DESCRIPTION (provided by applicant): Using a life-course framework, we propose to conduct a comprehensive and systemic investigation on preterm birth (PTB) and maternal and fetal metabolic characteristics in relation to child development of adverse metabolic outcomes. Seminal work by Barker and others has linked fetal growth restriction to adult chronic diseases including type 2 diabetes (T2D). The link between PTB and later metabolic risk is not well studied but of great clinical and public health importance. In the U.S., the rates of PTB are high, affecting 1 in 9 of all births and 1 in 6 African American births. Obesity and T2D have become epidemic, affecting all age groups including mothers and children, especially in poor minority populations. This proposal is motivated by our recent study in the Boston Birth Cohort (BBC), which demonstrated a significant dose-response relationship between degree of prematurity and elevated insulin levels that were detectable at birth and persistent through early childhood (Wang et al, JAMA, 2014). Our findings raise the possibility that PTB is an important early life risk factor of subsequent metabolic risk. We propose to study preterm and term mother-child pairs (n= 3,000 pairs for Aim 1 and 1,200 pairs for Aims 2 and 3) in the BBC, one of the largest NIH-funded urban low-income minority birth cohorts, to address three specific aims: Aim 1. We will test the hypothesis that PTB is associated with adverse child metabolic outcomes, including overweight or obesity, surrogates of total body and central adiposity, elevated insulin and glucose levels, abnormal lipid profiles, and elevated blood pressure and metabolic/inflammatory biomarkers during critical developmental windows from birth to age 15 years. Aim 2. We will examine the interrelationships between PTB and the maternal and cord blood metabolomes assessed at birth. We will also explore the impact of maternal factors such as lifestyle and dietary factors, obesity, diabetes, dyslipidemia, and hypertension on the maternal and cord blood metabolomes. Aim 3. We will test the hypothesis that PTB and unfavorable maternal and cord blood metabolome profiles can independently and jointly increase child metabolic risk; we further hypothesize that the cord blood metabolome may mediate, while the maternal metabolome may modify the adverse effect of PTB on child metabolic outcomes listed in Aim 1. We will focus on a panel of 300 well-developed and validated metabolites that have been implicated in obesity, diabetes, and metabolic risk. In addition, we will include non-targeted metabolites in our exploratory analyses. This would be the first large-scale study to integrate cutting-edge metabolomics with a prospective birth cohort to address critical questions about fetal origins of metabolic diseases in the context of preterm birth and in the setting of a U.S. high-risk, urban low-income, minority population. Findings from this project will shed new light on whether and how in-utero metabolic environments (maternal metabolome), prematurity, and the fetal metabolic state (cord blood metabolome) jointly influence future metabolic outcomes in children.

PUBLIC HEALTH RELEVANCE: In the U.S., preterm birth is very common, affecting 1 in 9 of all births and 1 in 6 of African American births. This proposal aims to investigate whether prematurity and maternal and fetal metabolic characteristics can jointly affect the future development of child adverse metabolic outcomes in a well-established U.S. urban low- income minority prospective birth cohort. Findings from this study may help to discover novel biomarkers that can be used to identify newborns at high-risk of future metabolic problems so that effective interventions can be initiated to halt or reverse the risk trajectory during critica developmental periods when interventions may have the greatest life-long impact.