Pregnancy and the cardiovascular system

International Journal of Cardiology 98 (2005) 179 – 189 www.elsevier.com/locate/ijcard

Review

Pregnancy and the cardiovascular system Amr E. Abbas a,*, Steven J. Lester a, Heidi Connolly b a

Division of Cardiovascular Diseases, Mayo Clinic, Scottsdale, AZ 85259, USA b Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA

Received 25 April 2003; received in revised form 13 August 2003; accepted 14 October 2003 Available online 24 May 2004

Abstract The cardiovascular system undergoes important adaptations during pregnancy to accommodate for fetal requirements. This causes a hemodynamic burden on patients with underlying heart disease, and is associated with significant morbidity and mortality. Moreover, certain cardiovascular diseases may be due to pregnancy. Although unusual, these diseases can pose a threat to the pregnant woman and her fetus. This review will discuss cardiovascular adaptations to pregnancy as well as the risk of pregnancy in patients with underlying heart disease. It will also provide a brief overview of cardiovascular disorders associated with pregnancy. D 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Pregnancy; Cardiovascular system; Fetus

1. Cardiovascular adaptations in pregnancy and delivery The demand on the cardiovascular system progressively increases during pregnancy and parturition; these changes appear in the first trimester, continue into the second and peak in the late second and early third trimester. The cardiovascular adaptations usually persist up to 2 –3 weeks postpartum but may not completely resolve until 12 weeks after delivery or even longer after Cesarean delivery or in lactating women (Table 1). Not surprisingly, the majority of cardiac related pregnancy complications occur late in pregnancy [1]. Pregnancy is a high volume, low-resistance state characterized by a 22% increase in cardiac output by 8 weeks. The cardiac output reaches a maximum of 30 –40% above prepregnancy levels by the late second and early third trimesters. The increase in cardiac output is mainly due to a 30% increase in stroke volume, and to a lesser extent is related to Abbreviations: ACEIs, angiotensin converting enzyme inhibitors; ARBs, angiotensin receptor blockers; CO, cardiac output; DIC, disseminated intravascular coagulopathy; DVT, deep venous thrombosis; EF, ejection fraction; GFR, glomerular filtration rate; HCM, hypertrophic cardiomyopathy; PPCM, peripartum cardiomyopathy; RPF, renal plasma flow; SVR, systemic vascular resistance. * Corresponding author. Tel. B: +1-480-301-8123/P: +1-480-301-8718; fax: +1-480-301-8018. E-mail address: [email protected] (A.E. Abbas). 0167-5273/$ - see front matter D 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2003.10.028

an increase in heart rate of 10– 15 beats per minute. The increase in cardiac output is associated with a drop in systemic vascular resistance by 30% at 8 weeks. This is secondary to the effect of gestational hormones, circulating prostaglandins, heat produced by the fetus, and the lowresistance placental bed. The net effect is a mild decrease in mean blood pressure with the decline in diastolic pressure being more so than systolic [1,2]. After 28 weeks, patients may be disposed to hypotension due to aortocaval compression when supine and up to 10% may develop signs of shock when assuming this position [1]. The blood volume increases mainly due to an increase in plasma volume from a base line of 40 up to 70 ml/kg. The red blood cell volume increases from 25 to 30 ml/kg, at a slower rate, accounting for the relative anemia of pregnancy. Finally, the O2 carrying capacity is increased due to increase in partial pressure of O2, cardiac output, a decrease in viscosity, and a rightward shift of the oxyHb dissociation curve [1,2]. Thus, the cardiovascular physiological adaptations of pregnancy represent an efficient oxygen carrying capacity state designed to provide adequate oxygen and nutrient demands for both the mother and fetus. During delivery, pain and apprehension further increase cardiac output and stroke volume by 45%. Each uterine contraction auto transfuses the patient and further increases blood volume and cardiac output by 10 –25%. After delivery of the baby, caval compression is relieved and after the

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Table 1 Cardiovascular adaptations during pregnancy Parameter

Average change during pregnancy

Blood volume Cardiac output Stroke volume Heart rate Systemic vascular resistance Mean arterial pressure Systolic blood pressure Diastolic blood pressure Central venous pressure Serum colloid osmotic pressure Hemoglobin

z35% z40 – 43% z30% z15 – 17% #15 – 21% No significant change #3 – 5 mm Hg #5 – 10 mm Hg No significant change #14% #2.1 g/dl

placenta is delivered, another auto transfusion occurs from the placental sinusoids into the maternal circulation, both increase cardiac output and stroke volume by up to 80% above base line [1,2]. Other significant changes include an increase in glomerlular filtration rate (GFR) and renal plasma flow (RPF) early in pregnancy with an increase in creatinine clearance. This renders the upper limits of normal for blood urea nitrogen and creatinine lower in pregnancy. GFR and RPF return to normal in the third trimester [1,2]. Maintenance of therapeutic levels of medications is difficult due to an increase in blood volume, a decrease in plasma proteins, increased renal clearance, increased hepatic clearance, and decrease in gastrointestinal absorption. This may necessitate changing the dose of medications. Another concern is the placental transfer of medications, and the excretion of medications in breast milk [1,2].

A hypercoagulable state due to increase in factors VII, VIII, X, and fibrinogen occurs in pregnancy and is associated with a higher incidence of thromboembolic complications. Finally, the amount of blood loss is approximately 500 cc for a non-complicated vaginal delivery and up to 1400 cc during cesarean section [1,2].

2. Pregnancy in patients with underlying cardiovascular disorders In an attempt to identify both the mortality and morbidity in pregnant patients with cardiovascular disease, the Canadian CARPREG trial (prospective multicenter study of pregnancy outcomes in women with heart disease) enrolled 562 pregnant women. The study followed patients through pregnancy, delivery and for 6 months after and showed a combined maternal, fetal, and neonatal mortality of 3% [3]. Morbidity outcomes were primary cardiac events, the most common of which were pulmonary edema and tachyarrhythmias, and secondary cardiac events in the form of worsening of the functional status or the need for intervention. Neonatal morbidity including preterm labor and small for gestational age occurred in 20%, while obstetric complications occurred in 4% [3] (Fig. 1). In this study, congenital heart disease accounted for 75% of cases of cardiovascular disease during pregnancy. In a multivariate analysis, the most significant predictor for morbidity or mortality was the presence of left ventricular dysfunction. Other predictors of adverse outcome included a prior cardiac event or arrhythmia, an advanced NYHA functional status or cyanosis (>II), and the presence

Fig. 1. Morbidity outcome in the CARPREG trial. The majority of cardiac complications occurred in patients with poor LVEF and included pulmonary edema, tachyarrhythmias, worsening functional status, and need for intervention [3].

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of left heart obstructive diseases (mitral stenosis, aortic stenosis, and hypertrophic obstructive cardiomyopathy) [3]. 2.1. Management guidelines 2.1.1. Before conception counseling Prognosis of patients with heart disease during pregnancy is largely dependent on the underlying cardiac lesion, functional status, left ventricular function, and comorbid illnesses. Clark et al. [4] developed a mortality risk factor prediction based on the underlying cardiac condition (Table 2). The New York Heart Association (NYHA) functional classification is another method of determining the outcome of pregnancy in patients with underlying heart disease and it has been shown to be a predictor of mortality [2]. As outlined in the CARPREG trial [3], multivariate analysis revealed that the most significant predictor for morbidity or mortality in pregnant women with heart disease was the presence of left ventricular dysfunction. In addition, because of a higher incidence of both maternal and fetal complications, patients with a history of peripartum cardiomyopathy are advised not to become pregnant again particularly if they have residual left ventricular dysfunction [5]. Other confounding factors that may increase the risk of pregnancy in patients with heart disease include the need for anticoagulation, other comorbid illnesses, and associated extracardiac abnormalities in patients with congenital heart disease [2]. Patients should be counseled about their need for future cardiac surgery prior to conception. Patients with congenital or valvular heart disease may require surgical intervention before the planned pregnancy to decrease the risk of cardiovascular complications. Patients with Marfan syndrome and an aortic root above 4 cm should avoid pregnancy. Surgery should be recommended for these patients and pregnancy can be considered if surgical intervention is successful [6].

Table 2 Clark’s mortality index (modified from Ref. [4]) Groups

Underlying cardiac disease

Mortality

Group 1

ASD, uncomplicated VSD, PDA in the absence of pulmonary hypertension, pulmonic and tricuspid disease, repaired tetralogy of Fallot, bioprosthetic valve (porcine and human), and mitral stenosis (functional class I and II). Mitral stenosis with atrial fibrillation, mechanical valve prosthesis, mitral stenosis (functional Class >II), aortic stenosis, uncomplicated coarctation of the aorta, unrepaired tetralogy of Fallot, previous myocardial infarction with preserved left ventricular function, and Marfan syndrome with aortic dimension < 40 mm. Pulmonary hypertension, complicated coarctation of the aorta, and Marfan syndrome with aortic dimension z 40 mm.

< 1%

Group 2

Group 3

5 – 15%

25 – 50%

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Another important aspect to be considered is the mother’s ability to care for the child. The life expectancy in patients with symptomatic complex congenital heart disease should be assessed. A thorough discussion of the mother’s ability to take care for her offspring as well as her survival should be undertaken with the family. Contraception should also be discussed as a means of delaying or preventing pregnancy. Patients with absolute contraindications to pregnancy require more definitive methods of contraception such as tubal ligation. Oral contraceptive agents may pose additional hypercoagulable risk in patients with underlying cardiovascular disease [2]. The risk of recurrence of the congenital heart defect must also be thoroughly discussed. There is a 0.5% risk of congenital heart disease in the general population. The chance of recurrence of congenital heart defects in the offspring if a first-degree relative is affected is increased 10 fold. The risk is higher with left-sided obstructive lesions [2]. Autosomal dominant conditions, such as Marfan syndrome, have a 50% chance of recurrence [2]. This risk should be discussed with the mother and partner. Fetal echocardiography may help identify fetal cardiac abnormalities. 2.1.2. Antepartum When pregnancy occurs, patients with cardiovascular disease require regular visits with medical personnel who are experienced in the management of pregnant patients with heart disease. A cardiologist, obstetrician, perinatologist, and an experienced anesthesiologist should be all involved in the care of the high-risk pregnant patient and determining the pregnancy and delivery plan. The frequency of evaluation depends on the status of the patient. Outlying the level of activity, date of hospital admission, and continuation of pre-pregnancy cardiac therapy while avoiding teratogenic drugs as angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) is essential. Specific-guided therapy may include avoiding vasodilators, maintaining preload and prophylactic heparin in patients with Eisenmenger syndrome who get pregnant and refuse interruption of pregnancy. In Marfan syndrome, h-blockers should be administered and serial echocardiograms should be performed [2]. Surgery should be considered if excess aortic root dilation is noted during pregnancy [6]. 2.1.3. Labor and delivery Vaginal delivery is the preferred method of delivery. However, Caesarian section should be considered in a patient with stable aortic dissection (in patients with acute, unstable dissection, cardiovascular surgery is performed), Marfan syndrome with a dilated aortic root, and failure to switch from warfarin to heparin 2 weeks before delivery [2] (due to the risk of fetal intracranial hemorrhage). Heparin should be discontinued 6 –12 h before induction, depending on the underlying condition, or reversed with protamine if sponta-

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neous delivery occurs. It may be resumed 6 – 12 h after delivery [7]. Careful attention to preload, blood pressure, and blood loss is essential and invasive monitoring is occasionally required. Epidural anesthesia does not decrease systemic vascular resistance (SVR) and may be useful in cases of congenital heart disease. Adequate volume loading is required to avoid hypotension as well as left lateral decubitus position to attenuate the hemodynamic effects of the supine position. Forceps or vacuum delivery is beneficial to shorten the second stage of delivery. In the absence of infection, the AHA and ACC do not recommend infective endocarditis prophylaxis except in high-risk patients [8]. However, individualized therapy is important. Post-partum monitoring for 72 h is generally recommended and up to 7 days for high-risk patients, such as patients with pulmonary hypertension, may be needed [2]. 2.1.4. Cardiovascular surgery and pregnancy 2.1.4.1. Effects of cardiac surgery. Cardiac surgery can be accomplished during pregnancy with relative safety for the mother, but fetal mortality is consistently reported at 20% secondary to reduction of placental blood flow [9]. Cardiopulmonary bypass has many potential side effects that may hamper uteroplacental perfusion and fetal development. These side effects are mediated through alteration of cellular proteins and coagulation, complement activation, particulate and air embolism, non-pulsatile flow, hypotension, and hypothermia [10]. Hypothermia may precipitate uterine contractions and causes coagulation disorders and arrhythmias that may reduce placental oxygen exchange. Extensive uterine contractions may occur during the rewarming phase after hypothermia for unknown reasons and occur more commonly with older gestational age and can result in placental failure and secondary fetal hypoxia [10]. One study found that embryo-fetal mortality rate to be 24% under hypothermic conditions versus 0% under normothermic conditions [11]. A prostaglandin-mediated increase in placental vascular resistance also occurs. In experimental studies, the use of pulsatile perfusion during extracorporeal circulation has shown to attenuate this placental process through maintenance of a high-perfusion pressure and flow rate [12]. 2.1.4.2. Mortality and morbidity. Valvular heart disease and aortic arterial wall disease are the most common indications for cardiovascular surgery during pregnancy. In one study [13], the highest mortality was associated with aortic arterial wall surgery and pulmonary embolectomy. The fetal and neonatal mortality and morbidity in this study was 9% and 30%, respectively. On the other hand, maternal morbidity and mortality varied according to the stage of pregnancy or delivery. Both morbidity and mortality were higher during the postpartum and delivery period than during pregnancy.

It is unclear why morbidity and mortality is higher during surgery performed immediately or shortly after delivery. This may be due to the following: 

Maternal – fetal conflict of interest: Women tend to defer any treatment that they perceive as dangerous to their offspring. This leads to progression of the condition throughout pregnancy (Obstetric vs. Cardiac management).  High hemodynamic load of late pregnancy: The cardiac output and blood volume progressively increase during pregnancy and thus increase the burden on pregnant women with heart disease who undergo surgery at a later date.  Occult presentation and delays in diagnosis: Normal cutoff values for clinical and laboratory data change during pregnancy. Values that are considered normal in non-pregnant women may be abnormal during pregnancy. The occurrence of these perceived normal values during pregnancy may signify the presence and progression of disease process. If these values are not identified as abnormal, there may be a delay in the diagnosis. 2.1.4.3. Surgery for aortic dissection. Most review articles make no distinction between patients suffering from Type A (ascending aorta, De Bakey I and II), Type B (De Bakey III), and aortic aneurysms [14]. However, the difference is crucial since type A dissections require immediate surgery, while type B may be conservatively managed in the absence of rupture or malperfusion. Aortic dissection in pregnancy is usually thoracic in location, the proximal tear is within the ascending aorta in 89% [14]. In one study, 70% of aortic dissections during pregnancy were De Bakey type I, 19% were type II, and only 11% were type III [15]. In a recent study, there was no difference in age, gestational week of occurrence of dissection, and the incidence of systemic disease between either type. Type A dissections were more common (79% vs. 21%) and more symptomatic than type B. Enlarged aortic root (>4 cm), increasing size during pregnancy, and low body surface area were risk factors for type A dissection. Only the presence of a systemic disease was an indicator for type B dissection, which was managed medically. In case of type A dissection before 30-week gestation, immediate surgery should be performed. After 30week gestation, emergency C-section followed by cardiac surgery is the best modality of therapy [14]. 2.2. Pregnancy in patients with underlying valvular heart disease 2.2.1. Native valvular heart disease The number of women with valve disease and pregnancy is increasing. This may be due to the fact that patients with heart disease are surviving to the childbearing age [13]. Mitral stenosis is the most common valve lesion encountered during pregnancy. The increased blood volume and

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heart rate during pregnancy leads to an increase in left atrial pressure with an increase likelihood of atrial fibrillation with rapid ventricular response and heart failure [2]. Mortality and morbidity is related to the functional class before pregnancy. Patients with mild to moderate mitral stenosis can generally be medically managed with h-blockers, digitalis, and diuretics. Patients with more severe mitral stenosis should have their valve lesion addressed prior to conception. If patients are first diagnosed during pregnancy and develop severe symptoms that are refractory to medical treatment and have a pliable mitral valve, balloon mitral commissurotomy is the treatment of choice [16]. Aortic stenosis is infrequently encountered during pregnancy and is usually due to a congenitally abnormal valve. Patients with mild aortic stenosis usually tolerate pregnancy well. Patients with moderate or severe aortic stenosis are very sensitive to preload changes and hypotension. They are unable to augment cardiac output (CO), with increase in LV systolic and filling pressures leading to heart failure and ischemia. Older data revealed a maternal mortality of 11% and perinatal mortality of 4% [17]. More recently, there has been no mortality data but a decline in functional status in 20% of cases [18]. Aortic valvuloplasty or valve replacement during pregnancy or immediately after delivery may be required. Mitral and aortic valve regurgitation are usually well tolerated during pregnancy due to a decrease in systemic vascular resistance and enhancement of forward flow. However, regurgitant lesions may still be associated with heart failure in severe cases [2]. 2.2.2. Prosthetic valves The ideal prosthetic valve during pregnancy is a matter of extensive research. Pregnancy does not seem to accelerate the rate of degeneration of bioprosthetic or homograft valves [19] and patients with tissue valves usually tolerate pregnancy well in the absence of obstruction. Mechanical valves carry a risk of thrombosis during pregnancy (3 – 14%), which is higher if unfractionated heparin, rather than warfarin is used for anticoagulation during pregnancy. Maternal mortality is up to 1– 4% in patients with mechanical valves [19 –21]. 2.2.3. Anticoagulation in pregnancy Pregnancy is a hypercoagulable state, which poses an increased risk of thromboembolic complications. The only consensus is that anticoagulation therapy is required for patients with prosthetic valves. There is no consensus, however, with respect to how anticoagulation therapy should be prescribed. The safest anticoagulation option for the mother is achieved with warfarin continued during pregnancy. However, the risk of prosthesis thrombosis is 4% and the risk of warfarin embryopathy may be as high as 6% [7,21]. The incidence of fetal complications in pregnant women on warfarin is related to the warfarin dose [22]. In one study, a warfarin dose of less than 5 mg was associated with a

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significantly lower risk of fetal complications than higher warfarin doses [22]. Substituting subcutaneous unfractionated heparin for warfarin between weeks 6 and 12 of the pregnancy decreases the risk of embryopathy. However, the use of unfractionated heparin increases the risk of thromboembolic complications [7,20,21]. This may in part be due to sub-optimal doses of heparin. Close monitoring of the partial thromboplastin time, achieving 2.5 –3.5 times control has been recommended [23]. Low-molecular weight heparin has not been studied in randomized trials [21,24]. A recent study of 36 women, who developed venous thromboembolism during pregnancy and immediately post partum, showed the safety and efficacy of enoxaparin in this population [25]. Pregnant women with prosthetic heart valves, who receive enoxaparin for anticoagulation, may be at higher risk for thromboembolism than patients continued on warfarin. In April 2002, the FDA issued an advisory against the use of enoxaparin for thromboprophylaxis in pregnant patients. In a letter from the manufacturer to health care professionals, there was a series of prosthetic heart valve thromboses that occurred in patients with prosthetic valves who had received enoxaparin for thromboprophylaxis [26]. Prosthesis thrombosis led to maternal and fetal deaths in some of these cases. There were also reports of congenital anomalies in infants born to women who received enoxaparin during pregnancy including cerebral anomalies, limb anomalies, hypospadias, peripheral vascular malformation, fibrotic dysplasia, and cardiac defect [26]. A cause-andeffect relationship was not established and the incidence has not been shown to be higher than in the general population. The estimated risk of major bleeding in patients on anticoagulation is 2.5%, 80% of which occurs at delivery. Fetal intracranial hemorrhage during vaginal delivery is a risk with warfarin therapy due to fetal anticoagulation, unless it has been stopped 2 weeks before delivery and heparin is substituted [7,20,21]. If labor begins while the patient is taking warfarin, a Caesarian section should be considered. Recent guidelines from the AHA/ACC for use of coumadin during pregnancy state that the inadequacy of heparin for prevention of maternal thromboembolism may outweigh the risk of warfarin embryopathy during the first trimester and suggest three methods of anticoagulation [27]. The first is administrating heparin throughout pregnancy. Recommendations for biweekly assessment of heparin dose with aPTT or heparin assays are recommended to ensure adequate dosing. The second method includes the administration of warfarin throughout pregnancy with switching to heparin in the last 2 weeks. The last method involves administrating heparin during the first trimester, and switching to coumadin throughout the remainder of pregnancy until the last 2 weeks prior to planned delivery or induction during which the patient receives heparin.

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2.3. Pregnancy in patients with congenital heart disease Congenital heart disease is the most common form of structural heart disease affecting women of childbearing age in North America. [28,29]. Maternal mortality in pregnant patients with congenital heart disease is 2 – 11/100,000 cases and the main causes of death are pulmonary hypertension and dissecting aortic aneurysm. Fetal death is related to the functional status of the mother. The absolute contraindications to pregnancy are primary and secondary pulmonary hypertension and Marfan syndrome with aortopathy and an ascending aorta diameter of more than 40 mm [6]. Pregnancy in a patient with Eisenmenger syndrome is associated with up to 50% maternal mortality, and a 30% risk of abortion, fetal and neonatal complications. Other relative contraindications include severe aortic stenosis, pulmonary vascular disease, cyanosis, and heart failure [28,29]. Surgically repaired patients have better outcomes during pregnancy than those who are untreated. In one study, untreated patients had a higher maternal death (12% vs. 0%), perinatal mortality (15% vs. 0%), and prematurity (32 vs. 7%) than those who were surgically corrected [30]. Both surgically corrected and untreated common forms of congenital heart diseases occurring in pregnancy warrant further discussion. 2.3.1. Left-to-right shunts The increase in blood volume and cardiac output is counteracted by the decrease in systemic vascular resistance. Consequently, in patients with atrial and ventricular septal defects as well as patent ductus arteriosus, left-to-right shunting is not increased and transient shunt reversal may occur due to low systemic vascular resistance [2]. In the absence of pulmonary hypertension, pregnancy is well tolerated. However, arrhythmias during pregnancy and the risk of a paradoxical embolism during pregnancy or after delivery are the major cardiovascular concerns in pregnant women with intracardiac shunts. Patients who have been operated upon and have no residua require no special treatment [2]. 2.3.2. Left ventricular outflow tract obstruction Patients with congenital aortic stenosis usually have bicuspid aortic valves. They run a course similar to patients with other etiologies for aortic stenosis. Aortic balloon valvuloplasty during pregnancy has been reported as a therapeutic modality [31]. In patients with unrepaired aortic coarctation, the mortality may be up to 3%. However, recent data show better outcomes. Aortic rupture is the main cause of death, and it usually occurs in the third trimester or in the postpartum period. Coarctation repair does not eliminate the risk of aortic complications, but rather decreases it. Upper body hypertension that may occur in patients with aortic coarctation should be managed with caution as excessive control may compromise placental blood flow.

Repair during pregnancy or immediately after delivery may be required [2]. Careful pre-pregnancy evaluation is required in all patients with a past history of coarctation repair, even in the absence of symptoms or hypertension. Occult aortopathy may have important implications on pregnancy. A retrospective study comparing the pregnancies of 41 women with hypertrophic cardiomyopathy (HCM) with those of 39 unaffected women from the same families showed no maternal or neonatal mortality. There was no deterioration of functional class or hospitalizations for heart failure. Only the women with symptoms before pregnancy had an increased risk of fetal prematurity compared with healthy women (18% vs. 5%). These results indicate the good tolerance of pregnancy in asymptomatic women with HCM [32]. These findings were validated in a more recent study of pregnant patients with HCM. Maternal mortality was slightly increased compared to the general population, but remained low and primarily confined to women with high risk profile for sudden cardiac death. Progression of symptom during pregnancy was significantly related to their functional class before conception [33]. Individual assessment is critical in this population prior to proceeding with pregnancy. Genetic counseling is indicated in these patients due to the autosomal dominant nature of the disorder. 2.3.3. Cyanotic heart disease With increase in cardiac output and decrease in systemic vascular resistance during pregnancy, right-to-left shunting increases with worsening of cyanosis and hypoxia. Cardiac events are common in cyanotic patients and in one series were reported to occur in 32%; one maternal mortality occurred for every 44 live births. The most common fetal complication is premature delivery, which occurs in up to 37% of pregnancies. Complications occur more often if oxygen saturation is less than 85% [34]. Patients with repaired tetralogy of Fallot are generally considered low risk for complications during pregnancy. However, these patients should be evaluated prior to pregnancy for possible residual shunts, right ventricular outflow tract obstruction, arrhythmias, pulmonary valve regurgitation and pulmonary hypertension, which places them at a greater risk [28,29]. Patients who have undergone atrial switch surgery for transposition of the great vessels are at risk of arrhythmias and sinus node dysfunction. From one series, reported cardiac complications occur in 14% of pregnancies with one mortality for every 44 live births [35]. Since the arterial switch procedure was initially performed in the 1970s, there are too few patients who have attempted pregnancy after this procedure to determine the prognosis. In a recent study of patients who have undergone the Fontan procedure, 33 pregnancies occurred in 21 women. There were 15 term pregnancies with no maternal deaths,

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2 cases of cardiac events and a 39% first trimester miscarriage rate [36]. The overall 10-year survival is 60 –80% in patients with Fontan. This should be discussed when pregnancy is being considered. Comprehensive prepregnancy evaluation is required in these complex patients. 2.4. Pregnancy in patients with pulmonary hypertension Pregnancy is contraindicated in patients with primary or secondary pulmonary hypertension. If pregnancy occurs, termination should be considered due to the poor prognosis. In one series, the maternal mortality in primary pulmonary hypertension was 30%, 36% in patients with Eisenmenger syndrome, and 56% in patients with secondary pulmonary hypertension. The majority of deaths occurred within 35 days after delivery. Previous pregnancy, timing of diagnosis and hospitalization, operative delivery, and pulmonary artery diastolic pressure were maternal risk factors associated with poor outcome. The neonatal mortality was 13% and was similar in all groups [37]. Careful attention to preload is an important consideration and successful treatment of primary pulmonary hypertension with intravenous epoprostenol during pregnancy has been reported [38]. 2.5. Pregnancy in patients with arrhythmias Palpitations are very common in pregnancy, mostly atrial and ventricular premature contractions. However, in one study there was no correlation between the presence of arrhythmias and the occurrence of symptoms as palpitations, dizziness, or syncope [39]. Only 10% of these symptoms were associated with arrhythmias, the majority of which were multifocal ventricular premature contractions [39]. The incidence and severity of both supraventricular and ventricular arrhythmias is increased during pregnancy. Pregnancy may exacerbate pre-existing arrhythmias due to hemodynamic, hormonal, and emotional changes that occur and include increases in plasma catecholamines and adrenergic receptor sensitivity. Atrial stretch and increased enddiastolic volumes due to intravascular expansion may also increase the incidence and severity of arrhythmias during pregnancy [40]. If persistent, arrhythmias may interfere with uteroplacental blood flow in addition to their effects on the mother [41]. 2.5.1. Pharmacological therapy All commonly used antiarrhythmic drugs cross the placenta and are increased in breast milk, teratogenicity is highest during the first 8 weeks, but uterine contractions and perfusion may also be affected in the latter half of pregnancy also (Table 3). Digoxin, h-blockers, adenosine, class 1C agents, sotalol, and procainamide can be safely used for the treatment of supraventricular arrhythmias during pregnancy.

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Procainamide, h-blockers, sotalol, and lidocaine may be used for the treatment of ventricular arrhythmias. Amiodarone should be avoided if possible due to the risk of fetal hypothyroidism [41]. 2.5.2. Non-pharmacological therapy Temporary and permanent pacing and AICD placement are safe in pregnancy [41]. Moreover, pregnancy does not increase AICD-related complications or result in increased discharges [42]. Electrophysiological studies, including ablation of various arrhythmias with primarily echocardiographic guidance have also been reported [41]. Direct current cardioversion with fetal monitoring is safe, the fetus has a high fibrillation threshold and the current reaching uterus is small. Finally, cardiopulmonary resuscitation (CPR) should be performed when necessary and appears to be safe before 25 weeks gestation as it would in non-pregnant patients, after 25 weeks CPR should be performed with an emergency C-section planned within 15 min to avoid fetal compromise [43]. Table 3 Antiarrythmic therapy during pregnancy (modified from Ref. [40]) FDA Pregnancy Lactation Remarks

Use

Class IA Quinidine C Procainamide C Disopyramide C

+ + ?

+ + ?

Class IB Lidocaine

B

+

+

VT

Class IC Flecainide Propafenone

C C

? ?

? ?

SVT SVT

Class II Propranolol Metoprolol

C C

+ +

+ +

SVT/VT SVT/VT

Class III Sotalol

B

+

+/ 

Amiodarone

D

+/ 



Class IV Verapamil Diltiazem Digoxin

C C C

+  +

+ ? +

Adenosine

C

+

+

First Choice IA

SVT SVT/VT SVT

High dose in breast milk Only use if others fail

SVT/VT

First Choice IV

SVT SVT SVT

Toxicity may cause fetal death

SVT/VT

SVT

+: recommended, +/  : acceptable with important reservations,  : not recommended, ?: unknown. FDA risk classification of drugs. A: Controlled studies show no risk. B: No evidence of risk, either animal studies show risk, but human do not, or animal studies do not show risk and no adequate human studies. C: Studies in pregnant women are lacking, and animal studies are positive or lacking. D: Positive evidence for risk.

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3. Cardiovascular disorders associated with pregnancy

risk of hypertension during pregnancy, even after smoking cessation [46].

3.1. Pregnancy and hypertension Hypertension affects 10% of all pregnancies and it remains the leading cause of maternal and fetal morbidity and mortality [44]. The classification of hypertension and pregnancy has been recently revised [45] and includes the following. 3.1.1. Preeclampsia –eclampsia The presence of hypertension (BP>140/90) or the increase of blood pressure above pre-pregnancy levels (20 mm Hg systolic blood pressure increase or 10 mm Hg diastolic blood pressure increase) together with the presence of proteinuria (>300 mg/24 h or 1+ dipstick) occurring after 20 weeks of gestation defines preeclampsia. Edema is usually present. Eclampsia includes the above in addition to the occurrence of seizures. There appears to be no relationship between the degree of hypertension and the severity of the illness. Risk factors for development of preeclampsia include extremes of age, multiple gestations, a personal and family history, gestational trophoblastic disease, hypertension, diabetes, connective tissue disease, and chronic renal insufficiency [44]. Maternal complications include HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets), renal and liver failure, abruption placenta, stroke, and death. Fetal and neonatal complications include prematurity, growth retardation, and death [44]. The only definitive therapy is delivery. Control of blood pressure does not treat preeclampsia. However, antihypertensive therapy (a-methyl dopa) may help decrease maternal and fetal risks. MgSO4 during delivery and for 24 h after also helps decrease maternal complications [44]. 3.1.2. Chronic hypertension Chronic hypertension is the presence of hypertension preconception or prior to the 20th week of gestation. The pregnancy-induced drop in blood pressure may conceal hypertension until the third trimester leading to confusion with preeclampsia. Moreover, preeclampsia may be superimposed on underlying hypertension but is distinguished by the presence of proteinuria. Pre-pregnancy treatment should be continued as usual except for ACEIs and ARBs, which need to be replaced with other agents because of their known teratogenicity. It is unknown if treatment prevents superimposed preeclampsia [44]. 3.1.3. Gestational hypertension Gestational hypertension is the development of hypertension during the second half of pregnancy with no proteinuria and the return of BP to normal within 12-week postpartum. It has a benign course, tends to recur, and increases the risk for subsequent development of hypertension [44]. Of interest, smoking is associated with decreased

3.1.4. Antihypertensive medications Oral a-methyl dopa and intravenous hydralazine are the safest known antihypertensives used in pregnancy. h-blockers may also be used during pregnancy. However, atenolol has been shown to cause intrauterine growth retardation, small placenta, fetal bradycardia, and neonatal hypoglycemia. Calcium-channel blockers have limited data; these agents may cause dysfunctional uterine contraction and should be discontinued prior to the onset of labor. Finally, diuretics may be used but should not be used in preeclampsia to avoid intravascular volume depletion. ACEIs and ARBs are contraindicated as they have been shown to cause fetal anuria, oligohydraminos, limb abnormalities, lung hypoplasia, craniofacial deformities, and renal dysplasia [44]. 3.2. Peripartum cardiomyopathy According to the NHLBI definition of 1997, peripartum cardiomyopathy (PPCM) is the onset of heart failure with no identifiable cause within the last month of pregnancy or within 5 months after delivery [47]. The incidence is 1/ 3000 – 4000 live births. Risk factors include advanced maternal age, multiparity, black population, multiple gestation pregnancy, obesity, preeclampsia, and hypertension. Prolonged use of h-agonist for tocolysis has been associated with cardiomyopathy and could be due to an unmasking effect of the underlying condition. Myocarditis has been suggested as a cause of this form of cardiomyopathy due to the demonstration of myocardial inflammation in some biopsy studies [47 – 49]. There is a high morbidity and mortality in patients identified as having PPCM. Twenty percent of reported patients die or survive only because they receive a transplant and the rest recover partially or completely [50]. Felker et al. [51] showed that these patients had better outcomes than other conditions associated with cardiomyopathy regardless of age and sex. Persistence of left ventricular dysfunction beyond 6 – 12 months indicates irreversible myocardial damage [52,53]. Moreover, Lampert et al. [54] demonstrated that women who seemed to have recovered from the disease with a normal ejection fraction (EF) at rest had diminished contractile reserve on dobutamine stress echocardiogram. The question that commonly arises is whether these patients have an increased risk of morbidity and mortality with subsequent pregnancies, even if the left ventricular function returns to normal. In a recent study of 44 patients who had PPCM, 28 had recovered LV function (group 1) and 16 had persistent LV dysfunction (group 2) [5]. All mortality cases occurred in group 2 patients and they were also twice as likely to present with CHF and have decreased EF at follow up. The incidence of maternal complications is shown in Table 4.

A.E. Abbas et al. / International Journal of Cardiology 98 (2005) 179–189 Table 4 Incidence of maternal complications during the first subsequent pregnancy in women who had peripartum cardiomyopathy in a previous pregnancy (modified from Elkayam et al. [5]) Group

All women Group 1 (n = 44) (n = 28) Group 2 (n = 16) Full-term Group 1 (n = 35) (n = 23) Group 2 (n = 12)

C/O CHF >20% Decrease Decreased Death no. (%) in LVEF LVEF at no. (%) no. (%) follow-up no. (%) 6 (21)

6 (21)

4 (14)

0

7 (44)

4 (25)

5 (31)

3 (19)

6 (26)

4 (17)

2 (9)

0

6 (50)

4 (33)

5 (42)

3 (25)

The incidence of complications is shown in all the women included in the study (n = 44) as well as in those patients that did not have abortions and reached full-term pregnancy (n = 35). Group 1: Women with recovered LV function prior to subsequent pregnancy. LVEF >50%. Group 2: Women with persistent LV dysfunction. LVEF < 50%.

The majority of fetal complications occurred in group 2 patients [5] and included 9 abortions, 5 of which were therapeutic and 9 premature deliveries. There were 21 vaginal deliveries and 14 Caesarian sections. The treatment of peripartum cardiomyopathy is the same as for all heart failure patients except that ACEIs are generally avoided if the patient is still pregnant, anticoagulation may also be indicated. In addition, delivery is recommended if the patient is still pregnant. Thus, patients with a history of previous PPCM are advised not to become pregnant again particularly if they have residual left ventricular dysfunction.

187

3.3. Thromboembolic disorders 3.3.1. Venous thromboembolism Pregnancy is a hypercoagulable state with exacerbation of all the elements of Virchow’s triad during gestation. However, women with repeated episodes require work up for other hypercoagulable states. Thromboembolism accounts for 17% of maternal deaths during pregnancy with a 5% maternal mortality rate in all patients who have a thromboembolic manifestation. The incidence appears to be evenly distributed throughout gestation (Fig. 2). The occurrence of thromboembolism is not related to gestational age at delivery, birth weight, mode of delivery, or time of presentation [55]. The recommended prophylactic heparin for those with a history of deep venous thrombosis (DVT) (5000 U in first trimester q 12 h, 7500 U q 12 h in the second trimester, and 10,000 U q 12 h in the third trimester) seems to be too low with an 80% recurrence in one study and needs to be revisited [55]. Women with hypercoagulable states need to have adjusted-dose heparin when needed. The use of warfarin is similar to what has been previously discussed. Pregnant women receiving enoxaparin should be carefully monitored. Pregnant women and women of childbearing potential should be apprised of the potential hazard to the fetus and the mother if enoxaparin is administered during pregnancy. 3.3.2. Amniotic fluid embolism Although amniotic fluid embolism (AFE) accounts for only 10% of maternal deaths, it has the highest maternal mortality rate of 86%. Half of the patients will die within the first hour and the fetal survival is 39%. The incidence

Fig. 2. Timing of thromboembolic events during pregnancy and delivery as reported in the study by Witlin et al. [55].

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is 1/20,000 – 1/80,000 pregnancies and usually occurs with hard or violent labor. A tear in the membranes, and increased uterine pressure is required for amniotic fluid to escape. Amniotic fluid embolism occurs during labor in 90% of cases and should be suspected with an abrupt onset of cyanosis and respiratory distress, hypotension, shock, pulmonary edema, uterine bleeding without clotting (disseminated intravascular coagulopathy, DIC), and seizures. Squames of fetal origin may be found in the mother’s lungs as well as other organs, but are not pathognomonic and have been isolated from the pulmonary circulation in pregnant women who required pulmonary artery catheters for other reasons [55 – 57]. The mere presence of amniotic fluid in the maternal circulation does not constitute the presence of AFE. The amniotic fluid may be abnormal in composition. Prostaglandin E is present in early gestation, while prostaglandin F2 is present only at labor. Injection of prostaglandin F2 in laboratory animals has been shown to cause a similar reaction to AFE. Moreover, the amniotic fluid contains factor X-activating properties and has been found to have high procoagulant activity [55 –57]. The diagnosis of AFE depends on the detection of multiple filling defects on a lung perfusion scan with a sudden drop of O2 saturation. Other new diagnostic modalities include Zinc coproporphrin in maternal blood and monoclonal antibodies. The treatment entails maintenance of left ventricular output with cardiopulmonary resuscitation if necessary and treatment of DIC. Immediate delivery should be considered to avoid fetal compromise and when necessary postmortem C-section should be performed. Successful management has been reported but is rare and at least two patients have been reported to have successful repeat pregnancies after AFE [55 – 57]. 3.4. Varicose veins Up to 15% of pregnancies are associated with varicose veins and this may be due to uterine compression, hormonal changes associated with pregnancy, and thromboembolic disease [58]. Definitive management should be deferred until after delivery. 3.5. Acute myocardial infarction A few cases of acute myocardial infarction have been reported and have been related to coronary artery spasm spontaneous dissection or coronary artery disease in the presence of familial hypercholesterolemia or other risk factors [59]. Troponins are useful markers for myocardial injury and angiography with or without intervention may be required during pregnancy [60]. Myocardial infarction carries a high risk during pregnancy and aggressive intervention is important in order to decrease the risk to mother and fetus.

4. Conclusions Pregnancy is a high-flow, low-resistance state with progressive cardiovascular accommodations that persist weeks postpartum. Patients with pre-existing cardiac pathology or those who develop cardiovascular disease during pregnancy have an increased risk of maternal and fetal mortality and morbidity. A multidisciplinary approach is required for management of this complex group of patients. It is imperative to realize that the mother’s health and well being should be the primary goal of management. With comprehensive prepregnancy risk assessment and close follow-up during pregnancy, most patients with cardiovascular disease are able to have a successful pregnancy. References [1] Miller. Anesthesia. 5th ed. Churchill Livingston; 2000. [2] Siu SC, Colman JM. Heart disease and pregnancy. Heart 2001;85: 710 – 5. [3] Siu SC, Sermer M, Colman JM, Alvarez AN, Mercier LA, Morton BC, et al. Prospective multicenter study of pregnancy outcomes in women with heart disease. Circulation 2001;104:515 – 21. [4] Clark SL, Cotton DB, Hankins GD, Delan JP. Critical care obstetrics. 2nd ed. Boston: Blackwell; 1991. [5] Elkayam U, Tummala PP, Rao K, Akhter MW, Karaalp IS, Wani OR, et al. Maternal and fetal outcomes of subsequent pregnancies in women with peripartum cardiomyopathy. N Engl J Med 2001;344: 1567 – 71. [6] Elkayam U, Ostrzega E, Shotan A, Mehra A. Cardiovascular problems in pregnant women with the Marfan syndrome. Ann Intern Med 1995;123:117 – 22. [7] Hanania G. Management of anticoagulants during pregnancy. Heart 2001;86:125 – 6. [8] Bonow RO, Carabello B, de Leon AC, Edmunds Jr LH, Fedderly BJ, Freed MD, et al. ACC/AHA Guidelines for the management of patients with valvular heart disease. Executive summary. A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines (Committee on Management of Patients with Valvular Heart Disease). Circulation 1998;98:1949 – 1984. [9] Hextall A, Robinson VP, Banner NR, Yacoub MH, Parry AJ. Cardiopulmonary bypass during pregnancy. Thorax 1996;51:1162 – 4 [discussion 1164-5]. [10] Izdes S, Coskun D, Mahli A. Cardiac operations during pregnancy: review of factors influencing fetal outcome. Ann Thorac Surg 2000; 69:1622 – 6. [11] Pomini F. Cardiopulmonary bypass in pregnancy [comment]. [12] Champsaur G, Parisot P, Martinot S, Ninet J, Robin J, Ovize M, et al. Pulsatility improves hemodynamics during fetal bypass. Experimental comparative study of pulsatile versus steady flow. Circulation 1994; 90:II47 – 50. [13] Weiss BM, von Segesser LK, Alon E, Seifert B, Turina MI. Outcome of cardiovascular surgery and pregnancy: a systematic review of the period 1984 – 1996. Am J Obstet Gynecol 1998;179:1643 – 53. [14] Immer FF, Bansi AG, Immer-Bansi AS, et al. Aortic dissection in pregnancy: analysis of risk factors and outcome. Ann Thorac Surg 2003;76:309 – 14. [15] Konishi YTN, Kumada K. Dissecting aneurysm during pregnancy and the puerperium. Jpn Circ J 1980;44:726 – 33. [16] Ben Farhat M, Gamra H, Betbout F, Maatouk F, Jarrar M, Addad F, et al. Percutaneous balloon mitral commissurotomy during pregnancy. Heart 1997;77:564 – 7.

A.E. Abbas et al. / International Journal of Cardiology 98 (2005) 179–189 [17] Comport KA, Seng JK. Aortic stenosis in pregnancy: a case report. J Obstet Gynecol Neonatal Nurs 1997;26:67 – 77. [18] Lao TSM, McGee L. Congenital aortic stenosis and pregnancy—a reappraisal. Am J Obstet Gynecol 1993;169:540 – 5. [19] North RA, Sadler L, Stewart AW, McCowan LM, Kerr AR, White HD. Long-term survival and valve-related complications in young women with cardiac valve replacements. Circulation 1999;99: 2669 – 76. [20] Meschengieser SS, Fondevila CG, Santarelli MT, Lazzari MA. Anticoagulation in pregnant women with mechanical heart valve prostheses. Heart 1999;82:23 – 6. [21] Chan WS, Anand S, Ginsberg JS. Anticoagulation of pregnant women with mechanical heart valves: a systematic review of the literature. Arch Intern Med 2000;160:191 – 6. [22] Vitale N, De Feo M, De Santo LS, Pollice A, Tedesco N, Cotrufo M. Dose-dependent fetal complications of warfarin in pregnant women with mechanical heart valves. J Am Coll Cardiol 1999;33: 1637 – 41. [23] Elkayam U. Pregnancy through a prosthetic heart valve. J Am Coll Cardiol 1999;33:1642 – 5. [24] Chan WS, Ray JG. Low molecular weight heparin use during pregnancy: issues of safety and practicality. Obstet Gynecol Surv 1999;54: 649 – 54. [25] Rodie VA, Thomson AJ, Stewart FM, Quinn AJ, Walker ID, Greer IA. Low molecular weight heparin for the treatment of venous thromboembolism in pregnancy: a case series. BJOG 2002;109:1020 – 4. [26] Nader F. 2002 Safety alert—Lovenox: letter to the health care professionals. Aventis pharmaceuticals. NJ: Bridgewater; 2002. [27] Hirsh J, Fuster V, Ansell J, Halperin JL. American Heart Association/ American College of Cardiology F. American Heart Association/ American College of Cardiology Foundation guide to warfarin therapy. J Am Coll Cardiol 2003;41:1633 – 52. [28] Siu SC, Sermer M, Harrison DA, Grigoriadis E, Liu G, Sorensen S, et al. Risk and predictors for pregnancy-related complications in women with heart disease. Circulation 1997;96:2789 – 94. [29] Shime J, Mocarski EJ, Hastings D, Webb GD, McLaughlin PR. Congenital heart disease in pregnancy: short- and long-term implications. Am J Obstet Gynecol 1987;156:313 – 22. [30] Oliveira TAAW, Grinberg M. Obstetric and perinatal aspects in patients with congenital heart diseases. Rev Paul Med 1996;114: 1248 – 54. [31] Lao TT, Adelman AG, Sermer M, Colman JM. Balloon valvuloplasty for congenital aortic stenosis in pregnancy. Br J Obstet Gynaecol 1993;100:1141 – 2. [32] Probst V, Langlard JM, Desnos M, Komajda M, Bouhour JB. Cardiomyopathie hypertrophique familiale. Etude francaise du deroulement des grossesses et des accouchements. Arch Mal Coeur Vaiss 2002;95: 81 – 6. [33] Autore C, Conte MR, Piccininno M, Bernabo P, Bonfiglio G, Bruzzi P, et al. Risk associated with pregnancy in hypertrophic cardiomyopathy. J Am Coll Cardiol 2002;40:1864 – 9. [34] Adelman AG, Sermer M, Colman JM, Presbitero P. Pregnancy in cyanotic congenital heart disease. Outcome of mother and fetus. Br J Obstet Gynaecol 1993;100:1141 – 2. [35] Genoni Jr M, Hoerstrup SP. Pregnancy after atrial repair for transposition of the great arteries. Heart 1999;81:276 – 7. [36] Mair DD, van der Velde M, Koos BJ, Canobbio MM. Pregnancy outcomes after the Fontan repair. J Am Coll Cardiol 1996;28: 763 – 7. [37] Weiss BM, Zemp L, Seifert B, Hess OM. Outcome of pulmonary vascular disease in pregnancy: a systematic overview from 1978 through 1996. J Am Coll Cardiol 1998;31:1650 – 7. [38] Stewart R, Tuazon D, Olson G, Duarte AG. Pregnancy and primary

[39]

[40] [41] [42]

[43] [44] [45]

[46]

[47]

[48] [49]

[50]

[51]

[52] [53]

[54]

[55]

[56] [57] [58] [59]

[60]

189

pulmonary hypertension: successful outcome with epoprostenol therapy. Chest 2001;119:973 – 5. Shotan A, Ostrzega E, Mehra A, Johnson JV, Elkayam U. Incidence of arrhythmias in normal pregnancy and relation to palpitations, dizziness, and syncope. Am J Cardiol 1997;79:1061 – 4. Tan HL, Lie KI. Treatment of tachyarrhythmias during pregnancy and lactation. Eur Heart J 2001;22:458 – 64. Page RL. Treatment of arrhythmias during pregnancy. Am Heart J 1995;130:871 – 6. Natale A, Davidson T, Geiger MJ, Newby K. Implantable cardioverter-defibrillators and pregnancy: a safe combination? Circulation 1997;96:2808 – 12. Luppi CJ. Cardiopulmonary resuscitation: pregnant women are different. AACN Clin Issues 1997;8:574 – 85. Garovic VD. Hypertension in pregnancy: diagnosis and treatment. Mayo Clin Proc 2000;75:1071 – 6. Report of the national high blood pressure education program working group on high blood pressure in pregnancy. Am J Obstet Gynecol 2000;183:S1 – S22. Zhang J, Klebanoff MA, Levine RJ, Puri M, Moyer P. The puzzling association between smoking and hypertension during pregnancy. Am J Obstet Gynecol 1999;181:1407 – 13. Pearson GD, Veille JC, Rahimtoola S, Hsia J, Oakley CM, Hosenpud JD, et al. Peripartum cardiomyopathy: National Heart, Lung, and Blood Institute and Office of Rare Diseases recommendations and review. JAMA 2000;283:1183 – 8. Reimold SC, Rutherford JD. Peripartum cardiomyopathy. N Engl J Med 2001;344:1629 – 30. Thompson RE, Hare JM, Hruban RH, Clemetson DE, Howard DL, Baughman KL, et al. Myocarditis and long-term survival in peripartum cardiomyopathy. N Engl J Med 2000;342:1077 – 84. Heider AL, Kuller JA, Strauss RA, Wells SR. Peripartum cardiomyopathy: a review of the literature. Obstet Gynecol Surv 1999;54: 526 – 31. Felker GM, Thompson RE, Hare JM, Hruban RH, Clemetson DE, Howard DL, et al. Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. N Engl J Med 2000;342:1077 – 84. Veille JC. Peripartum cardiomyopathies: a review. Am J Obstet Gynecol 1984;148:805 – 18. Jaeger CJ, Klodas E, Thiemann DR, Hare JM, Hruban RH, Kasper EK, et al. Peripartum cardiomyopathies: a review. Am Heart J 2000; 140:785 – 91. Lampert MB, Weinert L, Hibbard J, Korcarz C, Lindheimer M, Lang RM. Contractile reserve in patients with peripartum cardiomyopathy and recovered left ventricular function. Am J Obstet Gynecol 2000; 183:S1 – S22. Witlin AG, Mattar FM, Saade GR, Van Hook JW, Sibai BM. Presentation of venous thromboembolism during pregnancy. Am J Obstet Gynecol 1999;181:1118 – 21. Martin RW. Amniotic fluid embolism. Clin Obstet Gynecol 1996;39: 101 – 6. Martin PS, Leaton MB. Emergency. Amniotic fluid embolism. Am J Nurs 2001;101:43 – 4. De Cossart L. Varicose veins and pregnancy. Br J Surg 2001;88: 323 – 4. Hameed AB, Tummala PP, Goodwin TM, Nuno I, Wani OR, Karaalp IS, et al. Unstable angina during pregnancy in two patients with premature coronary atherosclerosis and aortic stenosis in association with familial hypercholesterolemia. Am J Obstet Gynecol 2000;182:1152 – 5. Krahenmann F, Huch A, Atar D. Troponin I measurement in the diagnosis of myocardial injury during pregnancy and delivery: two cases. Am J Obstet Gynecol 2000;183:1308 – 10.