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Cardiopulmonary Complications of Pre-eclampsia Samuel Thomas Bauer, MD, and Kirsten Lawrence Cleary, MD, MSCE Pre-eclampsia affects 3 to 8% of all pregnancies. In the USA, pre-eclampsia remains a leading cause of maternal morbidity and mortality, comprising 17% of maternal deaths in advanced gestations in 1999. The pathophysiologic changes associated with pre-eclampsia can have a profound impact on the uteroplacental unit and fetal and neonatal outcome. Equally important are the adverse effects on the maternal hematologic, cardiovascular and pulmonary, neurologic, renal, and gastrointestinal system. This article aims to review complications of pre-eclampsia as they impact on the cardiovascular and pulmonary systems. Semin Perinatol 33:158-165 © 2009 Elsevier Inc. All rights reserved. KEYWORDS acute respiratory distress syndrome, cardiovascular disease, peripartum cardiomyopathy, pre-eclampsia Pre-Eclampsia and the Physiology of Cardiovascular System A lterations of the normal cardiovascular physiology occur in patients with pre-eclampsia. These are related to the following: (1) cardiac preload, which is affected by hemoconcentration and pathologically diminished hypervolemia of pregnancy; (2) increased cardiac afterload caused by hypertension; and (3) endothelial activation with extravasation into the extracellular space, especially the pulmonary system, which places patients at risk for pulmonary edema.1 Hemodynamic cardiovascular changes often occur before the onset of hypertension. Bosio and colleagues conducted a longitudinal study of 400 primigravidas, who were monitored throughout pregnancy using Doppler echocardiography. Gestational hypertension and pre-eclampsia developed in 24 (6%) and 20 (5%) women, respectively. Compared with normotensive controls, women who had pre-eclampsia had significantly elevated cardiac output before clinical diagnosis, but total peripheral resistance was not significantly different during this latent phase. After the diagnosis of preeclampsia was made, there was a marked reduction in cardiac output and increase in peripheral resistance. In contrast, Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, NY. Address reprint requests to Samuel Thomas Bauer, MD, Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Columbia University Medical Center, 622 West 168th Street, PH 16-66, New York, NY 10032. E-mail: [email protected] 158 0146-0005/09/$-see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1053/j.semperi.2009.02.008 women with gestational hypertension had no such hemodynamic crossover and maintained hyperdynamic circulation throughout pregnancy.2 Terrone and colleagues at the University of Mississippi studied and categorized cardiopulmonary morbidity in 979 patients with severe pre-eclampsia/hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome.3 Cardiopulmonary morbidity was categorized as congestive heart failure, pulmonary edema or effusion, acute lung injury/ acute respiratory distress syndrome (ARDS), mechanical ventilation, or a cardiopulmonary event (Table 1). Cardiopulmonary morbidity occurred in 7.6% of study patients. Patients with class 1 HELLP syndrome, defined as severe thrombocytopenia with a perinatal platelet nadir ⱕ50,000/L, a total serum lactate dehydrogenase of ⱖ600 IU/L, and serum transaminase level of ⱖ70 IU/L either as aspartate amino transferase and/or alanine aminotransferase, more frequently encountered cardiopulmonary morbidity (P ⬍ 0.003) than did any other group with an odds ratio of 2.2 (95% CI 1.4, 3.7). These patients were more likely to experience acute lung injury/ARDS and/or require continuous positive airway pressure/mechanical ventilation. As a group, preeclamptic patients with cardiopulmonary complications were more likely to have cesareans (11% vs. 6%, P ⫽ 0.019), have low birth weight neonates (1366 ⫾ 700 vs. 1734 ⫾ 892 g, P ⫽ 0.021), sustain higher peak postpartum blood pressures (P ⬍ 0.001), and have more abnormal laboratory values indicative of multisystem disease, compared with patients without cardiopulmonary complications. Patients with pre-eclampsia and concurrent cardiopulmonary morbidity took almost twice as long to achieve diuresis as comparison patients (22 ⫾ 23 vs. 12 ⫾ 11 h, P ⬍ 0.001).3 Cardiopulmonary complications of PE 159 Table 1 Comparison of Cardiopulmonary Morbidity in Patients With HELLP Syndrome and in Patients With Severe Pre-Eclampsia Without HELLP Syndrome3 Complication Class I HELLP Class II HELLP Class III HELLP Severe Pre-Eclampsia P Value Congestive heart failure Pulmonary edema/effusion Acute lung injury/ARDS Continuous positive airway pressure/mechanical ventilation Cardiopulmonary arrest Any cardiopulmonary event 7 11 12 14 1 26 (12.3%) 4 5 3 7 1 13 (4.3%) 8 10 4 4 1 23 (8.3%) 3 7 2 4 1 12 (6.2%) 0.365 0.149 0.004 0.004 * 0.008 *P value not reported because of insufficient data. During normal pregnancy, plasma and red cell volumes increase by approximately 42% and 24%, respectively. The total blood volume of an average size woman will increase from approximately 3500 mL in the nonpregnant state to near 5000 mL toward the end of the third trimester of pregnancy.4 When compared to normal nonpregnant subjects, patients with pre-eclampsia demonstrate increased vascular resistance, decreased circulatory volume, and decreased peripheral perfusion. Plasma volume reduction and hemoconcentration remains a hallmark of pre-eclampsia and occurs in proportion to the severity of the disease process.5 In the 1980s, Rafferty and Berkowitz studied 3 patients with severe pre-eclampsia using thermodilution tip pulmonary artery catheters during cesarean section under general endotracheal anesthesia. The left ventricular stroke work indexes (LVSWI) of these patients were higher than those of normal nonpregnant women, but there was no evidence of myocardial depression in either cardiac index or the LVSWI-pulmonary capillary wedge pressure relationship. Pulmonary arteriolar resistance was found to be within or below the normal nonpregnant range, suggesting that the pulmonary vasculature is not involved in a primary vasospastic process in severe pre-eclampsia. At delivery, a rise in cardiac index and mean pulmonary capillary wedge pressure occurred. The pulmonary capillary wedge pressure was higher in the postpartum period than before delivery, potentially representing an increase in circulating blood volume.6 Benedetti et al. substantiated these findings when they noted an increase in LVSWI and hyperdynamic ventricular function in 10 patients with severe pre-eclampsia and pulmonary artery catheters during labor.7 Cotton and colleagues later performed right-heart catheterization in 45 women with severe pre-eclampsia or eclampsia. Most patients had high-normal or elevated systemic vascular resistance indexes, hyperdynamic left ventricular function, normal or increased pulmonary capillary wedge pressure, and low central venous pressure (Table 2).8 In the setting of chronic hypertension with superimposed pre-eclampsia, systemic vascular resistance and left heart filling pressures are increased. This leads to a decrease in cardiac output and an increase in pulmonary vascular hydrostatic pressure, which culminates in the development of pulmonary edema. An additional feature that may predispose to the development of pulmonary edema in the setting of preeclampsia is an increase in capillary leak and capillary fluid extravasation secondary to vascular endothelial damage. Re- searchers measure capillary leak by measuring the interstitial fluid from subcutaneous tissue in the thorax and ankle by implanted wicks and interstitial fluid hydrostatic pressure.9 Pulmonary artery catheter research in pregnancy consists of retrospective data: case reports, small series, or reviews. No randomized trials support their routine use in women with severe pre-eclampsia. Most of the reports primarily describe hemodynamic parameters and fluid status of preeclampsia and do not mention particular complications. Given the known complications of pulmonary artery catheters, including cardiac arrhythmias, pneumothorax, hemothorax, neurologic injury, and pulmonary hemorrhage, we do not recommend invasive monitoring for routine clinical cases. However, invasive hemodynamic monitoring may prove beneficial in women with pre-eclampsia and severe cardiac disease, severe renal disease, refractory hypertension, oliguria, or pulmonary edema.10,11 Pulmonary artery catheters aided in clinical management decisions in 93% of cases of severe pre-eclampsia complicated by renal failure or pulmonary edema in a small, retrospective series of 17 women with eclampsia. The pulmonary artery catheter was considered subjectively helpful if the initial readings (central venous pressure and pulmonary capillary wedge pressure) clarified patients’ fluid status and helped guide decision-making. Catheter placement was not helpful if the initial readings were unobtainable, inconsistent, or not used to influence or determine decision-making.12 Table 2 Hemodynamic Findings in Severe Pre-Eclampsia8 Cardiac output is variable Mean arterial pressure is elevated; systemic vascular resistance is normal (early) or elevated (late) Central venous pressure is usually low to normal and does not correlate with pulmonary capillary wedge pressure Pulmonary hypertension and pulmonary vascular resistance are not present, but low pulmonary artery pressure may occur in the presence of hypovolemia Pulmonary capillary wedge pressure may be low, normal, or high Oliguria may not reflect volume depletion Ventricular function is usually hyperdynamic but may be depressed in the presence of marked elevation in systemic vascular resistance Colloid oncotic pressure is usually low 160 If pulmonary edema remains refractory to initial management or is accompanied by persistent oliguria, insertion of a pulmonary artery catheter and transfer to an intensive care unit where mechanical ventilatory support could be provided may be considered.13 Pulmonary Edema Pulmonary edema is the most common cardiopulmonary complication of pre-eclampsia and refers to an excessive accumulation of fluid in the pulmonary interstitial and alveolar spaces. The development of pulmonary edema is usually multifactorial. According to the Starling equation, any factor that results in a reduction in colloid osmotic pressure, an increase in capillary permeability, or an increase in intravascular hydrostatic pressure will lead to extravasation of fluid from the vasculature and predispose to the development of pulmonary edema.14 The underlying physiological changes in the maternal cardiovascular system, including increased plasma blood volume, cardiac output, heart rate, and capillary permeability and a decrease in plasma colloid osmotic pressure, are exaggerated in pre-eclampsia and predispose women to develop pulmonary edema. Plasma colloid osmotic pressure decreases from around 22 mm Hg at term to 16 mm Hg after delivery, in normal pregnancies, and from 18 mm Hg at term to 14 mm Hg postpartum in pregnancies complicated by pre-eclampsia. The reduction in postpartum colloid osmotic pressure may result from excessive blood loss, fluid shifts secondary to increased capillary permeability, especially in pregnancies complicated by pre-eclampsia. Such changes help to explain why 70%-80% of cases of pulmonary edema in the setting of pre-eclampsia develop after delivery.15 Sibai described a series of 37 severe preeclamptic or eclamptic patients with pulmonary edema in which the incidence of pulmonary edema was significantly higher in older patients (P ⬍ 0.0001) and in multigravidas (P ⬍ 0.05). Eleven (30%) had antepartum pulmonary edema with 10 (90%) of the 11 having pre-existing chronic hypertension. Twenty-six (70%) had postpartum onset of pulmonary edema with an average onset at 71 hours postpartum.16 In a retrospective cohort study of California birth records, Gilbert and colleagues reviewed 29,842 pregnant women with chronic hypertension. As compared to nonchronic hypertensive patients, pulmonary edema was increased: (OR 5.2; 95% CI 3.9, 6.7).17 Clinicians have often questioned whether magnesium sulfate, administered to preeclamptic women for seizure prophylaxis, leads to pulmonary edema. Yeast and colleagues measured the effect of intravenous magnesium sulfate administered for preterm labor or seizure prophylaxis on colloid osmotic pressure and the risk for pulmonary edema in 294 pregnant women. Only 4 of the 294 women developed pulmonary edema, and all 4 had low colloid osmotic pressure in the setting of severe pre-eclampsia. Magnesium sulfate did not significantly change colloid osmotic pressure and does not pose a significantly increased risk for developing pulmonary edema.18 S.T. Bauer and K.L. Cleary Pulmonary edema is a clinical diagnosis characterized by worsening dyspnea and orthopnea along with signs of respiratory compromise (tachypnea, auditory crackles and rales, and hypoxemia). Arterial blood gas and chest X-ray may assist in the diagnosis. On postanterior and lateral chest X-ray films, the early signs of pulmonary edema (interstitial edema) are Kerley B lines, which are horizontal lines seen laterally in the lower zones reaching the lung edge. As the edema progresses, alveolar edema is observed in a “butterfly-like” pattern, which is characterized by the central predominance of shadows with a clear zone at periphery lung lobes. Cardiac enlargement characterizes progression to cardiac failure. Pulmonary edema may resemble the initial stages of ARDS.19 In select patients, electrocardiography, echocardiography, spiral computed tomographic imaging, ventilation/perfusion scan, or pulmonary arteriography may be necessary to exclude other causes of cardiopulmonary compromise, such as pulmonary embolism, pneumonia, and cardiomyopathy. Two-dimensional and Doppler echocardiography provide an additional diagnostic modality for patient with preeclampsia complicated by pulmonary edema. Desai and colleagues diagnosed impaired left ventricular systolic function in 4 of 16 (25%) patients with pre-eclampsia and pulmonary edema. In the remaining 12 patients with preserved systolic function, left ventricular diastolic filling abnormalities were demonstrated in a significant proportion compared to control hypertensive and normotensive groups.20 Mabie and colleagues evaluated the role of echocardiography in determining the cause of pulmonary edema in pregnancy. Forty-five pregnant or recently postpartum women admitted to an obstetrical intensive care unit with pulmonary edema during a 6-year period were followed prospectively. In 21 patients (47%), echocardiography demonstrated clinically unsuspected findings, which altered the long-term management in 16. Because clinical and roentgenographic findings do not accurately differentiate patients with respect to the presence and type of cardiac dysfunction, we recommend echocardiography to evaluate all pregnant women with pulmonary edema.21 Prompt diagnosis of pulmonary edema and intervention are critical. The morbidity and mortality associated with preeclampsia complicated by pulmonary edema have been greatly reduced by accurately assessing cardiovascular function and aggressive treatment. The presence of hypertension, proteinuria, and pulmonary edema satisfies the criteria for severe pre-eclampsia and precludes further conservative management. The diagnosis of severe pre-eclampsia requires immediate hospitalization in labor and delivery. Intravenous magnesium sulfate prevents seizures and antihypertensive medications lower severe levels of hypertension (systolic pressure greater than 160 mm Hg and/or diastolic pressure of at least 110 mm Hg). Patients with pulmonary edema deliver within 24-48 hours irrespective of fetal gestational age.22 Medical therapies to treat pulmonary edema should be optimized to expedite treatment results. Furosemide (Lasix) can be administered intravenously as a single dose of 10-40 mg over 2 minutes to promote diuresis. Bladder catheterization allows for accurate measurement of urine output. While Cardiopulmonary complications of PE most patients will respond to initial diuresis therapy, if adequate response is not seen within 30-60 minutes, the dose should be increased to 40-60 mg administered by slow intravenous injection to a maximum of 120 mg in 1 hour. Electrolytes should be monitored closely and repleted as indicated. Morphine sulfate can be administered intravenously as needed both for pain as well as in an attempt to reduce the adrenergic vasoconstrictor stimuli to the pulmonary arteriolar and venous beds. As with the management of all parturients with pre-eclampsia, sodium and water should be modestly restricted, and maternal fluid balance should be strictly monitored. Oxygen saturation can be monitored using a pulse oximeter, and oxygen supplementation using a nonrebreather facemask can be used to treat maternal hypoxemia. In addition to these standard measures, it is appropriate to follow the patient’s blood pressure, electrocardiogram, and fetal heart rate tracing. Afterload reduction using vasodilators may be necessary, especially in parturients with chronic hypertension and superimposed pre-eclampsia. Because most obstetrical patients have normal left ventricular systolic function, inotropic support is rarely necessary.13 Acute Respiratory Distress Syndrome ARDS is a form of respiratory failure characterized by acute hypoxemia and increased alveolar-capillary permeability resulting from diffuse and ongoing pulmonary inflammation.23 Patients experience acute hypoxemic respiratory failure, often accompanied by dyspnea, tachypnea, cyanosis, and tachycardia. Diffuse bibasilar crackles or wheezing can be appreciated on auscultation of the chest. Minimal evidence exists regarding the management of ARDS in pregnancy; mortality remains high, and few strategies have shown a mortality benefit. The treatment of ARDS in pregnancy is often extrapolated from studies performed in the general ARDS patient population, with consideration given to the normal physiological changes of pregnancy. Definitions vary for pregnancy-related ARDS, including ARDS during pregnancy or within 1 week or 1 month postpartum. Expanding this definition to several weeks postpartum may be appropriate, as it can take up to 6 weeks postdelivery for most of the physiological changes of pregnancy to resolve.24 Pre-eclampsia complicated by HELLP syndrome, pulmonary edema, and/or cardiopulmonary disease can advance to pregnancy-related ARDS. In a series of 83 obstetrical patients with ARDS from all causes, the antepartum mortality rate was 23% and the postpartum mortality rate was 50%.25 The effect of maternal ARDS on neonatal outcomes is not well studied, but high rates of fetal death, spontaneous preterm labor, and non-reassuring fetal heart rate tracing are reported. In a series of 10 antepartum patients in the third trimester ventilated for ARDS, only 5 of the neonates survived intact after delivery.24 Spontaneous preterm labor and delivery was reported in 6 patients. Fetal heart rate abnormalities were reported in 6 of these pregnancies and occurred 161 within 4 days of admission. Of the 4 infants who did not survive intact, 2 suffered perinatal asphyxia, 1 suffered perinatal asphyxia and cerebral palsy, and 1 suffered perinatal death. Respiratory support provides the cornerstone to management of ARDS in pregnancy, especially as respiratory alkalosis develops. Although a Pao2 of 55 mm Hg and an Sao2 of 88% would be tolerated in the general population, adequate fetal oxygenation requires a Pao2 of ⱖ70 mm Hg, which corresponds to a maternal Sao2 of about 95%.24 The broad goals of ventilatory support in a pregnant woman with ARDS are no different from the general population, namely, to manage blood-gas variables while avoiding ventilator-associated lung injury. Likewise, the clinical criteria for intubating a pregnant patient remain the same and include increased work of breathing, mental status deterioration, hemodynamic instability, and inability to protect the airway or manage secretions.26 Little literature exists to guide the decisions on the mode of delivery in patients with ARDS. A small retrospective study suggests that cesarean delivery may improve the maternal status in ventilated women in late pregnancy that have ARDS but are clinically stable.24 Other studies have not supported an improvement.21 Pregnant women with ARDS may not tolerate a vaginal delivery due to increased oxygen consumption. Cesarean delivery results in larger and more rapid fluid shifts and blood loss than with vaginal delivery and may present a greater physiological stress. Until further data are available, the decision for a mode of delivery should be based on standard obstetrical indications. Attempts should be made to optimize maternal oxygenation and pain control during vaginal deliveries.27 Although ARDS during pregnancy is uncommon, when it does occur, optimum management requires multidisciplinary care from maternal-fetal medicine, critical care medicine, obstetrical anesthesiology, pulmonology, and neonatology. Peripartum Cardiomyopathy Peripartum cardiomyopathy (PPCM) affects patients late in pregnancy or in the early postpartum period. It is an infrequent complication of pre-eclampsia, but a history of preeclampsia can be found in up to 70% of those who develop PPCM. The 4 following criteria are needed to meet the definition of peripartum cardiomyopathy: (1) development of cardiac failure in the last month of pregnancy or within 5 months of delivery; (2) absence of an identifiable cause for the cardiac failure; (3) absence of recognizable heart disease before the last month of pregnancy; (4) left ventricular systolic dysfunction (for example, left ventricular ejection fraction (EF) below 45%).28 The etiology remains unclear, but risks factors include multiple pregnancy, pre-eclampsia, multiparity, and advanced maternal age. Pre-eclampsia is associated with peripartum cardiomyopathy; however, peripartum cardiomyopathy is an infrequent complication of pre-eclampsia.29 S.T. Bauer and K.L. Cleary 162 Etiology The etiology of peripartum cardiomyopathy remains unknown despite significant research. No distinct hormonal disorder has been identified in patients with PPCM, even though estrogen, progesterone, and prolactin have significant effects upon the cardiovascular system. There are multiple factors, including hemodynamic changes of pregnancy, which may contribute to the physiological process. Blood volume and cardiac output increase during pregnancy, which results in transient left ventricular remodeling and hypertrophy. These changes may produce an exaggerated decrease in left ventricular systolic function in women who develop peripartum cardiomyopathy. The hemodynamic stress of gestational hypertension and acute pre-eclampsia is more common in women with peripartum cardiomyopathy and may contribute to the development of heart failure.30 The clinical course of peripartum cardiomyopathy varies, with 50%-60% of patients showing complete or near-complete recovery of clinical status and cardiac dysfunction, usually within the first 6 months postpartum. Maternal mortality rate is reported to be 25%-50%, but more recent studies show a 95% 5-year survival rate. Women with residual cardiac dysfunction postpartum should be counseled against future pregnancy given associated risk for worsening left ventricular function.31 Elkayam and colleagues reviewed data obtained from 123 women with a history of cardiomyopathy diagnosed during pregnancy and/or the postpartum period. Peripartum cardiomyopathy patients had a mean age of 31 ⫾ 6 years and were mostly Caucasian (67%). Common associated conditions were hypertension/pre-eclampsia (43%), tocolytic therapy (19%), and twin pregnancy (13%). Left ventricular EF at the time of diagnosis was 29% ⫾ 11% and improved to 46% ⫾ 14% (P ⬍ 0.0001) at follow-up. Normalization of left ventricular EF occurred in 54% and was more likely in patients with left ventricular EF ⬎30% at diagnosis. Maternal mortality was 9%.32 Witlin and colleagues reviewed 28 patients without an antecedent history of heart disease who were diagnosed with peripartum cardiomyopathy. Pre-eclampsia was identified in 19 of the 28 (68%) patients. The unique hemodynamic stresses of pregnancy in combination with a history of preeclampsia can unmask previously undiagnosed cardiomyopathy in otherwise medically stable women.33 Habli and colleagues were the first to report a correlation between left ventricular EF in women with peripartum cardiomyopathy at initial presentation and at subsequent pregnancy and long-term outcome. The patients were categorized by their initial EF into EFs of 25% or less and EF of greater than 25%. Among 28 patients with EF of 25% or less, 16 (57%) had end-stage cardiac disease. One had a transplant and 15 were on a transplant list. All 16 had a baseline EF of 25% or less at index pregnancy: 4 had improved (EF ⬎40%) at interval follow-up and 3 at last follow-up available. Women with a history of postpartum cardiomyopathy had a higher rate of progression of symptoms of heart failure in a subsequent pregnancy. These findings offer providers with important counseling information for patients with an obstetrical history complicated by peripartum cardiomyopathy.34 Ischemic Heart Disease—Myocardial Infarction Myocardial infarction associated with pregnancy is a rare event, usually related to maternal risk factors for ischemic heart disease, such as hypertension, diabetes mellitus, and coronary atherosclerosis. However, a mechanism of coronary spasm has been suggested to be a cause of myocardial infarction in patients with normal coronary arteries or in those with minimal nonobstructive coronary artery disease, especially infarction related to pre-eclampsia, after administration of ergot alkaloids, bromocriptine, oxytocin, and prostaglandin. Early diagnosis of acute myocardial infarction in pregnancy is often hindered by the normal changes of pregnancy and low level of suspicion. Epidemiology The incidence of myocardial infarction in women of reproductive age is less than 1% and approximately 150 cases of myocardial infarction during pregnancy have been documented in the literature worldwide.35 Despite the high frequency of hypertensive disease during pregnancy, little research has assessed long-term sequelae. The Royal College of General Practitioners’ oral contraception study demonstrated that women with a recorded diagnosis of pre-eclampsia had nearly 3 times the risk of myocardial infarction as non-preeclamptic women.36 Hannaford and colleagues reviewed the data from this study and found that parous women with a history of pre-eclampsia had a statistically significant increased risk of ischemic heart disease and that increases were seen in the 3 following major subcategories: (1) acute myocardial infarction; (2) chronic ischemic heart disease; and (3) angina pectoris. Compared with parous women with no history of pre-eclampsia, those who had experienced preeclampsia had a significantly increased risk of hypertensive disease, acute myocardial infarction, chronic ischemic heart disease, angina pectoris, and ischemic heart disease (Table 3).37 Women with a history of hypertension in pregnancy are at an increased risk for ischemic heart disease compared with the general population. In a population-based study of 7543 Table 3 Incidence of Vascular Disease in Parous Women With and Without a Preceding History of Pre-Eclampsia41 Condition Hypertensive disease Acute myocardial infarction Chronic ischemic heart disease Angina pectoris All ischemic heart disease Relative Risk Parous Pre-Eclampsia (95% CI) 2.35 (2.08, 2.65) 2.24 (1.26, 2.16) 1.74 (1.06, 2.86) 1.53 (1.09, 2.15) 1.65 (1.26, 2.16) Cardiopulmonary complications of PE 163 Table 4 Risk of Cardiac Disease After Pre-Eclampsia/Eclampsia in Case-Control Studies49 Study Weight (%) Odds Ratio (Random) 95% CI Mann46 Rosenberg47 Croft36 Haukkamaa40 Total (95% CI) 6.47 42.30 32.00 19.23 100.00 3.60 (0.26, 50.70) 1.30 (0.65, 2.60) 3.60 (1.42, 9.10) 4.80 (1.21, 19.00) 2.47 (1.22, 5.01) cases, Jonsdottir and colleagues reviewed the association between hypertension in pregnancy, pre-eclampsia, and eclampsia and death rates from ischemic heart disease. The relative risk of dying from ischemic heart disease was significantly higher among eclamptic women (RR 2.61; 95% CI 1.11, 6.12) and those with pre-eclampsia (RR 1.90; 95% CI 1.02, 3.52) than those with hypertension alone. Parous women at the index pregnancy had a 2-fold higher risk of dying from ischemic heart disease than primigravid women (RR 2.05; 95% CI 1.19, 3.55; P ⫽ 0.01).38 Etiology and Pathophysiology Fleming and colleagues have suggested that cardiac troponin levels are elevated in women with pre-eclampsia.39 Fleming examined troponin I levels in 69 women with pre-eclampsia or gestational hypertension. There were 43 controls, 20 patients with gestational hypertension, and 6 patients with preeclampsia. Troponin I levels were significantly higher in the gestational hypertensive groups compared with controls, suggesting that coronary ischemic may be missed in patients with hypertensive disorders in pregnancy, including preeclampsia. Pre-Eclampsia Impacts Long-Term Cardiovascular Health Pre-eclampsia and coronary artery disease share common risk factors for endothelial dysfunction and damage, such as hypertension, diabetes, and obesity. The associated maternal physiological changes from pre-eclampsia include increased inflammatory markers, dyslipidemia, insulin resistance, endothelial dysfunction, and oxidative stress and are associated with an increased risk for cardiovascular disease in later life. A history of pre-eclampsia has been reported to be a risk factor for several distinct cardiovascular conditions later in life. Haukkamaa and colleagues40 reviewed the history of hypertensive pregnancies and conventional risk factors in 141 relative young parous women with angiographically documented coronary artery disease and showed that hypertension and pre-eclampsia were independent risk factors for subsequent coronary artery disease, with adjusted odd ratios of 5.2 (2.6, 11.0; P ⬍ 0.001) and 4.8 (95% CI 1.2, 19; P ⫽ 0.03), respectively. Patients with coronary artery disease had pre-eclampsia more often in the first or any subsequent pregnancy than did the control groups (17% vs. 3.0% and 1.8%, P ⬍ 0.001). With the recognition of hypertensive diseases of pregnancies as an etiology for subsequent heart disease later in life, Wikstrom and colleagues investigated the question of whether the risk of developing ischemic heart disease in later life increases with severity of hypertensive disease during pregnancy. After a review of 403,550 women in the Swedish Medical Birth Register over a 9-year period with up to 15 years of follow-up, the adjusted incidence rate ratio for later development of ischemic heart disease was 1.6 (95% CI 1.3, 2.0) when the first pregnancy was complicated by gestational hypertension without proteinuria, 1.9 (95% CI 1.6, 2.2) for mild pre-eclampsia, and 2.8 (95% CI 2.2, 3.7) for severe pre-eclampsia. Women with hypertensive disease in both pregnancies had an RR of 2.8 (95% CI 2.0, 3.9) compared with women with 2 normal pregnancies.41 In a recent systematic review and meta-analysis, McDonald and colleagues reviewed the existing literature to determine if women with a history of pre-eclampsia/eclampsia are at increased risk of long-term cardiovascular sequelae. Relative to women with uncomplicated pregnancies, women with a history of pre-eclampsia/eclampsia had an increased risk of subsequent cardiac disease in both the case-control studies and the cohort studies, as well as an increased risk of cardiovascular mortality. Women with a history of preeclampsia/eclampsia have approximately double the risk of early cardiac and cardiovascular mortality (Tables 4 and 5).42 After a pregnancy complicated by pre-eclampsia, women have an increased risk of vascular disease, including the following: hypertension after 14.1 years (3.70, 95% CI 2.70, 5.05), ischemic heart disease after 11.7 years (2.16, 95% CI 1.86, 2.52), stroke after 10.4 years (1.81, 95% CI 1.45, 2.27), and venous thromboembolism after 4.7 years (1.79, 95% CI 1.37, 2.33). Overall mortality after pre-eclampsia was increased after 14.5 years: 1.49 (95% CI 1.05, 2.14).43 Irgens and colleagues demonstrated that mothers have increased cardiovascular morbidity and mortality risk after a pregnancy complicated by pre-eclampsia. Women who had pre-eclampsia had a 1.2-fold higher long-term risk of death (95% CI 1.02, 1.37) than women who did not have preeclampsia. The risk in women with pre-eclampsia and a preterm delivery was 2.71-fold higher (1.99-3.68) than in Table 5 Risk of Cardiac Disease After Pre-Eclampsia/Eclampsia in Cohort Studies49 Study Weight (%) Relative Risk (Random) 95% CI Jonsdottir38 Hannaford37 Irgens44 Smith48 Kestenbaum49 Wilson50 Funai51 Kaaja52 Ray53 Wikstrom41 Total (95% CI) 8.51 16.10 11.11 8.39 11.19 4.43 13.04 4.78 10.62 11.82 100.00 2.12 (1.29, 3.49) 1.65 (1.26, 2.16) 2.12 (1.42, 3.16) 3.54 (2.14, 5.85) 2.53 (1.70, 3.77) 1.24 (0.58, 2.68) 3.07 (2.18, 4.33) 2.50 (1.20, 5.20) 2.85 (1.88, 4.32) 2.27 (1.56, 3.32) 2.33 (1.95, 2.78) 164 women who did not have pre-eclampsia and whose pregnancies went to term. In particular, the risk of death from cardiovascular causes among women with pre-eclampsia and a preterm delivery was 8.12-fold higher (4.31, 15.33).44 Finally, a recent review has demonstrated that women with severe, very early onset pre-eclampsia have an increased risk of pre-eclampsia in future pregnancies. Women with early onset severe pre-eclampsia exhibit more cardiovascular risk factors. Gaugler-Senden and colleagues reviewed 20 women with early onset pre-eclampsia, before 24 weeks’ gestation. Cardiovascular risk profiles were compared to controls. Of the 20 women with history of early onset severe pre-eclampsia, 17 women had 24 subsequent pregnancies, of which 12 (50%) were complicated by pre-eclampsia. Severe pre-eclampsia developed in five (21%) pregnancies. No perinatal deaths occurred. Women with a history of early onset severe pre-eclampsia in a previous pregnancy had significantly more chronic hypertension than controls (55% vs. 10%, P ⫽ 0.002), as well as increased microalbuminuria (P ⬍ 0.05).45 Women with early onset, recurrent, or severe pre-eclampsia appear to be at highest risk of cardiovascular disease later in life, including during the premenopausal period. These women may have unrecognized chronic hypertension, an inherited thrombophilia, or other genetic or environmental factors predisposing them to hypertension during and after pregnancy. Conclusions Cardiovascular and cardiopulmonary complications due to pre-eclampsia continue to affect thousands of women annually. Maternal morbidity and mortality from placental syndromes, including gestational hypertension and pre-eclampsia, probably arise from coexisting cardiovascular risk factors. Cardiovascular complications can include peripartum cardiomyopathy, ischemic and coronary artery heart disease, and pulmonary edema, acute lung injury, and acute respiratory distress syndrome. Further research is needed to understand the etiology of the increased risk of cardiopulmonary complications from pre-eclampsia and who pre-eclampsia/eclampsia might be incorporated into cardiopulmonary and cardiovascular risk assessment along with other new risk factors. 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