Improving Cognition and Gestational Duration With Targeted Nutrition

Not Applicable

Recruiting

• Conditions: Malnutrition in Pregnancy; Preterm Birth; Antepartum Depression; Child Development; Postpartum Depression
• Interventions: Dietary Supplement: M-RUSF+ (Maternal Ready-to-Use Supplementary Food + DHA/EPA/choline); Dietary Supplement: M-RUSF (Maternal Ready-to-Use Supplementary Food); Drug: Azithromycin; Drug: Albendazole; Drug: Sulfadoxine pyrimethamine; Behavioral: Cognitive behavioral therapy; Other: Insecticide-treated mosquito net

• Registration Number: NCT05949190
• Lead Sponsor: Washington University School of Medicine

Brief Summary

The goal of this clinical trial is to test (1) a novel maternal ready-to-use supplementary food and (2) a novel cognitive behavioral therapy intervention in undernourished Sierra Leonean women. The main questions it aims to answer are:

* Will the addition of omega-3 long-chain polyunsaturated fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), as well as choline, to a maternal ready-to-use supplementary food (M-RUSF+) prolong gestation when compared with a similar supplementary food except that it lacks DHA, EPA, and choline (M-RUSF)?

* Will M-RUSF+ improve infant cognitive development at 9 months of age when compared with M-RUSF?

* Will the novel CBT program improve ante- and post-partum depression?

Detailed Description

Undernutrition in pregnancy is common, affecting nearly 10% of women worldwide and 25% of women in Sub-Saharan Africa, and increases risks for both mothers and their offspring, including bleeding, preterm birth, neonatal mortality, and impaired infant cognitive development. Available treatments have limited impact on these outcomes, which affect millions annually. A recent trial in Sierra Leone showed that pairing high-quality supplementary nutrition with anti-infective measures led to greater maternal weight gain, longer and heavier newborns, and reduced neonatal mortality. In addition, ante- and postpartum depression are underrecognized and undertreated in rural Sub-Saharan Africa.

The goal of this clinical trial is to test (1) a novel maternal ready-to-use supplementary food (M-RUSF+) and (2) a novel cognitive behavioral therapy (CBT) program developed for illiterate users, in undernourished pregnant women in Sierra Leone. The main questions it aims to answer are:

* Will the addition of omega-3 long-chain polyunsaturated fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), as well as choline, to a maternal ready-to-use supplementary food (M-RUSF+) prolong gestation when compared with a similar supplementary food except that it lacks DHA, EPA, and choline (M-RUSF)?

* Will M-RUSF+ improve infant cognitive development at 9 months of age when compared with M-RUSF?

* Will the novel CBT program improve ante- and post-partum depression?

Participants will present to government-run antenatal clinics for screening. If they quality for enrollment and consent to participate, they will undergo:

ANTENATALLY

* randomization to intervention vs. control group

* bi-weekly anthropometric measurements

* ultrasound gestational age estimation

* demographic, socioeconomic, and health history questionnaires

* bi-weekly blood pressure measurement

* bi-weekly screening for ante- and post-partum depression

* two blood spot collections

POSTNATALLY

* birth measurements of mother and offspring

* cord blood and placental sampling for a subset

* 5 clinic visits for mother and offspring anthropometric measurements, health history, breastfeeding practice, maternal mental health questions

* offspring developmental assessments

All participants will receive:

ANTENATALLY

* 100g/day of M-RUSF+ or M-RUSF, containing 530 Kcal, 19g protein, United Nations International Multiple Micronutrient Antenatal Preparation (UNIMMAP) equivalent

* insecticide-treated bed nets

* a single dose of albendazole de-worming medicine

* monthly malaria chemoprophylaxis

* single doses of azithromycin in the second and third trimesters

* safe birth kits

If participants develop ante- or postpartum depression and are randomized to CBT, they will receive 6 sessions of CBT.

Study Timeline

• Study First Submitted: 2023-06-29
• Study First Submitted QC: 2023-07-14
• Study First Posted: 2023-07-17
• Study Start: 2023-08-18
• Status Verified: 2024-03
• Last Update Submitted: 2024-03-11
• Last Update Posted: 2024-03-13
• Primary Completion: 2026-02
• Study Completion: 2026-02

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 1600

Inclusion Criteria

In order to be eligible to participate in the M-RUSF+ vs. M-RUSF element of the study, an individual must meet all of the following criteria:

1. Provision of signed (or thumb-printed) and dated informed consent form 1a. Women who are ≥ 18 years of age or married will be allowed to consent for themselves 1b. Women who are < 18 years of age and unmarried must provide assent and a parent or guardian must provide consent
2. Stated willingness to comply with all study procedures and availability for the duration of the study, including no plan to move from the catchment area of a participating clinic
3. ≥ 13 years of age
4. Pregnant
5. Mid-upper arm circumference ≤ 23 cm or body-mass index < 18.5

In order to be eligible to participate in the CBT vs. no CBT element of the study (factorial design with the above), an individual must be enrolled in the M-RUSF+ vs. M-RUSF study and meet the following criteria:

1. Provision of signed (or thumb-printed) and dated informed consent form 1a. Women who are ≥ 18 years of age or married will be allowed to consent for themselves 1b. Women who are < 18 years of age and unmarried must assent and a parent or guardian consent must provide consent
2. Stated willingness to comply with all study procedures and availability for the duration of the study, including no plan to move from the catchment area of a participating clinic
3. Patient Health Questionnaire-9 score ≥ 9

Exclusion Criteria

1. Participation in a concomitant supplementary feeding program
2. Known allergy to components of intervention or control study food or medications
3. Known gestational diabetes
4. Hypertension
5. Severe anemia, or other condition requiring immediate hospitalization

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: FACTORIAL

Arm && Interventions

Group	Intervention	Description
M-RUSF+ (Maternal Ready-to-Use Supplementary Food + DHA/EPA/choline) and CBT	Sulfadoxine pyrimethamine	Factorial 1. A daily dose of 500mg DHA, 500mg EPA, and 550mg choline will be added to the maternal balanced energy-protein RUSF. One sachet (daily dose) will provide 520 Kcal, 18g protein, and the same quantities of micronutrients as the United Nations International Multiple Micronutrient Antenatal Preparation (UNIMMAP) for women. M-RUSF+ will be vacuum sealed and packaged in foil sachets containing 100g of food. Factorial 2. Among participants randomized to receive M-RUSF+ vs. M-RUSF, those who develop ante- or postpartum depression will receive 6 sessions of CBT adopted for use in illiterate populations will be provided.
M-RUSF+ (Maternal Ready-to-Use Supplementary Food + DHA/EPA/choline) and no CBT	Sulfadoxine pyrimethamine	Factorial 1. A daily dose of 500mg DHA, 500mg EPA, and 550mg choline will be added to the maternal balanced energy-protein RUSF. One sachet (daily dose) will provide 520 Kcal, 18g protein, and the same quantities of micronutrients as the UNICEF/World Health Organization/United Nations multiple micronutrient supplement for pregnant/lactating women. M-RUSF+ will be vacuum sealed and packaged in foil sachets containing 100g of food. Factorial 2. Participants who develop ante- or postpartum depression will not receive CBT.
M-RUSF (Maternal Ready-to-use Supplementary Food without DHA/EPA/choline and CBT	Sulfadoxine pyrimethamine	Factorial 1. M-RUSF will be similar to M-RUSF+, except it will not contain added DHA or EPA, and will only contain 5mg of added choline to help with flavor masking. One sachet (daily dose) will provide 520 Kcal, 18g protein, and the same quantities of micronutrients as the UNIMMAP for pregnant/lactating women. M-RUSF+ will be vacuum sealed and packaged in foil sachets containing 100g of food. Factorial 2. Participants who develop ante- or postpartum depression will receive 6 sessions of CBT adopted for use in illiterate populations will be provided.
M-RUSF (Maternal Ready-to-use Supplementary Food without DHA/EPA/choline and no CBT	Sulfadoxine pyrimethamine	Factorial 1. M-RUSF will be similar to M-RUSF+, except it will not contain added DHA or EPA, and will only contain 5mg of added choline to help with flavor masking. One sachet (daily dose) will provide 520 Kcal, 18g protein, and the same quantities of micronutrients as the UNIMMAP for pregnant/lactating women. M-RUSF+ will be vacuum sealed and packaged in foil sachets containing 100g of food. Factorial 2. Participants who develop ante- or postpartum depression will not receive CBT.
M-RUSF+ (Maternal Ready-to-Use Supplementary Food + DHA/EPA/choline) and CBT	Cognitive behavioral therapy	Factorial 1. A daily dose of 500mg DHA, 500mg EPA, and 550mg choline will be added to the maternal balanced energy-protein RUSF. One sachet (daily dose) will provide 520 Kcal, 18g protein, and the same quantities of micronutrients as the United Nations International Multiple Micronutrient Antenatal Preparation (UNIMMAP) for women. M-RUSF+ will be vacuum sealed and packaged in foil sachets containing 100g of food. Factorial 2. Among participants randomized to receive M-RUSF+ vs. M-RUSF, those who develop ante- or postpartum depression will receive 6 sessions of CBT adopted for use in illiterate populations will be provided.
M-RUSF+ (Maternal Ready-to-Use Supplementary Food + DHA/EPA/choline) and CBT	Insecticide-treated mosquito net	Factorial 1. A daily dose of 500mg DHA, 500mg EPA, and 550mg choline will be added to the maternal balanced energy-protein RUSF. One sachet (daily dose) will provide 520 Kcal, 18g protein, and the same quantities of micronutrients as the United Nations International Multiple Micronutrient Antenatal Preparation (UNIMMAP) for women. M-RUSF+ will be vacuum sealed and packaged in foil sachets containing 100g of food. Factorial 2. Among participants randomized to receive M-RUSF+ vs. M-RUSF, those who develop ante- or postpartum depression will receive 6 sessions of CBT adopted for use in illiterate populations will be provided.
M-RUSF+ (Maternal Ready-to-Use Supplementary Food + DHA/EPA/choline) and CBT	M-RUSF+ (Maternal Ready-to-Use Supplementary Food + DHA/EPA/choline)	Factorial 1. A daily dose of 500mg DHA, 500mg EPA, and 550mg choline will be added to the maternal balanced energy-protein RUSF. One sachet (daily dose) will provide 520 Kcal, 18g protein, and the same quantities of micronutrients as the United Nations International Multiple Micronutrient Antenatal Preparation (UNIMMAP) for women. M-RUSF+ will be vacuum sealed and packaged in foil sachets containing 100g of food. Factorial 2. Among participants randomized to receive M-RUSF+ vs. M-RUSF, those who develop ante- or postpartum depression will receive 6 sessions of CBT adopted for use in illiterate populations will be provided.
M-RUSF+ (Maternal Ready-to-Use Supplementary Food + DHA/EPA/choline) and no CBT	M-RUSF+ (Maternal Ready-to-Use Supplementary Food + DHA/EPA/choline)	Factorial 1. A daily dose of 500mg DHA, 500mg EPA, and 550mg choline will be added to the maternal balanced energy-protein RUSF. One sachet (daily dose) will provide 520 Kcal, 18g protein, and the same quantities of micronutrients as the UNICEF/World Health Organization/United Nations multiple micronutrient supplement for pregnant/lactating women. M-RUSF+ will be vacuum sealed and packaged in foil sachets containing 100g of food. Factorial 2. Participants who develop ante- or postpartum depression will not receive CBT.
M-RUSF (Maternal Ready-to-use Supplementary Food without DHA/EPA/choline and CBT	Insecticide-treated mosquito net	Factorial 1. M-RUSF will be similar to M-RUSF+, except it will not contain added DHA or EPA, and will only contain 5mg of added choline to help with flavor masking. One sachet (daily dose) will provide 520 Kcal, 18g protein, and the same quantities of micronutrients as the UNIMMAP for pregnant/lactating women. M-RUSF+ will be vacuum sealed and packaged in foil sachets containing 100g of food. Factorial 2. Participants who develop ante- or postpartum depression will receive 6 sessions of CBT adopted for use in illiterate populations will be provided.
M-RUSF (Maternal Ready-to-use Supplementary Food without DHA/EPA/choline and CBT	Cognitive behavioral therapy	Factorial 1. M-RUSF will be similar to M-RUSF+, except it will not contain added DHA or EPA, and will only contain 5mg of added choline to help with flavor masking. One sachet (daily dose) will provide 520 Kcal, 18g protein, and the same quantities of micronutrients as the UNIMMAP for pregnant/lactating women. M-RUSF+ will be vacuum sealed and packaged in foil sachets containing 100g of food. Factorial 2. Participants who develop ante- or postpartum depression will receive 6 sessions of CBT adopted for use in illiterate populations will be provided.
M-RUSF+ (Maternal Ready-to-Use Supplementary Food + DHA/EPA/choline) and no CBT	Insecticide-treated mosquito net	Factorial 1. A daily dose of 500mg DHA, 500mg EPA, and 550mg choline will be added to the maternal balanced energy-protein RUSF. One sachet (daily dose) will provide 520 Kcal, 18g protein, and the same quantities of micronutrients as the UNICEF/World Health Organization/United Nations multiple micronutrient supplement for pregnant/lactating women. M-RUSF+ will be vacuum sealed and packaged in foil sachets containing 100g of food. Factorial 2. Participants who develop ante- or postpartum depression will not receive CBT.
M-RUSF (Maternal Ready-to-use Supplementary Food without DHA/EPA/choline and CBT	M-RUSF (Maternal Ready-to-Use Supplementary Food)	Factorial 1. M-RUSF will be similar to M-RUSF+, except it will not contain added DHA or EPA, and will only contain 5mg of added choline to help with flavor masking. One sachet (daily dose) will provide 520 Kcal, 18g protein, and the same quantities of micronutrients as the UNIMMAP for pregnant/lactating women. M-RUSF+ will be vacuum sealed and packaged in foil sachets containing 100g of food. Factorial 2. Participants who develop ante- or postpartum depression will receive 6 sessions of CBT adopted for use in illiterate populations will be provided.
M-RUSF (Maternal Ready-to-use Supplementary Food without DHA/EPA/choline and no CBT	Insecticide-treated mosquito net	Factorial 1. M-RUSF will be similar to M-RUSF+, except it will not contain added DHA or EPA, and will only contain 5mg of added choline to help with flavor masking. One sachet (daily dose) will provide 520 Kcal, 18g protein, and the same quantities of micronutrients as the UNIMMAP for pregnant/lactating women. M-RUSF+ will be vacuum sealed and packaged in foil sachets containing 100g of food. Factorial 2. Participants who develop ante- or postpartum depression will not receive CBT.
M-RUSF (Maternal Ready-to-use Supplementary Food without DHA/EPA/choline and no CBT	M-RUSF (Maternal Ready-to-Use Supplementary Food)	Factorial 1. M-RUSF will be similar to M-RUSF+, except it will not contain added DHA or EPA, and will only contain 5mg of added choline to help with flavor masking. One sachet (daily dose) will provide 520 Kcal, 18g protein, and the same quantities of micronutrients as the UNIMMAP for pregnant/lactating women. M-RUSF+ will be vacuum sealed and packaged in foil sachets containing 100g of food. Factorial 2. Participants who develop ante- or postpartum depression will not receive CBT.
M-RUSF+ (Maternal Ready-to-Use Supplementary Food + DHA/EPA/choline) and CBT	Azithromycin	Factorial 1. A daily dose of 500mg DHA, 500mg EPA, and 550mg choline will be added to the maternal balanced energy-protein RUSF. One sachet (daily dose) will provide 520 Kcal, 18g protein, and the same quantities of micronutrients as the United Nations International Multiple Micronutrient Antenatal Preparation (UNIMMAP) for women. M-RUSF+ will be vacuum sealed and packaged in foil sachets containing 100g of food. Factorial 2. Among participants randomized to receive M-RUSF+ vs. M-RUSF, those who develop ante- or postpartum depression will receive 6 sessions of CBT adopted for use in illiterate populations will be provided.
M-RUSF+ (Maternal Ready-to-Use Supplementary Food + DHA/EPA/choline) and CBT	Albendazole	Factorial 1. A daily dose of 500mg DHA, 500mg EPA, and 550mg choline will be added to the maternal balanced energy-protein RUSF. One sachet (daily dose) will provide 520 Kcal, 18g protein, and the same quantities of micronutrients as the United Nations International Multiple Micronutrient Antenatal Preparation (UNIMMAP) for women. M-RUSF+ will be vacuum sealed and packaged in foil sachets containing 100g of food. Factorial 2. Among participants randomized to receive M-RUSF+ vs. M-RUSF, those who develop ante- or postpartum depression will receive 6 sessions of CBT adopted for use in illiterate populations will be provided.
M-RUSF+ (Maternal Ready-to-Use Supplementary Food + DHA/EPA/choline) and no CBT	Azithromycin	Factorial 1. A daily dose of 500mg DHA, 500mg EPA, and 550mg choline will be added to the maternal balanced energy-protein RUSF. One sachet (daily dose) will provide 520 Kcal, 18g protein, and the same quantities of micronutrients as the UNICEF/World Health Organization/United Nations multiple micronutrient supplement for pregnant/lactating women. M-RUSF+ will be vacuum sealed and packaged in foil sachets containing 100g of food. Factorial 2. Participants who develop ante- or postpartum depression will not receive CBT.
M-RUSF+ (Maternal Ready-to-Use Supplementary Food + DHA/EPA/choline) and no CBT	Albendazole	Factorial 1. A daily dose of 500mg DHA, 500mg EPA, and 550mg choline will be added to the maternal balanced energy-protein RUSF. One sachet (daily dose) will provide 520 Kcal, 18g protein, and the same quantities of micronutrients as the UNICEF/World Health Organization/United Nations multiple micronutrient supplement for pregnant/lactating women. M-RUSF+ will be vacuum sealed and packaged in foil sachets containing 100g of food. Factorial 2. Participants who develop ante- or postpartum depression will not receive CBT.
M-RUSF (Maternal Ready-to-use Supplementary Food without DHA/EPA/choline and CBT	Azithromycin	Factorial 1. M-RUSF will be similar to M-RUSF+, except it will not contain added DHA or EPA, and will only contain 5mg of added choline to help with flavor masking. One sachet (daily dose) will provide 520 Kcal, 18g protein, and the same quantities of micronutrients as the UNIMMAP for pregnant/lactating women. M-RUSF+ will be vacuum sealed and packaged in foil sachets containing 100g of food. Factorial 2. Participants who develop ante- or postpartum depression will receive 6 sessions of CBT adopted for use in illiterate populations will be provided.
M-RUSF (Maternal Ready-to-use Supplementary Food without DHA/EPA/choline and CBT	Albendazole	Factorial 1. M-RUSF will be similar to M-RUSF+, except it will not contain added DHA or EPA, and will only contain 5mg of added choline to help with flavor masking. One sachet (daily dose) will provide 520 Kcal, 18g protein, and the same quantities of micronutrients as the UNIMMAP for pregnant/lactating women. M-RUSF+ will be vacuum sealed and packaged in foil sachets containing 100g of food. Factorial 2. Participants who develop ante- or postpartum depression will receive 6 sessions of CBT adopted for use in illiterate populations will be provided.
M-RUSF (Maternal Ready-to-use Supplementary Food without DHA/EPA/choline and no CBT	Albendazole	Factorial 1. M-RUSF will be similar to M-RUSF+, except it will not contain added DHA or EPA, and will only contain 5mg of added choline to help with flavor masking. One sachet (daily dose) will provide 520 Kcal, 18g protein, and the same quantities of micronutrients as the UNIMMAP for pregnant/lactating women. M-RUSF+ will be vacuum sealed and packaged in foil sachets containing 100g of food. Factorial 2. Participants who develop ante- or postpartum depression will not receive CBT.
M-RUSF (Maternal Ready-to-use Supplementary Food without DHA/EPA/choline and no CBT	Azithromycin	Factorial 1. M-RUSF will be similar to M-RUSF+, except it will not contain added DHA or EPA, and will only contain 5mg of added choline to help with flavor masking. One sachet (daily dose) will provide 520 Kcal, 18g protein, and the same quantities of micronutrients as the UNIMMAP for pregnant/lactating women. M-RUSF+ will be vacuum sealed and packaged in foil sachets containing 100g of food. Factorial 2. Participants who develop ante- or postpartum depression will not receive CBT.

Primary Outcome Measures

Name	Time	Method
Malawi Developmental Assessment Tool (MDAT) global z-score	9 months post-birth	Infant global age-adjusted z-score on MDAT
Adapted Patient Health Questionnaire-9 (PHQ-9) score	8 weeks after diagnosis with ante- or post-partum depression	Among participants who develop ante- or post-partum depression, adapted Patient Health Questionnaire-9 score, (range 0-27, higher scores are worse)
Gestational duration	Enrollment to birth (range 2 to 26 weeks)	Enrollment ultrasound estimated gestational age plus time between enrollment and delivery. For the primary outcome, this will only be assessed among participants enrolled \<= 30 weeks gestational age and with singleton live births

Secondary Outcome Measures

Name	Time	Method
Infant mortality	Birth to end of follow-up (9 months)	Infant death
Low birth weight	Birth	Birth weight \< 2.5 kg
Neonatal mortality	Birth to 28 days of age	Infant death within the first 28 days of life
Depressive symptoms	Through study completion, an average of 1.25 years	Adapted Patient Health Questionnaire-9 score (range 0-27, higher scores are worse)
Maternal and infant DHA status	From Enrollment to delivery, an average of 15 weeks	Maternal plasma, cord blood DHA status
Birth weight	Birth	Infant weight at birth
Early preterm birth	Enrollment to 34 weeks' gestation	Birth \< 34 weeks gestational age
Birth length	Birth	Infant length at birth
Malawi Developmental Assessment Test sub-domain z-scores	9 months after birth	Gross motor, fine motor, language, and social domain z-scores (expected range -4 to 2, higher scores are better)
Preterm birth	Enrollment to 37 weeks' gestation	Birth \< 37 weeks gestational age
Post-term delivery	From Enrollment to delivery, an average of 15 weeks	Delivery \> 42 weeks' gestation
Maternal weight gain	From Enrollment to delivery, an average of 15 weeks	Average weekly weight gain
Infant length-for-age z-score at 6 weeks, 3 months, 6 months, 9 months	Birth to 9 months	Infant length-for-age z-score
Maternal and infant choline status	From Enrollment to delivery, an average of 15 weeks	Blood choline concentration
Depression incidence	8 weeks from time of depression diagnosis	Adapted PHQ-9 \>= 9
Birth chest circumference	Birth	Infant chest circumference
Birth head circumference	Birth	Infant head circumference
Infant weight at 6 weeks, 3 months, 6 months, 9 months	Birth to 9 months	Infant weight
Infant length at 6 weeks, 3 months, 6 months, 9 months	Birth to 9 months	Infant length
Placental weight	Birth	Weight of placenta in grams
Birth thigh circumference	Birth	Infant thigh circumference
Gestational duration	From Enrollment to birth, an average of 15 weeks	Enrollment ultrasound estimated gestational age plus time between enrollment and delivery. For this secondary outcome, all enrolled women will be included in analysis.
Small for gestational age (SGA)	Birth	Under 10th percentile in birth weight for gestational age

Trial Locations

Locations (10)

Blama Massaquoi; 🇸🇱 Blama Massaquoi, Southern, Sierra Leone

Sahn Malen; 🇸🇱 Sahn, Southern, Sierra Leone

Zimmi; 🇸🇱 Zimmi, Southern, Sierra Leone

Bendu Malen; 🇸🇱 Bendu, Southern, Sierra Leone

Pujehun Static; 🇸🇱 Pujehun, Southern, Sierra Leone

Bandajuma; 🇸🇱 Bandajuma, Southern, Sierra Leone

Futa Peje; 🇸🇱 Futa Peje, Southern, Sierra Leone

Gbondapi; 🇸🇱 Gbondapi, Southern, Sierra Leone

Nyandehun Malen; 🇸🇱 Nyandehun, Southern, Sierra Leone

Potoru; 🇸🇱 Potoru, Southern, Sierra Leone