Pulmonary hypertension (PH) is a serious, progressive circulatory disease that places enormous strain on the heart and significantly impacts quality of life. While this condition affects patients of all backgrounds, its most severe subtype, pulmonary arterial hypertension (PAH), also called Group 1, disproportionately affects women.

Not only is PAH a life-altering and potentially life-threatening diagnosis for women, it carries significant implications for pregnancy, reproductive planning, and sexual health. Consequently, understanding the epidemiology, diagnosis, and treatment considerations is essential for providers, says Mrinalini Krishnan, MD, FACC, Associate Director of the Advanced Pulmonary Hypertension, Right Heart Failure, and CTEPH Program at Temple University Hospital.

Epidemiology of PH/PAH in Women

The WHO classifies PH into five clinical groups:

• Group 1, Pulmonary Arterial Hypertension (PAH)
• Group 2, PH associated with left heart disease
• Group 3, PH associated with lung disease
• Group 4, PH associated with pulmonary artery obstructions including Chronic Thromboembolic Pulmonary Hypertension (CTEPH)
• Group 5, PH with unclear or multifactorial mechanisms

Group 1 (PAH) predominantly affects women, with women representing 65% to 85% of all cases. However, the reasons why women are more susceptible are still poorly understood. The so-called “estrogen paradox” is a mystery in two parts, Krishnan notes:

• Although animal models have shown that estrogen generally has a protective effect on lung blood vessels, PAH is more prevalent in human females.
• Despite being more likely to develop PAH, women generally are more responsive to treatment and have better survival compared to men. 

Proposed explanations include differential BMPR2 expression, sex hormone interactions with serotonin signaling, and estrogen metabolite effects on pulmonary vascular remodeling. 

Diagnostic Approach

Because PH has so many potential causes, a comprehensive, multidisciplinary approach to diagnosis is essential. 

Work-up typically starts with electrocardiogram, where abnormal findings are more likely with severe disease. Red flags include signs of right heart strain or enlargement, abnormal electrical patterns like right axis deviation, and prolonged QRS/QTc intervals.

Echocardiography (TTE) can be used to stratify PH risk probability and determine whether more invasive testing is recommended. 

Right heart catheterization (RHC) is a key test to confirm PH diagnosis and distinguish pre-capillary from post-capillary disease. In some cases, a vasoreactivity challenge can be performed during RHC, potentially identifying a small subset of patients (fewer than 8%) whose PH can be managed with calcium channel blockers. 

Cardiac MRI can also be performed to assess heart size and function. The presence of LGE, especially at the level of the RV septal anterior and inferior insertion points, and reduced PA distensibility and retrograde flow are highly predictive of PH. However, no single CMRI finding can rule out PH, Krishnan notes. 

Treatment Considerations for PAH

For women with PAH, the goals of therapy are to improve hemodynamics, exercise capacity, functional class, and quality of life, while preventing clinical worsening and premature death. 

Traditional therapeutic targets focus on three major pathways:

• The endothelin pathway, with endothelin receptor antagonists.
• The nitric oxide pathway, including phosphodiesterase-5 inhibitors and soluble guanylate cyclase stimulators.
• The prostacyclin pathway, with prostacylin analogues and selective IP receptor agonists.

An additional new approach targets the pathobiology of PAH with Sotatercept, an activin signaling inhibitor. Krishnan notes that PAH is driven by pulmonary vascular remodeling caused, at least in part, by an imbalance in anti-proliferative and pro-proliferative signaling pathways. This approach would “reverse-remodel” the vascular structures by rebalancing these signaling pathways.

Combination therapy outperforms monotherapy, with multiple trials showing that using two or even three drugs from different pathways is more effective than any single drug alone.

Other PH Types

The Temple Heart & Vascular Institute Advanced PH Program provides expert care for all pulmonary hypertension diagnoses. For women with Group 2 PH (left heart disease related), therapy should focus on treating the underlying heart condition. Importantly, PAH-specific drugs should not be used in these patients, as they can actually worsen outcomes.

For Group 3 (lung disease related), inhaled treprostinil (Tyvaso) showed a 21-meter improvement in walking distance in clinical trials in PH associated with Interstitial Lung Disease.

For Group 4 (CTEPH), treatment options include riociguat (Adempas), pulmonary thromboendarterectomy (PTE) surgery to remove clots, or balloon procedure (BPA). 

For patients who remain high-risk even after exhausting therapeutic options, lung transplantation may be considered.

Pregnancy and Other Special Considerations

Historically, maternal mortality rates with PAH were reported as high as 30%-50%. While more recent data shows improved outcomes with careful management, pregnancy with PAH remains very high risk, with a high chance of mortality and potential fetal complications including miscarriage (5.6%), fetal loss (2%), preterm delivery (21.7%), fetal growth restriction (19%) and neonatal mortality (0.7%). 

The recommendation is generally to avoid pregnancy with thorough counseling and reliable contraception. Therapeutic abortion, if elected, should be performed in the first trimester with full multidisciplinary support to minimize risk.

For women with PAH who choose to pursue pregnancy, careful management by a multidisciplinary team that includes an experienced PAH specialist is essential. The Temple Heart and Vascular Institute Advanced PH Program is one of the few programs in the world with 100% maternal and fetal survival in PAH with pregnancy.

Key considerations include avoiding teratogenic medications, including all endothelin receptor antagonists, riociguat, and selexipag. Optimization of non-teratogenic PAH therapies, close hemodynamic monitoring, and planned delivery timing should also be part of any pregnancy management plan. 

In addition to pregnancy, sexual dysfunction is a significant concern for women with PH, with 71.8% of patients reporting sexual dysfunction. Negative body image associated with treatment modalities like catheters and infusion pumps, fatigue and reduced exercise tolerance, fear of pregnancy, and the partner’s fear of causing physical harm are all contributing factors. 

Krishnan notes that providers should proactively screen for and address sexual health concerns as part of their overall management of female patients with PAH. 

For Referrals

To make a referral to the Temple Advanced Pulmonary Hypertension, Right Heart Failure, and CTEPH Program, email PHapptRequest@tuhs.temple.edu.