Pregnancy is a hypercoagulable state associated with increased risk of thromboembolism. Managing anticoagulation during pregnancy has implications for both the mother and the fetus. CardioNerd Amit Goyal joins Dr. Akanksha Agrawal (Cardiology Fellow at Emory University), Dr. Natalie Stokes (Cardiology Fellow at UPMC and Co-Chair of the Cardionerds Cardio-Ob series), and Dr. Katie Berlacher (Program Director of the Cardiovascular Disease Fellowship and Director of the Women’s Heart Program at UPMC) as they discuss the common indications for anticoagulation and their management before, during, and after pregnancy. In this episode, we focus on management of pregnant patients with mechanical valves and venous thromboembolism.

Audio editing by CardioNerds Academy Intern, Dr. Maryam Barkhordarian.

Pearls • Notes • References • Guest Profiles • Production Team

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Pearls- Pregnancy and Anticoagulation

1. Pregnancy is a hypercoagulable state. Pregnancy-associated VTE is a leading cause of maternal morbidity and mortality.
   
2. The use of anticoagulation requires a balance between the risks and benefits to the mother and her fetus.
   
3. The agent of choice for anticoagulation during pregnancy depends on the indication, pre-pregnancy dose of vitamin K antagonist (VKA), and the trimester of pregnancy. For instance, patients with mechanical heart valves, warfarin is generally recommended in the first trimester if the daily dose is less than 5 mg and as the first option for all patients with mechanical valves in the 2^nd and 3^rd trimester. Use of direct oral anticoagulants (DOACs) has not been systematically studied, they do cross the placenta and their safety remains untested.
   
4. Warfarin crosses the placenta but is not found in breast milk. LMWH does not cross the placenta and is not found in breast milk. Thus, both these agents can be used by a lactating mother.
   

Quatables – Pregnancy and Anticoagulation

“[We] can’t highlight enough that good communication and documentation is vital in such situations” says Dr. Berlacher while discussing the role of a multidisciplinary team including cardiologists, obstetricians and fetal medicine physicians in taking care of a pregnant patient on anticoagulation.

“What I love about cardio-obstetrics is that we really can help women in a time that is so important in their life…this is one of the most memorable times in their life..” says Dr. Berlacher when asked what makes your heart flutter about cardio-obstetrics.

“Knowledge is power…not just for providers, but also for the patients” says Dr. Berlacher emphasizing the importance of clear communication between physicians and patients.

Show notes – Pregnancy and Anticoagulation

1. What makes pregnancy a hypercoagulable state?

• Pregnancy is a hypercoagulable state associated with higher risk of thromboembolic phenomenon. The three components of Virchow’s triad: hypercoagulability, stasis, and endothelial injury are all present during pregnancy. This leads to a 5-fold increased risk of venous thromboembolism (VTE) during pregnancy that persists for 12 weeks postpartum. The risk for VTE seems to be highest in the first 6 weeks postpartum, with a higher prevalence of clot in the left lower extremity.
  
• There are additional risk factors for developing VTE in the postpartum period besides pregnancy itself, and this includes but is not limited to preeclampsia, emergent c-section, hypertension, smoking, and postpartum infection.
  
• Choosing anticoagulant therapies during pregnancy involves a fine balance between the risks and benefits to both the mother and fetus. A multidisciplinary team involving the obstetrician, cardiologist, and maternal-fetal medicine team is critical to guide anticoagulation in pregnancy.
  

2. What are some of the common indications for anticoagulation during pregnancy?

• One of the most common indications for anticoagulation in pregnancy is valvular disease, and specifically mitral valve stenosis with atrial fibrillation or a prior embolic event.
  
• Patients with a mechanical heart valve will require anticoagulation during pregnancy. Patients with a bioprosthetic valve (surgical or transcatheter) are generally continued on low dose Aspirin; in the uncommon scenario of pregnancy in the first 3-6 months following implantation of a bioprosthetic valve, the decision to pursue anticoagulation is individualized.
  
• Other indications include acute VTE, atrial fibrillation, antiphospholipid syndrome, and inherited thrombophilias that may predispose a patient to developing VTE during pregnancy.
  

3. For mechanical heart valves, how do anticoagulation recommendations vary based on trimester?

• The European Society of Cardiology has divided various valvular heart diseases into 4 classes as per the modified World Health Organization classification of maternal cardiovascular risk, and having a mechanical valve falls under Class III where the maternal cardiac event rate varies between 19-27%. Such patients should get their care at expert centers for pregnancy and cardiac disease.
  
• Anticoagulation for mechanical valve during pregnancy varies with each trimester to balance the risks and benefits. During the first trimester, the period of organogenesis, the decision of whether to continue warfarin (a potential teratogenic) depends on the dose of warfarin. If a patient has been taking </=5 mg/day of warfarin, one can either continue taking warfarin (Class IIa) or switch to LMWH/ UFH (Class IIb). However, if a patient is on >5 mg/day of warfarin, the American Heart Association (AHA) recommends stopping warfarin and using alternate agents like LMWH/UFH (Class IIa).
  
• During the second and third trimesters, it is typically advised to continue warfarin until prior to the vaginal delivery when continuous infusion of UFH should be used as the anticoagulant agent of choice. Expert multidisciplinary teams are needed not only to guide these general recommendations, but to individualize the treatment based on patient preferences and specific factors (e.g., previous prosthetic valve thromboembolic complication).
  
• For a mechanical mitral valve replacement, 2014 AHA/CC guidelines recommend a goal INR of 3.0. For a mechanical aortic valve replaceent, the goal depends on the presence or absence of risk factors. In a patient with high-risk conditions like atrial fibrillation, previous thromboembolism, LV dysfunction, hypercoagulable condition, and older-generation mechanical valve, a goal INR of 3.0 (2.5 to 3.5), similar to MVR is recommended. However, if no high-risk features exist, then an INR goal of 2.5 (2.0 to 3.0) is recommended. Additionally, no additional bridging is required in the latter group of patients if their VKA therapy is interrupted for non-cardiac procedures. With certain AVR valves and no other risk factors (e.g. ON-X), a lower INR goal may be pursued.
  

4. What are the major differences between Warfarin, Heparin products, and DOACs in pregnancy and lactation?

• Warfarin crosses the placenta and has a dose-dependent relationship with adverse fetal outcomes (e.g., miscarriage, stillbirth, embryopathy). Warfarin’s teratogenic effects are also trimester-dependent with fetal bone and cartilage abnormalities occurring in the 1^st trimester and CNS abnormalities (e.g., microencephaly, spasticity, hypotonia, optic atrophy) if teratogenic levels are reached in the 2^nd and 3^rd trimester. 
  
• When compared with LMWH and UFH, warfarin has the least maternal risk for those with mechanical heart valves, but lowest rates of livebirths. [4] LMWH does not cross the placenta and is associated with the highest number of livebirths. However, the challenges of using LMWH include its monitoring. Weight-based LMWH should be accompanied by peak anti-Xa levels drawn 4-6 hours post-dose to achieve a goal level of 1.0-1.2 U/ml.
  
• UFH is the preferred agent of choice at the time of delivery, since this is the highest period of bleeding for a pregnant woman. It is usually stopped 4-6 hours before delivery and restarted 4-6 hours after delivery if there is no bleeding.
  
• DOACs have not been studied in pregnant patients on a large scale. And the limited data present revealed a high miscarriage rate and possible embryopathy. There use is not recommended in pregnant women.
  
• Anticoagulants such as UFH, LMWH, warfarin, fondaparinux, or danaparoid are all recommended as safe options for breastfeeding women with indication for anticoagulation. DOACs are not recommended for lactating women.
  

5. What are the recommendations for VTE management during pregnancy?

• Venous thromboembolism (VTE) complicates ∼1.2 of every 1000 deliveries. Despite these low absolute risks, pregnancy associated VTE is a leading cause of maternal morbidity and mortality.
  
• Women with VTE on chronic anticoagulation are recommended to continue anticoagulation during (and after) pregnancy. Weight-based LMWH guided by Xa levels (to achieve a goal level of 1.0-1.2 U/ml) is the preferred agent, but warfarin (daily dose ≤5 mg) is an alternative.
  
• In patients with recent pulmonary embolism (PE), postpartum heparin treatment should be restarted 6 hours after a vaginal birth and 12 hours after a caesarean delivery if no significant bleeding has occurred. There should be subsequent overlap with VKAs for at least 5 days.
  
• In the absence of significant bleeding, VKAs may be started on the second day after delivery and continued for at least 3 months, or for 6 months if PE occurred late in pregnancy. The goal INR should be between 2 and 3.
  
• Anticoagulation decisions are complex and should be determined in collaboration with a multidisciplinary cardio-obstetrics team.
  

References

1. Alshawabkeh L, Economy KE, Valente AM . Anticoagulation During Pregnancy: Evolving Strategies With a Focus on Mechanical Valves. J Am Coll Cardiol 2016;68:1804-1813.
   
2. Regitz-Zagrosek V, Roos-Hesselink JW, Bauersachs J, et al. 2018 ESC Guidelines for the management of cardiovascular diseases during pregnancy. The Task Force for the Management of Cardiovascular Diseases during Pregnancy of the European Society of Cardiology. European Heart Journal. 2018, 39, 3165-3241.
   
3. Nishimura RA, Otto CM, Bonow RO et al. 2014 AHA/ACC Guideline for the Management of Patients with Valvular Heart Disease: Executive Summary. A Report of the AMerican College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014; 129:e521-e643.
   
4. Richardson A, Shah S, Harris C, McCulloch G, Antoun P. Anticoagulation for the Pregnant Patient with a Mechanical Heart Valve, No Perfect Therapy: Review of Guidelines for Anticoagulation in the Pregnant Patient. Case Rep Cardiol. 2017;2017:3090273.
   
5. Shannon M. Bates, Anita Rajasekhar, Saskia Middeldorp, Claire McLintock, Marc A. Rodger, Andra H. James, Sara R. Vazquez, Ian A. Greer, John J. Riva, Meha Bhatt, Nicole Schwab, Danielle Barrett, Andrea LaHaye, Bram Rochwerg; American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy. Blood Adv 2018; 2 (22): 3317–3359.
   
6. Lameijer H, Aalberts JJJ, van Veldhuisen DJ, Meijer K, Pieper PG. Efficacy and safety of direct oral anticoagulants during pregnancy; a systematic literature review. Thromb Res. 2018 Sep;169:123-127.
   

Guest Profiles

Dr. Katie Berlacher

Katie Berlacher, MD, is a cardiologist and is certified in cardiovascular disease by the American Board of Internal Medicine and adult echocardiography by the National Board of Echo. She is the medical director of the Magee Women’s Heart Program, the program director of cardiovascular fellowship, and is an assistant professor of medicine at the University of Pittsburgh School of Medicine. She received her medical degree from The Ohio State University and completed her residency and fellowship at the University of Pittsburgh Medical Center.

Dr. Berlacher joined the UPMC Heart and Vascular Institute in 2012. Her clinical interests include women’s heart disease, including pregnancy and heart disease risks, as well as medical education. She has published numerous articles in peer-reviewed journals and is a member of the American College of Cardiology and the American Heart Association. She lives in the city and is an avid cyclist, boxer, and hiker.

Dr. Akanksha Agrawal

Akanksha is a cardiology fellow at Emory University. She did her medical school from Maulana Azad Medical College, India, and Internal Medicine Residency at Einstein Medical Center, Philadelphia, where she did a year of chief residency as well. She is interested in cardio-obstetrics and advanced heart failure, and plans to pursue Advanced Heart Failure and Cardiac Transplant fellowship.

CardioNerds Cardioobstetrics Production Team

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  Natalie Stokes, MD
  
  
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  Sonia Shah, MD
  
  
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  Amit Goyal, MD
  
  
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  Daniel Ambinder, MD
  
  

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