EBM Tools for Practice: Finding Familial Hypercholesterolemia in the Perinatal Period

Familial hypercholesterolemia (FH) is an autosomal codominant genetic disorder of lipoprotein metabolism associated with disproportionately high levels of lowdensity lipoprotein cholesterol (LDL-C) and an increased risk of developing premature atherosclerotic cardiovascular disease (ASCVD) and valvular aortic stenosis.(1,2) Heterozygous FH (HeFH) affects all races and ethnicities and is prevalent in approximately 1 in 220 individuals, though an estimated 90% of those affected are presently undiagnosed.(3) If left untreated, women with HeFH have a 30% increased risk of developing coronary heart disease before the age of 50.(4) Considering the significant underdiagnosis rate of FH and the elevated cardiovascular risk among women,(5) novel strategies are urgently required to not only identify FH in women and their families, but also to prevent early ASCVD and improve health outcomes.

According to recent data from the U.S. Census Bureau, an estimated 86% of women between 40-44 years of age will have experienced at least one pregnancy.(6) In 2018, approximately 78% of women reported receiving prenatal care during the first trimester of pregnancy, while less than 7% of women received late prenatal care beginning in the third trimester or no prenatal care at all.(6) While nearly 44% of women’s preventive care visits were to OB/GYNs, these visits focused primarily on reproductive health-related services.(7) As a result, women of reproductive age who see their OB/GYN mainly for preventive care may not be receiving the complete spectrum of preventive screening and counseling. Despite U.S. Preventive Services Task Force (USPSTF) recommendations and multi-society guidelines from the American Heart Association (AHA) and American College of Cardiology (ACC) for targeted screening of lipid disorders starting in early adulthood, fewer than one in two women have had prior lipid screening.(8-10) Accordingly, the perinatal period represents a unique and currently underutilized opportunity to screen for FH and other lipid disorders, as well as to implement preventive cardiovascular care and risk reduction strategies.(11)

Maternal hyperlipidemia represents one of the most common metabolic changes during pregnancy, with plasma cholesterol and triglyceride levels increasing by 25% to 50% and 150% to 300%, respectively, primarily during the second and third trimesters of pregnancy.(12) Accordingly, the first trimester, when the majority of women receive prenatal care, represents a unique and reliable period for integrating lipid screening prior to significant changes in lipid metabolism. Women with HeFH experience comparable relative changes in plasma lipid levels during pregnancy and therefore have an absolute increase in lipid levels that is greater compared to unaffected women.(12,13) Moreover, maternal hyperlipidemia has been shown to be associated with adverse pregnancy outcomes (APOs) including preterm birth, gestational diabetes, and hypertensive disorders of pregnancy, conditions that have only recently been recognized as risk factors for the development of ASCVD among younger women.(14,15) While statins and other lipid-lowering medications such as ezetimibe and PCSK9 (proprotein convertase subtilisin/kexin 9) inhibitors are not recommended for the treatment of FH and hyperlipidemia during pregnancy and breastfeeding, it is advised that women with FH receive pre-pregnancy counseling and continued consultation with their healthcare practitioner to discuss available therapies and develop personalized treatment plans.(16)

LIPID-Women Aims and Preliminary Research
To better understand the utility of integrating lipid screening into routine prenatal care for women along with potential barriers to screening, Lipid Testing In Pregnancy to Improve Diagnosis in Women (LIPID-Women) was developed collaboratively among a multi-disciplinary team of cardiologists, obstetricians, lipid specialists, and primary care physicians at the University of Pennsylvania Health System (Penn). Concurrent with advancements made in the growing subspecialty of cardio-obstetrics, the research aims of LIPID-Women include, (1) assessing awareness of lipid screening and trends in clinical practice among obstetricians and gynecologists; (2) evaluating the impact of dyslipidemia during early pregnancy on excess fetal growth and pregnancy outcomes; (3) describing patterns of postpartum healthcare-seeking behaviors among women who underwent lipid screening; and (4) describing racial/ethnic and sociodemographic disparities in screening among women receiving prenatal care.

Preliminary results derived from LIPIDWomen studies provide evidence for significant racial/ethnic and sociodemographic differences in both the presence of a prior lipid screening and an awareness of high cholesterol as a key cardiovascular risk factor among women who received prenatal care at Penn. These findings are consistent with prior literature showing that screening rates and risk factor awareness were lower among individuals who were non-white, belonging to a lower income subgroup, received less formal education, and without a usual source of care.(17-20) Similar trends in lipid screening rates were also observed upon data abstraction and review of participants’ electronic medical records (EMR).

Clinical Applications
From the clinical practice perspective, LIPID-Women aims to incorporate standard lipid panels (fasting or non-fasting) before or during the 1st trimester for all pregnant women to identify undiagnosed lipid disorders, initiate cascade or family screening when relevant, and establish sustainable disease management plans throughout pregnancy and during follow-up care. Moreover, a tested and formalized screening algorithm will be implemented in the EMR to aid in the identification of lipid abnormalities among women receiving prenatal care from an Obstetric/ Gynecologic team.

There is fundamental evidence for the utility and feasibility of algorithms to screen for and identify suspected FH cases. Developed and managed by the FH Foundation, the FIND FH® Machine Learning model has proven effective in scanning large, diverse healthcare encounter databases to detect patients with FH. Specifically, a review of the flagged individuals identified through the model found that 87% of the individuals in the national database and 77% in the healthcare delivery system dataset were classified as having a high enough likelihood of FH warranting further guideline-directed treatment. (21) Considering the machine learning model’s novel integration of HIPAAcompliant referral schemes, we believe that incorporating an EMR-based algorithm will be critical in connecting at-risk women receiving prenatal care to continued healthcare services and identifying additional case among family members.

While considering a multidisciplinary approach to women’s cardiovascular health, it is imperative to address potential concerns and challenges facing OB/ GYN practitioners in screening their patients for FH. Based on early feedback from Penn practitioners, a particular concern includes the lack of immediate treatment options for women diagnosed with FH during pregnancy. While key lipid-lowering medications such as statins are contraindicated during pregnancy, enhanced lifestyle modifications along with certain pharmacologic treatments such as bile-acid sequestrants may be recommended until it is safe to initiate higher intensity statin and/or combination therapy after pregnancy and breastfeeding. Importantly, the identification of FH during the perinatal period allows for appropriate risk-reducing counseling and a more accurate stratification of risk during pregnancy to help guide necessary referrals and supplementary care for the patient and her family.(22) Current recommendations provided by the American College of Obstetricians and Gynecologists (ACOG) may not effectively promote the early identification of FH and other lipid disorders. Therefore, there is an urgent need to reconsider current guidelines and highlight the advantages conferred by developing multidisciplinary team-based care, improving training and education initiatives pertaining to FH and ASCVD risk during pregnancy, and recognizing the need for contemporary research and quality improvements projects, core tenants of the expanding subspecialty of cardio-obstetrics focused on prevention, early detection, and management of ASCVD during pregnancy.(14)

Conclusion
An estimated 1.3 million adults in the United States are suspected to have FH, yet an estimated 90% of affected individuals remain undiagnosed. The perinatal period represents a unique and underutilized opportunity to identify FH in women and initiate cascade screening in close relatives. Researchers at Penn will test whether using the perinatal period to identify FH and other lipid disorders will be clinically useful. We are confident that this investigation will result in revised recommendations for focused perinatal screening among women that will enhance cardiovascular risk assessment and guide treatment counseling during follow-up care and improved outcomes for young women and their families.

Disclosure statement:
Mr. Mszar has no financial disclosures to report. Dr. Gopal has no financial disclosures to report. Dr. Lewey has no financial disclosures to report. Dr. Nemiroff has no financial disclosures to report. Dr. Soffer has served as Consultant for Amgen Inc, Akcea Therapeutics, Medicure, Regeneron, and has been a disease management Speaker on disease states (FCS and FH respectively) for Amgen Inc and Sanofi.

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