Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED)

Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development

Malnutrition is considered one of the most prevalent risk factors for morbidity and mortality in children under five. An estimated 20% of children in the developing world are malnourished [1] and poor nutrition is linked to more than half of all child deaths worldwide [2]. Malnutrition in early childhood may lead to cognitive and physical deficits and may cause similar deficits in future generations as malnourished mothers give birth to low birth weight children [3]. In addition, malnutrition increases susceptibility and incidence of infections and is associated with diminished response to vaccines.

The MAL-ED Project is designed to determine the impact of enteric infections/diarrhea that alter gut function and impair children's nutrition, growth and development to help develop new intervention strategies that can break the vicious enteric infection-malnutrition cycle and reduce its global burden.

The overall objective of the MAL-ED Project is to quantify the associations of specific enteric pathogens, measures of physical and mental development, micronutrient malnutrition, gut function biomarkers, the gut microbiome, and immune responses in very young children in resource-limited settings across eight sites that vary by culture, economics, geography, and climate.

The central hypothesis of the MAL-ED Project is that infection (and co-infection) with specific enteropathogens leads to impaired growth and development and to diminished immune response to orally administered vaccines by causing intestinal inflammation and/or by altering intestinal barrier and absorptive function. Data analyses will test for associations between enteropathogen infections and growth/development to help illuminate:

• which micro-organisms or mixed infections are most frequently associated with growth faltering and poor development; and
• at what age specific infections cause the most disruption to growth and development and impair immune response.

Study Overview

• Status: Unknown
• Conditions: Immune Response; Diarrhea; Malnutrition; Wasting; Stunting; Cognitive Development

• Study Type: Observational
• Enrollment (Anticipated): 1796

Contacts and Locations

Study Locations

• Bangladesh
  • Dhaka, Bangladesh
    • International Centre for Diarrheal Disease Research, Bangladesh
• Brazil
  • Fortaleza, Brazil
    • Universidade Federal Do Ceara
• India
  • Vellore, India
    • Christian Medical College
• Nepal
  • Kathmandu, Nepal
    • Institute of Medicine
• Pakistan
  • Karachi, Pakistan
    • Aga Khan University
• Peru
  • Iquitos, Peru
    • JHSPH Satellite Laboratory
• South Africa
  • Limpopo, South Africa
    • University of Venda
• Tanzania
  • Haydom, Tanzania
    • Haydom Lutheran Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 minute to 2 weeks (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

The study population for the MAL-ED Project is a birth cohort. Pregnant women were identified from their communities, consented and the child will be enrolled.

Description

Inclusion Criteria:

• Less than 17 days old.

Exclusion Criteria:

• Mother is less than 16 years of age.
• Mother has another child inthe MAL-ED study.
• Pregnancy resulted in multiple birth (e.g., twins).
• Child has a severe disease requiring hospitalization for something other than for a typical healthy birth.
• Child has a severe or chronic condition diagnosed by a medical doctor (e.g., neonatal disease, renal disease, chronic heart failure, liver disease, cystic fibrosis, congenital conditions).
• Child has enteropathies diagnosed by medical doctor.
• Mother is living and unable to provide informed consent.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

8

Cohorts and Interventions

Group / Cohort
Bangladesh; Birth cohort study community in Bangladesh is urban, and located in the Mirpur neighborhood of Dhaka. Case control study is being conducted in the same catchment area. Cases defined as children 6-24 months of age with <-2WAZ (weight for age) score, controls are age and community matched with >-1WAZ.
Brazil; Birth cohort study community in Brazil is urban, and located within the Papoco area of Fortaleza. Case control study is being conducted in the same area as the cohort study. Cases are children 6 - 24 months of age, with <-2 WAZ (weight for age) score, controls are age and community matched children with >-1 WAZ.
India; Birth cohort study community in India is urban, and located in the southern state of Tamil Nadu, specifically in Vellore.
Nepal; Birth cohort study community in Nepal is semi-urban, and located in Bhaktapur, approximately 25km from Kathmandu.
Pakistan; Birth cohort study community in Pakistan is rural, and located in Naushero Feroze, Sindh.
Peru; Birth cohort study community in Peru is rural, and located approximately 15km from Iquitos in Loreto.
South Africa; Birth cohort study community in South Africa is rural/peri-urban, and comprised of nine settlements within Limpopo Province.
Tanzania; Birth cohort study community in Tanzania is rural, and located within Haydom.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Diarrhea	All diarrheal samples are analyzed for the presence of bacterial, viral, and parasitic pathogens. Normal stool is collected monthly and analyzed for the same list of 57 different pathogens.	Each diarrheal episode willbe recorded for up to 24 months of age.
Anthropometry	Head Circumference, length, and weight are measured monthly on the anniversary of the child's birth.	Anthropomentry will be recorded each month for up to 24 months of age.
Cognitive development	A battery of tests include the Bayley Scales of Infant Development, MacArthur Words and Gestures, Infant Temperament Scale, HOME inventory, SRQ-20 and Raven's Combined Progressive Matrices.	Cognitive development will be recorded at 6 months of age.
Vaccine response	Antibody titers will be determined following immunization against rotavirus, polio virus, tetanus toxoid, pertussis toxin and measles vaccines.	Vaccine response will be recorded at 7 months of age.
Cognitive development	A battery of tests include the Bayley Scales of Infant Development, MacArthur Words and Gestures, Infant Temperament Scale, HOME inventory, SRQ-20 and Raven's Combined Progressive Matrices.	Cognitive development will be recorded at 8 months of age.
Cognitive development	A battery of tests include the Bayley Scales of Infant Development, MacArthur Words and Gestures, Infant Temperament Scale, HOME inventory, SRQ-20 and Raven's Combined Progressive Matrices.	Cognitive development will be recorded at 15 months of age.
Vaccine response	Antibody titers will be determined following immunization against rotavirus, polio virus, tetanus toxoid, pertussis toxin and measles vaccines.	Vaccine response will be recorded at 15 months of age.
Cognitive development	A battery of tests include the Bayley Scales of Infant Development, MacArthur Words and Gestures, Infant Temperament Scale, HOME inventory, SRQ-20 and Raven's Combined Progressive Matrices.	Cognitive development will be recorded 24 months of age.
Vaccine response	Antibody titers will be determined following immunization against rotavirus, polio virus, tetanus toxoid, pertussis toxin and measles vaccines.	Vaccine response will be recorded at 24 months of age.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Gut inflammation	Stool biomarkers will be evaluated to detect gut and systemic inflammation.	Gut inflammation will be recorded each month for up to 24 months of age.
Gut integrity	Intestinal absorptive capacity and barrier function will be assessed by dual sugar permeability test.	Gut integritywill be recorded at at 3 months of age.
Gut integrity	Intestinal absorptive capacity and barrier function will be assessed by dual sugar permeability test.	Gut integritywill be recorded at at 6 months of age.
Gut integrity	Intestinal absorptive capacity and barrier function will be assessed by dual sugar permeability test.	Gut integritywill be recorded at at 9 months of age.
Gut integrity	Intestinal absorptive capacity and barrier function will be assessed by dual sugar permeability test.	Gut integritywill be recorded at at 15 months of age.

Collaborators and Investigators

• Sponsor: Foundation for the National Institutes of Health
• Collaborators: Johns Hopkins University; Aga Khan University; Penn State University; University of Virginia; Fogarty International Center of the National Institute of Health; Henry M. Jackson Foundation for the Advancement of Military Medicine; Christian Medical College, Vellore, India
• Investigators: Principal Investigator: Michael Gottlieb, Ph.D., Fountation for the National Institutes of Health; Principal Investigator: Roger Glass, M.D., Fogarty International Center of the National Institute of Health

Publications and helpful links

General Publications

• Arndt MB, Richardson BA, Mahfuz M, Ahmed T, Haque R, Gazi MA, John-Stewart GC, Denno DM, Scarlett JM, Walson JL; coordination with The Interactions of Malnutrition & Enteric Infections: Consequences for Child Health and Development Project Network. Plasma Fibroblast Growth Factor 21 Is Associated with Subsequent Growth in a Cohort of Underweight Children in Bangladesh. Curr Dev Nutr. 2019 Mar 30;3(5):nzz024. doi: 10.1093/cdn/nzz024. eCollection 2019 May.
• Colston JM, Ahmed T, Mahopo C, Kang G, Kosek M, de Sousa Junior F, Shrestha PS, Svensen E, Turab A, Zaitchik B; MAL-ED Network. Evaluating meteorological data from weather stations, and from satellites and global models for a multi-site epidemiological study. Environ Res. 2018 Aug;165:91-109. doi: 10.1016/j.envres.2018.02.027. Epub 2018 Apr 21.
• Colston JM, Penataro Yori P, Colantuoni E, Moulton LH, Ambikapathi R, Lee G, Rengifo Trigoso D, Siguas Salas M, Kosek MN. A methodologic framework for modeling and assessing biomarkers of environmental enteropathy as predictors of growth in infants: an example from a Peruvian birth cohort. Am J Clin Nutr. 2017 Jul;106(1):245-255. doi: 10.3945/ajcn.116.151886. Epub 2017 Jun 7.
• Platts-Mills JA, Taniuchi M, Uddin MJ, Sobuz SU, Mahfuz M, Gaffar SA, Mondal D, Hossain MI, Islam MM, Ahmed AS, Petri WA, Haque R, Houpt ER, Ahmed T. Association between enteropathogens and malnutrition in children aged 6-23 mo in Bangladesh: a case-control study. Am J Clin Nutr. 2017 May;105(5):1132-1138. doi: 10.3945/ajcn.116.138800. Epub 2017 Apr 5.

Helpful Links

• "The Malnutrition and Enteric Disease Study (MAL-ED): Understanding the Consequences for Child Health and Development: CID supplement V59 suppl4; 2014

Study record dates

Study Major Dates

• Study Start: November 1, 2008
• Primary Completion (Anticipated): February 1, 2017
• Study Completion (Anticipated): April 1, 2017

Study Registration Dates

• First Submitted: May 4, 2015
• First Submitted That Met QC Criteria: May 7, 2015
• First Posted (Estimate): May 12, 2015

Study Record Updates

• Last Update Posted (Estimate): May 12, 2015
• Last Update Submitted That Met QC Criteria: May 7, 2015
• Last Verified: May 1, 2015

More Information

Terms related to this study

• Keywords: Micronutrients; Cognitive development; Malnutrition; Breast feeding; Antibiotic use; Diarrheal disease; Enteric infections; Vaccine Response; Enteropathy; Gut inflammation
• Additional Relevant MeSH Terms: Signs and Symptoms, Digestive; Nutrition Disorders; Infections; Diarrhea; Malnutrition
• Other Study ID Numbers: MAL-ED-47075