Familial Hypercholesterolemia and Pregnancy

Familial hypercholesterolemia (FH) is an autosomal dominant genetic defect that is strongly associated with premature coronary artery disease (CAD). Currently four genes are known to result in the phenotype of FH when affected by a mutation: the low-density lipoprotein receptor (LDLR); apolipoprotein B (ApoB); LDLR adaptor protein 1 (LDLRAP1) and proprotein convertase subtilisin/kexin type 9 (PCSK9). Homozygous FH (HoFH) carriers have extremely high levels of low-density lipoprotein cholesterol (LDL-C) at birth and evidence of CAD very early in life and, if untreated, early mortality as young as 30 years of age.1 Heterozygous FH (HeFH) carriers are much more common than previously thought and may be as common as 1 in 250 people.2 FH is associated with a 2.5 to 10-fold increased risk of heart disease.1 It is estimated that 90% of FH carriers are still undiagnosed.3 The diagnosis of FH is based on family history of premature CAD and levels of LDL-C over 190 mg/dL in adults and over 160 mg/dL in children.1 FH is found in all races and equally in both genders.

Women with FH face unique lifetime risks given that they are unable to remain on cholesterol reduction therapy with statins during pregnancy. All childbearing-age women with FH on lipid lowering therapy should receive pre-pregnancy counseling as well as contraception advice. The preferred methods for contraception in women with FH are low-dose estrogen oral agents, intrauterine devices and barrier techniques, although in women older than 35 years of age the latter two methods are preferable.4 Early diagnosis of FH in women with early medical intervention is critical to reducing risks of cardiovascular disease (CVD) events long-term. When a non-pregnant woman is diagnosed with FH, aggressive medical management with statins, cholesterol absorption inhibitors and possibly PCSK9 inhibitors are advised to reduce LDL-C to normal levels. Women with FH need counseling on risk reduction and management with particular attention on therapy during pre-conception, pregnancy, childbirth and lactation. With early identification of FH in women and proper planning, most women with FH can have healthy pregnancies and healthy children.

While statins are very effective in lowering LDL-C levels, they are contraindicated during pregnancy and lactation. Non-statins such as ezetimibe, niacin and fibrates have also been associated with teratogenicity and are therefore not indicated during pregnancy. PCSK9 inhibitors have not been tested for safety during pregnancy and are not currently approved during pregnancy. The only medications currently acceptable during pregnancy are bile acid sequestrants,1 since they are not systemically absorbed and therefore not felt to pose fetal risk. Use is limited due to side effects of elevated triglycerides and constipation. Mipomersen, an antisense inhibitor of APoB synthesis, is an injection that may be considered during pregnancy in HoFH women.5 Lomitapide, in capsule form, is contraindicated during pregnancy as there is a risk of embryo-fetal toxicity. Lipoprotein apheresis is also approved during pregnancy and considered safe for very high risk women with known significant atherosclerotic disease or HoFH.1 Healthy lifestyle with low-fat, low-cholesterol diet and routine exercise are strongly recommend before, during and after pregnancy.

When a woman with FH is ready to conceive, statins, ezetimibe and niacin should be stopped at least 4 weeks prior to discontinuing contraception according to the NLA recommendations for FH,1 whereas others recommend discontinuing statins approximately three months prior to attempting conception.4,6 Women who become pregnant while on statin therapy should stop the statin immediately and undergo fetal assessment with a maternal-fetal specialist as soon as possible.1 These women who accidentally become pregnant on statin therapy may also be reassured that the likelihood is low for fetal complications.4 More recent observational studies reviewing multiple clinical studies and case reports did not report an increased risk of congenital anomalies with statin exposure in pregnancy when compared to control groups or the prevalence of congenital anomalies in the general population.7

Women with FH may have more conditions associated with pregnancy-related complications such as diabetes, hypertension disorders, renal dysfunction and polycystic ovarian syndrome, which is also associated with infertility. Women with FH have similar fertility rates compared to women without FH.8 Women with FH who receive fertility treatments should be followed closely by their cardiologist or lipid specialist as these drugs can increase cholesterol and triglyceride levels. Some studies suggest that women with FH are also more likely to have preeclampsia during pregnancy. Emerging information suggests that pravastatin may reduce the risk for preeclampsia in high-risk women; however, larger clinical trials are necessary.9,10

During pregnancy in the general population, total cholesterol can increase 25 to 50% while LDL-C can increase up to 66%. Triglycerides can increase up to 200 to 400% during pregnancy.11 Women with FH already have significantly elevated cholesterol levels at baseline and can see tremendous elevations during pregnancy, which drive the recommendation for women to start statin therapy early after the diagnosis of FH and then withhold statin therapy during attempts at conception and while pregnant or lactating. After a woman stops breastfeeding, she should resume her statin therapy or PCSK9 inhibitor until her next planned pregnancy. Women and their physicians should discuss the risk of delaying cholesterol therapy while breastfeeding against the length of time she plans to breastfeed. Breastfeeding tends to improve both blood glucose levels and lipid profile. A recent commentary on statins and breastfeeding in FH suggests that the practice of withholding statin therapy during breastfeeding in women with FH should be reconsidered as there are natural benefits to breastfeeding for the mother and the newborn.12 Also, there may be limited risk of the statins in the breast milk as statins are cleared in the liver and have minimal pharmacologic effect on the child. It is not known whether lomitapide or mipomersen are excreted in breast milk.

Pregnancy in women with FH and no atherosclerotic CVD is relatively safe. However, women with FH and previous myocardial infarction, myocardial ischemia or left ventricular dysfunction should have counseling on risk of CVD during pregnancy. There is no increase in risk of preterm delivery, low birth weight or congenital malformation in infants born to women with FH. There is also no increased risk for preeclampsia, gestational diabetes or pregnancy-induced hypertension in pregnant women with FH.8

Women with HoFH will pass the FH gene to all their children who will be HeFH carriers if the father is not a FH carrier. Women with HeFH have a 50% chance of passing the FH gene to each child if the father is not a FH carrier; preconception genetic counselling can be considered. FH is one of the most common genetic disorder found in children.13 All children of FH mothers should undergo lipid screening by age 2. FH cascade screening is extremely important in all families with FH and all patients with FH are encouraged to join a FH registry. Serial single-gene testing involves sequence analysis of LDLR first followed by LDLR deletion/duplication analysis if no pathogenic variant is found. If no pathogenic variant is still found, sequence analysis of APoB and PCSK9 can be performed next. An alternative testing method is a multi-gene panel that includes APoB, LDLR, PCSK9 and other genes of interest.14 Children with FH on a heart-healthy diet could be started on statin therapy as early as age 8-10 years.1,4

On a side note, autosomal recessive hypercholesterolemia (ARH) shares clinical similarities with HoFH due to LDLRAP1 gene mutations. A recent study of mostly Italian patients showed significant premature atherosclerotic cardiovascular disease (ASCVD) and aortic stenosis. This study showed that treated ARH patients had a 6-fold increased risk of ASCVD in men but a 19-fold increased risk of ASCVD in women. Also, the ASCVD outcomes were worse in this population if treatment was started after the age of 30 years.15 There was no information provided on pregnancy in these ARH females, but limitations in lipid treatment during pregnancy would be similar to those with FH.

FH can be safely managed during pregnancy. The decision to have children and duration of breastfeeding are personal choices for each woman and these choices need to be individually examined by her health care providers. FH women are best managed by a care team with experts in lipids, pregnancy and CVD. Cardiologists, lipidologists, obstetricians and genetic counsellors need to collaborate and plan ahead for a successful pregnancy for the woman, her infant and her family.

References

  1. Goldberg AC, Hopkins PN, Toth PP, 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:S1-8.
  2. de Ferranti SD, Rodday AM, Mendelson MM, Wong JB, Leslie LK, Sheldrick RC. Prevalence of familial hypercholesterolemia in the 1999 to 2012 United States National Health and Nutrition Examination Surveys (NHANES). Circulation 2016;133:1067-72.
  3. Nordestgaard BG, Chapman MJ, Humphries SE, et al. Familal 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;34:3478-90a.
  4. Watts GF, Gidding S, Wierzbicki AS, et al. Integrated guidance on the care of familial hypercholesterolemia from the International FH Foundation. J Clin Lipidol 2014;8:148-72.
  5. Jcobson TA, Maki KC, Orringer CE, et al. National Lipid Association: recommendations for patient-centered management of dyslipidemia: part 2. J Clin Lipidol 2015;9:S1-122.
  6. Wierzbicki AS, Humphries SE, Minhas R, Guideline Development Group. Familial hypercholesterolaemia: summary of NICE guidelines. BMJ 2008;337:a1095.
  7. Karalis DG, Hill AN, Clifton S, Wild RA. The risks of statin use in pregnancy: a systematic review. J Clin Lipidol 2016;10:1081-90.
  8. Toleikyte I, Rettterstol K, Leren TP, Iversen PO. Pregnancy outcomes in familial hypercholesterolemia: a registry-based study. Circulation 2011;124:1606-14.
  9. Constantine MM, Cleary K, Eunice Kennedy Shriver National Institute of Child Health and Human Development Obstetric-Fetal Pharmacology Research Units Network. Obstet Gynecol 2013;121:349-53.
  10. Katsi V, Georgountzos G, Kallistratos MS, et al. The role of statins in prevention of preeclampsia: a promise for the future? Front Pharmacol 2017;8:247.
  11. Eapen DJ, Valian K, Reddy S, Sperling L. Management of familial hypercholesterolemia during pregnancy: case series and discussion. J Clin Lipidol 2012;6:88-91.
  12. Holmsen ST, Bakkebo T, Seferowicz M, Retterstol K. Statins and breastfeeding in familial hypercholesterolaemia. Tidsskr Nor Laegeforen 2017;137:686-7.
  13. De Castro-Oros I, Pocovi M, Civeira F. The genetic basis of familial hypercholesterolemia: inheritance, linkage, and mutations. Appl Clin Genet 2010;3:53-64.
  14. Youngblom E, Pariani M, Knowles JW. Familial Hypercholesterolemia. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews. Seattle: University of Washington, Seattle: 2014.
  15. D'Erasmo L, Minicocci I, Nicolucci A, et al. Autosomal recessive hypercholesterolemia: long-term cardiovascular outcomes. J Am Coll Cardiol 2018;71:279-88.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Homozygous Familial Hypercholesterolemia, Lipid Metabolism, Nonstatins, Novel Agents, Primary Hyperlipidemia, Statins, Hypertension

Keywords: Pregnancy, Hyperlipoproteinemia Type II, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Cholesterol, LDL, Pravastatin, Hypercholesterolemia, Anticholesteremic Agents, Blood Glucose, Fibric Acids, Triglycerides, Breast Feeding, Coronary Artery Disease, Polycystic Ovary Syndrome, Diabetes, Gestational, Hypertension, Pregnancy-Induced, Family Planning Services, Pre-Eclampsia, Early Medical Intervention, Pharmaceutical Preparations, Estrogens, Congenital Abnormalities, Myocardial Infarction, Contraception, Registries, Ventricular Dysfunction, Left, Risk Reduction Behavior, Primary Prevention, Secondary Prevention


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