Friday, March 10, 2023

Topic Discussion: Calcium and Pre-eclampsia

Interesting data is emerging that calcium supplementation may help prevent pre-eclampsia(PEC). There are in vitro studies that have demonstrated that calcium has an anti-inflammatory effect and reduces the endothelial activation and dysfunction resulting from trophoblastic debris in pre-eclampsiaThis may be mediated through the effect of calcium on the nitric oxide synthetase pathway, and the subsequent increased production of nitric oxide. 

At a population level, there is some evidence that dietary calcium intake and incidence of PEC is inverse. This cochrane based review back in 2017 showed that High-dose calcium supplementation (≥ 1 g/day) may reduce the risk of PEC and preterm birth, particularly for women with low calcium diets (low-quality evidence). The treatment effect may be overestimated due to small-study effects or publication bias. It reduces the occurrence of the composite outcome 'maternal death or serious morbidity', but not stillbirth or neonatal high care admission. There was an increased risk of HELLP syndrome with calcium supplementation, which was small in absolute numbers. The limited evidence on low-dose calcium supplementation suggests a reduction in PEC, hypertension and admission to neonatal high care. 

A recent review in JACC does put calcium in the benefit category for prevention of PEC.

Then came the CAP study published in Lancet. The CAP study was a double-blind RCT, which aimed to assess whether 500 mg of calcium supplementation before pregnancy and in early pregnancy prevents pre-eclampsia in a population group of women at a high-risk for PEC and with a generally low dietary calcium intake. In this study of 1,355 women with a history of PEC, there was no difference in the incidence of PEC between the treatment or placebo group (RR 0.80, 95% CI 0.61–1.06). However, the compliance rates were low (only 50% of the population took at least 80% of the expected tablets), which may limit the validity of these results. Interestingly, in a subgroup analysis of participants with adequate compliance (defined as >80%), the rate of PEC was significantly lower in the calcium group in comparison to the placebo controls (RR 0.66, 95% CI 0.44–0.98). Another limitation of this study was the dosage of calcium used, which at 500 mg appeared to be lower than the doses prescribed in previous trials.

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Finally, a more recent meta-analysis published is adding some mixed data. The meta-analysis included 30 trials (N = 20 445 women), and the network meta-analysis to evaluate calcium dosage included 25 trials (N = 15 038). Calcium supplementation prevented PEC similarly with a high dose (RR 0.49, 95% CI 0.36–0.66) or a low dose (RR 0.49, 95% CI 0.36–0.65). By network meta-analysis, high-dose (vs low-dose) calcium did not differ in effect (RR 0.79, 95% CI 0.43–1.40). Calcium was similarly effective regardless of baseline PEC risk, vitamin D co-administration or timing of calcium initiation, but calcium was ineffective among women with adequate average baseline calcium intake.

The authors conclude that by using direct and indirect trial evidence in meta-analysis and network meta-analysis, calcium supplementation (vs placebo/no therapy) decreases the incidence of PEC, defined traditionally as gestational hypertension and new proteinuria. This effect is similar with high- or low-dose calcium, regardless of baseline PEC risk, timing of calcium initiation. But, the effectiveness of calcium is restricted to populations with low average baseline calcium intake. The small increase (of an absolute 0.2%) in HELLP syndrome with calcium was more than balanced by a reduced incidence of death or severe maternal morbidity (by 1.0%). 

In summary, very fascinating science here and perhaps something that needs a closer look. At this point, based on data, perhaps women with low calcium intake maybe the best that benefit from this preventive strategy. The International Federation of Gynecology and Obstetrics (FIGO), women with low calcium intake (<80 mg/day) calcium replacement (<1 g/day) or supplementation (1.5–2 g/day) is recommended. In populations where baseline dietary calcium intake is low, the World Health Organization recommends for 1500 to 2000 mg elemental calcium supplementation per day for pregnant individuals to reduce the risk of PEC, particularly among those at higher risk of developing hypertension. The WHO recommendation is based on positive results from systematic reviews as discussed above.

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