Improving Cognition and Gestational Duration With Targeted Nutrition

Study Overview
=================
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.

Official Title
-----------------
Improving Cognition and Gestational Duration With Targeted Nutrition

Conditions
-----------------
Malnutrition in Pregnancy, Preterm Birth, Child Development, Postpartum Depression, Antepartum Depression

Intervention / Treatment
-----------------
* 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


Participation Criteria
=================
Eligibility Criteria
-----------------
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: 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 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 ≥ 13 years of age Pregnant 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: 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 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 Patient Health Questionnaire-9 score ≥ 9 Exclusion Criteria: Participation in a concomitant supplementary feeding program Known allergy to components of intervention or control study food or medications Known gestational diabetes Hypertension Severe anemia, or other condition requiring immediate hospitalization

Ages Eligible for Study
-----------------
Minimum Age: 13 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Interventional Model Description: 2x2 factorial design
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: M-RUSF+ (Maternal Ready-to-Use Supplementary Food + DHA/EPA/choline) and CBT<br>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. | Dietary Supplement: M-RUSF+ (Maternal Ready-to-Use Supplementary Food + DHA/EPA/choline)<br>* Balanced energy protein supplement with added DHA/EPA/choline, micronutrients<br>Drug: Azithromycin<br>* 1g dose<br>Drug: Albendazole<br>* 400mg dose<br>Drug: Sulfadoxine pyrimethamine<br>* Monthly, 1,500/75mg dose<br>Behavioral: Cognitive behavioral therapy<br>* Novel program developed for illiterate end-users<br>Other: Insecticide-treated mosquito net<br>* Bed net to prevent malaria<br>|
| Experimental: M-RUSF+ (Maternal Ready-to-Use Supplementary Food + DHA/EPA/choline) and no CBT<br>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. | Dietary Supplement: M-RUSF+ (Maternal Ready-to-Use Supplementary Food + DHA/EPA/choline)<br>* Balanced energy protein supplement with added DHA/EPA/choline, micronutrients<br>Drug: Azithromycin<br>* 1g dose<br>Drug: Albendazole<br>* 400mg dose<br>Drug: Sulfadoxine pyrimethamine<br>* Monthly, 1,500/75mg dose<br>Other: Insecticide-treated mosquito net<br>* Bed net to prevent malaria<br>|
| Experimental: M-RUSF (Maternal Ready-to-use Supplementary Food without DHA/EPA/choline and CBT<br>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. | Dietary Supplement: M-RUSF (Maternal Ready-to-Use Supplementary Food)<br>* Balanced energy protein supplement with added micronutrients<br>Drug: Azithromycin<br>* 1g dose<br>Drug: Albendazole<br>* 400mg dose<br>Drug: Sulfadoxine pyrimethamine<br>* Monthly, 1,500/75mg dose<br>Behavioral: Cognitive behavioral therapy<br>* Novel program developed for illiterate end-users<br>Other: Insecticide-treated mosquito net<br>* Bed net to prevent malaria<br>|
| Experimental: M-RUSF (Maternal Ready-to-use Supplementary Food without DHA/EPA/choline and no CBT<br>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. | Dietary Supplement: M-RUSF (Maternal Ready-to-Use Supplementary Food)<br>* Balanced energy protein supplement with added micronutrients<br>Drug: Azithromycin<br>* 1g dose<br>Drug: Albendazole<br>* 400mg dose<br>Drug: Sulfadoxine pyrimethamine<br>* Monthly, 1,500/75mg dose<br>Other: Insecticide-treated mosquito net<br>* Bed net to prevent malaria<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Gestational duration | 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 | Enrollment to birth (range 2 to 26 weeks) | 
| Malawi Developmental Assessment Tool (MDAT) global z-score | Infant global age-adjusted z-score on MDAT | 9 months post-birth | 
| Adapted Patient Health Questionnaire-9 (PHQ-9) score | Among participants who develop ante- or post-partum depression, adapted Patient Health Questionnaire-9 score, (range 0-27, higher scores are worse) | 8 weeks after diagnosis with ante- or post-partum depression | 

Secondary Outcome Measures

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