The Division of Neonatal Medicine joined the National Institute for Child Health and Development (NICHD) Neonatal Research Network in 2000 and was renewed in 2006 and again in 2011. Duke is one of 16 major U.S. intensive care units that belongs to the Network. The mission of the Network is to join hospitals together to answer questions about the health of newborn babies that cannot be answered by one hospital alone. Ronald Goldberg, MD is the principal investigator and Michael Cotten, MD is the alternate.

 

In a single year, the Network collects information on characteristics and outcomes of over 3,000 VLBW infants in a generic database, which now includes over 40,000 subjects. Drs. Cotten, Goldstein, Benjamin, and Goldberg are leading Network collaborations on epidemiologic investigations of infectious disease, necrotizing enterocolitis and brain injury. Drs. Cotten, Goldberg, and Goldstein continue to work with the Network to develop protocols to explore the impact of common genetic variations on risk of morbidity and mortality among high risk infants. Drs. Cotten and Goldberg received Network funding for development of the largest and most comprehensive DNA bank for extremely premature infants. The goal of this resource is to allow initial investigations of genetic associations with the complex diseases associated with premature birth.

Neurodevelopmental Follow-up, Community-Based Education and Outcomes Research

The Developmental Team in the Intensive Care Nursery, developed and headed by Ricki Goldstein MD, provides a continuum of developmental care for infants, and education and support for parents from the time of admission through the first couple of years following discharge. The members of the Developmental Team have established a close working relationship with community interventionists and child service coordinators. Together, they provide evaluation and intervention services after discharge until school age.

The Developmental Team initiated a program of early intervention for hospitalized infants and young children (ages birth to three) and their families. Through this program, funded by a grant from The Duke Endowment, these developmental specialists support and educate parents to be health care and developmental advocates for their high-risk infant or young child. Information is gathered to make infants eligible for the Infant Toddler Early Intervention Program in the community after discharge. In the hospital, they communicate with their child's health care providers and buy necessary items prior to discharge home. This program is being evaluated through a series of pre and post-program questionnaires that measure family needs and parent empowerment.

Dr. Goldstein also received funding from the Duke Endowment to establish an educational program for well-child care providers and community interventionists concerning the post-discharge medical and developmental needs of premature and other high-risk infants. Through a series of educational workshops presented on a local, state, and national level and development of a website, this program will provide pediatricians, family practitioners, and community interventionists with the knowledge needed to manage the complicated health care and developmental issues that these babies often experience after discharge.

In addition, a collaboration between Dr. Goldstein and Dr. Amy Needham, in the Department of Psychological and Brain Sciences, has begun to study the efficacy of premature babies wearing "sticky mittens" in order to enhance the development of proper reaching skills in early infancy. Dr. Goldstein will work with Dr. Needham, who has previously studied normal motor and cognitive development in healthy full-term infants, to determine if the development of premature infant skills can be influenced in the same ways as full term babies. This may lead to better understanding the differences in development of full term and premature infants and enable more effective intervention strategies to be developed.

Finally, Dr. Goldstein and members of the Developmental Team have also partnered with the NC affiliate of the March of Dimes in their campaign to reduce the occurrence of prematurity and improve the health and developmental outcomes of those born prematurely.

NPRI and the NICHD Neonatal Research Network

Clinical Studies

Duke faculty have taken lead roles in Neonatal Research Network trials: "Early Diagnosis of Candidiasis," Dr. Danny K. Benjamin, Jr., Protocol Chair; and the "Anonymized DNA Bank and Linked Databases," initiated and developed by Dr. Michael Cotten. The latter study links population-based assessment of genetic markers with diseases of premature infants. They and other collaborators at Duke have submitted proposals to assess variations in candidate genes for associations with gram negative bacterial and Candida infections. Dr. Cotten is developing a prospectively collected DNA sample bank for premature infants. Dr. Ricki Goldstein proposed and wrote the NRN's first candidate gene association studies for apolipoprotein E (apoE) and cytokine polymorphisms and clinical outcomes. Her studies provided the impetus for developing the Anonymized DNA Bank.

Active and Recently Completed NRN Projects

• The Generic Database (GDB): the GBD is the cornerstone of the NRN's activity. Over the past four years, Dr. William Malcolm in our division has successfully proposed a two year observational study to further our understanding of the diagnosis and treatment of gastroesophageal reflux disease (GERD) in premature infants as a foundation for a prospective interventional study.
• Generic Database Follow-up Study of ELBW Infants (401-1000 g): We have used GBD follow-up data to measure the impact of gestational age on neurodevelopmental outcome among preterm infants stratified by severity of intracranial hemorrhage (IVH), as well as outcome after Candida infection.
• Improved Diagnosis of Candida Infections in ELBW Infants: the Duke site has been able to make a unique contribution to NRN through the Candida project. The Candida project is a unique public-private partnership between three industry partners, the NICHD and a private research foundation. The Candida study tests the sensitivity of practitioners' clinical judgment and the utility of three novel diagnostic tests to identify candidiasis. Dr. Benjamin is the Principal Investigator. Dr. Benjamin has collaborated with faculty from the Duke Medical Mycology Research Unit, including Drs. John Perfect and Tom Mitchell, as well as Dr. Thomas Walsh at the National Cancer Institute, in developing this study. Dr. Brian Smith, a Duke neonatology fellow, is working on the PCR diagnostic test for Candida. Drs. Benjamin and Mitchell are collaborating with industry to develop point-of-care and rapid PCR testing using nanotechnology and fluidics to diagnose candidiasis. As a secondary to this study, Dr. Cotten is collecting DNA test samples to assess the associations between immune factor genetic variation and infection risks.
• A Randomized Controlled Trial of Induced Hypothermia for Hypoxic Ischemic Encephalopathy (HIE).
• Aggressive or Conservative Phototherapy for Extremely Low Birth Weight (ELBW).
• A Randomized Trial of Benchmarking Intervention to Increase Survival Without Bronchopulmonary Dysplasia (BPD) in Infants <1250 g.
• SUPPORT "Surfactant Positive Airway Pressure and Pulse Oximetry Trial" is a factorial design study testing routine intubation and treatment with surfactant against delivery room CPAP and the effect of maintaining oxygen saturation between 86-89% vs 91-94%.
• Surgical NEC Observational Study: the goal of this study was to collect data outcomes of infants treated with exploratory laparotomy vs drain placement.
• aEEG to Predict Outcome after HIE.
• Blood Inositol Status Among Neonates.

NRN-Duke Genomic Protocols

• Anonymized DNA Bank and Linked Database: Dr. Cotten successfully proposed that NRN enter the field of Genomic Medicine with development of an anonymized DNA bank linked with each sample's anonymized clinical data. The NRN created a Genomics Subcommittee for which Dr. Cotten serves as a pivotal consultant. The DNA bank, which will be developed from samples obtained from 1,000 ELBW infants during the NRN Cytokines Study, received NRN funding in 2004-05. The Bank will be the largest collection of samples from ELBW infants with extensive clinical follow-up data to be used for candidate gene association studies. This resource is an important initial step in uncovering genetic links with diseases unique to ELBW infants.
• Association of Inflammatory Cytokine Genotypes with Brain Injury, Neurologic Recovery and Neurodevelopmental Outcome in ELBW Infants (R. Goldstein and C. Cotten).
• Association of Apolipoprotein E (APOE) Genotype with Brain Injury, Neurologic Recovery and Improved Neurodevelopmental Outcome in ELBW Infants (R. Goldstein, C. Cotten). These NRN studies stimulated development of the anonymized DNA bank concept. They will test the association between genetic variation in factors related to risk of neural impairment following injury and outcome in ELBW infants.

Duke Proposed NRN Protocols in Development

• Probiotics - Phase I Study: Dr. Cotten is developing Phase I studies of probiotic safety and dosing and methodologies to monitor colonization by various microorganisms. Phase I studies began in fall 2005. Dr. Cotten is collaborating with Dr. Ken Wilson (Department of Medicine, Infectious Diseases), who has done extensive research in commensal bacterial interaction with host immunity.

Duke Initiated Candidate Gene Association Studies

• Coagulation Factor Polymorphisms and Risk of Intracranial Hemorrhage in ELBW Infants (T. Mitchell, R. Morris, C. Thornburg, A. James, R. Goldberg, C. Cotten). This study will test associations between a panel of genetic variants in coagulation factors with risk of severe IVH.
• Innate and Adaptive Immune System Polymorphisms and Risk of Gram Negative Sepsis in ELBW Infants (C. Cotten, R. Goldberg, M. Speer, D. Benjamin). This study will test associations between polymorphisis inTNF, mannose binding lectin, toll-like receptor 4 (TLR4), IL-6 and IL-10 with risk of gram negative infections.
• Innate and Adaptive Immune System Polymorphisms and Risk of Candidiasis in ELBW Infants (C. Cotten, R. Goldberg, M. Speer, D. Benjamin). This study will test associations between these polymorphisms and risk of Candidiasis.

Recently Completed Multicenter Research, Non-NRN

• Selective head cooling with mild systemic hypothermia after HIE: The Cool Cap Trial.
• INO for Prevention of CLD.
• Early Treatment for Retinopathy of Prematurity (ETROP) Randomized Trial. Duke enrolled 36 patients.
• CINRGI Trial - INO for Treatment of Term Infants with Persistent Pulmonary Hypertension.
• NABI-1408: Double Blind, Randomized, Multicenter Stratified Study to Assess the Safety of an Intravenous Staphylococcus aureus Immune Globulin (Human) [Altastaph T ] in VLBW Neonates (D. Benjamin, PI).

Single Center Studies: Ongoing

• Development of Inhaled Ethyl Nitrite (ENO) for the Treatment of Pulmonary Hypertension (R. Goldberg, R. Auten, J. Stamler, R. Califf). Investigations at Duke have shown that inhaled ENO is a potentially safer and more potent pulmonary vasodilator than inhaled nitric oxide since it avoids oxidative activation and formation of higher order nitrogen oxides. The initial work that eventually resulted in a clinical trial was done by Dr. Martin Moya (PNAS, Lancet), a Neonatology fellow. Dr. Michael Brandler, a neonatology fellow, also working with Dr. Jonathan Stamler, evaluated a new pulmonary vasodilator in piglets.
• Investigation of Impedance Monitoring in the Diagnosis of GERD (Gerber Foundation): (W. Malcolm, R. Goldberg, R. Goldstein, D. Benjamin, C. Cotten). Dr. Malcolm is studying the use of impedance monitoring to diagnose GERD in growing preterm infants. This grant will support a randomized clinical trial of pharmacologic vs feeding strategy intervention for reflux.
• NIH Pediatric Pharmacology Research Unit (PPRU) pK and pD of Antimicrobials in Infants: (C. Cotten, D. Benjamin). Dr. R. McKinney is the site PI for the joint Duke-UNC site for the NIH PPRU. Dr. D. Benjamin is the alternate. Drs. Cotten and Benjamin will collect population pK samples from premature infants.
• ApoE Genotype and Risk of BPD in Premature Infants: Dr. Goldstein completed follow-up and genotyping on 200 infants and identified an association of the apoE4 allele with risk of BPD. Confirmation of this finding could lead to new approaches and hypotheses regarding pathophysiology, treatment, and prevention of BPD.
• DNA Feasibility Pilot Study: In this pilot study by Dr. Cotten, cord and scavenged blood samples are being evaluated to assess quality and quantity of DNA from these sources. The first samples have been extracted and amplified and plans to do qualitative genotyping to assess contamination with maternal DNA are underway. This study will provide background information for the optimal samples to use for the NRN Prospective DNA Bank. The study is fully supported by the NPRI.
• Preterm Infants: Light Effects on Health and Development: Dr. Debra Brandon is extending her previous work on the effects of cycled light vs continuous near darkness in ELBW infants (5R01NR008044-02). Cycled light promotes circadian rhythms and appears to have advantages over keeping infants in continuous near darkness, but it is unclear at what gestational age the intervention should be initiated.
• Effects of No Sting® Skin Protectant Vs Aquaphor® on Skin Maturation and Condition in Infants < 33 Weeks Gestation: this was a randomized control trial evaluating the effects of No Sting® vs Aquaphor® on preterm infant skin integrity and transepidermal water loss. Dr. Brandon plans to use this pilot study to design a multicenter trial aimed at determining best practices for preterm infant skin care.
• Education of Families and Caregivers to Improve Care and Outcome of High Risk Infants (R. Goldstein, Duke Endowment). This is a two-part study: 1) Community Pathways - Early Intervention for hospitalized children and their families. This is part of an ongoing multicentered demonstration project evaluating the benefit of beginning early intervention while the child is still in the hospital. One hundred fifty (150) families have been enrolled in the first two years. Preliminary data analysis confirms education improves family satisfaction and empowers parents to advocate for their child's intervention after discharge. 2) Improving the post-discharge care of high risk infants and young children. This portion of the study seeks to develop an educational program for primary care providers concerning the special medical and developmental needs of high risk infants.
• Development of a Tandem Mass Spectrometry-based Assay for Pharmaceuticals and Physiologic Substances in Neonates (D. Millington, Ph.D. Co-PIs: C. Cotten, T. Michell [former Duke neonatology fellow]). This study will assess accuracy of a new assay for measure caffeine, gentamicin, and cortisol levels in blood spots.

Databases and Surveys

• PICC Practice: Dr. Debra Brandon has surveyed academic tertiary care centers to evaluate practice variation in peripherally inserted central catheters (PICCs). Her work will provide background information for planning a multicenter trial to identify best PICC line practices to reduce risk of nosocomial infections associated with PICC line use.
• Inhaled Nitric Oxide Registry: Kathy Auten, the Duke NRN coordinator, developed with the CINRGI study PI (Dr. Reese Clark, former division faculty) a global registry of information on full term neonates who had been treated with inhaled nitric oxide (INO) for hypoxic respiratory failure. The de-identified dataset contains information on 742 infants from 38 medical centers and has been queried regarding the effect.