Pulmonary arterial hypertension in pregnancy

Purpose of review

Although pregnancy in pulmonary arterial hypertension (PAH) is considered high risk and contraindicated, the incidence is rising. It is paramount to understand the pathophysiology and effective management strategies to ensure optimal outcomes for maternal and fetal survival.

Recent findings

In this review, we highlight the outcomes of recent case series of PAH patients in pregnancy, with a focus on proper risk assessment and target goals of PAH therapy. These findings support the notion that the pillars of PAH management, including pulmonary vascular resistance reduction resulting in right heart functional improvement, and widening of the cardiopulmonary reserve, should serve as a blueprint for PAH management in pregnancy.

Summary

Multidisciplinary and tailored management of PAH in pregnancy, with emphasis on optimizing right heart function prior to delivery, can result in excellent clinical outcomes in a referral pulmonary hypertension center.

INTRODUCTION

Pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is defined by the presence of pulmonary hypertension (mean pulmonary artery pressure >20 mmHg), a pulmonary arterial wedge pressure 15 mmHg or less, and pulmonary vascular resistance (PVR) at least 3 mmHg/l/min. It is a disease that is characterized by stiffness of the pulmonary vasculature, often leading to debilitating right heart failure. Without treatment, right heart dilatation and dysfunction occur, and in turn, often an increasing degree of tricuspid regurgitation, leftward interventricular septal displacement, and subsequential reductions in left atrial and left ventricular (LV) cavity size. The net result is falling cardiac stroke volume, cardiac output (CO), rising central venous pressure and hepatic and renal venous congestion. In patients with PAH, these pathologic limitations lead to hemodynamic vulnerability in pregnancy, in which intravascular volume expansion and falling systemic vascular resistance are characteristic. 

Box 1.

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PHYSIOLOGICAL CHANGES IN PREGNANCY

Normal physiological changes in pregnancy include a marked increase in plasma volume and CO and a decrease in systemic vascular resistance. Cardiac output increases by 45% above prepregnancy baselines, with plasma volumes also increasing 45% above baseline [1,2]. There is also a significant increase in maternal baroreceptor sensitivity and sympathetic activation with subsequent elevation in heart rate up to 25%. Hormonal changes also contribute to hemodynamic changes and fluid shifts. Progesterone is known to activate the renin–angiotensin–aldosterone system, leading to retention of sodium and volume, further potentially straining the cardiovascular system [3].

Pregnancy is also a relatively prothrombotic state, due to increased circulating coagulation factors, most of which steadily rise from the time of conception. Furthermore, there are decreases in venous outflow due to inferior venal caval compression from the uterus. In this state of hypercoagulability, there is a higher risk of developing an acute pulmonary embolism, leading to sudden increases in afterload and overwhelming an already diseased right ventricle (RV).

Adequate RV function is required to accommodate the numerous physiological changes that occur in pregnancy. In Fig. 1, the illustration in panel (a) represents the normal changes of pregnancy, in which there is a decrease in systemic vascular resistance and increase in CO. Panel (b) represents the changes which develop if the PAH goes untreated. The RV cannot accommodate the increased venous return. Eventually, there is RV dilation and increased wall tension. This further leads to decreased RV wall perfusion, worsening contractility, lower LV preload and CO. Once this deleterious cascade begins, there is a spiral of decline, which can be incredibly difficult to interrupt, leading to cardiovascular collapse.

FIGURE 1.

Physiological changes occurring in pregnancy and pulmonary arterial hypertension. CO, cardiac output; CVP, central venous pressure; LV, left ventricular; PAH, pulmonary arterial hypertension; PVR, pulmonary vascular resistance; RV, right ventricular; SVR, systemic vascular resistance.

THE CLINICAL IMPLICATIONS

Due to the pathophysiology described, there is a high risk of morbidity and mortality during pregnancy for the mother and the fetus [4,5]. Therefore, when patients of child-bearing age are diagnosed with PAH, there is a particular emphasis on contraception and prevention of pregnancy. In fact, the WHO advises against pregnancy and according to guidelines, pregnancy is contraindicated in patients with PAH [6].

Despite these risks, however, pregnancy does occur in patients with PAH. Recent data suggest that incidence of pregnancy in women with PAH is increasing [7]. A substantial number of women are opting to enter such pregnancies, likely because of recent advancements in diagnosis and medical therapies that have made it possible for women with PAH to live through child-bearing age. Termination of pregnancy may not be an option based on maternal preference or gestational age at presentation. Moreover, pregnancy termination may not be most appropriate for PAH patients possessing disease characteristics that lend toward effective PAH management and a positive maternal and fetal outcome. Therefore, it is becoming increasingly more important to understand effective management strategies in these patients.

Recent case series highlight the importance of aiming to optimize the central pathophysiology of the condition, to best provide the greatest degree of achievable physiologic reserve in anticipation of the physiologic stresses inherent to pregnancy, labor, and delivery. These studies show that multidisciplinary and tailored management of PAH in pregnancy with emphasis on optimized right heart function prior to delivery can result in excellent clinical outcomes in a pulmonary hypertension referral center [8^▪,9].

RISK ASSESSMENT

Patients with PAH represent a heterogenous group with a wide range of associated conditions, chronicity, and severity. Therefore, risk stratification at the time of pregnancy is a key step in managing this complex disease course. This involves a comprehensive assessment of clinical parameters that are typically used for PAH risk assessment. At the core of this assessment is the evaluation of clinical right heart failure by way of jugular venous pressure (JVP), B-type natriuretic peptide (BNP), and exercise capacity assessments, including functional class and 6-min walk distance (6MWD). Figure 2 highlights the importance of recognizing the distinguishing features of PAH and normal pregnancy. JVP, BNP, and RV function become particularly important in the assessment of PAH in pregnancy due to the nonspecific nature of lower leg edema, functional status, and the 6MWD. These particular factors can all be affected in normal pregnancy, making them less specific in the risk assessment of PAH.

FIGURE 2.

‘Pulmonary arterial hypertension-specific parameters’ vs. ‘Nonspecific parameters in pregnancy’. BNP, B-type natriuretic peptide; JVP, Jugular venous pressure; PAH, pulmonary arterial hypertension; RV, right ventricular.

Echocardiography should be performed at the start of pregnancy and serially reassessed during the course of pregnancy, with a focus on RV function, degree of tricuspid regurgitation, and other echo-Doppler parameters relevant to right heart-pulmonary vascular coupling, including the degree of systolic interventricular septal flattening and the presence and degree of ‘notching’ in the RV outflow tract pulse wave Doppler profile. These parameters, in conjunction with hemodynamics obtained from right heart catheterization [with emphasis on right atrial pressure (RAP) and cardiac index (CI)], serve to risk stratify each patient and individualize therapy as needed [10].

MANAGEMENT

Primary goals of treatment

The most important concept to understand in treatment of PAH is that of RV-PA coupling, or the relationship between the RV and the pulmonary hypertension. The primary goal in management of PAH is to medically decrease the PVR to a point where the right heart can adapt to that load and function at a near normal level. The schematic in Fig. 3 illustrates the key features in assessing right heart function with echocardiography. The top panel demonstrates a diseased RV with a high degree of afterload. This causes RV dysfunction, intraventricular septal flattening, significant tricuspid regurgitation and the presence of a ‘notch’ in the RV outflow tract (RVOT) pulse wave Doppler profile. The ‘notch’ is very predictive of the presence of PVR elevation in PAH [11]. The bottom panel represents the goals of PAH therapy. With an effective treatment regimen, there should be near normal RV function, resolution of intraventricular septal flattening, minimal tricuspid regurgitation, and no ‘notch’ in the RVOT. In recent work by D’Alto et al.[12] right heart reverse remodeling, reductions in RV size, and normalization of RV systolic function was primarily a result of decreased PVR. The clinical implications of this are paramount, for improvement in RV size and function are closely linked to improved WHO functional status and exercise capacity.

FIGURE 3.

A schematic illustrating the key features in assessing right heart function with echocardiography. (a) Apical 4 chamber view, (b) parasternal short axis view, (c) tricuspid regurgitation (d) Right ventricular outflow tract pulse wave Doppler profile. PW, Pulse wave.

These principles of PAH management should serve as a guide for treating PAH patients during pregnancy. Medical therapy should be individualized to each patient and titrated to reduce PVR with the deliberate intent of achieving normal or near-normal RV size and function. By tailoring therapy with these specific goals in mind, the patient has more cardiovascular reserve and is able to withstand the physiologic stresses inherent to pregnancy, labor, and delivery with a wider margin of safety.

Yang et al.[13] reported on seven patients and seven pregnancies, with five of the seven having known PAH before pregnancy. All patients were indiscriminately treated with prostacyclin therapy, without tailoring of treatment based on RV size or function. Two of the seven patients died within days after delivery, and these patients had PVR values of 7.4 and 16.6 Wood units (WU) during pregnancy, suggesting a relative lack of significant hemodynamic improvement during pregnancy.

Jais et al.[14] reported 26 pregnancies in women with PAH. Among the women who did not have a planned or spontaneous abortion and carried pregnancy to delivery, 16 of 20 had a successful delivery and survived without transplantation (those who had a successful pregnancy and delivery had a much lower PVR (6.3 WU) and far better RV function (CI 3.2 l/min/m², RAP 4 mmHg) than the four subjects who died or required transplantation (PVR 20 WU, CI 2.0 l/min/m², RAP 11 mmHg).

Vaidya et al.[8^▪] at Temple University Hospital (TUH) in Philadelphia most recently published a case series of seven pregnancies in patients with PAH from a nationally accredited center. This study was notable and unique in that there was 100% maternal and fetal survival, despite an average baseline mean PVR of 9.8 WU. In this patient series, echocardiographic reassessment at a mean of 34 weeks gestation revealed that in six of the seven pregnancies, patients had either mild RV systolic dysfunction or normal RV systolic function combined with either mild or no tricuspid regurgitation just before delivery. Prior to delivery, the average BNP was 54 pg/ml (with five of the seven pregnancies having a BNP < 100 pg/ml) and average JVP was 8 cmH₂O, indicative of a well compensated right heart. This was the first case series of its kind that used an integrated assessment of RV performance as its main target during treatment with an individualized regimen to improve RV-PA coupling.

The favorable outcome in PAH patients during pregnancy in the Vaidya et al. study parallels the observation of Ghio [15] who showed that in nonpregnant PAH patients, a TAPSE more than 1.7 cm combined with grade 0–1+ tricuspid regurgitation have markedly better survival than subjects with a TAPSE of 1.7 cm or less combined with at least 2+ tricuspid regurgitation. Similarly, in six of the seven pregnancies, there was either no RVOT Doppler notching or only late Doppler notching, consistent with a lower PVR just before delivery [8^▪]. All patients were in the low-risk PAH category by European Society of Cardiology/European Respiratory Society Guidelines by the time of delivery [16]. This finding is consistent with recent studies showing a strong relationship between lower PVR, improved right heart function and low-risk clinical status in nonpregnant PAH patients [12,17].

Taken together, these findings support the notion that the pillars of PAH management, including PVR reduction, right heart functional improvement, and widening of the cardiopulmonary reserve, should serve as a blueprint for PAH management in pregnancy.

Medical therapies

There are four major classes of medication for the treatment of PAH. These include prostacyclins, phosphodiesterase five inhibitors, endothelin receptor antagonists, and soluble guanylate cyclase stimulators. Inhaled and parenteral prostacyclins and phosphodiesterase-5 inhibitors are considered acceptable, safe medications during pregnancy. Oral phosphodiesterase-5 inhibitors can also be safely combined with parenteral or inhaled prostacyclin therapy during pregnancy.

Endothelial receptor antagonists (bosentan, macitentan, ambrisentan) and soluble guanylate cyclase stimulator (riociguat) classes have a significant risk for fetal birth defects and should be immediately discontinued during pregnancy [18]. The FDA recommends discontinuation of these agents 1 month prior to attempts at conception. Therefore, patients with PAH should always be counseled on the importance of prospective family planning so that these medications can be transitioned to safe therapies prior to pregnancy [19].

It is worth emphasizing the necessity of an individualized approach when treating pregnant patients with PAH. The medical regimen should be of intensity that matches the patient's disease. Serial JVP, BNP, and echocardiography should be assessed during pregnancy to provide specific insight into right heart performance. Case reports show that outcomes are superior when PAH therapy is tailored to what each patient needs to optimize right heart function and provide sufficient physiologic reserve to ensure a low-risk pregnancy and delivery.

In the case series done by Vaidya et al.[8^▪], all seven pregnancies had excellent outcomes, largely due to this type of approach. Reflexive use of prostacyclin therapy was deliberately avoided. The indiscriminate use of this therapy can often lead to unintended consequences of excess systemic vasodilation, hypotension, gastrointestinal losses, inappropriately high CO and prostacyclin-related side effects, including but not limited to nausea, diarrhea, flushing, and headache that can adversely affect the health of mother and fetus. Thrombocytopenia from parenteral prostacyclin use may additionally impede the ability to provide neuraxial anesthesia at the time of delivery, which can have unintended consequences of pain-induced catecholamine surges that drive right heart dysfunction.

Preparation

A fundamental aspect of a successful delivery of a pregnant patient with PAH is the preparation that takes place beforehand. As discussed, the PAH should be optimized throughout the entire pregnancy. The goal should be to widen the cardiopulmonary reserve with optimized RV performance, so when there are physiological disruptions during labor, delivery, and postpartum, the patient's optimized hemodynamics and physiology can tolerate those inevitable insults.

Regarding the delivery specifically, planning should begin early in the third trimester. Improved outcomes have been described when there is a tailored multidisciplinary approach [20]. This team should consist of PH cardiology, maternal fetal medicine (MFM), obstetrics anesthesia, labor and delivery nursing, and pharmacy. There should be a core team that consists of the same members throughout the pregnancy, including the delivery and postpartum care. The meetings that take place include discussions about anticipated mode of delivery, resources for clinical monitoring, and location of the planned delivery within the hospital setting.

LABOR AND DELIVERY

In the TUH experience, the location and teams chosen for delivery was one in which staff was most experienced with labor and delivery [8^▪]. As such, anesthesiology with obstetrics expertise, rather than cardiac anesthesiology, was preferred. Similarly, delivery occurred in the usual labor and delivery unit or obstetrics operating room, rather than in the cardiac ICU or operating room. This is an important principle that is often overlooked. By allowing the MFM and obstetrics anesthesiology teams to lead the delivery in their environment, the patient's delivery can occur in a manner in which their physician providers and surrounding nursing and pharmacy staff are most skilled and prepared to provide swift and expert care. The pulmonary hypertension team, of course, should always be present at the time of labor and delivery, to guide PAH specific monitoring and to help mobilize any urgent additional resources if needed in these cases. JVP assessment can be done using pulmonary hypertension expertise in physical exam. Routine use of invasive hemodynamics with pulmonary artery catheterization is not recommended, and in fact, can lend itself toward inappropriate utilization of vasoactive therapy if erroneously responding to expected, elevated PA pressures.

Although expert consensus recommends cesarean delivery, there is no significant clinical evidence to support this as a superior option over a vaginal delivery [21]. The decision to pursue vaginal versus cesarean delivery requires careful clinical judgment and should be based on each patient's individual obstetric needs. Although cesarean delivery may be considered more controlled clinically, it may come with increased risks of bleeding, volume shifts, infection, greater hemodynamic effects of anesthesia, postpartum need for pain control, and limited mobility. In patients undergoing vaginal delivery, the associated volume changes and increased adrenergic stimulation with pain (i.e., tachycardia or arrhythmia) can precipitate right heart dysfunction. Therefore, active labor should be accelerated with oxytocin and the use of vacuum or forceps-assisted delivery with epidural anesthesia as well for pain management. Anesthesia with neuro-axial blockade is preferred over general, as worst outcomes are associated with the physiological insults that come with intubation and sedation in PAH.

As emphasized, the preparation phase over the duration of pregnancy is critically important. This is the period in which the cardiopulmonary reserve is widened and RV performance is optimized. Therefore, at the time of the delivery, the goal is that the patient can appropriately augment their CO when faced with the stresses of hemodynamic shifts, ideally without the use of inotropic agents. Although providing inotropy may rarely be necessary, the threshold to start these agents should be very high. Inotropic medications come with the risk of precipitating atrial arrythmias. The loss of sinus rhythm in a PAH patient is known to be poorly tolerated and can have significant deleterious effects on the patient's cardiac function, as studied and shown by Sivak et al.[22].

POSTPARTUM CARE

The immediate postpartum period is a vulnerable time for the PAH patient. There is autotransfusion of blood from the contracting uterus, which can lead to marked increases in blood volume. All patients should be monitored for at least 72 h after delivery by pulmonary hypertension specialists, with daily BNP monitoring, along with serial JVP assessment, monitoring for interval development of right heart congestion [8^▪,9]. At the first sign of JVP elevation or clinical heart failure, diuretics should be initiated to avoid the deleterious effects of worsening volume overload.

Breast feeding is sometimes encouraged, but data supporting this are limited [13,23]. Diuretic use may affect the milk supply [20]. The impact of PAH medical therapy on breast milk is not well studied. There have been published experiences of patients treated with PDE5i and inhaled or parenteral prostacyclin therapy that have breastfed. However, for patients receiving ERA therapy, it is not recommended [8^▪].

CONCLUSION

PAH is a progressive and potentially fatal form of pulmonary vascular disease and afterload-dependent right heart failure. Although considered high risk and contraindicated, pregnancy in patients with PAH still does occur. In these cases, it is paramount to have the patients cared for by an experienced and specialized pulmonary hypertension medical team with careful baseline and serial PAH assessments throughout the pregnancy. It is key that each patient has individually tailored pulmonary hypertension medical therapy with the deliberate intention to optimize right heart performance. With this focus in mind, the patient has more cardiovascular reserve and is able to withstand the physiologic stresses inherent to pregnancy, labor, and delivery with a wider margin of safety. A multidisciplinary approach including pulmonary hypertension, MFM, and obstetric anesthesia with clear labor and delivery planning and communication is necessary to ensure the safest possible maternal and fetal outcomes for this high-risk medical condition.

Acknowledgements

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Conflicts of interest

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REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

• ▪ of special interest

• ▪▪ of outstanding interest