Clinical trial NCT06568315: Co-administration of Calcium and Multiple Micronutrient Supplements for Maternal and Newborn Hemoglobin and Iron Status
Official title: 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
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE3
Conditions: Anemia, Iron Deficiency
Keywords: calcium
iron
supplementation
anemia
pregnancy
Lead sponsor: Johns Hopkins Bloomberg School of Public Health
Sponsor class: OTHER
Collaborators: name: Institut Africain de Santé Publique (African Institute of Public Health)
name: Aga Khan University
First posted: 2024-08-23
Enrollment: 3200
Sex: FEMALE
Minimum age (years): 15
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Hemoglobin concentration of pregnant women
timeFrame: 30<34 weeks of gestation
Secondary outcomes:
measure: Ferritin concentration
timeFrame: 30<34 weeks of gestation
measure: Soluble transferrin receptor (sTfR) concentration
timeFrame: 30<34 weeks of gestation
measure: Hepcidin concentration
timeFrame: 30<34 weeks of gestation
measure: Erythropoietin (EPO) concentration
timeFrame: 30<34 weeks of gestation
measure: sTfR-Ferritin index
timeFrame: 30<34 weeks of gestation
measure: Hepcidin-EPO ratio
timeFrame: 30<34 weeks of gestation
measure: Red blood cell (RBC) count
timeFrame: 30<34 weeks of gestation
measure: Mean corpuscular volume (MCV)
timeFrame: 30<34 weeks of gestation
measure: Mean corpuscular hemoglobin (MCH)
timeFrame: 30<34 weeks of gestation
measure: Mean corpuscular hemoglobin concentration (MCHC)
timeFrame: 30<34 weeks of gestation
measure: Hemoglobin concentration of infants
timeFrame: within 72 hours of birth
measure: Ferritin concentration of infants
timeFrame: within 72 hours of birth
Other outcomes:
measure: Proportion of women with anemia
timeFrame: 30<34 weeks of gestation
measure: Proportion of women with severe anemia (intervention safety)
timeFrame: 20<24 weeks or 30<34 weeks of gestation
measure: Proportion of women with iron deficiency
timeFrame: 30<34 weeks of gestation
measure: Proportion of women with iron-deficient erythropoiesis
timeFrame: 30<34 weeks of gestation
measure: Proportion of women with iron deficiency anemia
timeFrame: 30<34 weeks of gestation
measure: Birth weight
timeFrame: within 72 hours of birth
measure: Proportion of infants born low birth weight
timeFrame: within 72 hours of birth
measure: Gestational age
timeFrame: within 72 hours of birth
measure: Proportion of infants both preterm
timeFrame: within 72 hours of birth
measure: Weight-for-gestational age Z-score
timeFrame: within 72 hours of birth
measure: Proportion of infants born small for gestational age
timeFrame: within 72 hours of birth
measure: Proportion of pregnancies ending in miscarriage
timeFrame: <20 weeks of gestation
measure: Proportion of pregnancies ending in stillbirth
timeFrame: ≥20 weeks of gestation
Locations:
city: Ouagadougou
country: Burkina Faso
facility: Institut Africain de Santé Publique (African Institute of Public Health)
city: Karachi
country: Pakistan
facility: Aga Khan University
Study officials:
affiliation: Johns Hopkins University
name: Amanda Palmer, PhD
role: PRINCIPAL_INVESTIGATOR
References: