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Pulmonary Hypertension in Pregnancy: Treatment With Pulmonary Vasodilators

From the Departments of Obstetrics and Gynecology and Pulmonary Medicine, University of Washington, Seattle, Washington.

Address reprint requests to: Thomas R. Easterling, MD, University of Washington, Box 356460, 1959 Pacific Street N.E., Seattle, WA 98105, E-mail: easter{at}u.washington.edu

	Abstract

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Objective: To describe the clinical course of pregnancies complicated by pulmonary hypertension and treated with the pulmonary vasodilators nifedipine and prostacyclin.

Methods: Four pregnant women with pulmonary hypertension were treated with pulmonary vasodilators. Therapy with oral nifedipine and intravenous prostacyclin was guided by right pulmonary artery catheterization and Doppler measurements of cardiac output.

Results: Three of four women responded to vasodilator therapy and successfully completed their pregnancies. Two who conceived at least 1 year after successful treatment and normalized right ventricle function carried three uncomplicated pregnancies. The woman who did not respond died. Delay in diagnosis contributed to her outcome. Noninvasive measurement of cardiac output helped diagnosis of right ventricular failure and offered reassurance in women who remained compensated. Postpartum decompensation in one woman was characterized by a negative Starling response as central venous pressure increased from 4 to 11 mmHg. She responded positively to diuresis.

Conclusion: Early diagnosis of pulmonary hypertension is critical. Volume overload postpartum might significantly contribute to decompensation. We recommend a year of successful therapy after a response to vasodilator therapy and near-normal right ventricular function before pregnancy is considered. In complicated pregnancies, women must balance the best estimate of risk with the value they put on pregnancy.

The incidence of primary pulmonary hypertension is one to two per million.¹ Women are affected four to five times more often than men. Familial (autosomal dominant) primary pulmonary hypertension accounts for 6% of all cases and expresses a pattern of genetic anticipation. Secondary pulmonary hypertension can develop as a complication of cardiac and pulmonary disease or as a complication of drugs such as cocaine or appetite suppressants.¹ If pulmonary hypertension is untreated, the median survival after diagnosis is 2.5 years.² Of the minority of patients who initially respond to nifedipine, 5-year survival rate is 95%.³ The 5-year survival rate of those who require treatment with prostacyclin is 54%.⁴ The beneficial hemodynamic effects of prostacyclin infusion can be sustained for longer than 1 year.⁵ Maternal mortality rate from severe pulmonary hypertension was reported as high as 50%.^6–8 Sudden, irreversible deterioration in the postpartum period is common.^6,7,9 A single case of short-term treatment of pulmonary hypertension with nifedipine in pregnancy was reported.¹⁰ The prognosis for pregnancy in women who had good responses to vasodilator therapy is unknown. The goal of the present study was to review our experience with pulmonary vasodilation and develop recommendations for the treatment and counseling of women with pulmonary hypertension.

	Materials and Methods

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We retrospectively assessed pregnant women with pulmonary hypertension. Subjects included were pregnant women with pulmonary hypertension, without evidence of intracardiac shunt, with systolic pulmonary pressure exceeding 60 mmHg, with evidence of right ventricular dysfunction, and who were treated with nifedipine or prostacyclin. Patients were evaluated with echocardiography, pulmonary arterial catheterization, and Doppler measurement of cardiac output.^11,12 Laboratory assessment was directed by clinical management teams. Data were gathered from clinic charts.

	Results

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Four women with pulmonary hypertension carried a total of five pregnancies. At the time of diagnosis, each had severe, life-threatening pulmonary hypertension with systolic pulmonary pressures exceeding 70 mmHg and right ventricular dilatation and dysfunction. Each woman was treated with the pulmonary vasodilators nifedipine, prostacyclin, or both. Pregnancy outcomes varied depending on response to therapy and interval between diagnosis and treatment, and on the pregnancy itself.

Clinical presentations are given in Table 1. In two women, pulmonary hypertension was diagnosed during pregnancy, and in two, a year or more before conception. Each had nonspecific symptoms for months before diagnosis. Table 2 gives the results of pertinent diagnostic tests. Pulmonary artery pressures and pulmonary vascular resistance were increased; cardiac output was reduced. Echocardiography was used to assess that right ventricular function was severely impaired.

View larger version (49K): [in this window] [in a new window]   Figure 1. Cardiac output of Subject 2 during gestation, showing initial response to nifedipine and the subsequent failure to respond (thick line). The solid line represents mean cardiac output (thin line), the shaded area represents one standard deviation.13

Patient 4 presented at 11 weeks’ gestation with an unexpected pregnancy. She was also counseled about her uncertain prognosis in pregnancy. Although prostacyclin was not expected to have adverse effects in pregnancy, we could find no published studies to validate its safety. She was counseled on the risks of coumadin embryopathy, and we changed her prescription to subcutaneous heparin. She elected to continue the pregnancy.

Patients 3 and 4 had normalized pulmonary artery pressures and recovered right ventricle function before pregnancy. They carried their pregnancies without major complications. Patient 3 completed a second pregnancy without complications 1 year after the first. Patient 4 was converted successfully from prostacyclin to nifedipine 8 weeks postpartum and remained well compensated 1 year after conversion.

Patient 2 had a complicated postpartum course. On the third postpartum day, her hematocrit level fell to 25%, she was transfused with 2 units of packed cells, and became progressively short of breath. Central venous pressure increased from 4 to 11 mmHg, and her weight increased 2 kg. Cardiac output decreased from 6.8 to 2.5 L/minute with an increase in pulmonary vascular resistance from 447 to 1256 dyne • sec • cm^-5. Systemic pressure was supported with dopamine, prostacyclin dose was increased, and we believed she might die.

Figure 2 shows the patient’s Starling curve during the 24 hours of deterioration and recovery. As her central venous pressure increased from 4 to 11 mmHg, her cardiac output did not increase but decreased precipitously from 6 to 2.5 L/minute. The acute volume load might have further dilated the right ventricle, increasing displacement of the intraventricular septum into the left ventricle, compromising left ventricular filling, and decreasing stroke volume.¹⁴ Her right ventricle was functioning entirely on the failure side of the Starling curve; therefore, she was carefully diuresed. Over 24 hours she lost 2 kg of weight. Central venous pressure decreased to 2 mmHg, cardiac output increased to 6.1 L/minute, and pulmonary vascular resistance decreased to 509 dyne • sec • cm^-5. Her hemodynamic findings stabilized over the next 2 weeks.

View larger version (16K): [in this window] [in a new window]   Figure 2. Cardiac output versus central venous pressure for Subject 2 during postpartum decompensation.

	Discussion

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Patients 2, 3, and 4 showed the effects of improved diagnostic and therapeutic modalities. Patient 2 presented similarly to patient 1, but her hypertension was diagnosed earlier in her clinical course. The insidious nature of her worsening symptoms delayed diagnosis. She had volume overload and right ventricle failure. She was hypoxic but only mildly acidotic (HCO₃ was 13 mEq/L). Her initial response to pulmonary vasodilation with nifedipine improved systemic perfusion and initiated diuresis. During the next 4 weeks her cardiac output increased from 4.8 to 7.2 L/minute. Her subsequent deterioration and need for treatment with prostacyclin was determined by decreasing cardiac output measured noninvasively.

Patient 2 had postpartum decompensation that was well described in women with pulmonary hypertension.^6,7,9 Diuresis had a greater effect on her improvement than afterload reduction with prostacyclin. When the patient lost 2 kg, central venous pressure returned to previous levels, and cardiac output improved. Diuresis to treat systemic hypotension and worsening perfusion might not seem intuitively sound and might even seem misguided; however, we suspect that severity of right ventricular failure is frequently not appreciated. Early, careful diuresis immediately postpartum might improve the outcomes of women with pulmonary hypertension.

Patients 3 and 4 showed the potential for long-term improvement of patients treated with pulmonary vasodilators. Concurrent pregnancy at the time of diagnosis of pulmonary hypertension might have had a grave prognosis. In both cases, pulmonary artery pressures decreased significantly, and right ventricular function normalized before conception. Pregnancy was well tolerated, and right ventricular function did not deteriorate during pregnancy. From those two cases, we cannot estimate accurately the risk of undertaking pregnancy; however, given the lack of deterioration of ventricular function during pregnancy, we believe that the risk is closer to that of untreated patients with similar clinical findings than it is to women with disease comparable to theirs at diagnosis.

From these cases, we believe the following observations can be made: 1) Early diagnosis is critical. Fatigue and shortness of breath are common in pregnancy. Progressive symptoms, a cough, hoarseness, or disproportionate lower edema should reduce the threshold to test. The number of tests with negative results should exceed the number with positive results. 2) Right ventricular failure postpartum might be precipitated by increased pulmonary vascular resistance or insidious volume overload, leading to Starling failure when cardiac output decreases as ventricular volume increases. We believe that reduction of preload postpartum might be as important as pulmonary vasodilation. 3) Noninvasive measurement of cardiac output facilitated diagnosis of recurring right ventricular failure and offered reassurance in women who remained well compensated. 4) We recommend at least a year of successful vasodilator therapy and near-normal right ventricular function before pregnancy is considered. Cardiac function and pulmonary pressures at the time of pregnancy might be better predictors than the patient’s previous conditions.

	Footnotes

 
PII S0029-7844(98)00524-9

Received August 17, 1998. Received in revised form October 22, 1998. Accepted November 5, 1998.

	References

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