Co-administration of Calcium and Multiple Micronutrient Supplements for Maternal and Newborn Hemoglobin and Iron Status (CaMMS)

Co-administration of Calcium and Multiple Micronutrient Supplements for Maternal and Newborn Hemoglobin and Iron Status: A Randomized Non-inferiority Trial in Burkina Faso and Pakistan

The World Health Organization (WHO) currently recommends the pregnant women receive iron-containing supplements and, in settings where calcium intake is low, calcium supplements. Supplements are to be taken at two separate times of the day as calcium may interfere with iron absorption. The goal of this clinical trial is to learn whether taking daily calcium supplements and iron-containing multiple micronutrient supplements together, at the same time, has any negative impact on the hemoglobin or iron status of pregnant women or the woman's infants. Participants will be randomly assigned and counseled to either take the supplements together every morning or to take the multiple micronutrient supplement in the morning and the calcium supplement in the evening. Participants will visit the antenatal clinic monthly and be asked to provide a blood sample in early, mid, and late pregnancy. Researchers will also take blood samples from infants at the time of birth.

Study Overview

• Status: Recruiting
• Conditions: Anemia, Iron Deficiency
• Intervention / Treatment: Dietary supplement: Concurrent multiple micronutrient and calcium supplementation; Dietary supplement: Separate multiple micronutrient and calcium supplementation

Detailed Description

Women of reproductive age in low-and-middle-income countries typically consume diets inadequate in many micronutrients. Resulting micronutrient deficiencies are further exacerbated during pregnancy by the increased demands of the developing fetus. Studies show that antenatal micronutrient supplementation can have important benefits for maternal and infant health. While WHO currently recommends daily iron and folic acid supplementation, many countries are transitioning to multiple micronutrient supplementation (MMS) based on evidence of its further benefit in reducing risk of low birth weight, small-for-gestational age births, stillbirths, and preterm delivery. WHO also recommends calcium supplementation for women in settings where calcium intake is low to reduce high blood pressure and prevent preeclampsia and preterm birth.

Women are instructed to take calcium supplements separately from iron-containing supplements to avoid any negative impact of calcium on iron absorption. However, evidence that calcium limits iron absorption is largely from studies of single test meals. Research on the longer-term implications of consuming the two nutrients together for iron status and hemoglobin is limited, particularly in pregnancy. This is an important research question as limiting the number of times per day that a woman needs to take supplements is likely to improve adherence to the regimen. There is also interest in designing a new MMS formulation that includes calcium such that women could take a single tablet daily.

This individually randomized controlled non-inferiority trial will enroll 1,600 women in both Burkina Faso and Pakistan to assess the impact of co-administering calcium (500 mg elemental calcium as calcium carbonate) and multiple micronutrient supplements (including 30 mg elemental iron), compared with the currently recommended practice of taking the supplements at two separate times of the day, on hematological and iron status of pregnant women and the women's infants. The sample size is based on a non-inferiority margin of -3.0 g/L, 90% power, a one-sided α=0.025, a standard deviation of 17 g/L for the primary hemoglobin outcome, and 15% loss to follow-up.

Potentially eligible women will be identified through antenatal care visits in Burkina Faso and household visits in Pakistan. For those who consent to screening, research staff will measure hemoglobin and conduct a fetal ultrasound exam. Inclusion and exclusion criteria are provided below. Research staff will obtain written documentation of informed consent.

At enrollment, women will be randomized, and research staff will collect socio-demographic data, take anthropometric and blood pressure measurements, and collect a venous blood sample. Women will receive counseling based on the randomly assigned intervention and be given a supply of study supplements. Research staff will see women monthly at antenatal visits to collect information on adherence by recall and pill count, side effects, signs/symptoms of anemia, and information on any iron treatment that women may have received between visits. Iron treatment prescribed by providers outside of the trial will also be abstracted from medical records. At the mid-pregnancy (20<24 weeks) and late pregnancy (30<34 weeks) visits, research staff will take hemoglobin (HemoCue), anthropometric and blood pressure measurements and collect venous blood samples. Women with severe anemia (<70 g/L) will be referred for treatment. Within 72 hours of birth, research staff will collect a heel prick blood sample from infants. Blood samples will be processed at antenatal clinics and transferred to central laboratories for measurement of hematological parameters, iron status, and inflammation.

• Study Type: Interventional
• Enrollment (Estimated): 3200
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Amanda C Palmer, PhD; Phone Number: 1 (410) 955-2061; Email: acpalmer@jhu.edu
• Study Contact Backup: Name: Monica Pasqualino, PhD; Email: mpasqua2@jhmi.edu

Study Locations

• Burkina Faso
  • Ouagadougou, Burkina Faso
    • Recruiting
    • Institut Africain de Santé Publique (African Institute of Public Health)
    • Principal Investigator: Seni Kouanda, PhD
    • Contact: Seni Baguiya, PhD; Phone Number: 70 26 14 62; Email: senikouanda@gmail.com
    • Sub-Investigator: Adama Baguiya, MD
• Pakistan
  • Karachi, Pakistan
    • Recruiting
    • Aga Khan University
    • Contact: Saleem Jessani, MBBS; Phone Number: 021-34864885; Email: saleem.jessani@aku.edu
    • Principal Investigator: Sarah Saleem, MBBS
    • Sub-Investigator: Saleem Jessani, MBBS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Burkina Faso: married or unmarried pregnant women aged ≥15 years
• Pakistan: married pregnant women ≥18 years
• Willing to receive all antenatal care at a study clinic
• Willing to stop iron folic acid supplementation to receive the study intervention
• Hb ≥70 g/L
• 6<20 weeks of gestation based on fetal ultrasound

Exclusion Criteria:

• Burkina Faso: <15 years or unmarried pregnant women <18 years without consent from parent / guardian
• Pakistan: pregnant women <18 years.
• Unwilling to receive antenatal care at a study clinic
• Unwilling to stop iron folic acid supplementation to receive the study intervention
• Hemoglobin < 70 g/L
• <6 weeks of gestation or ≥20 weeks of gestation
• Non-viable or extrauterine pregnancy
• Any contraindications to study supplements

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Concurrent MMS / Calcium; Daily multiple micronutrient supplement (providing 30 mg iron) taken concurrently with daily calcium supplement (500 mg)	Dietary supplement: Concurrent multiple micronutrient and calcium supplementation; Participants counseled to take United Nations International Multiple Micronutrient Antenatal Preparation (UNIMMAP) multiple micronutrient supplement providing 30 mg elemental iron and calcium supplement providing 500 mg elemental calcium as 1250 mg calcium carbonate together every morning from enrollment through the end of pregnancy
Active Comparator: Separate MMS / Calcium; Daily multiple micronutrient supplement (providing 30 mg iron) taken separately from daily calcium supplement (500 mg)	Dietary supplement: Separate multiple micronutrient and calcium supplementation; Participants counseled to take United Nations International Multiple Micronutrient Antenatal Preparation (UNIMMAP) multiple micronutrient supplement (MMS) providing 30 mg elemental iron every morning and calcium supplement providing 500 mg elemental calcium as 1250 mg calcium carbonate every evening from enrollment through the end of pregnancy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hemoglobin concentration of pregnant women	Hemoglobin measured by hematology analyzer	30<34 weeks of gestation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ferritin concentration	Ferritin (μg/L)	30<34 weeks of gestation
Soluble transferrin receptor (sTfR) concentration	sTfR (mg/L)	30<34 weeks of gestation
Hepcidin concentration	Hepcidin (ng/mL)	30<34 weeks of gestation
Erythropoietin (EPO) concentration	EPO (mIU/mL)	30<34 weeks of gestation
sTfR-Ferritin index	sTfR:log10(ferritin)	30<34 weeks of gestation
Hepcidin-EPO ratio	Hepcidin:EPO	30<34 weeks of gestation
Red blood cell (RBC) count	RBC count	30<34 weeks of gestation
Mean corpuscular volume (MCV)	MCV (fL)	30<34 weeks of gestation
Mean corpuscular hemoglobin (MCH)	MCH (pg)	30<34 weeks of gestation
Mean corpuscular hemoglobin concentration (MCHC)	MCHC (g/dL)	30<34 weeks of gestation
Hemoglobin concentration of infants	Hemoglobin (g/L) measured by HemoCue	within 72 hours of birth
Ferritin concentration of infants	Ferritin (μg/L)	within 72 hours of birth

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of women with anemia	Hemoglobin < 110 g/L	30<34 weeks of gestation
Proportion of women with severe anemia (intervention safety)	Hemoglobin < 70 g/L	20<24 weeks or 30<34 weeks of gestation
Proportion of women with iron deficiency	Ferritin <15 μg/L (adjusted for inflammation)	30<34 weeks of gestation
Proportion of women with iron-deficient erythropoiesis	Elevated sTfR concentration	30<34 weeks of gestation
Proportion of women with iron deficiency anemia	Concurrent anemia and iron deficiency	30<34 weeks of gestation
Birth weight	Infant's birth weight (g)	within 72 hours of birth
Proportion of infants born low birth weight	Infant weight <2500 g	within 72 hours of birth
Gestational age	Gestational age at birth (weeks)	within 72 hours of birth
Proportion of infants both preterm	Gestational age <37 weeks	within 72 hours of birth
Weight-for-gestational age Z-score	Calculated using INTERGROWTH-21st standard	within 72 hours of birth
Proportion of infants born small for gestational age	<10th percentile of weight-for-gestational age using INTERGROWTH-21st standard	within 72 hours of birth
Proportion of pregnancies ending in miscarriage	Fetal loss <20 gestational weeks	<20 weeks of gestation
Proportion of pregnancies ending in stillbirth	Fetal loss ≥20 gestational weeks	≥20 weeks of gestation

Collaborators and Investigators

• Sponsor: Johns Hopkins Bloomberg School of Public Health
• Collaborators: Bill and Melinda Gates Foundation; Aga Khan University; Children's Investment Fund Foundation; Institut Africain de Santé Publique (African Institute of Public Health)
• Investigators: Principal Investigator: Amanda Palmer, PhD, Johns Hopkins University

Study record dates

Study Major Dates

• Study Start (Actual): August 25, 2025
• Primary Completion (Estimated): August 1, 2026
• Study Completion (Estimated): August 1, 2026

Study Registration Dates

• First Submitted: August 19, 2024
• First Submitted That Met QC Criteria: August 21, 2024
• First Posted (Actual): August 23, 2024

Study Record Updates

• Last Update Posted (Estimated): September 17, 2025
• Last Update Submitted That Met QC Criteria: September 16, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: anemia; pregnancy; supplementation; iron; calcium
• Additional Relevant MeSH Terms: Metabolic Diseases; Hematologic Diseases; Iron Metabolism Disorders; Anemia, Hypochromic; Nutritional and Metabolic Diseases; Hemic and Lymphatic Diseases; Iron Deficiencies; Anemia; Anemia, Iron-Deficiency; Calcium-Regulating Hormones and Agents; Physiological Effects of Drugs; Bone Density Conservation Agents; Calcium, Dietary; Calcium; Micronutrients; Trace Elements
• Other Study ID Numbers: IRB00030029; INV036663 (Other Grant/Funding Number: Bill and Melinda Gates Foundation); 1911-04269 (Other Grant/Funding Number: Children's Investment Fund Foundation)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data (IPD) will be available on request by contacting the investigative team.
• IPD Sharing Time Frame: IPD will be available after publication of the trial's outcomes
• IPD Sharing Access Criteria: To be agreed upon with investigators
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No