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Featured Clinical Topic - Anticoagulation Use in pregnant patients with a history of mechanical heart valve replacement

21 Sep 2017 10:56 AM | MSHP Office (Administrator)

Authors:

Sara Massey, PharmD Candidate 2018: UMKC School of Pharmacy
Kylie Barnes, PharmD, BCPS: Clinical Assistant Professor at UMKC School of Pharmacy

Pregnant women have an estimated 4- to 5-fold increased risk of thromboembolism when compared with non-pregnant women.1 Complicating the risk, pregnancy is also associated with physiologic and anatomic changes that increase a woman’s risk of thromboembolism. Those risks include hypercoagulability, increased venous stasis, decreased venous outflow, compression of the inferior vena cava and pelvic veins by the enlarging uterus, and decreased mobility.2 The increased risk begins in the first trimester, and intensifies throughout the third trimester and postpartum period, with the highest risk occurring during the first week postpartum. Personal history of thrombosis or increased hypercoagulable state is also an important risk factor to consider.

Women with a mechanical heart valve are at particularly increased risk for a thromboembolic event during pregnancy. The risk of thromboembolic event differs from patient to patient, and depends upon the type and location of the valve, as well as the patient’s clinical presentation and other baseline risk factors. Women with a history of a prior thromboembolic event, atrial fibrillation, prosthesis in the mitral position, or multiple prosthetic valves are at the highest risk of an event.3 Regardless of the valve type or position, all women with a mechanical heart valve are recommended to be treated with therapeutic anticoagulation throughout pregnancy to reduce the risk of complications. Maternal thromboembolic complications during pregnancy may lead to required valve replacement or result in maternal death, which can also lead to fetal loss.3 Unfortunately, due to lack of adequate prospective controlled trials, the optimal anticoagulant therapy may vary and often depends on patient presenting factors, history, and personal preferences.

Determining the most appropriate anticoagulant for a pregnant patient can be challenging, especially for practitioners who do not routinely care for patients throughout the antepartum period. According to the American Heart Association and American College of Cardiology (AHA/ACC) Valvular Heart Disease guidelines and the American Congress of Obstetricians and Gynecologists (ACOG) guidelines, warfarin, low molecular weight heparin (LMWH), and unfractionated heparin (UFH) are all potential treatment options for pregnant patients with a mechanical heart valve, depending upon the anticoagulation indication and gestation of the patient.2,4 Before starting an anticoagulation medication, patients should fully understand the importance of treatment and the potential associated risks with each treatment option. 

Of the three treatment options, warfarin is the most effective agent in preventing valve thrombosis and thromboembolism. A systematic review of 28 studies, including 976 women with 1234 pregnancies from 1966 to 1997 evaluated the risks of maternal and fetal complications in women with mechanical heart valves treated with different anticoagulation regimens during pregnancy. Women treated with warfarin throughout pregnancy were associated with the lowest risk of valve thrombosis (3.9%; 95% CI, 2.9-5.9%). In comparison, heparin use during weeks 6 to 12 gestation, followed by warfarin for the remainder of pregnancy was associated with an increased risk of valve thrombosis (9.2%; 95% CI, 5.9-13.9%).5 Unfortunately, none of the included studies were randomized, and close to half of the women had older model valves, that are known to be more thrombogenic at baseline, compared to current valves used, making it difficult to assimilate the risks to current practice. Additionally, compliance was not reported in all of the included studies, and poor compliance and subtherapeutic regimens could have potentially contributed to the higher rate of valve thrombosis.

There are no randomized controlled trials comparing LMWH use verses warfarin or UFH in pregnant patients with a mechanical heart valve. One retrospective review including 16 studies and 81 pregnancies from 1996 to 2003 reported thromboembolic complications occurred in 12.3% of pregnancies. When including only women who received therapeutic doses of LMWH, the incidence of thromboembolic complications decreased to 2.7%, suggesting the increased risk may be associated with use of subtherapeutic doses of LMWH, inadequate anti-Xa monitoring, and/or poor patient compliance with LMWH therapy.6 When comparing LMWH use to heparin, LMWH has a more predictable dosing regimen to attain therapeutic levels.

When considering which anticoagulant to use, it is important to also consider maternal and fetal safety with each agent. Warfarin crosses the placenta, and is associated with an increased risk of late fetal loss.3 Exposure during the first trimester is associated with a pattern of congenital malformations termed the fetal warfarin syndrome that occurs in roughly 25% of exposed fetuses.  Additionally, warfarin has been linked to increased risk of spontaneous abortion, stillbirth, and neonatal death. In total, only 70% of pregnancies exposed to warfarin use are expected to result in a normal, healthy infant at delivery.7 However, lower doses of warfarin, less than or equal to 5 mg per day, have shown a reduction in potential fetal risks. From 1987 to 1997, one study investigated fetal and pregnancy risks of dosing warfarin less than or equal to 5mg daily or greater than 5 mg daily throughout 58 pregnancies. Pregnant patients receiving greater than 5 mg per day resulted in 3 full term deliveries and 22 fetal complications (spontaneous abortion, fetal growth retardation, warfarin embryopathy, stillbirth, or ventricular septal defect), whereas, pregnant patients who received less than or equal to 5 mg of warfarin daily resulted in 28 healthy deliveries and only 5 fetal complications.8 It has been theorized that warfarin embryopathy and fetal loss impact is dose-dependent, and patients should be treated with doses < 5 mg / day when appropriate. The clinical relevance of this finding can be lacking, as warfarin dosing is guided by therapeutic international normalized ratio monitoring to achieve adequate anticoagulation.  

UFH is unable to cross the placenta, and has no known direct harm to the fetus.  According to the AHA/ACC guidelines, only continuous infusion UFH, not subcutaneous UFH, is recommended in this pregnant population, due to increased protection against thromboembolic events.3,4 Long-term use of UFH may cause bone loss due to reduced bone mineral density. One study, including 184 women, evaluated the effects of long-term treatment with heparin during pregnancy. Osteoporotic vertebral fractures were found in 2.2% of the women.9 Bone mineral density is thought to recover after heparin is discontinued, but the long-term impact is unclear.  UFH also has an increased risk for bleeding and thrombocytopenia, which is another potential risk in pregnant women with mechanical heart valves.10 LMWH also does not cross the placenta, and is associated with less effect on bone mineral density, less bleeding, and less thrombocytopenia when compared to UFH. However, LMWH has a longer half-life than UFH, and does not have a full reversal agent in the event the patient goes into labor.

Anticoagulation management during pregnancy in the presence of a mechanical valve is complex. Warfarin, UFH, and LMWH are all potential anticoagulation treatment options in this population, and treatment decisions are guided, based on individual patient scenarios. Warfarin has clinically been the most effective in this patient population, however carries significant concerns to fetal development and safety. Below, the chart from the AHA/ACC Valvular Heart Disease guidelines, shows a general anticoagulation treatment approach for pregnant women with a mechanical heart valve.4 It is important to fully inform patients regarding the importance of therapeutic anticoagulation and continued medication compliance and monitoring throughout pregnancy. Additionally, patients must be informed of the maternal and fetal risks associated with each anticoagulation treatment option, and participate in the decision making process.

Figure from the 2014 AHAACC Management of Patients with Valvular Heart Disease Guidelines4

Figure from the 2014 AHA/ACC Management of Patients with Valvular Heart Disease Guidelines4

References:

  1. Heit JA, Kobbervig CE, James AH et al. Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30-year population-based study. Ann Intern Med 2005;143:697-706.
  2. Thromboembolism in pregnancy. ACOG Practice Bulletin No. 123. American College of Obstetricians and Gynecologists. Obset Gynecol 2011;123:987-96. doi: 10.1097/AOG.0000000000000230.
  3. North RA, Hunt B, Gaasch WH. Management of pregnant women with prosthetic heart valves. UpToDate 2017;8126(16).
  4. Nishimuara RA, Otto CM, Bonow RO, et al. 2014 AHA/ACC Guideline for the Management of Patients with Valvular Heart Disease: Executive Summary. American Heart Association Journals 2014;129:e521-643. 
  5. Chan WS, Anand S, Ginsberg JS. Anticoagulation of pregnant women with mechanical heart valves: a systemic review of the literature. Arch Intern Med 2000;160:191.
  6. Oran B, Lee-Parritz A, Ansell J. Low molecular weight heparin for the prophylaxis of thromboembolism in women with prosthetic mechanical heart valves during pregnancy. Thromb Haemost 2004;92:747.
  7. Briggs GG, Freeman RK, Towers CV, et al. Drugs in Pregnancy and Lactation, 11th ed. Philadelphia, PA: Lippencott Williams & Wilkins 2015:341-344.
  8.  Vitale N, Feo MD, De Santo LS, et al. Dose-dependent fetal complications of warfarin in pregnant women with mechanical heart valves. Journal of American College of Cardiology 1999;33(6):1637-41.
  9. Dahlman TC. Osteoporotic fractures and the recurrence of thromboembolism during pregnancy and the puerperium in 184 women undergoing thromboprophylaxis with heparin. Am J Obstet Gynecol 1993;168:1265.
  10. Hull RD, Garcia DA. Heparin and LMW heparin: dosing and adverse effects. UpToDate 2017;1348(60).

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