Abstract
Despite advances in the treatment of pulmonary hypertension and improvements in obstetric care, pulmonary hypertension (PH) remains a leading cause of cardiac maternal death in the developed world. The last three decades have seen the development of effective therapies for specific forms of PH, improving patients’ symptoms and more than doubling survival in some forms of PH. Consequently there are an increasing number of women of childbearing potential with PH. Women may present for the first time, with PH in pregnancy, in the early post-partum period or patients with PH may consider pregnancy despite counselling regarding the high risks.
Introduction
Despite advances in the treatment of pulmonary hypertension and improvements in obstetric care, pulmonary hypertension (PH) remains a leading cause of cardiac maternal death in the developed world. The last three decades have seen the development of effective therapies for specific forms of PH, improving patients’ symptoms and more than doubling survival in some forms of PH. Consequently there are an increasing number of women of childbearing potential with PH. Women may present for the first time, with PH in pregnancy, in the early post-partum period or patients with PH may consider pregnancy despite counselling regarding the high risks. Over the last 70 years there have been progressive improvements in reported maternal mortality in women with PH, but it remains significant at 10–38%. Guidelines and statements from expert bodies recommend that women with known PH be counselled regarding the high risks of pregnancy, be provided with clear contraceptive advice and in its eventuality be offered termination of pregnancy. For patients with previously undiagnosed PH who present at an advanced stage of pregnancy, or those with known PH who wish to plan pregnancy despite counselling regarding the high risks, there is evidence that expert care in PH centres adopting a multiprofessional approach may improve survival, although the mortality remains high.
Pulmonary Hypertension: Definition and Classification
International guidelines define pulmonary hypertension (PH) at cardiac catheterization as a mean pulmonary artery pressure (mPAP) of at least 25 mmHg.1 More recently, the 6th World Symposium on Pulmonary Hypertension (WSPH) proposed a change in the definition to a mPAP of greater than 20 mmHg and a pulmonary vascular resistance of a least 3 Wood Units (240 dyn sec cm−5).2 This change is based on new data from normal subjects that the mPAP is 14.0±3.3 mmHg, with mPAP>20 mmHg corresponding to above the 97.5th centile.
Pulmonary hypertension has many causes. Improved understanding of pathophysiology and a desire to group patients together who are likely to benefit from similar therapeutic approaches has led to an internationally recognized system of classification.3 Despite minor changes, this system of classification has remained similar over the last two decades.2 There are five major groups: Group 1, pulmonary arterial hypertension (PAH),Group 2, PH due to left heart disease (PH-LHD),Group 3, PH due to lung disease and/or hypoxia (PH-RESP), Group 4, PH due to pulmonary artery obstructions, with the vast majority of these patients having chronic thrombo-embolic pulmonary hypertension (CTEPH) and Group 5, PH with unclear and/or multifactorial aetiologies1 (Table 11.1). Identification of the form of PH is key. Not only does this define the optimal treatment, but also the prognosis.4Despite concerns regarding the risks of conducting investigations in pregnant patients and the impact on the fetus, systematic evaluation of pregnant women with suspected PH is essential to aid counselling and treatment decisions. This assessment should be conducted in a specialist PH centre, ideally one with experience in managing PH and pregnancy.3
Table 11.1 Updated clinical classification of pulmonary hypertension
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Reproduced from reference 2 PH = pulmonary hypertension, PAH = pulmonary arterial hypertension
In the general population, the majority of patients with PH have mild elevations of pulmonary artery pressure in the setting of cardiac (Group 2) and respiratory disease (Group 3). In patients presenting with severe PH in pregnancy the vast majority of patients are in Group 1 (PAH) and Group 4 (CTEPH).
Group 1 PAH
In PAH, a small vessel vasculopathy results in progressive obliteration of the pulmonary vascular bed, increased right ventricular afterload and, if untreated, right heart failure and death, with a median survival of less than three years. In the general population and also among pregnant women with PAH, the three most commonly encountered forms are: idiopathic PAH (IPAH), previously known as primary pulmonary hypertension for which no cause is identified, PAH in association with connective tissue diseases, most commonly systemic sclerosis (PAH-CTD) or in association with congenital heart disease (PAH-CHD).4 IPAH is rare, with a prevalence estimated between 15–52/million.3–8 Genetic abnormalities are described in patients with PAH and this may have implications for patients considering pregnancy or wishing to explore potential options such as surrogacy. Between 11% and 40% of patients with IPAH and 70% of patients with a family history of PAH have a mutation in the gene encoding bone morphogenetic receptor-2 (BMPR2). IPAH is more common in women, although female carriers of genetic abnormalities are significantly more likely to develop IPAH than their male counterparts. The mechanism underlying the increased incidence of IPAH in women is not well understood. PAH in association with congenital heart disease is a common form of PH presenting in pregnancy, and the long-term prognosis is related to the underlying form of congenital heart disease. In patients with an underlying connective tissue disease, systemic sclerosis-related PAH is the commonest form seen (the prevalence of PAH is approximately 10% in patients with systemic sclerosis and <1% in systemic lupus erythematosus). Before the advent of specific PH therapies, the median survival was 2.8 years in IPAH. This has improved, with women of childbearing age having an approximate 75% chance of being alive at five years,8 better than their male counterparts. Specific drug therapies are available for PAH and include oral therapies targeting: (i) the nitric oxide pathway, such as phosphodiesterase inhibitors (sildenafil and tadalafil) and cyclic GMP stimulators (riociguat) and (ii) the endothelin-1 pathway, using endothelin receptor antagonists (ambrisentan, bosentan and macitentan). Prostanoid analogues generally require more complex delivery systems (epoprostenol (intravenous (iv)), iloprost (nebulized (neb), iv) and treprostinil (subcutaneous (sc), neb, iv)) although an orally active selective IP (prostacyclin receptor) agonist (selexipag) has recently been licensed for the treatment of PAH. There are limited data on the safety and use of drugs used to treat PAH in pregnancy and the risk and benefit of these therapies needs to be considered on an individual basis.9
Group 4 PH due to Pulmonary Artery Obstructions Including CTEPH
CTEPH occurs following pulmonary thromboembolism (PTE) in approximately 3.8%10 of cases. The elevated pulmonary artery pressure is due to obstructions in the pulmonary vascular bed as a consequence of an organized clot and the development of a small vessel vasculopathy similar to the changes seen in PAH. The effects on the heart in CTEPH are very similar to those in PAH. In contrast to other forms of PH this form can be potentially cured by an operation (pulmonary endarterectomy). This is a major operation requiring open heart surgery and a prolonged period on cardiopulmonary bypass. Drug therapies such as those for PAH can be considered in patients with CTEPH. Randomized controlled studies have demonstrated benefit in patients with disease considered too distal for surgery or in patients with residual disease following surgery. These include the cGMP stimulator, riociguat, and the endothelin receptor antagonist, macitentan. A number of prospective and retrospective studies have highlighted potential benefits using other PAH therapies, although the evidence for their use is suboptimal.3,5 More recently, balloon pulmonary angioplasty has shown benefit in selected patients with CTEPH, but this requires repeated interventions. Given the risks of undertaking major cardiothoracic interventions in pregnant women with CTEPH wishing to continue pregnancy, targeted drug therapy has been used to bridge patients to delivery and successful pulmonary endarterectomy.11
Group 2 PH Owing to Left Heart Disease, Group 3 PH Owing to Lung Disease and/or Hypoxia and Group 5 PH Owing to Multifactorial Mechanisms
In contrast to patients with PAH and CTEPH, where treatment directed at the pulmonary vasculature improves outcome, in PH due to cardiac and respiratory disease, treatment should be aimed at the underlying cause. Treatment with drugs that dilate the pulmonary arterioles and increase blood flow into the lungs can precipitate pulmonary oedema in patients with pulmonary venous hypertension. In areas of the world where mitral stenosis remains common, patients may present with pulmonary hypertension as a consequence of mitral stenosis. In these patients, urgent therapy directed at the mitral valve is warranted. PH owing to lung disease and/or hypoxia is much less common in younger patients. In general, the extent of lung disease needed to cause PH tends to be severe and the degree of pulmonary artery pressure elevation usually modest. In the authors’ experience, although cystic fibrosis can cause extensive lung destruction, pulmonary hypertension is rarely seen in this group of patients and is usually confined to those with end-stage disease in the setting of ventilatory failure. Patients with PH due to unclear and/or multifactorial aetiologies have a variety of conditions with varied mechanisms. There is limited data regarding treatment of these conditions and the use of drug therapies is described in small numbers of patients.
Clinical Features of Pulmonary Hypertension
Patients who present with PH usually complain of progressive shortness of breath and fatigue.3 These symptoms are related to the inability of the right heart to generate a sufficient cardiac output as a consequence of right ventricular dysfunction. The initial symptoms can be mild and occur only on exertion. However, symptoms progress and in more advanced cases are accompanied by chest pain (similar to angina, reflecting right ventricular ischaemia) and presyncope or syncope on exercise. Syncope usually reflects a low cardiac output and indicates severe disease. As right heart failure develops, patients may develop ankle oedema and ascites. It should be noted that ankle swelling occurs very late in the natural history of disease, and in young patients may never occur. Signs on examination may initially be subtle and include tachycardia, elevated jugular venous pulsation, right ventricular heave, loud second heart sound, pan-systolic murmur due to tricuspid regurgitation, early diastolic murmur due to pulmonary regurgitation, and ascites and pedal oedema in advanced disease. It should be noted that hypoxaemia is rare in PAH in the absence of a right-to-left shunt or co-existing respiratory disease, and physicians should not be reassured by the absence of hypoxaemia.
Diagnosis of Pulmonary Hypertension in Pregnancy
In the pregnant patient, in whom the circulation is hyperdynamic, a loud second heart sound and flow murmurs are not uncommon. A new diagnosis of PH in pregnancy, although very rare, requires a high degree of awareness. Of pregnant patients managed with PH, just under half the patients will present for the first time with PH in pregnancy.
This diagnosis should be considered in pregnant patients with increasing breathlessness in the first and second trimesters, particularly if significant and associated with syncope (reflecting an inability to cope with the cardiovascular demands of pregnancy). In the immediate post-partum period, rapid decompensation of patients can occur and occasionally this is the first presentation of PH.
Electrocardiogram (ECG) and Chest X-ray (CXR) may be abnormal in up to 90% of cases with severe disease, but cannot be used in clinical practice to exclude PH. These investigations are more likely to identify an alternative cause for breathlessness. Lung function testing should also be performed in suspected pulmonary hypertension. It may identify an alternative potential cause for breathlessness, although caution should be exercised if the abnormalities in lung function are minor and the woman remains very limited. The most common abnormality in lung function seen in IPAH is a reduction in gas transfer (TLCO, also referred to as DLCO) in the setting of normal spirometry. Although a normal TLCO is uncommon in PH in the absence of a left-to-right shunt, a normal TLCO does not exclude the diagnosis. The diagnosis of PH is usually suggested by echocardiography.1 The European Society of Cardiology (ESC) and European Respiratory Society (ERS) Guidelines1 recommend echocardiography as the first-line non-invasive investigation in patients with suspected pulmonary hypertension. These guidelines recommend establishing a probability of pulmonary hypertension based on an estimate of systolic pulmonary artery pressure and other echocardiographic signs of pulmonary hypertension (including paradoxical septal motion, dilated right atrium and right ventricle). Systolic pulmonary artery pressure (sPAP) can be estimated by adding an estimate of right atrial pressure (usually estimated at 5 mmHg) to the tricuspid gradient (TG) which is equal to 4V2 where ‘V’ is the peak velocity of the jet of tricuspid regurgitation. A jet of tricuspid regurgitation can be seen in approximately 90% of patients and is normal. Due to difficulties and confusion in interpreting the results of echocardiography, the ERS/ESC guidelines recommend using the TG peak velocity rather than estimating sPAP. Those with a peak velocity of >3.4 ms–1 (equivalent to a TG of 46 mmHg) are considered at high risk of having PH. In patients with idiopathic PAH, the peak TG velocity is often in >4 ms–1 with an estimated sPAP in excess of 70 mmHg. The diagnosis may also be suggested by other investigations, e.g. computed tomography pulmonary angiography (CTPA) performed for other reasons such as suspected pulmonary embolism. Review of the CT may show evidence of pulmonary artery enlargement (>3 cm) and dilated right-sided chambers which are easily appreciated, but often overlooked.12 It is absolutely essential that if a diagnosis of PH is suspected, patients are referred to specialists experienced in the assessment of PH to confirm or refute the diagnosis. Right heart catheterization should be considered in patients with suspected pulmonary hypertension to confirm its presence or absence, but this should be performed in a specialist centre. Depending on the clinical presentation, this may be delayed until after delivery. Facilities for emergency caesarean section must be available at the time of right heart catheterization in the unlikely event of complications.
Hormonal and Cardiopulmonary Changes During Pregnancy, Labour and the Post-partum Period
Pregnancy results in major physiologic changes to meet the metabolic demands of both the fetus and the mother, and this has recently been extensively reviewed in the Pulmonary Vascular Research Institute (PVRI) statement on pregnancy and pulmonary hypertension.13 These changes include haemodynamic, anatomical and biochemical changes throughout pregnancy, during delivery and the post-partum period.
Pregnancy causes well-known hormonal changes and initially there is a rise in serum β human chorionic gonadotropin (hCG) which triggers the release of relaxin, a substance with vasodilatory properties. Following increases in hCG, progesterone and oestrogen, there is a reduction in systemic and pulmonary vascular resistance in pregnancy in the absence of disease. Overall mean pulmonary arterial pressure remains unchanged due to increased cardiac output, which increases steadily as a result of an increase in both heart rate and stroke volume throughout pregnancy. Cardiac output reaches a peak at approximately 28 weeks, and in the final trimester may plateau, increase or slightly decrease until the onset of labour.
Blood volume rises over the course of gestation, due to an increase in plasma volume, and exceeds the non-pregnant level by 10% in the 8th week, reaching a peak of 40–50% above pre-pregnancy levels between the 32nd and 36th weeks and then remaining unchanged until full term. This causes dilutional anaemia and decreased blood viscosity that may aid in decreasing cardiac work in the normal state. Furthermore, progesterone-mediated increases in respiratory tidal volume compensate for an increase in oxygen consumption of approximately 30% during pregnancy. Sex hormones blunt hypoxic pulmonary artery vasoconstriction via increased endothelial nitric oxide (NO) and prostacyclin production and decreased endothelin-1 (ET-1) activity, all key players altered in the PAH disease state and direct targets of PAH-specific therapies.
During labour, each uterine contraction increases the cardiac output by a further 10–40%, resulting in a total increase of 60–80% above pre-pregnancy levels. This can be attenuated, but not abolished, by analgesia. Changes in cardiac output are affected by body posture, particularly in the third trimester. Delivery results in aortocaval decompression and the redistribution of blood volume, with a transient increase in cardiac output, although variable amounts of blood loss due to either vaginal delivery or caesarean section leads to unpredictable changes in circulating blood volume, cardiac output and blood pressure. Whereas blood volume rapidly returns to normal, it takes up to two weeks for major haemodynamic changes to return to pre-pregnancy levels after vaginal delivery and takes longer after caesarean section. It may take more than six months for subtle haemodynamic changes to return to normal.
Maternal Risks of Pregnancy in Pulmonary Hypertension
The maternal risks of continuing pregnancy in patients with pulmonary hypertension reflect the effects of pregnancy on PH, other medical co-morbidities and obstetric-related risk factors.
Data on maternal mortality in PH in pregnancy come from various sources, including single centre reports, systematic analyses of the published literature and, to date, a single prospective multicentre study. Each has inherent limitations. They include predominantly patients with PAH and a number have concentrated on PAH-CHD. Gleicher et al.14 identified a maternal mortality of 52% in Eisenmenger syndrome between 1948–1978. Weiss et al.15 undertook a comprehensive systematic evaluation of the literature between 1978–1996. Patients with IPAH had a mortality of 30%, PAH-CHD 36% and those with PH associated with other conditions, including PAH-CTD, Takayasu’s arteritis and others, had a mortality of 56%. In the most recent systematic review, Bedard et al.16 compared the outcome of PH in pregnancy between 1997–2007 with data from Weiss 1978–1996, using similar methodology. In addition to highlighting that published cases of PH in pregnancy are uncommon, with only 73 pregnant women with PH, the mortality remained significant (although lower than reported by Weiss) with an overall mortality at 25% vs 38% for all patients.16 The mortality in IPAH was 17%, PAH-CHD 28% and 33% in other forms of PH. This study also reported a high mortality in the first week post-partum, a higher mortality in first pregnancies and with the use of general anaesthesia compared to regional anaesthetic techniques. Interestingly, there was also a higher proportion of premature deliveries and a lower proportion of vaginal deliveries suggesting a more proactive approach to managing PH in pregnancy compared to the earlier data presented by Weiss.
There are reports from several single-centre and multicentre studies, including our own. Over the last 20 years these have suggested that outcomes may be improved when patients receive specialist care involving a multiprofessional team, with an overall mortality in the region of 10%, although numbers in these studies tend to be small 11,17–20. A prospective multicentre study enrolled 26 pregnancies with PAH at PH specialist centres; there were 6 terminations, with 20 patients continuing pregnancy of whom 2 had miscarriages (both died), 18 delivered, and 2 patients underwent transplantation due to deterioration in the post-partum period, with an overall mortality of 10% of those continuing pregnancy. This group of patients included a large number of patients who were long-term responders to calcium antagonists (these patients represent just 5% of patients with IPAH).21 Nonetheless, survival was excellent for patients with IPAH who were vasodilator responders who were stable on treatment with calcium channel blockers at the time of pregnancy.
Despite improvements in the medical management of pulmonary hypertension, better obstetric care and evidence of a multiprofessional approach to high-risk pregnancy, the risk of maternal death remains very high in patients with pulmonary hypertension. The risk for an individual patient depends on a variety of factors, including disease severity, but in expert centres the risk appears to be at least 10%, and for those with severe PAH and poorly controlled disease, the risk will be significantly higher. Whether a ‘low-risk’ group can be identified will only be answered over time, but current international guidelines recommend that patients with PAH avoid pregnancy.1,9 In addition, there is very little data on long-term maternal outcomes following pregnancy in patients with PH.
Factors Influencing Maternal Mortality
The pre-existence or development of PH in pregnancy poses a severe risk of maternal death. This is related to interactions between cardiovascular stresses and complex physiological changes occurring during pregnancy in the context of impaired right ventricular function and pulmonary vascular disease.22 Studies in pregnancy are limited due to the small numbers of patients and the non-invasive assessment of haemodynamic pararmeters. Nonetheless, if patients with PH are considering pregnancy, or patients with PH present already pregnant, an understanding of factors influencing mortality is key to counselling patients and establishing management plans.
Understanding physiological changes in pregnancy and how they may impact on cardiac function in PH, in addition to understanding the unpredictable nature of PH, is also key to understanding how to optimize management strategies during various stages of pregnancy and the post-partum period. The risk of maternal death is particularly high in the first week post-partum and in clinically deteriorating patients in the first two trimesters of pregnancy.
Inability to Meet the Cardiovascular Demands of Pregnancy
The increased blood volume and cardiac output in pregnancy and during labour have been described above. For patients with PAH and significantly impaired cardiovascular function, the cardiovascular demands of pregnancy may not be met. Typically these patients will deteriorate in the first or second trimesters, and without intervention, the prognosis is very poor. In a single-centre series from France, three patients deteriorated between 12 and 23 weeks, with two dying and one patient surviving following termination of pregnancy.27 For patients contemplating pregnancy, it is important to emphasize that the natural history of pulmonary hypertension in pregnancy is very variable. Although patients may initially be relatively well if they do embark on pregnancy, they may deteriorate in the second trimester and, if so, may need to undergo pregnancy termination to save the life of the mother. In societies where abortion is restricted, this may be impossible.
Direct Effects of Vasoactive Peptides on the Pulmonary Vasculature
Pregnancy is a ‘vasodilatory state’ with a number of hormones and vasoactive peptides causing a reduction in both systemic and pulmonary vascular resistance. In the post-partum period, changing levels of hormones and vasoactive constrictors and vasodilators may result in intense pulmonary vasoconstriction. This may be an important factor in the high mortality observed in the early post-partum period.
Impact of Fluid Shifts in the Peri-partum Period
A number of changes occur around the time of delivery. Some of these changes may be mitigated by performing elective caesarean section prior to the onset of labour. The third stage of labour with delivery of the placenta and uterine contraction releases up to 500 ml of blood into the circulation.28 In addition, decompression of the aorta and vena cava following delivery increases the venous return. This may be partly offset by blood losses during delivery. Careful peri-partum management of fluid balance is crucial, as fluid shifts can increase right atrial pressure and have severe adverse effects on right ventricular function. Volume-mediated right ventricular dilation can cause a precipitous reduction in cardiac output29 due to a negative Starling response, which can be life-threatening. This can be mitigated by careful monitoring of fluid status, measurement of central venous pressures and augmentation of the physiological diuresis occurring around delivery with diuretic therapy.
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