The Maternal EED Study

NCT05862363 | Recruiting

• 1 other identifier: PR-22117
• Study Type: interventional
• Target: 180
• Locations: 1 country
• Sites: 1

Brief Summary

Undernutrition among women of reproductive age is more common in South Asia than in any other region. In South Asia, the prevalence of maternal undernutrition varies between 10 and 40%. There is a scarcity of data on the contribution of small intestinal (SI) microbiota to pathogenesis of Environmental Enteric Dysfunction (EED) of malnutrition, as it is difficult to obtain gut biopsy specimens from malnourished individuals, especially children. The Bangladesh Environmental Enteric Dysfunction (BEED) study, involving participants who live in an urban slum (Mirpur) in Dhaka, provided an opportunity to examine the role of the duodenal microbiota in the pathogenesis of EED in children and also performed esophagogastroduodenoscopy (EGD) on thirty-eight 18-45-year-old malnourished (BMI\<18.5 kg/m2) women residing in the same resource-poor setting of Mirpur, Dhaka who failed to respond to an egg/milk/micronutrients- based nutritional intervention comparable to that given to children. In this intervention component, beginning at the end of the first trimester, low-BMI (\<18.5 kg/m2) pregnant women (aged 18-35 years) will be randomly assigned to receive either Microbiota-directed Balanced Energy Protein (MD-BEP) or Ready-to-Use-Supplementary Food Balanced Energy Protein (RUSF-BEP) for the duration of their pregnancy and during the first 3 postnatal months, in addition to standard antenatal care. A parallel cohort of age-matched normal-BMI pregnant women who will not receive any nutritional intervention will serve as a reference control group.

Conditions

Environmental Enteric Dysfunction (EED); Malnutrition; Women of Reproductive Age; Gut Microbiota; Balanced Energy Protein (BEP)

Keywords

Balanced energy protein (BEP); Environmental enteric dysfunction (EED); Gut microbiota; Malnutrition; Women of reproductive age

Outcome Measures

Primary Outcomes (21)

• Change of weight in women of reproductive age before and after nutritional intervention

  In this study, nutritional status will be assessed through anthropometry. Body weight will be collected in kg using a standard weighing machine, and determined at the time of enrolment for all groups, days 30, 60, 90, 120, 180, 210, 270, and 360 for non-pregnant cohort; and days 30, 60, 90, 120, 164, 178, 180, 210, 280, 360, 390, 450, and 540 for pregnant cohort.

  Enrolment to 360 days for non-pregnant cohort, and up to 540 days for pregnant cohort

• Height of women of reproductive age before and after nutritional intervention

  In this study, nutritional status will be assessed through anthropometry. Height will be collected in centimeters using stadiometer. Anthropometry will be collected at the time of enrolment for all groups, days 30, 60, 90, 120, 180, 210, 270, and 360 for non-pregnant cohort; and days 30, 60, 90, 120, 164, 178, 180, 210, 280, 360, 390, 450, and 540 for pregnant cohort.

  Enrolment to 360 days for non-pregnant cohort, and up to 540 days for pregnant cohort

• Change in BMI of women of reproductive age before and after nutritional intervention

  In this study, nutritional status will be assessed through anthropometry. Body weight in kilogram and height in cm will be determined at the time of enrolment for all groups, days 30, 60, 90, 120, 180, 210, 270, and 360 for non-pregnant cohort; and days 30, 60, 90, 120, 164, 178, 180, 210, 280, 360, 390, 450, and 540 for pregnant cohort.

  Enrolment to 360 days for non-pregnant cohort, and up to 540 days for pregnant cohort

• Change in body composition of total fat and fat-free mass of women of reproductive age before and after nutritional intervention before and after nutritional intervention

  Bioelectric Impedance Analysis (BIA) will be used to measure total fat and fat-free mass before, during and after the intervention. BIA is a method of assessing the body composition by measuring the body fat in relation to lean body mass. It is an integral part of a health and nutrition assessment. BIA will be used to measure total fat and fat-free mass before and after intervention with each of the three arms. 60 low-BMI women (18-35 years) provided with MD-BEP/RUSF-BEP intervention, with an age-matched cohort of 30 healthy (normal-BMI) women and subsequent serial fecal and plasma sampling (without nutritional intervention) serving as a control group will be selected for this analysis. Data will be collected on days 1, 180, and 360 days for non-pregnant women and days 0, 180, 360, and 540 days for pregnant women, and the unit of measurement will be the percentage of fat.

  Enrolment to 360 days for non-pregnant, up to 540 days for pregnant cohort

• Validated plasma biomarker (sCD14)

  Blood will be collected at enrolment, and days 30, 90, 180, 270, 360 for non-pregnant women; days 0, 30, 90, 180, 270, 360, 450, and 540 for pregnant women; and days 30, 180, 270, and 360 for offspring cohort, , to determine changes in the representation of plasma biomarkers of EED as a function of treatment. Plasma sCD14 will be measured by ELISA method and it serves as a marker for Systemic inflammation

  Enrolment to 360 days for non-pregnant and children, up to 540 days for pregnant cohort

• Validated plasma biomarker (CRP)

  Blood will be collected at enrolment and on days 30, 90, 180, 270, 360 for non-pregnant women; days 0, 30, 90, 180, 270, 360, 450, and 540 for pregnant women; and days 30, 180, 270, and 360 for the offspring cohort to determine changes in the representation of plasma biomarkers of EED as a function of treatment. Plasma c-reactive protein (CRP) will be measured by the ELISA method.

  Enrolment to 360 days for non-pregnant and children, up to 540 days for pregnant cohort

• Validated plasma biomarker (AGP)

  Blood will be collected at enrolment, and days 30, 90, 180, 270, 360 for non-pregnant women; days 0, 30, 90, 180, 270, 360, 450, and 540 for pregnant women; and days 30, 180, 270, and 360 for offspring cohort, to determine changes in the representation of plasma biomarkers of EED as a function of treatment. alpha-1-acid glycoprotein (AGP) will serve as a marker for Systemic inflammation and it will be measured by ELISA method.

  Enrolment to 360 days for non-pregnant and children, up to 540 days for pregnant cohort

• Hormonal regulators of appetite and satiety (Leptin)

  Blood will be collected at enrolment, and days 30, 90, 180, 270, 360 for non-pregnant women; days 0, 30, 90, 180, 270, 360, 450, and 540 for pregnant women; and days 30, 180, 270, and 360 for offspring cohort, to determine changes in the representation of plasma biomarkers of EED as a function of treatment. Leptin will serve as a marker for Hormonal regulators of appetite and satiety and it will be measured by ELISA method from plasma.

  Enrolment to 360 days for non-pregnant and children, up to 540 days for pregnant cohort

• Hormonal regulators of appetite and satiety (Ghrelin)

  Blood will be collected at enrolment, and days 30, 90, 180, 270, 360 for non-pregnant women; days 0, 30, 90, 180, 270, 360, 450, and 540 for pregnant women; and days 30, 180, 270, and 360 for offspring cohort, , to determine changes in the representation of plasma biomarkers of EED as a function of treatment. Ghrelin will serve as a marker for Hormonal regulators of appetite and it will be measured by ELISA method from Plasma.

  Enrolment to 360 days for non-pregnant and children, up to 540 days for pregnant cohort

• Hormonal regulators of appetite and satiety (IGF-1)

  Blood will be collected at enrolment, and days 30, 90, 180, 270, 360 for non-pregnant women; days 0, 30, 90, 180, 270, 360, 450, and 540 for pregnant women; and days 30, 180, 270, and 360 for offspring cohort, , to determine changes in the representation of plasma biomarkers of EED as a function of treatment. Insulin-like growth factor 1 (IGF-1) will serve as a marker for Hormonal regulators of appetite and satiety and it will be measured from plasma using ELISA method.

  Enrolment to 360 days for non-pregnant and children, up to 540 days for pregnant cohort

• Hormonal regulators of appetite and satiety (Glucagon-like peptide-2 (GLP-2))

  Blood will be collected at enrolment, and days 30, 90, 180, 270, 360 for non-pregnant women; days 0, 30, 90, 180, 270, 360, 450, and 540 for pregnant women; and days 30, 180, 270, and 360 for offspring cohort,, to determine changes in the representation of plasma biomarkers of EED as a function of treatment. Glucagon-like peptide-2 (GLP-2)will serve as a marker for Hormonal regulators of appetite and satiety and it will be measured from plasma using ELISA method.

  Enrolment to 360 days for non-pregnant and children, up to 540 days for pregnant cohort

• Micronutrients level in plasma (Ferritin)

  Blood will be collected at baseline (at the time of EGD),enrolment, and days 30, 90 and, 180, 270, 360 for non-pregnant women; days 0, 30, 90, 180, 270, 360, 450, and 540 for pregnant women; and days 30, 180, 270, and 360 for offspring cohort,, to determine changes in the representation of plasma biomarkers of EED as a function of treatment. Ferritin will serve as a marker for micronutrient level in the blood and it will be measured by ELISA method from Plasma.

  Enrolment to 360 days for non-pregnant and children, up to 540 days for pregnant cohort

• Micronutrients level in plasma (Zinc)

  Blood will be collected at baseline (at the time of EGD),enrolment, and days 30, 90 and, 180, 270, 360 for non-pregnant women; days 0, 30, 90, 180, 270, 360, 450, and 540 for pregnant women; and days 30, 180, 270, and 360 for offspring cohort,, to determine changes in the representation of plasma biomarkers of EED as a function of treatment. Zinc will serve as a marker for micronutrient level in the blood and the plasma zinc will be measured by atomic absorption spectrometry method.

  Enrolment to 360 days for non-pregnant and children, up to 540 days for pregnant cohort

• Validated fecal biomarkers of health status including mediators of growth, systemic inflammation, gut inflammation/enteropathogenic burden, stool pH

  Fecal samples will be collected at the time Of enrolment, days 30, 60, 90, 120, 180, 210, 270, 360 for non-pregnant women; days 0, 30, 60, 90, 120, 180, 210, 270, 360, 390, 450, and 540 for pregnant women; and days 0, 30, 90, 180, 210, 270, and 360 for offspring cohort, of enrolment, days 30, 60, 90, 120, 180, 210, 270, 360 for non-pregnant women; days 0, 30, 60, 90, 120, 180, 210, 270, 360, 390, 450, and 540 for pregnant women; and days 0, 30, 90, 180, 210, 270, and 360 for offspring cohort, for analysis of the effects of intervention on the microbiota-microbiome. Stool pH will be measured on freshly collected stool samples by portable stool pH meter from Hanna instruments, USA.

  Enrolment to 360 days for non-pregnant and children, up to 540 days for pregnant cohort

• 15. Validated fecal biomarkers of health status including mediators of growth, systemic inflammation, gut inflammation/ enteropathogenic burden) (Myeloperoxidase)

  Fecal samples will be collected at the time of enrolment, days 30, 60, 90, 120, 180, 210, 270, 360 for non-pregnant women; days 0, 30, 60, 90, 120, 180, 210, 270, 360, 390, 450, and 540 for pregnant women; and days 0, 30, 90, 180, 210, 270, and 360 for offspring cohort, for analysis of the effects of intervention on the microbiota-microbiome. Myeloperoxidase will be measured from fecal samples using ELISA method.

  Enrolment to 360 days for non-pregnant and children, up to 540 days for pregnant cohort

• Validated fecal biomarkers of health status including mediators of growth, systemic inflammation, gut inflammation/enteropathogenic burden (neopterin)

  Fecal samples will be collected at the time of enrolment, days 30, 60, 90, 120, 180, 210, 270, 360 for non-pregnant women; days 0, 30, 60, 90, 120, 180, 210, 270, 360, 390, 450, and 540 for pregnant women; and days 0, 30, 90, 180, 210, 270, and 360 for offspring cohort, for analysis of the effects of intervention on the microbiota-microbiome. Neopterin will be measured from fecal sample using ELISA method

  Enrolment to 360 days for non-pregnant and children, up to 540 days for pregnant cohort

• Validated fecal biomarkers of health status including mediators of growth, systemic inflammation, gut inflammation/enteropathogenic burden (calprotectin)

  Fecal samples will be collected at the time of enrolment, days 30, 60, 90, 120, 180, 210, 270, 360 for non-pregnant women; days 0, 30, 60, 90, 120, 180, 210, 270, 360, 390, 450, and 540 for pregnant women; and days 0, 30, 90, 180, 210, 270, and 360 for offspring cohort, for analysis of the effects of intervention on the microbiota-microbiome. Calprotectin will be measured from fecal sample using ELISA method.

  Enrolment to 360 days for non-pregnant and children, up to 540 days for pregnant cohort

• Validated fecal biomarkers of health status including mediators of growth, systemic inflammation, gut inflammation/enteropathogenic burden (Dual oxidase 2 (DUOX2)

  Fecal samples will be collected at the time of enrolment, days 30, 60, 90, 120, 180, 210, 270, 360 for non-pregnant women; days 0, 30, 60, 90, 120, 180, 210, 270, 360, 390, 450, and 540 for pregnant women; and days 0, 30, 90, 180, 210, 270, and 360 for offspring cohort, for analysis of the effects of intervention on the microbiota-microbiome. Fecal DUOX2 will be measured by ELISA method.

  Enrolment to 360 days for non-pregnant and children, up to 540 days for pregnant cohort

• Validated fecal biomarkers of health status including mediators of growth, systemic inflammation, gut inflammation/enteropathogenic burden (Oxidation-Reduction Potential (Redox potential))

  Fecal samples will be collected at the time of enrolment, days 30, 60, 90, 120, 180, 210, 270, 360 for non-pregnant women; days 0, 30, 60, 90, 120, 180, 210, 270, 360, 390, 450, and 540 for pregnant women; and days 0, 30, 90, 180, 210, 270, and 360 for offspring cohort, for analysis of the effects of intervention on the microbiota-microbiome. Redox potential will be measured in millivolt (mV)

  Enrolment to 360 days for non-pregnant and children, up to 540 days for pregnant cohort

• Validated fecal biomarkers of health status including mediators of growth, systemic inflammation, gut inflammation/enteropathogenic burden Lipocalin 2 (Lcn2)

  Fecal samples will be collected at the time of enrolment, days 30, 60, 90, 120, 180, 210, 270, 360 for non-pregnant women; days 0, 30, 60, 90, 120, 180, 210, 270, 360, 390, 450, and 540 for pregnant women; and days 0, 30, 90, 180, 210, 270, and 360 for offspring cohort, for analysis of the effects of intervention on the microbiota-microbiome. Lipocalin 2 (Lcn2) will be measured by ELISA method using fecal sample.

  Enrolment to 360 days for non-pregnant and children, up to 540 days for pregnant cohort

• Pregnancy-related change in weight

  Pregnant women will be enrolled and followed up over a period of 9 months. Enrolment will be done before 2nd trimester. Low-BMI pregnant women will be provided with daily supplementation of supplemental food (MD-BEP/RUSF-BEP) and normal-BMI women will be followed without any intervention. For the low-BMI pregnant women, antenatal care (ANC) services from nearby healthcare facility will be ensured by study staff. Trained Health Workers (HWs) will visit the homes of all enrolled pregnant women once a month. During the follow up, the investigators will collect anthropometry data from each participant every four-weekly. The unit of data collection for pregnant women is kg. Relevant laboratory investigation that will be done among pregnant women will follow previously described methods.

  Enrolment to pregnancy termination and three months post-birth

Study Arms (4)

Normal BMI women

ACTIVE COMPARATOR

A total of 30 women with functional dyspepsia will be recruited as a control arm of AIM 1A. The women will be recruited who will present with GI symptoms. A total of 100 women will undergo EGD, out of which 30 women will be enrolled based on their diagnosis of functional dyspepsia and willingness to participate in the study.

Procedure: Esophagogastroduodenoscopy (EGD); Behavioral: Counselling and follow-up

Low- BMI women

ACTIVE COMPARATOR

A total of 60 women from low-socioeconomic status (SES) and with low BMI will be included in the intervention arm of aim A1. They will be recruited based on their willingness to participate and through meeting the inclusion criteria. They will under EGD, including collection of duodenal aspirates and 6-8 biopsy samples. After EGD, 30 participants will receive MD-BEP and 30 will receive RUSF-BEP upon randomization.

Dietary Supplement: Microbiota-directed balanced energy protein (MD-BEP); Dietary Supplement: Ready-to-use supplementary food-balanced energy protein (RUSF-BEP); Procedure: Esophagogastroduodenoscopy (EGD); Behavioral: Counselling and follow-up

Low-BMI pregnant women

ACTIVE COMPARATOR

We will recruit 60 pregnant women with low-BMI before 14 weeks of gestation. 30 participants will receive MD-BEP and 30 will receive RUSF-BEP upon randomization. They will be followed to note changes in weight gain, BMI, changes in EED biomarkers, gut microbial community repair, and pregnancy related outcomes.

Dietary Supplement: Microbiota-directed balanced energy protein (MD-BEP); Dietary Supplement: Ready-to-use supplementary food-balanced energy protein (RUSF-BEP); Behavioral: Counselling and follow-up

Normal BMI pregnant women

ACTIVE COMPARATOR

We will recruit 30 pregnant women with normal-BMI before 14 weeks of gestation. They will be provided with standard antenatal care. They will be followed to note changes in weight gain, BMI, changes in EED biomarkers, gut microbial community repair, and pregnancy related outcomes.

Behavioral: Counselling and follow-up

Interventions

Microbiota-directed balanced energy protein (MD-BEP) DIETARY_SUPPLEMENT

Prototypes for nutritional interventions that are composed of locally available, affordable, culturally acceptable complementary foods commonly consumed in Bangladesh have recently been developed.

Low- BMI women; Low-BMI pregnant women

Ready-to-use supplementary food-balanced energy protein (RUSF-BEP) DIETARY_SUPPLEMENT

RUSF-BEP is composed of rice, lentil, sugar, soybean oil, and skimmed milk powder mixed with vitamin-mineral premix. MD-BEP is composed of chickpea flour, peanut flour, soy flour, green banana pulp, sugar, soybean oil, and vitamin-mineral premix. The results from previous studies support the notion that repair of impaired gut microbial community development could represent a new therapeutic concept for restoring healthy growth. RUSF-BEP will be given to one arm of low-BMI women of reproductive age and low-BMI pregnant women.

Low- BMI women; Low-BMI pregnant women

Esophagogastroduodenoscopy (EGD) PROCEDURE

Aim 1A consists of performing EGD to women with low-BMI and normal BMI women with function dyspepsia. In order to enroll 30 participants with normal duodenal mucosal histology, we are planning to perform EGD on 100 healthy women (BMI 20-24.9 kg/m2) of childbearing age who have been referred for evaluation of functional dyspepsia. Undernourished low-BMI (\<18.5kg/m2; 18-35 years) women of childbearing age will be enrolled from Bauniabadh and adjacent slum area of Mirpur, Dhaka and EGD will be performed among 60 women. A total of 6-8 biopsy samples from SI and a dry duodenal aspirate will be collected for biopsy, histochemical and immunocytochemical analysis.

Low- BMI women; Normal BMI women

Counselling and follow-up BEHAVIORAL

Normal BMI pregnant women will be counseled and followed up as per standard guidelines and will be provided routine antenatal care.

Low- BMI women; Low-BMI pregnant women; Normal BMI pregnant women; Normal BMI women

Eligibility Criteria

• Age: 18 Years - 35 Years
• Gender Eligibility Details: For this study, we will enroll pregnant women and non-pregnant women of reproductive age with low-BMI. They will be compared with a matched cohort of women with normal BMI. The women will be within reproductive age.
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Bangladeshi female, age 18-35 years
• BMI 20-24.9 kg/m2
• Middle-upper socioeconomic class (≥ $11/day family income)
• Functional dyspepsia
• Willing to sign the consent form
• Willing to provide biological samples during the study period of 6 months
• BMI \<18.5 kg/m2
• No antibiotics for 1 month
• Willing to sign the consent form
• Willing to undergo endoscopy and biopsy
• Willing to provide biological samples during the study period of 6 months
• Willing to receive food supplementation for 3 months
• Bangladeshi female, age 18-35 years
• BMI 20-24.9 kg/m2
• Middle-upper socioeconomic class (≥ $11/day family income)

You may not qualify if:

• Received antibiotics during the last one month
• Presence of any chronic disease including diabetes mellitus or any congenital disorder or deformity
• Ongoing episode of diarrhea, history of persistent diarrhea in the past month or history of acute diarrhea in the past 7 days
• Severe anemia (\<8 g/dl), TB and other chronic diseases, including diabetes mellitus, urogenital infections or any congenital disorder or deformity
• Pregnancy, lactation, drug abuse, known psychiatric disorders
• Chest x-ray
• Urine for R/E
• Ultrasonography of whole abdomen
• Fasting blood glucose/ HbA1c
• Stool for OBT (occult blood test)
• Cancer markers (ie. CEA, CA 15.3, CA 19.9)
• Known allergy to any components of nutrition intervention
• Nugent Score/Amsel Criteria to exclude bacterial vaginosis: A Nugent score 3-4 is consistent with Bacterial vaginosis (BV). The modified Amsel criteria with a cut-off value of 2 (pH+VD; sensitivity 71%, specificity 90%, accuracy 88% or KOH+VD; sensitivity 75%, specificity 91%, accuracy 89%) might be considered for this purpose20.
• Ongoing episode of diarrhea, history of persistent diarrhea in the past month or history of acute diarrhea in the past 7 days
• Received antibiotics during the last one month

Sponsors & Collaborators

• International Centre for Diarrhoeal Disease Research, Bangladesh: lead
• Washington University School of Medicine: collaborator
• Bangladesh Specialized Hospital: collaborator
• Sheikh Russel National Gastroliver Institute & Hospital: collaborator

Study Sites (1)

International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b)

Dhaka, Dhaka Division, 1212, Bangladesh

RECRUITING

MeSH Terms

Conditions

Malnutrition

Interventions

Endoscopy, Digestive System; Counseling

Condition Hierarchy (Ancestors)

Nutrition Disorders; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Diagnostic Techniques, Digestive System; Diagnostic Techniques and Procedures; Diagnosis; Endoscopy; Diagnostic Techniques, Surgical; Digestive System Surgical Procedures; Surgical Procedures, Operative; Minimally Invasive Surgical Procedures; Mental Health Services; Behavioral Disciplines and Activities; Community Health Services; Health Services; Health Care Facilities Workforce and Services

Study Officials

• Md. Shabab Hossain, MBBS

  International Centre for Diarrhoeal Disease Research, Bangladesh

  PRINCIPAL INVESTIGATOR

Central Study Contacts

M. A. Salam Khan

CONTACT

+880-2-9827001-10; salamk@icddrb.org

Md. Shabab Hossain, MBBS

CONTACT

+880-2-9827001-10; dr.shabab@icddrb.org

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Masking Details: The participants will be randomly assigned either RUSF or MDCF-2 (as dietary supplements). The participants will be made unaware of the supplement they are receiving; however, the field staff and investigators will be made aware of the dietary supplement allocation.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: All the activities in both Aim 1A and 1B are divided into two parallel arms. In 1A, EGD will be performed for both women within reproductive age with low-BMI and with normal-BMI. The interventions are designed in two arms. The first arm will enroll women from ages 18-35years with low BMI. They will be subdivided into two groups, each of which will receive either RUSF-BEP or MD-BEP. There will be cohort of healthy women with normal BMI for comparison. The second arm will consist of pregnant women from ages 18-35 years with low BMI. They will also be subdivided into two groups, each of which will receive either RUSF-BEP or MD-BEP. There will be cohort of healthy pregnant women with normal BMI for comparison.

Study Record Dates

• First Submitted: February 8, 2023
• First Posted: May 17, 2023
• Study Start: January 2, 2023
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2026
• Last Updated: May 14, 2025

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will not share

Locations

BA (1)