FORUM
Outcomes After Pregnancy in Living Lobar Lung Transplantation Christina L. Greene, Mark L. Barr, Felicia A. Schenkel, Stephanie G. Worrell, Vaughn A. Starnes, and P. Michael McFadden Pregnancy after lung transplantation has been described, but pregnancy after living donor lobar lung transplantation (LDLT) has not been reported. The aim of this study was to evaluate outcomes after pregnancy with LDLT and discuss current recommendations regarding pregnancy and lung transplantation. A total of four LDLT patients and five pregnancies were identified, all from our institution. No patient has developed worsening pulmonary function or acute or chronic rejection. The complications of pulmonary hypertension and rejection may be overestimated in this population, and recommendations for preventive sterilization at transplantation or abortion at the time of conception are likely unwarranted and unnecessary. Keywords: Living donor lobar lung transplantation, Pregnancy, Cystic fibrosis. (Transplantation 2014;98: 692Y694)
regnancy after lung transplantation has been described (1), but pregnancy after living donor lobar lung transplantation (LDLT) has not been reported. Living donor lobar lung transplantation was originally developed to decrease transplant waiting list mortality because of a lack of available organs. As female patients with LDLT matured, physicians were faced with advising patients on family planning. Generally, most physicians recommend abstaining from pregnancy after lung transplantation because of the required alterations in immunosuppressive therapy that could increase the risk of rejection. Pregnancy after LDLT carries the additional risk of hemodynamic changes associated with smaller than normal total lung volumes. The aim of this study was to evaluate outcomes after pregnancy with LDLT and discuss current recommendations regarding pregnancy and lung transplantation.
P
MATERIALS AND METHODS A retrospective review was conducted to identify all patients who received LDLT and subsequently became pregnant. Institutions which previously published on LDLT were contacted to identify all LDLT patients that had become pregnant. This included our own institutional results as well The authors declare no funding or conflicts of interest. Division of Cardiothoracic Surgery, Department of Surgery, Keck School of Medicine of the University of Southern California, Los Angeles, CA. Address correspondence to: P. Michael McFadden, M.D., Division of Cardiothoracic Surgery, Department of Cardiothoracic Surgery, Keck School of Medicine of the University of Southern California, 1520 San Pablo Street, Suite 4300, Los Angeles, CA 90033. E-mail: [email protected] Received 16 May 2014. Revision requested 4 June 2014. Accepted 16 June 2014. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0041-1337/14/9807-692 DOI: 10.1097/TP.0000000000000363
692
www.transplantjournal.com
as those of Massachusetts’s General Hospital, St. Louis Children’s Hospital, the National Transplantation Pregnancy Registry, and the experiences from Okayama, Japan and Middlesex County, United Kingdom. This study was approved by the institutional review board of the University of Southern California.
RESULTS A total of four LDLT patients and five pregnancies were identified, all from our institution. The median age at transplant was 24 years (range, 21Y29). The indication for transplant in all patients was cystic fibrosis, and each received bilateral living related LDLTs on cardiopulmonary bypass. Median left lung ischemic time was 43 min, median right lung ischemic time was 62 min, and median pump time was 150 min. Initial immunosuppressive regimen included prednisone, cyclosporine-FK506, and azathioprine-mycophenolate (2). All patients received standardized prophylaxis against Candida species, Pneumocystis carinii, and cytomegalovirus (2). Mean time to pregnancy was 4 years after transplantation (range, 1Y8 years). Mean gestation time was 36 weeks (range, 34Y37 weeks). Two patients suffered preeclampsia. Cardiac catheterization or hemodynamic monitoring was not routinely performed during pregnancy or in the peripartum period because no patient developed symptoms of pulmonary hypertension. Additionally, no patient developed acute rejection. Mean time from transplant to telephone interview was 18 years (range, 17Y19 years). No patient has developed worsening pulmonary function or acute-chronic rejection. One patient developed lymphoma which is in remission. All five children of these LDLT patients are well and none has cystic fibrosis (Table 1).
DISCUSSION To date, there have been 253 LDLTs performed in the United States in comparison to the nearly 27,000 deceased Transplantation
& Volume 98, Number 7, October 15, 2014
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Greene et al.
* 2014 Lippincott Williams & Wilkins
TABLE 1.
693
Operative and pregnancy details of LDLT recipients Patient 1
Patient 2
Patient 3
Patient 4
24 38 38 122 8 37 17 0 0
21 64 62 136 1 37 5/7 18 0 0
23 44 61 208 6 34 17 0 0
29 41 75 164 2 31 19 0 0
Age at Transplant Left lobar ischemic time, min Right lobar ischemic time, min Pump time, min Years post-Tx at delivery Gestation of first child, weeks Years follow-up Gestational or postpartum pulmonary hypertension Offspring with Cystic Fibrosis
Operative and pregnancy details of each of the four LDLT recipients are shown above in Table 1. No patient developed pulmonary hypertension during or after pregnancy.
donor lung transplants performed in the United States alone (1, 3). Pregnancy after deceased donor lung transplantation has been described but concerns exist regarding life-threatening complications to the mother and fetus. The primary concern centers on the effect that pregnancy has on the allograft. Increased circulating blood volume and altered hemodynamics of pregnancy can compromise pulmonary function and increase hypoxia. Additional concerns regarding the teratogenic effects of immunosuppressive agents complicate the management of these patients. Lung transplant patients can and do become pregnant. Thirty pregnancies with 18 live births have been reported, reaffirming the fact that successful pregnancy is possible (1). Living donor lobar lung transplantation evolved out of a need to save critically ill patients who could not wait for a deceased donor lung. In LDLT two healthy donors are selected, and each undergoes removal of their respective lower lobe. The lower lobes are then implanted into the recipient in place of whole right and left lungs as in cadaveric lung transplantation (4). Reorganization of the Organ Procurement and Transplantation Network allocation system better served these critically ill patients and the need for LDLT decreased. In the last 5 years alone, there have only been four LDLTs performed in the United States (3). Patients receiving LDLT tend to be younger and have more severe disease than the cadaveric lung transplant patients. A large proportion of patients are affected by cystic fibrosis and as this patient population ages the question of family planning begins to have a prominent role. There are no clear cut recommendations regarding pregnancy and lung transplantation. Although it has been reported, it is still widely viewed by the medical community as an adverse event in the life of a transplant recipient because it increases their risk of rejection and places the children at risk of being orphaned. The idea that a lung transplant recipient might purposefully get pregnant inspires heated debate among clinicians regarding values spanning from personal responsibility for putting a valuable organ at risk to child endangerment (5, 6). In her editorial in the New England Journal of Medicine, Ross (7) evaluates the ethics of pregnancy after transplantation. Though almost all the data is based on abdominal organ transplantation, she repeatedly points out the lack of evidence for most recommendations.
The common recommendation to delay pregnancy 2 years after transplantation is not based on solid evidence. Although azathioprine and cyclosporine have been shown to be teratogenic in animals, rates of birth defects in women who took these immunosuppressive drugs while pregnant are not statistically different (8Y10). Azathioprine was found to minimally increase the risk of teratogenic effects whereas the rate of malformations in patients taking corticosteroids was the same as the background population (3.5%) (11, 12). The teratogenic effect of tacrolimus is also minimal though it is known to cause transient hyperkalemia and mild reversible renal impairment (13). A recent prospective trial has confirmed the teratogenic effects of mycophenolate mofetil, especially when continued 7 weeks after the last menstrual period (14). Recommendations for prophylactic sterilization or even abortion also lack scientific merit, yet they are pervasive throughout the medical community. The patients in the present study were encouraged at some point in their course to obtain a tubal ligation or consider abortion of their fetus at conception. All four disregarded these recommendations and instead sought clinicians who helped them navigate this milestone in life. All proceeded to successful pregnancies and post-operative courses. A common sentiment expressed by the patients was that they went through the transplantation process not only to increase their lifespan but also to experience a more normal life. This begs the question, are we as physicians denying patients a much desired life experience out of personal bias and unsubstantiated concerns? Our series of four patients and five births is the first report of successful pregnancy after LDLT. Cystic Fibrosis was the indication for transplantation in all patients but none of them developed the complications of pulmonary hypertension or chronic rejection. Each of the patients had successful, uneventful pregnancies and their children are healthy and normal. A possible explanation for the low incidence of rejection is that all lobar donors were closely related (i.e. sisters, brother, aunts, uncles or cousins). Although we previously reported no differences in rejection between related and unrelated donors (15), some degree of immunologic tolerance may still exist. Optimal patient management is paramount. After the initial postoperative care at our institution each recipient and their pregnancy was managed by their local physicians in the United States and Canada.
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
694
www.transplantjournal.com
It is our impression that although pregnancy after LDLT is a rare event, it seems to be safe and has good outcomes in well-managed patients. The complications of pulmonary hypertension and rejection may be overestimated in this population, and recommendations for preventive sterilization at the time of transplantation or abortion at the time of conception are likely unwarranted and unnecessary. REFERENCES 1. 2. 3. 4. 5.
Shaner J, Coscia LA, Constantinescu S, et al. Pregnancy after lung transplant. Prog Transplant 2012; 22: 134. Baker CJ, Barr ML, Schenkel FA, et al. Living donor lung transplantation. In: Baumgartner WA, Reitz B, Kasper E, Theodore J, eds. Heart and lung transplantation. Philadelphia, PA: WB Saunders; 2002: 503. US Department of Health and Human Services: Organ Procurement and Transplantation Network: www.hhs.gov Barr ML, Schenkel FA, Bowdish ME, et al. Living donor lobar lung transplantation: current status and future directions. Transplant Proc 2005; 37: 3983. Hope T, Lockwood G, Lockwood M, et al. Should older women be offered in vitro fertilization? The interests of the potential child. BMJ 1995; 310: 1455.
Transplantation
6. 7. 8. 9. 10. 11. 12. 13. 14. 15.
& Volume 98, Number 7, October 15, 2014
Dickenson D. Carriers of genetic disorders and the right to have children. Acta Genet Med Gemellol 1995; 44: 75. Ross LF. Ethical considerations related to pregnancy in transplant recipients. N Engl J Med 2006; 12: 1313. Armenti VT, Mortiz MJ, Davison JM. Drug safety issues in pregnancy following transplantation and immunosuppression: effects and outcomes. Drug Saf 1998; 19: 219. Hou S. Pregnancy in renal transplant recipients. Adv Chronic Kidney Dis 2013; 20: 253. Østensen M, Fo¨rger F. How safe are anti-rheumatic drugs during pregnancy? Curr Opin Pharmacol 2013; 13: 470. Friedman JM, Polifka JE. The effects of drugs on the fetus and nursing infant: a handbook for health care professionals. Baltimore, MD: John Hopkins University Press; 1996. Fraser FC, Sajoo A. Teratogenic potential of corticosteroids in humans. Teratology 1995; 51: 45. Jain A, Venkataramanan R, Fung JJ, et al. Pregnancy after liver transplantation under tacrolimus. Transplantation 1997; 64: 559. Hoeltzenbeein M, Elefant E, Vial T, et al. Teratogenicity of mycophenolate confirmed in a prospective study of the European Network of Teratology Information Services. Am J Med Genet A 2012; 158: 588. Starnes VA, Bowdish ME, Woo MS, et al. A decade of living lobar lung transplantation: recipient outcomes. J Thorac Cardiovasc Surg 2004; 127: 114.
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Outcomes After Pregnancy in Living Lobar Lung Transplantation Christina L. Greene, Mark L. Barr, Felicia A. Schenkel, Stephanie G. Worrell, Vaughn A. Starnes, and P. Michael McFadden Pregnancy after lung transplantation has been described, but pregnancy after living donor lobar lung transplantation (LDLT) has not been reported. The aim of this study was to evaluate outcomes after pregnancy with LDLT and discuss current recommendations regarding pregnancy and lung transplantation. A total of four LDLT patients and five pregnancies were identified, all from our institution. No patient has developed worsening pulmonary function or acute or chronic rejection. The complications of pulmonary hypertension and rejection may be overestimated in this population, and recommendations for preventive sterilization at transplantation or abortion at the time of conception are likely unwarranted and unnecessary. Keywords: Living donor lobar lung transplantation, Pregnancy, Cystic fibrosis. (Transplantation 2014;98: 692Y694)
regnancy after lung transplantation has been described (1), but pregnancy after living donor lobar lung transplantation (LDLT) has not been reported. Living donor lobar lung transplantation was originally developed to decrease transplant waiting list mortality because of a lack of available organs. As female patients with LDLT matured, physicians were faced with advising patients on family planning. Generally, most physicians recommend abstaining from pregnancy after lung transplantation because of the required alterations in immunosuppressive therapy that could increase the risk of rejection. Pregnancy after LDLT carries the additional risk of hemodynamic changes associated with smaller than normal total lung volumes. The aim of this study was to evaluate outcomes after pregnancy with LDLT and discuss current recommendations regarding pregnancy and lung transplantation.
P
MATERIALS AND METHODS A retrospective review was conducted to identify all patients who received LDLT and subsequently became pregnant. Institutions which previously published on LDLT were contacted to identify all LDLT patients that had become pregnant. This included our own institutional results as well The authors declare no funding or conflicts of interest. Division of Cardiothoracic Surgery, Department of Surgery, Keck School of Medicine of the University of Southern California, Los Angeles, CA. Address correspondence to: P. Michael McFadden, M.D., Division of Cardiothoracic Surgery, Department of Cardiothoracic Surgery, Keck School of Medicine of the University of Southern California, 1520 San Pablo Street, Suite 4300, Los Angeles, CA 90033. E-mail: [email protected] Received 16 May 2014. Revision requested 4 June 2014. Accepted 16 June 2014. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0041-1337/14/9807-692 DOI: 10.1097/TP.0000000000000363
692
www.transplantjournal.com
as those of Massachusetts’s General Hospital, St. Louis Children’s Hospital, the National Transplantation Pregnancy Registry, and the experiences from Okayama, Japan and Middlesex County, United Kingdom. This study was approved by the institutional review board of the University of Southern California.
RESULTS A total of four LDLT patients and five pregnancies were identified, all from our institution. The median age at transplant was 24 years (range, 21Y29). The indication for transplant in all patients was cystic fibrosis, and each received bilateral living related LDLTs on cardiopulmonary bypass. Median left lung ischemic time was 43 min, median right lung ischemic time was 62 min, and median pump time was 150 min. Initial immunosuppressive regimen included prednisone, cyclosporine-FK506, and azathioprine-mycophenolate (2). All patients received standardized prophylaxis against Candida species, Pneumocystis carinii, and cytomegalovirus (2). Mean time to pregnancy was 4 years after transplantation (range, 1Y8 years). Mean gestation time was 36 weeks (range, 34Y37 weeks). Two patients suffered preeclampsia. Cardiac catheterization or hemodynamic monitoring was not routinely performed during pregnancy or in the peripartum period because no patient developed symptoms of pulmonary hypertension. Additionally, no patient developed acute rejection. Mean time from transplant to telephone interview was 18 years (range, 17Y19 years). No patient has developed worsening pulmonary function or acute-chronic rejection. One patient developed lymphoma which is in remission. All five children of these LDLT patients are well and none has cystic fibrosis (Table 1).
DISCUSSION To date, there have been 253 LDLTs performed in the United States in comparison to the nearly 27,000 deceased Transplantation
& Volume 98, Number 7, October 15, 2014
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Greene et al.
* 2014 Lippincott Williams & Wilkins
TABLE 1.
693
Operative and pregnancy details of LDLT recipients Patient 1
Patient 2
Patient 3
Patient 4
24 38 38 122 8 37 17 0 0
21 64 62 136 1 37 5/7 18 0 0
23 44 61 208 6 34 17 0 0
29 41 75 164 2 31 19 0 0
Age at Transplant Left lobar ischemic time, min Right lobar ischemic time, min Pump time, min Years post-Tx at delivery Gestation of first child, weeks Years follow-up Gestational or postpartum pulmonary hypertension Offspring with Cystic Fibrosis
Operative and pregnancy details of each of the four LDLT recipients are shown above in Table 1. No patient developed pulmonary hypertension during or after pregnancy.
donor lung transplants performed in the United States alone (1, 3). Pregnancy after deceased donor lung transplantation has been described but concerns exist regarding life-threatening complications to the mother and fetus. The primary concern centers on the effect that pregnancy has on the allograft. Increased circulating blood volume and altered hemodynamics of pregnancy can compromise pulmonary function and increase hypoxia. Additional concerns regarding the teratogenic effects of immunosuppressive agents complicate the management of these patients. Lung transplant patients can and do become pregnant. Thirty pregnancies with 18 live births have been reported, reaffirming the fact that successful pregnancy is possible (1). Living donor lobar lung transplantation evolved out of a need to save critically ill patients who could not wait for a deceased donor lung. In LDLT two healthy donors are selected, and each undergoes removal of their respective lower lobe. The lower lobes are then implanted into the recipient in place of whole right and left lungs as in cadaveric lung transplantation (4). Reorganization of the Organ Procurement and Transplantation Network allocation system better served these critically ill patients and the need for LDLT decreased. In the last 5 years alone, there have only been four LDLTs performed in the United States (3). Patients receiving LDLT tend to be younger and have more severe disease than the cadaveric lung transplant patients. A large proportion of patients are affected by cystic fibrosis and as this patient population ages the question of family planning begins to have a prominent role. There are no clear cut recommendations regarding pregnancy and lung transplantation. Although it has been reported, it is still widely viewed by the medical community as an adverse event in the life of a transplant recipient because it increases their risk of rejection and places the children at risk of being orphaned. The idea that a lung transplant recipient might purposefully get pregnant inspires heated debate among clinicians regarding values spanning from personal responsibility for putting a valuable organ at risk to child endangerment (5, 6). In her editorial in the New England Journal of Medicine, Ross (7) evaluates the ethics of pregnancy after transplantation. Though almost all the data is based on abdominal organ transplantation, she repeatedly points out the lack of evidence for most recommendations.
The common recommendation to delay pregnancy 2 years after transplantation is not based on solid evidence. Although azathioprine and cyclosporine have been shown to be teratogenic in animals, rates of birth defects in women who took these immunosuppressive drugs while pregnant are not statistically different (8Y10). Azathioprine was found to minimally increase the risk of teratogenic effects whereas the rate of malformations in patients taking corticosteroids was the same as the background population (3.5%) (11, 12). The teratogenic effect of tacrolimus is also minimal though it is known to cause transient hyperkalemia and mild reversible renal impairment (13). A recent prospective trial has confirmed the teratogenic effects of mycophenolate mofetil, especially when continued 7 weeks after the last menstrual period (14). Recommendations for prophylactic sterilization or even abortion also lack scientific merit, yet they are pervasive throughout the medical community. The patients in the present study were encouraged at some point in their course to obtain a tubal ligation or consider abortion of their fetus at conception. All four disregarded these recommendations and instead sought clinicians who helped them navigate this milestone in life. All proceeded to successful pregnancies and post-operative courses. A common sentiment expressed by the patients was that they went through the transplantation process not only to increase their lifespan but also to experience a more normal life. This begs the question, are we as physicians denying patients a much desired life experience out of personal bias and unsubstantiated concerns? Our series of four patients and five births is the first report of successful pregnancy after LDLT. Cystic Fibrosis was the indication for transplantation in all patients but none of them developed the complications of pulmonary hypertension or chronic rejection. Each of the patients had successful, uneventful pregnancies and their children are healthy and normal. A possible explanation for the low incidence of rejection is that all lobar donors were closely related (i.e. sisters, brother, aunts, uncles or cousins). Although we previously reported no differences in rejection between related and unrelated donors (15), some degree of immunologic tolerance may still exist. Optimal patient management is paramount. After the initial postoperative care at our institution each recipient and their pregnancy was managed by their local physicians in the United States and Canada.
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
694
www.transplantjournal.com
It is our impression that although pregnancy after LDLT is a rare event, it seems to be safe and has good outcomes in well-managed patients. The complications of pulmonary hypertension and rejection may be overestimated in this population, and recommendations for preventive sterilization at the time of transplantation or abortion at the time of conception are likely unwarranted and unnecessary. REFERENCES 1. 2. 3. 4. 5.
Shaner J, Coscia LA, Constantinescu S, et al. Pregnancy after lung transplant. Prog Transplant 2012; 22: 134. Baker CJ, Barr ML, Schenkel FA, et al. Living donor lung transplantation. In: Baumgartner WA, Reitz B, Kasper E, Theodore J, eds. Heart and lung transplantation. Philadelphia, PA: WB Saunders; 2002: 503. US Department of Health and Human Services: Organ Procurement and Transplantation Network: www.hhs.gov Barr ML, Schenkel FA, Bowdish ME, et al. Living donor lobar lung transplantation: current status and future directions. Transplant Proc 2005; 37: 3983. Hope T, Lockwood G, Lockwood M, et al. Should older women be offered in vitro fertilization? The interests of the potential child. BMJ 1995; 310: 1455.
Transplantation
6. 7. 8. 9. 10. 11. 12. 13. 14. 15.
& Volume 98, Number 7, October 15, 2014
Dickenson D. Carriers of genetic disorders and the right to have children. Acta Genet Med Gemellol 1995; 44: 75. Ross LF. Ethical considerations related to pregnancy in transplant recipients. N Engl J Med 2006; 12: 1313. Armenti VT, Mortiz MJ, Davison JM. Drug safety issues in pregnancy following transplantation and immunosuppression: effects and outcomes. Drug Saf 1998; 19: 219. Hou S. Pregnancy in renal transplant recipients. Adv Chronic Kidney Dis 2013; 20: 253. Østensen M, Fo¨rger F. How safe are anti-rheumatic drugs during pregnancy? Curr Opin Pharmacol 2013; 13: 470. Friedman JM, Polifka JE. The effects of drugs on the fetus and nursing infant: a handbook for health care professionals. Baltimore, MD: John Hopkins University Press; 1996. Fraser FC, Sajoo A. Teratogenic potential of corticosteroids in humans. Teratology 1995; 51: 45. Jain A, Venkataramanan R, Fung JJ, et al. Pregnancy after liver transplantation under tacrolimus. Transplantation 1997; 64: 559. Hoeltzenbeein M, Elefant E, Vial T, et al. Teratogenicity of mycophenolate confirmed in a prospective study of the European Network of Teratology Information Services. Am J Med Genet A 2012; 158: 588. Starnes VA, Bowdish ME, Woo MS, et al. A decade of living lobar lung transplantation: recipient outcomes. J Thorac Cardiovasc Surg 2004; 127: 114.
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
