This cluster-randomized controlled trial is designed to address linear growth faltering in 6-12-mo-old Bangladesh infants through a proof-of-concept package of interventions to a) increase intake of high quality protein and b) control enteric pathogens.
Stunting a major public health problem in Bangladesh, where 36% of children under the age of five are too short for their age. While dietary data indicate that protein intakes of infants and young children are largely in line with requirements, the extent to which requirements derived for healthy infants and young children are relevant in the context of frequent infections remains an important research question. Recent investigations indicate widespread pathogen carriage among Bangladeshi infants, with virtually all having at least one detectable pathogen in nondiarrheal stools by six months of age. Campylobacter and pathogenic E. Coli predominate in this setting. Enteric pathogens can compete with the host for available nutrients or alter nutrient metabolism. Acting via environmental enteric dysfunction, they can alter both digestion-through loss of digestive enzymes-and absorption of nutrients. Microbial translocation may further alter specific amino acid requirements. Even in the absence of acute diarrheal disease, enteric pathogen carriage is strongly associated with linear growth faltering. Combining the effects of high pathogen burden and poor diet, as indicated by low energy and protein from complementary foods, observational evidence suggests that the potentially preventable length-for-age Z-score deficit may be as high as 0.98. The present trial will test the combination of a) protein supplementation in the form of a protein-rich blended food or an egg, both fed daily to infants 6-12 months of age, and b) azithromycin treatment for enteric pathogens. The primary outcome will be change in length-for-age Z-score from the 6 to 12 months. Biochemical, microbiological and clinical intermediates will be measured to inform our secondary aims.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
QUADRUPLE
Enrollment
5,283
Azithromycin oral suspension (10 mg/kg; 3 days) administered by study personnel at 6 and 9 months of age
Contain inert excipients only
Blended food providing 125 kcal and 10 g protein as egg white powder prepared as porridge and fed daily to infants from 6-12 months of age
JiVitA Maternal and Child & Nutrition Research Site
Gaibandha, Bangladesh
Length-for-age Z-score (LAZ) at 12 months of age
Time frame: 12 months
Nutrient biomarkers
Serum essential, conditionally essential amino acids and choline (by metabolomic analysis); retinol and tocopherols (HPLC); vitamin B12 (microbiological assay); zinc (AAS); ferritin and thyroglobulin (ELISA)
Time frame: 6 and 12 months
Growth hormone and stress axes biomarkers
Serum insulin-like growth factor 1 (IGF-1), IGF binding protein 3, cortisol, by ELISA
Time frame: 6 and 12 months
Enteropathogen burden
Campylobacter, enterotoxigenic Escherichia coli (ETEC), enteroaggregative Escherichia coli (EAEC), enteropathogenic Escherichia coli (EPEC), Shigella and Cryptosporidium, by quantitative polymerase chain reaction (qPCR)
Time frame: 6, 6.5, 9, 9.5, 12, 15, and 18 months
Gut microbiota composition
Microbial diversity and abundance, by 16S ribosomal RNA sequencing
Time frame: 6, 6.5, 9, 9.5, 12, 15, and 18 months
Environmental enteric dysfunction biomarkers
Stool myeloperoxidase and intestinal fatty acid-binding protein concentrations and plasma Endogenous endotoxin-core antibody (EndoCAb), by ELISA
Time frame: 6 and 12 months
Inflammatory biomarkers
Plasma alpha-1 acid glycoprotein, C-reactive protein and interleukin-6, by ELISA; stool inflammatory cytokines, by ELISA
Time frame: 6 and 12 months
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Blended food providing 125 kcal and 1 g protein as rice powder prepared as porridge and fed daily to infants from 6-12 months of age
Egg provided daily to infants from 6-12 months of age
Monthly messaging on infant and young child feeding
Bone biomarkers
Plasma collagen type X and N-Terminal Pro-C-Type Natriuretic Peptide (NT-ProCNP), by ELISA
Time frame: 6 and 12 months
Morbidity incidence
Incident diarrhea/dysentery or respiratory infection, based on weekly recalls
Time frame: 6-12 months
Body composition
Fat mass by bioelectrical impedence
Time frame: 6, 9, 12, 15, and 18 months
Antibiotic resistance
Resistance of commensal E. coli (stool) or S. pneumoniae (nasopharyngeal swab) to panel of antibiotics, by culture
Time frame: 6, 9, 12, 15, and 18 months