Published online February 1, 2005
PEDIATRICS Vol. 115 No. 2 February 2005, pp. 468-474 (doi:10.1542/10.1542/peds.2004-2556)
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SPECIAL ARTICLE

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

Tonse N.K. Raju, MD*, Ronald L. Ariagno, MD{ddagger}, Rosemary Higgins, MD* and Linda J. Van Marter, MD, MPH§

* Pregnancy and Perinatology Branch, Center for Developmental Biology and Perinatal Medicine, National Institute of Child Health and Human Development, Bethesda, Maryland
{ddagger} Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University, Stanford, California
§ Children’s Hospital of Boston and Harvard Medical School, Boston, Massachusetts


   ABSTRACT
TOP
 ABSTRACT
BACKGROUND
 NEONATAL CARE IN THE...
 SUMMARY AND CONCLUSIONS
 REFERENCES
 
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.

Key Words: newborn infant • education • brain injury • bronchopulmonary dysplasia • necrotizing enterocolitis • research training • research infrastructure • minority health • health education • board certification

Abbreviations: NICHD, National Institute of Child Health and Human Development • AAP, American Academy of Pediatrics • IMR, infant mortality ratio • VLBW, very low birth weight • ELBW, extremely low birth weight • GI, gastrointestinal


   BACKGROUND
TOP
 ABSTRACT
 BACKGROUND
NEONATAL CARE IN THE...
 SUMMARY AND CONCLUSIONS
 REFERENCES
 
In January 2004, the National Institute of Child Health and Human Development (NICHD) and the Section on Perinatal Pediatrics of the American Academy of Pediatrics (AAP) convened the NICHD-AAP Workshop on Research in Neonatology in Bethesda, Maryland. The workshop addressed the basic and translational research issues in neonatal-perinatal medicine, identifying knowledge gaps and reviewing the role of promising methods such as genomics, proteomics, imaging, and molecular biology. Other issues addressed were the training needs for physician-scientists in neonatal-perinatal medicine and strategies to overcome the dwindling pool of physician-scientists and especially of women and underrepresented minorities in academic medicine.

This is the executive summary of the scientific topics presented and discussed at the workshop. Training and workforce issues are presented in a separate article. The topics identified may help the scientific community to formulate program agendas and the policy makers and funding agencies to develop research initiatives.


   NEONATAL CARE IN THE 21ST CENTURY
TOP
 ABSTRACT
 BACKGROUND
 NEONATAL CARE IN THE...
SUMMARY AND CONCLUSIONS
 REFERENCES
 
The US infant mortality ratio (IMR) was 6.8 per 1000 live births in 2001 but rose to 7.0 per 1000 in 2002.1 However, there has been an improvement in the survival rates for sick newborn infants of all birth weight subgroups. This encouraging trend also has led to an increase in the absolute number of survivors of neonatal intensive care, who remain at higher risks for long-term morbidities. The consequences of these trends have widespread implications for health care delivery and research requirements in rehabilitation and outcome, affecting all medical disciplines.

Despite the general improvement in IMR, the US rate still exceeds that of 25 other countries. There is a large racial disparity in all measures of perinatal health outcomes. The black and American Indian IMRs remain high,2 and in the former, the rates for low birth weight, very low birth weight (VLBW), preterm birth, multiple birth, and higher-order multiple birth remain nearly double that of the corresponding rates for the white population.2 These disparities need to be addressed urgently in all research endeavors.

Neuroscience
Research Opportunities
Basic and translational research is urgently needed in a wide range of neurologic topics (Table 1). In part this need is because of dramatic improvements in survival rates for extremely preterm infants at highest risk for long-term neurologic morbidity. Basic science research should extend our knowledge in molecular and biological mechanisms concerning the biochemical, nutritional, and environmental influences on brain growth and function, especially as related to neuronal differentiation, dendritic arborization, synaptogenesis, and glial functions. Other needed studies in the neurosciences include characterizing developmental patterns of neurotransmitters and their subtypes, their regional specificity, and role in brain function; studies in molecular biological processes (such as signal transduction pathways); and age- and gender-dependent differences in protein expression in the developing nervous system.


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  		TABLE 1. Neuroscience Research

 
These fields of basic science research might lend themselves into productive translational research. The new and exciting field of "cerebral immunology" can be explored to study cerebral inflammation response to hypoxia, ischemia, repair, and their long-term consequences. Studies should be designed to develop innovative strategies for providing "brain-friendly" care.

Resources
Developmental neuroscience research has long been performed in animal models to match the human brain. However, studies based on human tissues will offset the limitations of extrapolating data from animal studies. To this end, a concerted effort is needed to develop repositories of human tissues and organs. In this context, the existing NICHD-supported repository of brain tissues should be used more widely.3

Cardiopulmonary Research
Lung-related problems account for 20% of infant deaths, and along with heart-related conditions, they account for 24% of all infant deaths.4 The survivors of lung and heart diseases also tend to be at risks for long-term morbidities.

Research Opportunities
Research is needed to develop new approaches to prevent respiratory distress syndrome and reduce the burden of chronic lung disease and poor neurodevelopmental outcomes in surviving, very preterm infants. The identification of single-gene-deficiency lung diseases in infants will continue to increase our understanding of rare causes of lung disease. This is exemplified superbly in the discovery of the surfactant genetic ABCA3 transporter gene defect in term infants that causes lethal lung disease.5 The identification of complex genetic and environmental modifiers will also contribute to our understanding of disease susceptibilities.6

Research on molecular and genetic models of congenital heart diseases may help develop strategies for prevention. At present, only 6 genetic abnormalities are known to be associated with ~30% of cases of tetralogy of Fallot; more studies are needed in this field. Characterizing cardiac functions in newborns is also critically needed. Other research priorities are listed in Table 2.


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  		TABLE 2. Research in Cardiopulmonary Topics: Suggested Priorities

 
Resources
As in neurologic research, sophisticated genetic, molecular, and physiologic methods are needed for new and innovative cardiopulmonary research. Clinical research networks should continue to test new and established drug therapies that affect cardiovascular functions (eg, dopamine, dobutamine). In this context, the Newborn Drug Initiative being developed by the NICHD and the Food and Drug Administration, under the Best Pharmaceuticals for Children’s Act,7 may be useful.

Fetal and Neonatal Nutrition
Research Opportunities
Even with the best available nutritional support, VLBW and extremely low birth weight (ELBW; <1000 g birth weight) infants remain "growth restricted" at term gestational ages and have smaller head circumferences compared with healthy infants born at term. They also suffer from continued poor growth into childhood and adolescence, with a higher proportion remaining <5th percentile for height, weight, and head circumference. Of greatest concern is the high incidence of intellectual deficits and poor developmental outcomes in this group. Some of the long-term adverse outcomes could be secondary to nutritional deficiencies during critical phases of body and brain growth and associated long-term programming of growth-controlling messengers in the body.8–10

To reverse such trends, new information is needed about perinatal nutrition. A starting point in this endeavor could be to study the unique nutritional, metabolic, and growth requirements of the normally growing healthy fetus, which may enable us to translate the information learned from such studies into improved nutritional support for the high-risk preterm infant.

At a practical level, no nutritional regimen has been consistently shown to provide optimal growth and development of VLBW and ELBW infants. What is good for the normally grown infant may not be good for the VLBW infant. Thus, macro- and micronutrient requirement needs for infants at different degrees of maturity and growth need to be established. Likewise, most often it is forgotten that oxygen is a "nutrient."11,12 We need to define optimal oxygen therapy for growth while preventing multiorgan toxicity11 due to excess oxygen and pathophysiologic conditions such as patency of the ductus arteriosus and increased pulmonary vascular resistance due to oxygen insufficiency. Other research needs include studies to determine optimal glucose infusion rates; the lower and upper limits of normal plasma glucose concentrations beyond which deviations in plasma glucose concentrations might lead to reversible and irreversible morbidities13; and the roles and requirements of {omega}-3 and the {omega}-6 essential polyunsaturated fatty acids and of macronutrients such as proteins and fats14–17 (Table 3).


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  		TABLE 3. Fetal and Neonatal Nutrition: Suggested Research Priorities

 
Gastrointestinal Research
Research Opportunities
Developmental gastrointestinal (GI) science should be viewed as a complex array of wide-ranging topics, extending beyond necrotizing enterocolitis. During physician training and while planning research studies, one must consider incorporating topics in GI-tract development, GI-tract immunology, and the role of GI-tract dysfunction as foundations for adult-onset disorders.

The fetal GI tract is exposed to a continuous influx of large quantities of amniotic fluid during much of the second half of pregnancy, only to be interrupted after premature birth. The impact of this transition and the effects of GI-tract exposure to a "nonsterile" environment and to supplemental nutritional mixtures are unknown. Critically ill infants are not fed for long periods, and the resulting lack of luminal nutrients may lead to mucosal atrophy, reduced trophic hormones levels, and increased polymorphonuclear attraction and an increased risk for systemic inflammatory response syndrome. These aspects of GI development and physiology need to be studied.

The developmental biology of the intestinal microflora needs to be studied. The lumen of the intestine contains ~1013 microorganisms with ~300000 genes, which is 1 order of magnitude greater than all the somatic cells and genes of the human body. Yet, in healthy individuals, the GI tract acts as an important barrier. A better understanding of normal barrier function is needed to understand how dysfunctional barrier systems might cause diseases.18–22

The so-called leaky gut has been implicated in several diseases having their origins during infancy that manifest in later life. These diseases include atopy, food allergies, celiac enteropathy, and inflammatory bowel disease. The contribution of early neonatal GI maturation and injury and mechanisms involved in causing such later disorders need to be studied. We also need to learn if manipulations of the GI tract with proper enteral nutritional support may prevent long-term chronic illness such as type 1 diabetes, allergies, and asthma.23,24 Other needed GI research areas are listed in Table 4.


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  		TABLE 4. Neonatal Gastroenterology: Suggested Research Priorities

 
Research in Perinatal Epidemiology
Traditionally, scientists in all medical fields have addressed research in 2 broad categories: basic and translational. Although these are much needed as foundations for patient care, there is also a need for understanding the factors that might influence the practice patterns of health care providers at large. There may be barriers for implementing the best available care that need to be understood. This is the third category of research, generally called "operational research" or "health outcomes research." This area of work seeks to understand the origins of outcome by characterizing the social and genetic factors leading to poor outcomes. It also strives to find the factors that shape the practitioner’s perception of a need for intervention, comparing the observed result to an "ideal" outcome demonstrated in similar patients. These steps involve the analytic approaches developed by epidemiology and quality-of-care research.

There are major methodologic challenges in analyzing large databases for assessing grades of poor outcomes and for delineating factors contributing to bad outcomes. For instance, treatment interventions that are used rarely in term infants (assisted ventilation, vasoactive medications for blood pressure support) are used commonly in preterm infants. Thus, one must develop strategies to characterize morbidity regardless of gestational age by integrating both clinical and epidemiologic research findings.25,26

With increasing survival of high-risk infants, it may also be valuable to consider developing a nationwide database of neonatal intensive care unit survivors as a continued source for research in a wide range of epidemiology and health services research.

Opportunities in Perinatal Health Care Research
A series of studies on the variability of illnesses, hospitalizations, and outcomes in the 1970s revealed that medical outcomes varied across institutions and population subgroups. Some hospitals consistently document better outcomes even after controlling for differences in case mix, highlighting the role of quality of care in affecting outcomes. Assessing the quality of care as part of outcomes research has now assumed a great importance. However, for research and training in this field and for developing benchmarking strategies, there is a need for large, multiinstitutional databases.27–32

Structural Factors on Outcomes
Factors such as staffing, staff competency, the availability of support services, and organizational structure may modify the quality of perinatal outcomes. Yet, there has been little investigation in this area. Recent investigations on the role of time of birth on the risk of neonatal death among Swedish newborns showed that after controlling for differences in case mix, the first-week mortality of singletons born at night was increased 28%. These excess deaths accounted for almost 12% of all early neonatal deaths. This and similar studies in California draw attention to factors such as staffing, support services, organizational structure, and workforce-fatigue issues. Research aimed at identifying and ameliorating the factors responsible for large mortality burden should be a high research priority (Table 5).


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  		TABLE 5. Epidemiology and Healthcare Research: Suggested Research Priorities

 
Basic and Translational Research in Neonatal Pharmacology
Compared with the dramatic pace of improvement in survival rates for ELBW infants over the past 2 decades, research in pharmacology has lagged behind considerably. As a result, drug therapy for tiny infants has been largely empirical, based on data extrapolated from studies in more mature newborns, infants, children, and even adults.33–35 There is also a paucity of animal models comparable to ELBW infants in maturity for investigating the mechanisms of drug actions and toxicity.

For instance, it remains unclear if recent innovative therapies such as surfactant, inhaled nitric oxide,36 and newer antimicrobials contribute to long-term morbidities in ELBW infants. Because of differences in volume of distribution, protein binding, and other metabolic variables in ELBW infants, the concentrations of unbound drugs at the sites of their action may be quite different. Site-specific factors such as receptor numbers, binding affinity, and coupling of receptors to intracellular organelles also may alter drug effects. Similarly, barrier functions such as the blood-brain barrier and cutaneous barrier might also affect drug kinetics. The developmental aspects of these parameters have not been studied.

In a study of the effect of developmental changes in enzyme systems on drug metabolism, Lacroix et al37 evaluated the human hepatic cytochrome P450 3A family of enzymes. They found that as the enzymes switched from the fetal to the adult form (from CYP 3A7, testerone 16-{alpha} hydroxylation, to CYP 3A4, testosterone 6-ß hydroxylation), the activity of the fetal form remained higher in infants born before 30 weeks, with a further increase for 1 week before, tapering off thereafter. Such changes can have significant impact on drug handling and, if not fully realized, might lead to unanticipated complications, as has been reported for chloramphenicol, tolazoline, propylene glycol solvent, and dexamethasone.38,39

The mechanisms of adverse outcomes due to medications in ELBW infants are difficult to study, in part because of small numbers of subjects at single institutions and variation in care practices.40,41 Thus, there is a great need for multiinstitutional collaborative studies focusing on translational research to identify how medications may cause adverse effects in immature infants. Studies must integrate clinical findings, data from translational studies in animals, and data from research on molecular mechanisms to enable us to understand drug actions and side effects. Thus, there is a need for combining simple clinical pharmacology studies of pharmacokinetics, safety, and efficacy with complex translational studies in animal models and in vitro molecular approaches to explain molecular mechanisms. The extremely immature newborns who now survive represent a new frontier of pharmacology, requiring repetition of older studies in these infants, whose extreme immaturity may create a unique physiology.42–44 Suggestions for pharmacologic research are shown in Table 6.


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  		TABLE 6. Pharmacology Research: Suggested Research Priorities and Training Issues

 

   SUMMARY AND CONCLUSIONS
TOP
 ABSTRACT
 BACKGROUND
 NEONATAL CARE IN THE...
 SUMMARY AND CONCLUSIONS
REFERENCES
 
Remarkable advances in proteomics, genomics, imaging sciences, and other research methods are helping to decipher disease mechanisms and to treat conditions considered untreatable until recently. In this workshop organized by the NICHD and the AAP, opportunities for research in neonatal-perinatal medicine were discussed. It is hoped that future investigators will focus on these areas of research and that the funding agencies and institutes would consider prioritizing research in areas highlighted in this executive summary from the workshop.


   ACKNOWLEDGMENTS
 
The following is an alphabetical list of speakers at the workshop: Duane Alexander, MD (NICHD, Bethesda, MD); Ronald L. Ariagno, MD (Stanford University School of Medicine, Stanford, CA); Phyllis Dennery, MD (University of Pennsylvania, Philadelphia, PA); JoAnne Goodnight, PhD (National Institutes of Health, Bethesda, MD); Jeffrey B. Gould, MD (Stanford University School of Medicine, Stanford, CA); William W. Hay, Jr., MD (University of Colorado, Denver, CO); Rosemary Higgins, MD (NICHD, Bethesda, MD); Alan H. Jobe, MD, PhD (University of Cincinnati, Cincinnati, OH); Steven Klein, PhD (NICHD, Bethesda, MD); Gail A. McGuinness, MD (American Board of Pediatrics, Chapel Hill, NC); Josef Neu, MD (University of Florida, Gainesville, FL); William Pearce, PhD (Loma Linda University School of Medicine, Loma Linda, CA); Anna Penn, MD, PhD (Stanford University School of Medicine, Palo Alto, CA); Tonse N. K. Raju, MD (NICHD, Bethesda, MD); Catherine Y. Spong, MD (NICHD, Bethesda, MD); Marta Valcarcel, MD (University of Puerto Rico School of Medicine, San Juan, Puerto Rico); Linda Van Marter, MD, MPH (Children’s Hospital Boston, Boston, MA); and Robert M. Ward, MD (University of Utah, Salt Lake City, UT). The meeting agenda and the names of all registered participants will be published on the NICHD Web page (www.nichd.nih.gov).


   FOOTNOTES
 
Accepted Nov 23, 2004.

Reprint requests to (T.N.K.R.) National Institute of Child Health and Human Development, 6100 Executive Blvd, Room 4B03, Bethesda, MD, 20892. E-mail: rajut{at}mail.nih.gov

No conflict of interest declared.


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 NEONATAL CARE IN THE...
 SUMMARY AND CONCLUSIONS
 REFERENCES
 

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PEDIATRICS (ISSN 1098-4275). ©2005 by the American Academy of Pediatrics

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