Clinical trial NCT05121935: MAL-ED Metabolic: A Follow-Up of Chronic Disease at Puberty
Official title: MAL-ED Metabolic: A Follow-Up of Chronic Disease at Puberty
Study type: OBSERVATIONAL
Overall status: NOT_YET_RECRUITING
Conditions: Growth Failure
Intestinal Infection
Metabolic Syndrome
Glucose Intolerance
Lead sponsor: University of Virginia
Sponsor class: OTHER
Collaborators: name: Haydom Lutheran Hospital
First posted: 2021-11-16
Enrollment: 254
Sex: ALL
Minimum age (years): 9
Maximum age (years): 17
Standard ages: CHILD
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: This is a follow-up study of children who were originally in the MAL-ED cohort.

Brief summary: The concept that the roots of cardiometabolic disease start in early life was established by Dr. David Barker, who documented relationships between low birthweight (as a marker for challenges during gestation) and later cardiovascular disease (CVD). Later work has suggested that post-natal challenges (similar to prenatal ones) may also exhibit links to later cardiometabolic disease, with the strongest links appearing to be between low weight in early childhood and later hypertension and high waist circumference (WC). However, assessments for the relationship between early childhood challenges and insulin resistance and glucose regulation have been lacking and long-term cohort studies are few. In this project, we aim to assess children initially followed as part of The Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health (MAL-ED) study, where they received frequent measures of anthropometry and laboratory assessments for intestinal pathogens. These children are now of peri-pubertal age--a time period associated with metabolic shifts. We will assess for glucose dysregulation and findings associated with the metabolic syndrome, and we will analyze potential associations between current chronic disease risk findings with early life poor growth and intestinal pathogen carriage rate. As such, we hope to uncover potential targets in early life health to reduce later chronic disease risk.

Detailed description: The relationship between prenatal challenges and later risk for chronic disease has been well established. Our group previously assessed the hypothesis that post-natal challenges (similar to prenatal ones) would exhibit links to later cardiometabolic disease. This was performed using retrospective data from a long-term cohort of children in Guatemala, demonstrating novel findings that higher degrees of diarrhea burden in the first 6 months of life (as a marker of nutritional and/or inflammatory stressors) were associated with a greater risk of metabolic syndrome as adults The causes of these findings are not known, though postulated mechanisms include epigenetic reprograming of metabolic rate, hormonal regulation and vascular tone. Unfortunately, long-term cohort studies are few, limiting opportunities to evaluate these links prospectively.

The Haydom Global Health Research Center in north central Tanzania represents an important rural setting for performing high-quality medical research in sub-Saharan Africa (5). The region around Haydom has a high degree of stunting and enteric pathogen carriage among a cohort of children followed in the area from 2009-2013 as part of the multi-country study "The Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health (MAL-ED)."

These children followed in Haydom during MAL-ED had monthly anthropometry and stool pathogen analysis, as well as extensive demographic data. This provides an opportunity to follow up on these children to assess for potential links between early life challenges (both enteric disease, infections and nutritional deficiencies) and later chronic disease risk, including lipid abnormalities, glucose intolerance and blood pressure elevations. The current proposal is to follow up on these children at the age of typical entry into puberty, as this is a common shift in metabolism when many children begin to exhibit metabolic abnormalities. We will assess these children for multiple measures:

* Anthropometry (height, weight, BMI, waist circumference)
* Assessment of pubertal stage by exam or questionnaire
* Blood pressure
* Lipids (LDL, HDL, triglycerides)
* CRP
* Oral glucose tolerance test (OGTT)
* Fasting insulin
* Metabolic syndrome (MetS) severity score
* Blood saved for future epigenetic testing

We will use linear and and logistic regression to determine associations between 1) mean number of monthly pathogens (individual pathogens and in aggregate) and 2) reported symptoms (fever, cough, diarrhea), with multiple MetS-related outcomes: BMI percentile, WC, fasting insulin, 2-hour glucose following OGTT, triglycerides, HDL cholesterol, normalized BP and a MetS diagnosis.

The underlying hypothesis is that there will be consistent links between features of MetS (in particular blood pressure, waist circumference and insulin resistance) with 1) enteric pathogen burden (overall and for particularly virulent pathogens such as Enterotoxigenic E.coli) and 2) poor early life growth.

Eligibility criteria: Inclusion Criteria:

* Participated in original MAL-ED cohort

Exclusion Criteria:

* Did not participate in original MAL-ED cohort

Primary outcomes:
measure: Current Systolic BP--relationship to number of enteric pathogens by age 2 years
timeFrame: Measured during current study (1 year +/- 3 months)
Secondary outcomes:
measure: Current Systolic BP--relationship to BMI z-score at age 2 years
timeFrame: Measured during current study (1 year +/- 3 months)
measure: Current Diastolic BP--relationship to number of enteric pathogens by age 2 years
timeFrame: Measured during current study (1 year +/- 3 months)
measure: Current Diastolic BP--relationship to BMI z-score at age 2 years
timeFrame: Measured during current study (1 year +/- 3 months)
measure: Current BMI z-score--relationship to number of enteric pathogens by age 2 years
timeFrame: Measured during current study (1 year +/- 3 months)
measure: Current waist circumference--relationship to number of enteric pathogens by age 2 years
timeFrame: Measured during current study (1 year +/- 3 months)
measure: Metabolic syndrome (MetS) severity score--relationship to number of enteric pathogens by age 2 years
timeFrame: Measured during current study (1 year +/- 3 months)
measure: Current metabolic syndrome (MetS) severity score--relationship to BMI z-score at age 2 years
timeFrame: Measured during current study (1 year +/- 3 months)
measure: Current glucose from oral glucose tolerance test (OGTT) at 2 hours--relationship to number of enteric pathogens by age 2 years
timeFrame: Measured during current study (1 year +/- 3 months)
measure: Current glucose from oral glucose tolerance test (OGTT) at 2 hours--relationship to BMI z-score at age 2 years
timeFrame: Measured during current study (1 year +/- 3 months)
measure: Current fasting triglycerides--relationship to number of enteric pathogens by age 2 years
timeFrame: Measured during current study (1 year +/- 3 months)
measure: Current fasting triglycerides--relationship to BMI z-score at age 2 years
timeFrame: Measured during current study (1 year +/- 3 months)
measure: Current HDL cholesterol--relationship to number of enteric pathogens by age 2 years
timeFrame: Measured during current study (1 year +/- 3 months)
measure: Current HDL cholesterol--relationship to BMI z-score at age 2 years
timeFrame: Measured during current study (1 year +/- 3 months)
measure: Current fasting glucose--relationship to number of enteric pathogens by age 2 years
timeFrame: Measured during current study (1 year +/- 3 months)
measure: Current fasting glucose--relationship to BMI z-score at age 2 years
timeFrame: Measured during current study (1 year +/- 3 months)
Other outcomes:
Locations:
Study officials:
affiliation: University of Virginia
name: Mark D DeBoer, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Haydom Global Health Research Centre
name: Estomih Mduma, MPH
role: STUDY_DIRECTOR
References:
citation: DeBoer MD, Lima AA, Oria RB, Scharf RJ, Moore SR, Luna MA, Guerrant RL. Early childhood growth failure and the developmental origins of adult disease: do enteric infections and malnutrition increase risk for the metabolic syndrome? Nutr Rev. 2012 Nov;70(11):642-53. doi: 10.1111/j.1753-4887.2012.00543.x.
citation: DeBoer MD, Chen D, Burt DR, Ramirez-Zea M, Guerrant RL, Stein AD, Martorell R, Luna MA. Early childhood diarrhea and cardiometabolic risk factors in adulthood: the Institute of Nutrition of Central America and Panama Nutritional Supplementation Longitudinal Study. Ann Epidemiol. 2013 Jun;23(6):314-20. doi: 10.1016/j.annepidem.2013.03.012. Epub 2013 Apr 19.
citation: Mduma ER, Gratz J, Patil C, Matson K, Dakay M, Liu S, Pascal J, McQuillin L, Mighay E, Hinken E, Ernst A, Amour C, Mvungi R, Bayyo E, Zakaria Y, Kivuyo S, Houpt ER, Svensen E. The etiology, risk factors, and interactions of enteric infections and malnutrition and the consequences for child health and development study (MAL-ED): description of the Tanzanian site. Clin Infect Dis. 2014 Nov 1;59 Suppl 4:S325-30. doi: 10.1093/cid/ciu439.
citation: Scharf RJ, Rogawski ET, Murray-Kolb LE, Maphula A, Svensen E, Tofail F, Rasheed M, Abreu C, Vasquez AO, Shrestha R, Pendergast L, Mduma E, Koshy B, Conaway MR, Platts-Mills JA, Guerrant RL, DeBoer MD. Early childhood growth and cognitive outcomes: Findings from the MAL-ED study. Matern Child Nutr. 2018 Jul;14(3):e12584. doi: 10.1111/mcn.12584. Epub 2018 Feb 2.