Trial trustworthiness assessment: commentary on the Cochrane 2025 systematic review on calcium supplementation during...

Hypertensive disorders of pregnancy remain a major cause of maternal and perinatal morbidity and mortality worldwide. Calcium supplementation during pregnancy is recommended by guidelines and the World Health Organization to prevent preeclampsia largely based on successive versions of a Cochrane systematic review (SR). However, the 2025 update of this SR reported that calcium supplementation may result in little to no reduction in preeclampsia risk, a conclusion that diverges from all previous versions. This change was driven primarily by the exclusion from meta-analyses of several previously included trials due to concerns about study trustworthiness.

We critically examine trustworthiness assessments in the 2025 SR and identify inconsistencies in how criteria were interpreted and applied across trials. Using two trials as illustrative examples, we show that concerns related to ethics and effect size were applied inconsistently. We further demonstrate that the same trials were deemed trustworthy and included in another Cochrane SR updated in 2024, on calcium supplementation during pregnancy for related outcomes. Sensitivity analyses illustrate how the inclusion of these two excluded trials would significantly change the pooled effect estimates for preeclampsia in the 2025 SR. We argue that reliance on unvalidated trial trustworthiness assessment tools risks subjective exclusion of evidence, potentially impacting guidelines and policies. We recommend that the review authors reassess all trials excluded from the meta-analyses due to trustworthiness issues and conduct sensitivity analyses to transparently assess their impact on the 2025 SR conclusions and related policy recommendations.