Saudi Guidelines on the Diagnosis and Treatment of Pulmonary Hypertension: Pregnancy in pulmonary hypertension.

Pregnancy in pulmonary hypertension (PH) is known to be associated with high morbidity and mortality. The physiological changes occur during normal pregnancy, such as increase blood volume and cardiac output (CO) may be detrimental in PH patients. Several practice guidelines advise against pregnancy and even recommend termination of pregnancy. Occasionally PH may be diagnosed for the first time during pregnancy, as stress of pregnancy can unmask previously undiagnosed PH in an asymptomatic individual. This narrative review provides a detailed discussion about the physiologic parameters associated in pregnancy and their negative effect on the right ventricle. It also gives practical evidence-based recommendations about different management issues in PH pregnant patients.

Pregnancy in pulmonary hypertension (PH) is known to be associated with high maternal mortality in all defined clinical groups of PH, with observational studies having estimated maternal death between 30% and 60% even in patients with little or no significant functional impairment before pregnancy.[1] Several practice guidelines advise against pregnancy and even recommend termination of pregnancy.[2345] WHO modified risk classification considers PH of any cause as risk Class 4 (pregnancy contraindicated).

Occasionally, PH may be diagnosed for the first time during pregnancy, as stress of pregnancy can unmask previously undiagnosed PH in an asymptomatic individual.

Physiology of Pregnancy

Several physiological changes occur during normal pregnancy to meet the metabolic demands of mother and fetus. Of particular relevance to PH include increase in blood volume and cardiac output (CO) and decrease in pulmonary and systemic vascular resistance. CO increases significantly in early pregnancy due to combination of increase in stroke volume and progressive reduction in after load resulting from decrease in peripheral vascular resistance. Late in pregnancy, increase in heart rate is also a contributory factor.[678]

Pregnancy is also regarded as a hypercoaguable state due to several reasons, such as increase in coagulation factors, decrease serum level of protein S, and relative resistance to protein C.[91011]

In normal pregnancy almost 50% increase in CO can be accommodated in pulmonary circulation through a subsequent decrease in pulmonary vascular resistance (PVR), and there is usually no effect on right ventricle (RV) afterload and/or function. Nevertheless, these normal physiological changes are poorly tolerated by PH patients, as these patients already have higher RV afterload from preexisting increase in PVR. Furthermore, RV is unable to cope with such an increase in CO and is overstretched. This can result in progressive RV failure and even sudden death from cardiac arrhythmias. In addition, higher RV pressures shifts intervetricular septum leftward, thus impairing diastolic filling of left ventricle which further compromises the CO.[4]

Pregnant patient with Eisenmenger syndrome or patent foramen ovale are at increased risk of having paradoxical emboli from increase in right to left shunting.[12] In addition, due to hypercoaguable state, there is increased risk of thromboembolic events, which are poorly tolerated by PH patients with already compromised RV.

Pregnant PH patients are also at increased risk of developing complications during puerperal period. Several cardiac events occur during this period, including further increase in heart rate and blood pressure and increase in myocardial oxygen consumption, basically due to labor pains causing sympathetic nervous stimulation. The pain may also induce severe vasovagal responses resulting in hypotension and sudden death.[1314] Another contributory factor during labor is diversion of approximately 500 ml of blood from uterine to maternal circulation due to uterine contractions and valsalva maneuvers, thus further augmenting CO.[15] Even after delivery, CO may increase by 80% due to auto transfusion from uterine involution.[16]

Clinical Features

Most PH patients complain of increasing dyspnea and fatigue due to low CO. Since these symptoms are also present during normal pregnancy, it is likely that patient and/or physician may attribute these symptoms to pregnancy and PH is not suspected, which may cause delay in diagnosis. Some patients, however, may have chest pain from RV ischemia or even syncope from low CO.

As symptoms of disproptionate dyspnea, chest pain, or syncope during pregnancy may be first manifestation of previously undiagnosed PH, hence a high index of suspicion is required.

All these patients warrant further investigations by echocardiography for evaluation of cardiac status and in particular for PH. It is prudent first to exclude pulmonary embolism by appropriate investigations. There is no evidence of increased fetal risk or pregnancy loss at doses of radiation to pregnant mother <50 mGy.[17] Estimated fetal/maternal effective doses for various radiological procedures, such as chest X-ray (≤0.01 mGy-0.1 mGy), computed tomography chest (0.3 mGy-7 mGy) and pulmonary angiogram (1.5 mGy-7 mGy) are considered safe for both fetus and mother.[1819]

If PH is suspected by echocardiography, it should be confirmed by right heart catheterization (RHC), which can be performed safely during pregnancy.[202122]

Prognosis of Pregnancy in Patients with Pulmonary Hypertension

Maternal outcome

Pregnancy with PH is regarded as a very high-risk pregnancy. An earlier study by Mccaffrey and Dunn in 1964 has described that 9 out of 16 patients died in 23 pregnancies; most of deaths have occurred in the last 2 months of pregnancy or early in puerperium.[16] In 1979, Gleicher et al. reviewed 70 pregnancies in women with Eisenmenger syndrome and found 52% maternal mortality mostly during labor, delivery and early in postpartum period. The perinatal fetal mortality was 28%.[23]

Another overview of outcome of 125 pregnancies in women with Eisenmenger syndrome, idiopathic pulmonary arterial hypertension (IPAH) and PH due to other secondary causes showed maternal mortality of 36%, 30%, and 56%, respectively.[1] Bédard et al. performed a systematic review of all cases of pregnancy-related death in patients with IPAH, congenital heart disease associated with PAH (CHD-PAH), or PAH associated with other diseases (APAH) published between (1997 and 2007) and compared it with data published between 1978 and 1996 to find out whether there has been any progress made in pregnancy outcome among women with PH using newer therapies.[24] The authors observed that mortality remains prohibitively high, though appears to have decreased more recently with the use of new treatments in all three major subgroups (IPAH from 30% to 17%; CHD-PAH 36% to 28%; APAH 56% to 33%), [Table 1]. Most patients died in the 1st month after delivery in both series. The main cause of death was RV failure in both reviews; other causes included sudden death and pulmonary thromboembolism.[25] Predictors of poor outcome are shown in Table 2.

Table 1

Outcome of pregnant women with PAH

Table 2

Risk factors for maternal mortality

Recent report from a single center of 10 consecutive pregnancies has shown significant improvement with combination of multidisciplinary approach, early initiation of specific drug therapy, and a planned caesarean delivery under regional anesthesia. There was no fetal or maternal mortality during pregnancy or in early postpartum period.[24] Another multicenter prospective study of 26 pregnancies showed better outcome with 16 (62%) patients delivering normal healthy babies without complications. Three (12%) patients died and one required urgent heart-lung transplantation.[26]

Fetal outcome

Neonatal or fetal death rate also remains high in PH pregnant patients. One series has reported death rate in IPAH, CHD-PAH, and APAH as 10%, 7%, and 13%, respectively. In addition, high rate of intrauterine growth retardation and premature delivery have been reported.[25]

Diagnosis

Once PH is suspected in pregnant woman, it always warrants further investigations by trans-thoracic echocardiography (TTE). As a screening tool, TTE has shown a good correlation between pulmonary arterial pressure (PAP) measured by RHC and TTE. Nevertheless, the presence of PH by echocardiography requires confirmation by RHC as discrepancy between these diagnostic tools has been reported. In one study, 8 out of 25 patients diagnosed to have PH by TTE had normal PAP when measured by RHC.[17] Similarly, in another study, 30% of pregnant patients diagnosed to have PH by echocardiography did not have PH when measured by RHC.[18] Furthermore, TTE could also underestimate PAP in this patients’ population, as 5 out of 8 patients were found to have more severe PH when measured by RHC.[18] RHC has been shown to be a safe procedure in the second and third trimesters of pregnancy.

Management

The class of recommendation and the level of evidence for PH management in pregnant PH patients are summarized in Table 3.

Table 3

Class of recommendation and level of evidence for management of PH in pregnancy

During pregnancy

At present, all guidelines consider PH as a contraindication to pregnancy. PH patients should be advised to practice safe contraception; however, should the patient become pregnant and wishes to continue with pregnancy, and then she should be managed as a high-risk pregnancy by a specialized multidisciplinary team in a center familiar with management of PH patients. Patient should be followed regularly on monthly bases and physicians are to have a low threshold for admission, should there be any deterioration or worsening of symptoms.

General management

General measure includes adjustment of activities in order to decrease extra cardiac demand, adequate rest, and low salt intake. Patient is encouraged to lay down/sleep on the left lateral position to avoid compression of the inferior vena cava, which may cause decrease in venous return. Hypoxemia should be avoided and supplementary oxygen should be provided to keep PaO2 ≥ 70 mmHg.[27] Pregnant women should also receive the flu vaccine.

Anticoagulation

There is no consensus on anticoagulation in a pregnant PH patient. Pregnant patients are at increased risk of thromboembolism, which is generally very poorly tolerated by PH patients. In addition as mentioned earlier, pregnant PH patient with either Eisenmenger syndrome or patent foraman ovale are also at increased risk of paradoxical emboli. This would suggest that anticoagulation should be continued throughout pregnancy. Conversely, there is an increased risk of bleeding, especially in patients with Eisenmenger syndrome and portal hypertension.[152328] Bleeding risk increases further at the time of delivery, which is also poorly tolerated by PH patient. Anticoagulation should be considered on case-by-case basis. If anticoagulation is chosen, it needs to be closely monitored, as requirements change with progress of pregnancy.

Furthermore, there is no consensus regarding level of anticoagulation, and whether the patient should be fully anticoagulated or just given a prophylactic anticoagulation dosage.[2930] Low molecular weight heparin is generally recommended during pregnancy (Food and Drug Administration [FDA] Category B), unfractioned heparin at near term and during delivery (FDA Category B), and warfarin after delivery (FDA Category D during pregnancy).[31] Fondiparinux, a factor Xa inhibitor, may be used as a prophylactic agent in patients with heparin induced thrombocytopenia; however, there is a limited data about its rule in pregnancy.[32] Anticoagulation should continue for 2-6 months after delivery as there is evidence of increased maternal morbidity and mortality during postpartum period.[33]

Diuretics

Patient may need diuretic therapy for cardiac failure and hypervolemia. Furosemide is preferable choice (FDA Category C). Spironolactone should be avoided because of its anti-androgenic effect (FDA Category D).[34]

Pulmonary arterial hypertension specific therapy

Recent guidelines on management of pregnant patient with heart disease advise that PH patient who are on specific drug therapy should continue with this treatment, (class of recommendation II a, level of evidence C).[2] Patients who are well-controlled on calcium channel blockers should continue with same drug. Prostacyclin (Flolan) is effective and safe in pregnancy and is the drug of choice (FDA Category B).[3536] Inhaled Iloprost has also shown good efficacy, but some studies have reported adverse fetal effects (FDA Category C).[37] Oral agent sildenafil is find to be safe in animal and human studies (FDA Category B).[38] Endothelin receptors antagonist (bosentan and ambrisentan) are contraindicated because of their teratogenic effects (FDA Category X).[39] Patients already on these drugs should be advised about fetal risk and switched to other drugs. It is perhaps plausible to use prostacyclin analog or/and oral Sildenafil early in pregnancy as specific pulmonary vasodilators.

During delivery, puerperium and postdelivery

Pulmonary hypertension pregnant patients should be closely observed through the second trimester onwards and admitted for any deterioration of condition. A planned admission for delivery is advised. General measures include control of labor pain, anxiety and avoidance of hypovolemia, and hypoxemia. Please refer to the review of “perioperative management in patient with PH” in this issue of the journal for more details.

Although, there is no optimal mode of delivery, earlier reports suggest higher mortality due to cesarean section particularly when performed under general anesthesia. More recent reports however suggests better outcome of planned cesarean delivery using regional anesthesia.[25] Cesarean delivery avoids prolonged labor and associated hemodynamic stress.

Several physiological changes occur during vaginal delivery. Blood volume shifts during contractions and sympathetic stimulation from labor pains may result in sudden increase in CO, which is often poorly tolerated by PH patient. In addition, pain may also produce serous vasovagal response, though assisted vaginal delivery has shown low mortality rate in some centers.[15] Since general anesthesia is associated with several disadvantages, including increase PVR during intubation and positive pressure ventilation and cardiac depression from anesthetic agents, all producing hypotension, therefore regional anesthesia is preferred which may avoid these complications.

Patient is usually monitored for weeks after delivery. Several reports have suggested increased mortality during peripartum period, and so anticoagulation and specific pulmonary vasodilators agents should be continued after delivery.