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.