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Impairment of cardiac function in a successful full-term pregnancy in a homozygous beta-thalassemia major: does chelation have a positive role?
European Journal of Obstetrics & Gynecology and Reproductive Biology 120 (2005) 117–118 www.elsevier.com/locate/ejogrb
LETTER TO THE EDITOR—BRIEF COMMUNICATION Impairment of cardiac function in a successful full-term pregnancy in a homozygous beta-thalassemia major: does chelation have a positive role? Dear Editors, The introduction of modern therapeutic strategies in thalassemia major has improved patients’ life expectancy and fertility, making pregnancy a challenge for them, and leading to the medical permission for gestation in women with normal cardiac performance [1]. However, reports about the potential use of the iron chelator deferroxamine during gestation and its teratogenicity are contradictory [2]. We would like to report the case of a thalassemia major pregnant who received deferroxamine throughout her third trimester, because of great cardiac function impairment despite the pregestational normal left ventricular (LV) function. She was an homozygous beta-thalassemic woman, transfused twice a month well-used to the conventional deferroxamine chelation therapy. At the age of 28, she had an induced intrauterine pregnancy. Her pregestational cardiac function, according to clinical estimation, chest Xray, ECG and main echocardiographic parameters (Table 1) was normal. Deferroxamine was discontinued when pregnancy was diagnosed, while hemoglobin was maintained above 10 g/dl. About the 20th week of gestation, she was experiencing increasing dyspnea at rest and fatigue. Clinical examination revealed gallop rhythm, ECG showed inversion of T waves at the precordial leads, while LV dilatation and declining values of the systolic function indexes shortening fraction (SF 30%) and ejection fraction (EF 57%) were echocardiographically noted (Table 1). Ferritin levels were 3200 ng/ml. She was treated with furosemide(20 mg once a day), digoxin (0.125 mg five days a week) and potassium supplements. Since then, the patient was followed-up closely by the cardiologists, with a weekly echo-Doppler study. In the 22nd week of gestation, LV function deteriorated further (SF 25%), becoming echocardiographically compatible to dilating cardiomyopathy (Table 1), and the patient was advised to resume deferroxamine chelation treatment (50 mg/kg IV 5 days/week). During the following weeks, the patient was clinically stable while the systolic indices presented progressive improvement (Table 1), allowing pregnancy continuation, until fetal maturity was reassured.
Cesarean section was performed at 31 weeks of gestation. She gave birth to a normal baby (2080 kgrs), with no findings of deferroxamine toxicity at birth and the annual reevaluation. After delivery myocardial iron deposition was quantified, using myocardial T2 and T2* techniques and the reduced MRI T2 and T2* values (15.3 and 8.3 ms correspondingly) were reflecting a highly iron-loaded myocardium. In the first simester and the annual patient’s reevaluation visit, left ventricular dimensions were within normal limits and systolic indexes were increased (Table 1). During pregnancy, mainly in the first and second trimesters, volume overload increases cardiac output leading to a reversible ‘physiological’ left ventricular hypertrophy, chamber enlargement, and mild functional multivalvular regurgitation. Furthermore, pregnancy may be responsible for a specific type of cardiomyopathy, peripartum cardiomyopathy, a rare condition with unpredictable outcome, occurring in the last month or during the fine following months [1]. According to the reports, thalassemic pregnants, with normal resting cardiac performance and intensive pregestational chelation therapy usually carry out successfully gestation and delivery [1]. It is questionable, though, if a woman with marginal impaired cardiac performance or with myocardial hemosiderosis, which can be present even in well-chelated patients, can cope with the pregnancy stress and the above referred hemodynamic changes. In this case the impairment of left ventricular systolic function, the question arose as to whether it was another case of peripartum cardiomyopathy or just the result of myocardial hemosiderosis. According to the era of the symptoms’ beginning, the improving LV function in the short period following deferroxamine administration, mainly acting on the unbound toxic iron and the notification of highly iron-loaded myocardium in the MRI study, we think that peripartum cardiomyopathy should be excluded. The dynamic multiple system changes during pregnancy result in increased basal oxygen consumption and susceptibility to oxidative stress. The human placenta, rich in mitochondria and macrophages, influences maternal homeostasis, and favors the local production of free radicals. The highly vascular placenta matures, exposed to high maternal oxygen partial pressure and changes to an oxygen-rich environment, generating superoxides and reactive oxygen
0301-2115/$ – see front matter # 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ejogrb.2004.08.005
118
Letter to the Editor—Brief Communication / European Journal of Obstetrics & Gynecology and Reproductive Biology 120 (2005) 117–118
Table 1 Echocardiographic measurements before, during and one year after gestation Echo measurements
Pre
20th week
22nd week
24th week
26th week
28th week
Delivery
One year follow-up
N.R.
LVEF (%) SF (%) LVDD LVSD
71 40 5.03 2.97
57 30 5.61 3.9
42.5 25 5.8 4.35
45 26.5 5.7 4.19
49.5 29 5.7 4.05
52 30.5 5.6 3.9
55 32 5.55 3.8
69 40 5.2 3.1
67 8 34–44 3.6–5.6 cm 2.3–3.9 cm
LVEF, left ventricular ejection fraction; SF, fractional shortening; LVDD, left ventricular diastolic diameter; LVSD, left ventricular systolic diameter.
species. Furthermore, nitric oxide (NO) is locally produced there and, along with other reactive nitrogen species, contributes (especially in the presence of transition metals) to oxidative stress, peaking by the second trimester of pregnancy, in what appears to be a vulnerable period for foetal health and gestational progress [3]. In thalassemic patients or those with hereditary hemochromatosis, iron overload increases the oxidative stress of pregnancy and the risk for cardiovascular events, in a high cardiac output state, is augmented [4]. The use of deferroxamine in thalassemic pregnants has been generally avoided due to the fear of its potential teratogenicity, according to animal studies. Despite the data on animals, similar toxic effect is not yet reported in human cases and there is some doubt that drug can cross the placenta due to its large molecular size and charge [2]. However, eliminating chelation during pregnancy, when transfusion needs are increased, worsens tissue iron accumulation aggravating oxidative stress, and women with preexisting cardiac hemosiderosis or borderline LV function may then experience cardiac complications. Our patient developed LV dysfunction and received deferroxamine throughout her third trimester with heart function improvement and without any fetal side effects. Concerning myocardial iron deposition and heart function of thalassemics, we should emphasize the possible underestimation of subclinical cardiac impairment, when using only ferritin values or echocardiography. Serum ferritin, although easy to measure, subjects to variability and false values in relation to body iron accumulation. An accurate determination of the total amount and distribution of body iron stores is essential for prognosis and evaluation of the chelation efficacy. MR imaging is usefully employed to this purpose and heart MRI T2* values shorten with increasing myocardial iron concentrations predicting with credibility LV dysfunction development [5]. Obstetricians’, cardiologists’ and hematologists’ collaboration during gestation is critical for thorough maternal and fetal surveillance. We suggest myocardial iron estimation for possible myocardial hemosiderosis using MRI techniques, to be included in the preconceptional heart evaluation of thalassemic women. Furthermore, in cases of LV dysfunction development, despite limited evidence, chelators should be considered, if the maternal benefits
outweigh the potential fetal risks, especially after the critical period of organogenesis.
References [1] Aessopos A, Karabatsos F, Farmakis D, Katsantoni A, Hatziliami A, Youssef J, et al. Pregnancy in patients with well-treated beta-thalassemia: outcome for mothers and newborn infants. Am J Obstet Gynecol 1999;180:360–5. [2] Singer ST, Vichinsky EP. Deferoxamine treatment during pregnancy: is it harmful? Am J Hematol 1999;60(1):24–6. [3] Casanueva E, Viteri FE. Iron and oxidative stress in pregnancy. J Nutr 2003;133(5 Suppl 2):1700S–8S. [4] Gaenzer H, Marschang P, Sturm W, Neumayr G, Vogel W, Patsch J, et al. Association between increased iron stores and impaired endothelial function in patients with hereditary hemochromatosis. J Am Coll Cardiol 2002;40(12):189–94. [5] Brittenham GM, Badman DG. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Workshop: noninvasive measurement of iron. Report of an NIDDK workshop. Blood 2003; 101(1):15–9.
M. Tsironi* S. Deftereos A. Aessopos First Department of Internal Medicine University of Athens, Athens, Greece V. Ladis Ch. Kattamis First Department of Pediatrics University of Athens, Athens, Greece Z. Margellis Iaso Maternity Hospital, Athens, Greece *Corresponding author. Present address: Business: Department of Internal Medicine Sparta General Hospital, Sparta 23100, Greece Home: 22 N. Plastira str., 15772 Athens, Greece Tel.: +30 6932483226; fax: +30 2731025605 E-mail address: [email protected] 13 August 2004
LETTER TO THE EDITOR—BRIEF COMMUNICATION Impairment of cardiac function in a successful full-term pregnancy in a homozygous beta-thalassemia major: does chelation have a positive role? Dear Editors, The introduction of modern therapeutic strategies in thalassemia major has improved patients’ life expectancy and fertility, making pregnancy a challenge for them, and leading to the medical permission for gestation in women with normal cardiac performance [1]. However, reports about the potential use of the iron chelator deferroxamine during gestation and its teratogenicity are contradictory [2]. We would like to report the case of a thalassemia major pregnant who received deferroxamine throughout her third trimester, because of great cardiac function impairment despite the pregestational normal left ventricular (LV) function. She was an homozygous beta-thalassemic woman, transfused twice a month well-used to the conventional deferroxamine chelation therapy. At the age of 28, she had an induced intrauterine pregnancy. Her pregestational cardiac function, according to clinical estimation, chest Xray, ECG and main echocardiographic parameters (Table 1) was normal. Deferroxamine was discontinued when pregnancy was diagnosed, while hemoglobin was maintained above 10 g/dl. About the 20th week of gestation, she was experiencing increasing dyspnea at rest and fatigue. Clinical examination revealed gallop rhythm, ECG showed inversion of T waves at the precordial leads, while LV dilatation and declining values of the systolic function indexes shortening fraction (SF 30%) and ejection fraction (EF 57%) were echocardiographically noted (Table 1). Ferritin levels were 3200 ng/ml. She was treated with furosemide(20 mg once a day), digoxin (0.125 mg five days a week) and potassium supplements. Since then, the patient was followed-up closely by the cardiologists, with a weekly echo-Doppler study. In the 22nd week of gestation, LV function deteriorated further (SF 25%), becoming echocardiographically compatible to dilating cardiomyopathy (Table 1), and the patient was advised to resume deferroxamine chelation treatment (50 mg/kg IV 5 days/week). During the following weeks, the patient was clinically stable while the systolic indices presented progressive improvement (Table 1), allowing pregnancy continuation, until fetal maturity was reassured.
Cesarean section was performed at 31 weeks of gestation. She gave birth to a normal baby (2080 kgrs), with no findings of deferroxamine toxicity at birth and the annual reevaluation. After delivery myocardial iron deposition was quantified, using myocardial T2 and T2* techniques and the reduced MRI T2 and T2* values (15.3 and 8.3 ms correspondingly) were reflecting a highly iron-loaded myocardium. In the first simester and the annual patient’s reevaluation visit, left ventricular dimensions were within normal limits and systolic indexes were increased (Table 1). During pregnancy, mainly in the first and second trimesters, volume overload increases cardiac output leading to a reversible ‘physiological’ left ventricular hypertrophy, chamber enlargement, and mild functional multivalvular regurgitation. Furthermore, pregnancy may be responsible for a specific type of cardiomyopathy, peripartum cardiomyopathy, a rare condition with unpredictable outcome, occurring in the last month or during the fine following months [1]. According to the reports, thalassemic pregnants, with normal resting cardiac performance and intensive pregestational chelation therapy usually carry out successfully gestation and delivery [1]. It is questionable, though, if a woman with marginal impaired cardiac performance or with myocardial hemosiderosis, which can be present even in well-chelated patients, can cope with the pregnancy stress and the above referred hemodynamic changes. In this case the impairment of left ventricular systolic function, the question arose as to whether it was another case of peripartum cardiomyopathy or just the result of myocardial hemosiderosis. According to the era of the symptoms’ beginning, the improving LV function in the short period following deferroxamine administration, mainly acting on the unbound toxic iron and the notification of highly iron-loaded myocardium in the MRI study, we think that peripartum cardiomyopathy should be excluded. The dynamic multiple system changes during pregnancy result in increased basal oxygen consumption and susceptibility to oxidative stress. The human placenta, rich in mitochondria and macrophages, influences maternal homeostasis, and favors the local production of free radicals. The highly vascular placenta matures, exposed to high maternal oxygen partial pressure and changes to an oxygen-rich environment, generating superoxides and reactive oxygen
0301-2115/$ – see front matter # 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ejogrb.2004.08.005
118
Letter to the Editor—Brief Communication / European Journal of Obstetrics & Gynecology and Reproductive Biology 120 (2005) 117–118
Table 1 Echocardiographic measurements before, during and one year after gestation Echo measurements
Pre
20th week
22nd week
24th week
26th week
28th week
Delivery
One year follow-up
N.R.
LVEF (%) SF (%) LVDD LVSD
71 40 5.03 2.97
57 30 5.61 3.9
42.5 25 5.8 4.35
45 26.5 5.7 4.19
49.5 29 5.7 4.05
52 30.5 5.6 3.9
55 32 5.55 3.8
69 40 5.2 3.1
67 8 34–44 3.6–5.6 cm 2.3–3.9 cm
LVEF, left ventricular ejection fraction; SF, fractional shortening; LVDD, left ventricular diastolic diameter; LVSD, left ventricular systolic diameter.
species. Furthermore, nitric oxide (NO) is locally produced there and, along with other reactive nitrogen species, contributes (especially in the presence of transition metals) to oxidative stress, peaking by the second trimester of pregnancy, in what appears to be a vulnerable period for foetal health and gestational progress [3]. In thalassemic patients or those with hereditary hemochromatosis, iron overload increases the oxidative stress of pregnancy and the risk for cardiovascular events, in a high cardiac output state, is augmented [4]. The use of deferroxamine in thalassemic pregnants has been generally avoided due to the fear of its potential teratogenicity, according to animal studies. Despite the data on animals, similar toxic effect is not yet reported in human cases and there is some doubt that drug can cross the placenta due to its large molecular size and charge [2]. However, eliminating chelation during pregnancy, when transfusion needs are increased, worsens tissue iron accumulation aggravating oxidative stress, and women with preexisting cardiac hemosiderosis or borderline LV function may then experience cardiac complications. Our patient developed LV dysfunction and received deferroxamine throughout her third trimester with heart function improvement and without any fetal side effects. Concerning myocardial iron deposition and heart function of thalassemics, we should emphasize the possible underestimation of subclinical cardiac impairment, when using only ferritin values or echocardiography. Serum ferritin, although easy to measure, subjects to variability and false values in relation to body iron accumulation. An accurate determination of the total amount and distribution of body iron stores is essential for prognosis and evaluation of the chelation efficacy. MR imaging is usefully employed to this purpose and heart MRI T2* values shorten with increasing myocardial iron concentrations predicting with credibility LV dysfunction development [5]. Obstetricians’, cardiologists’ and hematologists’ collaboration during gestation is critical for thorough maternal and fetal surveillance. We suggest myocardial iron estimation for possible myocardial hemosiderosis using MRI techniques, to be included in the preconceptional heart evaluation of thalassemic women. Furthermore, in cases of LV dysfunction development, despite limited evidence, chelators should be considered, if the maternal benefits
outweigh the potential fetal risks, especially after the critical period of organogenesis.
References [1] Aessopos A, Karabatsos F, Farmakis D, Katsantoni A, Hatziliami A, Youssef J, et al. Pregnancy in patients with well-treated beta-thalassemia: outcome for mothers and newborn infants. Am J Obstet Gynecol 1999;180:360–5. [2] Singer ST, Vichinsky EP. Deferoxamine treatment during pregnancy: is it harmful? Am J Hematol 1999;60(1):24–6. [3] Casanueva E, Viteri FE. Iron and oxidative stress in pregnancy. J Nutr 2003;133(5 Suppl 2):1700S–8S. [4] Gaenzer H, Marschang P, Sturm W, Neumayr G, Vogel W, Patsch J, et al. Association between increased iron stores and impaired endothelial function in patients with hereditary hemochromatosis. J Am Coll Cardiol 2002;40(12):189–94. [5] Brittenham GM, Badman DG. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Workshop: noninvasive measurement of iron. Report of an NIDDK workshop. Blood 2003; 101(1):15–9.
M. Tsironi* S. Deftereos A. Aessopos First Department of Internal Medicine University of Athens, Athens, Greece V. Ladis Ch. Kattamis First Department of Pediatrics University of Athens, Athens, Greece Z. Margellis Iaso Maternity Hospital, Athens, Greece *Corresponding author. Present address: Business: Department of Internal Medicine Sparta General Hospital, Sparta 23100, Greece Home: 22 N. Plastira str., 15772 Athens, Greece Tel.: +30 6932483226; fax: +30 2731025605 E-mail address: [email protected] 13 August 2004