Women with pulmonary hypertension have a high risk of morbidity and mortality during pregnancy. The inability to increase cardiac output leads to heart failure while further risks are introduced with hypercoagulability and decrease in systemic vascular resistance. There is no proof that new advanced therapies for pulmonary hypertension decrease the risk, though some promising results have been reported. However, pregnancy should still be regarded as contraindicated in women with pulmonary hypertension. When pregnancy occurs and termination is declined, pregnancy and delivery should be managed by multidisciplinary services with experience in the management of both pulmonary hypertension and high-risk pregnancies.
Keywords: Pregnancy, Heart disease, Pulmonary hypertension, Eisenmenger syndrome, Management
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Introduction
Pulmonary hypertension is a rare disorder that can be present in women of child-bearing age. During pregnancy it is associated with high morbidity and mortality in all defined clinical groups of pulmonary hypertension (Table 1). Therefore, pulmonary hypertension is regarded a contraindication for pregnancy [1–4]. However, sometimes women become pregnant despite being advised against pregnancy, or pulmonary hypertension is newly diagnosed during pregnancy. These women are usually advised to terminate the pregnancy even though termination itself is also associated with maternal risks. Some women do not regard termination as an acceptable option and carry on with their pregnancy. This special article discusses the definition, classification, pathophysiology and clinical features of pulmonary hypertension during pregnancy, it reviews the literature on outcome and covers the management of pregnancy in women with pulmonary hypertension, including the effects of advanced anti-pulmonary hypertension therapies.
Table 1
Table 1
Summarised clinical classification of pulmonary hypertension
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Definition and classification
Pulmonary hypertension is defined as an increase in mean pulmonary arterial pressure (mPAP) ≥25 mmHg at rest as assessed by right heart catheterisation [2]. It can be present in multiple clinical conditions. The clinical classification of pulmonary hypertension is summarised in Table 1 [2]. Haemodynamically, group 1, 3, 4, and 5 are characterised by a pulmonary wedge pressure 15 mmHg. The histopathology differs between the clinical groups and can include medial hypertrophy, intimal proliferation, fibrosis, thrombotic lesions and venous thickening. Complex plexiform lesions are only present in group 1 (pulmonary arterial hypertension). Vasoconstriction, obstruction, vascular remodelling and endothelial dysfunction contribute to the increase in pulmonary vascular resistance [2, 5].
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Pathophysiology related to pregnancy
The normal physiological changes of pregnancy are poorly tolerated by women with pulmonary hypertension. Pregnancy is associated with increased plasma volume and decreased systemic vascular resistance, both resulting in an increase in cardiac output. In healthy women a decrease in pulmonary vascular resistance accommodates the requirements for increased cardiac output. In women with pulmonary hypertension, pulmonary vascular disease prevents the fall in pulmonary vascular resistance, leading to a rise in pulmonary artery pressure with increased cardiac output. Ultimately, the necessary increase in cardiac output can not be achieved resulting in right heart failure. The leftward shift of the interventricular septum increases, impairing diastolic filling of the left ventricle and further compromising cardiac output. Moreover, the hypercoagulability of pregnancy increases the risk of pulmonary emboli and pulmonary arterial thrombosis. Paradoxical emboli are a risk in women with a patent foramen ovale or Eisenmenger syndrome. Women with Eisenmenger syndrome are at particular risk of increased right-to-left shunting due to the decrease in systemic vascular resistance, which results in increased hypoxia, thus aggravating pulmonary vasoconstriction and right heart failure [5, 6]. Hypoxia can also lead to syncope and sudden death in this group of patients.
During labour and delivery the risk of complications increases due to volume shifts resulting from blood loss and uterus contractions, vasovagal reaction to pain, acidosis and hypercarbia leading to a further increase in pulmonary vascular resistance, and an increased risk of thromboembolic complications.
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Clinical features and diagnosis
Fatigue and exertional dyspnoea are the most frequent presenting symptoms. They are due to reduced cardiac output and impaired oxygen transport. Since these symptoms also occur in healthy pregnant women, the diagnosis during pregnancy can be delayed. Usually the symptoms aggravate during the course of pregnancy and dyspnoea can occur at rest. Chest pain is often present and reflects right ventricular ischaemia. Syncope can result from low cardiac output. Several signs of right heart failure, such as hepatomegaly, ascites, and ankle oedema, may be hard to identify during pregnancy or resemble normal pregnancy. Elevated jugular venous pressure and a loud pulmonary component of the second heart sound are useful signs that point to the diagnosis. Echocardiography will usually reveal the diagnosis. The threshold to perform echocardiography should be low during pregnancy in women with dyspnoea [1]. Right heart catheterisation is required to confirm the diagnosis and gives useful additional information on pulmonary vascular resistance and cardiac output. It can be performed with relatively low foetal risk since radiation can be avoided. During pregnancy it should be reserved for women in whom the results have therapeutic consequences, because of the associated risks of thromboembolism and infection. Functional capacity needs to be evaluated (New York Heart Association or World Health Organization functional class [2]) and exercise capacity can be assessed with an un-encouraged six-minute walking test.
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Prognosis of pregnancy in women with pulmonary hypertension
In two large series identifying predictors of maternal cardiac complications during pregnancy in women with heart disease, pulmonary hypertension did not emerge as a predictor of adverse outcome [7, 8]. This is probably due to low prevalence since women with pulmonary hypertension are generally advised against pregnancy. Based on disease-specific literature, there is no doubt that pulmonary hypertension is associated with severe maternal complications and high mortality. Two systematic literature reviews have described the outcome of pregnancy in women with pulmonary hypertension, covering a total period of almost 30 years and comprising 198 pregnancies [9, 10]. The mortality of women with Eisenmenger syndrome (N = 102) was 36% in the first review (1978–1996) and 28% in the second review (1997–2007). Most women died in the first month after delivery and the main causes of death were heart failure and sudden death, while pulmonary thromboembolism was another frequent cause. In women with idiopathic pulmonary hypertension (N = 56) mortality was 30% in the first and 17% in the second review. Again most women died after delivery and heart failure was an important cause of mortality. Women with other causes of pulmonary hypertension (N = 40) had a mortality of 56% and 33% respectively. Nearly all fatalities occurred early post-partum and death was mainly due to heart failure while sudden death and thromboembolism also contributed. Total mortality was significantly higher in the earlier period (1978–1996) compared with the last 10 years (1997–2007), 38% versus 25% (p = 0.047). However, since many case reports or very small series were included in the reviews, publication bias can not be excluded. In the first review (1978–1996), late diagnosis of pulmonary hypertension (p = 0.002, odds ratio 5.4) and late hospital admission (p = 0.001, odds ratio 1.1 per week of pregnancy) were independent predictors of maternal mortality. In the second review (1997–2007), primigravidae and women who received general anaesthesia at delivery had a higher risk of death. Women with previous pregnancies may have had a lower risk because they had less severe disease, since they have already survived a pregnancy. The higher risk for women who had general anaesthesia may be due to the inherent risks of general anaesthesia, or because general anaesthesia was more often applied in women with a more grave clinical condition [10].
It is not known if women with lower pulmonary pressures and resistance are at lower risk. Systolic or mean pulmonary artery pressures did not predict mortality in either of the reviews, but this is possibly explained by missing data. In the first review (1978–1996) diastolic pulmonary artery pressure was a univariate risk factor for adverse outcome. In both reviews, the majority of women who died had severe pulmonary hypertension, but also some women with mild or moderate pulmonary hypertension deteriorated. A safe cut-off value is not known [1, 2, 9, 10].
In the period covered by the second review, advanced therapy for pulmonary hypertension was becoming increasingly available, but though a significant percentage of women were treated with NO or prostacyclin analogues, the institution of advanced therapy did not predict a better outcome. The authors comment that advanced therapy was in most cases commenced late in the course of the disease, when patients were unstable or had refractory heart failure [10], and that an earlier start of these therapies will possibly improve outcome. Until recently, no evidence concerning this subject was available. In 2010 a single-centre series of 10 consecutive pregnancies during 2002–2009 reported