Newborn Health, Multiple Micronutrient Deficiencies During Pregnancy, Nutrition During Pregnancy, Adaptive Trial, Postnatal Growth, Neurodevelopment Outcome
Conditions
Keywords
Antenatal Phase, Postnatal Phase, Micro Nutrient Supplementation, Infant Growth
Brief summary
This clinical trial aims to learn if MMS Plus improves infant health compared to standard MMS during pregnancy and the postnatal period in women living in peri-urban areas of Karachi, Pakistan. It will also evaluate how MMS Plus affects infant growth during the first 6 months of life. The main questions it aims to answer are: 1. Does MMS Plus during pregnancy reduce the risk of poor infant outcomes compared to standard MMS, as measured on a 5-point ordinal scale ranging from perinatal mortality to term birth with appropriate, small, or large-for-gestational-age infants? 2. Does postnatal MMS Plus improve infant length velocity at 6 months of age among exclusively breastfed infants compared to standard MMS and iron/folic acid (IFA) supplementation? Researchers will compare: 1. MMS Plus versus standard MMS during pregnancy (antenatal phase) 2. MMS Plus versus standard MMS versus IFA after birth (postnatal phase) Participants will: 1. Be randomly assigned to receive either MMS Plus or standard MMS during pregnancy 2. Be re-randomized after delivery to receive either MMS Plus, standard MMS, or IFA supplements during the postnatal period 3. Receive supplements under double-blind conditions 4. Be followed through childbirth and until the infant is 6 months of age 5. Attend regular clinic visits for health monitoring, infant assessments, and data collection. This phase III adaptive randomized controlled trial will occur in three peri-urban catchment areas of Karachi, Pakistan.
Detailed description
This is a two-phase, Phase III double-blind, adaptive randomized controlled trial designed to evaluate the effects of enhanced multiple micronutrient supplementation (MMS Plus) compared to standard UNIMMAP MMS and iron/folic acid (IFA) supplementation on maternal and infant health outcomes in peri-urban Karachi, Pakistan. The trial is being conducted by The Aga Khan University and is funded by the Bill Gates Foundation. Study Phases and Design: Antenatal Phase: Pregnant women between 8-14 weeks of gestation will be enrolled and randomized (1:1) into one of two arms: MMS Plus (enhanced formulation) Standard MMS (UNIMMAP formulation) Both groups will also receive standard antenatal care (ANC) and nutrition counseling. The primary endpoint is a composite 5-point ordinal scale of infant health at 28 days post-birth, which includes perinatal mortality and growth-for-gestational-age outcomes - Small for gestational age (SGA), Appropriate for Gestational Age (AGA) and Large for Gestational Age (LGA), along with preterm or term. The trial employs a Bayesian adaptive design, with interim analyses beginning after 500 participants have birth outcomes, and subsequent evaluations every 250 outcomes. The design allows early stopping for superiority or continuation based on posterior probabilities. Postnatal Phase: Women with live births will be re-randomised (1:1:1) within one week postpartum into one of three arms: MMS Plus Standard MMS IFA (standard care) All groups receive standard postnatal care and nutrition counselling. The primary endpoint is infant length velocity (cm/month) at 6 months among exclusively breastfed infants. Secondary outcomes include additional anthropometric measures and neurodevelopmental assessments. Adaptive analyses in this phase also begin after 500 infants have outcome data. Interventions: MMS Plus includes 22 micronutrients with additional components: choline (450 mg), DHA (200 mg), calcium (500 mg), and a higher dose of nicotinamide (118 mg NE). Standard MMS follows the UNIMMAP formulation with 15 micronutrients. IFA includes 60 mg of iron and 400 mcg folic acid. All supplements are administered daily via single-dose sachets, indistinguishable in packaging and taste to preserve blinding. Products are manufactured by Remington Pharma. Setting and Recruitment: The trial is implemented through the Clinical Trials Unit (CTU) of Aga Khan University. Recruitment will occur in three peri-urban catchment communities: Ali Akbar Shah Goth (AG), Bhains Colony (BH), and Qayyumabad (QB). Two sites (AG and BH) are located in District Malir and one (QB) in District East. These communities have been selected due to high burdens of maternal undernutrition and established surveillance systems through the Integrated Research Platform (IRP). Pregnant women will be recruited during Antenatal Care (ANC) visits and confirmed eligible via ultrasound. Postnatal re-randomization occurs for women with eligible live-born infants. Follow-up includes scheduled home and clinic visits until 6 months postpartum. Participants will receive all clinical services and transportation free of charge. Data Management and Monitoring: Data will be collected using a digital platform developed on OpenSRP, enabling longitudinal tracking of mother-child dyads. Unique IDs link all clinical encounters and supplement adherence records. Data quality assurance includes weekly field audits, double-entry verification, and remote monitoring by the trial coordination team. A Data Safety Monitoring Board (DSMB) will review interim results and safety data. Trial governance includes a Trial Management Group (TMG) and an independent Trial Steering Committee. All adverse events will be reported following institutional and national regulatory guidelines. Scientific Rationale: Despite global efforts to improve maternal and infant nutrition, Pakistan continues to report high levels of maternal anaemia, low birth weight, and childhood stunting. While MMS is being piloted for national scale-up, the evidence base for extended formulations remains limited, especially regarding postnatal supplementation. MMS Plus is hypothesised to offer superior outcomes due to its inclusion of neurodevelopmentally and metabolically relevant nutrients (choline, DHA, calcium, and high-dose nicotinamide). These additions are based on recent findings from the MUMTA trial and other global data highlighting their role in fetal brain development, infant growth, and maternal health. This trial addresses critical knowledge gaps in the timing (antenatal vs. postnatal), formulation, and impact of micronutrient interventions, using robust adaptive methodologies to optimise power, efficiency, and ethical participant exposure.
Interventions
DIETARY_SUPPLEMENTMMS
Pregnant women in this arm will receive 6gms of MMS (UNIMAPP MMS) in a ready to use sachet form which includes 15 nutrients.
DRUGMMS Plus
Pregnant women in this arm will receive 6gms of MMS Plus in a ready to use sachet form which includes 18 nutrients.
DIETARY_SUPPLEMENTIFA
Pregnant women in this arm will receive 6gms of IFA (Iron/Folic Acid) in a ready to use sachet form which includes 2 nutrients.
Sponsors
Vital Pakistan Trust
Aga Khan University
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
During the antenatal phase, participants will be randomized into one of two arms (MMS vs MMS Plus). However during the postnatal phase, those same participants will be re-randomized into three arms (MMS vs MMS Plus vs IFA).
Eligibility
Sex/Gender
FEMALE
Age
15 Years to 49 Years
Healthy volunteers
Yes
Inclusion criteria
Antenatal Phase:: Inclusion Criteria: * Gestational age confirmed by ultrasound to be 8-14 weeks * Singleton and viable fetus on ultrasound * A resident of the catchment area for at least the last six months * Plans to stay within the catchment area during the pregnancy duration, during delivery and after birth of the baby. * Has provided voluntary written informed consent
Exclusion criteria
* Women with known allergies or intolerance to any components of the MMS or MMS PLUS being studied * Women with pre-existing health conditions such as history of uncontrolled diabetes and hypertension or other chronic illnesses * Substance abuse, such as recreational drugs or smoking tobacco. Women chewing tobacco will not be excluded. Postnatal Phase:: Inclusion Criteria: * Birth weight available within 72 hours * Intention to breastfeed for 6 months * Resides in the study area for the duration of the trial * Has provided voluntary written informed consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Postnatal Phase: Infant linear growth velocity at 6 months | Birth to 6 months | Infant linear growth velocity, calculated as: Length Velocity (cm/month) = Length at 6 months - Length at birth / Age in days / 30.4 Only infants exclusively/predominantly breastfed through 6 months will be included in this analysis. Method of Aggregation: Mean length velocity per intervention group Analysis Metric: Continuous variable; analysed using ANOVA or regression models with pairwise comparisons |
| Antenatal Phase: Composite Infant Health Score at 28 Days Post-Birth | 28 days after birth | Infant health will be assessed using a 5-point ordinal categorical scale, defined as follows: Stillbirth, miscarriage, or early neonatal death (0-6 days); Preterm birth with Small for Gestational Age (SGA) infant; Preterm birth with Appropriate or Large for Gestational Age (AGA or LGA) infant; Term birth with SGA infant; Term birth with AGA or LGA infant Method of Aggregation: Proportion of participants in each outcome category Analysis Metric: Ordinal regression (e.g., Bayesian cumulative logistic regression) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Intrauterine Growth Restriction (IUGR) | GA 20 and 32 weeks | Episodes of IUGR measured at two timepoints during antenatal phase measured through ultrasound to assess growth of fetus in relation to weight and size |
| Gestational age at birth | Within 72 hours of birth | Gestational age at birth, measured in completed weeks, will be assessed using first-trimester ultrasound dating (8-14 weeks gestation). Higher gestational age indicates a better outcome in terms of fetal maturity and reduced risk of neonatal complications. Method of aggregation: Mean gestational age (weeks); proportion of births in each gestational age category (preterm, term, post-term) |
| Birth Weight (gm) | Within 72 hours of birth | Weight of the newborn assess in gram to assess the difference between the arms |
| Birth length (cm) | within 72 hours of birth | Length of the newborn assess in cm to assess the difference between the arms |
| Head circumference (cm) | within 72 hours of birth | Head circumference of the newborn assess in cm to assess the difference between the arms |
| Infant MUAC (cm) | within 72 hours of birth | Infant MUAC at birth of the newborn assess in cm to assess the difference between the arms |
| Gestational Weight Gain (GWG) | At birth | Change in maternal weight during pregnancy, measured in kilograms (kg) from baseline (enrollment) to the time of delivery. Gestational weight gain will be reported both as: Absolute weight gain (kg) Z-scores and percentiles, adjusted for gestational age, based on WHO or INTERGROWTH standards Greater weight gain within recommended ranges is considered indicative of improved maternal nutritional status and better fetal outcomes. |
| Stunting, wasting and underweight Stunting <-2 LAZ ( Length for age Z) scores; Wasting <-2 WHZ (Weight for height Z) scores; underweight <-2WAZ (Weight for age Z) scores | 2, 4, 6, 12, 24 months of life | Mean difference in LAZ, WHZ and WAZ scores to look at comparison between multiple arms |
| Global Scale for Early Development (GSED) Assessment | 6, 12 and 24 months of life | Neurodevelopmental functioning will be assessed using the Global Scales for Early Development (GSED), a standardised instrument developed by the World Health Organisation to measure early child development across cognitive, motor, language, and socio-emotional domains. The GSED yields a Developmental Score (D-score), which is a continuous score derived from observed developmental milestones. Minimum Value: \ 30 (varies slightly based on age and item completion) Maximum Value: \ 80 Interpretation: Higher scores indicate better neurodevelopmental status Scores will be analysed as continuous variables and categorised into: On track At risk Developmental delay based on GSED normative thresholds for age. |
| Infant Brain Morphology and Volume (MRI Assessment Using Hyperfine Portable MRI) | 6, 12 and 24 months of life | Infants enrolled in the postnatal phase will undergo brain imaging using the Hyperfine Swoop™ portable MRI system to assess brain morphology and total and regional brain volumes. Imaging will be conducted at 6, 12, and 24 months of age. Brain volume will be quantified in cubic centimetres (cc) for total brain, grey matter, white matter, and selected regions of interest (e.g., hippocampus, cerebellum). Morphological features (e.g., sulcal/gyral patterns, ventricular size, myelination status) will be qualitatively described and coded using standardised radiological criteria. Higher volumes and normal morphology are indicative of better neurodevelopmental outcomes. |
| Neonatal Mortality | within the first 28 days of life | Neonatal mortality to assess the difference between arms |
| Infant weight velocity | 1, 2, 4, 6, 12, 24 months of life | Mean difference in growth velocity of \>0.4 gram/kg/day to look at comparisons between multiple arms |
| Length-for-age z-score (LAZ) | 2, 4, 6, 12, 24 months of life | Mean difference in LAZ \>0.5 to look at comparisons between multiple arms |
| Weight-for-age z-score (WAZ) | 2, 4, 6, 12, 24 months of life | Mean difference in WAZ of \>0.5 to look at comparisons between multiple arms |
Other
| Measure | Time frame | Description |
|---|---|---|
| Maternal weight | 1, 2, 4, 6, 12, 24 months of life | Maternal body weight, measured in kilograms (kg), will be assessed after delivery to evaluate maternal nutritional status following supplementation during the postnatal phase. Weight will be measured using calibrated digital scales under standardized conditions. Higher weight (within normal postpartum range) indicates better nutritional recovery and health status. |
| Maternal MUAC (cm) | 1, 2, 4, 6, 12, 24 months of life | Mean difference of MUAC in cm to look at comparison between multiple arms |
| Maternal morbidity | Every ANC visit and within 72 hours of birth | Episodes of maternal morbidities such as preeclampsia, gestational diabetes mellitus, hypertensive disorders in between the arms |
Countries
Pakistan
Contacts
Primary ContactFyezah Jehan, MBBS; MSc
Backup ContactZahra Hoodbhoy, PhD
Outcome results
None listed