4M study-maternal metabolism, breast milk composition, and infant outcomes
Ellen Demerath, PhD (School of Public Health)
Katherine Jacobs, DO (Department of Obstetrics, Gynecology, and Women's Health), Cheryl Gale, MD (Department of Pediatrics), Dan Knights, PhD (Department of Computer Science and Biotechnology Institute), Samantha Hoffman, MD (Department of Obstetrics, Gynecology, and Women's Health), Stephanie Mackenthun, MD (Department of Obstetrics, Gynecology, and Women's Health)
The 4M cohort adds mothers with gestational diabetes to expand upon the MILK Study cohort, considering the entire range of potential maternal factors impinging on breast milk composition in obese as compared to normal weight women. With the addition of the 4M cohort, we will learn how breastmilk composition differs among women with and without gestational diabetes and how hormones and microbiome affect infant body composition and infant microbiome.
A prospective, observational, single-center study of the effects of illness and nutrition on growth and cognition in AGA VLBW preterm infants
Sara Ramel, MD (Department of Pediatrics)
Ellen Demerath, PhD (Department of Epidemiology and Community Health), Michael Georgieff, MD (Department of Pediatrics), Bridget Davern (Department of Pediatrics), Neely Miller (Department of Pediatrics), Heather Gray (Department of Maternal Fetal Medicine)
The objectives of this study are: 1) to investigate the relationship between linear growth and fat-free body mass (FFM), and subsequent cognitive function, and 2) to identify modifiable nutritional and non-nutritional factors that influence FFM accretion (and potentially cognition) during and after initial hospitalization in very low birth weight (VLBW) preterm infants. This study will test the following novel hypotheses: 1) cognitive function in VLBW preterm infants is a function of linear growth and FFM accretion; 2) both modifiable nutritional and non-nutritional factors influence FFM accretion during and after initial hospitalization in VLBW preterm infants and that these factors affect cognitive status at 24 months of age corrected for the degree of prematurity (CA); and 3) alterations in the growth hormone axis and increased pro-inflammatory cytokines mediate the relationship of slower length growth and FFM accretion to cognitive outcomes.
Assessment of body composition in infants with cystic fibrosis
Elissa M. Downs, MD, MPH (Pediatric Gastroenterology, Hepatology, and Nutrition)
Sarah Jane Schwarzenberg, MD (Pediatric Gastroenterology, Hepatology, and Nutrition), Terri Laguna, MD (Pediatric Pulmonary Medicine), Sara Ramel, MD (Department of Neonatology)
In a patient with cystic fibrosis, malnutrition has been directly associated with a worse prognosis due to negative effects on activity, quality of life, and pulmonary function. Obtainment of adequate weight during childhood has been associated with decreased hospital days, fewer acute pulmonary exacerbations, and increased survival at 18 years of age. Better nutrition, along with normalized fat absorption, lead to improved pulmonary function and survival rates. Current consensus guidelines stress that early identification of deficiencies is paramount to improve overall health and allow for proper intervention; however these guidelines are based on an assessment of body weight, a number that includes both lean body mass and fat mass. At the time of cystic fibrosis diagnosis, many infants already have poor weight gain, as well as failure to thrive, and exocrine pancreatic insufficiency. In those infants with cystic fibrosis that appear well and have a normal body weight, malabsorption of fat soluble vitamins and decreased lean body mass may be present.
A decreased proportion of lean body mass with a normal weight, so called “hidden depletion,” is important to identify. Decreased lean body mass correlates with worse disease status in older children and adolescents, increases morbidity, and may not be detected with the use of body mass index alone. An increased proportion of lean body mass has been associated with improved pulmonary function. The overall goal of this research is to improve nutrition in infants with CF to slow deterioration of pulmonary function and improve survival. A more accurate determination of body composition in infants with cystic fibrosis may allow targeting of children at highest risk of nutritional compromise and suggest improved nutritional interventions.
Choline supplementation as a neurodevelopmental intervention in fetal alcohol spectrum disorders
Jeffrey R. Wozniak, Ph.D., L.P. (Department of Psychiatry)
Michael K. Georgieff, M.D. (Department of Pediatrics), Stephanie Carlson, Ph.D. (Institute of Child Development)
Recent data indicate that 2-5% of the U.S. population has Fetal Alcohol Spectrum Disorder (FASD) – a set of physical anomalies and neurodevelopmental deficits caused by prenatal alcohol exposure (May, Fiorentino et al. 2011). Despite the profound public health burden posed by FASD, there have been very few treatment studies of any sort in this population and no clinical trials that have attempted to directly address the neurodevelopmental deficits that are so debilitating for these individuals. There is, however, a promising line of translational research that suggests a potential role for micronutrient interventions. At the top of the list is choline, an essential nutrient for humans that is critical for normal brain development during gestation and early childhood. Although the human body produces choline, the demand cannot be met entirely endogenously and thus, some choline must be consumed in food. Extensive pre-clinical work has provided evidence that choline supplementation is effective in attenuating the neurodevelopmental deficits caused by prenatal alcohol exposure in animal models (Thomas, Biane et al. 2007, Ryan, Williams et al. 2008). Our group has taken the initial steps toward translating this work to humans. We first conducted a two-year pilot study to ensure the feasibility, tolerability, and safety of choline supplementation in 20 children with FASD (Wozniak, Fuglestad et al. 2013). Next, we completed a three-year pilot study of 40 additional children with the goals of establishing a target dosage for young children and testing efficacy in the domain of memory (Wozniak, Fuglestad et al. under review). Together, data from these two studies demonstrate that choline supplementation in 2-3 year old children with FASD improves explicit memory – a core function that is essential for normal cognitive development. Based on the time periods in which choline is effective in pre-clinical models of FASD and on the fact that the first years of human life represent a period of intense brain development, choline supplementation in young children appears to have significant potential as an intervention for neurodevelopmental disorders including FASD.
Dyadic coordination of self-regulation and social engagement in infants and caregivers
Daniel Berry, PhD (Institute of Child Development)
Isabella Stallworthy, doctoral candidate (Institute of Child Development)
The ability to contingently and dynamically engage with others is critical for human functioning throughout life. In the first year, infants’ abilities evolve from simple social orienting to engaging in complex social interactions. This progression is foundational for their emerging social, self-regulatory, and learning abilities, and is driven in part by the developmental interplay of sensitive caregiving and infants’ nascent physiological reactivity systems. In infancy, when cortical control of behavior is immature, parasympathetic control of the heart is critical for infants’ abilities to regulate their internal states and engage with others (Bazhenova & Porges, 1997). Respiratory sinus arrhythmia (RSA), a measure of heart rate variability, indexes parasympathetic control of cardiac activity by the vagus nerve.
This study aims to examine: (1) how real-time changes in infants’ RSA relate to changes in infants’ social visual attention during a) social interaction and b) a naturalistic disruption to the interaction; (2) the extent to which infants’ social visual attention and RSA are coupled in time and relate to affect, within each infant; (3) how caregivers’ RSA coordinates with infants’ RSA; as well as (4) developmental changes in these associations over the first year of life.
Enhanced early nutrition for preterm infants to improve neurodevelopment and minimize metabolic risk
Sara Ramel, MD (Department of Pediatrics)
Ellen Demerath, Ph.D. (Department of Public Health)
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.The overall objective of the proposal is to demonstrate the feasibility of providing increased calories and protein in the first week of life to VLBW preterm infants, and to generate pilot data on the effects of this intervention on growth and neurodevelopmental outcomes.
Impact of the intestinal microbiome on infant neurodevelopment
Ellen Demerath, Ph.D. (Department of Epidemiology and Community Health)
Today the majority of pregnant women in the United States are either overweight or obese at conception with their offspring having greater adiposity at birth, a 2-fold greater risk of later obesity, and neonatal insulin resistance. Animal models indicate that maternal obesity may have deleterious effects on brain development in offspring. Preliminary data from our laboratory suggest that infants born to mothers with high pre-gravid BMI have altered cognitive processing of visual and audio stimuli compared to infants born to mothers with normal BMIs. Maternal obesity can also cause changes in the intestinal microbiome of offspring, both pre- and postnatally. Intestinal microbial communities are thought to affect the development immunity, metabolism, and brain function, with effects that extend across an individual’s lifespan. Our main objective is to determine how variations in microbiome signatures early in life correlate with variations in hippocampal development as indexed by ERPs. The specific aims are to 1) Examine the variation in the infant biome at one month and six months of age; and 2) Determine whether these variations are associated with poorer hippocampal-based electrophysiology outcomes and behavior, and slower myelination-dependent speed of processing not only at in the neonatal period but six months later as well.
Long-term follow-up of term survivors of hypoxic-ischemic encephalopathy: an evaluation of brain function and structure
Katie Pfister, MD (Pediatrics, Division of Neonatology)
Elizabeth Zorn, MD (Pediatrics: Division of Neonatology), Christopher Boys, PhD, LP (Department of Pediatrics), Katie Thomas, PhD (Institute of Child Development)
A prospective observational cohort study design will be used to determine whether survivors of HIE who were treated with therapeutic hypothermia have deficits in memory or executive function at age 4-5 years, and whether there are observable changes in brain structure or connectivity. MRI with diffusion tensor imaging will be used to assess brain volumes, structure, and white matter connectivity. Behavioral assessments (WPPSI-IV and NEPSY-II) and parental questionnaires (BRIEF-P) will be used to assess overall intellectual function, executive function, and memory.
Longitudinal assessment of asymptomatic congenital CMV infection in Minnesota infants identified by universal screening: what is risk of sequelae?
Mark Schleiss, MD (Department of Pediatrics)
Jed Elison, PhD (Institute of Child Development), Igor Nestrasil, MD, PhD (Department of Pediatrics), Erin Osterholm, MD (Department of Pediatrics)
Symptomatic congenital CMV (cCMV) infections are commonly encountered in clinical practice, affecting approximately 0.65% of all newborns. Such infections - in symptomatic newborns - carry a substantial risk for long-term neurodevelopmental sequelae including developmental delay, mental retardation, seizure disorders, cerebral palsy, and sensorineural hearing loss. Nucleoside antiviral therapy is associated with only modest improvements in audiological and neurodevelopmental outcomes. It is much less clear how to manage infants identified with asymptomatic cCMV infection. These infants have in the past essentially escaped clinical recognition, precisely because these children are asymptomatic at birth, and there is no universal newborn cCMV screen. However, the landscape of cCMV screening is rapidly evolving, and there is increasing interest in implementation of universal cCMV screening programs. In spite of recent progress, universal newborn screening for congenital CMV in many ways remains an area of scientific uncertainty. The optimal screening methodology remains uncertain. We don’t know if asymptomatic infants should undergo full laboratory and neuroimaging evaluations, or whether treatment of infants with asymptomatic congenital CMV with antivirals should be considered. Our proposal will conduct neurocognitive and neuroimaging studies in asymptomatic infants identified with congenital CMV infection in the context of a universal screening program to address these important areas of knowledge deficit.
Maternal obesity, breast milk composition and infant growth
Ellen Demerath, Ph.D. (Department of Epidemiology and Community Health)
Today, the majority of pregnant women in the US are either overweight or obese. Their offspring have a greater adiposity at birth, a greater risk of later obesity and neonatal insulin resistance. Breast feeding has many clear benefits that many include protection against obesity (its long term effects and sequelae). Recent evidence shows that breast milk is a highly complex fluid with significant variation both between and within lactating women. Little effort has been made to examine breast milk composition in obese women and its impact on infant metabolic status. The objective of this research study is to access whether or not variation in breast milk composition is related to both maternal adiposity and infant metabolic status.