Conducting bench and clinical research in the field of neonatal medicine is an essential mission of this division. Without research, the field of Neonatology does not go forward. The division is committed to studying the underlying processes of the diseases that affect our patients and bringing those discoveries to the bedside in a timely way in order to improve important health outcomes such as neurodevelopment, nutrition, metabolic and cardiovascular health and immune health. Our research investments span from fundamental laboratory science to clinical trials and occur globally as well as locally. The following is more information on our faculty’s areas of research effort.
Growth & Development
Infant Body Composition and Long-tern Health Outcomes
Sara Ramel, MD, Ellen Demerath, PhD, and Michael Georgieff, MD
The neonatal period encompasses a very critical growth period for multiple organ systems. Changes in body composition during this time have an effect on later cognition and potentially also future obesity risk. Research in this area is aimed at providing better care for premature babies in the future by determining optimal growth patterns and matching the clinical treatment and nutrition of infants to their individual needs. Our research team has developed the first set of reference curves for preterm infant body composition using air displacement plethysmography. We have also uniquely discovered that optimizing linear growth and fat free mass gains in infancy is associated with improved neurodevelopment out to preschool age and that early fat mass gains after hospital discharge are associated with increased blood pressure at preschool age. We continue to investigate the role of early body composition changes on long-term neurodevelopment, as well as several markers of later metabolic health in larger cohorts with longer term follow-up. This research has been funded by The March of Dimes Foundation and an Amplatz Scholar Award from the Department of Pediatrics
Enhanced Early Nutrition Intervention for Preterm Infants to Improve Neurodevelopment and Minimize Metabolic Risk
Sara Ramel, MD and Ellen Demerath, PhD
Preterm infants undergo early growth failure while in the Neonatal Intensive Care Unit (NICU) that persists for years after discharge home. This growth failure is occurring at a time of rapid brain development, and has been associated with negative long-term neurodevelopmental outcomes. In addition, early growth failure is often followed by rapid catch-up growth in childhood, which is associated with later metabolic (obesity/diabetes/hypertension) risk. Enhanced early nutrition has been associated with improved weight gain and neurodevelopment in several small observational studies, but is not routinely provided due to hesitancy surrounding possible intolerance and concern that increased nutrition will lead to increased adiposity. Lack of randomized controlled trials on this question create concern that the observed benefit of enhanced early nutrition is actually the result of confounding, whereby healthier babies are from the start inadvertently more likely to receive better nutrition, and also exhibit faster growth and better health outcomes. In this trial infants are randomized to higher amounts of calories and protein in the first week of life and are being followed up with close monitoring of their growth, body composition, neurodevelopment and blood pressure to determine if early optimized nutrition can improve both cognition and overall health. This research is funded by the Department of Pediatrics R Award.
Bedside Ultrasound to Assess Body Composition and Predict and Optimize Metabolic and Neurodevelopmental Outcomes in Premature Infants in the NICU
Sara Ramel, MD and Emily Nagel, PhD
Early body composition changes in preterm infants are associated with later neurodevelopmental and metabolic health. Tools to measure body composition in preterm infants are emerging, but each have their own set of limitations. Our previous work has utilized Air Displacement Plethysmography, however this method is limited to use in infants who are stable off of respiratory support. In contrast, ultrasound can be performed at the patient’s bedside, with minimal movement of the patient and without exposure to radiation, allowing for more frequent measurements regardless of medical stability. This study will determine if measures of adipose and muscle tissue thickness and area are predictive of whole body composition and also to identify clinical factors (nutritional and non-nutritional) which are associated with ultrasound measurements of muscle and adipose tissue. The overall goal is to determine whether these ultrasound measurements are predictive of later metabolic and neurodevelopmental outcomes in premature infants, a population at risk for developmental delay, obesity, and metabolic disease. We hypothesize that a better understanding of these relationships will lead to the incorporation of ultrasound into routine nutritional management of preterm infants and allow for future optimization of their overall health and development. This research is funded by The Gerber Foundation, Healthy Foods Healthy Lives, and The Caplan Foundation.
The 4M Project: Maternal Metabolism, Milk, and the Microbiome
Cheryl Gale, MD, Ellen Demerath, PhD, and Dan Knights, PhD
Prevalent maternal metabolic disease is an evolutionarily novel condition for the human species and increases the risk of offspring obesity by 3-fold. Breastmilk is a highly complex fluid and an important link between mother and infant, yet little effort has yet been made to systematically examine how maternal metabolic dysregulation is associated with variation in breastmilk, including breastmilk microbiota (communities of bacteria and fungi). We know that the gut microbiome develops during a critical period from fetal life to 2 years of age and appears to play a causal role in the origin of obesity and diabetes. However, the question of whether maternal obesity, gestational diabetes and other metabolic characteristics are transmitted to their infant via the alteration and vertical transmission of the breastmilk microbiome has not been answered. Our objective is to identify differences in the breastmilk bacterial and fungal microbiome among women in three metabolic status groups: gestational diabetics, obese non-diabetics, and normal weight non-diabetics, to discover metabolism-specific microbiome features that are vertically transmitted from breastmilk to the infant gut, and to correlate these features with infant growth during the first 6 months of life. This study is funded by the National Institute of Child Health and Human Development and the University of Minnesota Office of Academic and Clinical Affairs.
Gut Microbiomes and Early Human Neurodevelopment
Cheryl Gale, MD, Marie Hickey, MD, Ellen Demerath, PhD, Michael Georgieff, MD, and Dan Knights, PhD
Exciting pre-clinical research supports a role for gut microbes (microbiomes) in modulating brain function and behavior (the "Microbiome-Gut-Brain Axis"). An important observation stemming from studies in animals is that developing brains are more susceptible to the effects of microbiome modulation than mature brains, supporting the idea that there is an early-life sensitive period for brain developmental programming by the microbiome. The hippocampus, a brain region responsible for learning and memory, is a target of microbiome-mediated effects in adult mice; however a relationship between early-life microbiomes and hippocampal function in humans has not been studied. In this study, we are using state-of-the-art computational strategies to discover microbiome determinants of hippocampus function. Gut microbiomes are being characterized by next-generation sequencing of fecal DNA. Hippocampus function is being determined in infants using established auditory and visual recognition event-related EEG recordings. In particular, we are interested in determining the effect of microbiome disruption by early-life antibiotic exposure on hippocampal processing of auditory and visual stimuli. It is hoped that the results of this research will provide evidence that gut microbes affect the brain at very early times in postnatal human neurodevelopment with the potential, then, of being important for shaping long-term brain health. This research isbeing funded by the Department of Pediatrics and the National Institute of Child Health and Human Development.
Preterm Epo Neuroprotection Trial (PENUT Trial)
Raghavendra Rao, MD, Sara Ramel, MD, Erin Osterholm, MD, Nancy Fahim, MD, and Erin Stepka, MD
The purpose of this study is to prevent neurodevelopmental impairment associated with extreme prematurity (babies born at 24 to 28 weeks of gestation). These infants are at high risk for developing long-term problems with their growth and development. These problems include cerebral palsy, deafness, blindness, and mental retardation. We know that premature infants are most vulnerable in the first days after birth, but their brain remains at risk for injury until they are close to their due date. A medicine called Erythropoietin (Epo) may lessen the risk of long-term developmental problems if given when the baby’s brain is at risk. This medicine is commonly used in preterm infants to help them make red blood cells. The dose used for making red blood cells has been well tested and is safe in these babies, but the dose needed for brain protection is higher. We want to find out if Epo can work to protect premature babies from having neurological problems (brain problems), and if the higher dose of Epo is safe for premature babies. These children will be followed through school age. This study is funded by the National Institute of Neurological Disorders and Stroke (NINDS) and is being conducted in collaboration with neonatologists at The University of Washington.
Laryngeal Mask Airway for Surfactant Administration
Kari Roberts, MD
Respiratory distress syndrome (RDS) is a disease process where premature infant lungs are not able to produce a detergent-like substance, called surfactant, which coats the air sacs and helps keep them open for maximal breathing efficiency. Mainstays of treatment for RDS include mechanical ventilation (breathing machine), nasal continuous positive airway pressure (nCPAP) (prongs in the nose which push air into the lungs and help keep the air sacs open) and/or surfactant medication. Administration of surfactant currently requires placement of a breathing tube so the surfactant medication can be delivered into the lungs and the infant being on a breathing machine afterwards. This study investigates the use of a novel device, called a laryngeal mask airway (LMA) to administer surfactant into the lungs of infants born between 28 and 36 weeks gestation on nCPAP. The study showed 26% fewer babies required having a breathing tube placed and being on a breathing machine if surfactant was administered through an LMA. This method of delivering surfactant is now being used in NICUs across the USA and around the world. This study was funded by the Minnesota Medical Foundation and Children’s Hospital Association.
Neonatal Anemia and Its Treatments: Effects on Neurodevelopment
Michael Georgieff, MD
Anemia due to excessive phlebotomy is a common medical condition of preterm infants that affects neurodevelopmental outcomes. Potential therapies for PIA include erythropoietin (rHuEPO) administration and red blood cell transfusion (RBCTX). Each therapy has the potential advantage to relieve tissue hypoxia induced by anemia, but also expose the rapidly developing premature neonatal brain to potential neuropathologic processes. Treatment with rHuEPO may be neuroprotective or alternatively, shunt limited neonatal iron reserves into RBCs and thus restrict iron delivery, leading to worsening brain iron deficiency (ID), which profoundly affects the developing brain, including its genome, metabolome, structure, intracellular signaling pathways, electrophysiology and behavioral output. RBCTX, while alleviating tissue hypoxia due to anemia, places the brain at risk for iron overload, inflammation and suppression of endogenous EPO production – a potential neuronal growth factor. The overall research aim is to evaluate whether rHuEPO treatment or RBCTX to relieve PIA in a developmentally appropriate model of preterm infants, the newborn mouse pup between postnatal days (P) P3 and P13, improves regional brain development and function in the neonatal period and in young adulthood following resolution of anemia. This study is part of a Program Project Grant sponsored by the National Institutes of Health's National Heart, Lung, and Blood Institute.
Impact of Breast Milk-Acquired Cytomegalovirus Infections on Clinical Outcomes in Premature Infants
Erin Osterholm, MD and Mark Schleiss, MD
Infections with human cytomegalovirus (CMV) are common in children and babies. Most CMV infections that occur after birth do not cause illness or long-term issues, but CMV sometimes causes serious illness. Infants commonly acquire CMV infection by breastfeeding and normal term infants usually have no symptoms. In premature infants however, the spectrum of CMV disease is unknown. There is also no consensus on whether efforts should be made to prevent or treat breast milk-acquired CMV infections in premature infants. The goal of this study is to determine the rate of transmission of CMV via breast milk and the range of illness caused by CMV in very low birth weight infants in the University of Minnesota Children's Hospital NICU. This study is funded by the University of Minnesota Department of Pediatrics Cross Divisional Research Grant.
DCRI and PTN
Catherine Bendel, MD
Dr. Bendel is a member of the Duke Clinical Trials Network and Pediatric Trials Network, leading to participation in national multicenter clinical trials on the UMMCH NICU. Recent completed studies include SCAMP (Safety Study of Clindamycin, Ampicillin, Metronidazole, and Piperacillin-tazobactam in infants with complicated intraabdominal infections), the Fluconazole Prophylaxis Trial in ELBW infants, and the Multi-center Pediatric Data Repository Development Trial. New studies looking at the intestinal microbiome are under development.
Fungal-Bacterial Microbiome Interactions in the Developing Infant Gut
Cheryl Gale, MD and Dan Knights, PhD
Emerging research supports a role for gut microbes in early-life programming of metabolism and immunity. Although fungi are part of the commensal gut microbiota, particularly during infancy, they have received much less study for their role in health as compared to bacteria. Until recently, fungi were considered to have only pathogenic interactions with humans. However, new studies support that idea that commensal fungi provide protection from disease. Despite this probable importance to public health, we lack fundamental knowledge about the structure and dynamics of gut fungal microbiota (mycobiomes) and how they co-develop with bacterial microbiomes during early life. In this study, we are using next-generation sequencing to characterize fecal microbes in infants from birth to 6 mos of age to gain foundational knowledge about co-maturation of fungal and bacterial communities within the gut. This will provide a "healthy microbiome" benchmark for future studies seeking to understand how interkingdom microbial relationships during early life contribute to later-life health and disease outcomes. In addition, we are studying the extent to which antibiotics disrupt fungal and bacterial community structures and functions. Altogether, it is hoped that the results from this study will support further research toward discovering mechanistic links between gut microbes and human health along the life-span and will provide strong rationale for the development of clinical strategies for the promotion of healthy infant gut microbial communities. This research is being conducted in collaboration with investigators at the Children's Hospital of Philadelphia and is funded by the National Institutes of Health’s National Institute of Allergy and Infectious Diseases.
Evaluation of Critical Congential Heart Disease Screening in Minnesota
Melissa Engel, MD
Congenital Heart Disease (CHD) is one of the most common birth defects, occurring in 9/1000 live births. Critical Congenital Heart Disease (CCHD) is defined as cardiac lesions that require surgery or cardiac catheterization within the first year of life to prevent death or severe end-organ damage. This project evaluates which infants and their congenital heart defects were diagnosed in the prenatal period, after birth by physical exam, after birth by CCHD Screening or after being discharged to home from the newborn nursery. Although CCHD screening is a useful tool to aid in diagnosis of hypoxemic cardiac lesions along with routine prenatal ultrasound and a standard newborn physical exam, there are certain congenital heart disease lesions that are not diagnosed in the newborn period. This research is evaluating which lesions are being missed and will be evaluating new strategies to aid diagnosis in the newborn period to prevent significant morbidity and mortality for all cardiac infants.
Congenital Heart Disease and Neurodevelopmental Outcomes Research in Term and Preterm infants
Melissa Engel, MD and Katie Pfister, MD
Children with CHD are at risk for developmental delays and significant morbidity and mortality. A specialized clinic at the University of Minnesota, the Cardiovascular Neurodevelopmental Follow-up Clinic, evaluates the neurodevelopment of infants with congenital heart disease at specific times of development to assess any needs in early childhood. Children who will participate in this clinic are infants who have had or will have a cardiac surgery or catheterization for congenital heart disease at the University of Minnesota. The data collected at these clinic visits will be used to create a standardized developmental profile for congenital heart disease and provide resources for future infants in the state of Minnesota through early childhood.
Addressing early childhood malnutrition through a novel agricultural intervention in Rural Cambodia
Jameel J. Winter, MD
Children under 5 years of age living in floating fishing villages on the Tonlé Sap Lake in Central Cambodia are at a higher risk of all markers of malnutrition than their peers in other parts of the country. Human-influenced climate change, hydroelectric dam construction and irresponsible fishing practices have all led to marked declines in the fish stocks on the lake. As a result, access to food has become even more limited than it was previously. We are working with the population on construction of floating vegetable gardens to permit families to have access to nutritious foods. By working with families on novel techniques to grow vegetables, we aim to empower women and children to take control of their health and well-being. In addition to the potential direct health benefits of this program, it also affords numerous opportunities for educational sessions regarding the importance of nutrition, clean water and hygiene.
Improving the care and neurodevelopmental outcomes of neonates with jaundice in low resource settings.
Katie Satrom, MD
Severe neonatal jaundice (SNNJ) continues to be a significant problem globally affecting at least 481,000 neonates annually. For many neonates, neonatal jaundice (NNJ) is benign, but high levels of unconjugated bilirubin (UCB) are neurotoxic, leading to cerebral palsy, sensorineural hearing loss, and upward gaze palsy. These complications, which are preventable, lead to a lifetime of impairments and socio-economic disadvantages resulting in a significant personal and societal burden, which disproportionally affect those living in low-to-middle income countries. Through funding from the Thrasher Research Fund and the National Institutes of Health, our team is working to develop low cost technologies to improve the diagnosis and treatment of neonatal jaundice.
Bench (Lab) Research
Discovery of Strategies to Prevent Fungal Disease in Premature Infants
Cheryl Gale, MD
Candida species cause life-threatening fungal diseases in immunocompromised patients such as premature infants. Candida normally colonizes the intestinal tract and can invade into patients when their intestinal barrier is weakened by inflammation or immaturity. The goal of this research is to understand how the presence of fungal and bacterial organisms that normally live within the intestine (the intestinal microbiota) might increase the risk for Candida invasion and to learn how Candida penetrates into infant intestinal cells. With the knowledge gained from these studies, we hope to discover new therapies that prevent fungal invasion and fungal-associated diseases in premature infants and, in the future, other at-risk patient populations. This work is funded by the Minnesota Vikings Children’s Fund, the University of Minnesota Foundation, and the Division of Neonatology.
Yeast (Candida) Interactions with Neonatal Mucosa and Skin
Catherine Bendel, MD
The yeast Candida can be a major cause of infection in the preterm infant. The source of these infections is the particular yeast that is a part of the normal flora on the baby's skin or in their intestines. Our laboratory is interested in better understanding how the yeast interacts with the mucosa/skin to adhere and colonize normally; as well as the risk factors leading to abnormal invasion, inflammation and wide-spread infection. We have both animal and tissue culture models to evaluate these interactions, with the ultimate goal of developing therapies to prevent infection from ever happening. This work is funded by the Division of Neonatology.
Neonatal Iron Deficiency
Michael Georgieff, MD
Iron deficiency is one of the most common nutrient deficiencies worldwide, affecting two billion people and up to 30% of all pregnant women and their babies. We study the effect of iron deficiency in newborn babies and its effects on the developing brain, especially those areas of the brain involved in learning and memory. We are studying the mechanisms by which iron is necessary for normal growth, development and interconnection of the nerves in the brain, why iron deficiency early in life leads to long term learning and memory problems, and whether other dietary supplements to either the mother during pregnancy or the baby after delivery can lessen the effects of early iron deficiency. These studies are funded by the National Institutes of Health, the Minnesota Medical Foundation, and Alfred and Ingrid Lenz Harrison.
Metabolic Control of Brain Development
Thomas Bastian, PhD
The human brain is rapidly growing and changing during late gestation and early postnatal life reaching 75-80% of its adult size by age two. To support this rapid maturation, the developing brain has high energy and nutrient requirements. Dietary nutrient deficiencies, anemia, gestational diabetes, and hypoxic-ischemia are relatively common health problems during early life, disrupt brain energy metabolism, and can have lasting deleterious effects on cognitive function and mental health. Many neurodevelopmental and psychiatric disorders (e.g., autism spectrum disorder, schizophrenia, depression) are also characterized by impaired brain energy metabolism. Despite this, much is still unknown about how energy metabolism is controlled in the developing brain. We use nutritional, genetic, and pharmacological manipulations of important energy substrates and regulators (e.g, iron, thyroid hormone, glucose, oxygen) in developing brain cells, allowing us to study interactions between cellular metabolic processes that are critical for neurodevelopment. This research is funded by the Department of Pediatrics and the National Institutes of Health’s National Institute of Child Health and Development.
Nutrition and Brain Development
Raghavendra Rao, MD
Nutrients such as iron and glucose are important for normal brain growth and function. Deficiency of these nutrients is common in babies who are born premature or after certain pregnancy complications. Our research focuses on the effects of such deficiencies on the brain. Using powerful magnets (approximately 6 times more powerful than those used in clinical practice), cutting-edge “omics” technique and molecular methods, we study how nutritional deficiencies affect brain development and how the risk of brain injury could be detected early. With this knowledge, we hope to develop strategies for optimizing brain development in babies. This work is funded by the National Institutes of Health.
Reducing Brain Injury Using Ubillical Cord Blood Stem Cells
Raghavendra Rao, MD
Extremely preterm infants (those born before 28 weeks of gestation) are at risk of bleeding in the brain. This condition called intraventricular hemorrhage (IVH) can lead to cerebral palsy, memory impairment and behavioral problems. At present there are no effective prevention or treatment methods for IVH. Our research investigates whether stem cells that are present in the umbilical cord blood of these infants could be used to promote brain development in IVH. This research is funded by a grant from Regenerative Medicine Minnesota.
Inflammation and Brain Development
Tate Gisslen, MD
Infection and inflammation during pregnancy are the cause of nearly half of premature births. After birth, inflammation continues to affect these babies. Inflammation during this important time in their brain development might lead to long-term learning and memory problems. Our research focuses on discovering the mechanisms by which inflammation interferes with normal brain development so that we may find methods to improve long-term learning outcomes in these babies. This work is funded by the Minnesota Vikings Children’s Fund and the Division of Neonatology.
Fetal and Neonatal (Developmental) Origin of Adult Diseases
Phu V. Tran, PhD
Early-life environment (i.e., micronutrient deficiency, hypoglycemia, intrauterine growth restriction, hypoxic-ischemic encephalopathy) can have a long-term impact on adult health by increasing the risks of obesity, diabetes, hypertension, cardiovascular disease, and neurocognitive decline. Utilizing preclinical models, we investigate how early-life environment causes permanent change in expression of molecules (e.g., proteins, hormones) that maintain physiological homeostasis, including stress responses, fear and anxiety, and learning and memory. In particular, we focus on epigenetic mechanisms by which early-life environment changes expression of critical factors regulating brain development. Ultimately, we hope to provide insights into how fetal/neonatal conditions contribute to the risk of adult diseases. These will be essential in developing strategies for treatment and prevention of adulthood pathophysiologies. This work is supported by the National Institute of Neurological Disorders and Stroke.
Megan Paulsen, MD
Obesity is preventable. Obesity rates have tripled in the last four decades worldwide and is associated with metabolic diseases such as diabetes, cardiovascular disease, and early mortality. The crippling rise of obesity prevalence cannot be explained by genetics alone. Adverse fetal and neonatal exposures during critical periods of organ development can lead to permanent functional changes in gene expression, placing an individual at a lifetime risk of obesity and metabolic disease. This widely accepted concept is the hallmark of the burgeoning field of developmental origins of health and disease (DOHaD). Precision research dedicated to prevention of modifiable environmental exposures during critical windows of development is essential for reversing aberrant metabolic programming and thereby curtail obesity rates worldwide. Our research focuses on discovering critical mechanistic links between maternal and offspring metabolic health. Our purpose is to find modifiable ways to improve maternal-fetal metabolic health ultimately decreasing obesity and metabolic disease in future generations. This work is funded by the Department of Pediatrics and NIH National Institute of Child Health and Human Development (NICHD) Building Interdisciplinary Research Careers in Women’s Health (BIRCWH) K12 Scholar Program.
Retinopathy of Prematurity (ROP)
Ellen Ingolfsland, MD
ROP affects 50-75% of extremely low birth weight preterm infants and continues to threaten vision of these fragile infants. Its etiology is multifaceted and not completely understood, especially how complications of prematurity impact an infant’s risk of developing severe ROP. Our research uses a preclinical model to study how anemia, one such complication, impacts the severity of retinopathy. Our goal is to better understand how to manage anemia and other such complications in the NICU to prevent severe ROP among infants. This research is supported by a Career Starter Grant from the Knights Templar Eye Foundation and the Division of Neonatology.
Neonatal Jaundice and Brain Development
Katie Satrom, MD
Extremely preterm infants almost universally develop jaundice (high bilirubin levels), but there is a lack of evidence to guide the use of phototherapy in this population. There is also growing evidence that low amounts of bilirubin may be protective as an antioxidant and that phototherapy may cause harm through oxidative stress and DNA damage. I use an animal model (Gunn rat) of neonatal jaundice to study the effects of bilirubin, phototherapy, and superimposed oxidative stress on the developing preterm brain. I also am conducting a clinical study of jaundice in preterm infants, evaluating peripheral biomarkers of bilirubin and phototherapy effects using the metabolomic analysis of plasma.
SPIN and ONTPD
Catherine Bendel, MD
Dr. Bendel is a member of the national Subspecialty Pediatrics Investigator Network (SPIN). This mission of this group is to “improve the health of children by enhancing pediatric subspecialty training through innovation and research that establish best practices in education and assessment.” Studies are underway to assess the utility of EPAs in pediatric subspecialty training. Dr. Bendel is also a member of the Organization of Neonatal Training Program Directors (ONTPD) educational study group that is evaluation the development of a national curriculum and new methods of training fellows, including “flipped classrooms” and Simulation training.
Johannah Scheurer, MD
Dr. Scheurer is involved in efforts to enhance competency-based medical education along the continuum of medical training from undergraduate to graduate to continuing medical education. She directs simulation programming on the NICU at University of Minnesota Masonic Children’s Hospital and is involved in high fidelity simulation programming across the residency program and pediatric subspeciality fellowships, including leadership for the Pediatric End of Life Care Skills (PECS) Program. In particular, her educational projects aim to enhance formative assessment and feedback to promote trainee competence.