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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
2R01HD041702-12
Application #
9125533
Study Section
Infectious Diseases, Reproductive Health, Asthma and Pulmonary Conditions Study Section (IRAP)
Program Officer
Ilekis, John V
Project Start
2001-09-24
Project End
2021-03-31
Budget Start
2016-05-03
Budget End
2017-03-31
Support Year
12
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Miscellaneous
Type
Schools of Public Health
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
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Hong, Xiumei; Sherwood, Ben; Ladd-Acosta, Christine et al. (2018) Genome-wide DNA methylation associations with spontaneous preterm birth in US blacks: findings in maternal and cord blood samples. Epigenetics 13:163-172
Ji, Yuelong; Hong, Xiumei; Wang, Guoying et al. (2018) A Prospective Birth Cohort Study on Early Childhood Lead Levels and Attention Deficit Hyperactivity Disorder: New Insight on Sex Differences. J Pediatr 199:124-131.e8
Zheng, Zihe; Bennett, Wendy L; Mueller, Noel T et al. (2018) Gestational Weight Gain and Pregnancy Complications in a High-Risk, Racially and Ethnically Diverse Population. J Womens Health (Larchmt) :
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Zhang, Boyang; Hong, Xiumei; Ji, Hongkai et al. (2018) Maternal smoking during pregnancy and cord blood DNA methylation: new insight on sex differences and effect modification by maternal folate levels. Epigenetics 13:505-518
Okano, Lauren; Ji, Yuelong; Riley, Anne W et al. (2018) Maternal psychosocial stress and children's ADHD diagnosis: a prospective birth cohort study. J Psychosom Obstet Gynaecol :1-9
Cheng, Tina L; Mistry, Kamila B; Wang, Guoying et al. (2018) Folate Nutrition Status in Mothers of the Boston Birth Cohort, Sample of a US Urban Low-Income Population. Am J Public Health 108:799-807
Raghavan, Ramkripa; Riley, Anne W; Volk, Heather et al. (2018) Maternal Multivitamin Intake, Plasma Folate and Vitamin B12 Levels and Autism Spectrum Disorder Risk in Offspring. Paediatr Perinat Epidemiol 32:100-111

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