Pregnancy in Heart Transplant Recipients R. Miniero, MD,a I. Tardivo, MD,a P. Centofanti, MD,b C. Goggi, MD,c C. Mammana, MD,d F. Parisi, MD,e and A. M. Dall’Omo, MDf The aim of this report is to present data from Italian cardiac transplant centers assessing pregnancy after cardiac transplantation. Our retrospective survey included 10 pregnancies occurring in 7 patients during January 1991 to February 2002. Eight pregnancies were completed successfully and 2 abortions were reported (frequency rate 20%). No complications were observed during pregnancy or after delivery. Of 8 infants studied, 6 (75%) were born at term and 2 (25%) pre-term. One baby presented congenital talipes valgus. Pediatric development was uneventful. The data from the literature and our series show that a multidisciplinary approach is mandatory. The course of pregnancy is usually normal and the maternal and fetal outcomes are usually favorable. Although no fetal malformations have been reported, prolonged follow-up of these infants is required. J Heart Lung Transplant 2004; 23:898 –901.
Advances in surgical techniques and immunosuppressive therapy have rendered cardiac transplantation a reliable therapeutic option in the treatment of end-stage heart diseases.1,2 Currently, the survival rate at 5 years post-transplant exceed 85%.3–5 Consequently, the indications for heart transplantation have increased. The procedure is being done more often on younger patients for whom there is no alternative therapeutic solution. Heart-transplanted women often lead a normal lifestyle. They may desire pregnancy and can have children. Providing sufficient advice in terms of the risk that pregnancy represents for the patient and that of the fetus is difficult. In addition to the ethical issues concerning the uncertain life expectancy of patients, there are a number of purely medical issues regarding maternal and fetal welfare that must be evaluated on a case-by-case basis. In 1988, Lo ¨ wenstein and colleagues reported the first successful pregnancy after cardiac transplantation.3 However, information on the course and outcome of pregnancy in heart transplant recipients is still very limited.6
From the aDepartment of Pediatrics, University of Turin, San Luigi Hospital, Orbassano, Turin; bDepartment of Cardiac Surgery and Heart Transplant, University of Turin, San Giovanni Battista Hospital, Turin; cDepartment of Cardiac Surgery and Heart Transplant, IRCCS San Matteo, Pavia; dDepartment of Cardiac Surgery and Heart Transplant, Ospedali Riuniti, Bergamo; eDepartment of Pediatric Cardiology and Cardiac Surgery, Pediatric Hospital “Bambino Gesu ` ,” Rome; and f Department of Transplant Immunology, San Giovanni Battista Hospital, University of Turin, Turin, Italy. Submitted January 27, 2003; revised August 4, 2003; accepted August 7, 2003. Reprint requests: Roberto Miniero, MD, Department of Pediatrics, San Luigi Hospital, Orbassano, Regione Gonzole 10, 10043 Orbassano (TO), Italy. Telephone: ⫹39-011-9026506. Fax: ⫹39-011-3499382. E-mail: [email protected]
Copyright © 2004 by the International Society for Heart and Lung Transplantation. 1053-2498/04/$–see front matter. doi:10.1016/ j.healun.2003.08.002
The purpose of this study is to assess the results of a survey conducted by our group and to review the literature data. MATERNAL RISKS Three classes of maternal risk— cardiovascular, infectious and immune—are associated with post– hearttransplantation pregnancy. Cardiovascular Risks Physiologic responses to pregnancy and delivery vary among cardiac transplant recipients. Pregnancy induces hemodynamic changes such as an increased cardiac workload.7 As compared with before conception, blood volume increases by 40% and cardiac output increases by 30%, with marked maternal oxygen consumption both at rest and during exercise.8,9 The denervated cardiac transplant is known to respond to increased demand through 2 atypical physiologic adaptive mechanisms: (1) increased stroke volume in response to the higher central venous pressure and volume; and (2) increased heart rate and contractility in response to increased circulating catecholamines. Gestational hemodynamic changes could represent a risk for a transplanted heart, although these pregnancy/delivery-induced hemodynamic changes are usually welltolerated.9,10 Some of the women studied underwent heart transplantation for peri-partum cardiomyopathy. This is an idiopathic condition that develops either in the third trimester of pregnancy or in the first 6 months after delivery. Because the risk of recurrence and mortality rates are high, these patients are advised to avoid having more children.11–13 Rejection Pregnancy is often considered a “privileged” immunologic state, and thus it may be surprising that the
The Journal of Heart and Lung Transplantation Volume 23, Number 7
incidence of rejection is not lower than in non-pregnant recipients. No rebound increase in rejection rate has been reported in the post-partum period.10 Another possibility is that the mother could be allosensitized by the fetus, which in turn determines an augmented immune response during pregnancy. Although there is no evidence that the incidence of rejection increases in renal allograft recipients, the risk for cardiac allograft recipients is still not clear.8,14 Immunosuppressive therapy must be continued at unchanged doses throughout the entire pregnancy to prevent toxicity or rejection. There is a general consensus that antibiotic prophylaxis is mandatory in the case of cesarean section or vaginal operative delivery, but it is also advisable in spontaneous vaginal delivery.13,15 Infectious Risks Immunosuppressive therapy leads to an increased exposure to bacterial, viral, mycotic and opportunistic infections.11–13,17 During pregnancy, these infections may represent a serious risk for both the mother and fetus.6 Rigorous asepsis is recommended when performing a vaginal examination during pregnancy and labor; if an infection is suspected, cultures and antibiotics are advisable.16 FETAL RISKS Viral infections after immunosuppressive therapy can be a major complication in heart transplant patients.19 During pregnancy these infections may cause viremia.20 Cytomegalovirus (CMV) and Rubella infections—the former being frequent in transplant recipients—require some attention. CMV remains quiescent after primary infection but factors such immunosuppression, rejection or pregnancy-related hormonal changes may result in its reactivation.21 When early primary infection occurs, termination of pregnancy is generally not necessary.22,23 The abortion rate in cardiac graft recipients is not higher than in the general population.6,24 Pregnancy outcome does not seem to be influenced by the transplant-to-pregnancy time interval but rather by the patient’s clinical conditions and cardiovascular functions.11 No frequent or predominant fetal anomalies have been reported. Theoretically, a fetus should be protected from azathioprine teratogenic effects because it lacks the enzyme that can convert azathioprine to its active metabolite. Cyclosporine is teratogenic in animals only when high doses are administered.10 To our knowledge, 86 cases of pregnancy after heart transplantation have been reported so far.6,25–32 The largest survey was carried out by the U.S. National Transplant Registry, which included 47 pregnancies. Of
these, 35 women were in their first pregnancy and 12 had previous deliveries.6,30 LITERATURE REVIEW A review of the literature up to the year 2002 revealed 86 cases of pregnancy after cardiac transplantation. Eleven women underwent therapeutic abortion (12.4%), whereas in 7 patients miscarriage occurred (7.9%). In 22 cases (42.1%) the infants were pre-term (2 sets of twins), whereas 32 were born at term (57.9%) (1 set of twins). The most frequent maternal complications were hypertension, infection and pre-eclampsia. Immunosuppressive therapy included cyclosporine, azathioprine and steroids. Maternal age, the time interval elapsed from transplant, and the type of delivery were not recorded in all instances. The literature data show that pregnancy should be monitored through serial clinical examinations, ultrasound scans and laboratory tests.6,13,18,33,34 However, full attention must be given to monitoring cardiac function and also to prophylaxis and therapy of rejection and infection.35,36 In addition, fetal growth and morphology require close observation. All women presented with good cardiac function. In the largest series reported, 12 cases of rejection were observed in 8 pregnancies: 3 recipients were been treated with steroids, whereas the remaining patients did not receive anti-rejection therapy.33,34 Two of the 8 recipients who rejected the graft during or after pregnancy died. No structural malformations were identified; however, small-for-gestational-age (SGA) babies are frequently born after immunosuppressive therapy, with consequent neonatal risk. In 1 of the aforementioned series reported in the literature the percentage of infants with SGA was 23.5%. Neonatal complications were more common in premature newborns than in full-term babies. Prematurity incidence increased with subsequent pregnancies but did not reach statistical significance. Complications included respiratory distress, jaundice, patent ductus arteriosus, fetal hypotrophy and anemia. The daughter of 1 patient was diagnosed with dilated cardiomyopathy. The lack of data concerning the long-term effects of immunosuppressive therapy must be emphasized, and therefore infants must be monitored for a prolonged period. CASE REPORT Data regarding pregnancy after heart transplantation as observed by the Italian cardiac transplant centers, were collected for assessment of outcome (complications, miscarriages, stillbirths, therapeutic abortions and live births). Also, data were collected for pre– heart-trans-
plantation pregnancies at term and miscarriages/therapeutic abortions. A retrospective evaluation of the data obtained via questionnaires, hospital records and telephone interviews was then carried out. Finally information was obtained about the mother’s follow-up as a function of transplant rejection risk, time interval from transplantation to pregnancy and drugs received during the pregnancy. General health and detailed follow-up data for the infants were obtained, These findings were collected through telephone interviews with the mother and/or pediatrician. The following factors were evaluated: type of delivery (natural childbirth or by cesarean section) and the baby’s weight, length, head circumference, Apgar score and values during labor. Data concerning growth, vaccinations and allergic reactions; eventual laboratory tests; and the last measured height and weight were also obtained. RESULTS Four of the 14 heart transplant centers in Italy compiled and returned the questionnaires, 4 centers did not have post– heart transplantation pregnancies and 6 did not respond to our request. Our survey included 10 pregnancies observed in 7 patients from January 1991 to July 2002. Eight pregnancies were completed successfully, and 2 miscarriages were reported (frequency rate 20%). The average time from transplantation to childbirth was 83 months (range 49 to 145 months). All patients received immunosuppressive therapy during their pregnancy, which consisted of cyclosporine (CsA) in 6 patients and CsA and azathioprine (AZA) in 2 patients. At the time of transplant, the average age of the patients was 23.7 years (range 15 to 29.11 years); the average age at delivery was 29.6 years (range 21 to 37 years). None of the patients had had children before cardiac transplantation. No complications were observed during pregnancy (except 1 case of tachyarrhythmia) or after delivery. Of these 8 babies, 6 (75%) were born at term and 2 (25%) pre-term. The overall mean gestational age was 38.3 weeks (range 36 to 41 weeks). In all cases a cesarean section was performed. The mean birth weight was 2,929.7 g (range 2,500 to 3,600 g). Mean length was 49.2 cm (range 46 to 52 cm). Mean head circumference was 35.5 cm (range 35 to 36 cm). The Apgar score ranged between 8/10 and 10/10. No complications were observed. Mean cyclosporinemia was 142 ng/ml in the mothers (range 80 to 190 ng/ml) and 51 ng/ml in the newborns (range 12 to 90 ng/ml; non-determinable in 2 cases). No baby was breastfed, because the immunosuppressive drugs can be secreted in the mother’s milk.
The Journal of Heart and Lung Transplantation July 2004
All babies were vaccinated and no side effects were observed. The development of all babies was uneventful (follow-up 6 months to 11 years). DISCUSSION The data resulting from both the literature and our series show that management of pregnancy in heart transplant recipients is not very different from that of a healthy woman. However, it should be emphasized that a multidisciplinary approach is mandatory.40 – 42 The course of pregnancy is usually normal, and the maternal and fetal outcomes are usually favorable. Although no fetal malformations have been reported, prolonged follow-up of these babies is mandatory. The long-term effects of immunosuppressive therapy, including risk of malignancies and potential effects, on reproduction, are unknown. Classen et al reported that the incidence of autoimmune diseases may be higher in the offspring of patients treated with cyclosporine.39,43 As for timing and route of delivery, a heart-transplanted woman can theoretically undergo a vaginal delivery at term.37,38 Cesarean section is advised when obstetric indications are present. Finally, immunosuppressed patients are usually discouraged from breastfeeding to prevent any possible risk to the infant. The long-term results of cardiac transplantation should be considered when counseling these women, as well as the etiology of the cardiac disease, because the inheritance of certain conditions (e.g., cardiomyopathy) is well established. REFERENCES 1. Jamieson SW, Ogumarke HO. Cardiopulmonary transplantation. Surg Clin N Am 1986;66:491–501. 2. Schroeder JS, Hunt SA. Cardiac transplantation: where are we? N Engl J Med 1986;315:961E–3. 3. Kirk P. Organ transplantation and pregnancy. A case report and review. Am J Obstet Gynecol 1991;164:1629 – 34. 4. Kaye MP. The Registry of International Society for Heart and Lung Transplantation: ninth official report—1992. J Heart Lung Transplant 1992;11:506 –606. 5. Krakauer H, Shekar SS, Kaye MP. The relationship of clinical outcomes to status at a Medicare-approved heart transplant centre. Transplantation 1995;59:840 –6. 6. Morini A, Spina V, Oleandri V, Cantonetti G, Lambiasi A, Papalia U. Pregnancy after heart transplant: update and case report. Hum Reprod 1998;13:749 –57. 7. Pescetto G, De Cecco L, Pecorari D. Fisiologia della gravidanza. In: Manuale di Ginecologia e Ostetricia Societa`. Rome: Editrice Universo; 1989,pp 805–7. 8. Wagoner LE, Taylor DO, Olsen SL, Price GD, Rasmussen LG, Larsen CB. Immunosuppressive therapy, management and outcome of heart transplant recipients during pregnancy. J Heart Lung Transplant 1994;13:993–1000.
The Journal of Heart and Lung Transplantation Volume 23, Number 7
9. Metcalfe J, McAnulty JH, Ueland K. Cardiovascular physiology. Clin Obstet Gynecol 1981;24:693–5. 10. Hunt SA. Pregnancy in heart transplant recipients: a good idea? J Heart Lung Transplant 1991;10:499 –503. 11. Key TC, Resnik R, Dittrich HC. Successful pregnancy after cardiac transplantation. Am J Obstet Gynecol 1989;160: 367–71. 12. Camann WR, Goldmann GA, Johnson MD. Cesarean delivery in a patient with a transplanted heart. Anesthesiology 1989;71:618 –20. 13. Camann WR, Jarcho JA, Mintz KJ. Uncomplicated vaginal delivery 14 months after cardiac transplantation. Am Heart J 1991;121:939 –41. 14. Davison JM. Dialysis, transplantation and pregnancy. Am J Kidney Dis 1991;27:127–32. 15. Lou RJ, Scott JR. Pregnancy following renal transplantation. Clin Obstet Gynecol 1985;28:339 –50. 16. Wiel R, Barfield N, Schoter GPj. Children of mother with kidney transplant. Transplant Proc 1985;27:1569 –72. 17. Ahner R, Kiss H, Zuckermann A. Pregnancy and vaginal delivery 13 months after cardiac transplantation. Geburtshilfe Fruenheilkd 1993;53:574 –6. 18. Liljestrand J, Lindstrom B. Childbirth after post partum cardiac insufficiency treated with cardiac transplant. Acta Obstet Gynecol Scand 1993;72:406 –8. 19. Darbois Y, Seebacher J, Vauthier-Brouzes D. Heart transplantation: impact on female fertility. Bull Acad Natl Med 1991;175:521–540. 20. Kossoy LR, Herbert CM, Colston Wenz A. Management of heart transplant recipients: guidelines for the obstetrician-gynecologist. Am J Obstet Gynecol 1988;159:490 –9. 21. Rubin RH, Colman RB. Cytomegalovirus infection in renal transplantation: clinical importance and control. In: Williams GM, Burdick T, Solez K, eds. Kidney transplant rejection: diagnosis and treatment. New York: Marcel Dekker, 1986, 283–98. 22. Griffith PD, Baboonian C. A prospective study of primary cytomegalovirus infection during pregnancy: final report. Br J Obstet Gynecol 1984;91:307–15. 23. Horstmann DM. Viral infections. In: Burrow GN, Ferris TF, eds. Medical complications during pregnancy. Philadelphia: W. B. Saunders; 1999:333–50. 24. Nappi R. Lucidano F. Aborto e gravidanza ectopica. In: Zinchella I, Perrone G, Santoro A (eds): Ginecologia e Ostetricia, Bologna: Monduzzi Editore. 1987,pp 213–30. 25. Eskandar M, Gader S, Ong BY. Two successful vaginal deliveries in a heart transplant recipient. Obstet Gynecol 1996;87:880. 26. Dziatkowiak A, Zdebski Z, Tracz W, et al. Successful full-term pregnancy in a patient three and a half years after a heart transplantation. Ann Transplant 1996;1:65–6. 27. Yuh-Jer Shen A, Mansukhani PW. Is pregnancy contraindicated after cardiac transplantation? A case report and literature review. Int J Cardiol 1997;60:151–6. 28. Kreitmann B, D’Ercole C, Yao JG, et al. Successful preg-
nancy five years after cardiac transplantation for peripartum cardiomyopathy. Transplant Proc 1997;29:2457. Troche V, Ville Y, Fernandez H. Pregnancy after heart or heart–lung transplantation: a series of 10 pregnancies. Br J Obstet Gynaecol 1998;105:454 –8. Branch K, Wagoner LE, McGrory CH, Mannion JD, Radomski JS, Moritz MJ, Ohler L, Armenti VT. Risks of subsequent pregnancies on mother and newborn in female heart transplant recipient. J Heart Lung Transplant 1998;17:698 –702. de Jonge N, Kierkels JH, Klopping C, et al. Successful pregnancy after heart transplantation. Ned Tijdschr Geneeskd 1999;143:1664 –8. Bordignon S, Aramayo AM, Nunes e Silva D, et al. Pregnancy after cardiac transplantation. Report of one case and review. Arq Cardiol 2000;75:515–22. Scott JR, Wagoner LE, Olsen SL. Pregnancy in heart transplant recipients: management and outcome. Obstet Gynecol 1993;82:324 –7. Gruessner AC, Sutherland DER. Pancreas transplantation in the United States (US) and non US as reported to the United Network for Organ Sharing (UNOS) and the International Pancreas Transplant Registry. In: Terasaki PI, Cecka M, eds. Clinical transplants. Los Angeles, CA: UCLA Tissue Typing Laboratory, 1997, 47–51. Cunningham FG, Gant N. Prevention of pre-eclampsia—a reality? N Engl J Med 1989;321:606 –7. Perini GP, Bonadiman C, Fraccorioli GP. Azathioprine related cholestatic jaundice in heart transplant patients. J Heart Lung Transplant 1990;9:577–8. Lo ¨ wenstein BR, Vain NW, Perrone SV, Wright DR, Boullo ` n FJ, Favaloro RG. Successful pregnancy and vaginal delivery after heart transplantation. Am J Obstet Gynecol 1988;158:589 –90. Baxi LV, Rho RB. Pregnancy after cardiac transplantation. Am J Obstet Gynecol 1993;169:33–4. Rose ML, Dominguez M, Leaver N, Lachno R, Yacoub MH. Analysis of T cell subpopulation and cyclosporine levels in the blood of two neonates born to immunosuppressed heart–lung recipients. Transplantation 1989;48:223–6. Haugen G, Aass H, Ihlen H, Simonsen S, Geiran O, Bjortuft O, Bjerke G, Moe N. Pregnancy in heart and heart–lung transplant recipients. Acta Obstet Gynecol Scand 1998; 77:574 –81. Hosenpud JD, Novick RJ, Breen TJ, Keck B, Daily OP. The Registry of the International Society for Heart and Lung Transplantation: twelfth official report—1995. J Heart Lung Transplant 1995;14:805–15. Parry D, Hextall A, Banner N, Robinson V, Yacoub M. Pregnancy following lung transplantation. Transplant Proc 1997;29:629 –31. Classen JB, Shevach EH. Evidence that cyclosporine treatment during pregnancy predisposes offspring to develop autoantibodies. Transplantation 1991;51:652–57.