Co-administration of calcium and multiple micronutrient supplements for maternal and newborn haemoglobin and iron status: protocol for a randomised non-inferiority trial in Burkina Faso and Pakistan.

INTRODUCTION: The WHO recommends antenatal calcium supplementation (1500-2000 mg/day) to prevent pre-eclampsia in settings with low dietary calcium intake. Implementation is limited partly due to the need for three daily doses, although a lower 500 mg dose may be non-inferior. Current guidelines also recommend separating calcium from iron-containing supplements because concurrent intake may inhibit iron absorption. This individually randomised, controlled, non-inferiority trial will test whether co-administration of calcium and multiple micronutrient supplement (MMS) (CaMMS) is non-inferior to separate administration for haematological and iron status. METHODS AND ANALYSIS: We will recruit 1600 women at 6<20 weeks' gestation in Burkina Faso and Pakistan, evaluating non-inferiority independently in each setting, which differ in anaemia aetiology and diets. Participants will be randomly assigned to (a) take United Nations International Multiple Micronutrient Antenatal Preparation Multiple Micronutrient Supplements (30 mg elemental iron) and 500 mg elemental calcium together in the morning or (b) take MMS in the morning and calcium in the evening. Venous blood will be collected at 6<20, 20<24, and 30<34 weeks' gestation to measure complete blood count, ferritin, soluble transferrin receptor, hepcidin and erythropoietin. The primary outcome is haemoglobin concentration at 30<34 weeks. Co-administration will be considered non-inferior if the lower bound of the 95% CI for the difference in haemoglobin exceeds the non-inferiority margin of -3 g/L. Enrolment commenced in Pakistan on 25 August 2025 and in Burkina Faso on 12 September 2025. ETHICS AND DISSEMINATION: This protocol was approved by the Johns Hopkins School of Public Health Institutional Review Board, the Comité d'Ethique pour la Recherche en Santé, the Aga Khan University Ethics Review Committee and the Pakistan National Bioethics Committee. Findings will be disseminated through in-country meetings and in the peer-reviewed literature. TRIAL REGISTRATION NUMBER: NCT06568315.