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

Multicentre, double-blind, randomised, placebo-controlled trial in parous women with a previous pregnancy complicated by pre-eclampsia or eclampsia who were planning another pregnancy. Participants were recruited in South Africa, Zimbabwe, and Argentina; 678 women were randomised to calcium and 677 to placebo.

The active intervention was 500 mg elemental calcium daily as calcium carbonate, given as one chewable oral tablet from prepregnancy until 20 weeks' gestation. After 20 weeks' gestation, all participants received open-label calcium tablets at 1.5 g daily.

Calcium supplementation started before conception and continued through 20 weeks' gestation did not significantly reduce recurrent pre-eclampsia overall. In pregnancies continuing to at least 20 weeks, pre-eclampsia occurred in 69/296 (23%) of the calcium group versus 82/283 (29%) of the placebo group, RR 0.80 (0.61-1.06), p=0.121; when expressed among all randomised women, the rates were 69/678 (10%) versus 82/677 (12%), RR 0.84 (0.62-1.14), p=0.258. A broader composite of pre-eclampsia or pregnancy loss showed a borderline reduction, 107/323 (33%) versus 126/310 (41%), RR 0.82 (0.66-1.00), p=0.050. Per-protocol analyses among participants with compliance >80% suggested benefit, with pre-eclampsia 20/98 (20%) versus 33/100 (33%), RR 0.62 (0.38-1.00), p=0.045, but this did not change the overall interpretation.

The trial was powered to detect a large effect, so a smaller clinically relevant benefit cannot be excluded. Many enrolled women did not contribute to the primary outcome because no pregnancy occurred or follow-up ended before 20 weeks, and the apparent benefit depended on per-protocol analyses among highly compliant participants, making adherence a major limitation. Generalizability is also most applicable to populations with low dietary calcium intake in the studied settings.