A 31-year-old female patient with newly diagnosed hypercholesterolemia presents to the preventive cardiology clinic for new patient consultation. Approximately six months ago, she had her lipid levels measured as part of her annual physical and her low-density lipoprotein cholesterol (LDL-C) was elevated at 318 mg/dL (on no medical therapy). She has no other medical comorbidities. She is a non-smoker, and drinks approximately two alcoholic beverages twice monthly. She remains physically active, regularly participating in belly-dancing classes twice a week without any physical limitations. She reports that her father also had markedly elevated cholesterol levels and sustained his first myocardial infarction (MI) at the age of 36.
She had an uncomplicated first pregnancy and has a healthy three-year-old daughter. She has since had two miscarriages. On physical exam her vital signs are within normal limits. Physical exam is significant only for corneal arcus. Her body mass index (BMI) is 23 kg/m2. She continues to take an oral contraceptive and for the last six months has been on rosuvastatin 20 mg daily. Her lipid panel immediately prior to her current visit and relevant laboratory studies are shown below:
Total Cholesterol 248 mg/dL
Triglycerides 179 mg/dL
HDL-C 45 mg/dL
LDL-C 162 mg/dL
AST /ALT WNL
Normal sinus rhythm, no concerning ST/T abnormalities
The patient desires to get pregnant. What is the most reasonable method to manage her lipid levels during her pregnancy?
The correct answer is: D. Stop her statin, begin colesevelam and refer her to a dietician.
Our patient likely has heterozygous familial hypercholesterolemia (FH). The Simon Broome Register Group in the United Kingdom has outlined one set of clinical criteria for the diagnosis of possible FH. According to their guidelines, adults must have total cholesterol greater than 290 mg/dL OR LDL-C greater than 189 mg/dL AND at least one of the following: a family history of early MI (younger than 60 years old in a first-degree relative or younger than 50 years old in a second-degree relative), OR a family history of raised total cholesterol (greater than 290 mg/dL in an adult first or second degree relative or greater than 259 mg/dL in a child or sibling under 16 years old).1 Definitive diagnosis of FH calls for elevated lipid levels as above, plus tendon xanthomas in the patient or a first- or second-degree relative or DNA-based evidence of an LDL receptor mutation (familial defective apo B-100, or a PCSK9 mutation).
Hypercholesterolemia and hypertriglyceridemia of pregnancy are not unique to those with FH. Serum cholesterol levels can increase by as much as 25% to 50%, and triglyceride (TG) levels can double during the third trimester of pregnancy.1 Although the relative increase in TC and TG levels is about the same in those with FH compared with unaffected individuals, the absolute serum concentrations are usually much greater in those with FH.9 One contributing mechanism to explain the increase in cholesterol during pregnancy is thought to be increased cholesterol synthesis in the liver as the result of increased estrogen.9 Cholesterol synthesis up-regulation during pregnancy may be attributable to an increased need for sex steroid production and to possibly help maintain adequate nutrition for the mother and fetus.3
Current guidelines recommend that all adult patients with FH receive long-term cholesterol lowering therapy to reduce LDL-C levels by ≥ 50%.2 Achieving this goal usually requires the use of statin therapy. However, the use of statins is contraindicated during pregnancy and lactation (Category X). Animal studies have shown conflicting evidence on the teratogenicity of statins during pregnancy.2 While there is limited data on the teratogenicity of other lipid-lowering agents, ezetimibe, nicotinic acid, and fibrates have all been associated with teratogenic effects in animal studies.2 Therefore, the only current medications acceptable to use during pregnancy are the bile acid binding resins, cholestyramine and colesevelam, as these medications do not pass into the systemic circulation and have not been shown to have any adverse effects thus far.4
Current National Institute of Clinical Excellence (NICE) guidelines recommend that all women stop taking statins three months prior to attempting to conceive. Women who become pregnant while taking a statin or other systemically absorbed lipid-modifying agent, should be instructed to stop treatment immediately and be referred to an obstetrician for urgent fetal assessment.14 The guidelines do not recommend routinely checking cholesterol levels during pregnancy as cholesterol levels will increase and the use of most lipid-modifying agents are contraindicated.5 The effects of elevated cholesterol during pregnancy on the mother and fetus need further exploration with longitudinal studies that include an FH cohort. It has been suggested that maternal hyperlipidemia may induce acute atherosis in the uteroplacental spiral arteries that together with hypercoagulation, may result in local thrombosis and placental infarctions, leading to placental insufficiency and subsequent fetal compromise.6,7 This may explain why women with FH seem to have a lesser gestational decrease in uteroplacental vascular resistance than healthy pregnant women.8 Some studies, however, have shown no difference in actual pregnancy outcomes between those with FH and normal individuals despite having much higher serum cholesterol levels.9 Women with FH could be at increased risk for hypertensive disease during pregnancy because there is a link between preeclampsia and hypercholesterolemia.3
There is concern that exposing these women to higher cholesterol levels for several months to years without effective treatment during pregnancy and lactation may predispose them to develop premature cardiovascular disease. There is also some concern that exposing the fetus to high cholesterol levels may increase their cardiovascular risk in the future. Several autopsy studies have shown larger pre-atherosclerotic lesions and faster progression of lesions in offspring of hypercholesterolemic mothers as compared to normal mothers.3 Interestingly, offspring who had a maternal mode of FH transmission had slightly higher lipid levels later in life than those with a paternal inheritance.10
Diet modifies fetoplacental circulation. A low cholesterol, low saturated fat diet was associated with a greater decrease in the pulsatility index of the uterine artery and a prominent reduction in the incidence of preterm delivery (<37 weeks) in healthy pregnant women.11 Affected women should be encouraged to follow a cholesterol restricted diet during pregnancy because both cholesterol free diets (<50 mg/day) and cholesterol restricted diets (<300 mg/day) have been shown to decrease LDL-C levels, but do not have an effect on triglyceride levels.6 Of note, there are case reports that describe successful use of LDL apheresis in pregnant women largely with homozygous FH.12,13
DeMott K, Nherera L, Humphries SE, et al. Clinical Guidelines and Evidence Review for Familial hypercholesterolaemia: the identification and management of adults and children with familial hypercholesterolaemia. London: National Collaborating Centre for Primary Care and Royal College of General Practitioners, 2008.
Robinson JG, Goldberg AC. Treatment of adults with familial hypercholesterolemia and evidence for treatment: recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. Journal of Clinical Lipidology 2011;5:S18–S29.
Kusters DM, Homsma SJM, Hutten BA, et al. Dilemmas in treatment of women with familial hypercholesterolaemia during pregnancy. Netherlands Journal of Medicine 2010;68(1):299-303.
Avis HJ, et al. Pregnancy in women suffering from familial hypercholesterolemia: a harmful period for both mother and newborn. Curr Opin Lipidol 2009;20:484–49.
Thorogood M, Seed M, De Mott K, on behalf of the Guideline Development Group. Management of fertility in women with familial hypercholesterolemia: summary of NICE guidance. BJOG. 2009;116:478-9.
Robertson WB, Brosens I, Dixon G. Maternal uterine vascular lesions in the hypertensive complications of pregnancy. Perspect Nephrol Hypertens 1976;5:115-27.
De WF, Brosens I, Renaer M. Fetal growth retardation and the maternal arterial supply of the human placenta in the absence of sustained hypertension. Br J Obstet Gynaecol 1980;87:678-85.
Khoury J, Amundsen AL, Tonstad S, et al. Evidence for impaired physiological decrease in the uteroplacental vascular resistance in pregnant women with familial hypercholesterolemia. Acta Obstetricia et Gynecologica 2009; 88:222-6.
Amundsen AL, Khoury J, Iversen PO, et al. Marked changes in plasma lipids and lipoproteins during pregnancy in women with familial hypercholesterolemia. Atherosclerosis 2006;189:451-7.
Van der Graaf A, Vissers MN, Gaudet D, et al. Dyslipidemia of mothers with familial hypercholesterolemia deteriorates lipids in adult offspring. Arterioscler Thromb Vasc Biol 2010;30(12):2673-7.
Khoury J, Haugen G, Tonstad S, et al. Effect of a cholesterol-lowering diet during pregnancy on maternal and fetal Doppler velocimetry: the CARRDIP study. Am J Obstet Gynecol 2007;196:549–57.
Kroon AA, Swinkels DW, van Dongen PW, Stalenhoef AF. Pregnancy in a patient with homozygous familial hypercholesterolemia treated with long-term low-density lipoprotein apheresis. Metabolism 1994;43(9):1164-70.
Anedda S, et. al. HELP LDL-apheresis in two cases of familial hypercholesterolemic pregnant women Transfusion and Apheresis Science 2011;44:21-24
Eapen DJ, Valiani K, Reddy S, Sperling L. Management of familial hypercholesterolemia during pregnancy: case series and discussion. J Clin Lipidol 2012;6(1):88-91.