Prepregnancy and early pregnancy calcium supplementation among women at high risk of pre-eclampsia: a multicentre, double-blind, randomised, placebo-controlled trial

G Justus Hofmeyr,Sarah Manyame,Eunice Tahuringana,Natalia Novikova,Sue Fawcus,Justus Hofmeyr,Xoliswa Williams,Nolundi Mshweshwe,Jim Roberts,Eduardo Bergel,John Anthony,Peter Von Dadelszen,Adegboyega Oyebajo,Marianne Vidler,Annmarie De Greeff,Fernando Althabe,Armando Seuc,Sharla Drebit,Simpiwe Mose,Saadiqa Allie,Mvuseleli Kovane,Stephen Munjanja,Angel Phuti,Karlyn Frank,Susan Fawcus,David Hall,Diane Sawchuck,Pamela Njikelana,Erika Van Papendorp,Ana Pilar Betrán,Theresa A Lawrie,Emilia Makaza,Tina Dannemann,Patience Kovane,Gabriela Cormick,Velisa Mqikela,José M Belizán ,Laura A Magee ,Álvaro Ciganda ,Charla A Parker ,James M Roberts ,Mandisa Singata‐Madliki ,Bothwell Takaingofa Guzha ,France Donnay

doi:10.1016/s0140-6736(18)31818-x

Abstract

SummaryBackgroundReducing deaths from hypertensive disorders of pregnancy is a global priority. Low dietary calcium might account for the high prevalence of pre-eclampsia and eclampsia in low-income countries. Calcium supplementation in the second half of pregnancy is known to reduce the serious consequences of pre-eclampsia; however, the effect of calcium supplementation during placentation is not known. We aimed to test the hypothesis that calcium supplementation before and in early pregnancy (up to 20 weeks' gestation) prevents the development of pre-eclampsiaMethodsWe did a multicountry, parallel arm, double-blind, randomised, placebo-controlled trial in South Africa, Zimbabwe, and Argentina. Participants with previous pre-eclampsia and eclampsia received 500 mg calcium or placebo daily from enrolment prepregnancy until 20 weeks' gestation. Participants were parous women whose most recent pregnancy had been complicated by pre-eclampsia or eclampsia and who were intending to become pregnant. All participants received unblinded calcium 1·5 g daily after 20 weeks' gestation. The allocation sequence (1:1 ratio) used computer-generated random numbers in balanced blocks of variable size. The primary outcome was pre-eclampsia, defined as gestational hypertension and proteinuria. The trial is registered with the Pan-African Clinical Trials Registry, number PACTR201105000267371. The trial closed on Oct 31, 2017.FindingsBetween July 12, 2011, and Sept 8, 2016, we randomly allocated 1355 women to receive calcium or placebo; 331 of 678 participants in the calcium group versus 320 of 677 in the placebo group became pregnant, and 298 of 678 versus 283 of 677 had pregnancies beyond 20 weeks' gestation. Pre-eclampsia occurred in 69 (23%) of 296 participants in the calcium group versus 82 (29%) of 283 participants in the placebo group with pregnancies beyond 20 weeks' gestation (risk ratio [RR] 0·80, 95% CI 0·61–1·06; p=0·121). For participants with compliance of more than 80% from the last visit before pregnancy to 20 weeks' gestation, the pre-eclampsia risk was 30 (21%) of 144 versus 47 (32%) of 149 (RR 0·66, CI 0·44–0·98; p=0·037). There were no serious adverse effects of calcium reported.InterpretationCalcium supplementation that commenced before pregnancy until 20 weeks' gestation, compared with placebo, did not show a significant reduction in recurrent pre-eclampsia. As the trial was powered to detect a large effect size, we cannot rule out a small to moderate effect of this intervention.FundingThe University of British Columbia, a grantee of the Bill & Melinda Gates Foundation; UNDP–UNFPA–UNICEF–WHO–World Bank Special Programme of Research, Development and Research Training in Human Reproduction, WHO; the Argentina Fund for Horizontal Cooperation of the Argentinean Ministry of Foreign Affairs; and the Centre for Intervention Science in Maternal and Child Health.

Highlights

Hypertension is estimated to complicate 5% of all pregnancies and 11% of first pregnancies, and half of these cases are associated with pre-eclampsia.[1]
Evidence from a Cochrane systematic review of randomised trials shows that calcium supplementation after 20 weeks of pregnancy reduces the serious consequences of pre-eclampsia and the prevalence of pre-eclampsia
We report the findings of a randomised placebo-controlled trial among women who had pre-eclampsia or eclampsia in their previous pregnancy, designed to establish whether calcium supplementation started before pregnancy and continued during the first half of pregnancy might reduce the subsequent development of pre-eclampsia and other adverse outcomes, despite high dose supplementation to both groups after 20 weeks’ gestation

Summary

Introduction

Hypertension is estimated to complicate 5% of all pregnancies and 11% of first pregnancies, and half of these cases are associated with pre-eclampsia (gestational hypertension plus proteinuria).[1] Hypertensive disorders of pregnancy are the direct cause of death of about 30 000 women annually,[2] or approximately 14% of maternal deaths,[3] most of which occur in low-income countries. Participants were pregnant women who screened positive for low antioxidant status. This small study reported reductions in pre-eclampsia (two of 29 vs nine of 31) and miscarriage (none of 29 vs eight of 31) in favour of the intervention. Evidence from a Cochrane systematic review of randomised trials shows that calcium supplementation after 20 weeks of pregnancy reduces the serious consequences of pre-eclampsia and the prevalence of pre-eclampsia. We aimed to test the hypothesis that calcium supplementation before and in early pregnancy (up to 20 weeks’ gestation) prevents the development of pre-eclampsia

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