A pulmonary vasodilator, which reduces right ventricular afterload and improves cardiac function, is an important treatment of PAH [19]. There are three main mechanisms of PAH treatment: cyclic adenosine monophosphate, cyclic guanosine monophosphate and endothelin pathway [20]. However, the endothelin receptor antagonist group is a contraindication in pregnancy due to its teratogenic effects (category X). The following drugs are commonly administered in pregnancy. (1) Cyclic adenosine monophosphate pathway: (a) inhaled nitric oxide (iNO), (b) phosphodiesterase 5 inhibitor; sildenafil (category B) is commonly used in combination with prostaglandin, (c) guanylate cyclase stimulator is category X. (2) Cyclic guanosine monophosphate pathway: (a) prostacyclin derivatives; intravenous epoprostenol, inhaled iloprost.

The severity of patients who haven’t received treatment is classified by the World Health Organization functional classification (WHO FC) I to IV. Patients with WHO FC I–II should be treated with oral sildenafil and closely monitored, while WHO FC III-IV patients require hospital admission and administration of either intravenous prostacyclin derivatives or combined therapy (Table 1).

In the pre-delivery stage, TTE should be used for daily monitoring to detect early cardiac decompensation and evaluate fluid status. An arterial line and a central venous catheter can also be considered for hemodynamic monitoring, while a pulmonary artery catheter is not routinely required.

Due to their hypercoagulable state, these patients have a high risk of venous thromboembolism as acute pulmonary embolism and deep vein thrombosis during both pregnancy and the post-postpartum period [21]. As a result of increased estrogen levels, blood coagulation Factors 7, 8, 9, 10, 12, 13 and von Willebrand factor are markedly elevated, which significantly increases in the third trimester [11]. Additionally, the increased levels of several plasminogen inhibitors diminish the overall fibrinolytic capacity [22,23]. While blood coagulation inhibitors are unpredictable, their effects during pregnancy result in unchanged antithrombin and protein C levels and a markedly decreased protein S level. The reduction of venous flow in the lower limbs is another precipitating risk [11]. Consequently, it is recommended that PAH patients with pregnancy in the antepartum through postpartum periods should be treated with low molecular weight heparin [2,9,30,31]. Unfractionated heparin should also be considered, especially in the unpredictable peri-partum phase.

The gestation of 32 to 36 weeks is preferable for delivery [1,9] because of its many advantages, such as accessibly promoting fetal lung growth, absence of uterine contraction and well-planned delivery. Cardiac stabilization with an adequate PAH-targeted therapy and resuscitation are necessary to reduce maternal and fetal mortality. The mode of delivery between vaginal delivery (the previous decade) and caesarean section (the present) remains controversial [31,32]. Although the benefits of vaginal delivery consist of smaller blood volume loss, lower bleeding complication, lower infection rate, and less altered hemodynamics than caesarean section [9,33,34], it has some serious complications. First, labor pain could overstimulate the sympathetic nervous system. Second, the Valsalva effect during delivery could worsen maternal cardiac function due to low cardiac output by increasing intrathoracic pressure and thus decreasing venous return [35]. Currently, elective caesarean section is considered as a mode of delivery due to better control of hemodynamic outcomes and delivery duration [3,36,37].

There are many adverse effects from general anesthesia, especially increases of pulmonary arterial pressure and PVR during laryngoscopy and tracheal intubation. In addition, the positive pressure ventilation on venous return may lead to hemodynamic instability [3,38]. Regional anesthesia is commonly used by combining the spinal and epidural approach to provide ultimately effective anesthesia to minimize the dose of anesthetics [39]. Epidural anesthesia has a slow onset (15–20 minutes) but provides hemodynamic stability. In contrast, spinal anesthesia is rapid onset (1–2 minutes) but is associated with peripheral vasodilation. However, single-shot spinal anesthesia should be avoided because of its profoundly hemodynamic effect by sympathetic block [31]. Furthermore, the ultimate goal of anesthetic management is the control of pain, where hypoxemia and hypercapnia could be considered as hemodynamically sustaining effects [19,40].

The uterine contraction agent is a potential risk for deteriorating the circulatory system, although it can be necessary for the prevention of uterine atony [32]. In PAH patients, oxytocin should be given by infusion without a bolus dose to reduce systemic vasodilation. A slow infusion rate of oxytocin effectively minimizes the potential for hypotension, tachycardia, and fluid retention [41]. Ergotamine and prostaglandin F2 alpha should be cautiously used in PAH patients because of their effects to increase vasoconstriction, myocardial infarction and pulmonary venous congestion [15].

The majority of deaths in pregnant patients with PAH in the last decade have occurred in the post-partum period, mainly in the first to third month [31,42,43]. Most observational studies illustrated unprecedented events, such as severe right ventricular failure, hypotension, and circulatory collapse, which occurred within the first 7 days after delivery [1]. The treatment goals during the post-partum period, especially in the first 48 hours, are to avoid volume overload, maintain systemic blood pressure and closely observe right atrial pressure and cardiac function.

Drugs used to treat right heart failure are mostly in the Food and Drug Administration (FDA) pregnancy category C except dobutamine (category B). Fortunately, most pregnant patients with PAH develop cardiac decompensation after delivery because of the pathophysiology of increased venous return and PVR. Therefore, the treatment of right heart failure and cardiogenic shock is not significantly different from the non-pregnant group. However, the treatment of unhealthy right ventricular function and PAH largely deals with the preload sensitive character (i.e., avoiding over-corrected fluid or over diuresis), reduction in PVR as previously mentioned (optimizing afterload), and contractility promotion. The role of diuresis (furosemide is FDA pregnancy category C) may be essential in patients who have obvious pulmonary edema, and close monitoring is required. The increase of right ventricular contractility with inotropic agents has been proposed in various studies; however, there are some commonly used treatments in right heart failure that have smaller effects on the increased PVR, such as milrinone, dobutamine, and levosimendan [44-46]. In a hypotensive patient, either epinephrine or norepinephrine is preferable to add-on with minimally increased PVR concerns [47,48].

In a PAH patient who is unresponsive to maximal medical therapy, extracorporeal membrane oxygenation (ECMO) is a novel mechanical support for bridging to recovery or transplantation by unloading the right ventricle and enhancing oxygenation and ventilation [18,49]. While right ventricular assist device mainly supports right ventricular load without improving oxygenation and ventilation, it carries a potential to rupture the pulmonary artery. There is no current guideline on the use of ECMO during or after pregnancy [50]. The initial ECMO configurations reported in pregnancy are veno-venous, veno-arterial (VA) and veno-arterial-venous mode. However, VA-ECMO is widely considered to support hemodynamics in decompensated pregnant PAH patients, and some are extubated while continuing VA-ECMO. Although ECMO is one of the supporting procedures for recovery, time mostly being activated that was in postpartum period when refractory circulatory failure usually occurred. Several reports showed some benefits of ECMO during the peripartum stage [24,25,27,37,43,51]. Cannula size and route are also challenging for cannulation due to the anatomical changes during pregnancy. Femoral cannulation should be performed with caution, but there have been no reports of flow insufficiency from gravid uterus compression [26,43]. The duration of ECMO has been reported from 6 to 30 days, and bleeding is the most common complication [29,43]. Alternatively, atrial septostomy may be an additional method for unloading right ventricular pressure and particularly early promoting ECMO decannulation [29].

Pregnancy is classified by the WHO in category 4 as an extremely high risk of maternal morbidity and mortality, which is an absolute contraindication of pulmonary hypertension patient [28]. Termination should be discussed if it is plausible. The current practice is focusing on outpatient counselling for pregnancy prevention, as there are many issues surrounding methods of contraception [52]. Currently, estrogen-containing contraceptives and injectable progestins are not recommended because of their potentially increased risk of venous thromboembolism, while the progestin-only pill often has a high failure rate of contraception [35,53]. Alternatively, non-permanent devices, such as progestin-only intrauterine device and implantation, are acceptable, but they have imprecise efficacy and could alter levels of pulmonary vasodilator drugs. Consequently, permanent contraception is preferable. A report from the Mayo Clinic of a retrospective cohort showed that micro-insert hysteroscopic sterilization provided an effective advantage in patients who could undergo the procedure in an elective setting due to its small procedural risk [54]. Laparoscopic tubal ligation still requires general anesthesia [35]. Tubal ligation, however, could be performed in patients who underwent caesarean section (Figure 2).