Acute Cardiac Care, June 2014; 16(2): 78–82 Copyright © 2014 Informa UK, Ltd ISSN 1748-2941 print/ISSN 1748-295X online DOI: 10.3109/17482941.2014.902469
ORIGINAL ARTICLE
A fatal case of peripartum cardiomyopathy Ronny Cohen1,2, Thierry Mallet4, Brooks Mirrer1,2, Pablo Loarte4, Michael Gale4 & Paul Kastell2,3 1Division
of Cardiology, Woodhull Medical Center, Brooklyn, NY. USA, 2NYU School of Medicine, New York, NY, USA, of OBGYN, Woodhull Medical Center, Brooklyn, NY, USA, 4Department of Medicine, Woodhull Medical Center, Brooklyn, NY, USA
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3Department
Peripartum cardiomyopathy is a life-threatening cardiac condition affecting pregnant women either late in pregnancy or early in the post-partum period. The latest studies show a dramatic improvement in the mortality rates of women affected with this disorder, which has been correlated with advances in medical therapy for heart failure. However, patients continue to die of this condition. The following case report describes a typical patient with peripartum cardiomyopathy diagnosed on clinical grounds, along with echocardiogram findings of severe systolic dysfunction and global hypokinesis consistent with dilated cardiomyopathy. Emergency cesarean delivery had to be performed for fetal distress. There was significant improvement of the patient's condition with standard pharmacological management for heart failure at the time of discharge. However, five weeks after discharge, fatal cardiac arrest occurred. It is hoped that this article will raise awareness about this rare but potentially fatal condition and promote understanding of its main clinical features, diagnostic criteria, and conventional pharmacological management.
Case presentation A 37 year-old African-American woman, G6P5A0, 27 weeks gestation, presented to the ER with sudden onset of severe shortness of breath while walking, forcing her to stop and rest. Bystanders called emergency medical services, and the patient was transported to the ER. The medical history was significant for hypertension for which she was taking alphamethyldopa 500 mg daily. The surgical history was significant for a previous cesarean section. She denied any history of tobacco, alcohol or recreational drug use. On presentation at the ED the patient was in acute respiratory distress, hypertensive, tachycardic, tachypneic, hypoxemic, and diaphoretic: blood pressure of 160/120 mm Hg; a heart rate of 106 beats/min; a respiratory rate of 30/min; oxygen saturation varying between 70 and 80% on room air. She was alert and oriented. The cardiovascular exam. revealed regular heart sounds with an S3 gallop and apical holosystolic murmur, grade 2/6. No JVD and no carotid bruit was noted. Auscultation of the lungs revealed bibasilar crackles. No pedal edema was noted. Abdominal exam. with sonogram revealed a single intrauterine pregnancy with breech presentation. Fetal bradycardia with marked deceleration (HR in the 70s) was also noted. Laboratory evaluation showed a BNP of 151 pg/ml (normal 100 pg/ml) and a mild elevation of troponin I of 0.17 ng/ml (normal 0.1 ng/ml). Basic chemistries were within normal limits. Urine drug screen was negative. The electrocardiogram showed sinus tachycardia with a rate of 120 bpm, LBBB (QRS duration 150) and a normal axis (Figure 1). Portable chest X-ray revealed a right lower lobe opacity with a magnified cardiac silhouette. Transthoracic echocardiogram revealed dilated left atrium and left ventricle, severe LV systolic dysfunction, EF 25%, Global hypokinesis, paradoxical septal wall motion, and moderate pulmonary hypertension. Left ventricular end diastolic dimension (LViSD) was 5.9 cm (Figure 2). Lower extremity duplex did not reveal any DVT and chest CT with IV contrast did not show any evidence of pulmonary embolism.
Keywords: Cardiomyopathy, mortality, risk factors
Case report: A fatal case of peripartum cardiomyopathy Peripartum cardiomyopathy (PPCM) is a rare life-threatening cardiomyopathy of unknown cause that occurs in the peripartum period in previously healthy women (1). Clinician familiarity with this entity increases the probability of prompt appropriate treatment, offering patients the best possible prognosis. The reported mortality rate of peripartum cardiomyopathy (PPCM) is high, although the potential for spontaneous recovery of ventricular function is well established (2). In the present review, a fatal case of peripartum cardiomyopathy is reported. The general clinical manifestations, diagnosis and management of the clinical entity will also be reviewed.
Correspondence: Ronny Cohen, Chief of Cardiology, Woodhull Medical Center/NYU School of Medicine, 760 Broadway, Suite 3B321, Brooklyn, NY 11206, USA. Fax: 1 (718) 963 7881. E-mail: [email protected] (Received 16 December 2013; accepted 16 February 2014)
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Peripartum cardiomyopathy
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Figure 1. EKG—LBBB.
The diagnosis of peripartum cardiomyopathy was made. The patient received furosemide, metoprolol, aspirin, clopidogrel and hydromorphone. OBGYN was consulted, emergency cesarean section under regional anesthesia was performed because of severe fetal distress. A live male neonate was delivered. The patient was then transferred to the intensive care unit for post-op. monitoring. There were no surgical complications and the post-operative period was uneventful. ACE inhibitors were added and the patient was counseled against subsequent pregnancies in view of the increased mortality risk imposed by prior PPCM. A nuclear stress test before discharge showed no ischemia. Of note, Cardiology was consulted and advised the ACE inhibitors to be stopped in case breastfeeding was considered by the patient. The patient was discharged home five days after admission with appointments for the medicine and cardiology clinics. Unfortunately, five weeks later, she was found unconscious and was brought to the ER after being intubated in the field. Cardiac arrest occurred and resuscitation was unsuccessful
Figure 2. Left ventricular internal systolic dimension (LViSD) 5.9 cm. © 2014 Informa UK, Ltd.
Discussion Peripartum cardiomyopathy is a pregnancy-associated myocardial disease characterized by the development of heart failure due to marked left ventricular systolic dysfunction. Diagnostic criteria for PPCM are (3): 1. Cardiac failure developing in the last month of pregnancy or within five months of delivery 2. No identifiable cause of the cardiac failure 3. No recognizable heart disease before the last month of pregnancy 4. An ejection fraction of less than 45%. In our case the timeframe of the presentation is not typical for PPCM since the presentation was early (27 weeks of gestation), however, the patient still meets the criteria for PPCM, as she became ill in the third trimester, eventually leading to her demise five weeks after delivery. The absence of LVH on the EKG and the echocardiogram support that her heart failure is much less likely to be due to hypertensive heart disease-related cardiomyopathy. The fact that she was taking a low-dose of alpha methyldopa (500 mg daily) suggests that she had gestational hypertension onset before 20 weeks of pregnancy, excluding pre-eclampsia and a severe pre-existing chronic hypertension as the cause of cardiac failure. It is quite possible that a pre-existing asymptomatic state of peripartum cardiomyopathy in this multiparous patient made her especially vulnerable during the final pregnancy. Incidence and predisposing factors The real incidence is not known. A number of recent studies have provided some information regarding the incidence of PPCM in the United States, ranging from 1 in 1149 to 1 in 4350 live births (4–8), with a mean of 1 in 3186 live births. Important predisposing factors for PPCM are older maternal age, history of hypertension, multiple pregnancies, and African American background (4). It has been classified
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in the past as a nongenetic form of dilated cardiomyopathy (9), though a number of studies have reported familial clustering (see below, Genetics). Pathogenesis Peripartum cardiomyopathy is generally considered a form of idiopathic primary myocardial disease associated with the pregnant state (12). Despite many attempts to uncover a distinct etiology, the cause still remains unsettled and is probably multifactorial. Some of the factors that may contribute are myocarditis, cardiotropic viral infections, chimerism, (an abnormal immune response to pregnancy), apoptosis, inflammation, and an abnormal response to increased hemodynamic burden of pregnancy (4,12). Other possible factors include the absence of cardiomyocyte signal transducer and activator of transcription 3 (STAT 3), resulting in the cleavage of prolactin (13)—a mechanism that may be supported by the favorable effect of bromocriptine in preliminary studies (14). Genetics Familial clustering of peripartum cardiomyopathy (PPCM) and familial occurrences of PPCM and idiopathic dilated cardiomyopathy (IDCM) together have been observed giving rise to an idea that genetic factors play a role in the pathogenesis of PPCM. IDCM, phenotypically similar to PPCM, is now thought to be familial (familial dilated cardiomyopathy, FDC) in 20–50% of reported cases. This suggests that certain genetic variants characteristic of IDCM may contribute to the pathogenesis of PPCM (9,10). According to Morales et al., and the genetic data collected in the FDC Research Project, 4 cases which were found to carry nonsynonymous mutations (each in a different gene), and exhibited familial inheritance, were found to have mutations in the following genes: MYH7 (encoding the key sarcomeric beta-myosin heavy chain protein), SCN5A, PSEN2, and MYBPC3. Two cases with sporadic disease showed mutations in MYH6 (encoding alpha myosin heavy chain) and TNNT2 (10,11). Van Spaendock-Zwarts et al., following the review of the FDC database of the University Medical Centre Groningen (Netherlands) cardiogenetics clinic, identified a nonsynonymous mutation (c.149A G, p.Gln50Arg) in the gene encoding cardiac troponin C (TNNC1) not present in 300 control alleles and believed to be pathogenic based on cosegregation with disease in a IDCM family with a member with PPCM (10). Clinical features Patients with PPCM usually present with typical signs and symptoms of left ventricular failure, including fatigue, dyspnea, orthopnea and pedal edema (15), which unfortunately may be confused with similar but benign complaints in normal late pregnancy. In addition, cough, atypical chest pain, and abdominal pain are frequently encountered during pregnancy and tend to confuse the initial clinical evaluation (15). Because of the low incidence of PPCM, there is a lower expectation of serious disease. Therefore, the diagnosis is
often missed or delayed, allowing the development of preventable complications (16,17). Physical examination often reveals tachycardia and tachypnea, blood pressure may be elevated or reduced. There is usually increased jugular venous pressure, displaced apical impulse, left ventricular heave, murmurs of mitral and tricuspid regurgitation, third heart sound, pulmonary rales, and peripheral edema (4). Diagnosis When a diagnosis of PPCM is suspected, every effort must be made to exclude pre-existing cardiac disease or other underlying disorders. A detailed history is the most important tool to distinguish a pre-existent cardiomyopathy from PPCM (18). The diagnosis of PPCM ultimately rests on the echocardiographic identification of new left ventricular systolic dysfunction during a limited period surrounding parturition. Electrocardiography usually shows sinus tachycardia with nonspecific ST-T wave changes. LV hypertrophy can be found as well as left atrial enlargement and, occasionally, conduction abnormalities including left bundle branch block (4,5). Chest radiography usually shows cardiomegaly and pulmonary venous congestion or pulmonary edema, with or without pleural effusion (4,5,19). Echocardiography shows variable degrees of LV dilatation, with moderate to severe depression of systolic function. Right ventricular and biatrial dilatation as well as moderate to severe mitral and tricuspid regurgitation are commonly seen, with increased pulmonary pressures (3–6,19,20). Cardiac magnetic resonance imaging (MRI) has been used in a limited number of patients for the assessment of cardiac function and the detection of mural thrombi or myocardial fibrosis (12,21). Although MRI is probably safe during pregnancy (22), intravenous gadolinium crosses the placenta, and the 2007 American College of Radiology document on safe MRI practices recommends that it be avoided during pregnancy and used only if absolutely essential (22). Brain natriuretic peptide (BNP) levels could also help in diagnosing PPCM, particularly early in the course of the disease, as the levels have been shown to be markedly elevated (4,23). Management Treatment of PPCM is rather similar to other types of congestive heart failure. However, concerns regarding the adverse effects of this therapy for the mother, fetus or breastfeeding infant may complicate the management of patients with PPCM (18). Conventional pharmacological therapy with diuretics, sodium restriction, β-blockers, digoxin and afterload reduction forms the cornerstone of therapy (24). Angiotensin-converting enzyme (ACE) inhibitors are absolutely contraindicated during the second and third trimester of the pregnancy because of the risk of kidney disturbances of the fetus and oligohydramnios. Use of ACE inhibitors in breastfeeding patients is also not recommended (18,24). During pregnancy, hydralazine may be used as a substitute for ACE inhibitors or ARBs (4). Acute Cardiac Care
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Peripartum cardiomyopathy Patients with severely depressed left ventricular function (ejection fraction 35%) may benefit from anticoagulation therapy (heparin before delivery, warfarin afterwards) to prevent thrombosis and cardio-emboli (1). Anticoagulation seems particularly important during the peripartum-period and the first six to eight weeks postpartum because of persistent hypercoagulable state (4). Because of a high prevalence of premature labor and a possible need for urgent delivery owing to maternal or fetal instability, the use of unfractionated heparin is preferred during the peripartum period because of its shorter half-life and reversible effect (4,25). For the postpartum patient, either heparin or warfarin may be used safely. Neither drug is secreted into breast milk; therefore, the infant is not at risk of an anticoagulated state (1,24,25). Experimental therapies with immunoglobulin, pentoxifylline and bromocriptine have been tried, but further studies are needed before any of them can be recommended for the treatment of PPCM (4). Patients with severe heart failure despite maximal drug therapy need cardiac transplantation to survive and to improve their quality of life. Ventricular assist devices are indicated as a bridge to transplantation (12,26). Patients with symptomatic ventricular arrhythmias or persistent severe LV systolic dysfunction should be considered for defibrillator implantation (12). Prognosis A number of studies have evaluated the outcome of women with PPCM (18). In approximately two thirds of the PPCM patients, later post-partum improvement of left ventricular function was seen on echocardiogram, and 45% of the patients returned to a near normal or normal ejection fraction (EF 50%) (27,28). In contrast, 10% of the patients required heart transplantation (26). Recent studies by Mielniczuk et al. and Brar et al. revealed mortality rates of 2.1% and 3.3% (7,8). This is substantially lower than the 32% sixmonth mortality reported by Sliwa et al. in their series from South Africa (29). The variability in mortality may be related to improvement in medical therapy for heart failure and the more liberal use of mechanical circulatory support (18). PPCM can be associated with important and lasting complications: In addition to severe congestive heart failure, cardiogenic shock, cardiopulmonary arrest secondary to HF or arrhythmias, and thromboembolic complications (4). Goland et al. (17) provided detailed information regarding mortality in 13 patients, most of whom died either suddenly (38%) or of progressive HF (45%) between the day of delivery and eight years postpartum. Whitehead et al. (30) reported on 17 cases of death due to PPCM between 1991 and 1997. Mortality increased with maternal age, in women with live birth order of 4, and in black women, who were 6.4 times more likely to die compared with whites. Eighteen percent of deaths occurred within one week and 87% within six months of diagnosis, and mortality was due either to progressive HF or to sudden cardiac death (4). Mortality was found by Goland et al. (17) to be higher in women with baseline LVEFs 25% as well as in women in whom the diagnosis of PPCM was delayed. © 2014 Informa UK, Ltd.
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Factors that indicate a poor prognosis in PPCM include a lower left ventricular ejection fraction at six months after delivery ( 30%), larger left ventricular end-diastolic dimension ( 6 cm), age over 30 years old, African American descent and multiparity (18,24). Alternatively, higher likelihood of recovery is associated with lack of troponin elevation, a lower level of plasma BNP, absence of LV thrombus, practice of breastfeeding, and diagnosis made after, rather than before, delivery (4,23,28,31,32). Subsequent pregnancies Subsequent pregnancies in patients with PPCM generally are associated with a worse maternal and fetal outcome. It is important to inform all PPCM patients of the high risk of recurrence of PPCM during or after a subsequent pregnancy, even if their heart function seems to have recovered completely (18). In the United States, Elkayam et al. identified 44 women with peripartum cardiomyopathy who became pregnant again. Of these, 28 had recovered systolic function, with ejection fractions of 50% or higher before becoming pregnant again, and 16 had not. The ejection fraction fell in both groups during the subsequent pregnancy, but in the first group it fell by more than 20% in only 6 (21%), and none died. In contrast, in the second group it fell by more than 20% in 5 (31%), and 3 (19%) died (12,33). Based on these data, some recommendations can be given for further pregnancies (12): 1. If left ventricular function has recovered fully, subsequent pregnancy is not absolutely contraindicated, but the patient should be told that, although the risk is lower, it is not absent. If subsequent pregnancy cannot be avoided, at the very least it should be managed in a high-risk perinatal center (1). 2. If left ventricular function has recovered partially, perform dobutamine stress echocardiography. If the left ventricular inotropic response to dobutamine is normal, then patients can be counseled as above; if the left ventricular inotropic response to dobutamine is abnormal, then the risk is moderate and pregnancy is not recommended. 3. If left ventricular function has not recovered at all, the risk is high, and subsequent pregnancy is not recommended.
Conclusion Peripartum cardiomyopathy is a serious condition affecting women in the last month of pregnancy or during the first five months after delivery. Its diagnosis requires a high degree of suspicion and should be made early, as the prognosis is much better when treatment is initiated early. However the mortality remains significant, and death occurs from progressive heart failure, thromboembolic events or sudden cardiac death. The importance of regular clinical follow-ups after the diagnosis should be stressed, to avoid catastrophic events. Patients should be fully aware that recommendations regarding subsequent
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pregnancies will depend upon their recovery after the episode of illness and the risk benefit ratio derived from the patient's wishes and her physician's clinical evaluation.
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Acknowledgements The authors thank Jay Jacobs for Echo illustration, Carla Morris for excellent typing and Chigozie Moronu, Agnieszka Buniowska, Kevin Tsai, for their contributions. This is an original manuscript of original research and discussion presented for review and possible publication for advancement of medical education. It has not been submitted to any other journal. There are no financial interests tied to this original research, neither is there any other outside support. The authors listed originally prepared all materials. The authors listed have contributed to, read and approved the manuscript. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
References 1. Pearson GD, Veille JC, Rahimtoola S, Hsia J, Oakley CM, Hosenpud JD, et al. Peripartum cardiomyopathy: National Heart, Lung, and Blood Institute and Office of Rare Diseases (National Institutes of Health) workshop recommendations and review. J Am Med Assoc. 2000;283:1183–8. 2. Felker GM, Jaeger CJ, Klodas E, Thiemann DR, Hare JM, Hruban RH, et al. Myocarditis and long-term survival in peripartum cardiomyopathy. Am Heart J. 2000;140:785–91. 3. Hibbard JU, Lindheimer M, Lang R. A modified definition for peripartum cardiomyopathy and prognosis based on echocardiography. Obstet Gyneco. 1999;94:311–6. 4. Elkayam U. Clinical characteristics of peripartum cardiomyopathy in the United States: Diagnosis, prognosis, and management. J Am Coll Cardiol. 2011;58:659–70. 5. Witlin AG, Mabie WC, Sibai BM. Peripartum cardiomyopathy: An omnious diagnosis. Am J Obstet Gynecol. 1997;176: 182–8. 6. Chapa JB, Heiberger HB, Weinert L, DeCara J, Lang R, Hibbard JU. Prognostic value of echocardiography in peripartum cardiomyopathy. Obstet Gynecol. 2005;105:1303–8. 7. Mielniczuk LM, Williams K, Davis DR, Tang AS, Lemery R, Green MS, et al. Frequency of peripartum cardiomyopathy. Am J Cardiol. 2006;97:1765–8. 8. Brar SS, Khan SS, Sandhu GK, Jorgensen MB, Parikh N, Hsu JW, et al. Incidence, mortality, and racial differences in peripartum cardiomyopathy. Am J Cardiol. 2007;100:302–4. 9. van Spaendonck-Zwarts KY, van Tintelen JP, van Veldhuisen DJ, van der Werf R, Jongbloed JD, Paulus WJ, et al. Peripartum cardiomyopathy as a part of familial dilated cardiomyopathy. Circulation 2010;121:2169–75. 10. Anderson JL, Horne BD. Birthing the genetics of peripartum cardiomyopathy. Circulation 2010;121:2157–9. 11. Morales A, Painter T, Li R, Siegfried JD, Li D, Norton N, et al. Rare variant mutations in pregnancy-associated or peripartum cardiomyopathy. Circulation 2010;121:2176–82. 12. Ramaraj R, Sorrell VL. Peripartum cardiomyopathy: Causes, diagnosis and treatment. Cleve Clin J Med. 2009;76:289–96. 13. Hilfiker-Kleiner D, Kaminski K, Podewski E, Bonda T, Schaefer A, Sliwa K, et al. A cathepsin D-cleaved 16 kDa form of prolactin mediates postpartum cardiomyopathy. Cell 2007;128:589–600.
14. Sliwa K, Blauwet L, Tibazarwa K, Libhaber E, Smedema JP, Becker A, et al. Evaluation of bromocriptine in the treatment of acute severe peripartum cardiomyopathy: A proof of concept pilot study. Circulation 2010;121:1465–73. 15. Lang RM, Lampert MB, Poppas A, Hameed A, Elkayam U. Peripartal cardiomyopathy. In: Elkayam U, Gleicher N, editors. Cardiac problems in pregnancy. 3rd edition. New York, NY: Wiley-Liss; 1998. pp. 87–100. 16. Groesdonk HV, Dinse-Lambracht A, Doblanzki W, Doblanzki U, Galm C, Muth C-M. Unrecognized peripartum cardiomyopathy, case series and comprehensive review of literature. Appl Cardiopulm Pathophysiol. 2009;13:237–42. 17. Goland S, Modi K, Bitar F, Janmohamed M, Mirocha JM, Czer LS. Clinical profile and predictors of complications in peripartum cardiomyopathy. J Card Fail. 2009;15:645–50. 18. Lok SI, Kirkels JH, Klöpping C, Doevendans PAF, de Jonge N. Peripartum cardiomyopathy: The need for a national database. Neth Heart J. 2011;19:126–33. 19. Witlin AG, Mabie WC, Sibai BM. Peripartum cardiomyopathy: A longitudinal echocardiographic study. Am J Obstet Gynecol. 1997;177:1129–32. 20. Elkayam U, Akhter MW, Singh H, Khan S, Bitar F, Hameed A, et al. Pregnancy-associated cardiomyopathy: Clinical characteristics and a comparison between early and late presentation. Circulation 2005;11:2050–5. 21. Kawano H, Tsuneto A, Koide Y, Tasaki H, Sueyoshi E, Sakamoto I, et al. Magnetic resonance imaging in a patient with peripartum cardiomyopathy. Intern Med 2008;47: 97–102. 22. Webb JA, Thomsen HS, Morcos SK. The use of iodinated and gadolinium contrast media during pregnancy and lactation. Eur Radiol. 2005;15:1234–40. 23. Forster O, Hilfiker-Kleiner D, Ansari AA, Sundstrom JB, Libhaber E, Tshani W, et al. Reversal of IFN-gamma, oxLDL and prolactin serum levels correlate with clinical improvement in patients with peripartum cardiomyopathy. Eur J Heart Fail. 2008;10:861–8. 24. Murali S, Marie M, Baldisseri M. Peripartum cardiomyopathy. Crit Care Med. 2005;33:340–6. 25. Briggs GG, Freeman RK, Yatte SJ. Drugs in pregnancy and lactation. 8th edition Philadelphia, PA: Wolters Kluwer; 2008. 26. Rose EA, Gelijns AC, Moskowitz AJ, Heitjan DF, Stevenson LW, Dembitsky W, et al. Randomized evaluation of mechanical assistance for the treatment of congestive heart failure (REMATCH) study group. Long-term mechanical left ventricular assistance for end-stage heart failure. N Engl J Med. 2001;345:1435–43. 27. Bültmann BD, Klingel K, Näbauer M, Wallwiener D, Kandolf R. High prevalence of viral genomes and inflammation in peripartum cardiomyopathy. Am J Obstet Gynecol. 2005;193:363–5. 28. Amos AM, Jaber W, Russell SD. Improved outcome in peripartum cardiomyopathy with contemporary. Am Heart J. 2006;152: 509–513. 29. Sliwa K, Skudicky D, Bergemann A, Candy G, Puren A, Sareli P. Peripartum cardiomyopathy: Analysis of clinical outcome, left ventricular function, plasma levels of cytokines and Fas/APO-1. J Am CollCardiol. 2000;35:701–5. 30. Whitehead SJ, Berg CJ, Chang J. Pregnancy-related mortality due to cardiomyopathy: United States, 1991–1997. Obstet Gynecol. 2003;102:1326–31. 31. Hu CL, Li YB, Zou YG, Zhang JM, Chen JB, Liu J, et al. Troponin T measurement can predict persistent left ventricular dysfunction in peripartum cardiomyopathy. Heart 2007;93:488–90. 32. Safirstein JG, Ro AS, Grandhi S, Wang L, Fett JD, Staniloae C. Predictors of left ventricular recovery in a cohort of peripartum cardiomyopathy patients recruited via the internet. Int J Cardiol. 2012;154:27–31. 33. Elkayam U, Tummala PP, Rao K, Akhter MW, Karaalp IS, Wani OR, et al. Maternal and fetal outcomes of subsequent pregnancies in women with peripartum cardiomyopathy N Engl J Med. 2001;344:1567–71 Erratum: N Engl J Med. 2001;345: 552. Acute Cardiac Care
ORIGINAL ARTICLE
A fatal case of peripartum cardiomyopathy Ronny Cohen1,2, Thierry Mallet4, Brooks Mirrer1,2, Pablo Loarte4, Michael Gale4 & Paul Kastell2,3 1Division
of Cardiology, Woodhull Medical Center, Brooklyn, NY. USA, 2NYU School of Medicine, New York, NY, USA, of OBGYN, Woodhull Medical Center, Brooklyn, NY, USA, 4Department of Medicine, Woodhull Medical Center, Brooklyn, NY, USA
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3Department
Peripartum cardiomyopathy is a life-threatening cardiac condition affecting pregnant women either late in pregnancy or early in the post-partum period. The latest studies show a dramatic improvement in the mortality rates of women affected with this disorder, which has been correlated with advances in medical therapy for heart failure. However, patients continue to die of this condition. The following case report describes a typical patient with peripartum cardiomyopathy diagnosed on clinical grounds, along with echocardiogram findings of severe systolic dysfunction and global hypokinesis consistent with dilated cardiomyopathy. Emergency cesarean delivery had to be performed for fetal distress. There was significant improvement of the patient's condition with standard pharmacological management for heart failure at the time of discharge. However, five weeks after discharge, fatal cardiac arrest occurred. It is hoped that this article will raise awareness about this rare but potentially fatal condition and promote understanding of its main clinical features, diagnostic criteria, and conventional pharmacological management.
Case presentation A 37 year-old African-American woman, G6P5A0, 27 weeks gestation, presented to the ER with sudden onset of severe shortness of breath while walking, forcing her to stop and rest. Bystanders called emergency medical services, and the patient was transported to the ER. The medical history was significant for hypertension for which she was taking alphamethyldopa 500 mg daily. The surgical history was significant for a previous cesarean section. She denied any history of tobacco, alcohol or recreational drug use. On presentation at the ED the patient was in acute respiratory distress, hypertensive, tachycardic, tachypneic, hypoxemic, and diaphoretic: blood pressure of 160/120 mm Hg; a heart rate of 106 beats/min; a respiratory rate of 30/min; oxygen saturation varying between 70 and 80% on room air. She was alert and oriented. The cardiovascular exam. revealed regular heart sounds with an S3 gallop and apical holosystolic murmur, grade 2/6. No JVD and no carotid bruit was noted. Auscultation of the lungs revealed bibasilar crackles. No pedal edema was noted. Abdominal exam. with sonogram revealed a single intrauterine pregnancy with breech presentation. Fetal bradycardia with marked deceleration (HR in the 70s) was also noted. Laboratory evaluation showed a BNP of 151 pg/ml (normal 100 pg/ml) and a mild elevation of troponin I of 0.17 ng/ml (normal 0.1 ng/ml). Basic chemistries were within normal limits. Urine drug screen was negative. The electrocardiogram showed sinus tachycardia with a rate of 120 bpm, LBBB (QRS duration 150) and a normal axis (Figure 1). Portable chest X-ray revealed a right lower lobe opacity with a magnified cardiac silhouette. Transthoracic echocardiogram revealed dilated left atrium and left ventricle, severe LV systolic dysfunction, EF 25%, Global hypokinesis, paradoxical septal wall motion, and moderate pulmonary hypertension. Left ventricular end diastolic dimension (LViSD) was 5.9 cm (Figure 2). Lower extremity duplex did not reveal any DVT and chest CT with IV contrast did not show any evidence of pulmonary embolism.
Keywords: Cardiomyopathy, mortality, risk factors
Case report: A fatal case of peripartum cardiomyopathy Peripartum cardiomyopathy (PPCM) is a rare life-threatening cardiomyopathy of unknown cause that occurs in the peripartum period in previously healthy women (1). Clinician familiarity with this entity increases the probability of prompt appropriate treatment, offering patients the best possible prognosis. The reported mortality rate of peripartum cardiomyopathy (PPCM) is high, although the potential for spontaneous recovery of ventricular function is well established (2). In the present review, a fatal case of peripartum cardiomyopathy is reported. The general clinical manifestations, diagnosis and management of the clinical entity will also be reviewed.
Correspondence: Ronny Cohen, Chief of Cardiology, Woodhull Medical Center/NYU School of Medicine, 760 Broadway, Suite 3B321, Brooklyn, NY 11206, USA. Fax: 1 (718) 963 7881. E-mail: [email protected] (Received 16 December 2013; accepted 16 February 2014)
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Peripartum cardiomyopathy
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Figure 1. EKG—LBBB.
The diagnosis of peripartum cardiomyopathy was made. The patient received furosemide, metoprolol, aspirin, clopidogrel and hydromorphone. OBGYN was consulted, emergency cesarean section under regional anesthesia was performed because of severe fetal distress. A live male neonate was delivered. The patient was then transferred to the intensive care unit for post-op. monitoring. There were no surgical complications and the post-operative period was uneventful. ACE inhibitors were added and the patient was counseled against subsequent pregnancies in view of the increased mortality risk imposed by prior PPCM. A nuclear stress test before discharge showed no ischemia. Of note, Cardiology was consulted and advised the ACE inhibitors to be stopped in case breastfeeding was considered by the patient. The patient was discharged home five days after admission with appointments for the medicine and cardiology clinics. Unfortunately, five weeks later, she was found unconscious and was brought to the ER after being intubated in the field. Cardiac arrest occurred and resuscitation was unsuccessful
Figure 2. Left ventricular internal systolic dimension (LViSD) 5.9 cm. © 2014 Informa UK, Ltd.
Discussion Peripartum cardiomyopathy is a pregnancy-associated myocardial disease characterized by the development of heart failure due to marked left ventricular systolic dysfunction. Diagnostic criteria for PPCM are (3): 1. Cardiac failure developing in the last month of pregnancy or within five months of delivery 2. No identifiable cause of the cardiac failure 3. No recognizable heart disease before the last month of pregnancy 4. An ejection fraction of less than 45%. In our case the timeframe of the presentation is not typical for PPCM since the presentation was early (27 weeks of gestation), however, the patient still meets the criteria for PPCM, as she became ill in the third trimester, eventually leading to her demise five weeks after delivery. The absence of LVH on the EKG and the echocardiogram support that her heart failure is much less likely to be due to hypertensive heart disease-related cardiomyopathy. The fact that she was taking a low-dose of alpha methyldopa (500 mg daily) suggests that she had gestational hypertension onset before 20 weeks of pregnancy, excluding pre-eclampsia and a severe pre-existing chronic hypertension as the cause of cardiac failure. It is quite possible that a pre-existing asymptomatic state of peripartum cardiomyopathy in this multiparous patient made her especially vulnerable during the final pregnancy. Incidence and predisposing factors The real incidence is not known. A number of recent studies have provided some information regarding the incidence of PPCM in the United States, ranging from 1 in 1149 to 1 in 4350 live births (4–8), with a mean of 1 in 3186 live births. Important predisposing factors for PPCM are older maternal age, history of hypertension, multiple pregnancies, and African American background (4). It has been classified
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in the past as a nongenetic form of dilated cardiomyopathy (9), though a number of studies have reported familial clustering (see below, Genetics). Pathogenesis Peripartum cardiomyopathy is generally considered a form of idiopathic primary myocardial disease associated with the pregnant state (12). Despite many attempts to uncover a distinct etiology, the cause still remains unsettled and is probably multifactorial. Some of the factors that may contribute are myocarditis, cardiotropic viral infections, chimerism, (an abnormal immune response to pregnancy), apoptosis, inflammation, and an abnormal response to increased hemodynamic burden of pregnancy (4,12). Other possible factors include the absence of cardiomyocyte signal transducer and activator of transcription 3 (STAT 3), resulting in the cleavage of prolactin (13)—a mechanism that may be supported by the favorable effect of bromocriptine in preliminary studies (14). Genetics Familial clustering of peripartum cardiomyopathy (PPCM) and familial occurrences of PPCM and idiopathic dilated cardiomyopathy (IDCM) together have been observed giving rise to an idea that genetic factors play a role in the pathogenesis of PPCM. IDCM, phenotypically similar to PPCM, is now thought to be familial (familial dilated cardiomyopathy, FDC) in 20–50% of reported cases. This suggests that certain genetic variants characteristic of IDCM may contribute to the pathogenesis of PPCM (9,10). According to Morales et al., and the genetic data collected in the FDC Research Project, 4 cases which were found to carry nonsynonymous mutations (each in a different gene), and exhibited familial inheritance, were found to have mutations in the following genes: MYH7 (encoding the key sarcomeric beta-myosin heavy chain protein), SCN5A, PSEN2, and MYBPC3. Two cases with sporadic disease showed mutations in MYH6 (encoding alpha myosin heavy chain) and TNNT2 (10,11). Van Spaendock-Zwarts et al., following the review of the FDC database of the University Medical Centre Groningen (Netherlands) cardiogenetics clinic, identified a nonsynonymous mutation (c.149A G, p.Gln50Arg) in the gene encoding cardiac troponin C (TNNC1) not present in 300 control alleles and believed to be pathogenic based on cosegregation with disease in a IDCM family with a member with PPCM (10). Clinical features Patients with PPCM usually present with typical signs and symptoms of left ventricular failure, including fatigue, dyspnea, orthopnea and pedal edema (15), which unfortunately may be confused with similar but benign complaints in normal late pregnancy. In addition, cough, atypical chest pain, and abdominal pain are frequently encountered during pregnancy and tend to confuse the initial clinical evaluation (15). Because of the low incidence of PPCM, there is a lower expectation of serious disease. Therefore, the diagnosis is
often missed or delayed, allowing the development of preventable complications (16,17). Physical examination often reveals tachycardia and tachypnea, blood pressure may be elevated or reduced. There is usually increased jugular venous pressure, displaced apical impulse, left ventricular heave, murmurs of mitral and tricuspid regurgitation, third heart sound, pulmonary rales, and peripheral edema (4). Diagnosis When a diagnosis of PPCM is suspected, every effort must be made to exclude pre-existing cardiac disease or other underlying disorders. A detailed history is the most important tool to distinguish a pre-existent cardiomyopathy from PPCM (18). The diagnosis of PPCM ultimately rests on the echocardiographic identification of new left ventricular systolic dysfunction during a limited period surrounding parturition. Electrocardiography usually shows sinus tachycardia with nonspecific ST-T wave changes. LV hypertrophy can be found as well as left atrial enlargement and, occasionally, conduction abnormalities including left bundle branch block (4,5). Chest radiography usually shows cardiomegaly and pulmonary venous congestion or pulmonary edema, with or without pleural effusion (4,5,19). Echocardiography shows variable degrees of LV dilatation, with moderate to severe depression of systolic function. Right ventricular and biatrial dilatation as well as moderate to severe mitral and tricuspid regurgitation are commonly seen, with increased pulmonary pressures (3–6,19,20). Cardiac magnetic resonance imaging (MRI) has been used in a limited number of patients for the assessment of cardiac function and the detection of mural thrombi or myocardial fibrosis (12,21). Although MRI is probably safe during pregnancy (22), intravenous gadolinium crosses the placenta, and the 2007 American College of Radiology document on safe MRI practices recommends that it be avoided during pregnancy and used only if absolutely essential (22). Brain natriuretic peptide (BNP) levels could also help in diagnosing PPCM, particularly early in the course of the disease, as the levels have been shown to be markedly elevated (4,23). Management Treatment of PPCM is rather similar to other types of congestive heart failure. However, concerns regarding the adverse effects of this therapy for the mother, fetus or breastfeeding infant may complicate the management of patients with PPCM (18). Conventional pharmacological therapy with diuretics, sodium restriction, β-blockers, digoxin and afterload reduction forms the cornerstone of therapy (24). Angiotensin-converting enzyme (ACE) inhibitors are absolutely contraindicated during the second and third trimester of the pregnancy because of the risk of kidney disturbances of the fetus and oligohydramnios. Use of ACE inhibitors in breastfeeding patients is also not recommended (18,24). During pregnancy, hydralazine may be used as a substitute for ACE inhibitors or ARBs (4). Acute Cardiac Care
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Peripartum cardiomyopathy Patients with severely depressed left ventricular function (ejection fraction 35%) may benefit from anticoagulation therapy (heparin before delivery, warfarin afterwards) to prevent thrombosis and cardio-emboli (1). Anticoagulation seems particularly important during the peripartum-period and the first six to eight weeks postpartum because of persistent hypercoagulable state (4). Because of a high prevalence of premature labor and a possible need for urgent delivery owing to maternal or fetal instability, the use of unfractionated heparin is preferred during the peripartum period because of its shorter half-life and reversible effect (4,25). For the postpartum patient, either heparin or warfarin may be used safely. Neither drug is secreted into breast milk; therefore, the infant is not at risk of an anticoagulated state (1,24,25). Experimental therapies with immunoglobulin, pentoxifylline and bromocriptine have been tried, but further studies are needed before any of them can be recommended for the treatment of PPCM (4). Patients with severe heart failure despite maximal drug therapy need cardiac transplantation to survive and to improve their quality of life. Ventricular assist devices are indicated as a bridge to transplantation (12,26). Patients with symptomatic ventricular arrhythmias or persistent severe LV systolic dysfunction should be considered for defibrillator implantation (12). Prognosis A number of studies have evaluated the outcome of women with PPCM (18). In approximately two thirds of the PPCM patients, later post-partum improvement of left ventricular function was seen on echocardiogram, and 45% of the patients returned to a near normal or normal ejection fraction (EF 50%) (27,28). In contrast, 10% of the patients required heart transplantation (26). Recent studies by Mielniczuk et al. and Brar et al. revealed mortality rates of 2.1% and 3.3% (7,8). This is substantially lower than the 32% sixmonth mortality reported by Sliwa et al. in their series from South Africa (29). The variability in mortality may be related to improvement in medical therapy for heart failure and the more liberal use of mechanical circulatory support (18). PPCM can be associated with important and lasting complications: In addition to severe congestive heart failure, cardiogenic shock, cardiopulmonary arrest secondary to HF or arrhythmias, and thromboembolic complications (4). Goland et al. (17) provided detailed information regarding mortality in 13 patients, most of whom died either suddenly (38%) or of progressive HF (45%) between the day of delivery and eight years postpartum. Whitehead et al. (30) reported on 17 cases of death due to PPCM between 1991 and 1997. Mortality increased with maternal age, in women with live birth order of 4, and in black women, who were 6.4 times more likely to die compared with whites. Eighteen percent of deaths occurred within one week and 87% within six months of diagnosis, and mortality was due either to progressive HF or to sudden cardiac death (4). Mortality was found by Goland et al. (17) to be higher in women with baseline LVEFs 25% as well as in women in whom the diagnosis of PPCM was delayed. © 2014 Informa UK, Ltd.
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Factors that indicate a poor prognosis in PPCM include a lower left ventricular ejection fraction at six months after delivery ( 30%), larger left ventricular end-diastolic dimension ( 6 cm), age over 30 years old, African American descent and multiparity (18,24). Alternatively, higher likelihood of recovery is associated with lack of troponin elevation, a lower level of plasma BNP, absence of LV thrombus, practice of breastfeeding, and diagnosis made after, rather than before, delivery (4,23,28,31,32). Subsequent pregnancies Subsequent pregnancies in patients with PPCM generally are associated with a worse maternal and fetal outcome. It is important to inform all PPCM patients of the high risk of recurrence of PPCM during or after a subsequent pregnancy, even if their heart function seems to have recovered completely (18). In the United States, Elkayam et al. identified 44 women with peripartum cardiomyopathy who became pregnant again. Of these, 28 had recovered systolic function, with ejection fractions of 50% or higher before becoming pregnant again, and 16 had not. The ejection fraction fell in both groups during the subsequent pregnancy, but in the first group it fell by more than 20% in only 6 (21%), and none died. In contrast, in the second group it fell by more than 20% in 5 (31%), and 3 (19%) died (12,33). Based on these data, some recommendations can be given for further pregnancies (12): 1. If left ventricular function has recovered fully, subsequent pregnancy is not absolutely contraindicated, but the patient should be told that, although the risk is lower, it is not absent. If subsequent pregnancy cannot be avoided, at the very least it should be managed in a high-risk perinatal center (1). 2. If left ventricular function has recovered partially, perform dobutamine stress echocardiography. If the left ventricular inotropic response to dobutamine is normal, then patients can be counseled as above; if the left ventricular inotropic response to dobutamine is abnormal, then the risk is moderate and pregnancy is not recommended. 3. If left ventricular function has not recovered at all, the risk is high, and subsequent pregnancy is not recommended.
Conclusion Peripartum cardiomyopathy is a serious condition affecting women in the last month of pregnancy or during the first five months after delivery. Its diagnosis requires a high degree of suspicion and should be made early, as the prognosis is much better when treatment is initiated early. However the mortality remains significant, and death occurs from progressive heart failure, thromboembolic events or sudden cardiac death. The importance of regular clinical follow-ups after the diagnosis should be stressed, to avoid catastrophic events. Patients should be fully aware that recommendations regarding subsequent
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pregnancies will depend upon their recovery after the episode of illness and the risk benefit ratio derived from the patient's wishes and her physician's clinical evaluation.
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Acknowledgements The authors thank Jay Jacobs for Echo illustration, Carla Morris for excellent typing and Chigozie Moronu, Agnieszka Buniowska, Kevin Tsai, for their contributions. This is an original manuscript of original research and discussion presented for review and possible publication for advancement of medical education. It has not been submitted to any other journal. There are no financial interests tied to this original research, neither is there any other outside support. The authors listed originally prepared all materials. The authors listed have contributed to, read and approved the manuscript. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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