Specialty Corner: Lipid Management in Pregnancy and Lactation

Introduction

Normal pregnancy is characterized by physiologic increases in maternal levels of cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C). These lipoproteins are taken up by the placenta and support optimal fetal development and maternal health during pregnancy.¹ Patients with pre-existing dyslipidemia or those who develop dyslipidemia during pregnancy should have an evaluation with development of a management plan, as pathologic dyslipidemia is associated with adverse pregnancy complications including gestational diabetes, preterm birth, preeclampsia, hyperviscosity syndrome, large-for-gestational-age infants, and macrosomia. Dyslipidemia during pregnancy is considered a risk-enhancing factor for future atherosclerotic cardiovascular disease (ASCVD).^1-4 

A multi-disciplinary team, including a Lipid Specialist, is often helpful in diagnosing and treating dyslipidemia during pregnancy to support maternal-fetal health.⁵

Physiology: Lipids during Pregnancy and Lactation

In early gestation, triglyceride (TG) synthesis and adipocyte TG storage increase to support healthy fetal development and prepare for heightened fetal energy needs in late pregnancy.² These changes result from increased food intake by the mother, insulin resistance, as well as elevated levels of estrogen, lipoprotein lipase (LPL), and progesterone, which promote lipogenesis over lipolysis.^3,6,7 

Insulin resistance occurring in the later stages of pregnancy promotes lipolysis in adipose tissue, leading to increased plasma TG levels.⁸ This increase in plasma TG concentrations rises with increasing gestational age and peaks around time of delivery. This leads to a higher proportion of smaller atherogenic LDL particles, and associated increases in other lipoproteins including HDL-C, apolipoproteins (Apo) A-I, B, E, remnant-like particle (RLP)-cholesterol and lipoprotein(a) [Lp(a)] levels.^3,8,9

In the third trimester, a catabolic state favors the maternal use of lipids for energy, conserving glucose and amino acids for the fetus.^1,6 Fat storage diminishes, and reduced LPL activity limits the uptake of circulating triglycerides into adipose tissue.⁶ Post-delivery TG levels return to baseline within days, and the other lipoproteins over about one month.⁶ Ideal levels of lipids vary by trimester and are shown below.⁶

Breastfeeding assists in restoring maternal metabolism, as accumulated fat stores from pregnancy are mobilized thus leading to reduced TG levels and increased HDL-C.^3,6 Importantly, the duration of lactation has been shown to have an inverse association with subsequent subclinical atherosclerosis.¹⁰ Therefore, the decision of when to stop breastfeeding to resume lipid-lowering therapies should carefully consider the favorable impact of longer breastfeeding on lipid profiles and atherosclerosis.³

Management during Pregnancy: Initial Steps

Review of a recent lipid panel is recommended during the period when the patient is attempting conception or at the initial obstetric visit. Repeat screening at the beginning of the third trimester should be considered, even if lipids were normal on initial testing.² Specialized lipid testing, such as small dense LDL, apoB, apoA-I, are not needed; however, an Lp(a) measurement is reasonable in patients without prior testing as elevated levels may influence overall management plan.² High-risk patients with a personal or family history of dyslipidemia, hypertriglyceridemia, and obese women with certain risk factors (e.g., uncontrolled hypothyroidism, hypertension) should also be screened at the start of the second trimester and monthly during the third trimester.^2,4 Screening for secondary causes of dyslipidemia include thyroid-stimulating hormone (TSH), urinalysis to screen for albuminuria, renal function, liver enzymes, and testing for gestational diabetes.⁴

During history-taking, clinicians should assess lifestyle (e.g., alcohol, tobacco, exercise, and diet), and personal and familial history of dyslipidemia, cardiovascular disease, diabetes, pancreatitis, and thyroid disease.^4,11 Clinicians should also screen for medications affecting lipid levels (e.g., antipsychotics, beta-blockers) and lipid-lowering treatments which may require dose adjustments or discontinuation (Table 1).⁴ The physical exam should include measurements of body mass index, waist size, and blood pressure along with evaluation for bruits, murmurs, pulse characteristics, hepatosplenomegaly, lipemia retinalis, acanthosis nigricans, and xanthomata.^11,12 Risk for ASCVD can be estimated during pregnancy using the ACC ASCVD Risk Estimator Plus or other risk-prediction tools such as that outlined in the 2020 Consensus Statement by the American Association of Clinical Endocrinologists and American College of Endocrinology; however, there are no pregnancy-specific risk scoring systems. The only situation in which ASCVD risk during pregnancy is relevant is for women with heterozygous familial hypercholesterolemia (HeFh), or even homozygous familial hypercholesterolemia (HoFH) or prior clinical or subclinical atherosclerosis. In these cases, statins may be continued and/or lipoprotein apheresis may need to be initiated during pregnancy.¹⁷ Otherwise, the above-mentioned risk-enhancing pregnancy complications are important, but only for directed clinical management after pregnancy and lactation are completed.

Lifestyle modification should be addressed and referral to a registered dietitian for medical nutrition counseling is recommended, particularly for those with familial hypercholesterolemia (FH), severe hypertriglyceridemia (fasting TG > 500 mg/dL) or with a history of pancreatitis in pregnancy.⁴ Maintaining a healthy gestational weight gain via clinician-recommended dietary and exercise regimens are sufficient for most women to keep lipoproteins within acceptable pregnancy parameters. Dietary recommendations include a focus on vegetables, fruits, whole grains, legumes, lean protein, low-fat dairy, and dietary fiber, while limiting foods with large amounts of added sugar (whether high-fructose corn syrup or cane sugar, including candy, desserts, and sugar-sweetened beverages), as well as red meat, fried and fast foods.^2,3 Walking and other low-intensity physical activity are safe for most pregnant women, but an individualized exercise program can be discussed based on the woman’s overall health and medical conditions.

Shared decision making (choices made in discussion between the patient and her providers) is crucial to effective management. Points to consider are the current, observed lipid abnormalities, ASCVD risk, and the awareness of limited information on the safety of lipid medications during pregnancy and lactation.

Lipid Management during Pregnancy: Formulating a Plan

LDL-C
For women on LDL-C-lowering therapy prior to conception, all therapy except for bile acid sequestrants (BAS) should be stopped at least one month, and preferably three months, prior to conception. For women at low ASCVD risk who are already pregnant, all therapy (except BAS) should be stopped immediately and held until after pregnancy and lactation.^13,14

Referral to a lipid specialist is recommended for women at very high risk of ASCVD (with severe HeFH or HoFH), a pre-pregnancy history of ASCVD, presence of multiple risk enhancing factors, or very high triglycerides. While current clinical practice guidelines recommend withholding statin therapy in pregnancy, in July 2021 the Food and Drug Administration (FDA) requested removal of the contraindication (Category “X”) for statin use in all pregnant women noting, “the benefits of statins may include prevention of serious or potentially fatal events in a small group of very high-risk pregnant patients and contraindicating these drugs in all pregnant women is not appropriate.” ^2,13,15–17 Despite the removal from Category “X” there remains limited conclusive data and the FDA continues to advise against the use of statins in pregnancy although there can be consideration on a case-by-case basis.¹⁷ Lipoprotein apheresis is highly effective and safe when large reductions in LDL-C are needed during pregnancy in women with HoFH, or severe FH with ASCVD.^2,14,16 Women should feel empowered to speak to their healthcare provider, or seek referral to a lipid specialist, regarding on-going pharmacotherapy during pregnancy.^{13,14,16,18,19} See Table 1.

Triglycerides 

For non-pregnant women, normal fasting TG is < 150 mg/dL, moderate elevation ≥ 150 mg/dL and < 500 mg/dL, and severe ≥ 500 mg/dL. Values above 500 mg/dL increase risk for pancreatitis in pregnancy (as it does in the general population), and markedly so above 1000 mg/dL.²⁰

If fasting TG > 250 mg/dL, clinicians should check TG levels monthly and screen for secondary causes, in particular, gestational diabetes.^3,21

Hypertriglyceridemia is most often due to a poor diet, increase in body weight and/or insulin resistance. However, other secondary causes should be ruled out such as manifest diabetes, polycystic ovary syndrome, hypothyroidism, nephrotic syndrome, and Cushing’s syndrome. Several medications, including BAS, are also known to raise triglyceride levels.²

Lifestyle modifications including a heart healthy diet, weight management, and exercise are the mainstay of therapy for individuals with elevated triglycerides.If lifestyle modifications do not achieve the desired goal and TG remain > 500 mg/dL, medications can be considered. A very-low-fat diet is recommended to reduce risk of pancreatitis when TG > 500 mg/dL.² Lipid effects of changes in lifestyle and medication can be seen within a few weeks and are best monitored with fasting blood tests.
 
Fibrates have been little studied in pregnancy but may be considered starting in the 2nd trimester if potential benefits outweigh potential risks, especially if TG are > 1000 mg/dL with a history of pancreatitis.²²

Evidence for the use of prescription formulations of omega-3 fatty acids in pregnancy is limited, but neonatal supplements with DHA at a dose of 200 to 1000 mg/dL are universally recommended in pregnancy for fetal brain development. Above 1 g daily no additional fetal benefit is seen. TG can be lowered by about 40% with 2-4 g of prescription omega-3 acid ethyl esters (generic: Lovaza) daily and may be considered for use in pregnancy under the same terms as fenofibrate. Dietary supplement omega-3 fatty acids are not recommended for use in the general population and should be completely avoided in pregnancy as they are not regulated by the FDA and may contain harmful contaminants.²

Plasma exchange (also called plasma pheresis) is safe in pregnancy and may be used, if needed and available, to decrease TG levels of > 1000 mg/dL or > 500 mg/dL with symptoms of pancreatitis.² Lifestyle changes should be encouraged at the time of initial evaluation. Lipid impact of these changes in lifestyle and medication can be seen within a few weeks and are best monitored with fasting blood tests. 

Management during Lactation 

The 2022 American Academy of Pediatrics Policy Statement recommends infants be breastfed exclusively for 6 months with introduction of solid foods at about 6 months. Duration is suggested for up to 2 years, but individual circumstances and preferences should be considered.²³

Medications transfer into breast milk to different degrees through passive diffusion or active transport by membrane proteins, which can expose the baby to the medication. For many medications, there is little data on safety. Fasting lab tests can be taken about six weeks after delivery when lipids return to normal. Review of results and lifestyle factors will allow for determination of lipid goals and treatment plan.

Table 1 lists information on medication use in lactation. Statins should be avoided during lactation. Bile acid sequestrants can be used as they do not enter the mother’s bloodstream and breast milk.¹⁷ They can decrease absorption of fat-soluble vitamins and monitoring is advised. Prescription omega-3 fatty acids can be used for further reduction of triglycerides.

Ezetimibe lacks adequate studies in pregnant women and should not be used during lactation. As PCSK9 inhibitors such as evolocumab and alirocumab are large protein molecules, the amount in milk is likely low, however, until more data becomes available, they should be used with caution. Since bempedoic acid and its metabolites are 99% plasma-bound, amounts in milk are likely very low; however, at present it is not recommended for use during lactation (or pregnancy). Fenofibrate and gemfibrozil also should be avoided during lactation.

Summary

Management of dyslipidemia in pregnancy and lactation is an important part of medical care for women with both pre-existing and new lipid disorders that develop during pregnancy. Information on safety of lipid medications during pregnancy is usually scant or lacking altogether; therefore, weighing complexity of the dyslipidemia, patient’s ASCVD risk, and preferences are needed along with a multi-disciplinary team to develop an appropriate management plan. Referral to a lipid specialist should be considered for those with FH, markedly elevated TG that persist despite diet and lifestyle treatment, and those at high risk or with known ASCVD. Shared decision making with discussion between the patient and their health-care team allows for review of risks and benefits as the treatment plan is developed. 

 

Ms. Henry has no financial relationships to disclose. Ms. Papp has no financial relationships to disclose. Dr. Wild has received research grants from Bsoton Heart, MSU, and Quest Diagnostics. Dr. Brinton has received honorarium from Amgen, Amryt, CSL Behring, Kaneka, 89bio, Ionis, Merck, New Amsterdam, Novo Nordisck, and research support from Regeneron. Dr. Myerson has received honorarium from Novartis. 

References

1. Zhu SM, Zhang HQ, Li C, Zhang C, Yu J Le, Wu YT, et al. Maternal lipid profile during early pregnancy and birth weight: A retrospective study. Front Endocrinol (Lausanne) 2022;13. https://doi.org/10.3389/fendo.2022.951871.
2. Wild R, Feingold KR. Effect of Pregnancy on Lipid Metabolism and Lipoprotein Levels. Endotext 2023.
3. Kaur G, Gulati M. Considerations for treatment of lipid disorders during pregnancy and breastfeeding. Prog Cardiovasc Dis 2022;75. https://doi.org/10.1016/j.pcad.2022.11.001.
4. Bashir M, Navti OB, Ahmed B, Konje JC. Hyperlipidaemia and severe hypertriglyceridaemia in pregnancy. The Obstetrician & Gynaecologist 2023;25:196–209. https://doi.org/10.1111/tog.12887.
5. Kim J, Ayabe A. Obesity in Pregnancy. 2023.
6. F. Gary Cunningham, Kenneth J Leveno, Jodi S. Dashe, Barbara L. Hoffman, Catherine Y.Spong BMC. WILLIAMS OBSTETRICS 26TH EDITION. 2022.
7. Fanshawe AE, Ibrahim M. The current status of lipoprotein (a) in pregnancy: a literature review. J Cardiol 2013;61:99–106. https://doi.org/10.1016/j.jjcc.2012.09.009.
8. Herrera E. Lipid metabolism in pregnancy and its consequences in the fetus and newborn. Endocrine 2002;19:43–55. https://doi.org/10.1385/ENDO:19:1:43.
9. Ogura K, Miyatake T, Fukui O, Nakamura T, Kameda T, Yoshino G. Low-density lipoprotein particle diameter in normal pregnancy and preeclampsia. J Atheroscler Thromb 2002;9. https://doi.org/10.5551/jat.9.42.
10. Gunderson EP, Quesenberry CP, Ning X, Jacobs DR, Gross M, Goff DC, et al. Lactation Duration and Midlife Atherosclerosis. Obstetrics and Gynecology 2015;126. https://doi.org/10.1097/AOG.0000000000000919.
11. Pappan N, Rehman A. Dyslipidemia. 2023.
12. Hill MF, Bordoni B. Hyperlipidemia. 2023.
13. Lloyd-Jones DM, Morris PB, Ballantyne CM, Birtcher KK, Covington AM, DePalma SM, et al. 2022 ACC Expert Consensus Decision Pathway on the Role of Nonstatin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk. J Am Coll Cardiol 2022;80. https://doi.org/10.1016/j.jacc.2022.07.006.
14. Jacobson TA, Maki KC, Orringer CE, Jones PH, Kris-Etherton P, Sikand G, et al. National Lipid Association Recommendations for Patient-Centered Management of Dyslipidemia: Part 2. J Clin Lipidol 2015;9:S1-S122.e1. https://doi.org/10.1016/j.jacl.2015.09.002.
15. Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation 2019;139. https://doi.org/10.1161/CIR.0000000000000625.
16. Rao SJ, Martin SS, Lawson SM, Hailu T, Davis DM, Nasir K, et al. Evaluating the role of statins in prevention of preeclampsia: deeper insights into maternal cardiometabolic changes. J Clin Lipidol 2022;16. https://doi.org/10.1016/j.jacl.2022.04.007.
17. U.S. Food and Drug Administration (FDA). Statins: Drug Safety Communication - FDA Requests Removal of Strongest Warning Against Using Cholesterol-lowering Statins During Pregnancy 2021. https://www.fda.gov/safety/medical-product-safety-information/statins-drug-safety-communication-fda-requests-removal-strongest-warning-against-using-cholesterol.
18. Mehta LS, Warnes CA, Bradley E, Burton T, Economy K, Mehran R, et al. Cardiovascular Considerations in Caring for Pregnant Patients: A Scientific Statement from the American Heart Association. Circulation 2020;141. https://doi.org/10.1161/CIR.0000000000000772.
19. Bethesda. Drugs and Lactation Database (LactMed) [Internet]. Drugs and Lactation Database (LactMed) [Internet] 2022.
20. Virani SS, Morris PB, Agarwala A, Ballantyne CM, Birtcher KK, Kris-Etherton PM, et al. 2021 ACC Expert Consensus Decision Pathway on the Management of ASCVD Risk Reduction in Patients With Persistent Hypertriglyceridemia. J Am Coll Cardiol 2021;78. https://doi.org/10.1016/j.jacc.2021.06.011.
21. Gupta M, Liti B, Barrett C, Thompson PD, Fernandez AB. Prevention and Management of Hypertriglyceridemia-Induced Acute Pancreatitis During Pregnancy: A Systematic Review. Am J Med 2022;135:709–14. https://doi.org/10.1016/j.amjmed.2021.12.006.
22. Brown HL, Warner JJ, Gianos E, Gulati M, Hill AJ, Hollier LM, et al. Promoting risk identification and reduction of cardiovascular disease in women through collaboration with obstetricians and gynecologists: A presidential advisory from the American Heart Association and the American college of obstetricians and gynecologists. Circulation 2018;137. https://doi.org/10.1161/CIR.0000000000000582.
23. Meek JY, Noble L, Section on Breastfeeding. Policy Statement: Breastfeeding and the Use of Human Milk. Pediatrics 2022;150. https://doi.org/10.1542/peds.2022-057988.
24. Grant JK, Snow S, Kelsey M, Rymer J, Schaffer AE, Patel MR, et al. Lipid-Lowering Therapy in Women of Childbearing Age: a Review and Stepwise Clinical Approach. Curr Cardiol Rep 2022;24. https://doi.org/10.1007/s11886-022-01751-z.