DRUGS IN PREGNANCY
MOTHERISK ROUNDS
The Fetal Safety of Statins:
A Systematic Review and Meta-Analysis
Judith Zarek, MSc, Gideon Koren, MD
The Motherisk Program, Division of Clinical Pharmacology and Toxicology, Department of Pediatrics, Hospital for Sick Children, Toronto ON
Abstract
Although an initial case series suggested that use of statins in
pregnancy carried teratogenic risk, a recent meta-analysis of
controlled observational studies has failed to corroborate this. A large
number of potentially beneficial uses of statins in pregnant women
have prompted a new evaluation of the riskbenefit ratio of these
agents in pregnancy.
Rsum
Bien quune srie de cas initiale ait laiss entendre que lutilisation de
statines pendant la grossesse donnait lieu des risques tratognes,
une rcente mta-analyse dtudes observationnelles comparatives
nest pas parvenue corroborer de tels rsultats. Puisque les statines
comptent un grand nombre dutilisations potentiellement bnfiques
chez les femmes enceintes, une nouvelle valuation du rapport
risques-avantages de ces agents pendant la grossesse a t mise en
uvre.
H MG-CoA reductase inhibitors (statins) are
commonly prescribed for men and women with
cardiovascular disease. Their safety during pregnancy
has not been clearly determined. The Food and Drug
Administration (FDA) in the United States has designated
all statins category X, which means their use during
pregnancy is contraindicated. This determination is based
on the overarching concept that the benefits of statin
therapy during pregnancy do not outweigh potential
fetal risks of exposure.1 The essential role of cholesterol
during pregnancy, combined with teratogenic effects seen
in some animal studies with lovastatin, has supported
this contraindication. However, the use of statins has
become exceedingly popular in both men and women;
women are increasingly delaying pregnancy, and obesity
Key Words: Statins, cholesterol, pregnancy, congenital
malformations
506 l JUNE JOGC JUIN 2014
and associated cardiovascular risks have increased.1
With 50% of all pregnancies unplanned,2 these factors
substantially increase the likelihood that a woman who
is planning pregnancy, or who finds herself pregnant,
may be taking a statin. Furthermore, stopping statin
therapy may have detrimental health effects for both
the fetus and pregnant woman. Statins have been shown
to have additional potential benefits not related to their
cholesterol-lowering effects, as discussed below.314 These
new potential indications of statins may support their use
during pregnancy for obstetrical complications.
ANIMAL STUDIES
Developmental studies with lovastatin administration
in mice at doses 10 and 47 times the recommended
maximum dosage showed no increased risk of congenital
malformations, except for a slightly elevated incidence of
skeletal malformations except at maternally toxic doses.15
Similarly, in studies of the administration of simvastatin
in pregnant rats, no evidence of teratogenicity was
observed.1618 With atorvastatin, no teratogenic effects
were observed in rats or rabbits.19
THE SCARE
In 2004, a series of case reports collected by the FDA and
showing 31 fetal malformations among 70 spontaneously
reported statin-exposed pregnancies was published in
the New England Journal of Medicine.20 This report
was interpreted by many as providing proof of the fetal
risks of the statins, justifying their rating by the FDA
as category X drugs. Critics of this report noted that
there was no unique pattern consistent with lipophilic
statin use in the described malformations. Specifically,
SmithLemliOpitz syndrome, a known abnormality of
J Obstet Gynaecol Can 2014;36(5):506509

cholesterol biosynthesis, was not identified in any of the
case reports.21 Critically, these spontaneous case reports
were lacking a denominator of the total number of
exposed cases to allow calculation of the increased risk.
It is well known that retrospective reports of pregnancy
drug exposure typically describe an up to five-fold
increase in teratogenic risk because of over-reporting of
adverse outcomes.22
This case series was followed by a number of cohort
studies of statin exposure in pregnancy that failed to show
an increase in teratogenic risk.2328 However, because of
the limited number of studies, we felt it was important
to combine them in a meta-analysis, thus increasing the
overall statistical power to show risk in pregnancy.
SYSTEMATIC REVIEW AND META-ANALYSIS
In a recently published meta-analysis, we identified all
studies published up to January 28, 2013, on pregnancy
outcome following first trimester exposure to statins.1 The
inclusion criteria were:
1. retrospective or prospective controlled studies,
2. studies of pregnant women exposed to a statin, and
3. studies that included a control group of women
unexposed to statins.
We reviewed the full text of a large number of published
papers and found six studies that matched the inclusion
criteria.2328 The earliest reported study was the only
one to include disease-matched control subjects (hyper
cholesterolemic women). The remaining five studies
included non-hypercholesterolemic control subjects. There
was no increased risk of birth defects in the statin-exposed
pregnancies compared with the control subjects (RR 1.15;
95% CI 0.75 to 1.76) (Figure 1). In contrast, the relative
risk of miscarriage was increased in the statin-exposed
group compared to control subjects (RR 1.35; 95% CI 1.04
to 1.75) (Figure 2). There was an increased rate of elective
pregnancy terminations (RR 2.56; 95% CI 1.71 to 3.84).
NEW POTENTIAL REPRODUCTIVE
INDICATIONS FOR STATINS
This lack of demonstrated increased risk of teratogenicity
with use of statins further highlights the need to discuss
the potential benefits of statin therapy in pregnant women
or in women who might become pregnant. Potential uses
include therapy that would benefit women with obstetrical
complications, and this may shift the current view that
the benefits of statin therapy during pregnancy do not
outweigh potential risks of therapy.
The Fetal Safety of Statins: A Systematic Review and Meta-Analysis
One potential benefit is the use of statins for treating
endometriosis, in which excessive angiogenesis and invasion
of endometrial endothelial cells is associated with locally
elevated inflammatory cytokines.36 While current treatment
for endometriosis is surgical, the use of statins is being
investigated because of their anti-inflammatory effects.
They have been shown to decrease endothelial cell invasion,
inhibiting excessive cellular growth and decreasing the
elevated levels of inflammatory cytokines in this condition.36
Another potential indication is the use of statins for
treatment of women with polycystic ovary syndrome.
These women exhibit biochemical evidence of chronic
systemic inflammation, elevated serum androgen levels,
and endothelial dysfunction in a variety of vascular beds.7
In two randomized controlled studies, atorvastatin and
simvastatin decreased circulating androgen concentrations
compared with placebo, and simvastatin therapy resulted
in lower androgen levels than the standard therapy with
metformin.8,9 In two additional randomized controlled
trials, women exposed to simvastatin and atorvastatin
exhibited lower levels of pro-inflammatory markers in
addition to lower serum androgen levels than in control
subjects.10,11 Because of the FDAs category X classification,
women with endometriosis and polycystic ovary syndrome
who are planning a pregnancy are currently excluded from
exploring statin therapy, despite its potential in treating
these conditions.
Statins have also demonstrated potential efficacy in the
treatment of recurrent pregnancy loss. In an animal model
of recurrent pregnancy loss, pravastatin has been shown
to decrease thrombus formation, to increase uterine
blood flow and angiogenesis, and to rescue pregnancies in
miscarriage-prone mice.12
Finally, statin therapy is currently being explored for treating
preeclampsia. In animal models of preeclampsia, pravastatin
decreased the anti-angiogenic protein soluble fms-like
tyrosine kinase-1 (sFlt-1), increased placental growth factors
and blood flow, reversed intrauterine growth restriction,
and reduced hypertension and proteinuria.13,14 Currently,
a randomized double-blind placebo-controlled study is
underway in the United Kingdom investigating pravastatin
use in women with preeclampsia.29 As well, a multicentre
clinical trial is in progress in the United States to investigate
the use of pravastatin for the prevention of preeclampsia.30
CONCLUSIONS
Our meta-analysis has suggested that statin exposure is
not associated with a significant increase in birth defects
compared with control subjects (RR 1.15). However, there
JUNE JOGC JUIN 2014 l 507
Drugs in Pregnancy
Figure 1. Meta-analysis of birth defects
Figure 2. Meta-analysis of spontaneous abortions
was a modest, but significant increase in miscarriage risk
(RR 1.35), and women using statins were more than twice
as likely as control subjects to undergo elective terminations
of pregnancy.
The increase in miscarriage risk may reflect maternal
morbidity rather than statin therapy, as women reliant
on statin therapy tend to be older and to have metabolic
conditions that may predispose them to miscarriage.
However, the most significant association observed in our
meta-analysis was the increased rate of elective pregnancy
termination. This increase may have been caused by the
presence of maternal health conditions not compatible
with pregnancy and by pregnancies being unplanned,
leading to the decision to terminate. Having a perception
of fetal risks associated with statin exposure would be likely
to increase the likelihood of elective termination. Even in a
desired pregnancy, the putative risks associated with statins
would deter many women from continuing a pregnancy.
However, the results of our meta-analysis are reassuring
for the many women who unintentionally conceive while
on statins.
508 l JUNE JOGC JUIN 2014
Since the decision to initiate or continue statin therapy
affects the patient and her unborn child, the decision
regarding statin therapy needs to be made after careful
counselling and consideration of the benefits and risks.
This approach will not lead to the same conclusion for
every pregnancy.
Finally, the FDAs categorization of statins as category
X drugs has prevented the application of statins in
potentially important obstetrical indications. Our meta-
analysis suggests there is a need for re-evaluation of this
categorization.
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