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

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.

Study Overview

• Status: Completed
• Conditions: Prenatal Exposure Delayed Effects

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.

• Study Type: Observational
• Enrollment (Actual): 463

Contacts and Locations

Study Locations

• Ethiopia
  • Amhara
    • Bahir Dar, Amhara, Ethiopia
      • Health Centers in West Gojjam and South Gondar zones

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: Yes

• Sampling Method: Probability Sample

Study Population

The participants of this study will be recruited from 6 rural health centers (serving a ~25,000 population) involved in ENAT study in West Gojjam and South Gondar zones, Amhara, Ethiopia (Lee et al., 2022). In this infant follow-up study, up to 500 selected infants from the parent ENAT study will be followed for 24 months for general health, growth, and development. A subset of these infants (up to 480) whose mothers provided biospecimens or whose mothers had mid-upper arm circumference (MUAC) of <23 cm in the parent study will be recruited for an advanced neurodevelopmental assessment study.

Description

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

Study Plan

How is the study designed?

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort
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.
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.
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.
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Child resting brain function	Measured by absolute power of alpha frequency band on mobile electroencephalography	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Child resting brain function, secondary measures	Absolute and relative power of beta, theta, gamma frequency bands; relative alpha power, on mobile electroencephalography	24 months
Brain functional connectivity	Neural network efficiency and organization across brain regions measured by mobile electroencephalography	24 months
Neural processing speed	Visual Evoked Potential (VEP) P1 Latency	24 months
Visual Attention	Measured with infant eye tracking during Cecile Attention Task	12 months
Nonverbal Visual Attention	Multisensory Attention Assessment Protocol	12 months
Infant Neurologic Maturity	Hammersmith Infant Neurological Exam (HINE) Total Score	12 months
Infant Head Circumference	Occipito-frontal head circumference	12, 24 months
Child Cognitive Function	Bayley-III Cognitive Scale	24 months

Collaborators and Investigators

• Sponsor: Brown University
• Collaborators: Johns Hopkins University; New York University; Boston Children's Hospital; Brigham and Women's Hospital; Addis Continental Institute of Public Health
• Investigators: Principal Investigator: Yemane Berhane, Addis Continental Institute of Public Health; Principal Investigator: Anne CC Lee, Warren Alpert Medical School of Brown University

Study record dates

Study Major Dates

• Study Start (Actual): February 15, 2023
• Primary Completion (Actual): July 1, 2024
• Study Completion (Actual): July 1, 2024

Study Registration Dates

• First Submitted: February 29, 2024
• First Submitted That Met QC Criteria: February 29, 2024
• First Posted (Actual): March 6, 2024

Study Record Updates

• Last Update Posted (Actual): March 26, 2025
• Last Update Submitted That Met QC Criteria: March 24, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urogenital Diseases; Pathologic Processes; Female Urogenital Diseases and Pregnancy Complications; Pregnancy Complications; Prenatal Injuries; Inflammation; Prenatal Exposure Delayed Effects
• Other Study ID Numbers: 2023P000461

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No