“Lung of woman” series
Pulmonary arterial hypertension in women☆

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Summary

Introduction

Pulmonary arterial hypertension (PAH) is a rare condition characterized by sustained elevation in pulmonary arterial resistance leading to right heart failure.

Background

PAH afflicts predominantly women. Echocardiography is the initial investigation of choice for non-invasive detection of PAH but right-heart catheterization is necessary to confirm the diagnosis. Conventional treatment includes non-specific drugs (warfarin, diuretics, oxygen). The endothelin-1 receptor antagonist bosentan, the phosphodiesterase-5 inhibitor sildenafil, and prostanoids have been shown to improve symptoms, exercise capacity and haemodynamics. Intravenous prostacyclin is the first-line treatment for the most severely affected patients. Despite the most modern treatment, the overall mortality rate of pregnant women with severe PAH remains high. Therefore, pregnancy is contraindicated in women with PAH and an effective method of contraception is recommended in women of childbearing age. Therapeutic abortion should be offered, particularly when early deterioration occurs. If this option is not accepted, intravenous prostacyclin should be considered promptly.

Viewpoints and conclusion

Recent advances in the management of PAH have markedly improved prognosis and have resulted in more women of childbearing age considering pregnancy. A multidisciplinary approach should give new insights into cardiopulmonary, obstetric and anaesthetic management during pregnancy, delivery and the postpartum period.

Introduction

Pulmonary arterial hypertension (PAH) is a group of disorders affecting pulmonary microcirculation resulting in sustained elevation in pulmonary vascular bed pressures. Female predominance is commonly seen in idiopathic PAH, i.e. occurring without an associated condition. The prognosis, formerly particularly poor, has markedly improved in the past few years with the development of new treatments. This article discusses the epidemiological features, pathophysiological aspects, and treatment management, particularly during pregnancy.

Section snippets

New classification of pulmonary hypertension

A new classification of pulmonary hypertension was defined in 2003 at the 3rd WHO World Symposium on Pulmonary Arterial Hypertension [1]. This classification identifies five categories presenting similarities in their pathophysiology, clinical presentation, and mainly their management (Table 1). This new classification defines idiopathic PAH, formerly “primary” PAH, as onset of the disease in the absence of associated conditions such as connective tissue disease, congenital heart disease

Epidemiology

The incidence of PAH is difficult to establish because of the absence of specific symptoms and a simple confirming examination. Recently, a French national register estimated the prevalence of PAH at 15 cases per million population and the incidence at 2.4 cases per million population per year [2].

Female predominance is typically reported in PAH. However, there are some differences between subclasses. In idiopathic PAH, the gender ratio is 1.7 females for 1 male in the North American register

Clinical presentation and prognosis

Female gender is not associated with a different clinical presentation of the disease. Dyspnoea on exertion is the key symptom of the disease, but its obvious lack of specificity can be misleading when making the diagnosis. All patients present dyspnoea and it is often severe as nearly 75% of patients are New York Heart Association (NYHA) functional class III or IV when diagnosed [2]. There do not seem to be any differences in terms of severity of dyspnoea between males and females on diagnosis

Pathophysiology

Three factors combine to increase pulmonary vascular resistance: vasoconstriction, remodelling of small pulmonary vessel walls, and microthrombosis. Advances in the understanding of molecular mechanisms involved in this disease suggest that endothelial cell dysfunction plays a key role [11]. Chronic impairment of production by endothelial cells of vasodilators, such as nitric oxide (NO) or prostacyclin, associated with overexpression of vasoconstrictors such as endothelin-1, not only affect

Haemodynamic modifications in pregnancy

Pregnancy is accompanied by considerable physiological cardiovascular modifications [18]. From the first few weeks of pregnancy, hormonal activation and circulation of vasoactive substances (prostaglandins) result in a fall in systemic vascular resistance, an increase in blood volume (up to +50% in late pregnancy) and cardiac output (+50% in late pregnancy) [18]. During labour, uterine contractions further accentuate these haemodynamic modifications by increasing cardiac output by an extra 10

Contraception

The pregnancy-related risks thus require the use of effective contraception in women of childbearing age with PAH. Several contraception methods exist, highly variable in efficacy (Table 2) [49]. The combined oral contraceptive pill, mini- or microdose, is effective but theoretically contraindicated because of the increased thromboembolic risk [50]. However, its use can be considered in women under effective anticoagulant treatment and without any history of thromboembolism or known

Preimplantation genetic diagnosis

It is technically possible to sort embryos according to BMPR2 genotype. It is thus theoretically conceivable to apply this technique in the context of familial PAH with BMPR2 mutation, as proposed in other genetic disorders. Preimplantation genetic diagnosis would be particularly indicated when the father carries the mutation, as pregnancy is in any case contraindicated in women with PAH. Cases of asymptomatic female carriers of BMPR2 mutations are far more difficult. The risks of developing

Genetic counselling

The American College of Chest Physicians (ACCP) recommends that genetic testing and genetic counselling be proposed to relatives of patients with familial PAH, and that patients with sporadic idiopathic PAH and their relatives be informed of the possibility of genetic testing and genetic counselling [51]. The situation is very complex because of the genetic characteristics of PAH: the variable penetrance indicates that being a carrier of BMPR2 mutation, an obvious source of anxiety, does not

Conclusion

PAH is a rare disease that mainly afflicts women. Despite the considerable progress in the past few years in understanding the pathophysiology of PAH, no curative treatments are available to date. Improved prognosis, particularly in the most severe cases, has resulted in an increase in the number of patients of childbearing age. The maternal mortality rate is very high (30 to 50%). Therefore, pregnancy is contraindicated in women with PAH and an effective method of contraception is recommended

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    ☆

    To cite the present paper, use exclusively the following reference: Sanchez O, Marié E, Lerolle U, Wermert D, Israël-Biet D, Meyer G. Hypertension artérielle pulmonaire feminine (full text in english on http://www.em-consulte.com/revue/rmr). Rev Mal Respir 2008;25:451–60. Doi: RMR-04-2008-25-4-0761-8425-101019-200803264.

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    Coordinator: M. Murris-Espin.

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