SEPSIS Observational Cohort Study in Young Infants in Bangladesh

Globally, infectious diseases including sepsis, meningitis, and pneumonia are among the leading causes of neonatal deaths. In 2017, these three conditions were estimated to account for 540,000 newborn deaths worldwide, approximately 21% of all neonatal deaths globally. Previous studies have suggested that South Asia has a relatively high incidence of possible serious bacterial infection (pSBI) in young infants, particularly in areas where neonatal and under-five mortality rates are highest.

A large body of evidence from inpatient neonatal populations, and the recent evidence from the Panigrahi et al. community trial in India, support an important role of intestinal dysbiosis in the pathogenesis of sepsis/SI in young infants. This mechanism may be particularly important in low- and middle-income countries in Africa and South Asia, where low-cost routine interventions to reduce the burden of SI (e.g., probiotics or synbiotics) could have an important impact on the burden of morbidity and mortality in young infants. However, there are limited data regarding the composition of the early postnatal microbiome in the general population of infants (rather than selected groups of preterm or hospitalized newborns) in South Asia and the role of the microbiome in modulating the risk of SI.

This observational study will generate new knowledge about the incidence and risk factors of SI, including the composition of the intestinal microbiome, in young infants (birth to 60 days of age) in Dhaka, Bangladesh. The aims of this study are to:

1. Estimate the incidence of SI in a facility-recruited cohort of Bangladeshi newborns during the first 60 days of life, and examine the sensitivity of the estimates to variations in SI case definitions;

2. Explore the associations between maternal-infant characteristics (e.g., mode of delivery, feeding practices, gestational age, antibiotic exposure) and the risk of SI in the first 60 days of life;

3. Estimate the absolute and relative stool abundances and age at initial colonization of Bifidobacterium longum subspecies (ssp.) infantis (B. infantis), Bifidobacterium longum ssp. longum (B. longum longum), Bifidobacterium breve (B. breve) and all bifidobacteria species combined during the first 60 days of life in Bangladeshi newborns, overall and within sub-groups defined by: mode of delivery, feeding practices, prior or current infant exposure to antibiotics, and whether there is colonization with the specific bacterial species or subspecies;

4. Explore the associations between maternal-infant characteristics (e.g., mode of delivery, feeding practices, gestational age, antibiotic use) and stool abundance (or age at initial colonization) of B. infantis, B. longum longum, and B. breve;

5. Estimate the association between stool abundance of B. infantis and SI in Bangladeshi newborns during the first 60 days of life;

6. Describe the composition, diversity, and stability of the microbiome in Bangladeshi newborns at multiple time-points during the first 60-days of life, and examine how the composition, diversity, and stability varies by mode of delivery and other maternal-infant and household characteristics;

7. In a facility-recruited cohort of Bangladeshi newborns, estimate the incidence proportions and/or incidence rates and/or prevalence of the following clinical outcomes up to 7 days, 28 days, 60 days of life, 3 months, and 6 months of age:

1. Hospitalization for any reason other than for routine postnatal care

2. Upper respiratory tract infections (URTI);

3. Lower respiratory tract infections (LRTI);

4. Acute or persistent diarrhea;

5. Infant cry/fuss (only up to 3 months of age);

6. Significant neurological impairment or disability diagnosed by 6 months of age; and,

7. All-cause and non-injury-related mortality

8. Describe child anthropometry (length, weight, and head circumference) and standardized anthropometric indices (length-for-age, weight-for age, and weight-for-height, and head circumference-for-age z-scores) up to 60 days of age in a facility-recruited cohort of Bangladeshi newborns;

9. Describe ages of attainment of developmental milestones up to 6 months of age in a facility-recruited cohort of Bangladeshi newborns;

10. Estimate the cohort accrual rates of eligible newborns at two public maternal-child health care facilities in Dhaka, Bangladesh;

11. Enumerate the health facilities within the study catchment area that provide maternal and child care services to pregnant women and newborns.

Study personnel will conduct active and passive clinical surveillance and routine specimen collection (e.g. stool, nasal, skin and oral swabs etc.). Additional specimen collection may also be triggered in the event of physician-confirmed clinical severe infection.