Non-inferiority of low-dose compared to standard high-dose calcium supplementation in pregnancy: study protocol for two randomized, parallel group, non-inferiority trials in India and Tanzania

Pratibha Dwarkanath, Alfa Muhihi, Christopher R Sudfeld, Shobha Rani, Christopher P Duggan, Mary M Sando, Blair J Wylie, Ryan Fernandez, Shabani Kinyogoli, Cristina Munk, Nandita Perumal, John Michael Raj, Nirmala Buggi, Ndeniria Swai, Tinku Thomas, Molin Wang, Anura V Kurpad, Honorati Masanja, Andreas B Pembe, Wafaie W Fawzi, Pratibha Dwarkanath, Alfa Muhihi, Christopher R Sudfeld, Shobha Rani, Christopher P Duggan, Mary M Sando, Blair J Wylie, Ryan Fernandez, Shabani Kinyogoli, Cristina Munk, Nandita Perumal, John Michael Raj, Nirmala Buggi, Ndeniria Swai, Tinku Thomas, Molin Wang, Anura V Kurpad, Honorati Masanja, Andreas B Pembe, Wafaie W Fawzi

Abstract

Background: Hypertensive disorders of pregnancy are important causes of maternal morbidity and mortality, as well as preterm birth, the leading cause of death for children under 5 years globally. The World Health Organization currently recommends that pregnant women receive high-dose calcium supplementation (1500-2000 mg elemental calcium) for prevention of preeclampsia in populations with low dietary calcium intake. Trials of low-dose calcium supplementation (< 1000 mg elemental calcium/day) during pregnancy have also shown similar reductions in the risk of preeclampsia; however, no trials to date have directly compared low-dose to the standard high-dose calcium supplementation. Our objective is to assess the non-inferiority of low-dose as compared to standard high-dose calcium supplementation in pregnancy.

Methods/design: We will conduct two independent trials in Bangalore, India (n = 11,000 pregnancies), and Dar es Salaam, Tanzania (n = 11,000 pregnancies). The trial designs are individually randomized, parallel group, quadruple-blind, non-inferiority trials of low-dose calcium supplementation (500 mg elemental calcium/day) as compared to standard high-dose calcium supplementation (1500 mg elemental calcium/day) among nulliparous pregnant women. Pregnant women will be enrolled in the trial before 20 weeks of gestation and will receive the randomized calcium regimen from randomization until the time of delivery. The co-primary outcomes are (i) preeclampsia and (ii) preterm birth; we will test non-inferiority of the primary outcomes for low-dose as compared to the standard high-dose supplementation regimen in each trial. The trials' secondary outcomes include gestational hypertension, severe features of preeclampsia, pregnancy-related death, third trimester severe anemia, fetal death, stillbirth, low birthweight, small-for-gestational age birth, and infant death.

Discussion: The trials will provide causal evidence on the non-inferiority of low-dose as compared to the standard high-dose supplementation in India and Tanzania. A single tablet, low-dose calcium supplementation regimen may improve individual-level adherence, reduce programmatic costs, and ultimately expand implementation of routine calcium supplementation in pregnancy in populations with low dietary calcium intake.

Trial registration: ClinicalTrials.gov identifier: NCT03350516 ; registered on 22 November 2018. Clinical Trials Registry-India identifier: CTRI/2018/02/012119 ; registered on 23 February 2018. Tanzania Medicines and Medical Devices Authority Trials Registry identifier: TFDA0018/CTR/0010/5 ; registered on 20 December 2018.

Keywords: Calcium; Dietary supplements; Non-inferiority trial; Pre-eclampsia; Pregnancy; Pregnancy complications; Pregnancy-induced hypertension; Preterm birth.

Conflict of interest statement

No competing interests to report for any authors or trial staff member.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Trial flow diagram for the India and Tanzania trials
Fig. 2
Fig. 2
Schedule of enrollment, interventions, and assessments (SPIRIT figure)

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