Tonse N.K. Raju

Optimizing care and outcome for late-preterm (near-term) infants: A summary of the workshop sponsored by the national institute of child health and human development

In 2003, 12.3% of births in the United States were preterm (<37 completed weeks of gestation). This represents a 31% increase in the preterm birth rate since 1981. The largest contribution to this increase was from births between 34 and 36 completed weeks of gestation (often called the “near term” but referred to as “late preterm” in this article). Compared with term infants, late-preterm infants have higher frequencies of respiratory distress, temperature instability, hypoglycemia, kernicterus, apnea, seizures, and feeding problems, as well as higher rates of rehospitalization. However, the magnitude of these morbidities at the national level and their public health impact have not been well studied. To address these issues, the National Institute of Child Health and Human Development of the National Institutes of Health invited a multidisciplinary team of experts to a workshop in July 2005 entitled “Optimizing Care and Outcome of the Near-Term Pregnancy and the Near-Term Newborn Infant.” The participants discussed the definition and terminology, epidemiology, etiology, biology of maturation, clinical care, surveillance, and public health aspects of late-preterm infants. Knowledge gaps were identified, and research priorities were listed. This article provides a summary of the meeting.

Ischemic perinatal stroke : Summary of a workshop sponsored by the national institute of child health and human development and the national institute of neurological disorders and stroke

Ischemic perinatal stroke is a disorder associated with significant long-term neurologic morbidity. With an estimated incidence of 1 in 2300 to 5000 births, stroke is more likely to occur in the perinatal period than at any time in childhood. The incidence of ischemic perinatal stroke ranks second only to that of strokes in the elderly population. Although ischemic perinatal stroke is a well-recognized disorder, many aspects remain to be studied. There is no consensus on its terminology, definition, or classification. Several risk factors have been identified, but their precise roles in causing stroke are not well understood. There are no reliable predictors of ischemic perinatal stroke on which to base prevention or treatment strategies. To review these important issues and propose a research agenda, the National Institute of Child Health and Human Development and the National Institute of Neurological Disorders and Stroke convened a workshop in August 2006. This article provides a summary of the workshop.

Summary Proceedings From the Neonatal Pain-Control Group

Recent advances in neurobiology and clinical medicine have established that the fetus and newborn may experience acute, established, and chronic pain. They respond to such noxious stimuli by a series of complex biochemical, physiologic, and behavioral alterations. Studies have concluded that controlling pain experience is beneficial with respect to short-term and perhaps long-term outcomes. Yet, pain-control measures are adopted infrequently because of unresolved scientific issues and lack of appreciation for the need for control of pain and its long-term sequelae during the critical phases of neurologic maturation in the preterm and term newborn. The neonatal pain-control group, as part of the Newborn Drug Development Initiative (NDDI) Workshop I, addressed these concerns. The specific issues addressed were (1) management of pain associated with invasive procedures, (2) provision of sedation and analgesia during mechanical ventilation, and (3) mitigation of pain and stress responses during and after surgery in the newborn infant. The cross-cutting themes addressed within each category included (1) clinical-trial designs, (2) drug prioritization, (3) ethical constraints, (4) gaps in our knowledge, and (5) future research needs. This article provides a summary of the discussions and deliberations. Full-length articles on procedural pain, sedation and analgesia for ventilated infants, perioperative pain, and study designs for neonatal pain research were published in Clinical Therapeutics (June 2005).

New Therapies and Preventive Approaches for Necrotizing Enterocolitis: Report of a Research Planning Workshop

The National Institute of Child Health and Human Development and the Digestive Diseases Interagency Coordinating Committee held a workshop, chaired by Dr. W. Allan Walker, on July 10–11, 2006, to identify promising leads in necrotizing enterocolitis (NEC) research. The goals of the workshop were to identify new approaches to the prevention and treatment of NEC, to define basic and translational mechanisms of potential approaches to NEC, and to develop recommendations for clinical studies to reduce the incidence of NEC. Workshop participants implicated prematurity, introduction of enteral feedings, gastrointestinal bacterial colonization, gut motility, proinflammatory cytokines, impaired gut blood flow, and various neonatal complications in the pathogenesis of NEC. They concluded that a unifying hypothesis encompassing these pathogenetic factors is the uncontrolled exuberant inflammatory response to bacterial colonization that characterizes the intestine of premature infants. The inflammatory cascade appears to offer multiple targets for interventions with a variety of anti-inflammatory agents, including human milk and probiotics. Because of the rapidity with which the inflammatory response gets out of control in infants with NEC, workshop participants agreed that searching for ways to prevent NEC will be more rewarding than trying to identify ways to treat the condition once it has become established.

Vitamin E prophylaxis to reduce retinopathy of prematurity: A reappraisal of published trials

OBJECTIVE We conducted a meta-analysis of the published randomized clinical trials of vitamin E prophylaxis designed to reduce retinopathy of prematurity (ROP) to determine whether increased serum concentrations of vitamin E reduced the incidence of severe, threshold (Stage 3+) ROP in the very low birth weight (VLBW) infant subset. STUDY DESIGN Among the six trials considered eligible for analyses, the incidence for all stages of ROP and for Stage 3+ ROP was computed for all randomly assigned infants (intention-to-treat analysis) and for those infants completing the trials. Odds ratios (ORs) and pooled estimates for event rate reductions (and the respective 95% confidence intervals [CIs]) were calculated for these outcome end points. RESULTS There were 704 VLBW infants in the vitamin E prophylaxis groups and 714 in control groups; 536 (76.1%) infants in the vitamin E and 551 (77.2%) in the control groups completed the trials. In all trials the mean serum vitamin E concentrations were within or above the physiologic range in the vitamin-treated groups and at or below the physiologic ranges in the control groups. The overall incidence of any stage ROP was similar between the groups: 39.8% in the vitamin E group and 43.5% in the control group. The overall incidence for Stage 3+ ROP was lower in the vitamin E-treated groups than in the control group (2.4% in vitamin E vs 5.3% in control). The pooled OR for developing Stage 3+ ROP with vitamin E prophylaxis was 0.44 (95% CI, 0.21, 0.81, p < 0.02). The reciprocal of the pooled estimate of mean risk reduction (2.8%, 95% CI: 0.55%, 5.1%) for Stage 3+ ROP revealed that on average, vitamin E prophylaxis given to 35 VLBW infants would prevent one case of threshold, Stage 3+ ROP. CONCLUSIONS Considering that there was a 52% reduction in the incidence of Stage 3+ ROP, we suggest that the role of vitamin E in reducing severe ROP be re-evaluated. We could not assess the adverse effect rates from vitamin E therapy in the trials analyzed; therefore, we recommend a well-controlled and focused trial in which the issues of benefit, adverse effects, and cost can be assessed with vitamin E prophylaxis in extremely low birth weight (< 1000 gm) infants.

Hypothermia and other treatment options for neonatal encephalopathy: an executive summary of the Eunice Kennedy Shriver NICHD workshop.

HIE is not a single disease from a single cause, and is characterized by great diversity in the timing and magnitude of brain injury. It is therefore unreasonable to expect any single intervention to provide uniformly favorable outcome. The known heterogeneity in neuropathological changes after perinatal HIE combined with potential regional heterogeneity of treatment effects will lead to marked differential effects on outcomes among survivors of HIE (e.g. physical disability versus cognitive deficits). This underscores the need for longer term follow up of all infants with HIE undergoing any treatment. In spite of rapidly accumulating clinical and laboratory data related to hypothermia as a neuroprotective strategy for HIE, the speakers and discussants at the workshop underscored numerous gaps in knowledge in this field summarized in the Table, which compares the gaps identified at the 2005 NICHD workshop8 with current gaps. The participants noted that with only six completed studies1-6 providing information on follow-up for up to 18 months of age, the longer-term neurodevelopmental impact of hypothermia for HIE are pending.23,24 This, they concluded, should lead to an overall measure of caution in applying the new therapy of hypothermia indiscriminately for all cases of HIE. Table 1 Comparison of Categories of Gaps in Knowledge and Change from 2005 to 2010 Based on the available data and large knowledge gaps, the expert panel suggested that although hypothermia is unequivocally a promising therapy for HIE, a substantial proportion of infants still suffer from death or disability despite treatment. Further analysis of existing trial data, development of adjuvant therapies to hypothermia, development of biomarkers and further refinements of hypothermia therapy for use in infants suffering from HIE and clinical trials of therapeutic hypothermia in mid resource settings with different risk factors but adequate facilities and infrastructure are all urgently needed and were identified as areas of high priority for study.

Animal models for the study of perinatal hypoxic-ischemic encephalopathy: a critical analysis☆

We critically evaluated various design features from 292 animal studies related to perinatal hypoxic-ischemic encephalopathy (HIE). Rodents were the most frequently used animals in HIE research (26%), followed by piglets (23%) and sheep (22%). Asphyxia with or without ischemia was the most predominant method of producing experimental brain damage, but there were significant variations in specific details, particularly regarding the method and duration of brain insult. In 71% (207/292) of studies the CNS outcomes were tested within 24 h of experimental insult and in 29% (85/292) they were tested 24 h or more after the insult. Acute CNS metabolic end-points were assessed in 82-100% of all studies. In 90% of studies the chronological age of the animal was equivalent to that of human term newborn infant. However, in only 23% (67/292) were clinical neurological, developmental or behavioral outcomes evaluated, and in only 26% (76/292) was neuropathology assessed. While no single animal model was found to be ideal for all HIE research, some models were distinctly superior to others, depending upon the specific research question. The fetal sheep, newborn lamb and piglet models are well suited for the study of acute and subacute metabolic and physiologic endpoints, whereas the rodent and primate models could be used for long-term neurological and behavioral outcome experiments as well. We also feel that standardizing the study design features, including an HI insult method that produces consistent and predictable brain damage is urgently needed. Studies in neuro-ethology should explore how well brains of various animals compare with that of the newborn human infant. There is also a need for developing animal models that mimic clinical entities in which long-term neuro-developmental and behavioral outcomes can be assessed.

Pulmonary hemorrhage and exogenous surfactant therapy : a metaanalysis

A metaanalysis of surfactant clinical trials was carried out to assess whether or not an association exists between exogenous surfactant therapy and pulmonary hemorrhage. Trials that reported the pulmonary hemorrhage occurrence (group 1) and those that did not (group 2) were analyzed. Thirty-three treatment strategies were tested in 29 publications from 1980 through 1992. Eleven of these were group 1 trials, which reported a 3% overall incidence of pulmonary hemorrhage. The rates were significantly higher in both the treated and the control groups of natural surfactant trials than in synthetic surfactant trails (5.87% and 5.36% in the natural surfactant trials vs 2.51% and 1.04% in the synthetic surfactant trials, respectively). The pooled estimate of relative risk for pulmonary hemorrhage with any surfactant therapy was 1.47 (95% confidence interval 1.05, 2.07; p < 0.05). Logistic regression modeling revealed that the nature of surfactant, treatment strategy, and lower mean birth weight had a significant influence on the relative risk of pulmonary hemorrhage; a similar trend was seen with higher mortality rates. Variation in the rates of patent ductus arteriosus did not have an independent effect on the estimated pulmonary hemorrhage risk. Most group 2 trials were published before 1990, and the median total sample size was 73, compared with 402 for the group 1 trials (p < 0.05), most of which were published in the 1990s. In 10 (50%) of 20 group 2 trials, pulmonary hemorrhage data were collected methodically, in comparison with all group 1 trials, most of which collected data prospectively. We conclude that pulmonary hemorrhage is a rare complication of respiratory distress syndrome. An awareness of the possible association of pulmonary hemorrhage with surfactant use in later trials and the differences in definitions and reporting practices probably explain variations in the reported incidence among the trials. The risk of pulmonary hemorrhage increases slightly, on an average of 47%, with any surfactant therapy. This increased risk is small compared with the documented benefits of surfactant therapy in respiratory distress syndrome.

Hypothermia and other treatment options for neonatal encephalopathy

HIE is not a single disease from a single cause, and is characterized by great diversity in the timing and magnitude of brain injury. It is therefore unreasonable to expect any single intervention to provide uniformly favorable outcome. The known heterogeneity in neuropathological changes after perinatal HIE combined with potential regional heterogeneity of treatment effects will lead to marked differential effects on outcomes among survivors of HIE (e.g. physical disability versus cognitive deficits). This underscores the need for longer term follow up of all infants with HIE undergoing any treatment. In spite of rapidly accumulating clinical and laboratory data related to hypothermia as a neuroprotective strategy for HIE, the speakers and discussants at the workshop underscored numerous gaps in knowledge in this field summarized in the Table, which compares the gaps identified at the 2005 NICHD workshop8 with current gaps. The participants noted that with only six completed studies1-6 providing information on follow-up for up to 18 months of age, the longer-term neurodevelopmental impact of hypothermia for HIE are pending.23,24 This, they concluded, should lead to an overall measure of caution in applying the new therapy of hypothermia indiscriminately for all cases of HIE. Table 1 Comparison of Categories of Gaps in Knowledge and Change from 2005 to 2010 Based on the available data and large knowledge gaps, the expert panel suggested that although hypothermia is unequivocally a promising therapy for HIE, a substantial proportion of infants still suffer from death or disability despite treatment. Further analysis of existing trial data, development of adjuvant therapies to hypothermia, development of biomarkers and further refinements of hypothermia therapy for use in infants suffering from HIE and clinical trials of therapeutic hypothermia in mid resource settings with different risk factors but adequate facilities and infrastructure are all urgently needed and were identified as areas of high priority for study.

Isolated single umbilical artery anomaly and the risk for congenital malformations: a meta-analysis.

BACKGROUND/PURPOSE Single umbilical artery (SUA) is an associated finding in many chromosomal abnormalities and congenital malformations. However, SUAcan also be seen as an isolated finding. The extent of diagnostic investigation and follow-up needed in infants with SUA as an isolated finding has long been debated. In this study the authors examined this issue by an analysis of the published papers concerning SUA anomaly. METHODS A meta-analysis of 37 studies related to SUA published over a 40-year period was performed. Eleven of 37 studies were considered group 1 because the diagnosis of SUA was made using specimens obtained from early abortuses, fetal deaths, or autopsies. The remaining 26 studies were considered group 2 because the diagnosis of SUA was made from examining placental and umbilical cord specimens obtained from live-born infants or by examination of the umbilicus soon after birth. RESULTS The mean (and 95% CI) SUA incidence was 2.13% (1.92%, 2.34%) in group 1, and 0.55% (0.44%, 0.66%) in group 2. The mean incidence of congenital malformation associated with SUA was 66.3% (67.7%, 70.8%) in group 1, and 27% (21.6%, 32.3%) in group 2; these differences were significant (P< .05). In 7 of 26 group 2 studies, additional urologic investigations were performed in 204 infants who had an isolated SUA anomaly. Thirty-three of these 204 infants (16.2%, 95% CI, 7.7%, 25.6%) had some form of renal anomaly, but in 18 of 33 (54.5%) the anomalies were minor or self limiting. A cost-versus-benefit analysis showed that 14 isolated SUA cases need to be investigated to detect one major renal malformation; however, the value of detecting them early remained unclear because most of the anomalies would be apparent with good pediatric follow-up. CONCLUSIONS When SUA is an isolated anomaly in an otherwise healthy infant, there is a slight increase in the risk for renal malformations. This association is of similar magnitude to the coexistence of another anomaly with the presence of one anomaly. Most renal anomalies in isolated SUA cases are minor and self limiting, and even major anomalies are no different from those that are diagnosed during routine pediatric follow-up in otherwise healthy infants. Therefore, unless additional risk factors for malformations exist, the current data do not justify extensive urologic radiographic investigations in asymptomatic newborns having an isolated SUA anomaly.