Clinical trial NCT04012190: SEPSIS Observational Cohort Study in Young Infants in Bangladesh
Official title: Severe Infections and the Intestinal Microbiome in Young Infants in Dhaka, Bangladesh: an Observational Cohort Study
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Severe Infection and Non-injury Death
Keywords: Severe infection
Sepsis
Microbiome
Bangladesh
Young infants
Lead sponsor: The Hospital for Sick Children
Sponsor class: OTHER
Collaborators: name: International Centre for Diarrhoeal Disease Research, Bangladesh
name: Child Health Research Foundation, Bangladesh
name: Boston University
name: McGill University
name: University of California, San Diego
First posted: 2019-07-09
Enrollment: 2083
Sex: ALL
Minimum age (years): 0
Maximum age (years): 49
Standard ages: CHILD
ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Healthy Bangladeshi newborns, delivered at two public hospitals (Maternal and Child Health Training Institute and Mohammadpur Fertility Services and Training Centre), and their mothers in Dhaka, Bangladesh. Newborns will be enrolled between 0 and 4 days postnatal age (n=3,000).

Brief summary: Globally, infectious diseases such as sepsis, meningitis and pneumonia are among the leading causes of neonatal deaths. A recent observational study in South Asia highlighted the contribution of both bacterial and viral infections to the burden of illness in infants \<60 days of age; however, there remains a need to quantify the risk of severe infection (SI) among newborns in a Bangladeshi population. In collaboration with researchers in Bangladesh, investigators aim to generate knowledge regarding 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. Data will support the design and implementation of future trials to test the efficacy of novel interventions for the prevention of SI in young infants, to promote optimal growth and development, and to determine effects on other health outcomes in early infancy.

Detailed description: 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. Significant neurological impairment or disability diagnosed by 6 months of age; and,
   6. 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. Estimate the cohort accrual rates of eligible newborns at two public maternal-child health care facilities in Dhaka, Bangladesh

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, or if infants meet the case definition of LRTI (fast breathing with at least one of the following: cough, nasal congestion, or runny nose) or are hospitalized with diarrhea and/or vomiting.

Eligibility criteria: Core Inclusion Criteria:

* Infants up to and including 4 days of age
* Infants delivered at a study hospital
* Orally feeding currently
* Informed consent by parent or guardian
* Intends to maintain residence within the defined catchment areas (upon discharge from hospital) until 60 days of age

Core Exclusion Criteria:

* Birth weight \<1500g
* Death or major surgery considered to be highly probable within first week of life
* Major congenital anomaly of the gastrointestinal tract
* Maternal HIV infection and/or history of mother ever receiving anti-retroviral drug(s) for presumed HIV infection
* Current mechanical ventilation and/or cardiac support (e.g., inotropes) and/or administration/prescription of parenteral antibiotics
* Any prenatal or postpartum use of non-dietary probiotic supplement by mother (during current pregnancy)
* Any postnatal administration of non-dietary probiotic or prebiotic supplements to infant
* Enrolment of infant in any other clinical trial involving the administration of probiotics and/or prebiotics
* Resides in the same household as another infant previously enrolled in the study, or any study within the research platform, who is currently \<60 days of age; however, twins may all be enrolled simultaneously
* Multiple gestation for which the number of liveborn infants from the same pregnancy exceeds two (i.e., triplets or higher order multiples)

Primary outcomes:
measure: Incidence of severe infection (SI) and/or non-injury death
timeFrame: Up to 60 days of age
measure: Absolute abundance of Bifidobacterium infantis, Bifidobacterium longum longum and Bifidobacterium breve in stool
timeFrame: Up to 60 days of age
measure: Relative abundance of Bifidobacterium infantis, Bifidobacterium longum longum and Bifidobacterium breve in stool
timeFrame: Up to 60 days of age
measure: Infant age at initial colonization with bacterial strains
timeFrame: Up to 60 days of age
Secondary outcomes:
Other outcomes:
Locations:
city: Dhaka
country: Bangladesh
facility: Maternal Child Health Training Institute
city: Dhaka
country: Bangladesh
facility: Mohammadpur Fertility Services Training Centre
Study officials:
affiliation: The Hospital for Sick Children
name: Daniel Roth
role: PRINCIPAL_INVESTIGATOR
References: