Personalised medicine seeks to identify individuals who will benefit most (maximal effects and/or minimal risk) from a particular treatment. The use of aspirin in women at high-risk of preterm pre-eclampsia is an excellent example of personalised pre-eclampsia prevention (Rolnik et al. NEJM. 2017;377:613–22). What do we know about other preventative strategies, such as calcium supplementation?
In this issue, Kinshella et al. compared high- (≥1 g/day) and low-dose (<1 g/day) calcium supplementation for pre-eclampsia prevention through a systematic review of 30 randomised controlled trials (RCTs; 20 445 women) and a subsequent network meta-analysis (Kinshella et al. BJOG. 2022). They also extensively explored subgroup effects on baseline calcium intake, pre-eclampsia risk, co-interventions and intervention timing. They found that calcium supplementation, either high- or low-dose, was effective in pre-eclampsia risk reduction (elative risk [RR] 0.49, 95% confidence interval [CI] 0.39–0.61) when baseline calcium intake was low. There was a concern that the risk of HELLP syndrome with calcium supplementation doubled from an absolute risk of 0.2% to 0.4% (RR 2.09, 95% CI 1.09–4.02), highlighting possible adverse effects in pregnancy. Theoretically, excessive calcium causing hypercalcaemia may induce endothelial dysfunction and cardiovascular complications (Reid et al. Endocrinol Metab 2017;32:339–49).
Does this review bring us further towards personalised pre-eclampsia prevention? We need to evaluate the evidence supporting effectiveness, safety as well as personalisation. Effectiveness may be overestimated in view of the presence of small study effects (potential publication bias) and risk of bias arising from 70% of included trials. On the issue of safety, although there was an increased risk of HELLP syndrome, the absolute risk remained low and there was a reduction in severe maternal morbidity (from 6.1% to 5.1%); the authors correctly highlight the lack of evidence on long-term follow-up of pregnant patients. Personalisation centres on baseline calcium intake: to determine an individual’s baseline calcium intake requires tools such as food diaries or recall surveys, and should account for additional therapies, which may alter absorption/bioavailability. Low calcium intake (<900 mg/day) wasn’t always measured in trial participants, with some baseline intakes inferred from other sources, including national averages (Balk et al. Osteoporos Int 2017;28:3315–3324). As a result, differences in treatment effects between low and adequate calcium intake subgroups may reflect systematic differences between settings, instead of true differences in the effectiveness of calcium supplementation.
Calcium absorption is a complex process dependent on dietary protein, fortified foods, oxalates, vitamin D and other micronutrients, including oral iron supplementation. This systematic review is an important step towards individualised patient assessment to tackle this complex clinical problem. Individualised risk assessment to guide aspirin use for pre-eclampsia prevention considers the individual patient compared with a more generalised population. However, baseline dietary calcium intake of the individual is not straightforward, and population measures of calcium intake have significant limitations. Given the significant reduction in pre-eclampsia risk calcium supplementation achieves, the development of clear clinical recommendations accurately to identify those with low baseline calcium intake to support individualised care is imperative for the successful and safe clinical implementation of these findings, given the rare but real concerns of excessive calcium supplementation.
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