Nutrition and Inflammation in Pregnancy: Impacts on Early Human Brain Development in Ethiopia

NCT ID: NCT06296238

Last Updated: 2025-03-26

Basic Information

• Recruitment Status: COMPLETED
• Total Enrollment: 463 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2023-02-15
• Study Completion Date: 2024-07-01

Brief Summary

The goal of this observational child follow-up study is to examine the effects of prenatal nutrition and infection management interventions on long-term child neurodevelopment.

Participants are the offspring of mothers in the main study entitled "Enhancing Nutrition and Antenatal Infection Treatment (ENAT)" that was conducted in the rural Amhara region of Ethiopia. In the ENAT pragmatic clinical effectiveness study, 2399 pregnant women were randomized to receive routine prenatal care, a package of enhanced nutrition interventions (balanced energy protein supplement, iodized salt, iron-folic acid and counseling), a package of enhanced infection management interventions (genitourinary tract infection screening-treatment, deworming), or a combination of both packages. The impact of these antenatal nutrition and infection interventions on birth outcomes (infant birth size and gestational length) was examined in the main study. In this longitudinal cohort study, we will follow the offspring from the ENAT pregnancy cohort up to 24 months postnatal age and assess their growth, health and neurodevelopment.

The main questions it aims to answer are:

1. What are the effects of pregnancy interventions from the parent study (ENAT) on offspring neurodevelopmental outcomes?

2. What are the associations between maternal-newborn iron status and inflammation on infant neurodevelopment?

3. What are the associations between maternal iodine status and thyroid function on infant neurodevelopment?

We will follow children of mothers from the parent ENAT study to monitor their growth, health, and neurodevelopment up to 24 months postnatal age.

Detailed Description

In low-resource settings, undernutrition and infections during the first 1000 days of life are prevalent, modifiable risk factors that may have lifelong effects on a child's cognitive and psychological development, yet effective interventions addressing prevailing mechanisms are still to be validated. Iron, protein and energy are critical nutrients that support the rapidly developing fetal brain, however, among women of reproductive age in Sub-Saharan Africa, 10% are underweight and 20% have iron deficiency anemia. Pregnancy infections are also common in Africa, where one in three women have a geo-helminthic infection resulting in blood loss, iron deficiency and inflammation. The interaction between iron and inflammation in pregnancy is particularly complex. NICHD has identified the complex relationship between nutrition, inflammation, and neurodevelopment as a major research gap. A barrier to progress is that mechanistic understanding of prenatal brain development is based on animal or observational studies. We present a unique opportunity to leverage an ongoing randomized controlled trial (RCT) to examine the consequences of pregnancy nutrition and inflammation on child neurodevelopment.

The Enhancing Nutrition and Antenatal Infection Treatment (ENAT) RCT enrolled pregnant women in Amhara, Ethiopia to study independent and overlapping effects of prenatal nutrition and infection interventions on birth outcomes. Women were randomized to receive: 1) standard prenatal care, 2) enhanced nutrition package (ENP) (counseling, iron-folic acid [IFA], iodized salt, and balanced energy protein [BEP] supplementation), 3) enhanced infection management package (EIMP) (anti-helminthics, urinary tract infection treatment), or 4) ENP+EIMP. The current follow-up study (Longitudinal Infant Development and Growth; LIDG) will investigate biological pathways by which ENAT interventions, specifically iron, protein-energy, and inflammation, influence child neurodevelopment.

Our overarching hypotheses are that improving prenatal nutrition will improve brain structural and network development, reducing inflammation will improve white matter maturation, and the combination will have synergistic effects on child neuro-cognitive outcomes. This study will follow up to 500 ENAT children to assess neurodevelopment through 24 months of age, including neurobehavior and neural networks.

Conditions

Prenatal Exposure Delayed Effects

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Study Groups

Enhanced Nutrition Package (ENP) health center + Enhanced Infection Management Package (EIMP)

ENP: Health centers were strengthened to provide WHO/FMOH-recommended nutrition interventions in pregnancy. Pregnant women received a supply of adequately iodized salt for household use and iron-folate tablets from enrollment to birth. Women with undernutrition (MUAC \<23 cm), also received a daily balanced energy protein supplement. EIMP: Pregnant women were screened at enrollment for bacteriuria with urine culture and antimicrobial susceptibility testing and presumptive deworming with mebendazole 500mg. Some women also received screening for chlamydia and gonorrhea and symptomatic women were tested for bacterial vaginosis and trichomonas. For women with chlamydia or gonorrhea, the participant was treated per FMOH guidelines with recommended antibiotics. STI/RTI screening was eventually discontinued due to supply shortage and the low prevalence of STI. At ANC follow-up visits, infected women were treated with antibiotics and persistent infection was retreated.

No interventions assigned to this group

ENP health center, routine care infection management participant

ENP: The health centers were strengthened to provide WHO/FMOH-recommended nutrition interventions in pregnancy. Pregnant women received a supply of adequately iodized salt for household use and iron-folate tablets from enrollment to birth. Women with undernutrition (MUAC \<23 cm), also received a daily balanced energy protein supplement. Standard infection care: Maternal genitourinary tract infections is managed as per standard FMOH health center guidelines that utilize a syndromic management approach.

No interventions assigned to this group

Routine nutrition care health center, EIMP participant

Routine nutrition care: Maternal nutrition was managed as per standard FMOH health center guidelines.

EIMP: Pregnant women were screened at enrollment for bacteriuria with urine culture and antimicrobial susceptibility testing and presumptive deworming with mebendazole 500mg. Some women also received screening for chlamydia and gonorrhea and symptomatic women were tested for bacterial vaginosis and trichomonas. For women with chlamydia or gonorrhea, the participant (and partner) was treated per FMOH guidelines with recommended antibiotics. STI/RTI screening was eventually discontinued due to supply shortage and the low prevalence of STI. At ANC follow-up visits, infected women were treated with antibiotics and persistent infection was retreated.

No interventions assigned to this group

Routine of care nutrition and infection management

Pregnant women received routine strengthened antenatal care services at the health center per FMOH guidelines. Maternal genitourinary tract infections were managed as per standard FMOH health center guidelines that utilize a syndromic management approach.

No interventions assigned to this group

Eligibility Criteria

Inclusion Criteria

• Mothers who have participated in ENAT study who consent to participate in the infant follow up study
• Intention to stay in the study catchment area
• Healthy infants without severe clinical signs or symptoms including headache, vomiting, or dizziness

Exclusion Criteria

• Major congenital anomalies
• Infants with severe morbidity or developmental disorder
• Neonatal encephalopathy
• Plan to move out of study catchment area

• Minimum Eligible Age: 9 Months
• Maximum Eligible Age: 27 Months
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Addis Continental Institute of Public Health

OTHER

Sponsor Role: collaborator

Boston Children's Hospital

OTHER

Sponsor Role: collaborator

New York University

OTHER

Sponsor Role: collaborator

Johns Hopkins University

OTHER

Sponsor Role: collaborator

Brigham and Women's Hospital

OTHER

Sponsor Role: collaborator

Brown University

OTHER

Sponsor Role: lead

Responsible Party

Anne Shee CC Lee

Levinger Family Professor of Pediatrics

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Yemane Berhane

Role: PRINCIPAL_INVESTIGATOR

Addis Continental Institute of Public Health

Anne CC Lee

Role: PRINCIPAL_INVESTIGATOR

Warren Alpert Medical School of Brown University

Locations

Health Centers in West Gojjam and South Gondar zones

Bahir Dar, Amhara, Ethiopia

Countries

Ethiopia

References

Roy Paladhi U, Workneh F, Baye E, Derebe MM, Yibeltal K, Fasil N, Driker S, Van Dyk F, I Chin T, North K, Jensen SKG, Christian P, Worku A, Berhane Y, Lee AC. Investigating biological mechanisms of adverse birth outcomes and early child development in Amhara, Ethiopia: protocol of biospecimen collection and analysis of the Enhancing Nutrition and Antenatal Infection Treatment (ENAT) randomised effectiveness study. BMJ Open. 2025 Apr 28;15(4):e098686. doi: 10.1136/bmjopen-2024-098686.

Reference Type: DERIVED

PMID: 40295129 (View on PubMed)

Workneh F, Chin TI, Yibeltal K, Fasil N, North K, Jensen SKG, Kidane WT, Melese M, Tsegaye S, Berhane YY, Roy Paladhi U, Abate BH, Teklehaimanot A, Melka TL, Pihl S, An WW, Van Dyk F, Mullany LC, Folger LV, Cherkerzian S, Troller-Renfree SV, Thomason ME, Andersson M, Inder T, Nelson CA, Grant PE, Christian P, Worku A, Berhane Y, Lee AC. Impact of maternal antenatal nutrition and infection treatment interventions on Longitudinal Infant Development and Growth in rural Ethiopia: protocol of the LIDG child follow-up study. BMJ Paediatr Open. 2024 Dec 24;8(1):e002840. doi: 10.1136/bmjpo-2024-002840.

Reference Type: DERIVED

PMID: 39725450 (View on PubMed)

Other Identifiers

2023P000461

Identifier Type: -

Identifier Source: org_study_id