Statins and other lipid-lowering therapy and pregnancy outcomes in homozygous familial hypercholesterolaemia: A retrospective review of 39 pregnancies

  • Theunis C. Botha
    Corresponding author.
    Department of Medicine, Faculty of Health Sciences, University of the Witwatersrand, Private Bag 3, WITS, 2050, Johannesburg, South Africa
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  • Gillian J. Pilcher
    Carbohydrate & Lipid Metabolism Research Unit, Department of Medicine, Faculty of Health Sciences, University of the Witwatersrand, Private Bag 3, WITS, 2050, Johannesburg, South Africa
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  • Karen Wolmarans
    Division of Lipidology, Department of Medicine, Faculty of Health Sciences, University of Cape Town, 5th Floor Chris Barnard Building, Anzio Road Observatory, 7925, Cape Town, South Africa
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  • Dirk J. Blom
    Division of Lipidology, Department of Medicine, Faculty of Health Sciences, University of Cape Town, 5th Floor Chris Barnard Building, Anzio Road Observatory, 7925, Cape Town, South Africa
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  • Frederick J. Raal
    Carbohydrate & Lipid Metabolism Research Unit, Department of Medicine, Faculty of Health Sciences, University of the Witwatersrand, Private Bag 3, WITS, 2050, Johannesburg, South Africa
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      • Statin exposure during pregnancy might not be as detrimental to the fetus as previously thought.
      • Pregnancy complications in homozygous familial hypercholesterolaemia patients did not differ from healthy woman.
      • Birth weights between statin exposed and non-exposed pregnancies was similar.
      • No severe skeletal abnormalities or developmental delay occurred in statin exposed fetusses.


      Background and aims

      Pregnancy in HoFH females is associated with further elevation of already markedly elevated low density lipoprotein cholesterol (LDL-C) levels, particularly if lipid-lowering therapy is discontinued, placing the mother and fetus at increased cardiovascular risk. Lipoprotein apheresis is the current recommended treatment for pregnant HoFH patients. However, this is costly, time consuming, and is not available in many countries. Alternative treatment strategies to control hypercholesterolaemia during pregnancy in HoFH patients are necessary.


      This study was a retrospective review of 39 pregnancies from a cohort of 20 genotypically confirmed female HoFH patients.


      No maternal cardiac complications or deaths occurred during the pregnancies or during the first year postpartum. Twenty five pregnancies were exposed to lipid-lowering therapy, of which 18 were exposed to statin therapy, just prior to or during the pregnancy. Thirty three (84%) pregnancies carried to term, 3 (8%) premature deliveries and 3 (8%) miscarriages were observed. Complications associated with pregnancy in these HoFH patients, did not differ from those reported during pregnancies of otherwise healthy woman.


      HoFH is a severe disease impacting significantly on life expectancy. However, for many females with HoFH, despite the high cardiovascular risk, pregnancy is not uncommon. In resource poor settings and when LA is not available, lipid lowering therapy, particularly statin therapy during pregnancy, appears to be safe for both mother and fetus and is an acceptable alternative for LDL-C reduction in these high risk patients.


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        • Nordestgaard B.G.
        • Chapman M.J.
        • Humphries S.E.
        • Ginsberg H.N.
        • Masana L.
        • et al.
        Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European atherosclerosis society.
        Eur. Heart J. 2013; 34: 3478-3490a
        • Goldstein J.
        • Hobbs H.
        • Brown M.
        The Metabolic and Molecular Bases of Inherited Disease. McGraw-Hill Information Services Company, New York2001: 2863-2913
        • Seftel H.C.
        • Baker S.G.
        • Sandler M.P.
        • Forman M.B.
        • Joffe B.I.
        • et al.
        A host of hypercholesterolaemic homozygotes in South Africa.
        Br. Med. J. 1980; 281: 633-636
        • Raal F.J.
        • Santos R.D.
        Homozygous familial hypercholesterolemia: current perspectives on diagnosis and treatment.
        Atherosclerosis. 2012; 223: 262-268
        • Rallidis L.
        • Nihoyannopoulos P.
        • Thompson G.R.
        Aortic stenosis in homozygous familial hypercholesterolaemia.
        Heart. 1996; 76: 84-85
      1. Women with FH & Pregnancy. FH Foundation, 2018 (The FH Foundation)
        • Avis H.J.
        • Hutten B.A.
        • Twickler M.T.
        • Kastelein J.J.
        • van der Post J.A.
        • et al.
        Pregnancy in women suffering from familial hypercholesterolemia: a harmful period for both mother and newborn?.
        Curr. Opin. Lipidol. 2009; 20: 484-490
        • Napoli C.
        • D'Armiento F.P.
        • Mancini F.P.
        • Postiglione A.
        • Witztum J.L.
        • et al.
        Fatty streak formation occurs in human fetal aortas and is greatly enhanced by maternal hypercholesterolemia. Intimal accumulation of low density lipoprotein and its oxidation precede monocyte recruitment into early atherosclerotic lesions.
        J. Clin. Invest. 1997; 100: 2680-2690
        • Napoli C.
        • Glass C.K.
        • Witztum J.L.
        • Deutsch R.
        • D'Armiento F.P.
        • et al.
        Influence of maternal hypercholesterolaemia during pregnancy on progression of early atherosclerotic lesions in childhood: fate of Early Lesions in Children (FELIC) study.
        Lancet. 1999; 354: 1234-1241
        • Raal F.J.
        • Pilcher G.J.
        • Illingworth D.R.
        • Pappu A.S.
        • Stein E.A.
        • et al.
        Expanded-dose simvastatin is effective in homozygous familial hypercholesterolaemia.
        Atherosclerosis. 1997; 135: 249-256
        • Raal F.J.
        • Pappu A.S.
        • Illingworth D.R.
        • Pilcher G.J.
        • Marais A.D.
        • et al.
        Inhibition of cholesterol synthesis by atorvastatin in homozygous familial hypercholesterolaemia.
        Atherosclerosis. 2000; 150: 421-428
        • Raal F.J.
        • Pilcher G.J.
        • Panz V.R.
        • van Deventer H.E.
        • Brice B.C.
        • et al.
        Reduction in mortality in subjects with homozygous familial hypercholesterolemia associated with advances in lipid-lowering therapy.
        Circulation. 2011; 124: 2202-2207
        • Gagne C.
        • Gaudet D.
        • Bruckert E.
        Efficiency and safety of ezetimibe coadministered with atorvastatin or simvastatin in patients with homozygous familial hypercholesterolaemia.
        Circulation. 2002; 105: 2469-2475
        • Edison R.J.
        • Muenke M.
        Mechanistic and epidemiologic considerations in the evaluation of adverse birth outcomes following gestational exposure to statins.
        Am. J. Med. Genet. 2004; 131: 287-298
        • Bateman B.T.
        • Hernandez-Diaz S.
        • Fischer M.A.
        • Seely E.W.
        • Ecker J.L.
        • et al.
        Statins and congenital malformations: cohort study.
        BMJ. 2015; 350: h1035
        • Manson J.M.
        • Freyssinges C.
        • Ducrocq M.B.
        • Stephenson W.P.
        Postmarketing surveillance of lovastatin and simvastatin exposure during pregnancy.
        Reprod. Toxicol. 1996; 10: 439-446
        • Petersen E.E.
        • Mitchell A.A.
        • Carey J.C.
        • Werler M.M.
        • Louik C.
        • et al.
        Maternal exposure to statins and risk for birth defects: a case-series approach.
        Am. J. Med. Genet. 2008; 146A: 2701-2705
        • Pollack P.S.
        • Shields K.E.
        • Burnett D.M.
        • Osborne M.J.
        • Cunningham M.L.
        • et al.
        Pregnancy outcomes after maternal exposure to simvastatin and lovastatin.
        Birth Defects Res. Part A Clin. Mol. Teratol. 2005; 73: 888-896
      2. Zetia® (Ezetimibe) Tablets [product Information]. Merck/Schering-Plough Pharmaceuticals, North Wales, Pa2002
        • Gouni-Berthold I.
        • Berthold H.K.
        Mipomersen and lomitapide: two new drugs for the treatment of homozygous familial hypercholesterolemia.
        Atherosclerosis Suppl. 2015; 18: 28-34
      3. REPATHA® (Evolocumab) Subcutaneous Injection [product Information]. Amgen Inc, California2017
        • Ogura M.
        • Makino H.
        • Kamiya C.
        • Yoshimatsu J.
        • Soran H.
        • et al.
        Lipoprotein apheresis is essential for managing pregnancies in patients with homozygous familial hypercholesterolemia: seven case series and discussion.
        Atherosclerosis. 2016; 254: 179-183
        • Genest J.
        • Hegele R.A.
        • Bergeron J.
        • Brophy J.
        • Carpentier A.
        • et al.
        Canadian Cardiovascular Society position statement on familial hypercholesterolemia.
        Can. J. Cardiol. 2014; 30: 1471-1481
        • Bambauer R.
        • Schiel R.
        • Latza R.
        Low-density lipoprotein apheresis: an overview.
        Ther. Apher. Dial. 2003; 7: 382-390
        • Makino H.
        • Harada-Shiba M.
        Long-term effect of low-density lipoprotein apheresis in patients with homozygous familial hypercholesterolemia.
        Ther. Apher. Dial. 2003; 7: 397-401
        • Stefanutti C.
        • Mazza F.
        • Pasqualetti D.
        • Di Giacomo S.
        • Watts G.F.
        • et al.
        Lipoprotein apheresis downregulates IL-1alpha, IL-6 and TNF-alpha mRNA expression in severe dyslipidaemia.
        Atherosclerosis Suppl. 2017; 30: 200-208
        • Rosada A.
        • Kassner U.
        • Banisch D.
        • Bender A.
        • Steinhagen-Thiessen E.
        • et al.
        Quality of life in patients treated with lipoprotein apheresis.
        J. Clin. Lipidol. 2016; 10 (323–329 e326)
        • Betran A.P.
        • Ye J.
        • Moller A.B.
        • Zhang J.
        • Gulmezoglu A.M.
        • et al.
        The increasing trend in caesarean section rates: global, regional and national estimates: 1990-2014.
        PLoS One. 2016; 11 (e0148343)
        • Regan L.
        • Rai R.
        Epidemiology and the medical causes of miscarriage, Bailliere's best practice & research.
        Clin. Obstet. Gynaecol. 2000; 14: 839-854
        • Quinn J.A.
        • Munoz F.M.
        • Gonik B.
        • Frau L.
        • Cutland C.
        • et al.
        Preterm birth: case definition & guidelines for data collection, analysis, and presentation of immunisation safety data.
        Vaccine. 2016; 34: 6047-6056
        • Blencowe H.
        • Cousens S.
        • Oestergaard M.Z.
        • Chou D.
        • Moller A.-B.
        • et al.
        National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications.
        Lancet. 2012; 379: 2162-2172
        • Toleikyte I.
        • Retterstol K.
        • Leren T.P.
        • Iversen P.O.
        Pregnancy outcomes in familial hypercholesterolemia: a registry-based study.
        Circulation. 2011; 124: 1606-1614
        • Fahed A.C.
        • Nassar A.H.
        Pregnancy in a woman with homozygous familial hypercholesterolemia not on low-density lipoprotein apheresis.
        AJP reports. 2012; 2: 33-36
        • Henck J.W.
        • Craft W.R.
        • Black A.
        • Colgin J.
        • Anderson J.A.
        Pre- and postnatal toxicity of the HMG-CoA reductase inhibitor atorvastatin in rats.
        Toxicol. Sci. 1998; 41: 88-99
        • Schutte A.E.
        • Symington E.A.
        • du Preez J.L.
        Rosuvastatin is transferred into human breast milk: a case report.
        Am. J. Med. 2013; 126 (e7-8)
        • Christensen J.J.
        • Retterstol K.
        • Godang K.
        • Roland M.C.
        • Qvigstad E.
        • et al.
        LDL cholesterol in early pregnancy and offspring cardiovascular disease risk factors.
        J. Clin. Lipidol. 2016; 10 (e1367): 1369-1378
        • van der Graaf A.
        • Vissers M.N.
        • Gaudet D.
        • Brisson D.
        • Sivapalaratnam S.
        • et al.
        Dyslipidemia of mothers with familial hypercholesterolemia deteriorates lipids in adult offspring.
        Arterioscler. Thromb. Vasc. Biol. 2010; 30: 2673-2677
        • Elahi M.M.
        • Matata B.M.
        Effects of maternal high-fat diet and statin treatment on bone marrow endothelial progenitor cells and cardiovascular risk factors in female mice offspring fed a similar diet.
        Nutrition. 2017; 35: 6-13
        • Descamps O.S.
        • Tenoutasse S.
        • Stephenne X.
        • Gies I.
        • Beauloye V.
        • et al.
        Management of familial hypercholesterolemia in children and young adults: consensus paper developed by a panel of lipidologists, cardiologists, paediatricians, nutritionists, gastroenterologists, general practitioners and a patient organization.
        Atherosclerosis. 2011; 218: 272-280
        • France M.
        • Rees A.
        • Datta D.
        • Thompson G.
        • Capps N.
        • et al.
        HEART UK statement on the management of homozygous familial hypercholesterolaemia in the United Kingdom.
        Atherosclerosis. 2016; 255: 128-139
        • Robinson J.
        • Goldberg A.
        Treatment of adults with familial hypercholesteroleamia and evidence for treatment: recommendations from the national lipid association expert panel on familial hypercholesterolaemia.
        J. Clin. Lipidol. 2011; 5: S18-S29
        • Goldberg A.C.
        • Hopkins P.N.
        • Toth P.P.
        • Ballantyne C.M.
        • Rader D.J.
        • et al.
        Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients: clinical guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia.
        J. Clin. Lipidol. 2011; 5: S1-S8
        • Wang A.
        • Richhariya A.
        • Gandra S.R.
        • Calimlim B.
        • Kim L.
        • et al.
        Systematic review of low-density lipoprotein cholesterol apheresis for the treatment of familial hypercholesterolemia.
        J. Am. Heart Assoc. 2016; 5e003294
        • Khoo K.L.
        • Page M.M.
        • Liew Y.M.
        • Defesche J.C.
        • Watts G.F.
        Ten years of lipoprotein apheresis for familial hypercholesterolemia in Malaysia: a creative approach by a cardiologist in a developing country.
        J. Clin. Lipidol. 2016; 10: 1188-1194
        • Avis H.J.
        • Vissers M.N.
        • Stein E.A.
        • Wijburg F.A.
        • Trip M.D.
        • et al.
        A systematic review and meta-analysis of statin therapy in children with familial hypercholesterolemia.
        Arterioscler. Thromb. Vasc. Biol. 2007; 27: 1803-1810
        • Masana L.
        • Girona J.
        • Ibarretxe D.
        • Rodriguez-Calvo R.
        • Rosales R.
        • et al.
        Clinical and pathophysiological evidence supporting the safety of extremely low LDL levels-The zero-LDL hypothesis.
        J. Clin. Lipidol. 2018; : 292-299