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CardioNerd (Amit Goyal), cardioobstetrics series co-chair Dr. Sonia Shah (FIT, UT Southwestern) and episode lead Dr. Kayle Shapero (FIT, UPMC) discuss pregnancy in patients with pulmonary hypertension with Dr. Candice Silversides, Associate Professor of Medicine and the Director of the Pregnancy and Heart Disease program and head of the Obstetric Medicine program at the University of Toronto.

Disclosures: None

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Abstract • Pearls • Quotables • Notes • References • Guest Profiles • Production Team

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Episode Abstract

In this episode we discuss the important and challenging topic of pulmonary hypertension in pregnancy. We’ll start by discussing the prevalence of pulmonary hypertension in pregnancy, as well as the associated maternal morbidity and mortality associated with each WHO class. We will use a case to help us illustrate the appropriate workup for pulmonary hypertension patients and to help us broach the challenging topic of pregnancy termination. In this case we will further explore advanced management options including pulmonary vasodilators, anti-coagulation, and the use of mechanical support. Don’t miss this opportunity to hear Dr. Silversides’ share her wisdom on the importance of a multidisciplinary care team to plan both the delivery as well as post-partum care to help prevent adverse outcomes for both the mother and baby.

Pearls

1. Pregnancy in pulmonary hypertension, regardless of the class, is considered high risk. Even women who appear hemodynamically stable at baseline can easily decompensate in pregnancy, and thus the overall mortality and morbidity are very high.
   
2. Due to the high risk of maternal morbidity and mortality during pregnancy for women with pulmonary arterial hypertension, the option of termination of pregnancy should be discussed.
   
3.  Multidisciplinary care teams are the key to achieving optimal pregnancy outcomes in these patients. It is critical to create a team of experts with experience in pulmonary hypertension and plan for constant communication over the course of pregnancy.
   
4. Pulmonary vasodilators including CCBs, phosphodiesterase inhibitors, and prostacyclin analogues should be initiated early to mitigate adverse outcomes.
   
5. The majority of the complications in pulmonary hypertension patients occur after delivery, and so having a clear and safe postpartum plan is critical to a positive outcome.

Quotables

1. “We will someday identify the women who maternal morbidity and mortality is perhaps lower and we’ll be able to give a better, risk assessment. But we’re not quite there yet. And so currently, any woman who has pulmonary hypertension, true pulmonary hypertension in particular, pulmonary arterial hypertension, should be advised to avoid pregnancy.“ – Dr. Silversides
   
2. “Women with PH can be falsely reassuring because they can walk in and look pretty good. And they’re young, you know, they’re not like the normal 70-year-old you might see on the ward. And so, you think they’re going to be okay, but they can spiral downward very quickly. So I do think you also have to have a very high, um, uh, level of. Uh, caution in these patients.“- Dr. Silversides on assessing PH patients in pregnancy
   
3.  “I would tell you that I still think honesty is the best policy. I think you should offer women as much information as we currently know, so they can make informed decisions that are right for them. I think you also do have to really be sensitive to how you’re delivering this information, because remember (for) some women it will have never occurred to them that they can’t have a pregnancy. They may have been planning on having a kids and family and this information can really derail them. So you do have to use sensitivity, but I think you have to do it to accommodate to the patient that you’re seeing. I don’t think there can be a one size fits all approach.”- Dr. Silversides on the challenging topic of how to approach pregnancy termination conversations
   
4. “… continue to optimize your care, the better shape the woman is going into delivery. The better outcomes you’ll have at the time of labor and delivery.”- Dr. Silversides

Show notes

1. How do we define pulmonary hypertension (PH) and why is it such a big deal in pregnancy?

• According to recent guidelines pulmonary hypertension is a mean pulmonary artery pressure ≥ 20 mmHg.
• The WHO separates PH into 5 groups:
  • Group 1: Pulmonary arterial hypertension (e.g., idiopathic, heritable [BMPR2], anorexigen associated, drug or toxin-associated, HIV, connective tissue disease associated, schistosomiasis, portal hypertension, congenital heart disease, amongst other causes)
  • Group 2: Pulmonary hypertension due to left sided heart disease (e.g., HFrEF, HFpEF, left-side valvular heart disease)
  • Group 3: Pulmonary hypertension due to lung disease or hypoxia: (e.g.,COPD, ILD, OSA, hypoxia without lung disease such as high altitude, developmental lung disorders)
  • Group 4: PH due to pulmonary artery obstructions most commonly Chronic Thromboembolic Pulmonary Hypertension (CTEPH)
  • Group 5: Multifactorial causes such as hematologic disorders (chronic hemolytic anemia, as with myeloproliferative disorders), metabolic disorders (e.g., Gaucher disease, glycogen storage diseases, CKD), and systemic disorders (e.g., pulmonary Langerhans cell histiocytosis, neurofibromatosis, sarcoidosis)

• The prevalence of pulmonary hypertension and pregnancy is somewhere between 0.01¹ and 0.02%². Although rare, this number has been rising due to the number of congenital patients living to childbearing age, as well as the emergence of effective pulmonary vascular therapy.
• Complications of PH during pregnancy include:
  • The normal physiologic changes of pregnancy (increased plasma volume, increased stroke volume, increased cardiac output, decreased systemic vascular resistance), are poorly tolerated in PH due to an inability to decrease pulmonary vascular resistance and accommodate this increased plasma volume. This can lead to increased right ventricular overload.
  • Decrease in systemic vascular resistance and associated drop in blood pressure can also lead to decreased RV perfusion, contributing to RV failure and making it increasingly difficult to accommodate the extra afterload demand.
  • Pregnancy is both a prothrombotic and a pro-arrhythmic state, and maternal morbidity and mortality may also be related to complications from DVT/PE/arrhythmias, all of which are poorly tolerated by a failing RV with the increased afterload of PH and possible decreased perfusion from lower SVR.
  • Abnormal maternal hemodynamics in PH also contribute to increased fetal and neonatal complications including preterm birth, fetal and neonatal death.

2. How does the severity of PH or the patient’s WHO group impact maternal outcomes?

• Mortality
  • Overall mortality for PH patients during pregnancy is quite high: Two major systematic reviews covering a time span of 30 years in nearly 200 pregnancies cited total mortality to range between 25-38%. The majority of patients died within the first month after delivery and major causes of death were heart failure, sudden cardiac death and pulmonary embolism^4,5  
• Morbidity
  • A comprehensive study looking at approximately 1500 pregnant women with PH from the national inpatient sample (spanning from 2003-2012) found that the rate of major adverse cardiovascular events was around 24.8%.⁶
  • Karen et al assessed outcomes in ~150 pregnancies from the ROPAK study according to PH etiology (idiopathic PAH, PH due to congenital heart disease, PH due to left sided disease). Morbidity and mortality were highest in women with idiopathic PAH, and lowest in women with PH due to left sided heart disease. Complications were also higher in patient with severe PH (RVSP >70mmHg).⁷
  • Meng et al assessed 49 pregnancies from four large centers and found mortality to vary according to PH subgroup:  23% mortality in Group 1 patients, as compared to a 5% mortality in all other WHO groups. Similarly, patients with severe PH (RVSP >50mmHg) had a higher need for advanced therapies as compared to women with mild PH.¹
• Several variables determine risk during pregnancy related to PH, including the WHO group, etiology of PH, functional class, need for PAH medications at baseline, as well as cardiac size and function. 

3. What is the recommended initial workup to help identify and risk stratify patients with PH?

• Helpful baseline information includes BNP, prior echocardiograms, as well as hemodynamics from prior right heart catheterizations.
• For those patients previously treated for PH, it is important to identify which medications were used in the past or are currently being prescribed. This particularly important to identify teratogenic medications like endothelin antagonists.
• One of the most important factors is to identify the patient’s functional status including assessing six-minute walk tests, including O2 saturation, desaturation, and distance walked.
• Of note, while a RHC helps define the hemodynamic profile, the entire vascular bed is more fragile during pregnancy than in a non-pregnant state, and there have been reports of pulmonary artery rupture with interventions during pregnancy.⁸ This must be kept in mind when assessing the need for RHC.

4. How do you approach management of patients with PH during pregnancy?

• Frequent follow-ups and communication with the entire multidisciplinary team are vital. This team should include cardiology, a PH specialist and/or team, high risk obstetrics, and OB anesthesia.
• Patients should be monitored serially throughout pregnancy with the use of BNP, echocardiography, and assessment of functional status/symptoms.
• While every patient situation will be different, it is important to provide the patient with as much information as possible to make an informed decision. Given the high-risk nature of pregnancy in these patients, as well as the increased maternal morbidity and mortality, it is important to discuss the option of termination of pregnancy.

5. What is the role of pulmonary vasodilators, and which medications are considered safe in pregnancy?

• Pulmonary vasodilators should be implemented early to mitigate risk of adverse outcomes as outlined above.
• Options include: Calcium channel blockers, phosphodiesterase inhibitors (sildenafil, tadalafil), and prostacyclin analogs (epoprostenol, treprostinil).
• NOTE: endothelin receptor antagonists (such as bosentan, ambrisentan) are teratogenic(Category X) and are contraindicated during pregnancy and in women of childbearing age who are not using reliable contraception. Pregnancy must be excluded before initiation, serially during treatment, and for a period after treatment has been discontinued.
• CCB/PDE5 inhibitors have been the most commonly reported medications in the series of PH patients during pregnancy. Prostacyclin analogs are considered safe during pregnancy, but their IV formulation may cause challenges in medication administration given the need for continuous administration.

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6. How do you approach anticoagulation in PH patients during pregnancy?

• Pulmonary embolisms are one of the biggest contributors to morbidity and mortality in pulmonary hypertension patients as PE can acutely raise pulmonary artery, and therefore right sided pressures. Currently there are no clear recommendations for full dose anticoagulation in PH patients without risk factors for DVT/PE.
• Heparin is a large molecule that does not cross the placenta, and therefore considered safe in pregnancy. Typically, LMWH is used as it is considered superior to unfractionated heparin, especially in pregnancy. Other options such as warfarin are considered teratogenic (especially at does >5mg daily), and the class of DOACs have limited data on their safety in pregnancy and should be avoided.
• Initiation of anticoagulation should be coordinated in conjunction with obstetric hematologists.

7. What are some of the most important delivery considerations to keep in mind for these patients?

• Delivery timing and location: Consider delivering most patients by 37-weeks gestation (if not earlier) depending on the stability of the patient and fetus. While some women may follow at obstetric hospitals, delivery should take place in a location with backup of a cardiology, ICU, and advanced heart failure teams.
• Mode of delivery: IF women are stable, vaginal delivery- with an assisted second stage- is preferred as it is associated with fewer complications.
• Monitoring: In conjunction with OB, consider the use of arterial lines to assess blood pressure, central access for IV medication administration etc. Fetal monitoring is essential.
• Anesthesia: An epidural with good pain management is preferred, with avoidance of general anesthesia if possible (as GA is associated with greater complications in patients with PH).
• ECMO: If concerns for patient destabilization arise, VA-ECMO should be immediately available.
• Post-partum: The majority of complications occur after delivery, with the first post-partum week posing the highest risk period. Close monitoring must be initiated, preferably in a CCU/ICU for several days post-delivery. Early diuresis is paramount, as fluid mobilization after delivery can lead to fluid overload and right heart failure. 

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References

1. Meng ML, Landau R, Viktorsdottir O, et al. Pulmonary hypertension in pregnancy a report of 49 cases at four tertiary north American sites. Obstet Gynecol. Published online 2017. doi:10.1097/AOG.0000000000001896

2. Lima F V., Yang J, Xu J, Stergiopoulos K. National Trends and In-Hospital Outcomes in Pregnant Women With Heart Disease in the United States. Am J Cardiol. Published online 2017. doi:10.1016/j.amjcard.2017.02.003

3. Hemnes AR, Kiely DG, Cockrill BA, et al. Statement on pregnancy in pulmonary hypertension from the pulmonary vascular research institute. Pulm Circ. Published online 2015. doi:10.1086/682230

4. Bédard E, Dimopoulos K, Gatzoulis MA. Has there been any progress made on pregnancy outcomes among women with pulmonary arterial hypertension? Eur Heart J. Published online 2009. doi:10.1093/eurheartj/ehn597

5. Weiss BM, Zemp L, Seifert B, Hess OM. Outcome of pulmonary vascular disease in pregnancy: A systematic overview from 1978 through 1996. J Am Coll Cardiol. Published online 1998. doi:10.1016/S0735-1097(98)00162-4

6. Thomas E, Yang J, Xu J, Lima F V., Stergiopoulos K. Pulmonary hypertension and pregnancy outcomes: Insights from the national inpatient sample. J Am Heart Assoc. Published online 2017. doi:10.1161/JAHA.117.006144

7. Sliwa K, van Hagen IM, Budts W, et al. Pulmonary hypertension and pregnancy outcomes: data from the Registry Of Pregnancy and Cardiac Disease (ROPAC) of the European Society of Cardiology. Eur J Heart Fail. Published online 2016. doi:10.1002/ejhf.594

8. Barash PG, Nardi D, Hammond G, et al. Catheter-induced pulmonary artery perforation. Mechanisms, management, and modifications. J Thorac Cardiovasc Surg. Published online 1981. doi:10.1016/s0022-5223(19)39380-8

9. Marc Humbert, Olivier Sitbon GS. Hypertension, Treatment of Pulmonary Arterial. N Engl J Med. 2004;351:1425-1436.

Two additional excellent sources regarding Pregnancy in PH Patients:

1. Stout KK, Daniels CJ, Aboulhosn JA, et al. 2018 AHA/ACC Guideline for the Management of Adults With Congenital Heart Disease. J Am Coll Cardiol. Published online 2019.
2. Regitz-Zagrosek V, Blomstrom Lundqvist C, Borghi C, et al. ESC Guidelines on the management of cardiovascular diseases during pregnancy. Eur Heart J. Published online 2011. doi:10.1093/eurheartj/ehr218

Guest Profiles

CardioNerds Cardioobstetrics Production Team

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