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\begin{document}

\title{The effect of pravastatin on obstetrics complications associated with
uteroplacental insufficiency: A systematic review and meta-analysis}



\author[1]{Ayala Hirsch}%
\author[2]{Natali Ternovsky}%
\author[1]{Reut Rotem}%
\author[2]{Bruria Hirsh Raccah }%
\affil[1]{Shaare Zedek Medical Center}%
\affil[2]{Hebrew University of Jerusalem}%


\vspace{-1em}



  
  \date{May 18, 2024}


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\selectlanguage{english}
\begin{abstract}
ABSTRACT Background: Obstetrical complications involving uteroplacental
insufficiency associated disorders, such as preeclampsia, intrauterine
growth restriction, and obstetric antiphospholipid syndrome, share
pathophysiology and risk factors with cardiovascular diseases treated
with statins. Objective: To evaluate associations of statin treatment
with pregnancy prolongation, and neonatal and maternal morbidity, among
women with uteroplacental insufficiency disorders. Search Strategy:
Electronic databases including PubMed, Medline, Embase, Clinical Trials
Registry Clinicaltrials.gov, and The Cochrane Library were searched from
inception to January 2022. Selection Criteria: Cohort studies and
randomized controlled trials (RCTs) Data collection and analysis: Pooled
odds ratios were calculated using a random-effects model;
meta-regression was utilized when applicable. Main Results: The analysis
included ten studies describing 1391 women with uteroplacental
insufficiency-associated disorders: 703 treated with pravastatin and 688
not treated with statins. Women who received pravastatin showed
significant prolongation of pregnancy (mean difference 0.44 weeks,
95\%CI:0.01-0.87, p=0.04, I2=96\%) and less neonatal critical care unit
admission (OR=0.42, 95\%CI: 0.23-0.75, p=0.004, I2=25\%). Trends were
observed toward a decrease in preeclampsia diagnoses (OR=0.51,
95\%CI:0.25--105, p=0.07, I=44\%), and perinatal death (OR=0.32,
95\%CI:0.09-1.13, p=0.08, I2=54\%) and an increase in birth weight (mean
difference=102 grams, 95\%CI: -14--212, p=0.08, I2=96\%). A
meta-regression analysis revealed associations between earlier
gestational age at initiation of pravastatin treatment to lower risk for
development of preeclampsia (R2=1) and between longer duration of
pravastatin treatment to lower rate of NICU admission (R2=0.33). No
dose-response effect was demonstrated. Conclusions: Pravastatin
treatment in pregnancies with high risk for developing uteroplacental
insufficiency disorders may prolong pregnancy duration and improve
neonatal outcomes.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Preeclampsia and intrauterine growth restriction (IUGR) are serious
complications of pregnancy that increase the morbidity and mortality of
foetuses and parturients. Both these complications have been associated
with the development of placental insufficiency. Abnormal placentation
and its associated disorders may be encountered among parturients with
obstetric antiphospholipid syndrome; 20\%-30\% of pregnancies among
these parturients may result in preeclampsia, IUGR and foetal losses.
The spectrum of uteroplacental insufficiency disorders results from
various factors, including poor trophoblast uterine invasion early in
pregnancy, impaired transformation of the uterine spiral arteries to
high capacity-low impedance vessels, abnormalities in the development of
chorionic villi, endothelial dysfunction and pathologic changes in the
antiangiogenic environment. Prevention strategies for uteroplacental
insufficiency are not currently known. Therefore, preeclampsia or IUGR
occurring early in the course of pregnancy prompts early delivery, which
can lead to neonatal death and disability arising from prematurity, and
also maternal morbidity.

The role of statins in treating and preventing cardiovascular diseases
is well established; their potential benefit in treating multiple
non-cardiovascular outcomes is currently under investigation.
Endothelial dysfunction in preeclampsia, IUGR and obstetric
antiphospholipid syndrome has been associated with abnormalities in
lipid profile, high levels of triglycerides and oxidative stress.
statins inhibit HMG-CoA reductase, leading to reduced plasma cholesterol
levels. statins also have antioxidant, anti-inflammatory,
anti-thrombogenic and vasodilating effects. The preclinical evidence
supporting the use of statins in the treatment of preeclampsia has been
demonstrated in multiple animal models.

Current clinical knowledge regarding the efficacy of statins in the
treatment of preeclampsia is inadequate. Individual studies have
presented contradicting results. Accordingly, current guidelines do not
recommend the usage of statins in the prevention or treatment of
uteroplacental insufficiency disorders.

The aim of this systematic review and meta-analysis was to assess
pregnancy outcomes associated with pravastatin treatment, among
pregnancies with high risk for development of uteroplacental
insufficiency and pregnancies that already developed associated
disorders: preeclampsia and IUGR, with or without obstetric
antiphospholipid syndrome.

\textbf{Methods}

Search strategy

This systematic review followed the Preferred Reporting Items for
Systematic Reviews and Meta-Analyses (2020) framework guidelines
(PRISMA) and the Meta-analysis Of Observational Studies in Epidemiology
(MOOSE) guidelines. (Supplement table S1-S2)

We conducted three systematic database searches: the first included
articles from 1953 to February 2020, the second included articles
published from the last search to April 2021 and the third included
articles published from the last search to January 2022. The search
included PubMed/Medline, Embase, Clinical Trials Registry
Clinicaltrials.gov and The Cochrane Library. Language restrictions were
not set.

The search strategies incorporated index terms (Mesh) and free text
words for the search concepts: pravastatin, atorvastatin, rosuvastatin,
pregnancy combined by ``AND''; and in each domain, the terms were
combined by ``OR'' (Supplementary table S3) The first domain contained
terms on statins (including synonyms and abbreviations such as HMG-CoA
reductase inhibitors), the second domain related to pregnancy.

The detailed protocol is documented online in the International
Prospective Register of Systematic Reviews Registry (CRD42020165804).
Because this study was a review and meta-analysis, Helsinki board
approval was waived.

Data sources and searches

In the search strategy, we included randomized controlled trials (RCTs),
non-randomized controlled clinical trials, prospective and retrospective
comparative cohort studies, and case-control studies. Every study that
included women treated with statins during pregnancy was analysed.
Duplicated reports, case reports, case series, cross-sectional studies,
pharmacokinetic studies in healthy adults, animal studies, reviews,
expert opinion, editorials, letters to the editor, comments, and studies
with a high risk of bias were excluded.

Study selection and data extraction

Two investigators (A.H. and N.T.) independently identified and extracted
articles for potential inclusion, using the Rayyan QCRI web application
for systematic reviews. Disagreements were resolved by referral to a
third reviewer (B.H.R.). The full texts of the resulting references were
retrieved and analysed. If more than one study published data from the
same cohort, we included the report with the higher quality according to
the Risk of bias In Non-randomized Studies of Interventions (ROBINS-I)
tool (Newcastle-Ottawa Quality Assessment Scale- NOS) to avoid overlap.

Exposure to statins during pregnancy was defined as exposure to any dose
and in any trimester of pregnancy. Pregnancies that were defined as high
risk for future development of uteroplacental insufficiency disorder and
those that had developed uteroplacental insufficiency disorders were
included. The spectrum of uteroplacental insufficiency disorders
included: preeclampsia, early-onset IUGR (\textless{}28w), and
obstetrical antiphospholipid syndrome. Multiple pregnancies were
excluded in patient-level data to avoid bias. The primary outcome
included prolongation of pregnancy from study entry to delivery. The
secondary outcomes included neonatal outcomes such as admission to the
neonatal intensive care unit (NICU), birth weight and neonatal death,
and the maternal occurrence of a new diagnosis of preeclampsia. Neonatal
death was defined as stillbirth or death in the first month of life.
Data were extracted from the included studies by a single reviewer and
subsequently evaluated by the second reviewer. For studies that did not
report the outcomes, we contacted the authors and requested the missing
data.

Quality assessment and the risk of bias

The risk of bias and the quality of the observational studies were
assessed using the Newcastle-Ottawa Quality Assessment Scale (NOS). The
scale is based on eight criteria and provides a score ranging from 0
(high risk of bias) to 9 stars (low risk of bias). A 5-star rating and
below was designated high risk of bias, 6-7 stars intermediate risk of
bias, and 8-9 stars low risk of bias. Randomized controlled studies were
evaluated by the Cochrane Collaboration's Risk of Bias Tool. Summary
assessments of the risk of bias were derived for each study. Assessments
were carried out independently by two investigators (A.H and N.T.).

Data synthesis and analysis

Meta-analysis and meta-regression were performed using Comprehensive
Meta-Analysis software. Random-effect pooled odds ratios (ORs) were
calculated with the corresponding 95\% confidence intervals (CIs) to
summarize the results overall and within subgroups. Heterogeneity was
assessed by using the I\textsuperscript{2} statistic. We performed
subgroup analyses by study type (RCT, cohort). Random-effects
meta-analysis was used to pool analyses. Meta-regression analyses were
performed to evaluate whether differences in pravastatin dosage and
timing of treatment initiation modified the association between exposure
to pravastatin and outcomes, and to explain the heterogeneity in the
estimated effect size. The data were analyzed using the Comprehensive
Meta-Analysis software.

Publication bias

Assessment was planned, of publication bias by visual inspection of the
funnel plot, provided the analysis would include at least ten studies.

\textbf{Results}

Study selection

The database search yielded 3336 citations: PubMed (n=636), Embase
(n=1989), Cochrane Library (n= 621), clinicaltrials.gov (n=90). In
total, 667 were identical duplicates, and excluded. After abstract
assessment, 62 articles were extracted for full-text review. Ten
articles dropped out because they included normal pregnancies without
any risk factors, nor signs or symptoms that indicated placental
insufficiency.. One study was excluded because of wrong outcomes and
another was excluded due to lack of control group . Fourteen articles
were excluded because of publication type or study design. Studies
involving animals or human placenta were excluded, only clinical studies
were included. Due to a lack of standardization in studies investigating
biomolecular markers, those studies or results were excluded as well.
The selection process is illustrated in Figure 1. Ultimately, ten
studies were included in the analysis, with a total of 1391 pregnant
women. Of them, 703 (50.5\%) were treated with pravastatin and 688
(49.5\%) were not treated with statins. All ten studies described high
treatment adherence.

Characteristics of the studies

The studies were published between 2016 and 2021 and originated from the
United States (n=2), Indonesia (n=2), Serbia (n=2), UK (n=1), Spain
(n=1), Greece (n=1), and multicentre over Europe (n=1). Four were cohort
studies and six RCTs . Studies included women with uteroplacental
insufficiency defined as early onset of preeclampsia between gestational
age 24 and 31 weeks or high risk for developing preeclampsia. This risk
was defined in two studies as a history of severe preeclampsia in a
prior pregnancy that required delivery before 34 weeks gestation. In
another study, as a history of previous preeclampsia and birth before 37
weeks of gestation or at least two main risk factors for preeclampsia.
One study selected women with at least 20\% risk for developing
preeclampsia based on the presence of minimally 2 independent clinical
risk factors or abnormal doppler velocimetry index. and another selected
women with high risk for preeclampsia based on a survival-time model of
Bayes theorem . Two studies defined uteroplacental insufficiency as a
pregnancy with an obstetric antiphospholipid syndrome that developed
preeclampsia or IUGR associated with abnormal placental Dopplers. An
additional study defined a pregnancy with uteroplacental deficiency as
having a past poor obstetric history and abnormal placental Dopplers.
Abnormal placental Dopplers was defined as uterine artery pulsatility
index above the 95th percentile. One study also included the early onset
of IUGR, diagnosed earlier than 28 weeks of pregnancy.

Although the search algorithm included all types of statins, only
pravastatin was used in the studies included. The dosage of pravastatin
differed between studies: 40 mg in five studies, 20 mg in four studies
and 10 mg in one study. The comparator treatment included aspirin
together with low molecular weight heparin in two studies, aspirin alone
in one study, placebo in four studies and no treatment in two studies.
Most studies initiated treatment with pravastatin in the second
trimester, but in two studies a minority of the patients were diagnosed
and started treatment in their third trimester and one large RCT
included only women in their late third trimester. Table 1 shows a
summary of the key characteristics of the included trials.

Quality assessment

The overall risk of bias among the four nonrandomized studies according
to the Newcastle-Ottawa Quality Assessment Scale (NOS) was 7.5. The
overall risk of bias of the six randomized controlled studies evaluated
by the Cochrane Collaboration's Risk of Bias Tool was low. The risk of
bias assessment is summarized in Figures S1 and S2.

As ten studies were included in the meta-analysis, we were able to test
for funnel plot asymmetry to assess possible publication bias. Visual
inspection of the funnel plots revealed no indication of publication
bias, Egger test also indicates no statistical significance in asymmetry
(p=0.5). (Figure S3).

Synthesis of results

\emph{Pregnancy prolongation} \textbf{:}

Eight studies compared the difference in prolongation of pregnancy from
study entry to delivery between women treated with pravastatin and women
not treated. Pravastatin treatment was associated with a significant
prolongation of pregnancy from study entry to delivery of 0.44 weeks
(mean difference 0.44 weeks, 95\%CI:0.01-0.87, p=0.04,
I\textsuperscript{2}=96\%) (Figure 2).

\emph{NICU admission:}

Nine studies examined NICU admission with or without pravastatin
treatment. Pravastatin treatment was associated with a significantly
decreased risk for NICU admission compared to women not treated with
statins (OR=0.42, 95\%CI: 0.23-0.75, p=0.004, I\textsuperscript{2}=25\%)
(Figure 3)\textbf{.}

\emph{Perinatal death:}

Ten studies examined the association of pravastatin with perinatal
death. Although statistical significance was not reached, there was a
trend toward a decrease in the risk for perinatal death in newborns of
women treated with pravastatin (OR=0.32, 95\%CI:0.09-1.13, p=0.08,
I\textsuperscript{2}=54\%) (Figure 4).

\emph{Birth weight:}

Eight studies compared birth weight between newborns of women treated
with pravastatin and those who did not. The increase in birth weight
following pravastatin treatment was not statistically significant (Mean
difference=102 grams, 95\%CI: -14--212, p=0.08,
I\textsuperscript{2}=96\%) (Figure 5).

\emph{Maternal outcomes:}

Six studies described a new diagnosis of preeclampsia after initiation
of pravastatin treatment. Among women treated with pravastatin compared
to control groups, the risk for the development of preeclampsia was non
significantly decreased (OR=0.51, 95\%CI:0.25--105, p=0.07, I=44\%)
(Figure 6).

In a sensitivity analysis that excluded D\selectlanguage{ngerman}öbert et al study who selected
women only in their late third trimester, The risk for the development
of preeclampsia was significantly decreased (OR=0.37, 95\%CI:0.18--0.74,
p=0.01, I=0\%) (Figure 7).

\emph{Meta-regression:}

Due to the high heterogeneity found in the analyses, a meta-regression
analysis was conducted. A meta-regression revealed a statistically
significant association between early gestational age at initiation of
pravastatin treatment and decreased risk for the development of
preeclampsia (R\textsuperscript{2}=1) and NICU admission
(R\textsuperscript{2}=0.33). Statistically significant associations were
not found between higher pravastatin dose to prolongation of pregnancy
from study entry to delivery, birth weight, perinatal death or NICU
admission. Statistically significant associations were not found between
earlier gestational age at initiation of pravastatin treatment to
prolongation of pregnancy from study entry to delivery, birth weight or
perinatal death (Figure S4-S13).

\textbf{Discussion}

Main findings

In this meta-analysis and meta-regression, pravastatin usage for
uteroplacental insufficiency was associated with a significant
prolongation of pregnancy, mean 0.44 weeks, from study entry to
delivery. Prematurity is the main cause of neonatal mortality, and early
neonatal as well as late childhood morbidity. Preventing preterm births
has been delineated as one of the most urgent goals in current
obstetrics. Prolonging pregnancy has most probably resulted in the
significant decrease observed in NICU admission, and the trends towards
decreased perinatal death and increased neonatal birth weight. In
addition, a sensitivity analysis that excluded Döbert et al study, that
selected women only in their late third trimester, new onset of
preeclampsia was less common under pravastatin treatment.

Comparison with existing literature

The similarities in pathophysiology and risk factors shared by
uteroplacental insufficiency disorders and cardiovascular disease have
prompted the search for treatments of uteroplacental insufficiency with
agents used to treat vascular disease. The underlying mechanism of both
conditions involves vascular endothelial dysfunction with endothelial
inflammation. The American Heart Association included a history of
preeclampsia as a risk factor for future cardiovascular disease. This
association might relate to the shared risk factors for cardiovascular
diseases preceding pregnancy, such as obesity, hypertension, diabetes,
and dyslipidaemia or alternatively, to the metabolic and vascular
changes that preeclampsia itself induces.

Numerous clinical studies have confirmed the multiple therapeutic
benefits resulting from the pleiotropic effects of statins. Statins
improve endothelial dysfunction by protecting vascular endothelium and
stimulating its regeneration and its angiogenesis. The antioxidant
action of statins relates to their antithrombotic and vasodilating
activities and inhibition of free radical formation. The
anti-inflammatory action of statins results from their impact on the
immune response, which is expressed as increased blood level
inflammatory markers and mediators. The latter include C-reactive
protein, L-, E- and P-selectin, intercellular and vascular adhesion
molecule and Hmox-1, which inhibits sFlt-1 and sEng. According to this
pathophysiology, statins have been shown to directly improve endothelial
dysfunction and angiogenic imbalance in human placenta. Thus, statins
may be a promising agent in preventing and treating uteroplacental
dysfunction.

The safety profile of statin exposure during pregnancy is not well
defined. United States Food and Drug Administration labelling recommends
against the use of statins during pregnancy, based on animal data
showing teratogenic potential at high doses. Therefore, the current
practice encompasses the advice to discontinue statins when trying to
conceive. However, subsequent case registries did not demonstrate an
association between congenital anomalies and statin exposure. The
clinical benefits of statins in individuals with familial
hypercholesterolemia or cardiovascular diseases should be considered,
together with the growing evidence of statins' potential benefit in
preventing and treating uteroplacental insufficiency-associated
disorders. Accordingly, their benefit may fairly overcome their
controversial risk.

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 \emph{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.\textsuperscript{, ,} 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.

Conclusion

This meta-analysis suggests that treatment with pravastatin may prolong
pregnancy duration in women with uteroplacental insufficiency disorder.
An individualized assessment and a cautious approach are advised if
pravastatin usage is considered.

\textbf{Conflicts of interest-none}

\textbf{Acknowledgment- none}

\textbf{Contribution to authorship}

All authors contributed to the study protocol. The literature search was
performed by A.H, N.T and B.H.R. Literature screening, data extraction,
were performed by D.P, A.H, N.T and B.H.R. Risk of bias evaluation was
performed by A.H and N.T.

A.H and B.H.R conducted the analyses. The draft of the manuscript was
written by A.H, B.H.R and R.R., and all authors commented on earlier
versions of the manuscript. All authors read and approved the final
manuscript

\textbf{Disclosure statement:} The authors report no conflict of
interest.\textbf{Source of funding:} None

\textbf{Acknowledgments:} Not applicable



\textbf{References}

\par\null

\textbf{Table 1} :Methodologic characteristics of the included studies

\textbf{Figures:}

\emph{\textbf{Figure 1}: Publication selection process} .

\emph{\textbf{Figure 2}: Meta-analysis results of the association of
pravastatin treatment with a mean difference (weeks) in prolongation of
pregnancy from study entry to delivery.}

\emph{\textbf{Figure 3}: Meta-analysis results of the association of
pravastatin treatment with admission to the neonatal intensive care
unit.}

\emph{\textbf{Figure 4}: Meta-analysis results of Odds ratios for
perinatal death following pravastatin treatment versus a control group.}

\emph{\textbf{Figure 5}: Meta-analysis results of the Differences in
birth weight (grams) following pravastatin treatment versus a control
group.}

\emph{\textbf{Figure 6}: Meta-analysis results of the association of
pravastatin treatment with new diagnoses of preeclampsia.}

\emph{\textbf{Figure 7}: Sensitivity meta-analysis of the association of
pravastatin treatment with new diagnoses of preeclampsia.}

\textbf{Hosted file}

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