Imdad et al. BMC Public Health 2011, 11(Suppl 3):S18 http://www.biomedcentral.com/1471-2458/11/S3/S18 intake [11]. This conclusion was based on critical eva- luation of studies conducted in similar setting as that of USA; however no meta-analysis was performed. Our results are confirmatory for the above mentioned reviews. If we pool all the studies from both developed and developing countries, the estimates become RR 0.70 (95 % CI 0.57-0.86) for gestational hypertension, RR 0.47 (95 % CI 0.34-0.66) for pre-eclampsia and RR 0.76 (95 % CI 0.59-0.97) for risk of preterm birth. Estimates for gestational hypertension and pre-eclampsia are simi- lar to that of Hofmyer et al. [10] however the results for risk of preterm birth became statistically significant. This is due to addition of new study from India by Kumar et al which had shown a significant effect in reduction in risk of preterm birth [38]. When we sepa- rately pooled the results of studies from developed countries only [32-36], the estimate came to be RR 0.77 (95% CI 0.57, 1.03, random model) for gestational hypertension, RR 0.52 (95 % CI 0.27, 1.00, random model) for pre-eclampsia and RR 0.63 (95 % CI 0.33, 1.19, random model) for preterm birth (data not shown).This shows that calcium supplementation did not have any significant effect on risk of gestational hypertensive disorders in developed countries as is shown in the descriptive review of FDA [11]. What could be the explanation of protective effect of calcium supplementation during pregnancy in develop- ing countries and no effect in developed countries? The first and the foremost is the difference in baseline calcium intake. In most of the included studies from developing countries the baseline intake was low (Table 1),while it was adequate in most of the studies from developed countries as reported in review by FDA [11]. Low calcium intake has been hypothesized to cause increase in blood pressure by stimulating the release of parathyroid hormone and/or renin which leads to increased intracellular calcium concentration in vascular smooth muscle cells and causes vasocon- striction [48]. Role of calcium supplementation in reducing hypertensive disorders in pregnancy can pos- sibly be explained by reduction in parathyroid calcium release and intracellular calcium concentration, thereby reducing smooth muscle contractility and promoting vasodilatation [49]. Calcium supplementation could also prevent preterm labor and delivery by reducing uterine smooth muscle contractility [36] directly and indirectly by increasing magnesium levels [22]. The second explanation could be prevalent malnutrition in developing countries. It had been proposed that hor- mones involved in blood pressure control are altered during malnutrition and can lead to significant mor- bidity in malnourished pregnant women [47,50]. Our review has shown that calcium supplementation during pregnancy reduces all gestational hypertensive Page 10 of 13 related disorders. The reduction in pre-eclampsia was more than 50% in the present review. There was a great deal of heterogeneity in the pooled estimate which can primarily be explained by difference in the effect size, with significant results more strongly present in smaller trials (Figure 3). The two major contributors to hetero- geneity were studies by Villar et al. 2006 [44], the largest of included studies and study by Wanchu et al. 2001 [45] the second smallest study in the pooled data. Another explanation for this heterogeneity was the increased effect of intervention in trials with high risk women included, and on sub-group analysis the most marked reduction in pre-eclampsia was in the above group, and no heterogeneity was reported in the results (Figure 3). The funnel plot for risk of pre-eclampsia was not very symmetric (Figure 7). Studies with low SE con- tributed the most to the pooled effect size however two studies with high SE had the highest protective effect. Publication bias may be one of the reasons of this asym- metry of the funnel plot however this may also be due to smaller sample size of some of the included studies. Maternal mortality is a relatively rare event [2]. It is very difficult to design studies powered enough to detect a significant effect of an intervention on maternal mor- tality. According to CHERG rules, we had recommended reduction in severe maternal morbidity/mortality as a proxy for effectiveness of calcium supplementation dur- ing pregnancy in reducing maternal mortality related to gestational hypertensive disorders, for inclusion in the LiST model. This composite outcome included gesta- tional hypertensive related severe maternal morbidities that can lead to maternal death [44]. This approach of reporting potentially fatal gestational hypertensive related maternal morbidities have also been adopted in antioxidant trials for prevention of pre-eclampsia [51]. The overall grade evidence for this outcome was that of ‘moderate’ level which was downgraded to ‘low’ for its recommendation as a proxy for maternal mortality. We also applied CHERG rules to neonatal outcomes. Con- sidering mortality and morbidity outcomes, effect size for all-cause neonatal mortality was chosen for inclusion in the LiST based on its statistical significance and qual- ity grade. The overall quality grade was that of ‘moder- ate’ level which was downgraded to ‘low’ for translating all-cause onto cause specific mortality[47]. The benefi- cial effect of calcium supplementation in reducing neo- natal mortality seems to be related to reduction in preterm birth and birth asphyxia. There was a signifi- cant reduction of 12 % (95 % CI 1% to 22%) in preterm birth in calcium supplemented group compared to con- trol (Figure 5). This pathway can be related to severe gestational hypertensive morbidities (e.g. eclampsia) which can lead to preterm birth and birth asphyxia and calcium supplementation has shown reduction in all