close surveillance and monitoring throughout pregnancy and the puerperium (including serial imaging and biomarker testing).
6. It is important to identify the cause of the condition so therapy can be tailored appropriately.
7. Management in a tertiary center with advanced expertise in the management of pulmonary arterial hypertension is clearly vital .
Introduction
Pulmonary hypertension (PH) was previously thought to be a rare condition with a relentlessly progressive course and few treatment options. It is increasingly recognized in association with other conditions, and recent advances have resulted in the development of eff ective therapies. As a consequence, patients with PH
have an increased life expectancy and more women of childbearing age with known PH are considering pregnancy.
Pregnancy in patients with PH is associated with a high risk of maternal death regardless of the cause. Reports in the literature advocate a variety of approaches to the management of PH during preg- nancy but the mortality remains high. From 2004 onwards, a number of studies have shown improved outcomes compared with historical studies and reg- istries. Modern management strategies have included the early use of pulmonary vasodilator therapy, elective early delivery, the increasing use of cesarean section, and a multidisciplinary approach.
Currently, we recommend that patients with PH are strongly advised of the high risks of pregnancy, along with clear contraceptive advice and, if needed, early interruption of pregnancy. When patients who are fully informed and understand the risks of doing so choose to continue their pregnancies, early treatment with targeted pulmonary vascular therapy represents a realistic treatment option and may improve the chances of maternal survival. With timely admission to hospi- tal and close cooperation between a multidisciplinary team, a successful outcome for mother and fetus is pos- sible, although maternal mortality remains high .
Th is chapter provides an overview of the epidemi- ology, natural history, and treatment of PH and sub- sequently the challenge of managing a patient with pulmonary hypertension during pregnancy, labor, and the postpartum period.
Defi nition of PH
PH is defi ned at cardiac catheterization as a mean pul- monary artery pressure (MPAP) of ≥25 mmHg at rest,
Management of pulmonary hypertension in pregnancy
David G. Kiely , Charlie A. Elliot , Victoria J. Wilson , Saurabh V. Gandhi , and Robin Condliff e
15
although the diagnosis is usually fi rst suggested follow- ing echocardiography .[ 1 ]
Classifi cation of PH
PH is classifi ed into fi ve major groups ( Figure 15.1 ).
[ 2 ] Th is classifi cation illustrates the importance of identifying the cause of PH in defi ning both natural history and treatment. Patients with chronic thrombo- embolic pulmonary hypertension (CTEPH; Group 4) can potentially be cured by surgery (pulmonary endarterectomy).[ 3 ] Pulmonary arterial hypertension (PAH; Group 1), which includes those with idiopathic pulmonary hypertension (IPAH), PH associated with systemic to pulmonary shunts, and PH associated with connective diseases such as systemic sclerosis, is amenable to therapy with selective pulmonary arte- rial vasodilators.[ 4 ] PH may also be seen in the set- ting of cardiac disease such as mitral stenosis, and of respiratory disease, where treatment is best aimed at the underlying condition. It is rare to encounter res- piratory disease capable of causing severe PH in young
women of childbearing age. Although cystic fi brosis can cause extensive lung destruction, PH is uncom- mon, being confi ned to patients with end-stage dis- ease. Identifi cation of the cause of PH is therefore key in the pregnant patient because the cause determines the most appropriate treatment strategy .
Pathophysiology of PH
Th e hallmark of PH is an increase in workload placed on the right side of the heart. Th e precise pathological changes leading to this are dependent on disease etiol- ogy. In IPAH (formerly known as primary PH), typical changes are seen in the small arterioles, with medial smooth muscle hypertrophy, thickening or fi brosis of the intima of the vessels with in situ thrombosis and, in some cases, plexiform lesions (histological features shared with other forms of PAH).[ 5 ] In CTEPH, the increase in pulmonary vascular resistance is brought about partly by obstruction of the pulmonary vascular bed due to an “organized” thrombus that has become incorpo- rated into the vessel wall, although, interestingly, these
Figure 15.1 Classifi cation of pulmonary hypertension, identifying the forms of pulmonary hypertension for which specifi c treatment improves outcomes.
Reproduced with permission from Kiely et al .[ 2 ]
1. Pulmonary arterial hypertension Idiopathic
Heritable Drugs
Connective tissue disease HIV
Portal hypertension Congenital heart disease Schistosomiasis
Chronic obstructive pulmonary disease Interstitial lung disease
Sleep disorder Alveolar hypoventilation
Hematological
Chronic hematolytic anemia Myeloproliferative disease Splenectomy
Systemic disorders Sarcoidosis
Langerhans cell histiocytosis Lymphangioleiomyomatosis Neurofibromatosis Vasculitis Metabolic disorders Glycogen storage disease Gaucher’s disease Thyroid disorder Others
Tumor obstruction Fibrosing mediastinitis Chronic renal failure Systolic dysfunction
Diastolic dysfunction Valvular disease Pulmonary veno-
occlusive disease Pulmonary capillary hemagiomatosis
Operable Inoperable 1’
4. Chronic thromboembolic pulmonary hypertension
2. Pulmonary hypertension owing to left heart disease
5. Multifactorial/unless mechanisms
3. Pulmonary hypertension owing to lung disease/hypoxia
Optimal treatment not clear Defined treatments
Section 4: Antenatal Care: Specifi c Maternal Conditions
patients also have the histological changes of PAH.[ 6 ] Th is is the rationale for treating some of these patients with pulmonary arterial vasodilators as a bridge to pul- monary endarterectomy or as a defi nitive treatment in inoperable disease. In patients with left -sided heart dis- ease (such as impaired left ventricular function or mitral valve disease), the primary problem is that of pulmo- nary venous hypertension. In these patients, the clinical features and treatment is that of the underlying cardiac problem rather than directing therapy at the pulmonary arterial circulation. Pulmonary vaso-occlusive disease (previously known as pulmonary veno-occlusive dis- ease, but renamed to refl ect the involvement of both pulmonary arterial and venous circulations) is a rare cause of PH that has a particularly poor prognosis.[ 7 ] Th is may be worsened by pulmonary arterial vasodila- tors that can precipitate pulmonary edema.
Th is chapter concerns the management of PH involving the precapillary circulation (i.e. PAH and CTEPH) and does not discuss the management of those patients with postcapillary PH (PH associated with left -sided heart disease), for which the natural history and management diff er .
Clinical features of PH
Th e cardinal symptoms of PH are fatigue and breath- lessness due to inability of the right heart to generate a suffi cient cardiac output. Initially, this may be mild and occur only on strenuous exertion, but it is progres- sive and may later be accompanied by chest pain (simi- lar to angina, refl ecting right ventricular ischemia) and presyncope or syncope on exercise. Syncope usu- ally refl ects a low cardiac output and indicates severe disease. As right heart failure develops, patients may develop ascites and ankle edema. It should be noted that ankle swelling occurs very late in the natural his- tory of the disease, and in young patients may never occur. In patients with right to left shunts, either via a patent foramen ovale or intracardiac defect, “classical features” of right heart failure may not appear despite severe elevations of pulmonary artery pressure. Signs on examination may initially be very few, and PH may be diffi cult to identify in the pregnant patient in whom a hyperdynamic circulation, loud second heart sound, and fl ow murmurs are common ( Table 15.1 ) .
Making the diagnosis of PH
Th e nonspecifi c nature of the symptoms and the subtle nature of the signs of pulmonary vascular disease oft en
delay diagnosis.[ 2 ] Chest X-ray and/or electrocardiog- raphy are said to be abnormal in >80% of patients with established disease.[ 8 ] Th e most common noninvasive investigation suggesting PH is transthoracic echocar- diography (TTE). With TTE, an estimate of the sys- tolic pulmonary artery pressure can be derived from the jet of tricuspid regurgitation when present. Th is is calculated using the modifi ed Bernoulli equation ( p= 4× v 2 , where, “ p ” = the pressure gradient between the right atrium and ventricle and “ v ” = the peak tri- cuspid jet velocity) with an added estimate of right atrial pressure. In addition, other features may suggest PH (dilated right-sided chambers, right ventricular hypertrophy) and other causes of PH can be diagnosed (valvar heart disease, left ventricular dysfunction, intracardiac shunts). Subsequent investigation aims to confi rm or refute the presence of PH and, where pre- sent, identify the etiology and severity. Th is requires extensive investigation, including detailed imaging investigations such as computed tomography scan- ning and magnetic resonance imaging (which in add- ition to identifying a cause of PH may also be helpful in defi ning severity and prognosis [ Table 15.2 ] [ 9 – 12 ]), and usually right heart catheterization. In pregnancy, one may instinctively wish to delay investigation and have concerns regarding radiation exposure and the fi nite risk of invasive investigation, particularly when the mother wishes to continue with the pregnancy regardless of the risk to her health. However, it should be remembered that PH in pregnancy carries a grave prognosis and having more information available will help in making diffi cult management decisions. Th e need for investigation can be tailored depending on the individual patient’s presentation. Where features are classical, this may negate the need for a standard
Table 15.1 Clinical signs of advanced PH Tachycardia
Elevated jugular venous pressure Right ventricle heave
Loud P2
Pansystolic murmur from tricuspid regurgitation
Pulmonary diastolic murmur from pulmonary regurgitation Hepatomegaly ± pulsation
Ascites
Peripheral edema
P2 = pulmonary component of second heart sound; PH = pulmonary hypertension
battery of investigations. It is key that PH patients who are pregnant are managed in centers where there is experience in the management of PH and pregnancy .
Epidemiology and treatment of PH
PH is a challenging disease to diagnose, accurately classify, and treat. IPAH is a severe, progressive disease with an incidence of 1–2 cases per million of population per year and is three times more common in women.
[ 8 ] With “conventional” treatment, it has a median sur- vival time of 2.8 years from diagnosis; however, with new therapies there has been a doubling of the survival time. Younger patients have seen the greatest improve- ment in outcome, with 5-year survival approximating 80% in patients with IPAH.[ 13 ] In systemic sclero- sis, PH has a profound eff ect on the prognosis, with a 2-year survival rate of 80% in the absence of PH, in contrast to 40% with the development of PH.[ 14 ] In the setting of congenital heart disease (CHD), the pres- ence of PH has an adverse eff ect on prognosis, although
the presence of intracardiac defects (allowing blood to shunt from the right to left side in the face of high pulmonary artery pressures, thereby off -loading the right ventricle) and right ventricular hypertrophy con- fer a survival benefi t compared to that of other forms of PAH.
Until the advent of transplantation in the 1980s, no specifi c treatment was available for patients with PH. Th e last two decades have seen the development of novel therapies that have been shown to improve the symptoms and survival of patients with PH. Patients with severe disease have a 5-year survival rate of only 27% with supportive treatment, which increases to 54% with certain targeted therapies .[ 15 ] Th ese ther- apies include orally active agents such as endothelin receptor antagonists (bosentan,[ 16 ] macitentan,[ 17 ] and ambrisentan [ 18 ]), phosphodiesterase inhibitors (such as sildenafi l [ 19 ] and tadalafi l [ 20 ]), and the cyclic GMP stimulator, riociguat.[ 21 ] More complex therap- ies include prostaglandin therapy nebulized (iloprost [ 22 ]), subcutaneous (treprostinil [ 23 ]), or intravenous (epoprostenol [prostacyclin; 15 ], iloprost, [ 24 ] and treprostinil [ 25 ]). Th ere is growing experience with the use of these therapies in pregnancy, although a number, such as endothelin receptor antagonists, are contrain- dicated because of concerns regarding teratogenicity .
Targeted PH treatments are oft en complex, and their use and monitoring requires signifi cant expert- ise. As such, the investigation and treatment of certain forms of PH (particularly PAH and CTEPH) are oft en focused at nationally designated specialist centers. In the UK, centers currently exist in Sheffi eld, London (Royal Brompton, Hammersmith and Royal Free), Cambridge (Papworth), Newcastle, and Glasgow.
Th ere is also a specialist center in Dublin, Ireland .