Pregnancy: Maternal and Fetal Heart Disease

Pregnancy: Maternal and Fetal Heart Disease Afshan B. Hameed, MD, FACC, and Mark S. Sklansky, MD, FACC Abstract: Cardiac disorders complicate less than 1% of all pregnancies. Physiologic changes in pregnancy may mimic heart disease. In order to differentiate these adaptations from pathologic conditions, an in-depth knowledge of cardiovascular physiology is mandatory. A comprehensive history, physical examination, electrocardiogram, chest radiograph, and echocardiogram are sufficient in most cases to confirm the diagnosis. Care of women with cardiac disease begins with preconception counseling. Severe lesions should be taken care of prior to contemplating pregnancy. Management principles for pregnant women are similar to those for the non-pregnant state. A team approach comprised of a maternal fetal medicine specialist, cardiologist, neonatologist, and anesthesiologist is essential to assure optimal outcome for both the mother and the fetus. Although fetal heart disease complicates only a small percentage of pregnancies, congenital heart disease causes more neonatal morbidity and mortality than any other congenital malformation. Unfortunately, screening approaches for fetal heart disease continue to miss a large percentage of cases. This weakness in fetal screening has important clinical implications, because the prenatal detection and diagnosis of congenital heart disease may improve the outcome for many of these fetal patients. In fact, simply the detection of major heart disease prenatally can improve neonatal outcome by avoiding discharge to home of neonates with ductalThe authors have no conflicts of interest to disclose. Curr Probl Cardiol 2007;32:419-494. 0146-2806/$ – see front matter doi:10.1016/j.cpcardiol.2007.04.004

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dependent congenital heart disease. Fortunately, recent advances in screening techniques, an increased ability to change the prenatal natural history of many forms of fetal heart disease, and an increasing recognition of the importance of a multidisciplinary, team approach to the management of pregnancies complicated with fetal heart disease, together promise to improve the outcome of the fetus with congenital heart disease. (Curr Probl Cardiol 2007;32:419-494.)

hirty years ago, pediatric cardiologists were turning their attention to the in utero diagnosis of heart disease. At first, M-mode echo was employed to evaluate fetal arrhythmias and to detect asymmetric septal hypertrophy in the fetuses of diabetic women. At times, it seemed like watching an NBA game with a penlight. As two-dimensional echo became available in the late 1970s, the number of identifiable lesions mushroomed and soon complex lesions could be evaluated with a high degree of accuracy. Since that time, echocardiographers have had the privilege of looking in on the earliest evolution of congenital heart disease. Now, with high-resolution, three-dimensional imaging and sophisticated Doppler methods for functional evaluation, described herein, not only is diagnosis made earlier and with increasing reliability, but the images are believable to non-echocardiographers. Thirty years age, survival into adult life of patients with congenital heart disease was limited to simple septal defects, aortic and pulmonary stenosis, tetralogy of Fallot, and Ebstein anomaly of the tricuspid valve. Management of pregnancy in such patients was on an ad-hoc basis without modern monitoring aids and with minimal pharmaceutical and procedural options. In this case the difficulty of the problem has kept pace with the technological advances. Survival of the most complex lesions such as hypoplastic left heart syndrome is becoming commonplace. It is estimated that the number of adults with congenital heart defects is equal to, or greater than, the number of children with congenital heart defects, and the number of complex lesions is at least as great. It is the young adult group, in the childbearing age, where this emergence of very complex disease is most prominent. There is the potential for 1 in every 100 to 150 young adults to have congenital heart disease and roughly half of these will be women. This makes it increasingly important for the cardiology

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community to familiarize itself with the issues and resources needed to successfully manage these pregnancies. It is very appropriate to link the two disciplines, management of the fetus and management of the pregnant woman with heart disease in a “conjoined” state-of-the-art manner. After all, it is the circle of life, and there are many occasions where mother and fetus have cardiovascular issues where the well being of one is balanced against the other. This article provides an excellent overview of these two disciplines, based on unique expertise and vast experience. This is not only a good “read” but is a valuable reference guide for the optimal referral and management of these patients. Yes, the last thirty years have seen many exciting developments and our challenge now is to produce the very best long-term outcome of the congenital heart disease by the earliest diagnosis and the management of pregnancy that not only preserves the health of the mother but also the health of the child. Roberta Williams Professor Keck School of Medicine Los Angeles, CA

Maternal Heart Disease Cardiac disease complicates less than 1% of all pregnancies.1 It is estimated that about 3 million women of childbearing age have some form of cardiac disease. Often times, the signs and symptoms of a normal pregnancy may mimic heart disease. Physiologic changes in pregnancy are geared towards an increased blood supply to the fetal–placental unit. As these physiologic adaptations pose additional stress on an already compromised heart, it is not uncommon to discover a previously undiagnosed cardiac condition for the first time in pregnancy.

Physiologic Changes in Normal Pregnancy (Table 1) Knowledge of the hemodynamic changes that occur during a normal pregnancy is very important in the management of the patient with cardiovascular disease. A comprehensive understanding of such changes in pregnancy, labor and delivery, and the postpartum period is invaluable for the physicians caring for pregnant women with cardiac disease. Cardiovascular adaptations in pregnancy are meant to increase uterine perfusion to meet the demands of the growing fetal–placental unit. Maternal blood volume starts rising as early as 6 weeks of gestation; a rapid increase occurs until around 32 weeks, reaches a plateau thereafter, to a maximum increment of 50% above the nonpregnant state.2-4 Although the red cell mass and plasma Curr Probl Cardiol, August 2007

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TABLE 1. Cardiovascular changes in pregnancy-Antepartum Blood volume Systemic vascular resistance Pulmonary vascular resistance Systolic blood pressure Diastolic blood pressure Pulse pressure Heart rate Stroke volume Cardiac output Left ventricular ejection fraction Central venous pressure Hypercoagulability of blood

1 2 2 2 2 2 1 1 1 1 ↔ 1

50% 20% 5–10 mm Hg 10–15 mm Hg 10–15 bpm 30–50%

volume are both augmented, there is a relative increase in plasma volume compared to the red cell mass, causing the “physiologic anemia of pregnancy.” The rise in blood volume is related in part to the estrogen-induced increase in the plasma renin levels. In pregnancy, renin is not only produced from the kidneys, but also from the uterus and the liver.5,6 Maternal oxygen consumption rises by 30%,7,8 whereas cardiac output (CO) and heart rate increase by 40% above the nonpregnant levels at term.9 The rise in CO can be seen as early as 10 weeks of gestation. It generally peaks around 20-24 weeks and stabilizes thereafter.10 Central venous pressure (CVP) remains unchanged and blood pressure (BP) usually decreases through the gestation. Heidi M. Connolly: Knowledge of the hemodynamic changes which occur during a normal pregnancy is very important in the management of the patient with cardiovascular disease.

Supine Hypotension in Pregnancy. Supine hypotensive syndrome is a well-known phenomenon that occurs in 0.5 to 11.2% of all pregnancies.11,12 It is due to the compression of inferior vena cava by the gravid uterus. CO may decrease by 25 to 30% in the supine position and may lead to maternal hypotension, weakness, lightheadedness, nausea, dizziness, and even syncope.13 This is of particular importance in the delicately balanced cardiac patients, as sudden hemodynamic alterations may change the course of certain disease processes.

Signs and Symptoms of Normal Pregnancy The most common reason for cardiovascular referral in the pregnant patient is a murmur noted on physical examination. The murmurs are 422

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TABLE 2. Pregnancy related changes in common diagnostic tests EKG changes Left axis deviation by 15 degrees Low-voltage QRS may be present T-wave inversion in lead III Q-waves and inverted P-waves in lead III (abolished by inspiration) Sinus tachycardia Premature atrial and ventricular beats may be present Increased incidence of arrhythmias Chest X-ray changes Straightening of the left upper cardiac border Horizontal position of heart Increased lung markings Small pleural effusions in early postpartum period Echocardiographic changes Left ventricular end diastolic diameter increases by 7% Left ventricular end systolic diameter increases by 4–6% Left atrial enlargement by 12–16% Ejection fraction increases by 6% Valvular regurgitation in (%) pregnant women Mitral 28% Tricuspid 94% Pulmonary 94%

usually physiologic and are heard in more than 90% of pregnant women. The normal physical examination findings and symptoms of pregnancy are important to recognize. Most pregnant women complain of shortness of breath and lower extremity swelling during the course of a normal pregnancy. Other commonly encountered symptoms are fatigue, palpitations, and reduced exercise tolerance. Classically, the functional murmur of pregnancy is midsystolic in timing, II/VI in intensity, and is heard at the lower left sternal border and pulmonic area.14 There is an increased split of the second heart sound and a third heart sound may be heard.15 Moreover, the common diagnostic tests, ie, chest radiograph, electrocardiogram, and echocardiogram, demonstrate abnormalities in pregnancy that usually resolve in the postpartum period16-18(Table 2). Heidi M. Connolly: The most common clinical and echocardiographic cardiovascular referral in the pregnant patient is a murmur noted on physical examination. The murmur is usually physiologic. The normal physical examination findings which occur during pregnancy are important to recognize.

Cardiocirculatory Changes During Labor and Delivery With the onset of active labor, CO rises further by 20% above the pregnancy baseline to a maximum of 30% at the time of delivery.19 This Curr Probl Cardiol, August 2007

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TABLE 3. Antepartum management—Overview Maternal and fetal risk assessment at the initial visit Offer termination of pregnancy in high-risk conditions Multidisciplinary approach-Maternal fetal medicine specialist, cardiologist, anesthesiologist, and a neonatologist Meticulous follow-up in pregnancy with attention to subtle changes in symptoms etc. Consider prophylactic anticoagulation in Pulmonary hypertension Severe MS with left atrial enlargement ⬎5 cm Large ASD (⬎2.5 cm) to decrease the risk of paradoxical embolization Assure fetal well being Fetal echocardiogram @ 18–22 weeks in mothers with CHD Serial ultrasound examinations for assessment of fetal growth after 28 weeks Antepartum fetal surveillance at 28–32 weeks

increase is due to the uterine contractions, each of which squeezes about 300 to 500 ml of blood into the maternal circulation.20 This stage of pregnancy is associated with a rise in systolic BP by 10 mm Hg during each contraction and up to a 100% rise in the maternal oxygen consumption. Most of these changes are probably related to the pain and anxiety associated with labor and delivery.21 These responses are of particular significance for parturients with left-sided obstructive lesions, as they are exposed to a greater risk of pulmonary edema.

Cardiocirculatory Changes Postpartum A shift of blood from the evacuated uterus into the maternal circulation—a process called, “autotransfusion,” causes a further increment of 10 to 20% in the CO. In the period following delivery, the stroke volume remains high, whereas the heart rate tends to slow down. The cardiovascular changes extend well beyond labor and delivery and on average persist for 1 to 2 weeks into the postpartum period.

Management Principles The multidisciplinary management of the patient with cardiovascular disease in pregnancy is critically important. A close communication between maternal fetal medicine specialist, cardiologist, anesthesiologist, and a neonatologist is needed. This expert team approach aids in appropriate management planning and monitoring during pregnancy, peripartum, and the postpartum period. Management involves use of diagnostic testing, medications, and/or percutaneous or surgical intervention. Most medications cross the placental barrier and have the potential to harm the fetus. In addition, the 424

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TABLE 4. Intrapartum management of a cardiac patient Recommendations

Effects

Left lateral decubitus position Oxygen administration Continuous EKG monitoring Assessment of fluid intake and output Adequate pain relief Antibiotic prophylaxis (Table 8) Invasive hemodynamic monitoring (NYHA III & IV) in select cases Assisted second stage of labor via vacuum or foreceps

Maximizes venous return Improves oxygen delivery to the fetus Assesses changes in the rhythm Prevents fluid overload Prevents changes in BP Prevents endocarditis Enables assessment of fine hemodynamic details Minimizes the effects of valsalva

TABLE 5. Antibiotic prophylaxis for labor and delivery Drug

Dosage regimen standard regimen

Ampicillin, gentamicin, and amoxacillin

Ampicillin 2 g, plus gentamicin 1.5 mg/kg IV or IM, 30 min before the procedure; followed by amoxacillin 1.5 g orally 6 h after the initial dose; alternatively, parenteral regimen may be repeated once 8 h after the initial dose Ampicillin/amoxacillin/penicillin-allergic patient regimen Vancomycin 1 g IV over 1 h plus gentamicin 1.5 mg/kg IV or IM, 1 h before the procedure; may be repeated once 8 h after initial dose Alternate low-risk patient regimen 3 g orally 1 h before the procedure; then 1.5 g 6 h after the initial dose

Vancomycin and gentamicin

Amoxacillin

*Antibiotic prophylaxis is not recommended for cesarean section and uncomplicated vaginal delivery in the absence of infection. Adapted from Dajani AS, Bisno AL, Chung KG. Prevention of bacterial endocarditis: recommendations of the American Heart Association. JAMA 1990;264:2919.

hemodynamic effects of various therapeutic interventions may affect the developing fetus. If possible, all interventions should be delayed until after the delivery and the use of medications minimized to avoid unwanted effects on the pregnancy. Furthermore, attention must be paid to assure adequate growth and development of the fetus. Antepartum and intrapartum management of the mother with cardiac disease is summarized in Tables 3 and 4. Antibiotic prophylaxis is indicated in patients with valvular heart disease and complex congenital cardiac lesions undergoing complicated vaginal delivery22 (Table 5). Heidi M. Connolly: The multidisciplinary management of the patient with cardiovascular disease and pregnancy is critically important. An expert team Curr Probl Cardiol, August 2007

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TABLE 6. Mortality risk associated with pregnancy <5%

5-15%

25-50%

Uncomplicated ASD

Coarctation of aorta

Uncomplicated VSD

Uncorrected TOF

Uncomplicated PDA

Previous MI

Corrected tetralogy of Fallot (TOF) Porcine valve MS (NYHA I & II) PS TR

Marfans with normal aorta Mechanical valve Aortic stenosis MS with AF MS (NYHA III & IV)

Pulmonary hypertension Primary Secondary Complicated Coarctation of aorta Marfans with aortic root involvement PPCMP with LV dysfunction

Modified from Clark SL, Phelan JP, Cotton DB, editors. Critical Care Obstetrics: Structural Cardiac Disease in Pregnancy. Oradell, NJ: Medical Economics Company, Inc., 1987.

approach aids in appropriate management planning and monitoring during pregnancy, peripartum, and in the postpartum period.

Preconception Evaluation and Counseling Care of patients with cardiac disease should begin before conception. Preconception counseling constitutes an integral part of the patient management as it provides an opportunity to the physician to evaluate and counsel the patient regarding the safety of anticipated pregnancy. The goal is to identify risk factors, confirm the diagnosis, begin medical therapy, and sometimes intervene percutaneously/surgically prior to contemplating pregnancy in an attempt to achieve the best possible outcome for the mother and the fetus. On the other hand, it enables the patient to make an informed decision regarding pregnancy after factoring in the possible risks to herself and the fetus. Maternal Risks. Preconception evaluation including a comprehensive cardiovascular assessment and genetic counseling, when appropriate, is critically important in the patient with cardiovascular disease who wishes to proceed with pregnancy. Risk assessment for an individual entails the following: ● A thorough history and physical examination with particular attention to the history of prior cardiac events and baseline functional capacity. ● Relevant tests including chest X-ray, electrocardiogram (EKG), and echocardiogram ⫾ cardiac catheterization. In general, regurgitant valvular lesions are well tolerated in pregnancy due to decreased systemic vascular resistance. Stenotic lesions, on the 426

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other hand, are problematic because of the intravascular volume expansion in the pregnant state. Patients with the following conditions carry a maternal mortality of more than 25% and therefore should be advised against pregnancy (Table 6): 1. Primary and secondary pulmonary hypertension 2. Peripartum cardiomyopathy (PPCMP) with persistent reduced ejection fraction 3. Marfan’s syndrome with aortic root dilatation 4. Complicated coarctation of aorta Siu and colleagues identified the following prognostic indicators to predict cardiac events in pregnancy, ie, heart failure, arrhythmia, stroke, death23: ● New York Heart Association (NYHA) Functional Class ⱖII (or cyanosis) ● Outlet obstruction of the left heart ● Prior cardiac event (heart failure, arrhythmia, stroke) ● Ejection fraction ⬍40% The risk of a cardiac event with 0, 1, and ⬎1 prognostic indicators were estimated to be 5, 27, and 75%, respectively. Heidi M. Connolly: Preconception evaluation including a comprehensive cardiovascular assessment and genetic counseling, when appropriate, is critically important in the patient with cardiovascular disease who wishes to proceed with pregnancy.

Fetal Risks. There is an increased risk of spontaneous abortion, cardiac anomaly (4-14%) in the presence of maternal congenital heart disease (CHD), preterm labor, low birth weight, and intrauterine growth restriction (IUGR). IUGR is seen in the low CO conditions in the mother such as coarctation of aorta and aortic stenosis, and low oxygen delivery states as in the cyanotic heart disease. The risks posed by an individual lesion should be discussed in detail with the patient. Depending on the risk profile, the patient should be counseled regarding the anticipated morbidity, and in extreme cases even maternal mortality.24 Side effect profile and teratogenic potential of various medications must be reviewed in detail. The management plan should be formulated in conjunction with the obstetrician and maternal fetal medicine specialist. Once the pregnancy is confirmed, a comprehenCurr Probl Cardiol, August 2007

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FIG 1. Normal circulatory physiology. LV, left ventricle; LA, left atrium; PV, pulmonary vein.

sive plan should be outlined with input from the cardiologist, maternal fetal medicine specialist, anesthesiologist, and the neonatologist to ensure optimum maternal and fetal outcomes.

Cardiac Lesions in Pregnancy 1. 2. 3. 4. 5.

Acquired Congenital Arrhythmias PPCMP Myocardial infarction

Acquired Cardiac Disease The most common origins of valvular heart disease (VHD) in reproductive age women are congenital or rheumatic in nature. Although the frequency of rheumatic heart disease (RHD) is on the decline in the Western world, it is not uncommon to encounter women with rheumatic valvular lesions in certain parts of the country where the rate of immigration remains high. RHD results in mitral stenosis in 90% of the cases, mitral regurgitation in 7%, aortic regurgitation in 2%, and aortic stenosis in about 1%.25 Valvular stenosis is less well tolerated during pregnancy than valvular regurgitation. The increase in blood volume and cardiac output that occurs during pregnancy can cause hemodynamic deterioration and 428

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FIG 2. Pathophysiology of mitral stenosis. LV, left ventricle; LA, left atrium; PV, pulmonary vein; MS, mitral stenosis.

precipitate symptoms in patients with previously undetected valvular stenosis. Review of literature on VHD in pregnancy indicates that the worst maternal and fetal outcomes are seen in patients with severe mitral and aortic stenosis. Patients with pulmonary stenosis tend to have uncomplicated pregnancies.26 Heidi M. Connolly: Valvular stenosis is less well tolerated during pregnancy than valvular regurgitation. The increase in blood volume and cardiac output which occurs during pregnancy can cause hemodynamic deterioration and precipitate symptoms in patients with previously undetected valvular stenosis.

Mitral Stenosis (MS). MS is the most common valvular lesion encountered in pregnancy worldwide. MS impedes the flow of blood from left atrium (LA) to the left ventricle (LV), resulting in elevated LA and pulmonary pressures and a decrease in the LV filling (Fig 2). Normal cardiopulmonary circulation is shown in Figure 1). Symptoms. The most common symptoms in pregnancy are dyspnea due to increased LA pressure, fatigue due to fixed cardiac output, and ankle edema due to right heart failure. Exacerbation of symptoms and deterioration of the functional status often results from new onset atrial fibrillation (AF). Signs. Classically, a loud S1, an opening snap, and a diastolic rumbling murmur are heard at the apex. Electrocardiogram demonstrates LA Curr Probl Cardiol, August 2007

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enlargement, right ventricular hypertrophy (RVH), and right atrial (RA) enlargement in the presence of pulmonary hypertension. Concerns. Patients with MS require elevated LA pressures of 14 to 16 mm Hg to maintain an adequate CO. In preterm labor, ␤-mimetics that are commonly used for tocolysis are contraindicated in MS due to their chronotropic action. These patients are at increased risk of developing AF and thromboembolism, pulmonary edema, pulmonary hypertension, and right heart failure. Management. Medications are the first-line therapy in MS. ␤-Blockers decrease the heart rate and are particularly useful in pregnant women as they tend to be tachycardic. Diuretics should be considered in patients with evidence of volume overload and digoxin (Lanoxin; GlaxoSmithKline, Philadelphia, PA) for AF. In addition, all patients with AF should be anticoagulated (see section on prosthetic heart valves for detailed regimens). Surgical therapy is reserved for cases refractory to medical therapy as percutaneous balloon valvuloplasty (PBV) is often the treatment of choice in this population. PBV is safest when performed after 20 weeks of gestation.27 Mitral valve replacement should be performed when necessary but is associated with important maternal and fetal mortality. Preconception Counseling. Patients with severe MS should be offered PBV or valve replacement prior to pregnancy. In the mild to moderate group, assessment of functional capacity is useful, and patients with significant limitations should be considered for the relief of obstruction. Prognostic indicators for cardiovascular events in the mother are shown to be the severity of MS and the NYHA functional class prior to pregnancy.28 Mitral regurgitation (MR). MR is generally well tolerated in pregnancy and the symptoms are related to the limited CO. Severe MR may lead to LA enlargement, AF, and/or congestive heart failure (CHF) (Fig 3). Treatment. No treatment is indicated in an asymptomatic patient. Symptoms are usually related to CHF and respond well to digitalis, diuretics, and vasodilators. Anticoagulation should be used for AF. (Note: Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers should be avoided in pregnancy.) Mitral Valve Prolapse (MVP). MVP is the most common congenital cardiac lesion in adults, affecting 4% of the general population. However, only 2 to 4% of the affected individuals have significant MR. All patients with a history of MVP should undergo comprehensive prepregnancy clinical evaluation and echocardiography. MVP is generally is well tolerated in pregnancy unless associated with severe MR, LA enlargement, LV dysfunction, or AF. Severe MR can worsen during pregnancy, 430

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FIG 3. Pathophysiology of mitral regurgitation. LV, left ventricle; LA, left atrium; PV, pulmonary vein; MR, mitral regurgitation.

and patients may develop progressive atrial enlargement, AF, and clinical decline. Select patients should be referred for mitral valve repair before pregnancy. Antibiotic prophylaxis is recommended in the presence of murmur. MVP may be associated with arrhythmias, autonomic dysfunction, or cerebral embolization. Heidi M. Connolly: Although mitral valve prolapse with mitral regurgitation is generally well tolerated during pregnancy, all patients with a history of mitral valve prolapse should undergo comprehensive prepregnancy clinical evaluation and echocardiography. Severe mitral regurgitant can worsen during pregnancy, and patients may develop progressive atrial enlargement, atrial fibrillation, and clinical decline. Select patients should be referred for mitral valve repair before pregnancy.

Aortic Stenosis (AS). In reproductive years, the most common cause of AS is bicuspid aortic valve followed by RHD. Bicuspid aortic valve may be associated with aortic root enlargement and is important in the preconception evaluation and counseling. Pregnancy is contraindicated if the patient has severe AS without symptoms, history of symptomatic AS, including heart failure, syncope, or cardiac arrest.29 AS causes a fixed cardiac output, decreased coronary and cerebral perfusion, and an increase in the left atrial pressure (Fig 4). Hemodynamic changes of pregnancy put these patients at a particularly elevated risk. Curr Probl Cardiol, August 2007

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FIG 4. Pathophysiology of aortic stenosis. LV, left ventricle; LA, left atrium; PV, pulmonary vein; AS, aorta stenosis.

Symptoms. Common symptoms include chest pain due to decreased coronary perfusion, syncope due to decreased cerebral perfusion, and CHF due to increased LA pressure. Signs. Carotid pulse is diminished with late upstroke and small volume. LV apical impulse is usually displaced and sustained, and a harsh systolic ejection murmur can be heard in the second right intercostal space. EKG may demonstrate left ventricular hypertrophy (LVH) and LA enlargement. Treatment. Patients with mild to moderate AS who are asymptomatic should be advised to restrict their physical activity and can be managed expectantly during pregnancy. Patients with severe AS should strongly be considered for mechanical relief of their obstruction regardless of their symptomatology. Aortic PBV can be performed prior to pregnancy or after 20 weeks of gestation30-32 if the valve anatomy is favorable. Aortic valve replacement is considered a last resort and is associated with significant fetal loss and maternal morbidity.33 Concerns. Epidural anesthesia is contraindicated; narcotic epidural or general endotracheal anesthesia may be used. The key is to avoid hypotension and excessive blood loss at the time of delivery.

Aortic Regurgitation (AR). AR is generally tolerated well in pregnancy. Longstanding moderate to severe AR may lead to ventricular dilatation and CHF (Fig 5). Treatment. Asymptomatic patients do not require therapy. The symptoms of AR are of CHF and respond to the standard treatment with 432

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FIG 5. Pathophysiology of aortic regurgitation. LV, left ventricle; LA, left atrium; PV, pulmonary vein; AR, aortic regurgitation.

digoxin, diuretics, and/or hydralazine. Angiotensin converting enzyme inhibitors and angiotensin receptor blockers should be avoided. The key is to avoid volume overload. Pulmonary and Tricuspid Lesions. Ebstein’s anomaly and repaired congenital heart disease are the most common causes of tricuspid and pulmonary valve lesions. Isolated right-sided lesions are seen in intravenous drug abusers due to bacterial endocarditis. Most of the patients with these lesions do well during pregnancy. However, they are at risk for right ventricular failure and arrhythmias. The risk of arrhythmias is higher in the presence of right ventricular enlargement. Primary Pulmonary Hypertension. Severe pulmonary hypertension, whether primary or secondary, carries a very high risk of maternal mortality during pregnancy and in the early postpartum period. The risk of maternal death may approach as high as 50%.34 Patients with severe pulmonary hypertension should be strongly counseled against becoming pregnant and offered termination of pregnancy at an appropriate gestational age. Reliable contraception is critically important for patient well-being and survival, and detailed discussion of the options must be an integral part of routine patient care. It is important to note that echocardiography may overestimate pulmonary artery pressure in pregnancy. Therefore, right heart catheterization may be considered in doubtful cases for accurate assessment of pulmonary artery pressure and to gauge responsiveness to vasodilators.35,36 Curr Probl Cardiol, August 2007

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Heidi M. Connolly: Severe pulmonary hypertension, whether primary or secondary, carries a very high risk of maternal mortality during pregnancy and in the early postpartum period. Patients with severe pulmonary hypertension should be strongly counseled against becoming pregnant. Reliable contraception is critically important for patient well-being and survival, and detailed discussion of the options must be a part of routine patient care.

Signs. The common findings include RV lift, a loud pulmonary component of the second heartsound, and elevated jugular venous pressure with prominent A-wave. EKG may show RVH and RA enlargement. Concerns. Hypotension should be avoided to maintain adequate venous return and cardiac output. The use of prophylactic anticoagulation to prevent thromboembolic complications during pregnancy and the postpartum period is not a uniformly accepted modality. Meticulous leg care (elastic support stockings) in the peripartum period should be undertaken to minimize the chances of thromboembolic events.

Congenital Cardiac Lesions Most patients with congenital heart disease who are considering pregnancy have previously recognized CHD, often with prior repair. Comprehensive prepregnancy evaluation is critical with careful assessment of the underlying congenital disorder and potential residual and sequelae. In addition, genetic counseling is indicated in select subgroups. Occasionally, patients with previously unrecognized CHD are identified during pregnancy. Congenital cardiac defects may be classified as cyanotic or acyanotic. The most common acyanotic congenital cardiac lesion is bicuspid aortic valve. The presence of congenital cyanotic heart disease is not an absolute contraindication to pregnancy but does increase the risk of fetal loss. Heart failure occurs in 47% of patients with cyanotic heart disease versus 13% with acyanotic lesions, and maternal mortality approaches 4 to 16% in uncorrected lesions.37,38 Heidi M. Connolly: Most patients with congenital heart disease who are considering pregnancy have previously recognized congenital heart disease, often with prior repair. Comprehensive prepregnancy evaluation is critical with careful assessment of the underlying congenital disorder and potential residual and sequelae. In addition, genetic counseling and evaluation is indicated in select patient subgroups. Occasionally, patients with previously unrecognized congenital heart disease are identified during pregnancy.

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Aortic Stenosis. (See acquired cardiac lesions for details.) Coarctation of Aorta. The most common site of coarctation is distal to the left subclavian artery. Unoperated coarctation of aorta is rarely encountered in pregnancy. Postrepair coarctation patients require careful prepregnancy evaluation to exclude important cardiovascular residua or sequelae. It is a rare cause of secondary hypertension and may be associated with atrial septal defect (ASD) and ventricular septal defect (VSD), bicuspid aortic valve, Berry aneurysm of the circle of Willis, and hypertension. A gradient of ⬍20 mm Hg across the coarctation is associated with favorable maternal and fetal outcomes.39,40 Concerns. Patients with coarctation are at risk for aortic aneurysm, dissection and rupture, CHF, cerebrovascular accident due to uncontrolled hypertension or rupture of intracranial aneurysm, and bacterial endocarditis. The key is to avoid hypotension and excessive blood loss at the time of delivery. Atrial Septal Defect. ASD is the third most common CHD in adults. About 70% of the defects are secundum; 15% are primum, and 15% are of the sinus venosus type. Secundum ASD is the most common congenital cardiac defect identified during pregnancy, and the majority of these patients have uncomplicated pregnancies. Primum ASDs may be associated with cleft mitral valve. Partial anomalous pulmonary venous connection is characteristically associated with sinus venosus ASD. In addition, the patients are at risk for pulmonary hypertension and arrhythmias. Symptoms. Symptoms include fatigue, palpitations, and dyspnea. Signs. Signs include systolic ejection murmur at the left sternal border and wide fixed split second heart sound. EKG may reveal a partial right bundle branch block, right axis deviation ⫾ RVH, or left axis deviation in patients with ostium primum defects. Concerns. Patients with large defects are prone to CHF, AF, and paradoxical embolism. Prophylactic anticoagulation and meticulous leg care in the peripartum period (compression stockings, leg squeezers) should be considered in patients with large ASDs to prevent embolization. ASD is one of the conditions that does not require bacterial endocarditis prophylaxis. Systemic hypertension may lead to an increase in left-toright shunt, which may lead to pulmonary volume overload/CHF. The key is to avoid volume overload. Ventricular Septal Defect. Most VSDs that are encountered during pregnancy have either been repaired or are small and do not cause pulmonary hypertension. They are generally well tolerated during pregnancy. Patients with large defects are at risk for CHF, arrhythmias, and Curr Probl Cardiol, August 2007

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pulmonary hypertension. Systemic hypertension may lead to an increase in left-to-right shunt, which may lead to pulmonary volume overload/ CHF. The key is to avoid volume overload. Patent Ductus Arteriosus (PDA). Most cases of PDA are diagnosed and repaired in childhood and therefore are an uncommon lesion encountered in pregnancy. Most patients with small PDA tolerate pregnancy well. Symptoms. Symptoms include fatigue and dyspnea. Signs. Signs include a wide pulse pressure and a continuous murmur in the pulmonic area. EKG may be normal or show evidence of LVH. Concerns. Moderate size PDA may cause LA and LV enlargement with associated LV volume overload and HF. These patients are at risk for pulmonary hypertension, reversal of shunt (right to left) secondary to elevated pulmonary pressures—Eisenmenger’s syndrome. Systemic hypertension may lead to an increase in left-to-right shunt, which may lead to pulmonary volume overload/CHF. The key is to avoid volume overload. Eisenmenger’s Syndrome. Eisenmenger’s syndrome is the reversal of a left-to-right shunt (ASD, VSD, PDA) due to progressive pulmonary hypertension. Right-to-left shunting leads to systemic arterial oxygen desaturation and central cyanosis.41 The degree of cyanosis is determined by the extent of pulmonary vascular obstructive disease. Maternal mortality approaches 30 to 50% and fetal loss may be as high as 75%.42 It is one of the few conditions in which pregnancy is contraindicated. If the patient is seen for the first time early in pregnancy, she should strongly be advised to terminate pregnancy. Various pulmonary vasodilators have been successfully used in pregnancy43-45 to lower the pulmonary pressures, but the overall prognosis remains grim. Concerns. In patients with Eisenmerger’s syndrome, the pulmonary pressures may reach systemic levels and, therefore, a minimal lowering of systemic BP may cause massive right-to-left shunting. This may lead to worsening hypoxia, setting up a vicious cycle of further pulmonary vasoconstriction, and may result in rapid hemodynamic deterioration. Therefore, continuous pulse oximetry and oxygen administration to keep oxygen saturations above 90% may be beneficial. The use of invasive hemodynamic monitoring is controversial as there may be an increased risk of ventricular arrhythmias and damage to the pulmonary artery with the use of pulmonary artery catheters. Narcotic epidural or general endotracheal anesthesia should be used to avoid risk of systemic hypotension.46 Although these patients are at high risk for thromboembolism due to hypercoagulability of pregnancy and polycythemia, the benefit of anticoagulation has not been confirmed. We use prophylactic anticoagu436

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lation during pregnancy and full anticoagulation for 7 to 10 days after delivery for the theoretical risk of thromboembolism. Patients may undergo assisted vaginal delivery if they are stable, and cesarean section is reserved for obstetrical indications and/or for unstable patients. Patients with Eisenmenger’s syndrome may have serious complications in the postpartum period, and therefore, prolonged hospitalization is recommended. Pulmonary Stenosis (PS). PS is an uncommon valvular lesion and is well tolerated in pregnancy unless the right ventricular pressure exceeds the left ventricular pressure. Transvalvular pressure gradients of ⬎80 mm Hg may warrant relief of obstruction. RV failure may be seen. Tetralogy of Fallot (TOF). Patients with conotruncal abnormalities, including TOF, complex pulmonary atresia, or truncus arteriosus, have a recognized increased prevalence of 22q11.2 microdeletion. All adult patients considering pregnancy or reproduction should be screened for 22q11.2 microdeletion as this has an important impact on the chance of congenital heart disease in the offspring and be offered prepregnancy genetic counseling.47 TOF is a congenital lesion comprising VSD, overriding aorta, RVH, and PS. Pregnancy in an unoperated patient with TOF is extremely uncommon and a decrease in SVR may result in increased right-to-left shunting. Most patients with TOF have had prior intracardiac repair but they remain at increased risk of maternal and fetal complications.48Poor prognostic indicators in patients with TOF are hematocrit ⬎65%, history of syncope, CHF, cardiomegaly, RVH, and oxygen saturations ⬍90%. Heidi M. Connolly: Patients with conotruncal abnormalities, including tetralogy of Fallot, complex pulmonary atresia, or truncus arteriosus, have a recognized increased prevalence of 22q11.2 microdeletion. All adult patients considering pregnancy or reproduction should be screened for 22q11.2 microdeletion as this has an important impact on the chance of congenital heart disease in the offspring impacts and prepregnancy genetic counseling (Beauchesne LM, et al. JACC 2005;45:595-8).

Marfan’s Syndrome. Marfan’s syndrome is an autosomal-dominant condition that causes cystic medial necrosis of the aorta and may lead to dissecting aneurysm in pregnancy. There is an increased risk of rupture, dissection, and cardiovascular complications if aortic root diameter is more than 4 cm.49,50 Patients with aortic root dilatation ⱖ4 cm should be advised against pregnancy and offered termination if pregnant. Curr Probl Cardiol, August 2007

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Management. Patients with Marfan’s syndrome who elect to proceed with pregnancy should be monitored carefully with serial echocardiographic imaging to assess the ascending aorta. Hypertension should be aggressively treated. In addition, ␤-blocker therapy should be continued during pregnancy. Genetic evaluation prior to pregnancy is recommended and the option of mutation detection be discussed for prenatal diagnosis. Assisted vaginal delivery is preferred to AVOID VALSALVA. Concerns. Tachycardia and hypertension should be prevented in patients with Marfan’s syndrome to reduce shear stress on the aortic wall. Prophylactic ␤-blockers should be considered to retard the progression of aortic root dilatation in pregnancy. In addition to the more ominous cardiovascular complications,51 obstetrical morbidities including uterine inversion, postpartum hemorrhage, and rectovaginal perforation have been reported.

Heidi M. Connolly: Patients with Marfan’s syndrome who elect to proceed with pregnancy should be monitored carefully with serial echocardiographic imaging to assess the ascending aorta. In addition, ␤-blocker therapy should be continued during pregnancy. Genetic evaluation prior to pregnancy is recommended and the option of mutation detection for prenatal diagnosis should be discussed. There are currently no data on the safety of pregnancy following ascending aortic root replacement in patients with Marfan’s syndrome. Genetic evaluation prior to pregnancy and in utero genetic testing is feasible and should be discussed.

Hypertrophic Cardiomyopathy (HCM). HCM is a genetic disorder which is inherited in an autosomal-dominant fashion. Due to the genetic implications of HCM, careful prepregnancy evaluation including genetic counseling should be carried out. The hemodynamics of HCM often improve in pregnancy due to increased intravascular volume.52 Patients with severe diastolic dysfunction may have precipitous decline during pregnancy. Careful cardiovascular assessment and prepregnancy counseling is mandatory. The management principles are similar to those of valvular AS.

Heidi M. Connolly: Hypertrophic cardiomyopathy is a genetic disorder that is inherited in an autosomal-dominant fashion. Due to the genetic implications of hypertrophic cardiomyopathy, careful prepregnancy evaluation including genetic counseling should be carried out. Although pregnancy is usually well tolerated in patients with hypertrophic cardiomyopathy, those with severe 438

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TABLE 7. Fetal effects of various cardiovascular medications in pregnancy Medications (FDA risk category) Digoxin (C)

Dopamine (C) Dobutamine (B) Epinephrine (C) Nitroprusside (C)

Hydralazine (C) Nitroglycerin (B) Propranolol (C) Atenolol (D) Metoprolol (C) Labetolol (C) Esmolol (C) Verapamil (C) Nifedipine (C) Diltiazem (C) Ephedrine sulpha Lidocaine (B) Procainamide (C) Bretylium (C) Phenytoin (D) Amiodarone (D)

Adenosine

Fetal effects Crosses placenta Higher maternal maintenance dose required for fetal effect Not teratogenic No known adverse fetal effects No known adverse fetal effects Not teratogenic No known adverse fetal effects Potential for fetal cyanide toxicity Avoid prolonged use Not teratogenic Not teratogenic Not teratogenic Readily crosses placenta Fetal bradycardia IUGR Small placenta No known adverse fetal effects Rapid metabolism (1/2 life 11 min) also occurs in the fetus Fetal bradycardia Not teratogenic Not teratogenic 70% of maternal blood level in the fetus Not teratogenic Rapidly crosses placenta Unknown Teratogenic “Fetal hydrantoin syndrome” Teratogenic Transient bradycardia Prolonged QT No known adverse fetal effects

diastolic dysfunction may have precipitous decline during pregnancy. Careful cardiovascular assessment and prepregnancy counseling is mandatory.

Arrhythmias Dizziness and palpitation in pregnancy are mostly related to an increased incidence of atrial and ventricular premature contractions.53 Other arrhythmias in pregnancy include supraventricular tachycardia, AF, and, occasionally, ventricular tachycardia (VT).54 The various hormonal and emotional factors, increase in catecholemines, intravascular volume expansion, and stretching of cardiac chambers contribute to the generaCurr Probl Cardiol, August 2007

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tion of arrhythmias in the pregnant state.55,56 Persistent arrhythmias may interfere with the utero-placental blood flow by virtue of hemodynamic changes in the mother. In general, the management principles are similar to those in the nonpregnant state.57 Supraventricular Tachycardia responds to carotid sinus massage and/or use of adenosine. Other options include digoxin, calcium channel blockers, ␤-blockers, and cardioversion for unstable patients. Atrial Fibrillation needs therapeutic anticoagulation (see prosthetic heart valves section for details). Digoxin, ␤-blockers, calcium channel blockers, and in select cases, electrical cardioversion may be considered. Ablation is occasionally performed during pregnancy for refractory arrhythmias not controlled with maximum medical therapy. Ventricular tachycardias are rarely encountered in pregnancy and may sometimes require therapy. Automated implantable cardioverter defibrillators and ablation procedures have been reported without deleterious effects on the fetus.58 Patients with hereditary prolonged QT syndrome are at increased risk of cardiac events in pregnancy. Treatment with ␤-blockers should be considered as it is associated with a significant reduction in syncope and cardiac arrest.59 Sotalolol (Betapace; BayerHealthCare, Wayne, NJ) use may be associated with maternal hypotension.60 Antiarrhythmic drug therapy, especially amiodarone,61,62 is reserved for refractory cases due to fetal concerns (Table 7). Direct cardioversion is considered safe since the amount of current reaching the uterus is negligible. In a mother requiring cardiopulmonary resuscitation, consideration should be given to delivery via emergent cesarean section if attempts at resuscitation are unsuccessful for 15 minutes63 to improve maternal perfusion by removing the pressure of the gravid uterus.

Peripartum Cardiomyopathy Peripartum cardiomyopathy (PPCM) is a dilated cardiomyopathy of unknown cause and occurs in 1:1500 to 1:15,000 pregnancies.64,65 The diagnostic criteria include the following66: ● CHF in the last month of pregnancy or within 5 months after delivery ● Absence of determinable cause of cardiac failure ● Absence of demonstrable heart disease before the last month of pregnancy ● Echocardiographic demonstrable impairment of LV systolic function67 Although most of the patients are diagnosed with PPCMP in the immediate postpartum period, there is no significant difference in the outcomes of patients presenting in the antepartum versus the postpartum 440

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period.68 Outcomes of patients with previous history of PPCMP are related to recovery of LV ejection fraction. In a recent publication by our group, patients with recovered LV ejection fraction have a 20% risk of developing CHF during current pregnancy. On the other hand, patients with persistent LV dysfunction have a 30% risk of CHF and 17% risk of maternal mortality in their subsequent pregnancy.69 Echocardiographic evidence of fractional shortening of ⬍20% and LV end-diastolic diameter of ⬎6 cm is associated with three times increased risk of persistent LV dysfunction.70

Heidi M. Connolly: There is considerable controversy regarding the safety of subsequent pregnancy in patients with a history of peripartum cardiomyopathy and normalization of left ventricular function. It is recognized that left ventricular systolic function declines with the subsequent pregnancy even in patients who have had normalization of their left ventricular systolic function. Careful prepregnancy counseling and discussion about the risks including the potential for life-threatening complications should be outlined with the patient and partner prior to proceeding with a subsequent pregnancy.

Treatment. Patients with a diagnosis of PPCMP should be delivered after stabilization of the mother. Principles of therapy are similar to that in the nonpregnant state including supportive care including bed rest and fluid and salt restriction and medical therapy. Medical therapy includes diuretics, vasodilators, digitalis ⫾ ␤-blockers.71-73 Angiotensin-converting enzymes are contraindicated in pregnancy. Patients with ejection fraction of ⬍35% are at risk for thromboembolism and, therefore, prophylactic anticoagulation during pregnancy and full anticoagulation for 7 to 10 days after delivery should be considered. Prognosis. About half of the women with PPCMP normalize their ejection fraction in 6 months after delivery.74 Five-year survival in PPCMP is 94%, which is significantly better than other forms of cardiomyopathy.75 Patients with persistent LV dysfunction after a previous pregnancy have a high risk of maternal mortality and therefore should be offered termination of pregnancy. There is considerable controversy regarding the safety of subsequent pregnancy in patients with a history of PPCMP and normalization of LV function. It is recognized that LV systolic function may decline with the subsequent pregnancy even in patients who have had normalization of their LV function. Careful prepregnancy counseling and discussion about Curr Probl Cardiol, August 2007

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the risks including the potential for life-threatening complications should be outlined with the patient and partner prior to proceeding with a subsequent pregnancy.

Myocardial Infarction (MI) The incidence of MI in pregnancy is 1:10,000 to 1:36,000 pregnancies76,77 with maternal mortality ranging from 7 to 50%. MIs occur with equal frequency (40%) in the antepartum and postpartum period.77 About 30% of pregnant women with acute MI have normal coronaries. Etiologies include atherosclerosis, thrombosis, coronary artery spasm78 or dissection, embolism, and aortic dissection. Other risk factors include hypertension, diabetes, advancing maternal age,77,79 sickle cell disease tobacco or cocaine abuse, and pheochromocytoma. Diagnostic criteria are similar to those in the nonpregnant state including angina, EKG changes, and elevated cardiac enzymes.80 Treatment. The choices include thrombolytic therapy or percutaneous transluminal coronary angioplasty81 along with ASA, heparin, and ␤-blockers. Acute MI in pregnancy carries a poor prognosis and coronary angiography should be performed when possible to establish the diagnosis of coronary artery disease and facilitate intervention. Radiologic shielding is recommended during fluoroscopic imaging. Due to safety concerns of clopidogrel and glycoprotein IIb/IIIa inhibitor administration during pregnancy, these agents should be avoided. Thus, balloon dilatation or bare metal stent placement is preferred when percutaneous intervention is required for acute coronary syndrome or MI related to coronary artery disease during pregnancy. Heidi M. Connolly: Acute myocardial infarction during pregnancy carries a poor prognosis and coronary angiography should be performed when possible to establish the diagnosis of coronary artery disease and to facilitate intervention. Radiologic shielding of the fetus is recommended during fluoroscopic imaging. Due to safety concerns of clopidogrel and glycoprotein IIb/IIIa inhibitor administration during pregnancy, these agents should be avoided. Thus, balloon dilatation or bare metal stent placement is preferred when percutaneous intervention is required for acute coronary syndrome or myocardial infarction related to coronary artery disease during pregnancy.

Concerns. Delivery should be postponed for 2 to 3 weeks after an acute MI. Consider delivery at 32 to 34 weeks to minimize cardiovascular stress. Hypertension and tachycardia should be aggressively managed. There is accumulating experience of thrombolytic therapy use in preg442

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nancy. The effects of glycoprotein IIb/IIIa inhibitors and newer antiplatelet agents on pregnancy are unclear. Bleeding complications including massive subchorionic hematoma formation have been reported.82,83 The highest risk period for increased maternal mortality is in the third trimester of pregnancy. Other poor prognostic indicators are maternal age ⬍35 years, delivery ⬍2 weeks from acute MI, and cesarean delivery.84 Although rare, spontaneous coronary dissections occur with higher frequency in women and especially during pregnancy and the postpartum period. Mortality approaches 50% in such instances, and therefore, early coronary angiogram should be considered. Management involves medical therapy in conjunction with percutaneous coronary angioplasty, intracoronary stent placement,85 coronary artery bypass surgery, ventricular assist devices, and cardiac transplantation in select cases.

Cardiopulmonary Bypass During Pregnancy The first cardiopulmonary bypass in a pregnant woman was performed in 1958. Over the years, maternal and fetal outcomes have improved significantly. Maternal mortality is similar to that of their nonpregnant counterparts, ie, 3%, whereas the risk of fetal loss remains high, at 20%.86-89 Deleterious effects on the fetus are thought to be related to hypotension, hypothermia, embolic phenomenon, or activation of the coagulation and complement cascade.90 Therefore, cardiopulmonary bypass is reserved for refractory cases. Preoperative planning, multidisciplinary management, and a short cardiopulmonary bypass time are crucial for pregnant patients requiring cardiac surgery. Patients who require cardiovascular surgery during pregnancy should be managed at tertiary care centers with experience in the management of such high-risk patients. Heidi M. Connolly: The importance of preoperative planning, multidisciplinary management, and a short cardiopulmonary bypass time must be emphasized for the pregnant patient requiring cardiac surgery. Patients who require cardiovascular surgery during pregnancy should be managed at tertiary care centers with experience in the management of such high-risk patients.

Pregnancy Following Prosthetic Heart Valves Compared to mechanical valves, the high rate of bioprosthetic valve deterioration is primarily determined by the younger age group, ie, Curr Probl Cardiol, August 2007

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child-bearing years (29 versus 82%).91 Recent studies report no impact of pregnancy on the overall bioprosthetic valve longevity.91-93 The majority of pregnant women have a mechanical prosthesis in place these days. Management of such patients involves careful therapeutic anticoagulation. The options include oral anticoagulation with warfarin, unfractionated heparin, and low molecular weight heparin.22 Use of warfarin in the first trimester of pregnancy carries the risk of teratogenicity, as it crosses the placental barrier and can affect fetal cartilage and bone development.94 Warfarin in doses less than 5 mg/day has significantly lower risk of fetal complications.95 As warfarin crosses the placental barrier, it may cause fetal anticoagulation with risk of intracranial bleeding at the time of delivery. Therefore, warfarin is not a preferred agent towards the end of pregnancy and patients are generally switched to a heparin preparation at 36 weeks of gestation. Unfractionated heparin (UFH) and low molecular weight heparin (LMWH) do not cross the placental barrier and have no teratogenic threat to the fetus. Three regimens for anticoagulation during pregnancy are heparin throughout the pregnancy, warfarin throughout the pregnancy, or a combination of both drugs.96 In our practice, we use the following approach: ● First trimester (0-14 weeks): UFH or LMWH ● Second trimester (14 1⁄7 to 28 weeks): UFH or LMWH or warfarin ● Third trimester: Early (28 1⁄7 to 36 weeks) UFH or LMWH or warfarin. Switch to UFH after 36 weeks. The rationale for using heparin near term is twofold: one is the ability to reverse anticoagulation with protamine sulphate, and two, the risk of fetal intracranial bleeding is significant in mothers on warfarin at the time of delivery. Complications in pregnancy include thromboembolism, bleeding, structural deterioration of the prosthetic valve, and infection.97,98 Anticoagulation may be resumed at 6 hours after a vaginal delivery and 12 hours after a cesarean section.99 There is considerable controversy regarding the best approach to the patient who requires anticoagulation for a mechanical heart valve during pregnancy. The risk to the mother versus the risk to the fetus must be discussed and carefully reviewed. It should be emphasized that, regardless of the anticoagulation regimen used, meticulous monitoring and follow-up is mandatory. Heidi M. Connolly: There is considerable controversy regarding the best approach to the patient who requires anticoagulation for a mechanical heart 444

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valve during pregnancy. The risk to the mother versus the risk to the fetus must be discussed and carefully reviewed. Regardless of the method of anticoagulation used during pregnancy, meticulous monitoring and follow-up are required.

Pregnancy Following Corrective Surgery for Congenital Heart Disease With recent advances in the management of complex cardiac lesions, more and more pregnant women are being encountered with corrected congenital cardiac disease.100 Patients with prior cardiac surgery for CHD are at increased risk for arrhythmias and close follow-up during pregnancy is indicated. If a patient with a history of operated CHD develops AF or flutter, anticoagulation should be instituted. Patients with Fontan repair who are asymptomatic without evidence of cardiac dysfunction may tolerate pregnancy well and should be carefully evaluated prior to conception. These patients have a higher risk of spontaneous abortion, intrauterine growth restriction, premature rupture of membranes, preterm delivery and fetal demise, deterioration of the NYHA functional class, pregnancy-induced hypertension, and arrhythmias.101-103 Most patients have no cardiac complications during pregnancy.104 Pregnancy risk following TOF repair is comparable to the general population.105 Likewise, favorable outcomes have been reported after Mustard operation.106

Heidi M. Connolly: Patients with prior cardiac surgery for congenital heart disease are at increased risk for arrhythmias and close follow-up during pregnancy is indicated. If a patient with a history of operated congenital heart disease develops atrial fibrillation or flutter, anticoagulation should be instituted.

Pregnancy Following Cardiac Transplantation Successful pregnancy after cardiac transplantation was first reported in 1988.107 With recent advances in the immunosupressive medications, numerous pregnancies have been described. The management of such patients is complex, but favorable outcomes may be anticipated in most instances with careful follow-up. As most cases of transplant rejection are seen in the first year,108 it is prudent to delay childbearing until a year after a successful transplant. Curr Probl Cardiol, August 2007

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The patient should be stable on immunosuppressants with normal cardiovascular and renal function. Patients with cardiac transplantation respond normally to the hemodynamic stress. However, they are likely to have denervation related tachycardia and arrhythmias that respond well to ␤-blockers. Other risks include infection and transplant rejection. Complications related to pregnancy include preeclampsia, preterm delivery, and a higher risk of cesarean section.109-111

Anesthesia and Analgesia Anesthesiologist have a crucial role in the management of pregnant women with complex cardiac problems.112 In the decision-making process, a thorough understanding of the pathophysiology of the specific cardiac lesion, choice of anesthetics, and the effect of various anesthetic agents on the cardiovascular system is important.113,114 Physiology of Labor Pain. The first stage of labor begins with uterine contractions and ends with the full dilatation of the cervix. Pain during this stage arises from uterine contractions and progressive dilatation of the cervix. Analgesia can be achieved by peripheral nerve blockade—ie, paracervical block or centrally by paravertebral, epidural, or spinal blocks at the level of T10-L1. The second stage of labor starts with full dilatation of the cervix to the delivery of the infant. At this time, pain is somatic in nature arising primarily from the perineum. Relief is usually achieved by peripheral pudendal nerve blockade, by caudal, low epidural, or low subarachnoid block by interrupting S2-4 nerves. The key for pain relief during labor and delivery in a cardiac patient is to avoid hypotension associated with loss of the sympathetic tone seen with regional anesthesia. This is of particular importance in patients with right-to-left shunts. Narcotic epidural provides an excellent option in patients with cardiac disease due to its minimal effect on the maternal BP115-117 and is of benefit in patients with primary or secondary pulmonary hypertension, Eisenmenger’s syndrome, and cyanotic heart disease.

Cardiac Medications in Pregnancy The main concern for the use of medications during pregnancy is their potential for adverse effects on the fetus. Organogenesis takes place during the first 8 weeks of gestation— known as the “embryonic period.” The risk of teratogenicity is greatest during this time. Most medications cross the placental barrier to varying degrees and may affect fetal growth and development at later gestational ages. Moreover, the physiologic changes of pregnancy may influence the pharmacokinetics of various 446

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medications. Indications and fetal effects of commonly used cardiac medications are summarized in Table 10.118-124

Summary ● Most patients with a diagnosis of cardiac disease tolerate pregnancy well ● Stenotic valvular lesions pose higher maternal and fetal risk in pregnancy ● Regurgitant lesions are better tolerated in pregnancy due to a decrease in systemic vascular resistance ● High-risk patients should be offered termination of pregnancy ● Invasive hemodynamic monitoring may be considered for severe aortic stenosis, mitral stenosis, pulmonary hypertension, uncorrected TOF, and cardiomyopathy ● Narcotic epidural is the anesthesia of choice in aortic stenosis, coarctation of aorta, hypertrophic cardiomyopathy, TOF, and pulmonary hypertension ● Bacterial endocarditis prophylaxis is indicated for vaginal delivery in all cardiac conditions except atrial septal defect, cardiomyopathy, and Marfan’s syndrome without aortic regurgitation ● Avoid hypotension in: X Aortic stenosis X Coarctation of aorta X Hypertrophic cardiomyopathy X Cyanotic heart disease ● Prevent tachycardia in all cardiac patients, especially in Mitral stenosis

Fetal Heart Disease Introduction CHD represents by far the most common major congenital defect, responsible for well over half of neonatal morbidity and mortality related to structural defects of any kind.125 However, the fetus with heart disease poses unique diagnostic, therapeutic, and sometimes ethical challenges. In contrast to the diagnosis of heart disease in the adult, which incorporates symptoms, physical signs, and electrocardiographic and echocardiographic findings, the diagnosis of heart disease in the fetus relies strictly on sonography and heart rate monitoring. Moreover, as treatment of the fetus with heart disease may expose the mother to significant risk, the best interests of the fetus may compete with the welfare of the mother.126,127 The care of the fetus with heart disease may involve a variety of caregivers, including sonographer, obstetrician, perinatologist, pediatric Curr Probl Cardiol, August 2007

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TABLE 8. Benefits to prenatal diagnosis of congenital heart disease Medical Further testing Treatment Delivery Outcome Psychological Reassurance Preparation Informed consent Economical Transport Critical care

cardiologist, and, occasionally, radiologist, neonatologist, geneticist, or pediatric cardiothoracic surgeon. Ideally, each professional involved with the care of the fetus with heart disease should share a common understanding of fetal cardiovascular structure, function, diagnosis, treatment, and outcome. Towards that end, this article reviews many of the most important clinical aspects of the care of the fetus with heart disease. Topics include the following: (1) benefits to prenatal diagnosis of CHD; (2) risk factors for fetal heart disease; (3) prenatal screening for CHD; (4) conventional fetal cardiac imaging; (5) three-dimensional fetal cardiac imaging; (6) training in fetal cardiac imaging; (5) fetal congestive heart failure; (6) ductal-dependent lesions; (7) fetal arrhythmias; (8) lesions associated with systemic disorders; (9) diagnostic challenges; (10) interventions for fetal heart disease; (11) delivery considerations; and (12) impact of prenatal diagnosis of fetal heart disease.

Benefits to Prenatal Diagnosis of CHD Far from a whimsical academic exercise, the prenatal diagnosis of CHD has the potential for tremendous medical, psychological, and economical benefit (Table 8). The impact of prenatal detection of heart disease has become an extraordinarily active area of research, motivated by academic, clinical, economical, and ethical considerations. This section will briefly review areas of impact, with greater detail reserved for other respective portions of this article. The prenatal detection and diagnosis of CHD commonly may have important medical implications. First, the finding of CHD on routine screening should lead to a detailed fetal ultrasound and, in certain cases, amniocentesis. Such testing, prompted by the detection of CHD, may discover associated structural defects128,129 or aneuploidy.130 Extracar448

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diac malformations occur in roughly 25% of fetuses with CHD and normal chromosomes, and in up to 40% of fetuses with CHD and aneuploidy. Moreover, aneuploidy occurs in roughly 15% of fetuses with isolated CHD, and in 30% of fetuses with CHD and extracardiac malformations. Thus, for example, the finding of fetal heart block and a normal four-chamber view should prompt testing for maternal antiRo/La antibodies131,132; the finding of a complete atrioventricular canal should raise the concern for trisomy 21,130,133 and the finding of TOF should prompt the suspicion for vertebral or chromosomal abnormalities such as DiGeorge syndrome.134 Conversely, the finding of certain skeletal or visceral abnormalities on routine screening should prompt a thorough cardiovascular evaluation. Second, many forms of CHD may benefit from prenatal treatment, discussed in detail later in this article. In some cases, such treatment may be lifesaving. Treatment ranges from maternal oral or intravenous digoxin for fetal supraventricular tachycardia135 to percutaneous, transabdominal drainage of a fetal pericardial effusion.136 Percutaneous balloon dilation of the fetal aortic or pulmonary valve may prevent the development of ventricular hypoplasia.137 Surgical approaches involving fetal exteriorization remain limited by fetal and maternal morbidity, principally premature delivery.138-140 Third, certain forms of fetal heart disease may impact the preferred mode, location, or timing of delivery. For instance, congenital complete heart block, in contrast to sinus bradycardia related to fetal distress, represents a form of fetal bradycardia that would not benefit, in the absence of hydrops, from premature delivery. However, because the fetus with complete heart block does not have the normal heart rate response to uterine contractions, delivery via cesarean section may be the preferred approach. As another example, as certain forms of CHD require early (⬍24 hours) intervention (prostaglandin infusion (Alprostadil; Upjohn, Kalamazoo, MI), percutaneous atrial septostomy, or cardiac surgery), prenatal diagnosis may alter the optimal timing or location of delivery. The fourth medical benefit to the prenatal diagnosis of CHD may be improved outcome.141 For a host of reasons, many alluded to above, emerging data and common sense suggest that babies with prenatally diagnosed CHD do better than those babies with identical defects but without prenatal diagnosis.142-145 For instance, many newborns with severe, ductal-dependent heart disease may go undetected postnatally until the ductus arteriosus constricts, sometimes days after delivery and after discharge home. These babies commonly present to medical attention acidotic, desaturated, and in cardiogenic shock, requiring days Curr Probl Cardiol, August 2007

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of resuscitation prior to surgical intervention. Many such cases suffer permanent end-organ damage. Such morbidity could be avoided, in many cases, with prenatal diagnosis, although some studies have failed to demonstrate improved outcome with prenatal diagnosis.146,147 Psychological benefits to the prenatal diagnosis have been traditionally and unfairly overlooked. The demonstration of a normal heart can be tremendously reassuring to the mother whose previous child was born with hypoplastic left heart syndrome.148 In fact, many such women, without the ability to assess the fetal heart during the first and second trimesters, might not otherwise choose to have another child. Moreover, the mother’s psychological state during pregnancy can have important medical implications on the fetus and on the pregnancy itself.149,150 In contrast, the prenatal diagnosis of CHD allows the mother and her family the opportunity to prepare psychologically. Prospective parents of a child with CHD have the opportunity to learn more about their future child’s disease, anticipated surgeries, and prognosis. Chat rooms and support groups provide the opportunity to talk with other parents who have children with similar forms of CHD. Finally, the ability to adjust psychologically to the news that one’s child will be born with CHD, in conjunction with the ability to learn about treatment options and prognosis, allows parents the ability to provide truly informed consent for neonatal surgery once a child is born. Those mothers who deliver children with complex CHD without the benefit of prenatal diagnosis rarely are psychologically or intellectually capable of providing meaningful informed consent for procedures or surgeries during the early neonatal period. Although medical, psychological, and ethical considerations deservedly remain most important, the prenatal diagnosis of CHD does carry important financial implications. By delivering babies with ductal-dependent CHD at appropriate hospitals, and by avoiding delays in diagnosis of even severe forms of CHD, the prenatal diagnosis of CHD can limit the costs of transports and intensive care time for resuscitation. In addition, second-trimester termination of fetuses with severe forms of CHD may lead to a decreased neonatal incidence of these major congenital heart defects.151-153

Risk Factors for Fetal Heart Disease Risk factors for fetal heart disease have traditionally been divided into fetal, maternal, and familial risk factors (Table 9).154 Unlike severe coronary artery disease, which predictably occurs primarily in persons at risk (family history, hypercholesterolemia, hypertension, older men, 450

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TABLE 9. Risk factors for fetal heart disease Fetal Abnormal four-chamber view/outflow tracts Fetal arrhythmia Aneuploidy Extracardiac malformation Abnormal visceroatrial or cardiac situs Pericardial effusion/hydrops Two vessel cord Twins Increased nuchal translucency thickness Polyhydramnios Maternal Congenital heart disease Diabetes mellitus Phenylketonuria Teratogen exposure Systemic lupus erythematosus Sjogren’s syndrome Infection Familial First-degree relative with congenital heart disease Genetic syndrome with cardiac involvement

smokers, obesity, sedentary individuals), most cases of fetal heart disease do not occur in pregnancies identified as high risk. Of course, the finding of a cardiac structural or rhythm abnormality during a routine fetal ultrasound examination may be expected to have a relatively high positive-predictive value, but prenatal screening for CHD remains problematic. Because many screening examinations do not reliably visualize the four-chamber view and outflow tracts, most cases of CHD fail to be detected until sometime after birth, despite prenatal screening.155-157 While detailed fetal echocardiography has been shown to be highly effective in detecting the vast majority of CHD,157-161 such intensive and specialized testing must be reserved for pregnancies at increased risk for CHD. In some communities, referral for fetal echocardiography may be performed for any fetus felt to have an increased risk for fetal heart disease, such as the fetus with a cleft palate or the pregnant woman with diabetes or twins. In other settings, those who screen for CHD may feel comfortable not referring such “mildly at risk” pregnancies if the four-chamber view and outflow tracts look perfectly normal. Thus, risk factors for fetal heart disease may differ somewhat from indications for referral for formal fetal echocardiography. We believe that while all suspected cardiac abnormalities (other than premature atrial contractions) deserve referral to a pediatric cardiologist for assessment and counseling, Curr Probl Cardiol, August 2007

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TABLE 10. Extracardiac malformations associated with congenital heart disease Neurological Dandy–Walker malformation Hydrocephalus Agenesis of the corpus callosum Meckel–Gruber syndrome Meningomyelocele Mediastinal Tracheoesophageal fistula Dextrocardia/mesocardia Diaphragmatic hernia Pentalogy of Cantrell Gastrointestinal Omphalocele Imperforate anus Duodenal atresia Gastroschisis Urogenital Renal dysplasia/agenesis Ureteral obstruction Horseshoe kidney Skeletal Thrombocytopenia/absent radii Ellis Van Creveld Fanconi’s syndrome Apert syndrome Holt–Oram syndrome Miscellaneous Single umbilical artery Twins

the referral of other pregnancies at risk for fetal heart disease remains discretionary and related to physician expertise, comfort level, and community-wide standards. Fetal risk factors for heart disease include the finding of an abnormal four-chamber view or outflow tracts on a routine fetal ultrasound. Such findings deserve referral to a pediatric cardiologist. Other fetuses at risk for CHD, even in the absence of cardiac abnormalities noted on a screening fetal ultrasound, include those fetuses with aneuploidy, a two-vessel umbilical cord, increased nuchal translucency thickness,162,163 or fetal hydrops. Certain extracardiac malformations have variable associations with fetal heart disease (Table 10). Omphalocele, tracheoesophageal fistula, and neural tube defects have relatively strong associations with CHD, whereas cleft palate, clubfoot, and gastroschisis appear to have relatively weak associations with CHD.128,129 Again, the threshold for referral remains a decision for the obstetrician or perinatologist. 452

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TABLE 11. Cardiac teratogens Anticonvulsants Valproic acid Carbamazepine Trimethadione Phenytoin Lithium Coumadin Isotretinoin Alcohol Aspirin/ibuprofen

Maternal risk factors for fetal CHD may or may not predate the pregnancy. Maternal CHD, particularly left-sided obstructive lesions such as bicommissural aortic valve or coarctation of the aorta, place the fetus at risk for CHD.164-166 Maternal diabetes, particularly insulin-dependent or with a high HbA1c, confers a moderately increased risk on the fetus for CHD.167-169 Many medications and other drugs have been linked with fetal CHD following significant early first-trimester exposure (Table 11).170,171 Maternal systemic lupus erythematosus places the fetus at risk for the development of complete heart block,131,132 and early first-trimester viral infections (mumps, coxsackie, influenza, rubella) have been associated with both structural (pulmonary stenosis following rubella) and functional (myocarditis and dilated cardiomyopathy following mumps, influenza) fetal heart disease. Familiar risk factors for fetal CHD include first-degree relatives with CHD, or first-degree family members with genetic syndromes associated with CHD (ie, tuberous sclerosis, Noonan syndrome, long QT, or DiGeorge syndrome).172,173

Prenatal Screening for CHD Although CHD represents the most common major congenital anomaly responsible for an inordinate share of neonatal morbidity and mortality from congenital malformations, the prenatal detection of CHD remains problematic, requiring time and expertise frequently not available in obstetric offices where prenatal screening routinely takes place. As a result, despite routine and widespread prenatal screening programs for CHD, with an increasing percentage of pregnancies undergoing screening second-trimester fetal ultrasounds, most CHD still goes undetected until sometime after birth.155,157,174,175 This abysmal record of prenatal detection of CHD reflects the challenges inherent with fetal cardiac imaging. Curr Probl Cardiol, August 2007

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Fortunately, advances in screening techniques (outflow tracts, earlier imaging, and first-trimester nuchal translucency), new imaging modalities (threedimensional imaging and telemedicine), and increasingly standardized sonographer training promise to improve the prenatal detection of CHD. Advances in the approach to screening low-risk pregnancies for CHD have improved prenatal detection. Because many if not most cases of CHD still occur in pregnancies not identified as high risk, the prenatal detection of CHD still relies most heavily on the screening fetal ultrasound. During the 1990s, the American Institute of Ultrasound in Medicine and the American College of Radiology incorporated the four-chamber view into their formal guidelines for the second-trimester screening fetal ultrasound. The promotion of the four-chamber view to the level of standard of care has had a tremendous impact on the prenatal detection of CHD.176,177 Nevertheless, even in the best of hands, the four-chamber view fails to detect a significant percentage of major, commonly ductal-dependent CHD (ie, pulmonary atresia, TOF, double outlet right ventricle, transposition of the great arteries, and truncus arteriosus). More recently, many investigators have demonstrated an incremental value of adding outflow tracts to the routine screening four-chamber view.178-180 Unfortunately, both the four-chamber view and the outflow tracts remain tremendously dependent on the transducer, sonographer, and interpreter, and the standard of care remains the four-chamber view alone. In 2003, the American Institute of Ultrasound in Medicine issued revised guidelines for the routine screening fetal ultrasound. Those guidelines still include only the four-chamber view, with merely a recommendation to attempt visualization of the outflow tracts. The formal and widespread incorporation of the outflow tracts into the routine screening fetal ultrasound likely would represent an important advance in the prenatal detection of CHD. More recently, the detection of many cases of CHD has moved from the second into the late first trimester (10 to 14 weeks).181-185 For the mother with a fetus at high risk for heart disease who ends up having a normal study, earlier detection and diagnosis can provide six or more additional weeks of comfort than mid-second-trimester scanning. In the case of an abnormal study, early diagnosis can provide more time for further testing and education and allow for an earlier, safer, and less traumatic termination, when desired, in cases of severe disease. With current advances in ultrasound technology and image resolution, some forms of CHD can be reliably detected transabdominally as early as 13 to 15 weeks gestation, and transvaginally as early as 11 to 13 weeks gestation.182-185 454

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Nevertheless, first-trimester fetal cardiac imaging faces important limitations.185 As the technique requires specialized equipment and expertise, early fetal cardiac imaging currently remains limited to a relatively small number of specialized centers. Moreover, because of the progressive nature of many prenatal cardiac lesions,186-189 and because early imaging pushes to the limit the spatial resolution of ultrasound, early fetal cardiac imaging carries a relatively low specificity and sensitivity. Progression during the second and third trimesters has been described for aortic and pulmonary valvar stenosis, ventricular hypoplasia, valvar regurgitation, arrhythmias, cardiac tumors, or restriction of the ductus arteriosus or foramen ovale. Furthermore, with transvaginal imaging, certain views and planes cannot be obtained because of the fixed linear axis of the probe. For these reasons, first-trimester fetal cardiac imaging should be reserved as a specialized screening tool for particularly high-risk pregnancies and should be performed only in specialized centers with the necessary equipment and expertise. All normal studies should be repeated during the second trimester because of the potential for progression of disease not initially detected. Ultimately, routine fetal screening for CHD should be deferred until 18 to 22 weeks gestation. First-trimester nuchal translucency represents an important, relatively new, advance, certain to improve the prenatal detection of CHD.162,163 For still unclear reasons, increased nuchal thickness, between 10 and 14 weeks gestation, has been found to correlate closely with the presence of CHD even in the absence of aneuploidy, systemic syndromes, or heart failure. Such fetuses should probably be referred for formal fetal echocardiography during the first and/or second trimesters.

Conventional Fetal Cardiac Imaging This section describes the basic approach to fetal cardiac imaging using ultrasound and includes those views recommended for screening as well as those views, measurements, and Doppler findings that should be included with detailed fetal echocardiography. This section will emphasize the importance of 2D imaging and include a description of the role of spectral and color Doppler flow techniques in the evaluation of the fetal heart. With adequate training, a screening fetal cardiac evaluation can be performed in less than 1 or 2 minutes during routine obstetric scanning, leaving more detailed assessment for formal fetal echocardiography when indicated. Fetal cardiac imaging using 2D ultrasound first emerged approximately 25 years ago in the early 1980s.190-192 Over the years, image resolution has improved tremendously, such that most forms of CHD may be Curr Probl Cardiol, August 2007

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successfully detected with a basic screening evaluation at between 16 and 18 weeks gestation. Most forms of CHD can be reliably diagnosed between 18 and 22 weeks gestation using a combination of 2D, pulsed, and color flow Doppler modalities.158-161 Earlier imaging may be performed transvaginally (11-13 weeks) or transabdominally (13-15 weeks) but faces important limitations discussed earlier. Later imaging (24-28 weeks) may provide improved image quality but may be too late for low-risk amniocentesis or termination of pregnancy. Thus, screening the low-risk pregnancy for CHD should take place between 16 and 20 weeks. Detailed fetal echocardiography in the high-risk pregnancy typically should take place between 18 and 22 weeks gestation, although certain high-risk pregnancies may be evaluated for CHD between 11 and 16 weeks in certain specialized centers. Fetal cardiac imaging, for the purposes of both screening and detailed echocardiographic assessment, requires experience and skill in obtaining the proper sonographic window. In this regard, the sonographer typically may need to explore various locations on the maternal abdomen and have the pregnant patient move from side to side in an effort to obtain the most optimal windows to the fetal heart. Obtaining the proper windows probably represents the greatest challenge and rate-limiting step in fetal cardiac imaging. While screening for CHD in low-risk pregnancies involves visualization of the four-chamber view and, optimally, the outflow tracts, formal fetal echocardiographic evaluation begins with the fetal abdomen. Transverse imaging through the fetal abdomen should demonstrate the descending aorta just anterior and to the left of the spine, the inferior vena cava rightward and slightly farther anterior, and the stomach on the left. The absence of any of these normal markers may indicate a form of heterotaxy (asplenia or polysplenia). The four-chamber view should begin by demonstrating the four-chambered heart in the left thorax with the apex directed 45 degrees towards the left (Fig 6).193,194 The transverse cut should be cephalad to the coronary sinus (which may appear as an inferior ostium primum atrial septal defect), but caudal or inferior to the left ventricular outflow tract (aortic valve and ascending aorta). The right atrium and ventricle should be equal in size or slightly larger than the left atrium and ventricle. The inferior portion of the atrial septum should be visualized to be intact, just above the inlet portion of the ventricular septum, which also should appear to be intact. Occasionally, scanning parallel with the septae may generate artifactual dropout; in such cases, the transducer beam orientation should be reoriented perpendicular to the septae. The tricuspid valve should be 456

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FIG 6. Echocardiographic image of normal four-chamber view in a 20-week fetus. Note that the right heart appears slightly larger than the left heart.

equal in size or slightly larger than the mitral valve, and the leaflets should appear thin and delicate as they open during diastole. The left ventricle should form the apex, and the right ventricle should appear more heavily trabeculated, with the moderator band towards the apex. Both ventricles should appear to squeeze well qualitatively. While not required as part of the normal screening evaluation, optimal screening for CHD, even in low-risk pregnancies, should include visualization of the outflow tracts. By sweeping the ultrasound beam cephalad from the position of the four-chamber view, the aorta should be seen to arise from the left ventricle, fairly parallel to the plane of the ventricular septum (Fig 7). By sweeping the ultrasound beam just slightly more cephalad, the main pulmonary artery should be seen arising from the right Curr Probl Cardiol, August 2007

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FIG 7. Echocardiographic image of normal left ventricular long axis. Note outflow tract leads into aortic root, with continuity between ventricular septum and anterior wall of aortic root.

ventricle and crossing the aortic root at a 45- to 90-degree angle. The pulmonary valve and main pulmonary artery should be equal in size or slightly larger than the aortic valve and ascending aorta. This evaluation of the four-chamber view and outflow tracts completes the screening evaluation for CHD in low-risk pregnancies. Formal evaluation of the fetal heart in high-risk pregnancies involves further 2D imaging, as well as color flow mapping and judicious use of spectral Doppler and quantitative measurements.193,194 Imaging of the four-chamber view should include visualization of at least one to two pulmonary veins returning to the left atrium, often with a prominent ridge within the lateral left atrium reflecting the normal tissue reflection between the left atrial appendage and left pulmonary vein. The flap of the 458

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foramen ovale, increasingly prominent and aneurysmal as the second and third trimesters progress, should always be seen in the left atrium. The septal leaflet of the tricuspid valve should arise from the septum just slightly apical to that of the mitral valve septal leaflet. The moderator band should be visualized towards the right ventricular apex. The left ventricular outflow tract should be visualized perpendicular to the ultrasound beam, with continuity noted between the ventricular septum and the anterior aspect of the ascending aorta. Whereas imaging parallel to the ventricular septum commonly generates the illusion of aortic override, imaging the left ventricular outflow tract perpendicular to the ventricular septum allows aortic override to be ruled in or out. The aortic and pulmonary valves should appear thin and delicate, ideally disappearing during systole. Short-axis imaging of the main pulmonary artery should demonstrate the origin of both right and left pulmonary arteries, as well as the ductus arteriosus. Sagittal imaging of the ductal and aortic arches should demonstrate a more cephalad aortic arch, complete with head and neck vessels, and a more inferior, posteriorly directed ductal arch. In all of these views, any structure that appears small or large should be measured several times, with the best guess measurement plotted on normograms according to gestational age.193 Spectral Doppler should be used to assess flow across defects or valves with suspected pathology. Color flow mapping, exquisitely sensitive to valvar regurgitation, flow through small ventricular septal defects, and pulmonary venous return, should be used routinely to demonstrate normalcy or to detect pathology. Other than trace tricuspid regurgitation, any valvar regurgitation by color flow mapping should be considered abnormal and deserves follow-up.195 Formal fetal echocardiography also includes assessment of the peripheral fetal cardiovascular system through the use of spectral Doppler.196 Peripheral spectral Doppler can be used to assess umbilical venous or inferior vena cava flow in cases of suspected heart failure, umbilical arterial flow in cases of suspected placental insufficiency, and ductus arteriosus flow in cases of suspected ductal constriction. The pulsatility index (PI) can help identify and follow cases of placental insufficiency or ductal constriction. As the placental resistance decreases during the second and third trimesters, the umbilical artery PI decreases from 2 to 1. The PI of the ductus arteriosus stays relatively stable150-152 throughout the second and third trimesters.197

Three-Dimensional Fetal Cardiac Imaging Just as two-dimensional (2D) imaging dramatically transformed fetal cardiac imaging during the past 25 years, three-dimensional (3D) Curr Probl Cardiol, August 2007

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FIG 8. Echocardiographic rendered image of 23-week fetus with mitral atresia, ventricular septal defect, and hypoplastic left ventricle. Image acquired from 3D volume acquired in real-time over 2 seconds. (Color version of figure is available online.)

imaging promises to revolutionize fetal cardiac imaging over the next 25 years.198-207 Although 3D fetal cardiac imaging currently faces important limitations, the technique has the potential to improve both the prenatal detection and the diagnosis of CHD. By acquiring a comprehensive volume dataset within a few seconds from a single transabdominal window (Fig 8), 3D imaging may reduce scanning time and operator dependence. For screening the low-risk pregnancy, 3D imaging may facilitate visualization of the four-chamber view and outflow tracts, particularly when conventional 2D imaging fails because of time constraints, limited windows, or sonographer inexperience. Fully interactive, 3D imaging may improve interpretation and comprehension of fetal cardiac images by allowing the reviewer to display any plane within 460

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TABLE 12. Conventional fetal cardiac imaging: limitations Acquisition Operator dependent Time consuming Sonographic window Processing Minimal postprocessing potential Display and interpretation Review only planes from original acquisition Planar evaluation of multiplanar structures Flawed quantitative measurements

TABLE 13. Three-dimensional fetal cardiac imaging: advantages Acquisition Less operator dependent Rapid Requires only single sonographic window Processing Tremendous postprocessing potential Display and Interpretation Any plane available for review Rendered displays improve comprehension and communication More accurate and precise quantitative measurements

the volume dataset, or to view the heart from a surgeon’s perspective using volume rendering display techniques. If necessary to determine normalcy, volume datasets can be transmitted electronically to experts in remote locations, who can then perform virtual scanning as if actually scanning the patient themselves.206 Ultimately, three-dimensional volume datasets may enable complete, interactive evaluations of the fetal heart after a single, rapid (2-4 seconds) acquisition. Thus, 3D imaging has the potential to minimize the challenges faced by conventional fetal cardiac screening ( Tables 12 and Table 13). First, by allowing the acquisition of the entire fetal cardiac volume within a matter of seconds, 3D imaging likely will shorten acquisition times and operator-dependence. With conventional 2D imaging, one acquires a single plane at a time, requiring multiple sweeps, views, orientations, and, typically, windows during the actual scanning. In contrast, 3D imaging allows a rapid acquisition of the entire cardiac volume, with the sonographer needing only to find an optimal sonographic window. Second, while the four-chamber view resides within a single plane, lending itself well to tomographic evaluation using 2D ultrasound, the outflow tracts (and most forms of CHD) do not reside within a single Curr Probl Cardiol, August 2007

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plane. Three-dimensional imaging allows the reviewer to display any plane within the volume dataset, or to display life-like volume renderings of the four-chamber view and outflow tracts. Finally, by avoiding image plane positioning errors and geometric assumptions, 3D fetal cardiac imaging promises to allow quantitative measurements, such as ventricular volume, ejection fraction, and cardiac output, with greater accuracy and precision than those obtained with conventional, 2D imaging.201,202 For these and other reasons, 3D imaging of the fetal heart ultimately may improve the prenatal detection of outflow tract abnormalities and facilitate comprehension of complex forms of CHD.

Technique of 3D Imaging of the Fetal Heart As 3D imaging of the fetal heart likely will have an increasing clinical role both for screening low-risk pregnancies and for examining complex forms of fetal heart disease, brief mention should be made of some of the technical aspects of 3D fetal echocardiography. Acquisition of 3D fetal cardiac datasets may be performed with either of two distinct approaches: reconstructive205,207 or real-time.200,204 Reconstructive approaches, currently more widespread than real-time approaches, generate a volume (or volumes) of sonographic data from a series of planar images obtained sequentially over time as the sonographer sweeps the image plane across the fetal heart. Spatial coordinates of each pixel within each plane must be simultaneously acquired. Reconstructive fetal 3D echocardiography has historically interfaced conventional probes and equipment with external spatial positioning systems and computer graphic workstations.207 More recently, reconstructive approaches have expanded with the development of stand-alone commercially available 3D ultrasound imaging systems (Voluson 730 Expert, GE Medical Systems, Kretz Ultrasound, Austria).205 These systems utilize specialized handheld mechanical scanner assemblies equipped with internal position tracking systems. With the probe held still, an internal motor automatically performs a steady, regular sweep of the image plane across the fetal heart. Because of the absence of a fetal electrocardiogram, reconstructive approaches to 3D fetal cardiac imaging require specialized gating algorithms to identify each image with its appropriate place in the cardiac cycle; otherwise, data from multiple parts of the cardiac cycle would be combined into a single static volume.207 Patrick W. O’Leary: Although the beneficial impact of therapy for prenatal tachycardia and effusions has been well documented, the evidence supporting the benefits of other prenatal interventions is limited and evolving. The 462

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reports referred to here show promise but only additional time and experience will define the true impact and appropriate roles for prenatal intervention.

Alternatively, real-time 3D echocardiography acquires a truncated pyramidal volume of sonographic data virtually instantaneously, utilizing a specialized, 2D matrix phased-array transducer and a dedicated, commercially available stand-alone imaging system (Sonos 7500, Philips Medical Systems, Bothell, WA).198 Given the virtually immediate acquisition of an entire fetal cardiac volume, real-time 3D echocardiography lends itself particularly well to fetal cardiac imaging by obviating the need for cardiac gating, limiting artifacts related to random fetal or maternal motion during the acquisition, and avoiding inaccuracies and cumbersome processing related to gating and position-sensing devices. These strengths suggest that real-time 3D echocardiography may become the dominant means of fetal cardiac imaging in the future. For now, however, real-time approaches suffer from inferior image resolution and less commercial availability. Three-dimensional volumes of the fetal heart, whether reconstructive or real-time, may be interactively displayed in a variety of modes, all of which continue to evolve. Three-dimensional data may be displayed as three simultaneous, orthogonal reformatted planar images, with the reviewer able to display any plane within the volume dataset. Alternatively, data may be displayed in rendered formats, which incorporate data from a series of planes into a single image using various shading techniques and perspective clues. With surface rendering, specialized techniques to display reflection and shadowing properties of solids generate images of the fetal heart as a solid, 3D object. Such displays may be particularly useful for imaging the great arteries. Volume rendering algorithms display data as a “surgeon’s eye view,” enabling visualization of the internal architecture and anatomy of the fetal heart or great arteries, from any perspective. Volume renderings may be rotated and cropped to facilitate further visualization and comprehension of fetal cardiac structure and function. Such displays allow evaluation of myocardial and valvar function. Evolving technology also allows the 3D visualization of color-flow regurgitant and stenotic jets within volume-rendered displays or as stand-alone “angiograms.”203 Patrick W. O’Leary: Although it seems logical that prenatal detection of congenital cardiac malformations should improve outcome, the evidence is somewhat less than clear. As mentioned, most studies show that overall Curr Probl Cardiol, August 2007

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TABLE 14. Three-dimensional fetal cardiac imaging: Limitations Sonographic window Image resolution Three-dimensional artifacts Volume size Lost in space phenomenon Cumbersome, offline quantification Substantial learning curve

survival is not altered by prenatal detection. The best evidence is that biochemical markers of neonatal distress are slightly less abnormal in prenatally diagnosed babies, but survival and hospital stay have not been conclusively influenced. It should be noted that current screening practices tend to refer only to the most severely affected fetuses for detailed evaluation. This creates an unavoidable selection bias in all outcome studies reported to date.

Despite its rapid evolution from a clinical investigational tool for academic clinicians towards a clinically useful and commercially available adjunct (or alternative) to conventional, 2D imaging, 3D fetal cardiac imaging faces important limitations that must be overcome prior to the realization of the technique’s clinical potential (Table 14). First, image resolution remains suboptimal and needs to improve. Second, the development of faster frame rates with reconstructive approaches will allow shorter acquisition times and, as a result, less distortion from random fetal motion. Third, quantitative assessment methods remain cumbersome and would benefit from on-line measurements and automated boundarytracing algorithms, currently in development. Fourth, new artifacts unique to 3D imaging must be recognized, understood, and minimized. For instance, artifacts related to the angle of acquisition may cause false dropout of the membranous septum or artifactual septal hypertrophy. Fifth, orientation tools should be developed to help orient the reviewer in an attempt to minimize the “lost in space” phenomenon. Finally, as the sonographic window may remain the most critical limitation of fetal 2D or 3D ultrasound, a substantial learning curve for both the acquisition and the evaluation of 3D fetal cardiac datasets must be realized prior to 3D fetal cardiac imaging becoming a trusted and respected clinical tool.

Training in Fetal Cardiac Imaging Those who scan the fetal heart typically come from one of two backgrounds: experience either with general fetal ultrasound (general 464

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TABLE 15. Causes of fetal congestive heart failure Cardiac Hypertrophic cardiomyopathy (diabetes; twin-twin transfusion) Dilated cardiomyopathy (myocarditis; severe pulmonary/aortic stenosis) Sustained bradyarrhythmia/tachyarrhythmia Valvar regurgitation (primary structural abnormality; ductal constriction; myocarditis) Restrictive foramen ovale Ductal constriction Anemia Diaphragmatic hernia Twin-twin transfusion Arteriovenous malformation (high output failure)

obstetric sonographers, obstetricians, perinatologists, or radiologists) or with echocardiography (cardiac sonographers or “echo techs,” or pediatric cardiologists). While experience with scanning probably represents the single most important component of training, more formalized approaches to training those who scan fetal hearts have recently emerged. Obstetricians, perinatologists, radiologists, and sonographers comprise the vast majority of those who screen low-risk pregnancies for fetal heart disease. Expertise in screening the fetal heart for CHD typically is acquired through formal sonographer didactic coursework, hands-on experience, various texts, and occasional conferences. The American Registry of Diagnostic Medical Sonographers provides sonographer training and a formal licensing examination in Obstetrics/Gynecology. However, radiologists, obstetricians, and cardiologists all may develop expertise in screening the fetal heart for CHD. Whereas those who screen low-risk pregnancies for fetal CHD must learn to detect and discriminate normal from abnormal, those who perform formal fetal echocardiography must learn to assess and diagnose all forms of fetal heart disease. Towards this end, sonographers have gained expertise in fetal echocardiography with hands-on training with professionals experienced in fetal echocardiography. Recently, the American Registry of Diagnostic Medical Sonographers has developed a specialized examination to grant licensure to sonographers interested in formal fetal echocardiography. Guidelines for physicians who perform fetal echocardiography in high-risk pregnancies have been published by the American College of Cardiology, the American Heart Association, and the American Society of Echocardiography.208,209

Fetal Congestive Heart Failure CHF in the fetus may be caused by cardiac or noncardiac pathology (Table 15). Regardless of the etiology, fetal CHF may progress to hydrops Curr Probl Cardiol, August 2007

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TABLE 16. Diagnosis of fetal congestive heart failure Cardiomegaly Tricuspid regurgitation Diminished ventricular function Pericardial effusion Peripheral Doppler abnormalities

and, ultimately, lead to fetal death. As many causes of fetal CHF may be effectively treated, the detection of CHF, search for etiology, and initiation of treatment should proceed as quickly as possible. Unlike the newborn, child, or adult with CHF, the fetus with CHF does not present with tachycardia, tachypnea, hepatomegaly, or rales. Instead, the findings of CHF in the fetus include cardiomegaly, diminished ventricular systolic and/or diastolic function, pericardial effusion, tricuspid regurgitation and, often, abnormal waveforms in the inferior vena cava, ductus venosus, and umbilical vein (Table 15).210-212 As CHF progresses, fluid accumulations occur in the pleural space, peritoneum (ascites), and subcutaneous tissues, constituting fetal hydrops. The goal of fetal management is to prevent the progression of fetal CHF to fetal hydrops by identifying and treating the specific cause. This section will discuss cardiac causes of fetal CHF. CHF rarely complicates even complex forms of fetal CHD, but four categories of fetal CHD do predispose to CHF and hydrops: cardiomyopathy, sustained bradycardia/tachycardia, valvar regurgitation, or ductal constriction/foramen ovale restriction. All four types of disease states lead to elevated right atrial and systemic venous pressure.213 Fetuses with CHD associated with any of these conditions (Table 16) should be followed serially for the development of CHF or hydrops. Right or left ventricular cardiomyopathies, characterized by diminished ventricular function (systolic and/or diastolic), may be seen in the context of a dilated ventricle (dilated cardiomyopathy, arrhythmogenic right ventricular dysplasia) or thickened ventricle (hypertrophic cardiomyopathy, severe aortic stenosis). In either setting, elevated mean atrial pressure results in systemic venous congestion and CHF. Dilated cardiomyopathies may be primary, or secondary, to outflow tract obstruction or myocarditis. Likewise, hypertrophic cardiomyopathy may be primary or secondary to twin–twin transfusion syndrome, maternal diabetes, or severe aortic or pulmonary valve stenosis. Sustained bradycardia132 or tachycardia135 may also lead to fetal CHF. Sustained bradycardia may be sinus (related to fetal distress) or ventricular (complete heart block, blocked atrial bigeminy). Fetuses with 466

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TABLE 17. Ductal-dependent forms of congenital heart disease Ductal-dependent for Systemic blood flow Coarctation of the aorta Interrupted aortic arch Aortic stenosis Mitral stenosis Hypoplastic left heart syndrome/Shone syndrome Ductal-dependent for pulmonary blood flow Pulmonary atresia/intact ventricular septum Tetralogy of Fallot with severe pulmonary stenosis/atresia Tricuspid atresia Tricuspid valve dysplasia Ebstein’s anomaly of the tricuspid valve Ductal-dependent for adequate mixing Transposition of the great arteries Some forms of double outlet right ventricle

complete heart block and structurally normal hearts commonly develop hydrops when the ventricular rate stays below 55 beats per minute. Blocked atrial bigeminy may present as fetal bradycardia but rarely generates CHF. On the other hand, sustained tachycardia (typically supraventricular but occasionally ventricular) commonly does result in CHF, particularly at rates over 260 beats per minute. Finally, valvar regurgitation in the fetus leads to right atrial hypertension directly in the case of tricuspid regurgitation, via elevated right ventricular filling pressures in the case of pulmonary regurgitation (absent pulmonary valve), and via elevated left atrial pressure and diminished right-to-left atrial shunt with mitral or aortic regurgitation. Tricuspid regurgitation appears to be a common finding, or common denominator, for all forms of fetal CHF.195 Ductal-Dependent Lesions. Among fetuses with CHD, ductal-dependent cases (Table 17) represent the group most likely to require immediate medical attention following delivery. Most commonly, these newborns require central infusion of prostaglandin to keep the ductus arteriosus open. Prostaglandin, in turn, commonly decreases the ventilatory drive and may be associated with other side effects as well. Some forms of CHD, such as coarctation of the aorta, aortic stenosis, or hypoplastic left heart syndrome, are ductal-dependent for systemic blood flow. Other forms of CHD, such as pulmonary atresia, severe pulmonary stenosis, or Ebstein’s anomaly, may be ductal-dependent for pulmonary blood flow. Given the ductal-dependent nature of these lesions, fetuses diagnosed with any of these conditions warrant delivery at a facility equipped with appropriate equipment and personnel. Thus, the prenatal Curr Probl Cardiol, August 2007

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diagnosis of any of these conditions may avoid sudden, unexpected cardiovascular collapse, either at an ill-equipped nursery or at home. As several important forms of ductal-dependent CHD may have normal four-chamber views, the inclusion of outflow tracts as part of the routine screening fetal ultrasound may play a key role in optimizing the outcome of many of these newborn infants. Identification of any ductal-dependent lesion prenatally should prompt consultation with a pediatric cardiologist and neonatologist, and choice of site of delivery may be critical to the ultimate outcome.

Fetal Arrhythmias In addition to a normal-appearing four-chamber view and outflow tracts, the normal fetal screening ultrasound evaluation should demonstrate physiologic rate and variability of the fetal heartbeat. The fetal heart rate should be physiologic (roughly 110-180) and have a physiologic variability (small but real changes in heart rate during scanning, with prolonged or severe bradycardia only during periods of deep transducer pressure). Abnormal variability (irregular beats or extrasystoles) or abnormalities in rate (sustained bradycardia or tachycardia) should be noted, evaluated and, when appropriate, treated. Irregular Beats. Premature atrial contractions (PACs) represent the most common fetal arrhythmia.214,215 PACs present as an irregular variability in fetal heart rate, usually beginning between 18 and 25 weeks, but occasionally presenting initially during the third trimester. The diagnosis of PACs may be made empirically by observing the rhythm. However, to rule out the possibility of premature ventricular contractions, Doppler inflow and outflow evaluation of the left ventricle should be performed. PACs may be exacerbated by caffeine, decongestant medications (stimulants), and tobacco. Typically, PACs resolve spontaneously within 2 to 3 weeks of diagnosis. PACs do not represent any real risk to the fetus and do not require treatment. In the absence of hydrops, sustained bradycardia or tachycardia, or structural heart disease, PACs should just be observed on a weekly basis. Referral to a perinatologist or pediatric cardiologist should be considered when concerns persist regarding the diagnosis, the possibility of structural heart disease or sustained bradycardia or tachycardia, or when fetal well-being appears compromised.

Patrick W. O’Leary: Although it is an interesting association, the absence of nuchal translucency may be more useful than its presence. Nearly all of the 468

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“negative” fetuses (normal nuchal appearance) had normal hearts (negativepredictive value, 99.9%). However, the positive-predictive value of nuchal translucency is low, only between 1 and 6%, depending on the upper limit of normal used (95th or 99th percentile, respectively). I suspect that an increased emphasis on education about and use of standard findings during routine obstetric screening, such as ventricular or arterial disproportion, cardiac axis, and the spatial relationships of the great arteries (orthogonal or parallel), would have a greater impact on prenatal detection rates for CHD than will nuchal translucency criteria in the first trimester.

Sustained Bradycardia. A sustained fetal heart rate below approximately 110 beats per minute represents fetal bradycardia and merits further evaluation. In contrast, fetal bradycardia related to deep transducer pressure or a particular maternal lie may represent a normal fetal response to stress. In such cases, if the fetal heart rate normalizes after relief of transducer pressure or change in maternal/fetal position, no further cardiac evaluation may be necessary. In contrast, sustained fetal bradycardia always merits further investigation. The differential diagnosis of fetal bradycardia includes sinus bradycardia, blocked atrial bigeminy, atrial flutter with high-degree block, and complete heart block. Treatment approaches and prognosis depend on the precise diagnosis. Sinus bradycardia, presenting with a slow rate but with physiologic variability and with 1:1 conduction between the atria and ventricles, may represent fetal distress and thus should prompt a thorough evaluation of fetal well being and placental function. Particularly when associated with some degree of heart block, fetal sinus bradycardia may be the first sign of long QT syndrome.216 Affected fetuses and newborns are at risk for ventricular tachycardia. For this reason, fetuses in good health who demonstrate unexplained sinus bradycardia without fetal distress should undergo electrocardiographic evaluation following delivery. In addition, because long QT syndrome may run in families, a family history for long QT syndrome, recurrent syncope, or SIDS should be sought. Occasionally, fetal sinus bradycardia may represent blocked atrial bigeminy, in which every other beat represents a premature atrial contraction. In atrial bigeminy, the premature beats may be blocked if they occur very early, with the atrioventricular node still refractory. In such cases, only sinus beats conduct, generating a uniform ventricular rate exactly half of the atrial rate. No specific therapy is warranted other than observation and avoidance of caffeine, decongestant medications, and tobacco. Curr Probl Cardiol, August 2007

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Occasionally, atrial flutter conducts 3:1 or 4:1, with such fetuses presenting with bradycardia. Close inspection of the heart with 2D imaging, M-mode, or spectral Doppler can diagnose the arrhythmia and assess the degree of conduction. Like other fetal arrhythmias, fetal atrial flutter may be associated with structural heart disease. Treatment of atrial flutter, typically with maternal orally administered pharmacologic therapy (sotalol, digoxin, propranolol (Inderal; Wyeth-Ayerst, Madison, NJ), amiodarone, and others), can decrease the likelihood of the development of fetal CHF or hydrops.214 Complete heart block (CHB) in the fetus typically presents with a sustained fetal heart rate in the 40s to 70s. In this context, the atrial rate remains normal, but atrial contractions do not conduct to the ventricles. As a result, the ventricles depolarize with their own intrinsic rate. Approximately 50% of cases of fetal CHB occur in the presence of structural heart disease (L-looped ventricles, atrioventricular septal defects, or complex forms of heart disease associated with heterotaxy).132,214 These cases of CHB have a relatively poor prognosis, with a high rate of fetal demise related to progressive heart failure and hydrops. Therapy with maternal oral agents such as terbutaline or other sympathomimetics has not been shown to improve the outcome. The other 50% of cases of fetal heart block occur secondary to damage to the fetal atrioventricular node by maternal anti-Ro and/or anti-La antibodies, usually in the context of maternal systemic lupus erythematosus or related connective tissue disorders.131,132,217 In some such cases, maternal treatment with dexamethasone has been shown to improve fetal outcome, probably by improving myocardial function.218,219 Some investigators have also used sympathomimetic agents to increase ventricular rates in this setting, particularly when ventricular rates remain below 55 beats per minute, but sustained increases in fetal heart rate have not been achieved. Spectral Doppler evaluation of the fetal PR interval has been shown to be a useful way to identify fetuses in positive anti-Ro or anti-La pregnancies with evidence of atrioventricular node disease (first-, second-, or third-degree heart block). Treatment of fetuses at risk with firstor second-degree heart block may prevent the development of CHB, although investigations in this area are ongoing. Sustained Tachycardia. As the fetus has relatively little ability to increase its cardiac output with an increase in heart rate, supraventricular tachycardia (SVT) represents the vast majority of instances of sustained fetal tachycardia. Sinus tachycardia represents an unusual response to fetal heart failure or distress. Fetal ventricular tachycardia occurs still less commonly. 470

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Patrick W. O’Leary: Many would suggest that visualization of the outflow tracts should become a routine part of the standard obstetric screening ultrasound. As this review points out in a later section, the four-chamber view is often normal in hearts with ductal-dependent congenital cardiac malformations and it is these anomalies that may benefit most from prenatal detection. It has been shown that assessment of the size (symmetric or discrepant) and arrangement (orthogonal or parallel) of the great arteries improves the detection rate of prenatal screening exams from 47% with four-chamber evaluation alone to 78% when outflow tract images are included (Kirk et al. Ob Gyn 1994;84(3:427-31)).

Fetal SVT typically occurs via an accessory pathway, although autonomic forms of fetal supraventricular tachycardia occur relatively commonly as well. Fetal SVT, usually in the range of 240 to 280 beats per minute, occurs most frequently in fetuses with structurally normal hearts and relatively rarely occurs in the setting of structural CHD. However, fetal SVT may be associated with Wolff–Parkinson–White syndrome. The diagnosis of SVT may be suggested by 2D imaging, spectral Doppler assessment of the left ventricular inflow and outflow tracts, or by M-mode analysis.214,220,221 Ventricular tachycardia, typically slower but less well tolerated than SVT, may be associated with ventricular structural abnormalities or tumors, or may occur in the context of long QT interval. Ventricular tachycardia may be difficult to discriminate from fetal supraventricular tachycardia, even with M-mode or spectral Doppler analysis, although ventricular tachycardia is typically far less well tolerated. As fetal SVT typically presents as an intermittent, nonsustained arrhythmia, the presence of premature atrial contractions or atrial couplets can help to strengthen the certainty of the diagnosis. While few would dispute the benefit of treatment of fetal SVT in the face of hydrops and in the absence of lung maturity, no consensus exists on the approach to the fetus with SVT in the absence of hydrops.214,220,221 As would be expected, SVT in the fetus with structural heart disease is far less well tolerated than SVT with a structurally normal heart. However, treatment strategies for the nonhydropic, immature fetus with SVT remain largely divergent, with some advocating treatment for the fetus with any documented SVT, others recommending treatment only with the development of hydrops, and others somewhere in between. No consensus has been reached on the relationship between heart rate and the development of hydrops in the context of fetal SVT. Antiarrhythmic agent, dosing schedules, and routes of administration represent separate areas of controversy and disagreement, similarly without consensus. Curr Probl Cardiol, August 2007

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Although each case may be handled somewhat differently, depending on patient characteristics and physician biases, the following represents our institution’s general approach to the treatment of fetal SVT. The presence of structural heart disease in the context of SVT lowers the tolerance for shortened diastolic filling times and elevated central venous pressure, so such fetuses typically receive treatment earlier than do fetuses with structurally normal hearts. When fetal SVT becomes complicated by hydrops, the threshold for treatment falls much further. In the absence of fetal structural heart disease or hydrops, fetal SVT generally receives treatment when the tachycardia occurs over 25% of the time. However, beyond 34 to 35 weeks gestation, many cases of fetal tachycardia may be better approached with delivery than with maternally administered medications, all of which have variable efficacy as well as the potential for both maternal and fetal toxicity. Prior to treatment, all potential precipitating factors are withdrawn (tobacco, decongestant medications, and caffeine), and the fetal rhythm is monitored in-house for 8 to 24 hours to assess the percentage of time the fetus is in tachycardia. The mother is informed of all possible fetal and maternal risks to therapy, as well as the anticipated benefit to treatment. All antiarrhythmic agents have the potential for either maternal or fetal proarrhythmia. As maternal serum factors rarely may react with assays for digoxin, a maternal serum digoxin level is drawn along with a set of electrolytes and creatinine. A maternal electrocardiogram and, ideally, consultation with a medical cardiologist is performed prior to initiation of therapy. In our program, treatment begins with a digoxin load, using 0.5 mg intravenously every 6 to 8 hours, with a maternal serum digoxin level and electrocardiogram performed prior to each dose. Loading continues until effect (less than 25% tachycardia, improved fetal well being, or decreased hydrops), therapeutic level (2.1), maternal toxicity (maternal symptoms or electrocardiographic abnormalities beyond first-degree heart block), or fetal toxicity (worsening of arrhythmia), whichever comes first. Once a desired effect has been safely achieved, digoxin is administered orally two to four times daily, usually 0.25 to 0.5 mg per dose. Often consultation with the hospital pharmacologist may be useful. Patients are discharged when steady state has been achieved, with acceptable control of the fetal arrhythmia, acceptable maternal serum digoxin levels, and the absence of maternal or fetal toxicity. However, close outpatient follow-up is essential to confirm continued effect and lack of toxicity, and usually to increase dosing as maternal volumes of distribution continue to increase during the second and third trimesters. When digoxin fails to achieve adequate control, second-line agents such as sotalol, propranolol, 472

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flecainide (Tambocor; 3M, St. Paul, MN), or amiodarone (Cordarone; Wyeth-Ayerst, Madison, NJ) may be added, but the potential for toxicity increases and the likelihood for efficacy decreases.214

Patrick W. O’Leary: Although three-dimensional imaging is a promising modality with all of the potential described, it is not widely available and the learning curve for application by the “general” prenatal sonographer may be prolonged. For now, continued emphasis on education of examiners performing screening ultrasounds in the “signs” of CHD using four-chamber and outflow views is likely to have a more immediate and measurable impact.

Atrial Flutter. In contrast to fetal SVT, fetal atrial flutter ranges between 300 and 500 atrial contractions per minute, with a ventricular rate that may vary between less than 100 to over 300 beats per minute. In atrial flutter, the atrioventricular node refractory periods may vary, occasionally allowing 1:1 conduction, but more typically allowing only every two or three atrial contractions to conduct to the ventricles (2:1 or 3:1 conduction, respectively). Flutter generally presents in a much more sustained fashion than does SVT, which commonly presents with intermittent runs of tachycardia interspersed with periods of sinus rhythm. Compared with SVT, atrial flutter has a higher association with structural heart disease, typically with dilation of one or both atria. Finally, although flutter may be successfully treated with maternally administered digoxin, recent reports suggest that sotalol may be an excellent second-line agent; in fact, some centers have chosen sotalol as their first-line agent for fetal atrial flutter.222 Ventricular Tachycardia. Ventricular tachycardia in the fetus, as in newborns and children, represents a commonly fatal arrhythmia when sustained. Possibly for this reason, fetal ventricular tachycardia is diagnosed far less often than fetal SVT. Fetal ventricular tachycardia generally presents with fetal rates between 180 and 300 beats per minute and poor ventricular function. Discrimination of ventricular from SVT can be challenging. When associated with structural heart disease, ventricular tachycardia carries a particularly poor prognosis. Fetal ventricular tachycardia has been associated with tumors (usually rhabdomyomas), structural heart disease (cardiomyopathy, severe right or left ventricular hypertrophy, or coronary abnormalities), prolonged QT syndrome,216 and fetal distress/acidosis. Treatment may be attempted with maternally administered sotalol, propranolol, flecainide, or amiodarone, but prognosis remains guarded despite treatment. Curr Probl Cardiol, August 2007

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TABLE 18. Cardiac lesions associated with systemic disorders Dextrocardia Mesocardia Secundum ASD Primum ASD Inlet VSD HLHS HCM Rhabdomyoma Aortic stenosis Pulmonary stenosis Tetralogy of Fallot Coarctation

Situs inversus totalis; Scimitar syndrome; Heterotaxy Scimitar syndrome Scimitar syndrome; Holt-Oram; TAPVR Trisomy 21 Trisomy 21, 18, 13 Jacobsen’s syndrome; Trisomy 18, 13 Noonan’s syndrome Tuberous sclerosis William’s syndrome; Turner’s syndrome Rubella; Noonan’s syndrome DiGeorge syndrome; Trisomy 21; maternal diabetes Turner’s syndrome; Noonan’s syndrome

Abbreviations: ASD, atrial septal defect; HCM, hypertrophic cardiomyopathy; HLHS, hypoplastic left heart syndrome; TAPVR, total anomalous pulmonary venous return; VSD, ventricular septal defect.

Lesions Associated with Systemic Disorders While newborn infants with CHD have a relatively high incidence of associated chromosomal abnormalities or syndromes, an even greater percentage of fetuses with heart disease have associated systemic disorders. Some forms of CHD carry particularly close associations with systemic disorders, while other forms of CHD do not. Thus, the finding of certain cardiac lesions should prompt further testing more so than the finding of other forms of CHD.128,129,154 Known or suspected associations should be discussed with the mother. Table 18 lists some of the more common forms of heart disease that carry particularly tight associations with systemic disorders. These associations, as well as associations between heart disease and structural abnormalities (Table 10), should be considered when evaluating the fetus with CHD, an extracardiac abnormality, or systemic disorder.

Diagnostic Challenges While some forms of CHD (such as hypoplastic left heart syndrome or TOF) may be readily diagnosed prenatally with a great deal of certainty (Fig 9), several common defects remain difficult if not impossible to diagnose reliably before birth. This section will discuss atrial septal defects, coarctation of the aorta, and anomalous pulmonary venous return. Secundum Atrial Septal Defect. A secundum atrial septal defect represents deficiency in the middle portion of the atrial septum, in the same location as the normal foramen ovale. In contrast, sinus venosus and ostium primum atrial septal defects may be relatively easy to discriminate from normal, with deficiencies in the most superior or inferior portions of 474

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FIG 9. Echocardiographic image of 23-week fetus with mitral atresia, ventricular septal defect, and hypoplastic left ventricle. Note contrast of this 2D image with rendered image obtained from the same fetus (Fig 8).

the atrial septum, respectively. The normal fetus has a right-to-left shunt across the foramen ovale throughout gestation. Differentiating a normal foramen ovale from a secundum atrial septal defect, while sometimes challenging postnatally, may be nearly impossible prenatally. The flap of the foramen oval becomes progressively more aneurysmal and deviated into the left atrium throughout the second and third trimesters. In some cases, the flap may appear more aneurysmal than normal for a certain gestational age, or the foramen itself may appear to occupy a greater proportion of the atrial septum than normal. Despite these observations, no convincing association has been demonstrated to date between an Curr Probl Cardiol, August 2007

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FIG 10. Echocardiographic image of 24-week fetus with coarctation (documented postnatally). Note right heart disproportion.

abnormal prenatal appearance of the foramen ovale and the presence postnatally of a secundum atrial septal defect. Nevertheless, when a foramen ovale does appear abnormal, particularly in association with other abnormalities (cardiac or otherwise), or a family history of an atrial septal defect, follow-up postnatally may be prudent. Coarctation of the Aorta. One of the most difficult diagnoses to make prenatally, coarctation of the aorta represents one of the most common cardiac lesions to present with a dilated right heart (“right heart disproportion”) (Fig 10). As the ductus arteriosus typically remains widely patent until sometime after birth, the aortic isthmus may appear relatively well developed even in the presence of coarctation. However, possibly because of redistribution of flow to the right heart, coarctation commonly presents with a relatively dilated right atrium, right ventricle, and pulmonary artery, as well as a relatively diminutive left atrium, mitral valve, left ventricle, aortic valve, and aortic arch. Left heart measure476

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TABLE 19. Interventions for fetal heart disease Pharmacologic SVT Atrial flutter Heart Block Dilated CM VT Percutaneous Tamponade Twin-twin AS/PS Restrictive ASD Surgical In development

Digoxin, propranolol, flecainide, sotalol Digoxin, sotalol Dexamethasone, theophylline Digoxin Propranolol, flecainide, amiodarone Pericardiocentesis Ablation of bridging vessels Balloon valvuloplasty Balloon septostomy

Abbreviations: AS, aortic stenosis; ASD, atrial septal defect; CM, cardiomyopathy; PS, pulmonary stenosis; SVT, supraventricular tachycardia; VT, ventricular tachycardia.

ments below the fifth percentile should raise the suspicion for coarctation of the aorta, as should the presence of aortic valve pathology or a persistent left-sided superior vena cava. Because coarctation of the aorta, when severe, represents a form of ductal-dependent CHD, detection prenatally may prevent the discharge home, prior to ductal constriction, of affected infants. Following ductal constriction, coarctation may become manifest with the development of cardiac shock and acidosis, raising the likelihood of perioperative morbidity and mortality. Total Anomalous Pulmonary Venous Return. Total anomalous pulmonary venous return represents a less common but similarly difficult to diagnose lesion that may present prenatally with right heart disproportion. As screening fetal cardiac imaging typically does not include color Doppler or 2D imaging of the pulmonary veins, right heart disproportion may be the only clue to the presence of total anomalous pulmonary venous return. With detailed scanning, pulmonary veins may be visualized entering the left atrium in normal hearts, and color flow can facilitate visualization of anomalous pulmonary venous return when the scale has been adjusted for low velocity flows. In normal hearts, the pericardial reflection and tissue infolding between the left pulmonary vein and left atrial appendage, typically seen extending into the left atrium from the lateral wall, can be a clue that at least one pulmonary vein drains to the left atrium. Not being able to demonstrate pulmonary venous return to the left atrium with detailed scanning should prompt a detailed search for pulmonary venous drainage either below the diaphragm, towards the innominate vein or superior vena cava, or into a dilated coronary sinus. Partial anomalous pulmonary venous return may be still more challenging Curr Probl Cardiol, August 2007

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to detect, but occasionally will present with mesocardia or dextrocardia in conjunction with right heart disproportion (Scimitar syndrome).

Interventions for Fetal Heart Disease A small but enlarging group of prenatally diagnosed cases of CHD may benefit from various prenatal interventions. This section discusses the currently available pharmacologic,214 percutaneous,137 and surgical138 treatment modalities for the fetus with CHD (Table 19); some of these treatment modalities have been discussed in earlier portions of this article as well. Pharmacologic therapy for various forms of fetal heart disease will be summarized here, although discussed thoroughly in previous portions of this article. Fetal tachyarrhythmias (supraventricular tachycardia, atrial flutter, and ventricular tachycardia) may be successfully managed with maternally administered antiarrhythmic agents, although rarely these agents may be administered directly into the umbilical vein. Fetal bradycardia related to progressive second-degree heart block, in the context of antibody-mediated damage to the atrioventricular node, may be successfully treated with dexamethasone. Agents such as theophylline appear to have only nonsustained effects on ventricular rate. Finally, cases of decreased ventricular systolic function may benefit from maternally administered digoxin. Further study of currently available antiarrhythmic agents, as well as the development of new agents, may be expected to expand the pharmacologic arsenal available to treat the fetus with many forms of CHD.222 Percutaneous approaches to the fetus with heart disease continue to evolve rapidly, as methods to prevent complications (mainly premature delivery) improve. Pericardiocentesis for tamponade, such as seen with intrapericardial teratoma, have been available for many years, with minimal morbidity.136 More recently, recipient and donor twins suffering from twin–twin transfusion syndrome may benefit from ablation of communicating vessels.223 Finally, most recently, great progress has been made with percutaneous dilation of isolated aortic or pulmonary valve stenosis, with the hope of preventing the development of left or right ventricular hypoplasia, respectively.137 These procedures remain experimental, and limited not only to centers with the necessary expertise, but also to a select group of second-trimester fetuses expected to benefit the most. Likewise, percutaneous atrial septostomy has been shown to benefit certain fetuses with restrictive atrial communications in the context of hypoplastic left heart syndrome.224 Further work towards identifying 478

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appropriate fetuses and decreasing procedural morbidity/mortality needs to be made before such procedures may become widely accepted. Surgical approaches to the fetus with heart disease remain even more experimental than percutaneous procedures.138-140 Exteriorization of the fetus carries real risks for infection and premature delivery. However, once the technique has been perfected, surgical reconstruction of various cardiac lesions, such as pulmonary atresia with intact ventricular septum, may significantly improve the outcome for fetuses with many forms of CHD. Further experience with animal models, as well as with limited uterine exteriorizations as currently performed in some cases of percutaneous fetal balloon valvuloplasties, will be needed prior to adding surgery to the armamentarium for treating the fetus with CHD.

Delivery Considerations Timing. Although most fetuses with CHD do best when delivered as close to term as possible, several forms of fetal heart disease may benefit from early delivery. For the most part, these cases deserve early delivery because of either a progressive fetal deterioration or a need for treatment with potentially ineffective or toxic agents. When a fetus has progressive heart failure or hydrops, despite therapy, delivery at 32 to 36 weeks may be preferable to delivery of a more mature but more fulminantly hydropic or moribund newborn. Such cases require discussions between the treating obstetrician/perinatologists, pediatric cardiologist, and neonatologist to determine optimal timing for delivery. The other set of fetuses that may benefit from early delivery include those who present at 34 to 47 weeks with a new onset or poorly controlled tachyarrhythmia felt to require treatment. In such cases, the risks and benefits of fetal therapy need to be balanced against the risks of early delivery. Similarly, fetuses who have been treated with digoxin and/or other agents for some time should be considered for early delivery when they reach 34 to 36 weeks, depending on the balance of risks between ongoing fetal treatment and early delivery. Patrick W. O’Leary: Once a cause for fetal heart failure is identified, the scoring system promoted by Dr. Huhta and summarized in ref. 211, not only provides a convenient method for detecting a prehydropic fetus, but also can be used for monitoring improvement or progression during observation or treatment.

Route of Delivery. Most fetuses with CHD may be delivered vaginally, as delivery via cesarean section has not been demonstrated, in general, to Curr Probl Cardiol, August 2007

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improve neonatal outcome, even in cases of severe disease. Some cases of CHD, however, may have improved outcomes with cesarean deliveries. First, the presence of fetal complete heart block limits the utility of heart rate monitoring during labor to monitor fetal well being, so affected fetuses may benefit from cesarean delivery. Second, fetuses with heart disease complicated by severe hydrops may benefit from cesarean section, like any fetus with macrosomia or cephalopelvic disproportion. Finally, fetuses may benefit from cesarean delivery when CHD is associated with other fetal or maternal consideration that might complicate vaginal delivery, such as a large fetal abdominal wall defect, breech presentation, multiple gestation, or placenta previa.

Impact of Prenatal Diagnosis of Fetal Heart Disease Despite first- or second-trimester detection and diagnosis of CHD, little can be done to affect the prenatal development of most forms of CHD. As described earlier in this review, some forms of bradyarrhythmias and tachyarrhythmias may be successfully treated pharmacologically; some forms of CHF may be treated pharmacologically or with percutaneous pericardiocentesis; some fetuses with a restrictive foramen ovale may benefit from percutaneous septostomy; and some forms of aortic or pulmonary valve stenosis may be dilated percutaneously to improve subsequent ventricular growth. Taken together, however, these prenatally treatable forms of CHD probably represent less than 5% of all forms of prenatally diagnosed CHD. Nevertheless, those newborns with severe forms of CHD are probably far more likely to avoid hemodynamic deterioration and cardiovascular collapse following delivery than are similarly affected newborns without a prenatal diagnosis.141-145 The benefits to early postnatal treatment, when combined with the emerging possibilities for pharmacologic, percutaneous, and even surgical fetal cardiac interventions, suggest that the prenatal diagnosis of fetal heart disease, already salvaging many fetuses who might otherwise not have survived to term, will have an increasingly beneficial impact on those fetuses who survive to term. In addition to advantages to the individual fetus, prenatal diagnosis allows for an increased understanding of the natural prenatal evolution of CHD. On the flip side, as some women with severely affected fetuses choose to terminate their pregnancies, the prenatal diagnosis of heart disease has also been shown to affect the neonatal incidence of certain forms of CHD.151-153 Thus, the prenatal diagnosis of CHD optimizes the condition 480

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in which affected newborns present for medical or surgical treatment and may ultimately decrease the incidence of severe forms of CHD among newborn infants. Patrick W. O’Leary: Due to the superior temporal resolution inherent in M-mode scanning, it is often a preferable modality for determining the relationship of atrial to ventricular activation in sustained fetal tachycardias. In hearts with dilated atria, such as the fetus with flutter and hydrops, there may not be much atrial flow generated by the rapid contractions, further limiting the ability of Doppler techniques in these situations.

At the same time, the prenatal diagnosis of CHD has an important psychological impact on pregnant women and their families.148 The finding of a normal fetal heart can be tremendously reassuring to a pregnant woman whose previous child was born with a severe form of CHD. In contrast, following the diagnosis of heart disease in their unborn children, pregnant women may deal with feelings of guilt, confusion, anxiety, or depression as they attempt to cope with the reality of carrying a baby with a heart defect. Such stresses may have an impact on the pregnancy itself.149,150 While the prenatal diagnosis of CHD allows women and their families a chance to prepare emotionally and intellectually for the birth of a child with CHD, the stresses introduced by prenatal diagnosis should be anticipated and recognized, and appropriate support should be provided. Despite these stresses, women who have had a child prenatally diagnosed with CHD overwhelmingly would opt for prenatal diagnosis had they to do it over again, or if they were to become pregnant again.148

Summary Fetal cardiology represents one of the most exciting and rapidly advancing fields within pediatric cardiology. Screening approaches have entered the first trimester with improvements in transducer image quality and the discovery of nuchal translucency as a marker for CHD. In the near future, 3D fetal cardiac imaging may improve both the detection and the diagnosis of fetal heart disease and provide more accurate and precise quantitative measurements. Treatment for fetal heart disease has progressed beyond pharmacologic therapy to percutaneous pericardiocentesis, ablation of communicating vessels in twin–twin transfusion syndrome, dilation of isolated valvar aortic or pulmonary stenosis, and enlargement of restrictive atrial communications in the setting of hypoCurr Probl Cardiol, August 2007

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plastic left heart syndrome. As might be expected, these improvements appear to have an increasingly favorable impact on the outcome of affected fetuses. The outlook for the fetus with heart disease has never been brighter, but there remains a need for plenty of continued improvement in the prenatal detection, diagnosis, and treatment of CHD. Patrick W. O’Leary: This is a comprehensive review that covers the major uses, utility, limitations, and frontiers/challenges of/in prenatal echocardiography. Fetuses with placental insufficiency, CHF, CHD, and arrhythmias can often benefit from appropriate application of the technology described in this article. However, since current screening practices tend to refer only the most severely affected fetuses for detailed evaluation, this creates an unavoidable selection bias in all outcome studies reported to date. Thus, it has been difficult to show a concrete impact of prenatal detection on mortality and ultimate outcome. The cited observations of reduced preoperative morbidities in selected reports give reason for optimism that the widely held belief that prenatal detection should improve outcome in CHD may indeed be correct. Further critical review of outcomes will be needed to provide the solid evidence to support this conclusion. Education of the primary screening medical professionals regarding early/reliable signs of ductal-dependent CHD must continue if the rate of prenatal detection is to continue to increase. This process should be made simpler in the future, as newer technologies, like real-time three-dimensional scanning, become more widely available and user friendly.

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