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International Journal of Cardiology 97 (2004) 11 13 www.elsevier.


Pregnancy and pulmonary hypertension

Carole A. Warnes*
Mayo Clinic and Mayo Foundation, 200 First Street SW, Rochester, MN 55905, United States Available online 21 September 2004

Pulmonary hypertension, irrespective of the etiology, carries a high mortality when associated with a pregnancy. Causes of pulmonary hypertension include primary pulmonary hypertension (PPH), and pulmonary vascular disease secondary to other causes such as thromboembolic disease, connective tissue disorders, and side effects from certain drugs. The most common cause of pulmonary hypertension in young women of childbearing age however is due to the late consequences of a large cardiac shunt at any level (Eisenmenger syndrome). This review will focus on the latter, in which the risk of maternal death is approximately 3050% [14].

further increase pulmonary vascular resistance. Any hypovolemia resulting from blood loss or hypotension from a vasovagal response to pain may result in sudden death. In addition, death may also occur from pulmonary thromboembolism or in situ pulmonary infarction.

2. Clinical studies No single center has a large experience with pregnancy and Eisenmenger syndrome, but one of the largest reviews by Gleicher et al. [5] reported 44 well-documented cases, representing 70 pregnancies. Fifty-two percent of all patients died in connection with pregnancy with no difference in maternal mortality between the first, second and third pregnancies. Thus, a successful outcome with one pregnancy does not secure a similar successful outcome with subsequent pregnancies. A high incidence of maternal death was associated with hypovolemia and thromboembolic phenomena and 34% of all vaginal deliveries resulted in maternal death. Maternal mortality was highest during parturition and during the puerperium. Three out of four cesarean sections also resulted in maternal death although the numbers were small and it may be that those patients were the most hemodynamically unstable and represented a higher risk cohort. The authors concluded that termination of pregnancy was the safer option, although 1 of 14 pregnancy interruptions (the only one performed by hysterotomy) also resulted in maternal death. The offspring also did not fair well. Only 25.6% of pregnancies reached term and at least 54.9% of all deliveries occurred prematurely. Almost one-third of all infants showed intrauterine growth retardation. Perinatal mortality was 28.3% and was significantly associated with prematurity. A summary of published reports of pregnant patients with pulmonary vascular disease from various institutions

1. Hemodynamic perturbations Several of the hemodynamic changes that occur during a normal pregnancy contribute to the high maternal mortality in patients with pulmonary vascular disease. The progressive increase in plasma volume, which peaks at about 50% above baseline early in the third trimester, adds to the burden of a compromised right ventricle and may precipitate right heart failure. The pre-existing pulmonary vascular disease restricts this increased flow of blood to the lungs and increases right ventricular work. Systemic vasodilatation is a physiological adaptation of normal pregnancy and it is associated with an increase in the cardiac output and renal blood flow. As the peripheral vascular resistance falls, the patient with Eisenmenger syndrome may augment the right to left shunting that exacerbates the pre-existing hypoxia, which, in turn, may cause more pulmonary vasoconstriction. At the time of labor and delivery, severe hemodynamic compromise may occur. Acidosis and hypercarbia may
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and countries from 1978 to 1996 [6] noted a maternal mortality of 36% in those with Eisenmenger syndrome (n=73) and a similar mortality in those with PPH (n=27). Of 26 fatalities, 23 women died within 30 days of delivery, and late diagnosis and late hospital admission were predictive risk factors for maternal mortality. The cause of death was described as pulmonary hypertensive crisis with refractory heart failure (n=13), sudden death (n=7), autopsy-confirmed pulmonary thromboembolism (n=3), cerebral thromboembolism (n=1), and dissection and rupture of the pulmonary artery (n=1). The authors noted that maternal risks have changed little over the past two decades. Only cases of late pregnancy were reviewed, so no conclusions were drawn about overall fetal outcome, although the neonatal survival rate was higher than anticipated at 82%. A more recent single-center experience from Brazil with meticulous management [7] reported marginally better outcomes for mother and baby. Twelve cases with 13 pregnancies were associated with two maternal deaths before 28 weeks gestation, and only seven pregnancies reached the end of the second trimester. After hospital admission for bed rest and careful monitoring, administration of prophylactic heparin and cesarean section under general anesthesia, one woman died 30 days post partum.

3. Recommendations Because of the high maternal mortality, women with Eisenmenger syndrome should be counseled strongly not to have a pregnancy. If pregnancy occurs, she should be advised to have the pregnancy terminated. Dilatation and curettage in the first trimester is probably the procedure of choice, preferably with cardiac anesthesia. If she continues the pregnancy, some therapeutic strategies may be helpful: ! A combined follow-up with cardiologist and high-risk obstetrician monitoring both fetal and maternal well being. Minimizing the cardiac demands by rest, low salt diet, and maintenance of pre-natal vitamins. Bed rest should be undertaken in the lateral position to ensure that the fetus does not compress the inferior vena cava, thereby maintaining venous return. Hospital admission in the second trimester at a tertiary care center to facilitate timely preparation of the medical team. Oxygen may be delivered by facemask at night or during periods of dyspnea, although there is no objective evidence that it improves maternal or fetal outcome. Low-dose subcutaneous heparin may be administered, particularly during periods of bed rest, although this is controversial and there is no consensus that it improves

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maternal survival [8]. Evidence certainly implicates pulmonary thrombi as a cause for maternal demise and it is clear that pregnancy represents a hypercoagulable state. Conversely, cyanotic patients frequently have intrinsic bleeding problems with prolongation of the APTT, and abnormal platelet function, so the risk benefit ratio must be considered carefully. Most authors, however, appear to favor this strategy, with cesarean section delivery under general anesthesia and initiation of coumadin therapy post partum. Whichever mode of delivery is selected, careful monitoring of systemic oxygen saturation is necessary since this will facilitate early detection of increased right-to-left shunting as a surrogate for pulmonary blood flow. An intra-arterial line facilitates these measurements. A central venous pressure monitor will permit careful measurement of the right atrial pressure and avoid the potential complication of a pulmonary catheter in this setting. Acidbase status should be checked frequently, since undetected acidosis can exacerbate pulmonary hypertension. If the vaginal route is selected for delivery, it should be performed in the Intensive Care Unit. Delivery in the lateral position avoids fetal compression of the inferior vena cava and thereby maintains venous return. Epidural analgesia must be done carefully to minimize peripheral vasodilatation and can be accomplished without deterioration of the hemodynamics [9]. Bearing down should be avoided since the abrupt increase in systemic resistance may precipitate syncope. A prolonged second stage should be avoided, if necessary, with a facilitated delivery. Increasing the inspired oxygen concentration may produce mild reduction in the pulmonary artery pressure [9]. Thromboguards or compression pumps can be used to help prevent peripheral venous thrombosis. After delivery, anticoagulation can be restarted once there is no evidence of bleeding and then Coumadin can be given. Ambulation must be slow and gentle to avoid orthostasis. In-hospital monitoring should be continued for at least 2 weeks after delivery.

4. Pulmonary vasodilators More recently, case reports have noted a favorable response to some of the newer selective pulmonary vasodilators such as intravenous epoprostenol and inhaled nitric oxide [1013]. Nitric oxide can be given via a nasal cannula, facemask or an endotracheal tube, and successful delivery has been reported both by vaginal and cesarean section deliveries. While the response to nitric oxide might be attenuated in patients with Eisenmenger syndrome due to the morphologic changes in the pulmonary endothelium, reduction in pulmonary arterial pressure has been accom-

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plished in some patients. Maternal methemoglobin must be monitored during its use. The maternal outcome is not uniformly positive, however. Finally, one might speculate on the role of hormonal changes during pregnancy, and their role in the serious hemodynamic perturbations in patients with pulmonary hypertension. Relaxin is a hormone related to the insulin family, known sometimes as the bparturition hormoneQ since it has an important role in the growth and remodeling of reproductive and other tissues during pregnancy. Animal studies have demonstrated that relaxin has an important role in the adaptive vasodilatation which occurs in the kidneys during pregnancy [14]. Sources of relaxin include the ovary, decidua and placenta. Recently relaxin mRNA expression has been shown in the human left ventricle and atrium [15], and levels are increased in chronic heart failure. Recently relaxin has been shown to be a powerful endothelium dependent vasodilator of human systemic resistance arteries. Indeed it is a more potent vasodilator than ANP, and is equipotent to epoprostenol [16]. Interestingly, however, it is inert in preconstricted human pulmonary resistance arteries. It may be therefore that this hormone, which achieves the highest levels during pregnancy, contributes to the profound systemic vasodilatation and refractory hypoxia which occurs in patients with Eisenmenger syndrome and so often is the cause of their demise.

[1] Lieber S, Dewilde PH, Huyghens L, Traey E, Gepts E. Eisenmengers syndrome and pregnancy. Acta Cardiol 1985;40(4):421 4. [2] Heytens L, Alexander JP. Maternal and neonatal death associated with Eisenmengers syndrome. Acta Anaesthesiol Belg 1986;37(1):45 51. [3] Arias F. Maternal death in a patient with Eisenmengers syndrome. Obstet Gynecol 1977;50(Suppl. 1):76s 80s. [4] Neilson G, Gatea EG, Blunt A. Eisenmengers syndrome and pregnancy. Med J Aust 1971;1(8):431 4. [5] Gleicher N, Midwall J, Hochberger D, Jaffin H. Eisenmengers syndrome and pregnancy. Obstet Gynecol 1979;34(10):721 41. [6] Weiss BM, Zemp L, Seifert B, et al. Outcome of pulmonary vascular disease in pregnancy: a systematic overview from 1978 through 1996. J Am Coll Cardiol 1998;31(7):1650 7. [7] Avila WS, Grinberg M, Snitcowsky R, et al. Maternal and fetal outcome in pregnant women with Eisenmenger syndrome. Eur J Heart Fail 1995;16(4):460 4. [8] Pitts JA, Crosby WM, Basta LL. Eisenmenger syndrome in pregnancy: does heparin prophylaxis improve the maternal mortality rate? Am Heart J 1977;93(3):321 6. [9] Midwall J, Jaffin H, Herman MV, Kupersmith J. Shunt flow and pulmonary hemodynamics during labor and delivery in the Eisenmenger syndrome. Am J Cardiol 1978;42(2):299 303. [10] Goodwin T, Murphy MD, Gherman B, et al. Favorable response of Eisenmenger syndrome to inhaled nitric oxide during pregnancy. Am J Obstet Gynecol 1999;180(1):64 7. [11] Lust K, Boots RJ, Dooris M, Wilson J. Management of labor in Eisenmenger syndrome with inhaled nitric oxide. Am J Obstet Gynecol 1999;181(2):419 23. [12] Robinson JN, Banerjee R, Landzberg MJ, et al. Inhaled nitric oxide therapy in pregnancy complicated by pulmonary hypertension. Am J Obstet Gynecol 1999;180(4):1045 6. [13] Stewart R, Tuazon D, Olson G, et al. Pregnancy and primary pulmonary hypertension: successful outcome with epoprostenol therapy. Chest 2001;119(3):973 5. [14] Novak J, Danielson LA, Kerchner LJ, et al. Relaxin is essential for renal vasodilatation during pregnancy and conscious rats. J Clin Invest 2001;107(11):1469 75. [15] Dschietzig T, Richter C, Bartsch C, et al. The pregnancy hormone relaxin is a player in human heart failure. FASEB J 2001;15:2187 95. [16] Fisher C, MacLean M, Morecroft I, et al. Is the pregnancy hormone relaxin also a vasodilator peptide secreted by the heart? Circulation 2002;106(3):292 5.

5. Conclusions The mortality for patients with pulmonary hypertension who become pregnant remains prohibitively high. Appropriate advice regarding contraception should be given to all patients. If a patient becomes pregnant, therapeutic termination should be offered. If pregnancy continues against medical advice, treatment strategies as outlined above, may be helpful, with prolonged hospital care both pre and post partum.