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Fetal toxicity associated with statins: A systematic review and meta-analysis

  • Amir Vahedian-Azimi
    Affiliations
    Trauma Research Center, Nursing Faculty, Baqiyatallah University of Medical Sciences, Tehran, Iran
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  • Somayeh Makvandi
    Correspondence
    Corresponding author.
    Affiliations
    Department of Midwifery, School of Nursing and Midwifery, Islamic Azad University Ahvaz Branch, Ahvaz, Iran
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  • Maciej Banach
    Affiliations
    Department of Hypertension, Chair of Nephrology and Hypertension, Medical University of Lodz, Poland

    Polish Mother's Memorial Hospital Research Institute (PMMHRI), Lodz, Poland
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  • Željko Reiner
    Affiliations
    Department of Internal Diseases University Hospital Center Zagreb School of Medicine, Zagreb University, Zagreb, Croatia
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  • Amirhossein Sahebkar
    Correspondence
    Corresponding author. Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, 9177948564, Iran.
    Affiliations
    Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

    Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran

    School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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Open AccessPublished:May 15, 2021DOI:https://doi.org/10.1016/j.atherosclerosis.2021.05.006

      Highlights

      • Based on animal and case report studies, statins are not advised during pregnancy due to the risk of possible teratogenicity.
      • To our knowledge, this is the largest systematic review and meta-analysis aimed to investigate this issue.
      • Our results did not suggest a clear-cut answer as to whether statin use in pregnancy is associated with birth defects risk.
      • This meta-analysis indicated that statin use does not increase birth defects, e.g. cardiac and other congenital anomalies.

      Abstract

      Background and aims

      Statins are the drugs of choice for decreasing elevated low-density lipoprotein cholesterol. Based mostly on animal studies and case reports, they are forbidden to pregnant women and in the preconception period because of their possible teratogenic effects, for which causality has never been proven. The aim of this study was to systematically review the existing studies and to perform a meta-analysis on this topic.

      Methods

      The databases PubMed/MEDLINE, Scopus, and Web of Science were searched since the inception until May 16, 2020. The risk of bias for each clinical trial was evaluated using the Cochrane handbook criteria for systematic reviews. The National Institutes of Health (NIH) quality assessment tool was used for the evaluation of cohort and cross-sectional studies. Meta-analysis was performed on the extracted data. Heterogeneity was assessed using I2 measure and Cochrane's Q statistic. We calculated a pooled estimate of odds ratio (OR) and 95% confidence intervals (CI) using a random-effects model.

      Results

      23 studies (nine cohort studies, six case reports, six case series, one population-based case-referent study and one clinical trial) with 1,276,973 participants were included in the systematic review and 6 of them (n = 1,267,240 participants) were included in meta-analysis. The results of the critical review did not suggest a clear-cut answer to the question whether statin treatment during pregnancy is associated with an increased rate of birth defects or not, while the results of the meta-analysis indicated that statin use does not increase birth defects [OR (95%CI): 1.48 (0.90, 2.42), p = 0.509], including cardiac anomalies [2.53 (0.81, 7.93), p = 0.112] and other congenital anomalies [1.19 (0.70, 2.03), p = 0.509)].

      Conclusions

      We observed no significant increase of birth defects after statin therapy. Thus, there is still no undoubtful evidence that statin treatment during pregnancy is teratogenic, and this issue still needs to be investigated, especially there are more and more pregnant women at high CVD risk that could have benefited from the statin therapy.

      Graphical abstract

      Keywords

      1. Introduction

      Hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors – statins have been widely used for almost four decades as the drugs of first choice to decrease elevated low-density lipoprotein cholesterol (LDL-C) and thus reduce atherosclerotic cardiovascular disease (ASCVD) morbidity and mortality [
      • Reiner Ž.
      Statins in the primary prevention of cardiovascular disease.
      ,
      • Catapano A.L.
      • Graham I.
      • De Backer G.
      • et al.
      ESC/EAS guidelines for the management of dyslipidaemias.
      ,
      • Hobbs F.R.
      • Banach M.
      • Mikhailidis D.P.
      • et al.
      Is statin-modified reduction in lipids the most important preventive therapy for cardiovascular disease? A pro/con debate.
      ]. Besides, this class of drugs possesses a plethora of pleiotropic effects [
      • Mohammad S.
      • Nguyen H.
      • Nguyen M.
      • et al.
      Pleiotropic effects of statins: untapped potential for statin pharmacotherapy.
      ,
      • Afshari A.R.
      • Mollazadeh H.
      • Henney N.C.
      • et al.
      Effects of statins on brain tumors: a review.
      ,
      • Bagheri H.
      • Ghasemi F.
      • Barreto G.E.
      • et al.
      The effects of statins on microglial cells to protect against neurodegenerative disorders: a mechanistic review.
      ,
      • Kouhpeikar H.
      • Delbari Z.
      • Sathyapalan T.
      • et al.
      The effect of statins through mast cells in the pathophysiology of atherosclerosis: a review.
      ,
      • Mollazadeh H.
      • Tavana E.
      • Fanni G.
      • et al.
      Effects of statins on mitochondrial pathways.
      ,
      • Reiner Ž.
      • Hatamipour M.
      • Banach M.
      • et al.
      Statins and the Covid-19 main protease: in silico evidence on direct interaction.
      ,
      • Sahebkar A.
      • Serban C.
      • Ursoniu S.
      • et al.
      The impact of statin therapy on plasma levels of von Willebrand factor antigen: systematic review and meta-analysis of Randomised placebo-controlled trials.
      ,
      • Serban C.
      • Sahebkar A.
      • Ursoniu S.
      • et al.
      A systematic review and meta-analysis of the effect of statins on plasma asymmetric dimethylarginine concentrations.
      ], which are mostly independent of the impact on LDL-C. Since the data about their effects on pregnancy and fetal development were non existing or scarce, from the very beginning of their use women were advised to stop treatment with these drugs during the preconception period and pregnancy 12. A number of studies on animals were published in the last 25 years suggesting that statins might cause fetal anomalies [
      • Faqi A.S.
      • Prohaska D.
      • Lopez R.
      • et al.
      Developmental toxicity of the HMG‐CoA reductase inhibitor (PPD10558) in rats and rabbits.
      ,
      • Beverly B.E.
      • Furr J.R.
      • Lambright C.S.
      • et al.
      In utero exposure to simvastatin reduces postnatal survival and permanently alters reproductive tract development in the Crl: CD (SD) male rat.
      ]. However, in these reports, in which more fetal anomalies were reported in animals treated with statins, excessive doses were used compared with the doses commonly prescribed to humans. Based mostly upon these studies, but also on some case reports, the U.S. Food and Drug Administration (FDA) claims that statins are not recommended for pregnant women and they are rated as “Pregnancy Category X” drugs, which means that studies have shown that they might cause birth defects and that the risks outweigh the benefit. The same recommendations were repeated in the recent guidelines of the European Society of Cardiology (2018) [
      • Regitz-Zagrosek V.
      • Roos-Hesselink J.W.
      • Bauersachs J.
      • et al.
      ESC guidelines for the management of cardiovascular diseases during pregnancy: the task force for the management of cardiovascular diseases during pregnancy of the European Society of Cardiology (ESC).
      ]. However, some more recent observational studies could not find an increased risk of congenital anomalies caused by statins in pregnancy when compared to control groups or the prevalence of congenital anomalies in the general population [
      • Bateman B.T.
      • Hernandez-Diaz S.
      • Fischer M.A.
      • et al.
      Statins and congenital malformations: cohort study.
      ,
      • Karalis D.G.
      • Hill A.N.
      • Clifton S.
      • et al.
      The risks of statin use in pregnancy: a systematic review.
      ], especially in the group of patients with the extremely high levels of LDL-C such as those with heterozygous and homozygous familial hypercholesterolemia (FH), where no such complications were observed [
      • Catapano A.L.
      • Graham I.
      • De Backer G.
      • et al.
      ESC/EAS guidelines for the management of dyslipidaemias.
      ,
      • Hobbs F.R.
      • Banach M.
      • Mikhailidis D.P.
      • et al.
      Is statin-modified reduction in lipids the most important preventive therapy for cardiovascular disease? A pro/con debate.
      ,
      • Maierean S.M.
      • Mikhailidis D.P.
      • Toth P.P.
      • et al.
      The potential role of statins in preeclampsia and dyslipidemia during gestation: a narrative review.
      ,
      • Regitz-Zagrosek V.
      • Roos-Hesselink J.W.
      • Bauersachs J.
      • et al.
      ESC guidelines for the management of cardiovascular diseases during pregnancy: the task force for the management of cardiovascular diseases during pregnancy of the European Society of Cardiology (ESC).
      ].
      The main question of this systematic review and meta-analysis was: “Is there any scientific evidence that proves that statin therapy is associated with an increased rate of birth defects in women exposed to statins during pregnancy?”. Therefore, the aim of this study was to identify and analyze all the existing studies concerning this question, and to perform a meta-analysis if it could be meaningfully or reliably performed. To the best of our knowledge, this is the largest and the most comprehensive systematic review and meta-analysis aimed to investigate this issue.

      2. Materials and methods

      2.1 Literature search strategy

      The databases PubMed/MEDLINE, Scopus, and Web of Science have been searched since the inception until May 16, 2020. In the search strategy, the following MeSH and text keywords were used: (pregnancy OR pregnant* OR gestation* OR conception) AND (statins OR „statin therapy” OR „statins therapy” OR statin OR „HMG CoA reductase inhibitor” OR lovastatin OR fluvastatin OR pravastatin OR pitavastatin OR rosuvastatin OR atorvastatin OR simvastatin OR cerivastatin OR lipitor OR lescol OR “Lescol XL” OR mevacor OR altoprev OR pravachol OR crestor OR zocor OR livalo). To further identify potentially related studies, the references of primary articles were also reviewed. All relevant articles were evaluated using predefined selection criteria.

      2.2 Selection criteria

      All studies with original data, including any methodology performed on statin-exposed pregnant women in each trimester of pregnancy with adequate data about congenital anomalies or any birth defects that occurred during and after statin use by the pregnant women were included. Animal studies and articles in non-English languages were excluded.

      2.3 Data extraction

      Data extraction was done in three steps. First, the output of all three scientific databases was analyzed and the duplicate articles were removed. Studies were then screened separately by title and abstract by two researchers (AVA and SM) to identify seemingly related articles for the second screening. In the next step, two separate researchers (ZR and AS) carefully evaluated full texts of the remaining articles and identified studies that met the inclusion criteria for review. Data were extracted from the studies by a pre-designed form that included the following information: the author's name, year, country, the type of the study, population, statin exposure, and control group, trimester(s) of exposure to statins and outcomes. At all these stages, any ambiguities or disagreements between the evaluators were resolved through discussion and consensus.

      2.4 Critical appraisal

      Two authors (AVA and SM) independently assessed the quality of included studies. The risk of bias for each clinical trial was evaluated using the Cochrane handbook criteria for systematic reviews [
      ]. The National Institutes of Health (NIH) quality assessment tool was used for the evaluation of cohort and cross-sectional studies [
      National Institutes of Health
      Quality assessment tool for observational cohort and cross-sectional studies.
      ]. This tool has 14 questions and shows the quality as good, fair, and poor. No formal quality assessment was used for case reports and case series studies. Any disagreement between the researchers was resolved by discussion.

      2.5 Statistical analysis

      Meta-analysis was performed on the extracted data for dichotomous outcome of rate of birth defects. We calculated a pooled estimate of odds ratio (OR) and 95% confidence intervals (CI) by random effect with inverse variance (IV) weighting. We showed the result in the Forest plot by the subgroup analysis. Heterogeneity was assessed using I2 measure and Cochrane's Q statistic [
      • Higgins J.P.
      • Altman D.G.
      • Gøtzsche P.C.
      • et al.
      The Cochrane Collaboration's tool for assessing risk of bias in randomised trials.
      ] and illustrated by Radial plot. We performed subgroup analysis to find the potential source of the heterogeneity. Publication bias was evaluated by Egger's test [
      • Egger M.
      • Smith G.D.
      • Schneider M.
      • et al.
      Bias in meta-analysis detected by a simple, graphical test.
      ] and Funnel plot. All statistical analysis was performed using by STATA, version 14.0 (Stata Corp, College Station, TX) and R version 3.6.3.

      3. Results

      A total of 2128 studies were identified by searching three electronic databases and other sources (see methodology). After the removal of duplicates and apparently irrelevant studies, 98 articles remained to be screened by the full-text evaluation. After applying the selection criteria, 23 studies with 1,276,973 participants were included in the systematic review, and 6 studies with 1,267,240 participants were finally included in the meta-analysis (Fig. 1). The characteristics of these studies are shown in Table 1.
      Fig. 1
      Fig. 1PRISMA flow chart (preferred reporting items for systematic reviews and meta-analyses).
      Table 1Summary of characteristics of studies included in the systematic review.
      First author, (year)CountryType of studyPopulation (number of subjects)Statin exposureControlTrimesterOutcomes
      Bateman, (2015) [
      • Bateman B.T.
      • Hernandez-Diaz S.
      • Fischer M.A.
      • et al.
      Statins and congenital malformations: cohort study.
      ]
      United StatesCohort886,996 completed pregnancies linked to live born infants1152 women used a statin. Most commonly used statins: atorvastatin (n = 538), simvastatin (n = 319), and lovastatin (n = 132)885,844 women were unexposed to statinsFirstNo significant teratogenic effect from maternal use of statins was found.
      Botha, (2018) [
      • Botha T.C.
      • Pilcher G.J.
      • Wolmarans K.
      • et al.
      Statins and other lipid-lowering therapy and pregnancy outcomes in homozygous familial hypercholesterolaemia: a retrospective review of 39 pregnancies.
      ]
      South AfricaCohort39 pregnancies with homozygous familial hypercholesterolaemia18 women exposed to statin. Most common statins used was atorvastatin21 women used no statinBefore conception, first and second trimestersThere was no statistical difference in the rate of congenital malformations between the statin exposed and unexposed groups.
      Brownfoot, (2015) [
      • Brownfoot F.C.
      • Tong S.
      • Hannan N.J.
      • et al.
      Effects of pravastatin on human placenta, endothelium, and women with severe preeclampsia.
      ]
      JapanCase series4 pregnant women with preeclampsia presenting at 23–30 weeks of gestationPravastatin (n = 4)NoneSecond and thirdThere were no fetal or neonatal abnormalities and no neonatal deaths.
      Colvin, (2010) [
      • Colvin L.
      • Slack‐Smith L.
      • Stanley F.J.
      • et al.
      Linking a pharmaceutical claims database with a birth defects registry to investigate birth defect rates of suspected teratogens.
      ]
      AustraliaRegistry-based cohort51 pregnant women exposed to statins during pregnancy and non-exposed pregnant womenAtorvastatin (n = 33) and simvastatin (n = 18)106,074 women with a pregnancy eventFirstThe risk for any congenital anomaly for simvastatin was OR 1.2, 95% CI 0.2–8.9 and for atorvastatin was OR 0.6, 95% CI 5 0.1–4.6
      Costantin, (2016) [
      • Costantine M.M.
      • Cleary K.
      • Hebert M.F.
      • et al.
      Safety and pharmacokinetics of pravastatin used for the prevention of preeclampsia in high-risk pregnant women: a pilot randomized controlled trial.
      ]
      United StatesPilot randomized controlled trial21 women at high risk for preeclampsia10 women used daily pravastatinPlacebo (n = 10)Second and thirdThere were no significant differences between two groups regarding congenital anomalies.
      Daud, (2017) [
      • Daud A.N.
      • Bergman J.E.
      • Oktora M.P.
      • et al.
      Maternal use of drug substrates of placental transporters and the effect of transporter-mediated drug interactions on the risk of congenital anomalies.
      ]
      NetherlandsPopulation-based case-referent study4805 live born cases with congenital anomalyAtorvastatin, and SimvastatinReferent population (n = 31055)FirstThere was no difference between those exposed to statins and the referent population.
      Edison, (2004) [
      • Edison R.J.
      • Muenke M.
      Central nervous system and limb anomalies in case reports of first-trimester statin exposure.
      ]
      United StatesCase series178 pregnant women with statin exposure during pregnancyThere were 20 reports of malformations in 9 neonates of women who used cerivastatin, simvastatin,

      lovastatin, atorvastatin
      No controlFirstThere were five neonates with severe defects of the central nervous system and five unilateral limb deficiencies (one newborn had both of these malformations).
      Ghidin, (1992) [
      • Ghidini A.
      • Sicherer S.
      • Willner J.
      Congenital abnormalities (VATER) in baby born to mother using lovastatin.
      ]
      United StatesCase reportA pregnant woman with hypercholesterolaemiaLovastatin and dextroamphetamine for 5 weeksFirstMultiple congenital anomalies were detected: asymmetric chest, thoracic scoliosis, absent left thumb, foreshortened left forearm, and left elbow contracture, fusion of the ribs, butterfly vertebrae, left radial aplasia.
      Kozłowski, (2017) [
      • Kozłowski S.
      • Lipa M.
      • Lipa J.
      • et al.
      An experimental administration of pravastatin in patient with previous, multiple pregnancy losses.
      ]
      PolandCase reportA preeclamptic woman with previous four pregnancy losses and with a history of chronic hypertension, hypothyroidism, polycystic ovarian syndrome with insulin resistancePravastatin from 17 weeks of gestation to deliverySecond and thirdFetal growth restriction and decreasing volume of amniotic fluid at 33 weeks of gestation were found.

      There were no congenital anomalies.
      Lee, (2018) [
      • Lee M.-S.
      • Hekimian A.
      • Doctorian T.
      • et al.
      Statin exposure during first trimester of pregnancy is associated with fetal ventricular septal defect.
      ]
      United StatesCohort379,238 singleton pregnancies280 pregnancies exposed to atorvastatin (n = 28, 10.0%), lovastatin (n = 104, 37.1%), pravastatin (n = 8,2.9%), and simvastatin (n = 140,50%)378,950 pregnancies unexposed to statinFirstIn general, the percentage of congenital cardiac anomalies in neonates of the pregnant women who were exposed to statins was higher than in those who were not (p = 0.009).

      First-trimester statin exposure was associated with an increased risk of ventricular septal defect (p < 0.001).

      No association was found with atrial septal defect, conotruncal defect, single ventricle physiology, and patent ductus arteriosus after adjustment for maternal characteristics.
      Manson, J.M (1996) [
      • Manson J.M.
      • Freyssinges C.
      • Ducrocq M.B.
      • et al.
      Postmarketing surveillance of lovastatin and simvastatin exposure during pregnancy.
      ]
      Multinational study (12 countries)
      Australia, Belgium, Canada, France, Germany, Luxemburg, Mexico, Netherlands, Norway, South Africa, United Kingdom, and the USA.
      Case series134 reports of exposure to statins during pregnancy99 prospective and 35 retrospective reports of using lovastatin and simvastatin during pregnancyFirst trimester in 89% of casesThere was no relationship between exposure to statins during pregnancy and the occurrence of adverse pregnancy outcomes.

      There were nine reports of congenital anomalies (two cases with central nervous system defects, two reports of limb anomalies, and one hypospadias, VATER association, cleft lip, and trisomy 18).
      McElhatton, (2008) [
      • McElhatton P.
      • Stephens S.
      • Wilson G.
      • et al.
      Preliminary data on exposure to statins during pregnancy.
      ]
      United KingdomCase seriesPregnant women exposed to statins during pregnancy25 pregnancies exposed to atorvastatin, simvastatin, and pravastatin (no details)First trimester in 88% of casesThere was an increased rate of congenital malformations after exposure to statins (4 out of 18 live born).
      McGrogan, (2017) [
      • McGrogan A.
      • Snowball J.
      • Charlton R.A.
      Statins during pregnancy: a cohort study using the General Practice Research Database to investigate pregnancy loss.
      ]
      United KingdomCohort2924 pregnant women281 women exposed to simvastatin (n = 152), atorvastatin (n = 103), cerivastatin (n = 2), rosuvastatin (n = 6), pravastatin (n = 8), fluvastatin (n = 4), and combination (n = 6)2643 pregnancies unexposed to statinThree months before and/or during the first trimesterImportant differences in the proportions of pregnancy loss – it was significantly higher in those exposed to statins compared with the control group.

      There were nine anomalies in seven newborns in those exposed to statin compared to 49 anomalies in 48 newborns in the control group.
      Ofori, (2007) [
      • Ofori B.
      • Rey E.
      • Bérard A.
      Risk of congenital anomalies in pregnant users of statin drugs.
      ]
      CanadaRegistry-based cohort259 women were prescribed statins during or before pregnancy153 women exposed to atorvastatin, pravastatin and simvastatin during pregnancy106 women exposed to statins between 1

      year before and 1 month before pregnancy
      First trimesterThere was no detectable pattern in fetal congenital anomalies or evidence of an increased risk in the live-born infants of women who used statins during pregnancy compared to the control group.
      Otten, (2017) [
      • Otten L.A.
      • van der Ven K.
      • Kühr M.
      • et al.
      Pravastatin for Prevention of HELLP Syndrome: A Case Report.
      ]
      GermanyCase reportA 40 years old was pregnant with history of severe, recurrent early-onset HELLP syndromePravastatin was commenced at 13 weeks of gestation until deliveryThe final week of the first trimester to the third trimesterA neonate without major malformations was born at term.
      Petersen, (2008) [
      • Petersen E.E.
      • Mitchell A.A.
      • Carey J.C.
      • et al.
      Maternal exposure to statins and risk for birth defects: a case‐series approach.
      ]
      United statsCase series22 cases of birth defect with maternal exposure to statinsIn 22 cases, mothers took statins, including atorvastatin, simvastatin,

      cerivastatin, and pravastatin
      All but one were exposed in the first trimesterThe most common anomalies were congenital heart defects (n = 12) and cleft lip with or without cleft palate (n = 4)

      12 cases were exposed to atorvastatin.
      Pollack, (2005) [
      • Pollack P.S.
      • Shields K.E.
      • Burnett D.M.
      • et al.
      Pregnancy outcomes after maternal exposure to simvastatin and lovastatin.
      ]
      United statsCase series477 reports of exposure to statins during pregnancy386 prospective and 91 retrospective reports of exposure to simvastatin and/or lovastatinFirst trimester exposure was reported in 162 subjectsThe rate of congenital anomalies in the statin group and general population were not different
      Singh, (2013) [
      • Singh N.
      • Goyal M.
      • Kumar S.
      • et al.
      Successful outcome in a rare case of pregnancy with familial hypercholesterolemia and dilated cardiomyopathy.
      ]
      IndiaCase reportA pregnant woman with familial hypercholesterolemia and cardiomyopathyStatin was used until week 24. The type of statin was not mentionedBefore pregnancy, the first trimester and up to 24 weeks from the second trimesterA healthy neonate was born at 36 weeks of gestation.
      Taguchi, (2008) [
      • Taguchi N.
      • Rubin
      • Hosokawa A.
      • et al.
      Prenatal exposure to HMG-CoA reductase inhibitors: effects on fetal and neonatal outcomes.
      ]
      CanadaCohort128 pregnant women with hypercholesterolemia64 women used atorvastatin (n = 46), simvastatin (n = 9),

      pravastatin (n = 6),

      rosuvastatin (n = 3)
      64 women used non-teratogen lipid = lowering agentsFirstThere was no difference in the rate of major malformations between the statin group and the control group.
      Teelucksing, (2004) [
      • Teelucksingh S.
      • El Youssef J.
      • Sohan K.
      • et al.
      Prolonged inadvertent pravastatin use in pregnancy.
      ]
      IndiaCase reportA woman with the metabolic syndrome who was unaware of her pregnancyPravastatin was used until week 24 of gestationBefore pregnancy, the first trimester and up to 24 weeks from the second trimesterNo gross anatomic abnormalities were found at birth.

      Neonatal period was uncomplicated, and no early developmental abnormalities were found.
      Toleikyte, (2015) [
      • Toleikyte I.
      • Retterstøl K.
      • Leren T.P.
      • et al.
      Pregnancy outcomes in familial hypercholesterolemia: a registry-based study.
      ]
      NorwayRegistry-based cohort1093 familial hypercholesterolemic women with 2319 births.16 cases used a statin during pregnancy. The type of statins was not mentionedGeneral population (n = 2,304,067)Not mentionedThe frequency of all congenital malformations did not change significantly from the period before (years 1979–1991) and the period after (years 1992–2006) statin introduction in study population.
      Winterfeld, (2013) [
      • Winterfeld U.
      • Allignol A.
      • Panchaud A.
      • et al.
      Pregnancy outcome following maternal exposure to statins: a multicentre prospective study.
      ]
      Multinational study
      11 centers in Europe.
      Cohort598 pregnant women249 pregnant women who were seeking medical advice about statin exposure during pregnancy. They had used simvastatin (n = 124), atorvastatin (n = 67), pravastatin (n = 32),

      rosuvastatin, (n = 18),

      fluvastatin (n = 7), and cerivastatin (n = 1)
      249 women used no statinsFirst trimester in 86% of casesThere was no difference in the rate of major birth defects between those exposed to statin and the control group.
      Yaris, (2004) [
      • Yaris F.
      • Yaris E.
      • Kadioglu M.
      • et al.
      Normal pregnancy outcome following inadvertent exposure to rosiglitazone, gliclazide, and atorvastatin in a diabetic and hypertensive woman.
      ]
      TurkeyCase reportA diabetic and hypertensive woman with an unplanned pregnancyShe used rosiglitazone, gliclazide, and atorvastatin during the first 7 weeks of gestationFirstNo congenital abnormality was detected at birth.

      No developmental abnormalities were found in the first four months after birth.
      a Australia, Belgium, Canada, France, Germany, Luxemburg, Mexico, Netherlands, Norway, South Africa, United Kingdom, and the USA.
      b 11 centers in Europe.

      3.1 Quality assessment

      Nine cohort and one case-referent studies were evaluated using NIH quality assessment tool for observational cohort and cross-sectional studies. In total, 70% of the studies had good quality, 20% had fair, and 10% had poor quality. The highest-quality studies were prospective cohort studies [
      • Taguchi N.
      • Rubin
      • Hosokawa A.
      • et al.
      Prenatal exposure to HMG-CoA reductase inhibitors: effects on fetal and neonatal outcomes.
      ,
      • Winterfeld U.
      • Allignol A.
      • Panchaud A.
      • et al.
      Pregnancy outcome following maternal exposure to statins: a multicentre prospective study.
      ]. The quality of the clinical trial study [
      • Costantine M.M.
      • Cleary K.
      • Hebert M.F.
      • et al.
      Safety and pharmacokinetics of pravastatin used for the prevention of preeclampsia in high-risk pregnant women: a pilot randomized controlled trial.
      ] was assessed using the Cochrane risk of bias tool. This study concerning random sequence generation, blinding of participants, personnel, and outcomes assessors, incomplete outcome data, and selective reporting had a low risk of bias and in the domain of allocation concealment had an unclear risk of bias.

      3.2 Characteristics of studies

      The number of participants exposed to statins varied from one to 1152 subjects [
      • Bateman B.T.
      • Hernandez-Diaz S.
      • Fischer M.A.
      • et al.
      Statins and congenital malformations: cohort study.
      ]. Five studies were performed on pregnant women with hypercholesterolemia [
      • Taguchi N.
      • Rubin
      • Hosokawa A.
      • et al.
      Prenatal exposure to HMG-CoA reductase inhibitors: effects on fetal and neonatal outcomes.
      ,
      • Botha T.C.
      • Pilcher G.J.
      • Wolmarans K.
      • et al.
      Statins and other lipid-lowering therapy and pregnancy outcomes in homozygous familial hypercholesterolaemia: a retrospective review of 39 pregnancies.
      ,
      • Ghidini A.
      • Sicherer S.
      • Willner J.
      Congenital abnormalities (VATER) in baby born to mother using lovastatin.
      ,
      • Singh N.
      • Goyal M.
      • Kumar S.
      • et al.
      Successful outcome in a rare case of pregnancy with familial hypercholesterolemia and dilated cardiomyopathy.
      ,
      • Toleikyte I.
      • Retterstøl K.
      • Leren T.P.
      • et al.
      Pregnancy outcomes in familial hypercholesterolemia: a registry-based study.
      ] and three studies were performed on women who had preeclampsia or were at high risk for it [
      • Costantine M.M.
      • Cleary K.
      • Hebert M.F.
      • et al.
      Safety and pharmacokinetics of pravastatin used for the prevention of preeclampsia in high-risk pregnant women: a pilot randomized controlled trial.
      ,
      • Brownfoot F.C.
      • Tong S.
      • Hannan N.J.
      • et al.
      Effects of pravastatin on human placenta, endothelium, and women with severe preeclampsia.
      ,
      • Kozłowski S.
      • Lipa M.
      • Lipa J.
      • et al.
      An experimental administration of pravastatin in patient with previous, multiple pregnancy losses.
      ]. According to the methodology, the studies included nine cohort articles [
      • Bateman B.T.
      • Hernandez-Diaz S.
      • Fischer M.A.
      • et al.
      Statins and congenital malformations: cohort study.
      ,
      • Taguchi N.
      • Rubin
      • Hosokawa A.
      • et al.
      Prenatal exposure to HMG-CoA reductase inhibitors: effects on fetal and neonatal outcomes.
      ,
      • Winterfeld U.
      • Allignol A.
      • Panchaud A.
      • et al.
      Pregnancy outcome following maternal exposure to statins: a multicentre prospective study.
      ,
      • Botha T.C.
      • Pilcher G.J.
      • Wolmarans K.
      • et al.
      Statins and other lipid-lowering therapy and pregnancy outcomes in homozygous familial hypercholesterolaemia: a retrospective review of 39 pregnancies.
      ,
      • Toleikyte I.
      • Retterstøl K.
      • Leren T.P.
      • et al.
      Pregnancy outcomes in familial hypercholesterolemia: a registry-based study.
      ,
      • Colvin L.
      • Slack‐Smith L.
      • Stanley F.J.
      • et al.
      Linking a pharmaceutical claims database with a birth defects registry to investigate birth defect rates of suspected teratogens.
      ,
      • Lee M.-S.
      • Hekimian A.
      • Doctorian T.
      • et al.
      Statin exposure during first trimester of pregnancy is associated with fetal ventricular septal defect.
      ,
      • McGrogan A.
      • Snowball J.
      • Charlton R.A.
      Statins during pregnancy: a cohort study using the General Practice Research Database to investigate pregnancy loss.
      ,
      • Ofori B.
      • Rey E.
      • Bérard A.
      Risk of congenital anomalies in pregnant users of statin drugs.
      ], six case reports [
      • Ghidini A.
      • Sicherer S.
      • Willner J.
      Congenital abnormalities (VATER) in baby born to mother using lovastatin.
      ,
      • Singh N.
      • Goyal M.
      • Kumar S.
      • et al.
      Successful outcome in a rare case of pregnancy with familial hypercholesterolemia and dilated cardiomyopathy.
      ,
      • Kozłowski S.
      • Lipa M.
      • Lipa J.
      • et al.
      An experimental administration of pravastatin in patient with previous, multiple pregnancy losses.
      ,
      • Otten L.A.
      • van der Ven K.
      • Kühr M.
      • et al.
      Pravastatin for Prevention of HELLP Syndrome: A Case Report.
      ,
      • Teelucksingh S.
      • El Youssef J.
      • Sohan K.
      • et al.
      Prolonged inadvertent pravastatin use in pregnancy.
      ,
      • Yaris F.
      • Yaris E.
      • Kadioglu M.
      • et al.
      Normal pregnancy outcome following inadvertent exposure to rosiglitazone, gliclazide, and atorvastatin in a diabetic and hypertensive woman.
      ], six case series [
      • Brownfoot F.C.
      • Tong S.
      • Hannan N.J.
      • et al.
      Effects of pravastatin on human placenta, endothelium, and women with severe preeclampsia.
      ,
      • Edison R.J.
      • Muenke M.
      Central nervous system and limb anomalies in case reports of first-trimester statin exposure.
      ,
      • Manson J.M.
      • Freyssinges C.
      • Ducrocq M.B.
      • et al.
      Postmarketing surveillance of lovastatin and simvastatin exposure during pregnancy.
      ,
      • McElhatton P.
      • Stephens S.
      • Wilson G.
      • et al.
      Preliminary data on exposure to statins during pregnancy.
      ,
      • Petersen E.E.
      • Mitchell A.A.
      • Carey J.C.
      • et al.
      Maternal exposure to statins and risk for birth defects: a case‐series approach.
      ,
      • Pollack P.S.
      • Shields K.E.
      • Burnett D.M.
      • et al.
      Pregnancy outcomes after maternal exposure to simvastatin and lovastatin.
      ], one clinical trial [
      • Costantine M.M.
      • Cleary K.
      • Hebert M.F.
      • et al.
      Safety and pharmacokinetics of pravastatin used for the prevention of preeclampsia in high-risk pregnant women: a pilot randomized controlled trial.
      ], and one population-based case-referent study [
      • Daud A.N.
      • Bergman J.E.
      • Oktora M.P.
      • et al.
      Maternal use of drug substrates of placental transporters and the effect of transporter-mediated drug interactions on the risk of congenital anomalies.
      ]. The studies were published from 1992 to 2018.

      3.3 Types of statins and time of exposure

      Concerning the type of statin used, in most studies it was atorvastatin [
      • Bateman B.T.
      • Hernandez-Diaz S.
      • Fischer M.A.
      • et al.
      Statins and congenital malformations: cohort study.
      ,
      • Taguchi N.
      • Rubin
      • Hosokawa A.
      • et al.
      Prenatal exposure to HMG-CoA reductase inhibitors: effects on fetal and neonatal outcomes.
      ,
      • Winterfeld U.
      • Allignol A.
      • Panchaud A.
      • et al.
      Pregnancy outcome following maternal exposure to statins: a multicentre prospective study.
      ,
      • Botha T.C.
      • Pilcher G.J.
      • Wolmarans K.
      • et al.
      Statins and other lipid-lowering therapy and pregnancy outcomes in homozygous familial hypercholesterolaemia: a retrospective review of 39 pregnancies.
      ,
      • Colvin L.
      • Slack‐Smith L.
      • Stanley F.J.
      • et al.
      Linking a pharmaceutical claims database with a birth defects registry to investigate birth defect rates of suspected teratogens.
      ,
      • Lee M.-S.
      • Hekimian A.
      • Doctorian T.
      • et al.
      Statin exposure during first trimester of pregnancy is associated with fetal ventricular septal defect.
      ,
      • McGrogan A.
      • Snowball J.
      • Charlton R.A.
      Statins during pregnancy: a cohort study using the General Practice Research Database to investigate pregnancy loss.
      ,
      • Ofori B.
      • Rey E.
      • Bérard A.
      Risk of congenital anomalies in pregnant users of statin drugs.
      ,
      • Yaris F.
      • Yaris E.
      • Kadioglu M.
      • et al.
      Normal pregnancy outcome following inadvertent exposure to rosiglitazone, gliclazide, and atorvastatin in a diabetic and hypertensive woman.
      ,
      • Edison R.J.
      • Muenke M.
      Central nervous system and limb anomalies in case reports of first-trimester statin exposure.
      ,
      • McElhatton P.
      • Stephens S.
      • Wilson G.
      • et al.
      Preliminary data on exposure to statins during pregnancy.
      ,
      • Petersen E.E.
      • Mitchell A.A.
      • Carey J.C.
      • et al.
      Maternal exposure to statins and risk for birth defects: a case‐series approach.
      ,
      • Daud A.N.
      • Bergman J.E.
      • Oktora M.P.
      • et al.
      Maternal use of drug substrates of placental transporters and the effect of transporter-mediated drug interactions on the risk of congenital anomalies.
      ] and simvastatin [
      • Bateman B.T.
      • Hernandez-Diaz S.
      • Fischer M.A.
      • et al.
      Statins and congenital malformations: cohort study.
      ,
      • Taguchi N.
      • Rubin
      • Hosokawa A.
      • et al.
      Prenatal exposure to HMG-CoA reductase inhibitors: effects on fetal and neonatal outcomes.
      ,
      • Winterfeld U.
      • Allignol A.
      • Panchaud A.
      • et al.
      Pregnancy outcome following maternal exposure to statins: a multicentre prospective study.
      ,
      • Colvin L.
      • Slack‐Smith L.
      • Stanley F.J.
      • et al.
      Linking a pharmaceutical claims database with a birth defects registry to investigate birth defect rates of suspected teratogens.
      ,
      • Lee M.-S.
      • Hekimian A.
      • Doctorian T.
      • et al.
      Statin exposure during first trimester of pregnancy is associated with fetal ventricular septal defect.
      ,
      • McGrogan A.
      • Snowball J.
      • Charlton R.A.
      Statins during pregnancy: a cohort study using the General Practice Research Database to investigate pregnancy loss.
      ,
      • Ofori B.
      • Rey E.
      • Bérard A.
      Risk of congenital anomalies in pregnant users of statin drugs.
      ,
      • Edison R.J.
      • Muenke M.
      Central nervous system and limb anomalies in case reports of first-trimester statin exposure.
      ,
      • Manson J.M.
      • Freyssinges C.
      • Ducrocq M.B.
      • et al.
      Postmarketing surveillance of lovastatin and simvastatin exposure during pregnancy.
      ,
      • McElhatton P.
      • Stephens S.
      • Wilson G.
      • et al.
      Preliminary data on exposure to statins during pregnancy.
      ,
      • Petersen E.E.
      • Mitchell A.A.
      • Carey J.C.
      • et al.
      Maternal exposure to statins and risk for birth defects: a case‐series approach.
      ,
      • Pollack P.S.
      • Shields K.E.
      • Burnett D.M.
      • et al.
      Pregnancy outcomes after maternal exposure to simvastatin and lovastatin.
      ,
      • Daud A.N.
      • Bergman J.E.
      • Oktora M.P.
      • et al.
      Maternal use of drug substrates of placental transporters and the effect of transporter-mediated drug interactions on the risk of congenital anomalies.
      ], each of them was used in thirteen studies. Pravastatin was used in 11 studies [
      • Taguchi N.
      • Rubin
      • Hosokawa A.
      • et al.
      Prenatal exposure to HMG-CoA reductase inhibitors: effects on fetal and neonatal outcomes.
      ,
      • Winterfeld U.
      • Allignol A.
      • Panchaud A.
      • et al.
      Pregnancy outcome following maternal exposure to statins: a multicentre prospective study.
      ,
      • Costantine M.M.
      • Cleary K.
      • Hebert M.F.
      • et al.
      Safety and pharmacokinetics of pravastatin used for the prevention of preeclampsia in high-risk pregnant women: a pilot randomized controlled trial.
      ,
      • Ghidini A.
      • Sicherer S.
      • Willner J.
      Congenital abnormalities (VATER) in baby born to mother using lovastatin.
      ,
      • Brownfoot F.C.
      • Tong S.
      • Hannan N.J.
      • et al.
      Effects of pravastatin on human placenta, endothelium, and women with severe preeclampsia.
      ,
      • Kozłowski S.
      • Lipa M.
      • Lipa J.
      • et al.
      An experimental administration of pravastatin in patient with previous, multiple pregnancy losses.
      ,
      • Lee M.-S.
      • Hekimian A.
      • Doctorian T.
      • et al.
      Statin exposure during first trimester of pregnancy is associated with fetal ventricular septal defect.
      ,
      • McGrogan A.
      • Snowball J.
      • Charlton R.A.
      Statins during pregnancy: a cohort study using the General Practice Research Database to investigate pregnancy loss.
      ,
      • Ofori B.
      • Rey E.
      • Bérard A.
      Risk of congenital anomalies in pregnant users of statin drugs.
      ,
      • Teelucksingh S.
      • El Youssef J.
      • Sohan K.
      • et al.
      Prolonged inadvertent pravastatin use in pregnancy.
      ,
      • McElhatton P.
      • Stephens S.
      • Wilson G.
      • et al.
      Preliminary data on exposure to statins during pregnancy.
      ], lovastatin in 5 studies [
      • Bateman B.T.
      • Hernandez-Diaz S.
      • Fischer M.A.
      • et al.
      Statins and congenital malformations: cohort study.
      ,
      • Ghidini A.
      • Sicherer S.
      • Willner J.
      Congenital abnormalities (VATER) in baby born to mother using lovastatin.
      ,
      • Lee M.-S.
      • Hekimian A.
      • Doctorian T.
      • et al.
      Statin exposure during first trimester of pregnancy is associated with fetal ventricular septal defect.
      ,
      • Manson J.M.
      • Freyssinges C.
      • Ducrocq M.B.
      • et al.
      Postmarketing surveillance of lovastatin and simvastatin exposure during pregnancy.
      ,
      • Pollack P.S.
      • Shields K.E.
      • Burnett D.M.
      • et al.
      Pregnancy outcomes after maternal exposure to simvastatin and lovastatin.
      ], cerivastatin in 4 studies [
      • Winterfeld U.
      • Allignol A.
      • Panchaud A.
      • et al.
      Pregnancy outcome following maternal exposure to statins: a multicentre prospective study.
      ,
      • McGrogan A.
      • Snowball J.
      • Charlton R.A.
      Statins during pregnancy: a cohort study using the General Practice Research Database to investigate pregnancy loss.
      ,
      • Edison R.J.
      • Muenke M.
      Central nervous system and limb anomalies in case reports of first-trimester statin exposure.
      ,
      • Petersen E.E.
      • Mitchell A.A.
      • Carey J.C.
      • et al.
      Maternal exposure to statins and risk for birth defects: a case‐series approach.
      ], rosuvastatin in 2 studies [
      • Taguchi N.
      • Rubin
      • Hosokawa A.
      • et al.
      Prenatal exposure to HMG-CoA reductase inhibitors: effects on fetal and neonatal outcomes.
      ,
      • McGrogan A.
      • Snowball J.
      • Charlton R.A.
      Statins during pregnancy: a cohort study using the General Practice Research Database to investigate pregnancy loss.
      ], and fluvastatin in 2 studies [
      • Winterfeld U.
      • Allignol A.
      • Panchaud A.
      • et al.
      Pregnancy outcome following maternal exposure to statins: a multicentre prospective study.
      ,
      • McGrogan A.
      • Snowball J.
      • Charlton R.A.
      Statins during pregnancy: a cohort study using the General Practice Research Database to investigate pregnancy loss.
      ]. In two studies, the type of statin used was not mentioned [
      • Singh N.
      • Goyal M.
      • Kumar S.
      • et al.
      Successful outcome in a rare case of pregnancy with familial hypercholesterolemia and dilated cardiomyopathy.
      ,
      • Toleikyte I.
      • Retterstøl K.
      • Leren T.P.
      • et al.
      Pregnancy outcomes in familial hypercholesterolemia: a registry-based study.
      ].
      In most studies, women were exposed to statins during the first trimester of pregnancy [
      • Bateman B.T.
      • Hernandez-Diaz S.
      • Fischer M.A.
      • et al.
      Statins and congenital malformations: cohort study.
      ,
      • Taguchi N.
      • Rubin
      • Hosokawa A.
      • et al.
      Prenatal exposure to HMG-CoA reductase inhibitors: effects on fetal and neonatal outcomes.
      ,
      • Winterfeld U.
      • Allignol A.
      • Panchaud A.
      • et al.
      Pregnancy outcome following maternal exposure to statins: a multicentre prospective study.
      ,
      • Ghidini A.
      • Sicherer S.
      • Willner J.
      Congenital abnormalities (VATER) in baby born to mother using lovastatin.
      ,
      • Colvin L.
      • Slack‐Smith L.
      • Stanley F.J.
      • et al.
      Linking a pharmaceutical claims database with a birth defects registry to investigate birth defect rates of suspected teratogens.
      ,
      • Lee M.-S.
      • Hekimian A.
      • Doctorian T.
      • et al.
      Statin exposure during first trimester of pregnancy is associated with fetal ventricular septal defect.
      ,
      • McGrogan A.
      • Snowball J.
      • Charlton R.A.
      Statins during pregnancy: a cohort study using the General Practice Research Database to investigate pregnancy loss.
      ,
      • Ofori B.
      • Rey E.
      • Bérard A.
      Risk of congenital anomalies in pregnant users of statin drugs.
      ,
      • Yaris F.
      • Yaris E.
      • Kadioglu M.
      • et al.
      Normal pregnancy outcome following inadvertent exposure to rosiglitazone, gliclazide, and atorvastatin in a diabetic and hypertensive woman.
      ,
      • Edison R.J.
      • Muenke M.
      Central nervous system and limb anomalies in case reports of first-trimester statin exposure.
      ,
      • Manson J.M.
      • Freyssinges C.
      • Ducrocq M.B.
      • et al.
      Postmarketing surveillance of lovastatin and simvastatin exposure during pregnancy.
      ,
      • McElhatton P.
      • Stephens S.
      • Wilson G.
      • et al.
      Preliminary data on exposure to statins during pregnancy.
      ,
      • Petersen E.E.
      • Mitchell A.A.
      • Carey J.C.
      • et al.
      Maternal exposure to statins and risk for birth defects: a case‐series approach.
      ,
      • Daud A.N.
      • Bergman J.E.
      • Oktora M.P.
      • et al.
      Maternal use of drug substrates of placental transporters and the effect of transporter-mediated drug interactions on the risk of congenital anomalies.
      ]. In some other studies, statins were used in the second and third trimesters. Exposure time to statin has not been reported in the study of Toleikyte et al. [
      • Toleikyte I.
      • Retterstøl K.
      • Leren T.P.
      • et al.
      Pregnancy outcomes in familial hypercholesterolemia: a registry-based study.
      ].

      3.4 The qualitative reporting of the results

      3.4.1 Case reports

      In five case reports, in which women were exposed to statins during pregnancy, no congenital malformations were found at birth. However, in the case report by Ghidin et al. [
      • Ghidini A.
      • Sicherer S.
      • Willner J.
      Congenital abnormalities (VATER) in baby born to mother using lovastatin.
      ] a pregnant woman with hypercholesterolemia was exposed to lovastatin and dextroamphetamine sulphate for the first 5 weeks of pregnancy before a taking pregnancy test. No fetal abnormality was detected by prenatal ultrasound examinations. Nevertheless, at birth multiple congenital musculoskeletal abnormalities were detected in the newborn. Dextroamphetamine is rated as category C and lovastatin as category X. Although the drug was taken in a critical period (first trimester), the causal relationship was not proven. However, as previously described, lovastatin might produce skeletal malformations in rats (at amounts 500 times greater than the maximum recommended dose) [
      • Ghidini A.
      • Sicherer S.
      • Willner J.
      Congenital abnormalities (VATER) in baby born to mother using lovastatin.
      ].

      3.4.2 Case series studies

      In a case series study on 178 pregnant women who had been exposed to statins during the first trimester of pregnancy, five severe defects of the central nervous system and five limb deficiencies were observed [
      • Edison R.J.
      • Muenke M.
      Central nervous system and limb anomalies in case reports of first-trimester statin exposure.
      ]. Peterson et al. found based upon 22 cases of birth defects, in which exposure to statins occurred during pregnancy, that the most common anomalies were congenital heart defects and cleft lip with or without cleft palate. In 54.5% of cases, the statin used was atorvastatin [
      • Petersen E.E.
      • Mitchell A.A.
      • Carey J.C.
      • et al.
      Maternal exposure to statins and risk for birth defects: a case‐series approach.
      ]. In 99 prospective and 35 retrospective cases of exposure to lovastatin and simvastatin during pregnancy, Manson et al. found nine cases of congenital abnormalities. There were two cases of central nervous system defects, two reports of limb anomalies, and one hypospadias, one VATER (vertebral anomalies, anal atresia, tracheoesophageal fistula with esophageal atresia, renal and radial dysplasia), one cleft lip, and one trisomy 18 39. The authors have stated that while the number of prospective reports available for evaluation was only sufficient to rule out a three-to fourfold increase in the overall frequency of congenital anomalies, these proportions did not exceed what would be expected in the general population. The findings of another case series showed that the rate of congenital anomalies in the statin group and the general population was not different [
      • Pollack P.S.
      • Shields K.E.
      • Burnett D.M.
      • et al.
      Pregnancy outcomes after maternal exposure to simvastatin and lovastatin.
      ]. McElhatton et al. reported an increased rate of congenital malformations after exposure to statins in the first trimester of pregnancy (4 from 18 live born) [
      • McElhatton P.
      • Stephens S.
      • Wilson G.
      • et al.
      Preliminary data on exposure to statins during pregnancy.
      ]. Brownfoot et al. found no fetal or neonatal abnormalities in four women who were exposed to pravastatin during the second and third trimesters of pregnancy [
      • Brownfoot F.C.
      • Tong S.
      • Hannan N.J.
      • et al.
      Effects of pravastatin on human placenta, endothelium, and women with severe preeclampsia.
      ].

      3.4.3 Cohort studies

      In six cohort studies (n = 889,113), most of which involved statin exposure in the first trimester, there was no difference in birth defects between the group exposed to statin and the control group [
      • Bateman B.T.
      • Hernandez-Diaz S.
      • Fischer M.A.
      • et al.
      Statins and congenital malformations: cohort study.
      ,
      • Taguchi N.
      • Rubin
      • Hosokawa A.
      • et al.
      Prenatal exposure to HMG-CoA reductase inhibitors: effects on fetal and neonatal outcomes.
      ,
      • Winterfeld U.
      • Allignol A.
      • Panchaud A.
      • et al.
      Pregnancy outcome following maternal exposure to statins: a multicentre prospective study.
      ,
      • Botha T.C.
      • Pilcher G.J.
      • Wolmarans K.
      • et al.
      Statins and other lipid-lowering therapy and pregnancy outcomes in homozygous familial hypercholesterolaemia: a retrospective review of 39 pregnancies.
      ,
      • Toleikyte I.
      • Retterstøl K.
      • Leren T.P.
      • et al.
      Pregnancy outcomes in familial hypercholesterolemia: a registry-based study.
      ,
      • Ofori B.
      • Rey E.
      • Bérard A.
      Risk of congenital anomalies in pregnant users of statin drugs.
      ]. The results of a registry-based cohort by Colvin et al. showed that when pregnant women were exposed to atorvastatin and simvastatin in the first trimester, the risk for any congenital anomaly for simvastatin was OR 1.2, 95%CI 0.2–8.9 and for atorvastatin was OR 0.6, 95%CI 0.1–4.6 31. Another cohort study on 379,238 singleton pregnancies found that the percentage of congenital cardiac anomalies in pregnant women who were exposed to statins was higher than those who were not (p = 0.009) [
      • Lee M.-S.
      • Hekimian A.
      • Doctorian T.
      • et al.
      Statin exposure during first trimester of pregnancy is associated with fetal ventricular septal defect.
      ]. McGrogan et al. reported nine anomalies in seven newborns in the statin exposed cohort compared to 49 anomalies in 48 newborns in the control cohort. No details were given on the type of anomalies [
      • McGrogan A.
      • Snowball J.
      • Charlton R.A.
      Statins during pregnancy: a cohort study using the General Practice Research Database to investigate pregnancy loss.
      ].

      3.4.4 Case-control study

      A population-based case-referent study was performed by Daud et al. in 2017 on 4805 live-born cases with congenital anomalies compared to the referent population [
      • Daud A.N.
      • Bergman J.E.
      • Oktora M.P.
      • et al.
      Maternal use of drug substrates of placental transporters and the effect of transporter-mediated drug interactions on the risk of congenital anomalies.
      ]. The results showed that there were no differences between those who were taking statins and the referent population.

      3.4.5 Interventional study

      In a pilot, multicenter, double-blind, placebo-controlled, randomized trial, 21 women at high risk for preeclampsia were assigned to pravastatin (n = 10) and placebo (n = 10) in the second and third trimesters [
      • Costantine M.M.
      • Cleary K.
      • Hebert M.F.
      • et al.
      Safety and pharmacokinetics of pravastatin used for the prevention of preeclampsia in high-risk pregnant women: a pilot randomized controlled trial.
      ]. The results showed that there were no differences between the two groups in rates of congenital anomalies (one hypospadias and one coarctation of the aorta in the intervention group and one polydactyly and one ventriculomegaly in the control group).

      3.5 Results of the meta-analysis

      We analyzed six studies (n = 1,267,240) for the rate of birth defects following maternal exposure to statins. The results indicate that exposure to statins has caused a numerically increased (although not significant) rate of birth defects in sub-group analysis of cardiac anomalies (OR (95%CI) 2.53 (0.81, 7.93), p = 0.112), and other congenital anomalies (OR (95%CI) 1.19 (0.70, 2.03), p = 0.509) (Fig. 2). In the overall analysis, statin use does not increase birth defects (OR (95%CI) 1.48 (0.90, 2.42), p = 0.509) (Fig. 2). Heterogeneity was obtained in the radial plot (I2 = 56.4%, p = 0.025) (Fig. 3). There was no publication bias according to Egger's test (p = 0.263) (Fig. 4).
      Fig. 2
      Fig. 2Forrest plot for odds ratio of rate of birth defects following maternal exposure to statins.
      Fig. 3
      Fig. 3Radial plot for heterogeneity of rate of birth defects following maternal exposure to statins.
      Fig. 4
      Fig. 4Funnel plot for publication bias of rate of birth defects following maternal exposure to statins.

      4. Discussion

      The results of our critical review of case reports, case series studies, cohort studies, a case control study and an interventional study did not suggest a clear-cut answer to the question whether statin treatment during pregnancy is associated with an increased rate of birth defects or not. It has to be stressed that no causality between treatment with statins in pregnancy and birth defects could be clearly proven in any study. The results of our meta-analysis indicate that exposure to statins during pregnancy was not related to an increased rate of birth defects.
      There are only two critical reviews and meta-analyses published so far on the fetal safety of statins, one in 2012 and one in 2014 [
      • Kusters D.M.
      • Lahsinoui H.H.
      • Van De Post J.A.
      • et al.
      Statin use during pregnancy: a systematic review and meta-analysis.
      ,
      • Zarek J.
      • Koren G.
      The fetal safety of statins: a systematic review and meta-analysis.
      ]. The results of the first one indicated that statins were unlikely to be teratogenic, that congenital anomalies in newborns whose mothers were treated with statins during pregnancy were isolated, and that there was no consistent pattern to suggest that a common mechanism could underlie these defects [
      • Kusters D.M.
      • Lahsinoui H.H.
      • Van De Post J.A.
      • et al.
      Statin use during pregnancy: a systematic review and meta-analysis.
      ]. Neither the second report suggested that use of statins in pregnancy might carry teratogenic risk [
      • Zarek J.
      • Koren G.
      The fetal safety of statins: a systematic review and meta-analysis.
      ]. The results of our critical review and meta-analysis, to the best of our knowledge, present the largest and the most comprehensive view on the role of statin in pregnancy, both from case reports and case series, with the validation within meta-analysis of available studies.
      In contrast with the general perception and recommendations that treatment with statins in pregnancy and even in the preconception period should be avoided, most recent data indicate that statins could have beneficial effects in pregnancy. For example, it has been reported recently that statins might protect endothelial function in the mother and placenta thus rescuing fetal cardiovascular dysfunction in complicated pregnancies [
      • Itani N.
      • Skeffington K.L.
      • Beck C.
      • et al.
      Protective effects of pravastatin on the embryonic cardiovascular system during hypoxic development.
      ]. It seems also that statins might be useful (mainly pravastatin) for preventing or treating preeclampsia [
      • Vahedian-Azimi A.
      • Karimi L.
      • Reiner Ž.
      • et al.
      Effects of Statins on Preeclampsia: a Systematic Review.
      ]. The results of animal studies suggest that statins might reduce preterm labor and inhibit myometrial contractions thus preventing preterm birth [
      • Boyle A.K.
      • Rinaldi S.F.
      • Rossi A.G.
      • et al.
      Repurposing simvastatin as a therapy for preterm labor: evidence from preclinical models.
      ]. A case report has been published showing that a statin can reverse an angiogenic/anti-angiogenic imbalance and prevent fetal death in massive perivillous fibrin deposition of the placenta (MPFD) or maternal floor infarction (MFI), which is a serious condition associated with recurrent complications including fetal death and severe fetal growth restriction [
      • Kozłowski S.
      • Lipa M.
      • Lipa J.
      • et al.
      An experimental administration of pravastatin in patient with previous, multiple pregnancy losses.
      ]. It seems, therefore, that potential beneficial pleiotropic effects (besides those LDL-C lowering) of treatment with statins in pregnancy, which still have to be proven on a larger number of cases, might even outweigh the potential risks of possible teratogenic effects of these drugs, which were not clearly proven in any analysis, including this meta-analysis. Based on this, it seems that statins might be reconsidered to be used, especially in very high-risk CVD pregnant women, and especially in those with HoFH and HeFH with severe hypercholesterolemia, where the disease itself might be dangerous both for the mother and fetus, and only when the benefit outweighs the risk. Based on available data, it also seems that statin might have some additional beneficial effects, especially in the late 3rd trimester [
      • Maierean S.M.
      • Mikhailidis D.P.
      • Toth P.P.
      • et al.
      The potential role of statins in preeclampsia and dyslipidemia during gestation: a narrative review.
      ].
      In this study, it was shown that statin therapy has no effect on the development of fetal abnormalities. However, due to the fact that teratogenic factors have different effects depending upon the dose, route of exposure, duration of exposure, as well as individual conditions, statin treatment during pregnancy cannot be explicitly proven to be harmless. Since pregnancy and care during this period are very important for the health and development of the fetus and newborn, pregnant women should refrain from taking drugs arbitrarily and excessively during this period. Planning prevention, as well as education, to avoid the arbitrary use of herbal and synthetic drugs and exposure to factors whose risk is not clearly identified during pregnancy seems to be necessary.
      The present meta-analysis, while being the largest thus far, is limited by lack of sufficient evidence from large-scale prospective cohorts and interventional studies. Moreover, there is a lack of data on direct comparison of different statins as their impact on fetal health and birth defects. Another limitation of this study was that not enough data was available to take into account statin doses, which may have a major impact on this issue. Furthermore, recently some combined drugs, which contain statin and other lipid-lowering drugs, such as fenofibrate and ezetimibe are available. Effects of these drugs, as well as other novel lipid-lowering medications [
      • Filippatos T.D.
      • Liontos A.
      • Christopoulou E.C.
      • et al.
      Novel hypolipidaemic drugs: mechanisms of action and main metabolic effects.
      ,
      • Sahebkar A.
      • Watts G.F.
      New therapies targeting apoB metabolism for high-risk patients with inherited dyslipidaemias: what can the clinician expect?.
      ], during pregnancy should be carefully evaluated. There is also lacking evidence of any long-term effect of statin use during pregnancy on the growth and development of the neonate. Finally, the potential benefits of statin use in pregnant mothers with FH needs further investigations.
      In conclusion, the results of this meta-analysis indicate that treatment with statins during pregnancy is not linked to a significant increase in the rate of birth defects.

      CRediT authorship contribution statement

      Amir Vahedian-Azimi: conceived the study, prepared the first draft of manuscript. Somayeh Makvandi: prepared the first draft of manuscript. Željko Reiner: conceived the study, prepared the first draft of manuscript, supervised this study, critically revised the draft manuscript and the revised version, supervised this study. responsible for the submission of this paper and the revised version. Amirhossein Sahebkar: critically revised the draft manuscript and the revised version. All authors approved the final version for submission.

      Declaration of competing interest

      The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: MB - speakers bureau: Abbott/Mylan, Abbott Vascular, Actavis, Akcea, Amgen, Biofarm, KRKA, MSD, Polpharma, Sanofi-Aventis, Servier and Valeant; consultant to Abbott Vascular, Akcea, Amgen, Daichii Sankyo, Esperion, Freia Pharmaceuticals, Lilly, MSD, Polfarmex, Resverlogix, Sanofi-Aventis; Grants from Sanofi and Valeant. ZR has received honoraria from Sanofi-Aventis; MK has received honoraria (for lectures and consultancy) from Abbott and Menarini, and research funding from Amryt Pharma, Amgen, and Sanofi, and has participated in clinical trials with Amgen, Medicines Company, Regeneron, and Sanofi within the last 2 years. All other authors have nothing to disclose.

      Acknowledgments

      The authors thank the guidance and advice from the Clinical Research Development Unit of Baqiyatallah Hospital. We are also thankful for the financial support from the Mashhad University of Medical Sciences, Mashhad, Iran , the National Institute for Medical Research Development (NIMAD), Tehran, Iran (Grant no: 964334 ) and the National Iran Science Foundation (Grant no: 99014887 ).

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