Introduction

Pulmonary hypertension is a rare disease with different causes. Despite improvements in treatment options, it still carries a grave prognosis, with significant morbidity and mortality. The haemodynamic changes of pregnancy are not well tolerated in women with pulmonary hypertension. Mortality has been described in up to 50% of women with pulmonary hypertension . Prognosis has improved in recent years, but pregnancy is still contraindicated in women with pulmonary hypertension . In this chapter, we provide a brief overview of the diagnosis, classification and pathophysiology of pulmonary hypertension. We also review modern treatment options and available published research on pregnancy in women with pulmonary hypertension. Our specific aims are to establish what factors determine prognosis of pregnant women with pulmonary hypertension. We systematically reviewed the literature describing the outcome of pregnancy in women treated with targeted pulmonary hypertension treatments.

Definition, classification and pathology of pulmonary hypertension

Pulmonary hypertension is defined as an increase in mean pulmonary arterial pressure (mPAP) 25 mm Hg or over at rest as assessed by right heart catheterisation . At the fourth World Symposium on Pulmonary Hypertension in Dana Point (2008), a clinical classification of pulmonary hypertension was agreed upon ( Table 1 ), and this has now been incorporated into the European Guidelines . Haemodynamically, pulmonary hypertension associated with left heart disease (group 2) can be characterised as post-capillary pulmonary hypertension, with a pulmonary capillary wedge pressure greater than 15 mm Hg. All other groups (groups 1,3,4,5) are defined as pre-capillary pulmonary hypertension; in these conditions, pulmonary capillary wedge pressure is 15 mm Hg or less. In people with pulmonary hypertension, cardiac output can be normal or reduced. It is useful to realise that pulmonary hypertension comprises all peoples with increased mPAP 25 mm Hg or over at rest, whereas the term pulmonary arterial hypertension (PAH) is reserved for the clinical condition of group 1 pulmonary hypertension ( Table 1 ).

The pathophysiology differs between clinical groups. In group 1 (PAH), the distal pulmonary arteries show intimal proliferation, medial hypertrophy, inflammatory and thrombotic lesions, as well as complex plexiform lesions. Pulmonary veins are only affected in group 1′. The increase in pulmonary vascular resistance (PVR) is the result of multiple contributing factors. These include vasoconstriction resulting from an imbalance of vasodilator and vasoconstrictor substances associated with endothelial dysfunction, as well as inflammation, proliferation, and thrombosis. In group 2 (pulmonary hypertension caused by left heart disease), the backward transmission of the elevated left atrial pressure leads to an increase in capillary wedge pressure and mPAP. The pulmonary veins are enlarged and thickened, interstitial oedema is observed, and intimal fibrosis and medial hypertrophy may occur. When the mPAP is disproportionally elevated compared with the capillary wedge pressure (increased transpulmonary gradient) the PVR will also be increased. Reversible vasoconstrictive or fixed obstructive pulmonary hypertension can be present. Group 3 (pulmonary hypertension caused by lung diseases and hypoxia) is characterised by vasoconstriction reactive to hypoxia, as well as by inflammation, whereas toxic effects of smoke and mechanical effects (emphysema) may play a role. A loss of capillaries occurs and medial hypertrophy and obstruction of distal arteries caused by intimal proliferation are also seen.

Group 4 (chronic thrombo-embolic pulmonary hypertension) is characterised by organised thrombi leading to pulmonary arterial stenosis or occlusion. Coagulation abnormalities may play a role in the pathogenesis of thormbo-embolic pulmonary hypertension. Local thrombosis can occur. In non-obstructed areas, abnormalities indistinguishable from the lesions found in PAH are found.

Group 5 is a heterogeneous group, and the pathobiology and physiology is not well defined .

Definition, classification and pathology of pulmonary hypertension

Pulmonary hypertension is defined as an increase in mean pulmonary arterial pressure (mPAP) 25 mm Hg or over at rest as assessed by right heart catheterisation . At the fourth World Symposium on Pulmonary Hypertension in Dana Point (2008), a clinical classification of pulmonary hypertension was agreed upon ( Table 1 ), and this has now been incorporated into the European Guidelines . Haemodynamically, pulmonary hypertension associated with left heart disease (group 2) can be characterised as post-capillary pulmonary hypertension, with a pulmonary capillary wedge pressure greater than 15 mm Hg. All other groups (groups 1,3,4,5) are defined as pre-capillary pulmonary hypertension; in these conditions, pulmonary capillary wedge pressure is 15 mm Hg or less. In people with pulmonary hypertension, cardiac output can be normal or reduced. It is useful to realise that pulmonary hypertension comprises all peoples with increased mPAP 25 mm Hg or over at rest, whereas the term pulmonary arterial hypertension (PAH) is reserved for the clinical condition of group 1 pulmonary hypertension ( Table 1 ).

The pathophysiology differs between clinical groups. In group 1 (PAH), the distal pulmonary arteries show intimal proliferation, medial hypertrophy, inflammatory and thrombotic lesions, as well as complex plexiform lesions. Pulmonary veins are only affected in group 1′. The increase in pulmonary vascular resistance (PVR) is the result of multiple contributing factors. These include vasoconstriction resulting from an imbalance of vasodilator and vasoconstrictor substances associated with endothelial dysfunction, as well as inflammation, proliferation, and thrombosis. In group 2 (pulmonary hypertension caused by left heart disease), the backward transmission of the elevated left atrial pressure leads to an increase in capillary wedge pressure and mPAP. The pulmonary veins are enlarged and thickened, interstitial oedema is observed, and intimal fibrosis and medial hypertrophy may occur. When the mPAP is disproportionally elevated compared with the capillary wedge pressure (increased transpulmonary gradient) the PVR will also be increased. Reversible vasoconstrictive or fixed obstructive pulmonary hypertension can be present. Group 3 (pulmonary hypertension caused by lung diseases and hypoxia) is characterised by vasoconstriction reactive to hypoxia, as well as by inflammation, whereas toxic effects of smoke and mechanical effects (emphysema) may play a role. A loss of capillaries occurs and medial hypertrophy and obstruction of distal arteries caused by intimal proliferation are also seen.

Group 4 (chronic thrombo-embolic pulmonary hypertension) is characterised by organised thrombi leading to pulmonary arterial stenosis or occlusion. Coagulation abnormalities may play a role in the pathogenesis of thormbo-embolic pulmonary hypertension. Local thrombosis can occur. In non-obstructed areas, abnormalities indistinguishable from the lesions found in PAH are found.

Group 5 is a heterogeneous group, and the pathobiology and physiology is not well defined .

Haemodynamic and haemostatic changes in pregnant women with pulmonary hypertension

Early in pregnancy, plasma volume starts to increase and, by the end of the second trimester, an increase in plasma volume of 40% volume is achieved. Red blood cell mass increases by 20–30%. Systemic vascular resistance decreases. As a result of these changes, cardiac output increases. In normal pregnancy, this is achieved mainly by an increase in stroke volume in the first and second trimester, whereas, later in pregnancy, heart rate also increases and contributes to the increase in cardiac output. During delivery and postpartum, there is a further increase in cardiac output and blood volume, caused by pain, anxiety, and volume shifts, including autotransfusion during uterine contractions . In healthy women, the pulmonary circulation adapts to the increases in blood volume and cardiac output by pulmonary vasodilatation, preventing pulmonary pressures rising during pregnancy. In women with pulmonary hypertension, the pulmonary circulation is unable to cope with these haemodynamic changes as a result of pulmonary vascular remodelling. Therefore, pulmonary pressures will rise when cardiac output increases. Moreover, the right ventricle may not be able to sufficiently increase cardiac output, and dyspnoea, heart failure, and syncope may occur. Pulmonary hypertension is not uncommonly a new diagnosis during pregnancy, as the haemodynamic burden of pregnancy can provoke symptoms that were previously not present. In women with Eisenmenger syndrome, the combination of a fixed pulmonary vascular resistance and decrease in systemic vascular resistance leads to increased right-to-left shunt and hypoxia .

Pregnancy is a hypercoagulable state owing to increased platelet aggregation, increased concentrations of fibrinogen and clotting factors, and impairment of venous return by the enlarged uterus. This may result in enhancement of pulmonary vascular thrombosis, as well as peripheral venous thrombosis with risk of pulmonary embolism, further aggravating or causing pulmonary hypertension during pregnancy. Women with Eisenmenger syndrome, who have an intra-cardiac right-to-left shunt, are at increased risk of paradoxical emboli during pregnancy. These women frequently have a pro-thrombotic state, and are also at increased risk of bleeding.

Maternal pregnancy outcome

Despite the well-recognized risk of pregnancy, pulmonary hypertension could not be identified as a predictor of maternal outcome in two large studies on pregnancy outcome in women with heart disease . This can be explained by the low prevalence of pulmonary hypertension in these two studies, which were carried out in western countries. Pulmonary hypertension is a rare condition in women of fertile age and, with the diagnosis, women are generally advised against pregnancy. In a Korean study on pregnancy in women with congenital heart disease, pulmonary hypertension was an independent predictor of maternal as well as of offspring outcome . Pulmonary hypertension predicted the occurrence of heart failure during pregnancy in the European Registry on Pregnancy and Cardiac Disease .

Two previous systematic reviews described the outcome of pregnant women with pulmonary hypertension. The first review covered the years 1978–1996 and described 125 pregnancies. Maternal mortality was observed in 38% of these pregnancies and was 30% in primary pulmonary hypertension, 36% in Eisenmenger syndrome, and 56% in other causes of pulmonary hypertension . The second review was published in 2009, covered the years 1997–2007, and included 73 pregnancies. Maternal mortality was 25%, which was significantly lower than in the previous era ( P = 0.047). Women with idiopathic PAH had a mortality of 17%, mortality in women with pulmonary hypertension related to congenital heart disease was 28%, and, in women with other causes of pulmonary hypertension, it was 33% . Most deaths occurred after delivery in both reviews. Causes of death were right ventricular failure, sudden death, and pulmonary thrombo-embolism. Independent predictors of maternal mortality were late diagnosis and late hospital admission in the early era. In the systematic review covering the years 1997–2007, maternal mortality was higher in primips and in women who delivered by caesarean section under general anaesthesia. Importantly, pulmonary artery pressure was not a predictor of outcome in both reviews. New York Heart Association (NYHA) functional class and the use of advanced pulmonary hypertension treatments (which was reported in 73% in the last review) were also not found to predict maternal outcome.

In many studies of pregnant women with underlying heart disease, NYHA class is, however, an established predictor of pregnancy outcome .

Two studies describing a total of 54 pregnancies have been published since the last review, which specifically focus on the severity of pulmonary hypertension, functional class, and their relationship to maternal outcome ( Table 2 ) . Women with mild pulmonary hypertension (systolic pulmonary artery pressure (sPAP) less than 50 mm HG or mPAP less than 40 mm Hg) had less increase in pulmonary arterial pressure during pregnancy, were more often in NYHA class I or II in early pregnancy ( P < 0.0001), and deteriorated less often in NYHA class ( P < 0.0001). A few people with mild PAH deteriorated from NYHA class II to class III/IV. Maternal mortality was surprisingly low in these two studies, with only two deaths in 54 women (4%). Both deaths were in women with severe pulmonary hypertension. Terminations and miscarriages are excluded from this analysis. In both studies, women with severe pulmonary hypertension delivered earlier than women with mild pulmonary hypertension, with the decision to deliver based on clinical or haemodynamic deterioration. These planned early deliveries may have contributed to the good outcome. Advanced treatments (e.g. prostacyclin analogues, phosphodiesterase inhibitors, and endothelin receptor antagonists [ERA]) were not available for the women in these two studies.

In a recent Chinese study of 30 pregnancies, maternal mortality was reported in 17%. In this study, only a few women were treated with targeted pulmonary hypertension treatments .

In another recent study describing 20 pregnancies and six terminations, a poor maternal outcome (death or transplantation) occurred in four out of the 20 pregnancies (20%) . Women who died or required transplantation ( n = 4) had higher mPAP than women who survived and delivered healthy babies ( n = 16) (mPAP 71 ± 5 v 36 ± 15 mm Hg). Of note, all women that were responders to calcium channel blocker therapy ( n = 8) had successful pregnancies. These women had near normal pulmonary pressures with calcium channel blocker therapy (mPAP 30 ± 6 mm Hg), and treatment was continued throughout pregnancy. Several other women used advanced pulmonary hypertension treatments .

In summary, these four recent studies seem to confirm an improved prognosis of pregnancy in women with pulmonary hypertension. In these studies, prognosis seems better in women with mild pulmonary hypertension, especially when they are in NYHA class I or when they have well-controlled pulmonary hypertension with calcium blocker therapy.

Outcome of termination of pregnancy and miscarriage has rarely been described. A recent prospective study of 26 pregnancies in women with pulmonary hypertension included six induced abortions, mainly in women with severe pulmonary hypertension. No complications occurred . Another study included three miscarriages at 6–12 weeks of pregnancy; maternal outcome in these women was good .