Nisha Garg and Stephanie Martin
•Pulmonary hypertension is defined as an elevated mean pulmonary arterial pressure >25 mmHg at rest confirmed by right heart catheterization
•Pulmonary hypertension in pregnancy should be managed closely by a pulmonary hypertension specialist as part of a multidisciplinary team approach at an appropriate level of maternal care
•Pregnancy is contraindicated in all patients with pulmonary hypertension
•Epoprostenol is the most commonly used drug for pulmonary hypertension in pregnancy
•Both BNP and pro-BNP levels have been shown to correlate with survival in patients with pulmonary hypertension
Pulmonary hypertension is one of the highest risk medical conditions encountered in pregnancy. This rare, progressive condition has a prevalence of 9.7 cases per 100,000 that preferentially affects young women of child-bearing age  with a female to male ratio of almost 2:1 [2,3]. The physiologic burden of pregnancy in pulmonary hypertension is an area of great concern and is associated with high rates of maternal and fetal morbidity and mortality. Given the complexity of pulmonary hypertension in pregnancy, it is important to manage it with a multidisciplinary approach.
Pulmonary hypertension is defined as an elevated mean pulmonary arterial pressure (mPAP) ≥25 mmHg at rest confirmed by right heart catheterization, and is considered severe when mPAP is ≥50 mmHg .
Pulmonary hypertension encompasses a group of diseases with various pathophysiologies, including pulmonary arterial hypertension (PAH), pulmonary hypertension related to left heart disease, pulmonary hypertension related to lung disease, chronic thromboembolic pulmonary hypertension, and pulmonary hypertension with unclear and/or multifactorial mechanisms. PAH is characterized by precapillary pulmonary hypertension, that is, pulmonary artery wedge pressure of <15 mmHg and pulmonary vascular resistance of >3 Wood units in the absence of underlying lung parenchymal or thromboembolic/vascular disease . The World Health Organization (WHO) has classified pulmonary hypertension into five groups based upon etiology (Table 15.1).
World Health Organization Classifications of Pulmonary Hypertension
Pulmonary arterial hypertension
•Connective tissue diseases
•Congenital heart disease
Pulmonary hypertension due to left heart disease
Left ventricular systolic dysfunction
Left ventricular diastolic dysfunction
Left heart inflow/outflow tract obstruction
Pulmonary vein stenosis
Pulmonary hypertension due to lung disease and/or hypoxia
Chronic obstructive pulmonary disease
Interstitial lung disease
Restrictive/obstructive lung disease
Chronic thromboembolic pulmonary hypertension
Chronic thromboembolic pulmonary hypertension
Other pulmonary artery obstructions
Pulmonary hypertension with unclear multifactorial mechanisms
•Glycogen storage disease
Chronic renal failure with or without dialysis
Source: Adapted from Galiè N et al. Comments on the 2015 ESC/ERS Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension. Rev Esp Cardiol. 2016;69(2):102–8.
Familial or inherited PAH constitutes less than 10% of cases. Mutations in two genes in the transforming growth factor beta-receptor pathway, BMPR2 and activin-like kinase 1, have been linked to this condition, with the majority (50%–90%) attributed to BMPR2 mutations. Familial PAH is characterized by incomplete penetrance, however when expressed it is associated with earlier onset and more severe disease.
Drug-induced PAH is associated with certain appetite suppressants that increase serotonin release, such as fenfluramine and dexfenfluramine. Pulmonary hypertension is also associated with use of illicit drugs such as cocaine and methamphetamine.
Connective Tissue Diseases
Certain connective tissue diseases are associated with a primary pulmonary arteriopathy. This most commonly occurs in patients with CREST syndrome, or the limited cutaneous form of systemic sclerosis. At autopsy, up to 80% of patients have histologic evidence of pulmonary arterial hyperplasia, however less than 10% actually develop clinical disease.
Pulmonary hypertension has also been associated with other autoimmune disorders such as systemic lupus erythematosus, mixed connective tissue disease, and rheumatoid arthritis.
In patients with HIV, studies have suggested an incidence of pulmonary hypertension of 0.5%, which is significantly higher than the general population. In these cases, the development of pulmonary hypertension appears to be independent of CD4 count or opportunistic infections, and is directly proportional to the duration of HIV infection. The mechanism of action of PAH in HIV patients is unclear, and routine screening is not recommended.
Pulmonary artery hypertension also appears to be associated with portal hypertension with an estimated prevalence of 2%–6%, and the risk of developing disease increases with the duration of portal hypertension.
Pulmonary Arterial Hypertension
Finally, PAH is a well-recognized complication of uncorrected congenital heart disease involving increased pulmonary blood flow and systemic to pulmonary shunts. Common examples include unrepaired ventricular or atrial septal defects, and patent ductus arteriosus. These conditions may progress into Eisenmenger syndrome, that is, the reversal of left-to-right shunt flow due to elevation of pulmonary artery pressures above that of systemic pressures. Pulmonary hypertension is a known complication of sickle cell disease, with an estimated prevalence of 10%–30%. The etiology of pulmonary hypertension in these patients is felt to be pulmonary vasculopathy, but also may be secondary to thromboembolic events, restrictive lung disease, and/or left heart disease .
The diagnosis of pulmonary hypertension is established based on clinical presentation, physical examination, and the results of diagnostic testing summarized in Table 15.2.
Diagnosis of Pulmonary Hypertension
Shortness of breath
•Loud pulmonary component of second heart sound (P2)
•Third heart sound (S3)
•Left parasternal lift
•Systolic murmur of tricuspid regurgitation
•Diastolic murmur of pulmonary regurgitation
•Elevated jugular venous pressure
Tall P waves—P pulmonale, right axis deviation, right ventricular hypertrophy, prolonged QTc, atrial arrhythmias—flutter/fibrillation in 25% patients with longstanding disease 
Central pulmonary arterial dilation with peripheral “pruning” of vessels
◻Pulmonary function test
Reduced lung volume
Decreased lung diffusion capacity
Peripheral airway obstruction
Nocturnal hypoxemia and central sleep apnea 70%–80% 
◻Arterial blood gas
Hypoxemia with normal/decreased arterial carbon dioxide pressure
Elevated pulmonary artery systolic pressure
Dilated right ventricle
Flattening of the interventricular septum
◻Ventilation/perfusion lung scan
◻High resolution computed tomography and pulmonary angiography
◻Cardiac magnetic resonance imaging
•ANA, dsDNA, anti-Ro, U3 RNP, U1 RNP
◻Right heart catheterization with vasoreactivity testing
◻Minute walk test
◻Cardiopulmonary exercise testing
Clinical manifestations of pulmonary hypertension can be nonspecific and include exertional dyspnea and fatigue. The condition is progressive, and therefore symptoms typically worsen over time. As the disease progresses, increasing pulmonary pressures lead to right heart failure and symptoms become more pronounced. These include chest pain, syncope, peripheral edema, and right upper quadrant pain due to hepatic congestion. Because of the nonspecific nature of early symptoms, delays are common, and the diagnosis of pulmonary hypertension may not even be established prior to pregnancy. In fact, 24% of pulmonary hypertension due to congenital heart disease is diagnosed during pregnancy, often presenting in the second or third trimester with shortness of breath [8,9].
Findings of pulmonary hypertension include increased P2, prominent a-wave in the jugular venous pulse, right-sided S4, and right-sided murmurs.
Further evaluation includes EKG and B-type natriuretic peptide (BNP) level. If these are normal, then pulmonary hypertension is unlikely . Both BNP and pro-BNP levels have been shown to correlate with survival, and possibly with right ventricular enlargement and dysfunction .
If pulmonary hypertension is suspected, an echocardiogram is indicated. Echocardiography can estimate pulmonary artery pressures. Additional findings on echocardiogram related to severe pulmonary hypertension include right ventricular enlargement and tricuspid regurgitation. However, it is important to recognize that echocardiography is a screening tool and does not definitively diagnose pulmonary hypertension. It may especially have a higher false positive rate in detecting pulmonary hypertension in pregnant patients [11,12]. This may be related to the increased blood volume and decrease in systemic vascular resistance that are associated with pregnancy. This may lead to an increase in size of the inferior vena cava, thus exaggerating the estimated right atrial pressure and pulmonary artery systolic pressure. Right heart catheterization is required for definitive diagnosis of pulmonary hypertension and to accurately determine the severity. However, cardiac catheterization is an invasive procedure that carries a 1%–5% risk of complications including pneumothorax, bleeding, and infection . Therefore, the indications for right heart catheterization are based on initial echocardiographic findings. If echocardiogram shows findings suggestive of pulmonary hypertension (elevated peak tricuspid regurgitation velocity, flattening of the interventricular septum, increased pulmonary artery diameter, etc.), then further investigation of pulmonary hypertension with right heart catheterization is indicated [3,10].
Pregnancy Risks and Antepartum Care
Pulmonary hypertension in pregnancy carries a high maternal mortality rate estimated at 17%–33%, which represents an improvement in recent years, particularly in patients with severe pulmonary hypertension and Eisenmenger syndrome . Mortality is mostly the result of the inability of the right ventricle to accommodate the increased pulmonary artery pressure, leading to right heart failure . The risk of right heart failure is particularly high during the intrapartum and postpartum periods due to the changes in intravascular volume and pressure during these stages . A retrospective review of 49 pregnant women with pulmonary hypertension reported a mortality of 16% . Nearly all of these fatalities occurred in the postpartum period, with the primary cause of death being heart failure, followed by sudden death and thromboembolism. In addition, fetal risks include mortality (11%–28%), premature birth, and growth restriction  (Table 15.3). Because of the excess maternal morbidity and mortality risks, pregnancy is contraindicated in patients with PAH. Women who choose to continue pregnancy despite these risks should be followed closely throughout the pregnancy by a multidisciplinary team with expertise in this area . Better outcomes are anticipated in patients who maintain a long-term favorable response to calcium channel blockers (CCBs) . Poor outcomes have been reported in patients with decreased lung diffusion capacity at <45% of normal .
Maternal and Fetal Complications in Pulmonary Hypertension
Right heart failure
Bronchial artery rupture—hemoptysis
Pulmonary artery dilation leading to
•Left recurrent laryngeal nerve compression (hoarseness)
•Compression of left main coronary artery (ischemia)
•Compression of large airways (wheezing)