Hôpital Albert Schweitzer, Deschapelles, Haiti
Email: jdftlsc{at}techline.com
Sir,
The purpose of this letter is to alert those involved in assisted reproductive technology to consider the possibility that a precipitating factor for PPCM could be transferred, and to encourage further investigation of potential antigens, both infectious and non-infectious, that may initiate PPCM.
The case is described as follows: a surrogate mother was diagnosed with PPCM at term pregnancy. The embryo was received from the commissioning couple for whom the mother was diagnosed with PPCM following the delivery of her first child 5 years previously.
Prior to her surrogate pregnancy, K.L., aged 34 years, had three previous pregnancies, children aged 9, 5 and 2 years. She underwent IVF in July 2003, with two fertilized embryos resulting from oocytes and sperm harvested from the commissioning couple. She had an uneventful pregnancy until the onset of respiratory symptoms, in her 32nd week of pregnancy (NYHA Functional Class II). Diagnostic testing included an echocardiogram which showed left ventricular end-diastolic diameter (LVEDD) of 2.91 cm/m2 body surface area (normal <2.7 cm/m2) and mild global left ventricular dysfunction with ejection fraction (LVEF) of 0.400.45 (normal >0.50). No other causes for heart failure (HF) could be identified. With a diagnosis of stabilized PPCM, she underwent Caesarean section, with the delivery of healthy twins, a female weighing 5 pounds 1 ounce, and a male weighing 3 pounds 7 ounces. Her subsequent recovery was uneventful. Treatment for her PPCM included carvedilol, lisinopril, and enoxaparin (low molecular weight heparin). Six weeks postpartum her echocardiogram showed improved left ventricular systolic function, with an LVEDD of 2.63 cm/m2 and an LVEF of 0.55. Medications were subsequently phased out, but an echocardiogram done 1 year following diagnosis showed an LVEF of 0.45, and treatment with carvedilol and lisinopril was restarted.
The commissioning/biological mother had one previous pregnancy, with vaginal delivery of a healthy female, weight 11 pounds 6 ounces, in 1998. Investigation of mild clinical symptoms of palpitations (NYHA Functional Class II) included echocardiography, leading to a presumptive diagnosis of PPCM 6 weeks postpartum. At diagnosis, LVEF was 0.400.45. Five years later, at the time of embryo harvest for use in IVF, she continued to receive treatment with carvedilol. Left ventricular EF 6 years following diagnosis and 1 year following embryo harvest remained at 0.400.45. The two mothers are unrelated, and neither has any family history of cardiomyopathies or any previous history of heart disease.
Peripartum cardiomyopathy is a devastating disease whose aetiology is largely unknown. Diagnostic criteria require the onset of heart failure (HF) in the period 1 month prior to delivery to 5 months postpartum in a previously healthy mother for whom no other cause of HF can be determined (Pearson et al., 2000).
In the USA, mothers reported herein the presence of PPCM in both the surrogate and biological mother, strongly suggesting a causal link rather than a purely chance phenomenon. Leading suspects are transmissible agents, both infectious and non-infectious as well as genetic susceptibility factors. In humans, there is abundant evidence linking viral myocarditis to dilated cardiomyopathy and heart failure (Mason, 2003; Pauschinger et al., 2004
). In addition, transfer of virus (Takata et al., 2004
), cardiac proteins (Li et al., 2004
), anti-cardiac protein lymphocytes (George et al., 2004
), and cardiac-sensitized antigen- presenting dendritic cells (Eriksson et al., 2003
) have all been shown in experimental animals to be capable of causing a myocarditis which may subsequently lead to dilated cardiomyopathy and HF.
The PPCM Research Project has previously reported a very high incidence of this rare disease in rural Haiti (Fett et al., 2002a, b
, 2003
, 2004
). In the Hospital Albert Schweitzer (HAS) District of Haiti, PPCM occurs with an incidence of one case per 300 live births, which is
10 times that of the estimated incidence in the USA. The finding of a lymphocytic myocarditis in some Haitian PPCM patients suggests a possible viral infection as an initiating antigen, although non-viral antigens ultimately leading to an autoimmune myocarditis could also give a similar histological picture. Ongoing investigations include the search for antigens that may initiate an inflammatory (lymphocytic myocarditis) or non-inflammatory cardiomyopathy and subsequent dilated cardiomyopathy.
An hereditary predisposition is also suggested by familial reports of PPCM and by the Haitian series with PPCM in a motherdaughter pair as well as in a sistersister pair (Fett et al., 2002c). Both environmental and genetic factors could be playing a role. Although there are no major histocompatibility patterns known or studied for PPCM, there are reports of increased HLA-antigen patterns associated with idiopathic dilated cardiomyopathy (McKenna et al., 1997
; Murphy, 2003
; Taylor et al., 2004
).
In monitoring assisted reproductive treatment, the Centers for Disease Control and Prevention (2001) reported a total of 29 344 live-birth deliveries and 40 687 infants resulting from 107 587 assisted reproduction procedures in the USA and US territories in 2001. Of those procedures, 8592 (8%) used freshly fertilized embryos from donor oocytes, similar to the procedure used in this case report. Outcome analysis by CDC includes pregnancy success per transfer procedure, number of live births, number of singleton births, and number of multiple-birth deliveries.
There are no reports in the medical literature of the development of PPCM in a surrogate mother. An Internet PPCM support group (http://www.ppcmsupport.org and http://www.amothersheart.net) carries an entry from a 27 year old gravida 3, para 4 surrogate mother who was diagnosed with PPCM 2 weeks following the delivery of twins. The biological mother did not have a history of PPCM.
I conclude by raising the question: could a cardiomyopathy-precipitating antigen be transmitted during the process of harvesting embryos and subsequent IVF? Because of the increasing use of assisted reproduction technologies, it is very important to continue research efforts to better understand potential risks for the sake of both maternal and child health. Continuing investigation of these cases may also help to better understand the pathogenesis of human PPCM.
Acknowledgements
We offer profound thanks to Ms Krista Loveless who seeks to advance knowledge and awareness of PPCM as well as to promote the safety of assisted reproduction technologies. She contacted me through www.ppcmsupport.org (http://www.ppcmsupport.org and http://www.amothersheart.net), provided clinical information, and encouraged sharing her story.
References
Centers for Disease Control and Prevention (2004) Assisted Reproductive Technology SurveillanceUnited States. Morbility and Mortality Weekly Report 53(SS-1), 120.
Eriksson U, Kurrer MO, Sonderegger I, Iezzi G, Tafuri A, Hunziker L, Suzuki S, Bachmaier K, Bingisser Rm, Penninger JM and Kopf M (2003) Activation of dendritic cells through the interleukin-1 receptor is critical for the induction of autoimmune myocarditis. J Exp Med 197, 323331.
Fett JD, Dowell DE, Carraway RD, King ME and Pierre R (2002a) Peripartum cardiomyopathy in the Hospital Albert Schweitzer District of Haiti. Am J Obstet Gynecol 186, 10051010.[CrossRef][ISI][Medline]
Fett JD, Sundstrom JB, Ansari AA and Combs GF Jr (2002b) Peripartum cardiomyopathy: a selenium disconnection and an autoimmune connection. Int J Cardiol 86, 311315.[CrossRef][ISI][Medline]
Fett JD, Sundstrom JB, King ME and Ansari AA (2002c) Motherdaughter peripartum cardiomyopathy. Int J Cardiol 86, 331332.[CrossRef][ISI][Medline]
Fett JD, Carraway RD, Perry H and Dowell DL (2003) Emerging insights into peripartum cardiomyopathy. J Hlth Popln Nutr 21, 17.
Fett JD, Dowell DL, Carraway RD, Sundstrom JB and Ansari AA (2004) 100 cases of peripartum cardiomyopathy ... and counting: what's going on? Int J Cardiol 97, 571573.[CrossRef][ISI][Medline]
George J, Adler A, Barshack I, Keren G and Roth A (2004) Suppression of myosin-induced and adoptively transferred myocarditis by prior treatment with complete Freund's adjuvant. Cardiovasc Pathol 13, 221224.[CrossRef][ISI][Medline]
Li Y, Heuser JS, Kosanke SD, Hemric M and Cunningham MW (2004) Cryptic epitope identified in rat and human cardiac myosin S2 region induces myocarditis in the Lewis rat. J Immunol 172, 32253234.
Mason JW (2003) Myocarditis and dilated cardiomyopathy: an inflammatory link. Cardiovasc Res 60, 510.[CrossRef][ISI][Medline]
McKenna CJ, Codd MB, McCann HA and Sugrue DD (1997) Idiopathic dilated cardiomyopathy: familial prevalence and HLA distribution. Heart 77, 549552.[Abstract]
Murphy JG (2003) Peripartum cardiomyopathy. In Cooper LT (ed.) Myocarditis: from bench to bedside. Humana Press, Totowa, New Jersey. Chap 24, pp. 589608.
Pauschinger M, Chandrasekharan K, Noutsias M, Kuhl U, Schwimmbeck LP and Schultheiss HP (2004) Viral heart disease: molecular diagnosis, clinical prognosis, and treatment strategies. Med Microbiol Immunol (Berl) 193, 115119.[CrossRef][ISI][Medline]
Pearson GD, Veille JC, Rahimtoola S, Hsia J, Oakley CM, Hosenpud J, Ansari A and Baughman KL (2000) 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 283, 11831188.
Peripartum Cardiomyopathy Support Group. http://www.ppcmsupport.org and http://www.amothersheart.net.
Takata S, Nakamura H, Umemoto S, Yamaguchil K, Sekine T, Kato T, Nishioka K and Matsuzaki M (2004) Identification of autoantibodies with the corresponding antigen for repetitive coxsackievirus infection-induced cardiomyopathy. Circ J 68, 677682.[CrossRef][ISI][Medline]
Taylor JA, Havari E, McInerney MF, Bronson R, Wucherpfennig KW and Lipes MA (2004) A spontaneous model for autoimmune myocarditis using the human MHC molecule HLA-DQ8. J Immunol 172, 26512658.
Submitted on April 8, 2005; accepted on May 5, 2005.