Neonatology Research

MUSC Children’s Health Division of Neonatology is a national leader in efforts to change the recommendations for daily vitamin D intake for newborns and pregnant women, has pioneered the use of moderate hypothermia treatment to preserve neural function in asphyxiated neonates, and contributed importantly to the understanding of pulmonary development and mechanics in premature infants. The Division also supports a broad range of research, ranging from basic science to clinical investigation aimed at promoting the health of newborns. Research teams include physician investigators and trainees, doctorate trained investigators and trainees, research nurses and dieticians. We also have strong training programs for neonatology fellows, pediatric residents, and medical students, and they are often involved in research. Most faculty are involved in clinical/translational investigations through participation in multicenter trials and the emerging science of quality improvement/implementation science. The result is that patients in MUSC Children’s Health Neonatal Intensive Care Unit (NICU) have access to the latest cutting edge treatments and approaches to care, and to superior clinician-educator-scientists.

Nutrition and Metabolism:

The Neonatology Division’s World Class Nutrition Research Group focuses on the role of nutrition and growth in promoting improved neonatal outcomes. Active research projects include:

the influence of macronutrients on maternal and fetal health
the assessment and maintenance of neonatal growth, particularly of extremely preterm infants, with an emphasis on body composition (utilizing air displacement technology)
human milk bioactivity, gut microbiota and its effect on immune function and gut integrity
the balance of human milk and nutritional additives to optimize preterm infant growth and neurodevelopment
preterm infant calcium and phosphorus homeostasis and bone health
methods to increase maternal milk delivery to high-risk infants, a
vitamin D requirements during pregnancy and early infancy and childhood
the long-term effects of vitamin D on neurodevelopment, dental health, immune function and illness risk of preterm and term infants through childhood

Supporting these ongoing research endeavors is a long history of NIH and foundation grants (e.g., Thrasher Research Fund, Kellogg Foundation, March of Dimes).

Emphasis for ongoing and future research studies includes optimization of neonatal growth, the effects of human milk on body composition changes during infancy, and defining the role of gut microbiota during health and disease in the neonate. Currently with a 3 million-dollar grant from the Kellogg Foundation, we are conducting a large clinical trial to identify vitamin D’s effect on health and immune function during pregnancy from fetal development through the lifespan.

The overlap between research goals and clinical goals can be seen clearly as research in perinatal nutrition is applied in our neonatal nurseries. Projects promoting the use of human milk have had a substantial impact on our approach to the nutritional support of even our tiniest infants, and have saved lives due to a low rate of necrotizing enterocolitis. Additionally, a focus on the delivery of adequate calories and nutrients has led to a significant reduction in our rates of postnatal growth delay, a problem that is associated with long-term growth failure and brain developmental delay. A history of strong collaboration with Maternal Fetal Medicine has improved our understanding of maternal nutritional status and its impact on neonatal health.

Pulmonary Biology:

Led by a bench scientist with expertise in structural biochemistry and a physician neonatologist-researcher, our pulmonology group has a focus on three areas of lung development and lung disease in premature infants. The first of these is the study of lung surfactant associated proteins that are essential for normal lung function and preventing collapse of the air spaces in the lung. Most premature infants born six or more weeks early are deficient or lacking the most essential surfactant protein, referred to as Surfactant Protein B, or SP-B, and must be given surfactant mixtures derived from cow or pig lungs to improve survival and long term lung health. The goal of this area of research is to establish alternative approaches that would allow the infant to produce and secrete its own surfactant and make use of animal derived products unnecessary.

A second area of research involves the study of oxygen sensing proteins and pathways in alveolar cells and responses to low oxygen tensions observed during lung development or lung collapse. A very unique discovery by our lab is that pulmonary alveolar cells that are responsible for production of surfactant produce hemoglobin when exposed to conditions of low oxygen. Low oxygen tensions occur in several situations, including during lung development, as a result of specific lung diseases, and lung collapse. We aim to determine the role of hemoglobin in surfactant production by these cells. The third area of research focuses on the production of bioengineered scaffolds for culture of isolated primary cells in single or multi-cell type culture to mimic regeneration of lung tissue. This approach also allows very specialized studies required for the projects mentioned above. Most experiments designed to study lung health require the use of animal models or cell models that approximate human disease or development. To overcome this obstacle, we have developed a novel human lung tissue cryopreservation method that yields viable lung tissue and viable primary cells after thawing. This technique will allow us to expand our research beyond animal and cell culture models, thereby permitting specific examination of human lung development or disease.

Neuroprotection and Monitoring: Led by a Dr. Dorothea Jenkins, an academic neonatologist with almost 20 years’ experience at MUSC, with close collaboration from a team of physicians, bench researchers, and physical therapists, the primary research interest of this group is the pathophysiology of brain injury and neuroprotective strategies to mitigate such injury in vulnerable infants. Our research ranges from bench research using animal models of disease to translation research designed to bring bench advances to clinical fruition. After applying hypothermia to a baby boy with birth asphyxia in 1999 and having a good neonatal outcome, we conducted a seminal clinical trial investigating the use of hypothermia in prevention of secondary neuronal injury after brain injury in neonates. As a result of this clinical research study, and later, larger multicenter trials, the clinical use of hypothermia as a neuroprotective therapy was established as a national standard of care.

We are now investigating complex cytokine and chemokine interactions over time with hypothermia treatment after hypoxic ischemic injury in neonates. This work has led to interesting observations not only of increased inflammatory cytokines, but important modulatory actions of those cytokines at 24-36 hours after birth in the hypothermic group and resultant continued immunosuppression in those patients with worse outcomes. Through observations like these, we hope to improve the efficacy of current modalities of brain protection through adjunct therapies.

We have also been investigating neuroprotective interventions to add to the clinical effectiveness of hypothermia in neonatal animal models. We have extensive volumetric and behavioral data showing improved outcomes, including improved learning and working memory, in animals treated with hypothermia plus N-acetylcysteine and vitamin D.

Based on such pre-clinical data in an animal model of chorioamnionitis, the group is investigating the effectiveness of an existing pharmaceutical, N-Acetylcysteine, in chorioamnionitis. The study “Safety of N-Acetylcysteine in Maternal Chorioamnionitis” is an NINDS-funded pharmacokinetic study to determine the best dose of NAC administered to mothers with intrauterine infection, to protect the fetal brain against inflammatory injury. This work is been presented at national meetings and manuscripts addressing safety and pharmacokinetic data are ongoing. In addition, we have investigated MRS and DTI as MRI biomarkers in infants exposed to chorioamnionitis with Dr. Lakshmi Katikaneni, the Director of the Neonatal Follow-up Program, Dr. Denise Mulvihill, a pediatric radiologist, and biophysicists Drs. Helpern and Brown. With the collaboration of these individuals, we have demonstrated changes in myoInositol and N-acetyl aspartate in infants of women with chorioamnionitis which correlated with degree of fetal inflammatory response and neurodevelopmental outcome at 1 year of age in term infants who appear healthy in the nursery. As chorioamnionitis is a significant risk factor for developmental delay and cerebral palsy, these clinical investigations provide important new data indicating metabolic changes in the brain as a result of inflammation can be detected shortly after birth in otherwise healthy infants. We anticipate that these findings will ultimately allow us to identify otherwise well-appearing infants who require specialized follow-up developmental screening intervention.

Investigations of early neuromuscular biomarkers with the collaboration of Dr. Mulvihill (Pediatric Radiology), Dr. Moreau (Physical Therapy), Dr. Poon (Developmental Pediatrics) and Dr. Coker-Bolt (Occupational Therapy) are aimed at obtaining innovative neuromotor kinematic assessments as early measures of later motor and behavioral impairment after preterm birth or brain injury in young infants. Development of such quantifiable outcome measures benefits everyone involved in neuroprotective and behavioral outcomes research. In this pilot study, we followed high-risk infants through development, developed a novel scale for rapid assessment of motor deficits, and correlated this novel scale of ten motor items with neuroimaging to obtain reliable, early predictive measures for future neurodevelopmental consequences in several domains. We have obtained SCOR funding, completed enrollment of 22 preterm infants, and presented data on MRS, kinematics at 12 weeks corrected gestational age indicating ability to predict outcome at 12 months. This work spans several disciplines and resulted in presentations at NIH (invitational SCOR conference-2011), as well as at national meetings of the Pediatric Academic Society (3 abstracts), American Occupational Therapy Association (1 abstract), and the American Academy for Cerebral Palsy and Developmental Medicine (2 free papers) in 2012. Two publications are in preparation, one case report is accepted and another publication is in revision from this work. In addition, 8 occupational therapy students have won first or second place in the student research day presentations two years in a row exploring the many aspects of this data.

In these clinical and basic science research projects we aim to develop therapeutics at the same time that we try to better define the timeline of injury and recovery with biomarkers.

Clinical Investigation:

The division has been actively involved in multicenter trials of promising innovative treatments developed outside MUSC. Through such participation, our patients benefit from a range of emerging therapies that might not otherwise be available. Examples of participation in previous and ongoing multicenter trials include:

the delivery of surfactant to treat respiratory distress syndrome, a life-threatening disease of preterm infants, and severe respiratory failure in term infants,
the treatment of retinopathy of prematurity aimed at preserving vision in preterm infants progressing toward late stages of this disease,
the use of inhaled nitric oxide as a pulmonary vasodilator to treat severe respiratory failure in term and preterm infants and to prevent the progression of early lung disease in preterm infant.
the use of standardized approaches to the care of central catheters to prevent hospital acquired infections
use of antiviral therapy in congenital CMV infection, a serious congenital viral infection with significant morbidity.

Quality

The Division of Neonatology at MUSC Children’s Hospital has a history of dedication to quality and safety, and the integration of evidence into clinical practice. We are proud to have a division that merges scientific methodologies with the assessment of quality and safety and evidence-based medicine. The integration of information gained from multiple core conferences, interdisciplinary collaboration and application of research techniques to quality improvement enhances the ability for greater medical decision making and overall patient and family care.

An integrated Quality and Safety program based on Evidence-Based Medicine:

We benefit from an academic environment in which new and emerging approaches to medical care are available and in which there is an emphasis on continuous assessment of clinical outcomes as those approaches are integrated into practice. With systems of communication in place to disseminate information to staff nurses and clinicians, a comfort with the scientific method of data collection and analysis, and a multidisciplinary team approach to quality and safety, we have developed a robust system in which our staff expect to discuss approaches to patient care that require critical review.

Our approach to Quality, Safety and Evidence-Based Medicine permeates not only our clinical care but also clinical and educational conferences. The Quality and Safety Case Conference (Q’n’S) serves as a forum at which presentations and discussions will occur that support atmospheres of team development and practice assessment/improvement. The goals of this conference are to review care offered to patients in the nursery system and identify opportunities for improvement – either through analysis of processes that might be improved or through the analysis and expansion of processes that went well. Our Q’n’S meeting works in conjunction with our multidisciplinary practice management conference used to design and implement practice protocols in neonatal medicine. The goal of this meeting is to improve clinical care through the application of evidence or best practices to patient care. The third leg of this process is the analysis of evidence using a standardized approach to Journal Club.

Medical Simulation Training:

Practicing quality care is augmented through the use of medical simulations. The state-of-the-art simulation center at MUSC offers staff the opportunity to develop the skills to effectively use this exciting and very useful educational tool. The simulation project arose from a quality analysis of clinical performance, expanded into a response to changes in resident and fellow education and the educational needs of NICU staff, and incorporated a clearly defined process and outcome measures that will allow us to scientifically analyze effectiveness of this tool in education and clinical outcomes. Our teams participate in simulations of the first two hours of postnatal life (our Golden Hours Project) addressing the stabilization of sick newborns and initiation of therapies in a timely and standardized manner. The Golden Hours Simulation initially developed as a multidisciplinary tool by fellows, nurse practitioners, and faculty, but has grown into an important part of our training of NICU and Obstetrical Delivery Room clinical teams. Simulation mannequins have also provided practice for perfecting procedural techniques in the neonate. Our use of simulations emphasizes our integration of the application of scientific principles to quality and safety and the integration of quality and safety in education