.

This article presents the executive summary of the presentations and discussions at the Workshop on Research in Neonatology sponsored by the National Institute of Child Health and Human Development and the American Academy of Pediatrics Section on Perinatal Pediatrics convened in January 2004. In this article, the scientific aspects are summarized, highlighting the current knowledge gaps and identifying research priorities with a focus on emerging technologies. In a separate article, issues concerning workforce needs and shortages and board-certification requirements are presented. Full-length articles on the presented topics will be published in the Journal of Perinatology.

Neonatology research for the 21st century: executive summary of the National Institute of Child Health and Human Development-American Academy of Pediatrics workshop. Part II: training issues.

This is the second part of the executive summary based on the presentations and discussions at a workshop on research in neonatology sponsored by the National Institute of Child Health and Human Development and the American Academy of Pediatrics held in January 2004. In this article, neonatology fellowship training requirements and workforce issues are addressed, and the reasons for the shortage of physician-scientists, particularly of the underrepresented minority ethnic groups, are highlighted. Full-length articles from the presented topics are yet to be published.

Circadian and sleep development in preterm infants occurs independently from the influences of environmental lighting.

This study investigated the effect of intermediate nursery illumination on circadian rhythm and sleep development of preterm infants. Preterm infants were randomly assigned to one of two intermediate nursery rooms: a dimly lighted room, the dim (control) group, or a day-night lighted room, the cycled (intervention) group. Continuous rectal temperature and sleep were recorded at 36 wk postconceptional age (before discharge) and at 1 and 3 mo corrected age at home. Forty infants, 21 in the dim group and 19 in the cycled group, were recorded. The clinical demographic data and neonatal scores were similar between groups before the intervention. Circadian rhythms and sleep showed significant development with age, but there was no environmental lighting effect. Circadian and sleep organization seems to develop endogenously in preterm infants.

Candida (amphotericin-sensitive) lens abscess associated with decreasing arterial blood flow in a very low birth weight preterm infant.

In this report, we review the case of a candidal lens abscess in a premature infant girl who was 28 weeks' gestational age at birth. The culture obtained from the lens abscess grew Candida albicans sensitive to amphotericin B but resistant to flucytosine. This case is unique in that the infant developed a fungal lens cataract at 34 weeks' postconceptional age during the last week of a 30-day course of amphotericin B. The embryonic hyaloid artery system, which perfuses the developing lens, regresses between 29 and 32 weeks of gestation; thus, the mechanism for an infection of the lens may be inoculation of the lens by Candida before hyaloid artery system regression, followed by developmental loss of this blood supply, which makes the lens inaccessible to antimicrobial penetration. Candidal endophthalmitis with lens abscess is an uncommon morbidity that requires prompt recognition and surgical intervention for effective management.

Effect of position on sleep, heart rate variability, and QT interval in preterm infants at 1 and 3 months' corrected age.

OBJECTIVE: Prone sleeping position has a strong link to sudden infant death syndrome (SIDS), and the "Back to Sleep" campaign has played an important role in reducing SIDS. We tested the hypothesis that the mechanism of the sleep position effect is based on changes in sleep, arousal, heart rate variability (HRV), and the QT interval of the electrocardiogram. STUDY DESIGN: We studied 16 premature infants longitudinally, at 1 and 3 months' corrected age. Videosomnography recordings were made during the infants' normal daytime naps. Each infant was recorded in both supine and prone positions. The recordings were analyzed in 30-second epochs, which were classified as awake, active sleep (AS), quiet sleep (QS), or indeterminate sleep. Electrocardiogram data were sampled with an accuracy of 1 millisecond. Time domain analysis of HRV was measured by standard deviation of all R-R intervals and by the square root of the mean of the sum of the squares of the differences between adjacent R-R intervals. Frequency domain analysis was done for low frequency (0.04-0.14 Hz) and high frequency (0.15-0.5 Hz) HRV. We measured QT, JT, and R-R intervals during AS and QS for each position. RESULTS: We found no significant differences between supine and prone position, either in total sleep time or in percentage of QS. Percentage of AS was significantly lower in the supine position, but only at 1 month corrected age. The incidence of short, spontaneous, sleep transitions was significantly higher in supine, also only at 1 month corrected age. Time domain analysis of HRV showed a significantly lower variability in prone, but only during QS. Frequency domain analysis of HRV showed no differences between the 2 sleeping positions. Both QT and JT intervals were significantly longer in prone during QS, but only at 1 month corrected age. CONCLUSIONS: Despite the commonly held belief, prone position did not substantially increase total sleep at these ages. On the other hand, prone sleeping decreased the number of sleep transitions at 1 month corrected age, increased QT and JT intervals, and reduced HRV, thereby potentially increasing the vulnerability for SIDS. This study supports "Back to Sleep" as the position of choice not only for term but also for preterm infants after discharge home.

Neonatal brain magnetic resonance imaging before discharge is better than serial cranial ultrasound in predicting cerebral palsy in very low birth weight preterm infants.

OBJECTIVE: To compare the value of serial cranial ultrasound (US) with a single magnetic resonance imaging (MRI) before discharge in very low birth weight preterm infants to predict cerebral palsy (CP). METHODS: Infants who weighed <1250 g at birth and were <30 weeks' gestational age underwent conventional brain MRI at near term (36-40 weeks' postmenstrual age) using 1.5 Tesla MRI scanner. Sagittal and axial T1 and T2 fluid attenuated inversion recovery and gradient recalled echo images were obtained. Cranial US was also obtained at least twice during the first 2 weeks of life. MRI and US images were interpreted by 2 independent radiologists, who were masked to clinical outcome, and scored as follows: category 1, no abnormality; category 2, subependymal hemorrhage or mineralization; category 3, moderate to severe ventriculomegaly; category 4, focal parenchymal abnormality with or without ventriculomegaly. For the purpose of this study, 1 and 2 were categorized as "normal," and 3 and 4 were categorized as "abnormal." The infants were assessed at a mean age of 20 and 31 months using the Amiel-Tison standardized neurodevelopmental examination. RESULTS: The sensitivity and specificity of MRI for predicting CP were 71% and 91% at 20 month and 86% and 89% at 31 months, respectively. The sensitivity and specificity of US for predicting CP were 29% and 86% at 20 months and 43% and 82% at 31 months. CONCLUSIONS: As a predictor of outcome for CP, MRI at near-term in very low birth weight preterm neonates is superior to US. However, both US and MRI demonstrate high specificity.