Clinical trial NCT05730569: Description and Comparison of Biological Vulnerability in Small Vulnerable Newborns Versus Healthy Community Controls in Urban Burkina Faso
Official title: Description and Comparison of Biological Vulnerability in Small Vulnerable Newborns Versus Healthy Community Controls in Urban Burkina Faso (DenBalo): Gut Microbiota, Immune System, and Breastmilk Assembly and Development in the First Days and Weeks of Life
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Preterm Birth
Low Birth Weight
Small for Gestational Age at Delivery
Keywords: Preterm Birth
Low Birth Weight
Small for Gestational Age
Small Vulnerable Newborn
Lead sponsor: University Ghent
Sponsor class: OTHER
Collaborators: name: Institut de Recherche en Sciences de la Santé (IRSS)
name: Université NAZI BONI
name: Hasselt University
name: University of Virginia
name: University Hospital, Ghent
name: Cedars-Sinai Medical Center
name: Sapient Bioanalytics
name: Stanford University
name: Centre Muraz
name: University of Manitoba
name: Manitoba Interdisciplinary Lactation Center (MILC)
name: Agence de Formation, de Recherche & d'Expertise en Santé pour l'Afrique (AFRICSanté)
First posted: 2023-02-16
Enrollment: 140
Sex: ALL
Minimum age (years): 15
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: The study population is composed of all pregnant women at the beginning of the third trimester of their pregnancy attending regular antenatal consultations (ANC) at Accart-Ville, Colma 1 or Farakan health centers.

Brief summary: The aim of the DenBalo study is to apply integrated multi-omics methods to examine the biological mechanisms underlying this vulnerability in Small Vulnerable Newborns (SVNs) in LMICs, with the ultimate goal of identifying targeted interventions to reduce morbidity and mortality in this high-risk population. The evidence generated from this project will ultimately help promote healthy pregnancies and the birth of healthy babies.

To achieve this goal, three research objectives are proposed:

1. To describe and compare gut microbiota, immune system and breastmilk components in SVNs versus healthy community controls in urban Burkina Faso.
2. To describe and compare the development of the gut microbiota, the immune system and breastmilk components during the first six months of life in SVNs versus healthy community controls in urban Burkina Faso.
3. To investigate the relationship between the composition of the gut microbiota, the immune system and breastmilk components during the first six months of life in SVNs versus healthy community controls in urban Burkina Faso.

Detailed description: The first days and weeks of life are characterized by a truly impressive cascade of biological processes that drive neonatal growth and development-all of which are crucial to preparing the newborn for life outside the womb.

First, vaginal delivery exposes neonates to an important natural microbial inoculum from the vaginal microbiota in labor and from the maternal intestinal microbiota at birth. Together, these early colonization events lay the foundation for gut microbiota assembly, inform the arrival of subsequent species through microbial interactions, and dictate infant microbiota maturation. A recent study has shown that a handful of bacteria begin colonizing the infant gut within the first days of life, that gut microbes accumulate gradually over time, and that pioneer strains are retained after a month of life. Whether the gut microbial assembly, maturation, and functional potential differs between SVNs versus healthy, community controls, or is coupled to growth and development, remains unresolved.

Secondly, the first days and weeks of life represent a time of heightened vulnerability to infectious disease. Neonatal infections account for a tragic 40% of mortality in children under five years of age. This critical time period is increasingly seen as a key determinant in health over the entire lifespan. A recent study using a high-dimensional, unbiased approach to characterize neonatal immune system development reported a dramatic, purposeful trajectory in the first week of life. While much remains to be explored, what is known is that early microbial colonization is vital to optimal host immune development and protection from disease and that, after birth, the most important determinant of infant gut colonization is breastfeeding. The impacts of preterm birth, low birth weight, or small for gestational age on immune development and function remain enigmatic and the mediating effect of the gut microbiome unknown.

Thirdly, neonatal nutrition plays a vital role in the two aforementioned processes-because breastfeeding both initiates tropic priming of the newborn gut and transfers numerous immunological factors to the baby. However, few studies have explored the synergy between neonatal microbiome and immunome development, and even fewer through the lens of newborn nutrition. Moreover, virtually zero studies include an integrated characterization of these processes in the SVN. Evidence suggests that, compared to mothers of full-term neonates, the colostrum from mothers of preterm newborns has higher protein and fat content, free amino acids, sodium, and bioactive milk components including HMOs, cytokines, and lactoferrin. But because few studies have evaluated the association between early milk composition and infant growth and development, it is unclear which components are most imperative for a healthy gut microbiota and a robust immune system, particularly in the SVN.

Major advances in systems biology approaches allowing for unbiased, integrated analyses of high-dimensional -omic databases have provided the critical bioinformatic toolkit required to address these questions. Indeed, the ground has never been more fertile for a step-change in commitment to high-impact research on neonatal microbiome and immunome development and the synergy with newborn nutrition.

Eligibility criteria: INCLUSION CRITERIA

* Fundal height between 24 and 27 cm
* Woman living in the health zone of Accart-Ville, Colma 1 or Farakan
* Woman not planning to give birth or move outside the study area in the first 6 months of the infant's life
* Gestational age between 24 weeks 0 completed day and 29 weeks 6 days (ultrasound)
* Monofetal pregnancy without visible malformation
* Woman agreeing to give her informed consent to participate in the study
* Delivery of a live birth
* Vaginal birth
* Absence of severe infectious pathology, severe pneumopathy or respiratory distress in the neonate
* Neonates who did not receive corticosteroids or antibiotics at birth

For Small Vulnerable Newborns (SVNs):

* Low birth weight: \<2500g; and/or,
* Preterm: born between the 34th and 37th week of pregnancy; and/or,
* Small for Gestational Age: \<10 percentile of INTERGROWTH-21st birthweight standards.

For healthy community controls:

* Neonate born after the 37th week of pregnancy; and,
* Birth weight \>2500g; and,
* ≥10 percentile of INTERGROWTH-21st birthweight standards; and,
* Possible match with a SVN neonate already recruited into the study.

EXCLUSION CRITERIA

* Fundal height \<24 cm or \>27 cm
* Woman living outside the sanitary zone of the Accart-Ville, Colma 1 or Farakan
* Woman planning to give birth outside the study area or to move from it within the first 6 months of the infants's life
* Gestational age \<24 weeks or ≥30 weeks (ultrasound)
* Multi-fetal pregnancy
* Malformation visible on ultrasound
* Cesarean delivery
* Neonate with severe infectious disease, severe pneumopathy or respiratory distress
* Neonate who received corticosteroids or antibiotics just after birth

Primary outcomes:
measure: Differential abundances of bacterial genera in the infant gut microbiota
timeFrame: to be assessed at on days 3, 7, 14, 30, 60, 180 of life
Secondary outcomes:
measure: Infant gut microbiota α and β diversity
timeFrame: to be assessed at on days 3, 7, 14, 30, 60, 180 of life
measure: Infant plasma immunophenotyping
timeFrame: to be assessed at birth and on days 1, 3, 5, 7, 30, 60 of life
measure: Infant plasma chemokine and cytokine analyses
timeFrame: to be assessed at birth and on days 1, 3, 5, 7, 30, 60 of life
measure: Maternal breastmilk component* profiling
timeFrame: on days 3, 7, 14, 30, 60 of life
Other outcomes:
measure: Differential abundance of bacterial populations of pregnant or lactating woman (PLW) fecal microbiota
timeFrame: to be assessed within 28-30 weeks of gestation, within 33-34 weeks of gestation, on days 7, 14, 30, 60 and 180 of life
measure: PLW Infant fecal microbiota α and β diversity
timeFrame: to be assessed within 28-30 weeks of gestation, within 33-34 weeks of gestation, on days 7, 14, 30, 60 and 180 of life
measure: PLW fecal enteropathogens
timeFrame: to be assessed within 28-30 weeks of gestation, within 33-34 weeks of gestation, on days 30 and 180 of life
measure: Infant fecal enteropathogens
timeFrame: to be assessed within 28-30 weeks of gestation, within 33-34 weeks of gestation, on days 30 and 180 of life
measure: Maternal plasma immunophenotyping
timeFrame: to be assessed at birth
measure: Maternal plasma chemokine and cytokine analyses
timeFrame: to be assessed at birth
measure: Black carbon exposure in umbilical cord arterial blood
timeFrame: to be assessed at birth
measure: Placental DNA adductiomics
timeFrame: to be assessed at birth
measure: Relative telomere length (TL) in umbilical cord arterial blood
timeFrame: to be assessed at birth
measure: Infant untargeted metabolomics on capillary whole blood
timeFrame: to be assessed at birth, on days 1, 3, 5, 7, 14, 30 and 60 of life
measure: Infant untargeted plasma proteomics
timeFrame: to be assessed at birth, on days 1, 3, 5, 7, 14, 30 and 60 of life
measure: Infant multiple mycotoxin profiling on capillary whole blood
timeFrame: to be assessed at birth, on days 7, and 14 of life
measure: Maternal untargeted capillary whole blood metabolomics
timeFrame: to be assessed at birth
measure: Maternal untargeted plasma proteomics
timeFrame: to be assessed at birth
measure: Maternal multiple mycotoxin profiling on capillary whole blood
timeFrame: to be assessed at birth
measure: PLW shotgun vaginal metagenomics
timeFrame: to be assessed 29-30 weeks of gestation, 33-34 weeks of gestation and at birth
measure: Breastmilk volume intake
timeFrame: to be assessed on days 1, 3, 4, 13 and 14 of life
measure: Differential abundances of bacterial genera in the infant gut microbiota
timeFrame: to be assessed at birth and on days 1, 2, 4, 5, 6 of life
measure: Infant gut microbiota α and β diversity
timeFrame: to be assessed at birth and on days 1, 2, 4, 5, 6 of life
measure: Maternal breastmilk component* profiling
timeFrame: to be assessed at birth and on days 1, 3, 5 of life
measure: Vaginal cytokines
timeFrame: to be assessed at 29-30 weeks of gestation
Locations:
city: Bobo-Dioulasso
country: Burkina Faso
facility: Agence de Formation, de Recherche et d'Expertise en Santé pour l'Afrique (AFRICSanté)
Study officials:
affiliation: University Ghent
name: Trenton Dailey-Chwalibóg, MPH, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Ghent
name: Carl Lachat, MEng, PhD
role: PRINCIPAL_INVESTIGATOR
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