PAH and Pregnancy: Physiologic Changes, Challenges, and Outcomes
For most expectant mothers, pregnancy is a happy time. It is a time of scheduled obstetrical appointments, prenatal vitamins, prenatal classes, and baby showers, with the greatest concern being shopping for the anticipated family addition. No one “expects” complications or a new diagnosis during their pregnancy. When complications do occur, the majority are related to the development of the fetus, not the health of the mother. Unfortunately, idiopathic pulmonary arterial hypertension (IPAH) is an unforgiving and devastating disease, and as many as 80% of new diagnoses are made during the child-bearing years. Review of the usual cardiopulmonary and hemodynamic changes of a normal pregnancy, along with those that occur in the maladaptive state of pregnancy concurrently with pulmonary arterial hypertension (PAH), are therefore necessary to appreciate the treatment and management.
Citation: Advances in Pulmonary Hypertension 10, 3; 10.21693/1933-088X-10.3.173
PHYSIOLOGIC CARDIOVASCULAR AND PULMONARY CHANGES DURING A NORMAL PREGNANCY
The increased metabolic needs of pregnancy are met by many physiologic adaptive changes that permit adequate delivery of oxygenated blood to the peripheral tissues and the growing fetus. Women without heart disease will usually adapt well and cardiac complications are exceedingly rare. However, women with PAH will not respond favorably to these otherwise “normal” adaptive changes.
Hemodynamic and Cardiopulmonary Changes Normally Seen in Pregnancy
Blood volume. Blood volume increases progressively from 6–8 weeks' gestation, reaching a maximum at 32–34 weeks, with a total 40%–100% plasma volume increase from baseline. Most of this excess volume is contained in the uterus, breast, muscle, and skin. The red cell mass only increases by 20%–30%, thus creating a “physiologic anemia.” This reduces the impact of the delivery blood loss, typically 300–500 cc for a vaginal delivery and 750–1000 cc for a C-section. Immediately after delivery, there is an auto transfusion of the excess blood supply from the uterus, as it contracts postpartum.
Cardiac output. There is an increase in cardiac output that parallels the increased blood volumes. A 34% increase in cardiac output occurs during the first trimester, with a steady and gradual increase until the 36th–39th weeks of gestation. An average cardiac output by 8–11 weeks is 6.7 L/min, reaching a maximum of 8.7 L/min during the 36th–38th weeks. Most of these changes are accounted for by a 35% increase in the stroke volume. A minimal component (15%) is secondary to an increase in the basal heart rate. This hyperdynamic circulation associated with pregnancy and aided by a progesterone-mediated vascular relaxation causes a steady decrease in the systemic vascular resistance throughout the pregnancy. The decrease in vascular tone begins at the fifth week and reaches a nadir at 20–32 weeks. After 32 weeks, the resistance slowly begins to increase until term. A split S2 with inspiration (early), distended neck veins (mid), and an S3 gallop (late) may be heard with the progressive increases in vascular volume.
Blood pressure. By mid-pregnancy the diastolic pressure decreases, the systemic systolic pressure remains the same or slightly decreases, and the pulmonary artery pressure remains the same. Vascular tone is more dependent on sympathetic control, with more significant episodes of hypotension with sympathetic blockade with spinal or extradural anesthetics.
Cardiac position and EKG. Mild dilatation of both ventricles is normal, but contractility remains normal. The ventricular end diastolic volumes increase progressively beginning at the 10th week of gestation and peak in the third trimester. Bi-atrial dilatation is also seen in some normal patients. Mild dilatation of the tricuspid ring (secondary to right ventricular [RV] dilatation) commonly increases the tricuspid regurgitation flow to grade I-II/VI, with a detectable murmur. The enlarging uterus shifts the diaphragm upward. Commonly seen EKG changes with a gravid uterus include left axis deviation, sagging ST segments, and inversion or flattening of the T-wave in lead III. Premature atrial and ventricular contractions may become more frequent.
Aortocaval compression. Beginning in mid-pregnancy, the enlarging uterus compresses both the inferior vena cava and the aorta whenever lying supine. This obstruction of the vena cava can reduce venous return to the right heart, with a fall in cardiac output by as much as 24% near term. Obstruction of the lower aorta and its branches can decrease arterial flow to the kidneys, the utero-placental unit, and the lower extremities. Positioning on the left side (lateral position) will improve flow in both the vena cava and the aorta.
Venous dilatation. Venous pooling increases by 150% in most pregnant women. This process decreases the absorption/delivery of drugs administered subcutaneously or intramuscularly. Hands and feet are warm and erythematous, along with nasal congestion resulting from this.
Renal changes. Renal blood flow increases during pregnancy, peaking in the third trimester at 60%–80% above the pre-pregnancy level. This calculates to a 50% increase in the glomerular filtration rate (GFR). There is an increase in renin and angiotensin levels, resulting in increased retention of salt and water.
Hematologic changes. Pregnancy induces a relative hypercoagulable state including decreases in protein S, increases in factors I and X, and progressive resistance to protein C activity.
Respiratory changes. The respiratory rate remains unchanged. Minute ventilation, tidal volume, and oxygen consumption increase by 20%–40% beginning in the first trimester of pregnancy, and are mediated by elevated progesterone level. By term, the arterial carbon dioxide level falls to 28–32 torr, with a decreased plasma bicarbonate level of 18–21 mEq/L. This results in biologic hyperventilation and the sensation of dyspnea. The functional residual capacity decreases by 10%–25%, whereas the total lung capacity decreases only minimally due to the thoracic cage widening to compensate. Hypoxemia can rapidly develop in the setting of hypoventilation or apnea.
During labor, the cardiac output increases by another 10%–15% and is augmented by the return of 300–500 mL of blood to the central circulation from uterine contractions. Immediately postpartum, there is a marked increase in preload, resulting in an increased cardiac output that remains elevated for about 48 hours. There is a relatively vigorous and spontaneous diuresis during the first 72 hours postpartum, which is ongoing at a slower rate for the next 2 weeks. Hormone levels return to normal over the next 6 weeks.
PAH AND PREGNANCY: HEMODYNAMIC AND ECHO-CARDIOGRAPHIC CHANGES
The multiple cardiovascular and pulmonary changes seen in a normal pregnancy become pathologic adaptations in the pregnant patient with PAH. The increased plasma volume, increased cardiac output, increased renin and aldosterone levels, decreased systemic vascular resistance (SVR), venous dilatation and pooling, elevated progesterone levels, and increased metabolic rate rapidly bring forth the pregnant patient with new clinical right heart failure. The presentation of a pregnant and newly or previously diagnosed PAH patient frequently includes all or some of the following: dependent lower extremity edema, DOE, orthopnea, decreased exercise tolerance, widely split S2, pulmonic and tricuspid murmurs, early satiety secondary to liver congestion, hepatomegaly, RV-S3 gallop, and jugulovenous distention (JVD). This typically occurs during the 15th-18th weeks of gestation, but may present at any time. The marked increase in renin and angiotensin levels result in premature volume expansion and third-spaced fluid retention. In turn, this overloads the already compromised RV, which becomes progressively more dilated and hypocontractile. The pulmonary vascular disease from the PAH causes an increase in the pulmonary vascular resistance (PVR), resulting in a pressure overload of the RV, in addition to the already existing volume overload. Many times, the pressure-volume overload of the right heart results in opening of the PFO (patent foramen ovale), with resultant hypoxemia from a right to left or bidirectional shunting. Development of increasing tricuspid regurgitation, a natural dilatation with pregnancy, and a maladaptive finding from volume/pressure overload of the RV may lead to atrial fibrillation from a right atrial origin.
The pathologic changes found in the lung secondary to PAH are progressive and destructive (Figure 1).
Citation: Advances in Pulmonary Hypertension 10, 3; 10.21693/1933-088X-10.3.173
The pathologic changes frequently result in decreased gas exchange surface area, as well as decreased flow through tortuous and pruned peripheral vasculature of the lung. To compound these abnormalities, the increased plasma volumes associated with pregnancy result in increased flow to the lung, followed by further RV dysfunction and RV failure from the pressure/volume overload. The supply decreases and is not able to meet the demand of the high metabolic rate of supporting a pregnancy. The respiratory rate increases (not found in normal pregnancy) and the work of breathing increases because of the decreased cardiac output and the increased work of the respiratory muscles. This combination of pathophysiologic derangements may be fatal for the pregnant PAH patient and her fetus, with reported mortality rates ranging between 37% and 57% for the mother.1–3 Therefore, at present, all female patients with WHO Group 1 PAH should be counseled about the dangers of pregnancy and about the suitable contraceptive options (see article on Pregnancy and Contraception), as stated in the latest American Heart Association/American College of Cardiology Foundation guidelines.
Unfortunately, there are some women who aren't diagnosed until they are well into their pregnancy, and the clinician is faced with a seriously ill PAH patient with a high risk of mortality by the end of the pregnancy or shortly thereafter. If one suspects pulmonary hypertension during pregnancy, the initial management should include a complete diagnostic evaluation and confirmation of the PAH diagnosis, including a right heart catheterization. If confirmed, immediate treatment and close monitoring is necessary, which should be initiated as an inpatient. Treatment goals include reducing intravascular volume, reducing RV afterload by use of PAH pharmacologic agents (usually a prostacyclin), increasing RV systolic function by use of intravenous (IV)/inhaled prostacyclins, digoxin, and/or dobutamine, and control of any arrhythmias.
Diagnostic testing must include an echocardiographic study, with a bubble study immediately the day of presentation. Depending upon the severity of the disease, findings may include (Figure 2):
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Dilatation of the right atrium and ventricle
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Hypocontractility of the RV, abnormal tricuspid annular plane systolic excursion (TAPSE)
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Flattening of the interventricular septum with RV systolic pressure >50 mm Hg
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Dilated inferior vena cava (IVC), with decreased respiratory variation
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Tricuspid and pulmonic regurgitation (typically mild-moderate)
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Pericardial and pleural effusion
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Normal/near normal left heart
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Bubble study—right to left intracardiac shunt, late return to left heart with arteriovenous malformation (AVM)
The normal images (Fig 2, A and B) demonstrate the smaller size of the RV compared to the left ventricle (LV). The image shows the smaller size of the RV, while it shows the LV to be perfectly circular—no pressure/volume overload of the RV that compresses the interventricular septum (the D shaping we talk about in severe PAH). Note also that adequate views of the RV, as shown, allow visualization of the free wall and the size of the RV. Additionally, RV ejection fraction (RVEF) can be estimated on moving images and summed by looking at 3–4 different views. The other 2 images (Fig 2, C and D) are comparable images in a patient with severe PAH. The 4-chamber view shows significant dilatation of the RV and hypertrophy of the RV wall, while the moving image would show a significantly decreased RVEF. The short axis view demonstrates the ECHO findings of markedly elevated RV pressure, with D shaping of the LV (loss of the circular configuration of the LV). This is from pressure-volume overload of the RV. The RVSP is usually >60 mm Hg before the D shaping occurs, while flattening occurs at pressures >50 mm Hg.
Citation: Advances in Pulmonary Hypertension 10, 3; 10.21693/1933-088X-10.3.173
PATIENT SUBSETS
Congenital Heart Disease
The congenital heart patient requires complete evaluation of the RV, LV, and valves to guide therapy throughout the gestational period, as well as delivery and the peripartum period. Pathologically, the pulmonary vessels have been exposed to higher pressures over many years and have adapted. They are usually thick, stiff, and have luminal narrowing with the typical pruning of the peripheral pulmonary vessels that is seen in IPAH. Additionally, the shunt physiology often seen in this population will need to be monitored closely. Treatment strategies for the congenital heart patient with PAH are similar to the IPAH patient. The PAH drugs work in a similar fashion, except that inhaled nitric oxide tends to cause more intrapulmonary shunting than in other PAH etiologies. This patient population may have LV dysfunction along with RV dysfunction, compounding the complexity of the physiologic abnormalities. Standard treatment with loop diuretics, potassium and magnesium replacement, digoxin, PAH medications, oxygen if indicated, and low-dose hydralazine (if LV dysfunction is present) may be appropriate. Many of these patients are responsive to prostacyclins. Management of pregnancy with PAH will need to be individualized for the congenital heart disease patient, as this is a very heterogeneous population due to different congenital abnormalities and differences in the timing of any corrections that were performed. Patients with congenital heart disease have often had years to accommodate their anatomic and hemodynamic abnormalities, and patients with some forms of congenital heart disease may therefore tolerate a pregnancy better than patients with other forms of PAH. Reported outcomes in the literature, however, are still relatively poor, and patients with Eisenmenger's physiology in particular have high mortality rates with pregnancy. This can lead to very premature deliveries and de-compensation of the right and left ventricular function. Specific treatment strategies therefore need to be individualized for congenital disease PAH patients, dependent on the stage of their disease.12
Mitral Valve Disease
Patients with mitral valve disease can be divided into 3 groups: mitral regurgitation, mitral stenosis, and persistent PAH after mitral valve repair/replacement.
Mitral regurgitation. The increased plasma volume of pregnancy will equilibrate with the drop in the SVR and PVR in the pregnant patient with mitral regurgitation. Rarely are diuretics necessary, even if moderately severe. This valvular lesion is usually well tolerated in pregnancy and can be dealt with postpartum, unless there is a very high sodium/water intake secondary to dietary indiscretion.
Mitral stenosis. Mitral stenosis in a pregnant patient will be tolerated relatively well unless the valvular lesion is severe or if there is significant sodium/water dietary indiscretion. Late in the pregnancy, low-dose loop diuretics may be necessary, but use of these agents needs to be evaluated on an individual basis. Low-dose beta-blockers may be utilized for mild, moderate, and severe lesions. Echocardiographic studies of the mitral valve should be performed at all 3 trimesters, with particular caution in the mid to late third trimester.
The pro-inflammatory state of pregnancy can cause progression of the mitral stenosis in some patients. If the mitral stenosis is hemodynamically significant, mitral valvuloplasty is now the treatment of choice by the ACC guidelines and can be performed safely during pregnancy, by an experienced cardiologist, and in an experienced interventional center or catheterization laboratory. Hemodynamic instability most often occurs with the onset of atrial fibrillation and requires immediate control/treatment. It is best treated initially with rate control, utilizing metro-prolol, and/or amiodarone (IV/oral).
Persistent PAH after mitral valve repair/replacement. Persistent pulmonary hypertension following repair or replacement of the mitral valve is known to occur in some patients. Most of these patients have had a longstanding history of the valve lesion prior to intervention and likely have an element of precapillary pulmonary hypertension as well. The common identification time for this disorder is in the cardiovascular surgical ICU (while Swan-Ganz catheter is in place), as the pulmonary artery pressures remain elevated. The other commonly seen population is the <30-day readmission after mitral valve surgery. These patients will have had persistent elevation of the pulmonary artery pressures, which often smoldered postoperatively (some even re-intubated), followed by discharge to rehabilitation centers or home. The common characteristics include “failure to thrive” after surgery, chronic right heart failure with persistent lower extremity edema refractory to diuretics, poor appetite, and readmission via the emergency department with clinical right heart failure. Treatment for this population, once recurrent mitral valve obstruction is ruled out, is the same as any other PAH patients, with the diagnosis being PAH. The hemodynamic criteria for this population are the same as for other Group 1 PAH patients. Swan readings can be utilized from the postoperative time or a repeat right heart catheterization can be performed. The PVR and mean pulmonary artery pressure need to be evaluated as in any other case of PAH. Clinical treatment is no different and needs to be directed to improved inotropic performance of the RV (dobutamine), followed by IV loop diuretics, and initiation of PAH drugs. All drug classes have shown hemodynamic and clinical improvement.
PAH IN THE SICKLE CELL DISEASE PATIENT
PAH in sickle cell disease (SCD) is complicated, as there are issues with the mother and the fetus. The medical literature suggests that 6%–11% of patients with SCD will develop PAH. SCD is a hypercoagulable state (platelet activation and activation of the coagulation system), with hyperdynamic flow states, all of which will be worsened by pregnancy. The mother has greater risks of precipitous delivery/spontaneous abortion, higher risks of infections, greater incidence of hypertension and preeclampsia, pulmonary emboli (clots from hypercoagulable state, abnormal sickle cells occluding peripheral vessels, and hemolysis), pulmonary infarctions, and hypoxia. Use of prostacyclins, phosphodiesterase type 5 (PDE-5) inhibitors, and endothelin receptor antagonists (ERAs) have all been reported in the literature. Recent studies were discontinued early for monotherapy with bosentan and sildenafil; therefore, the data are limited with respect to sickle cell patients. Anticoagulation is often considered, but is always problematic during pregnancy. There is an increased risk of intracranial and retinal bleeding with SCD, so the use of anticoagulation needs to be weighed carefully. ERAs should be avoided as they are contraindicated in pregnancy. Delivery strategies are similar to other PAH patients. The fetus has a greater risk of intrauterine growth retardation, stillbirth, and fetal distress.
Systemic lupus erythematosus. The physiologic stressors of pregnancy may bring forth a quiescent diagnosis of lupus in patients not previously identified or lead to a lupus flare. These patients need close observation by all treating physicians, including the pulmonary hypertension physician, high-risk obstetrics physician, and rheumatologist. PAH needs aggressive therapy, frequently with an infusion of prostacyclin and another oral pharmacologic agent. A lupus flare may present atypically as volume overload, and will not respond with increased diuretics alone. An observation seen thus far is that the RV function in the lupus patient may remain somewhat depressed after delivery and does not return to the pre-pregnant measurements/function.
CONCLUSION
Even with the advances in PAH therapies over the past decade, pregnancy and PAH remain a fatal combination. Unfortunately, some women have their first presentation of PAH during pregnancy or shortly thereafter due to the rapid physiologic changes that occur, which are poorly tolerated by the pulmonary circulation and RV. For these patients, admission to a PH specialty center with the ability to administer IV prostanoids, inotropes, vasopressors, and the team and tools including high-risk obstetricians, cardiac anesthesia, extracorporeal membrane oxygenation, and a high-level NICU may permit survival beyond pregnancy for this high-risk group.
Medical Director
Pulmonary Hypertension Clinic at Aurora St. Luke's Medical Center
Clinical Associate Professor of Medicine
University of Wisconsin School of Medicine and Public Health
Milwaukee Clinical Campus
Milwaukee, WI
(A) Normal 3-layer arterial wall structure of a pulmonary artery, with a normal endothelial layer, normal medial elastic layer, and normal thickness outer layer. (B) Abnormal endothelial layer of cells that become dysfunctional, larger than normal, and mosaic pattern. The medial elastic structures begin to deteriorate and become fibrotic. The lumen begins to narrow. (C) The medial elastic layer architecture is nearly destroyed and thickened. This encroaches on the diameter of the vessel lumen. (D) In situ thrombosis occurs within the narrowed lumen and dysfunctional endothelial lining. (E) Prototype of a “plexogenic lesion,” with partial recanalization of the previously thrombosed pulmonary artery. Hemodynamically, very stenotic vessel with decreased perfusion downstream. (F) Severely diseased and fibrotic vessel, with a critically narrowed lumen that is hemodynamically compromising.
Transthoracic echo images, normal (A and B) vs severe PAH (C and D).
Contributor Notes