Strengths and limitations
To the best of our knowledge, this is the largest and the only study to pool results of pravastatin for uteroplacental insufficiency-associated disorders. This meta-analysis included all available published data and conducted a systematic analysis according to accepted guidelines. Six randomized control trials were included, and all ten studies described high treatment adherence.
As four studies included in this meta-analysis were retrospective, selection bias should be considered. We performed a quality assessment for the risk of bias using the NOS, which resulted in a low probability of selection bias. Due to the small numbers of studies and events, our results should be interpreted with caution, and further studies are required. The cohorts included in this meta-analysis were geographically diverse. This can potentially broaden the generalizability of our results yet highlights difference in management and background characteristics.
The potential weakness of this analysis rests in the high heterogeneity among the studies, and the inclusion of only six RCTs, with a small number of patients. The favourable outcomes of this meta-analysis are largely driven by ”cohort” studies which may have included biases, as the women included in the control groups represented very specific populations. Yet, to address this heterogeneity, a sub-group analysis and random effect model was used. High heterogeneity was also viewed in dosage regimes, treatment indications and the lack of standardization. To address the high heterogeneity, we conducted a meta-regression for pravastatin dosage, study type and early vs late initiation of pravastatin treatment. Although the analyses of perinatal death and birth weight showed trends toward better outcome, these trends were not statistically significant. This might also be attributed to the high heterogeneity and the small events in the studies.
The mutual mechanism of uteroplacental dysfunction justifies the shared analysis. However, while the pathophysiology of uteroplacental dysfunction lies in inadequate trophoblast invasion in the early stages of pregnancy, all the studies that investigated pravastatin therapy started in the second to the third trimester and the largest study included only parturients in late third trimester which might downgrade the accepted results. Earlier initiation of therapy might yield different results from those described. Biomolecular markers were measured in few studies. However, biases may have arisen due to lack of standardization of measurements performed over various periods of time, and the exclusion from the analysis of women who delivered after the first measurement. In addition, no data were found in the literature on other potent statins such as atorvastatin and rosuvastatin: this could also have affected the results.
In this analysis, we pooled studies that adjusted for confounders including pre-existing diabetes, a baseline score of biomolecule markers and laboratory findings; together with studies that did not perform any adjustments., , This raises the possibility that our results may not reflect the true effect size and may be susceptible to sources of bias. Although the studies are heterogeneous, as they represent real-life conditions, we decided to pool them together.