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Patient Summary – Pulmonary Hypertension in Pregnancy

A 33-year-old woman in the third trimester of pregnancy, with a known history of untreated PAH in the setting of TKI therapy, presents with shortness of breath. She is found to have PA pressure greater than systemic pressure with PASP >130. We describe the management of PH and RV failure in the context of a pregnancy. The patient was admitted to the ICU where a multidisciplinary team was mobilized, involving high risk ob-gyn, maternal fetal medicine, critical care, anesthesiology, and advanced heart failure. They began pulmonary vasodilators including treprostinil, tadalafil and inhaled nitric oxide. They also added inotropic and vasopressor support for right ventricular dysfunction with her severe PAH. Fetal heart monitoring was performed. PAH also led to worsening of known chronic thrombocytopenia in the setting of CML. HELLP syndrome was ruled out. The patient had preterm rupture of membranes at 32 weeks of gestation and the team pursued assisted vaginal delivery to prevent vagal response. Following successful delivery, the patient elected to undergo intra-uterine device placement. Post-delivery, vasopressors and inotropes were weaned, and she was discharged on treprostinil, ambrisentan and tadalafil. Thankfully both the mother and baby returned healthy and well at 1 month follow up.

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Case Media – Pulmonary Hypertension in Pregnancy

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Episode Teaching – Pulmonary Hypertension in Pregnancy

Pearls – Pulmonary Hypertension in Pregnancy

1. Pulmonary Hypertension is defined as a mean pulmonary arterial pressure (mPAP) of >20mmHg. There are 5 major types of pulmonary hypertension. Risk modifiers include symptom burden, exercise capacity, presence of pericardial effusion, RV function and hemodynamics.
2. Multidisciplinary care teams are the key to achieving optimal pregnancy outcomes in patients with PH. It is critical to create a team of experts with experience in pulmonary hypertension and plan for constant communication before, during, and after pregnancy.
3. Pregnant women who are already on PAH therapy outpatient should continue them during pregnancy (under the direction of PH experts) except for endothelin receptor blockers which fall in pregnancy category X.
4. PH during pregnancy is associated with up to 38% maternal mortality rate as the right ventricle (RV) is often unable to handle the volume shifts and hemodynamic changes that occur during pregnancy, labor, and delivery.
5. Patients with RV failure leading to low cardiac output and hypotension, like in this case, may benefit from vasopressors with the goal to maintain systemic blood pressure above pulmonary arterial pressures, preserving right coronary blood flow and preventing intracardiac shunting. Swan-guided management may be useful – to titrate inotropes and vasopressors, optimize pulmonary vasodilators and ensure that the patient is being adequately fluid-optimized to maintain a CVP of around 8-10.

Notes – Pulmonary Hypertension in Pregnancy

1. What are the different types of pulmonary hypertension (PH)?
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, etc)
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)

2. What is the role of TTE and RHC in the workup of PH?

• Tyrosine kinase inhibitors are known to cause PAH and there should be a low threshold to do screening TTEs in these patients when there is concern for the development of PAH.
• Echocardiogram is essential in the evaluation of PH –for positing the presence of PH, evaluating the left heart and congenital defects for clues to PH etiology, and assessing the structural consequences of PH on the right heart. In addition to estimating the pulmonary artery systolic pressure (PASP) by measuring the tricuspid regurgitant jet, we can characterize RV and RA size, RV function, and RV wall thickness, which may help both support the diagnosis and gauge prognosis for PH. Further, we can evaluate for left-sided heart disease contributing to PH. The presence of a pericardial effusion is a poor prognostic sign in those with pulmonary hypertension. Notably, the PASP is not of prognostic value due both to inaccuracies in measurement and falling values in the context of severe PH with failing RV function; a such PASP should not be used to surveil patients with PH or monitor response to PH therapies.

McLaughlin et al suggest using a checklist in the echocardiographic assessment of PH which includes the following¹:

Checklist	Salient points
Estimated PASP	To calculate mean PAP, usually PA diastolic pressure needs to be assessed which often requires a PR jet which is both difficult to obtain and not often present.
Evaluate RV size and function	Size: abnormal RV basal diameter >4.2 cm, wall thickness in subcostal view >5 mm   Function:  TAPSE (abnormal <16cm), RV tissue Doppler S’ velocity(abnormal <10cm/s at base) and RV fractional area change (abnormal <35%). Septal flattening: in systole = RV pressure overload and in diastole = RV volume overload
Evaluate severity of TR	Features suggestive of severe TR include dense TR jet on continuous-wave Doppler, V-wave cutoff sign; and systolic flow reversal on hepatic vein pulse-wave Doppler imaging
Evaluate for causes of PH	Left heart disease: look for overt LV systolic dysfunction, grade 2 or worse diastolic dysfunction, severe aortic or mitral valvular disease, and less common abnormalities of the left heart (e.g., hypertrophic cardiomyopathy, cor triatriatum).   Shunt lesions: perform agitated saline bubble study

• Right heart catheterization is necessary to confirm the diagnosis of PH. The updated hemodynamic definition of PH hinges on accurate hemodynamic assessment. In a PH crisis, such as our patient, it is also important to delineate the impact of PH on the RV. Invasive hemodynamic testing is the gold standard for differentiating isolated precapillary, isolated postcapillary and combined pre and post capillary PH (see table below).

When we consider the hemodynamic profiles of pulmonary hypertension, we break down PH into isolated pre-capillary, isolated post-capillary, or combined pre-and post-capillary pulmonary hypertension as shows in the table below.

	Mean Pulmonary Artery Pressure (mmHg)	Wedge Pressure (mmHg)	Pulmonary Vascular Resistance (Woods Units)	WHO Groups
Pre-capillary	> 20	≤ 15	≥ 3	1, 3, 4, 5
Post-capillary	> 20	> 15	< 3	2, 5
Combined pre- and post-capillary	> 20	> 15	≥ 3	2, 5, multifactorial

Furthermore, we can determine if a patient is “vasodilator responsive.” In the catheterization lab, a positive vasodilator response is defined as a decrease in mPAP ≥ 10 mmHg to an absolute value of ≤ 40 mmHg (without a decrease in cardiac output) with the use of inhaled nitric oxide or IV epoprostenol. If a patient has positive vasodilator test, calcium channel blockers can be initiated, however not all patients will be long term responders. We tend to do vasoreactivity testing in patients with PAH and not for other forms of PH (e.g., Pulmonary Veno-Occlusive Disease or Groups 2, 3, 4, or 5).

3. What are PAH-specific pharmacologic treatments?

• Remember that PAH is fundamentally a disease of increased pulmonary vascular resistance (PVR) causing elevated pulmonary pressures. The consequence of increased PVR includes increased RV afterload and hypoxemia and the subsequent clinical manifestations of PAH. Normally, the pulmonary vascular bed has a balance between vasodilators and vasoconstrictors that maintain a low-resistance, high-compliance state. This balance is disturbed in PAH and the goal of therapy is to “restore” balance between vasodilation and vasoconstriction.
• The management of PAH relies on 3 primary medication groups¹:

Nitric oxide pathway	PDE5 inhibitors: Sildenafil and tadalafil. These medications prevent the breakdown of cGMP which mediates the potent vasodilator and inhibitor of platelet aggregation, nitric oxide. Soluble guanylate cyclase (sGC) stimulators: riociguat. These medications stimulate sGC and thus increase sensitivity to NO. Riociguat is primarily used in CTEPH, but can also be used in PAH (PATENT-1 and -2 Trials) including PAH associated with sickle cell disease
Endothelin-1 (ET-1) pathway	Endothelin receptor antagonists (ERAs): macitentan, bosentan, ambrisentan. Common side effects are lower extremity edema and hepatotoxicity. NOTE: patients should not get pregnant on ERAs because of teratogenicity!
Prostacyclin Pathway	Prostacyclin analogs: epoprostenol, iloprost, treprostinil. Prostacyclin is a potent endogenous vasodilator and inhibits platelet aggregation. This class of medications have PO, SQ, IV, and inhaled formulations. Common side effects include headache, diarrhea, nausea, and jaw pain. PCA-receptor agonist: selexipag (oral).

Also remember calcium channel blockers in vasodilator responsive patients with PAH!

Other aspects of pharmacologic PAH treatment not discussed here include diuretics, digoxin, and oral anticoagulation, especially for patients with more advanced disease and on continuous parenteral prostacyclin therapy due to microthrombi in pulmonary arterioles.

4. What is the impact of pregnancy in PH?

• Prevalence of pulmonary hypertension has been rising due to the number of patient with congenital heart disease living to childbearing age, as well as the emergence of effective pulmonary vascular therapy.^2,3
• According to one widely quoted systemic analysis, although a publication bias cannot be excluded, overall maternal mortality was significantly lower compared with previous era (25 vs. 38%, P = 0.047). Seventy-eight per cent of deaths occurred within the first month after delivery. Primigravidae and parturients who received general anesthesia were at higher risk of death. Maternal mortality in parturients with PAH remains prohibitively high, despite lower death rates than in previous decades. Early counseling regarding pregnancy risks, including contraception, remains paramount. Women with PAH who become pregnant warrant a multidisciplinary approach with consideration of advanced therapies and discussion of pregnancy termination.^3-5
• Morbidity and mortality were highest in women with idiopathic PH, and lowest in women with PH due to left sided heart disease. Complications were also higher in patient with severe PH (RVSP >70mmHg).⁷
• 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
• Overall mortality for PH patients during pregnancy is quite high, up to 50%. 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^4,5,8
• Complications of PH during pregnancy:
  • 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 the increased pulmonary flow. 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 leading to RV failure.
  • Pregnancy is both a prothrombotic and a pro-arrhythmic state, and maternal morbidity and mortality may also be related to complications from veous thromboembolism and arrhythmias.
  • Abnormal maternal hemodynamics in PH also contribute to increased fetal and neonatal complications including preterm birth as well as fetal and neonatal death.

5. 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 of gestation, if not earlier, depending on the stability of the patient. While some women may be followed in obstetric hospitals, delivery should take place in a location with backup of a cardiology, critical care, and advanced heart failure teams. ⁸
• Mode of delivery: If women are stable, assisted vaginal delivery is preferred as it is associated with fewer complications. ⁸
• Monitoring: In conjunction with OB consider the use of an arterial line for invasive blood pressure monitoring, central access for IV medication administration etc. A PA catheter may be necessary to optimize PAH therapy and RV support.⁸ Be wary of increased vascular fragility and the increased risk of complications of invasive vascular procedures during pregnancy.
• Anesthesia: Epidural anesthesia with good pain management is preferred (to avoid sympathetic surge from pain), with avoidance of general anesthesia if possible (as GA is associated with greater complications in patients with PH)⁸
• VA-ECMO: If concerns for patient destabilization arise, VA-ECMO should be initiated. ⁸

Post-partum: The majority of complications occur after delivery, with the first 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.  ⁸

References

1. McLaughlin, V.V., Shah, S.J., Souza, R. and Humbert, M., 2015. Management of pulmonary arterial hypertension. Journal of the American College of Cardiology, 65(18), pp.1976-1997.

2. Meng, M.L., Landau, R., Viktorsdottir, O., Banayan, J., Grant, T., Bateman, B., Smiley, R. and Reitman, E., 2017. Pulmonary hypertension in pregnancy. Obstetrics & Gynecology, 129(3), pp.511-520.

3. Lima, F.V., Yang, J., Xu, J. and Stergiopoulos, K., 2017. National trends and in-hospital outcomes in pregnant women with heart disease in the United States. The American journal of cardiology, 119(10), pp.1694-1700.

4. Bedard, E., Dimopoulos, K. and Gatzoulis, M.A., 2009. Has there been any progress made on pregnancy outcomes among women with pulmonary arterial hypertension?. European heart journal, 30(3), pp.256-265.

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. Martin, S.R. and Edwards, A., 2019. Pulmonary hypertension and pregnancy. Obstetrics & Gynecology, 134(5), pp.974-987.

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