The problem of late-preterm (near-term) births: a workshop summary.
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Biomedical subjects
Publications and source records attributed to Tonse N K Raju.
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This essay presents the early history on the evolution of concepts about the etiology of cerebral palsy, especially the contributions of the early pioneers. Insight into how they derived their hypotheses, including the errors they made, can help one understand the complex processes of deciphering etiologic associations.
The preterm birth rate (births before 37 completed weeks of gestation) has been increasing in the United States, largely driven by an increase in infants delivered between 34 and 36 weeks, often called near-term, but referred to as late preterm in this article. In 2004, the preterm birth rate was 12.5%, the highest rate since the National Center for Health Statistics began tracking such data. This article reviews the epidemiology of late preterm births and proposes a research agenda.
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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).
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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.
OBJECTIVE: The purpose of this article is to summarize the clinical, methodologic, and ethical considerations for researchers interested in designing future trials in neonatal analgesia and anesthesia, hopefully stimulating additional research in this field. METHODS: The MEDLINE, PubMed, EMBASE, and Cochrane register databases were searched using subject headings related to infant, newborn, neonate, analgesia, anesthesia, ethics, and study design. Cross-references and personal files were searched manually. Studies reporting original data or review articles related to these topics were assessed and critically evaluated by experts for each topical area. Data on population demographics, study characteristics, and cognitive and behavioral outcomes were abstracted and synthesized in a systematic manner and refined by group members. Data synthesis and results were reviewed by a panel of independent experts and presented to a wider audience including clinicians, scientists, regulatory personnel, and industry representatives at the Newborn Drug Development Initiative workshop. Recommendations were revised after extensive discussions at the workshop and between committee members. RESULTS: Designing clinical trials to investigate novel or currently available approaches for analgesia and anesthesia in neonates requires consideration of salient study designs and ethical issues. Conditions requiring treatment include pain/stress resulting from invasive procedures, surgical operations, inflammatory conditions, and routine neonatal intensive care. Study design considerations must define the inclusion and exclusion criteria, a rationale for stratification, the confounding effects of comorbid conditions, and other clinical factors. Significant ethical issues include the constraints of studying neonates, obtaining informed consent, making risk-benefit assessments, defining compensation or rewards for participation, safety considerations, the use of placebo controls, and the variability among institutional review boards in interpreting federal guidelines on human research. For optimal study design, investigators must formulate well-defined study questions, choose appropriate trial designs, estimate drug efficacy, calculate sample size, determine the duration of the studies, identify pharmacokinetic and pharmacodynamic parameters, and avoid drug-drug interactions. Specific outcome measures may include scoring on pain assessment scales, various biomarkers and their patterns of response, process outcomes (eg, length of stay, time to extubation), intermediate or long-term outcomes, and safety parameters. CONCLUSIONS: Much more research is needed in this field to formulate a scientifically sound, evidence-based, and clinically useful framework for management of anesthesia and analgesia in neonates. Newer study designs and additional ethical dilemmas may be defined with accumulating data in this field.
OBJECTIVE: This study was designed to develop a piglet model of neonatal hypoxic-ischemic encephalopathy, which would allow for serial assessments of long-term neurodevelopmental impairment. METHODS: In 12 newborn piglets, we produced hypoxia by 8% oxygen breathing for 5-91 minutes. We combined ischemia by reversible bilateral common carotid artery occlusion for varying times. Outcome measures were clinical neurological evaluation, magnetic resonance spectroscopy studies and brain histology. RESULTS: Those animals which received intravenous sedation and no mechanical ventilation showed poor tolerance to hypoxia-ischemia and died early in the course of the experiments. The use of inhalation anesthesia during surgical procedures and mechanical ventilation during hypoxia-ischemia was associated with long-term survival. Seven of eight animals that survived > or = 48 hr showed clinical neurological abnormalities, that later resolved. Magnetic resonance spectroscopy measurements did not change significantly following hypoxia-ischemia. None of the animals had histopathological brain lesions. CONCLUSION: When subjected to acute hypoxia-ischemia, piglets were likely to survive only if they were given such supportive measures as anesthesia and mechanical ventilation. Even with hypoxic-ischemic injury sufficient to produce acute signs of neurological dysfunctions, longterm, stable survival with no evident brain histopathological abnormalities was possible.
One of the most complex areas in perinatal-neonatal medicine remains the care of the mother delivering a newborn infant at the border of viability, referred to as "periviable" gestation. To address the knowledge gaps that preclude optimal, evidence-based care in this critical field of perinatal medicine, the National Institute of Child Health and Human Development organized a workshop in March 2004. This article provides a summary of the discussions, focusing on major knowledge gaps and prioritized suggestions for studies in this area.
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.
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.
In 1908, William Sealy Gosset, a chemist in an Irish brewery, published his second article on statistics in Biometrika under the pseudonym "Student." He chose this pseudonym because his company did not allow its scientists to publish confidential data. In the article, Gosset described a procedure to assess population means by using small samples. This was the origin of the "Student's t test." Dr William Silverman (1917-2004), a pioneer neonatologist, also used the pseudonym "Student." He sent thousands of notes, clippings, anecdotes, and quotations to Pediatrics with the signature line "Submitted by Student" that appeared as blurbs at the ends of articles since 1977. Both Gosset and Silverman were rigorous students of science. Silverman chose pseudonyms to seek readers' responses to the message rather than the messenger. He also wished that one would remain a perpetual student, ready to say "I don't know," and strive to understand the human side of medicine. This brief article provides a perspective on these 2 "students" of science.
In this study, we investigated the effect of dexamethasone on the long-term learning and memory functions in developing rats. In Sprague-Dawley rat pups, we administered a daily dose of dexamethasone (0.5 mg/kg/day) for three consecutive days in three groups of animals: the "ultra-early" group received steroids on postnatal days (PND) 1-3; the "early" group received the drug on PNDs 8-10, and the "late" group received the drug on PNDs 28-30. The control group was not given any medication. All animals underwent structured CNS examinations beginning on PND 15, and continued through PND 20. The pups were tested for spatial learning and memory functions using the Morris Water Maze (MWM) on PNDs 31 through 35, 45 through 49, and 59 through 63. They were also tested for reward-based learning and memory functions using Radial Arm Maze (RAM) on PNDs 70 through 72. We analyzed the effect of dexamethasone, postnatal age, and sex on neurological milestones, and learning and memory functions. We found that neurological examination findings were similar in all groups, as were the results of the reward-based learning using RAM. However, in the MWM, the total distance of swimming and the total time to find the hidden platform showed considerable difference among the groups. Although these functions improved with postnatal age, the female pups in all three steroid groups, and the male pups in the late-steroid group lagged significantly in learning and memory functions compared to the controls, and such lags were transient. However, the interaction terms between dexamethasone, age, and sex were also significant in MWM test results. Steroids administered postnatally may have transient, retarding effect on learning and memory functions, and that animal age and sex may modify such effects. Such lags are not global, but specific to the types of memory tests used, implicating different neural circuitries in the pathogenesis of such abnormalities. Although transient, if such adverse effects occur at critical phases during brain maturation, the implications for poor, long-term outcomes may be more significant. The mechanisms underlying such changes need to be explored.