Improving Cognition and Gestational Duration With Targeted Nutrition

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.

• M-RUSF+ (Maternal Ready-to-Use Supplementary Food + DHA/EPA/choline) (Dietary supplement): Balanced energy protein supplement with added DHA/EPA/choline, micronutrients
• M-RUSF (Maternal Ready-to-Use Supplementary Food) (Dietary supplement): Balanced energy protein supplement with added micronutrients
• Azithromycin (Drug): 1g dose
• Albendazole (Drug): 400mg dose
• Sulfadoxine pyrimethamine (Drug): Monthly, 1,500/75mg dose
• Cognitive behavioral therapy (Behavioral): Novel program developed for illiterate end-users
• Insecticide-treated mosquito net (Other): Bed net to prevent malaria

Primary outcomes

• 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
• 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)

Secondary outcomes

• Early preterm birth [Enrollment to 34 weeks' gestation]: Birth < 34 weeks gestational age
• Birth weight [Birth]: Infant weight at birth
• Birth length [Birth]: Infant length at birth
• Low birth weight [Birth]: Birth weight < 2.5 kg
• 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
• Neonatal mortality [Birth to 28 days of age]: Infant death within the first 28 days of life
• Infant mortality [Birth to end of follow-up (9 months)]: Infant death
• 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
• Maternal and infant choline status [From Enrollment to delivery, an average of 15 weeks]: Blood choline concentration
• Maternal weight gain [From Enrollment to delivery, an average of 15 weeks]: Average weekly weight gain
• Post-term delivery [From Enrollment to delivery, an average of 15 weeks]: Delivery > 42 weeks' gestation
• Depression incidence [8 weeks from time of depression diagnosis]: Adapted PHQ-9 >= 9
• Birth chest circumference [Birth]: Infant chest circumference
• Birth thigh circumference [Birth]: Infant thigh 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
• 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
• 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.
• Placental weight [Birth]: Weight of placenta in grams
• Small for gestational age (SGA) [Birth]: Under 10th percentile in birth weight for gestational age

Other outcomes

• Intrauterine growth parameters [Subset of participants (enrollment GA <= 24 weeks) to undergo q4-6week serial ultrasounds]: Estimated weight, head circumference, femur length, placental size
• Gestational duration by baseline DHA status [From enrollment to birth, an average of 15 weeks]: Gestational duration modeled by enrollment DHA % of plasma fatty acids
• Gestational duration by baseline maternal MUAC [From enrollment to birth, an average of 15 weeks]: Gestational duration modeled by enrollment MUAC
• Gestational duration by enrollment gestational age [From enrollment to birth, an average of 15 weeks]: Gestational duration modeled by enrollment GA
• Gestational duration by enrollment maternal age [From enrollment to birth, an average of 15 weeks]: Gestational duration modeled by enrollment maternal age
• Gestational duration by maternal parity [From enrollment to birth, an average of 15 weeks]: Gestational duration compared across levels of maternal parity

Sex: All, ages: 13 Years to any

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

• Results publication: Kleban E, Lee A, Koroma A, Hendrixson DT, Duncan J, Manary MJ, Stephenson KB. Cognitive Behavioral Therapy for Individuals With Low Literacy and Perinatal Depression: A Randomized Clinical Trial. JAMA Netw Open. 2026 May 1;9(5):e2611101. doi: 10.1001/jamanetworkopen.2026.11101. PMID 42096203

• Mark J Manary, MD, Principal investigator, Washington University School of Medicine