- Email: [email protected]
Pregnancy After Liver Transplantation: Risks and Outcomes
Pregnancy After Liver Transplantation: Risks and Outcomes A. Baskirana,*, S. Karakasa, V. Incea, M. Kementb, F. Ozdemira, O. Ozsayc, K. Kutluturka, V. Ersana, C. Koca, B. Baruta, and S. Yilmaza a Department of General Surgery, Liver Transplantation Institute of Inonu University, Malatya, Turkey; bUniversity of Health Sciences, Kartal Training and Research Hospital, Istanbul, Turkey; and cUniversity of Katip Celebi, Ataturk Training and Research Hospital, Izmir, Turkey
ABSTRACT Objective. The aim of this study was to evaluate the outcomes of liver transplant recipients who became pregnant after transplantation. Methods. The clinical data of all patients who underwent liver transplantation between January 2007 and December 2016 in our liver transplantation institute were reviewed. The following data were analyzed: indications for transplantation, recipient age at the beginning of pregnancy, the interval between transplantation and pregnancy, maternal and fetal complications, type of delivery, the health condition of neonates, and modifications in immunosuppressive therapy. Results. During the study period, 1890 patients underwent liver transplantation. There were 185 women (9.8%) in childbearing age (15e45 years old), and 18 (9.7%) of them became pregnant during the study period. There were a total of 26 pregnancies. The mean age of patients at the time of operation was 25.3 5.2 years, and the mean interval between operation and conception was 32.7 15.3 months. Seventeen pregnancies (65.4%) ended in a live birth in the study. Six pregnancies (23%) resulted with no maternal or fetal complications. The most frequent maternal complication during pregnancy was pregnancyinduced hypertension (n ¼ 3; 16.6%). Conclusions. Despite advances in immunosuppressive therapy and increasing experience in the management of these patients, pregnancies in liver transplant recipients are still more risky than in the general population for both the mother and the fetus. Thus, the issues related to fertility should be comprehensively discussed with the patients and their partners, preferably before transplantation, and pregnancies in liver transplant recipients should be followed up more carefully by a multidisciplinary team.
L
IVER transplantation (LT) continues to be the only effective treatment method for end-stage liver failure, which can affect people from all age groups, including women of childbearing age. Thus, there will be a group of women who want to become pregnant after transplantation. Furthermore, infertility often seen in women with end-stage liver disease is usually treated with transplantation, with the goal of restoring reproductive endocrine functions. In the United States, w1000 women of childbearing age undergo LT each year [1]. The first successful pregnancy after LT was reported in 1978, w15 years after the first successful LT [2]. Today, pregnancy is a relatively common occurrence after LT. ª 2017 Elsevier Inc. All rights reserved. 230 Park Avenue, New York, NY 10169
Transplantation Proceedings, 49, 1875e1878 (2017)
Despite advances in immunosuppressive therapy and increasing experience in the management of these patients, pregnancies in LT recipients are still more risky than in the general population for both the mother and the fetus, and they need to be carefully followed up in specialized centers by a multidisciplinary team. These teams include an obstetrician experienced in high-risk pregnancies, a perinatologist, a transplant surgeon, and a transplant
*Address correspondence to Adil Baskiran, Liver Transplantation Institute of Inonu University, Malatya, 44280 Turkey. E-mail: [email protected] 0041-1345/17 http://dx.doi.org/10.1016/j.transproceed.2017.04.023
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BASKIRAN, KARAKAS, INCE ET AL Table 1. Delivery Data of the Patients Parameter
Value
Mean interval between operation and conception, mo Pregnancy outcomes (live birth/ stillbirth/miscarriage) Mean gestational age at delivery in live births Mean birth weight in live births, g Vaginal delivery/cesarean sections in live births
32.7 15.3 17/3/6 (65.4%/11.5%/23.1%) 37.4 1.7 3147 658 8/9 (47.1%/52.9%)
hepatologist [3]. Thus, issues related to fertility should be comprehensively discussed with the patients and their partners, preferably before transplantation, and the timing of pregnancy should be well planned. The most frequently reported complications in the fertile, prenatal, and postnatal periods of the pregnant LT recipient include anemia, pregnancy-induced hypertension (PIH), preeclampsia, intrauterine infections, cholestasis, pyelonephritis, congenital cytomegalovirus infection, perinatal infection with hepatitis B virus (HBV) and hepatitis C virus, prematurity (w40%), prenatal infections, intrauterine growth restriction (w20%), birth defects, and immune suppression [1,3e5]. The aim of the present study was to evaluate the outcomes of LT recipients who became pregnant after transplantation.
(range, 21e35 years), and the mean interval between operation and conception was 32.7 15.3 months (range, 7e76 months). Indications for LT
The etiology of end-stage liver disease was as follows in these study patients: HBV in 8 patients (44.4%), BuddChiari syndrome (BCS) in 4 patients (22.2%), hepatocellular carcinoma (HCC) in 2 patients (11.1%), cryptogenic chronic hepatitis in 2 patients (11.1%), fulminant hepatitis A in 1 patient (5.6%), and a1-antitrypsin deficiency in 1 patient (5.6%). Delivery Outcomes
Seventeen pregnancies (65.4%) ended in a live birth in this study. In the live births, the mean gestational age at delivery was 37.4 1.7 weeks (range, 32e40 weeks), and there were 6 (35.3%) preterm deliveries. The mean birth weight was 3147 658 g (range, 2200e4800). Four neonates (25%) were born at low birth weight. Cesarean sections were performed in 9 deliveries (52.9%). There were no differences in obstetric outcomes in terms of delivery methods (Table 1). Miscarriage and stillbirth occurred in 6 (23.1%) and 3 (11.5%) pregnancies, respectively. The miscarriages and stillbirths occurred at a mean of 10.2 2.8 weeks and 31.3 4.1 weeks. No congenital abnormalities were diagnosed in this study.
PATIENTS AND METHODS
Maternal Complications
Clinical data of all patients who underwent LT between January 2007 and December 2016 in our LT institute were reviewed. Data were obtained from a prospectively maintained database. Data of the patients who became pregnant during the follow-up period after LT were analyzed. The following data were analyzed: indications for transplantation, recipient age at the beginning of pregnancy, the interval between transplantation and pregnancy, maternal and fetal complications, type of delivery, the health condition of neonates, and modifications in immunosuppressive therapy. All data management and statistical analyses were performed by using IBM SPSS version 20.0 (IBM SPSS Statistics, IBM Corporation, Armonk, NY, United States). Means are reported with standard deviations. Continuous variables were compared with Student t tests or Mann-Whitney tests (for nonnormal data), and categorical data were compared with c2 tests.
Tacrolimus was the preferred immunosuppressive drug in all patients during the study period. Dosage adjustments of tacrolimus were required in 5 patients (27.8%) during pregnancy. Mycophenolate mofetil was additionally used in 1 patient (11.1%). Maternal complications during pregnancy were as follows: PIH in 3 patients (16.6%), preeclampsia in 2 patients (11.1%), gestational diabetes mellitus in 2 patients (11.1%), thrombocytopenia in 2 patients (11.1%), various infections in 2 patients (11.1), viral reactivation in 1 patient (11.1% of patients with HBV), chronic rejection in 1 patient (11.1%), and recurrence of HCC in 1 patient (50% of HCC patients) (Table 2). Table 2. Maternal Complications
RESULTS Patients
A total of 1890 patients underwent LT during the study period. There were 185 women (9.8%) in childbearing age (15e45 years old), and 18 of them (9.7%) became pregnant during the study period. Six patients (2.7%) had multiple pregnancies (2 in 4 patients, 3 in 2 patients), and there were a total of 26 pregnancies. All of the 18 patients received an adult-to-adult living donor LT in our study. The mean age of the patients at the time of operation was 25.3 5.2 years
Complication
No. (%)
No complication Hypertension Preeclampsia Gestational diabetes mellitus Thrombocytopenia Infections Viral reactivation HCC recurrence
6 (23) 3 (16.6) 2 (11.1) 2 (11.1) 2 (11.1) 2 (11.1) 1 (11.1 of patients with HBV) 1 (50 of patients with HCC)
Abbreviations: HBV, hepatitis B virus; HCC, hepatocellular carcinoma.
PREGNANCY AFTER LIVER TRANSPLANTATION
Six pregnancies (23%) occurred with no maternal or fetal complications. The mean interval between operation and conception was 49.3 13.7 months in the uncomplicated pregnancies and significantly higher than the complicated pregnancies (27.7 12 months; P < .01). There were no maternal deaths during pregnancy or in the early postpartum period. In the follow-up period, 2 patients (11.1%) died of HCC recurrence and chronic rejection, respectively. DISCUSSION
Approximately 15,000 female LT recipients of childbearing age are currently living in the United States, and an additional 500 women will undergo LT annually [1]. Although experiences in pregnancies of LT recipients have gradually increased, the rate of complications in these pregnancies is still relatively high. The mother, fetus, and allograft are at high risk of complications. Thus, they should be assigned to high-risk pregnancy groups and need to be monitored carefully by a multidisciplinary team. In addition to routine pregnancy checkups, close monitoring of allograft function parameters is also necessary. Bilirubin, international normalized ratio, lactate dehydrogenase, aspartate and alanine aminotransferase levels, and platelet counts should be frequently assessed even if the patient does not have any clinical signs. Although most LT recipients resume their menstrual cycle and are capable of conception within 1 year after LT, there is no proven optimal interval between LT and pregnancy. Currently, the American Society of Transplantation advises that LT recipients postpone pregnancy at least 1 year to stabilize graft functions and immunosuppression dosage [1]. Also, numerous reports have confirmed that the longer the interval between transplantation and conception, the lesser the risk of pregnancy complications [6e8]. In our study, the mean interval between operation and conception was w49 months in the uncomplicated pregnancies and significantly higher than the complicated pregnancies (w28 months), in accordance with the literature. A comprehensive meta-analysis and systematic review study analyzing the US National Transplantation Pregnancy Registry (NTPR) data and several hundred unique reports have been published by Deshpande et al [1]. In this metaanalysis, they reported 450 pregnancies of 306 LT recipients, which resulted in live births in 77%. This finding indicates a marked improvement over a 2006 study published by NTPR, in which only 58% of 202 pregnancies in 121 LT recipients resulted in live births [6]. Interestingly, the live birth rate was higher for LT recipients vs the general population (77% vs 67% in the United States) in the United States, the United Kingdom, and European countries. Correspondingly, they only reported 28 abortions (6.2%) and 4 stillbirths (0.9%), which is significantly less than the 39% reported by NTPR in 2006 [1,8]. Moreover, the miscarriage rate was lower for LT recipients vs the general population (15.6% vs 17.1%). In the present study, 65.3% of
1877
pregnancies ended in a live birth, and the miscarriage and stillbirth rates were 23.1% and 11.5%, respectively. Concerns about complications that may arise in patients undergoing immunosuppression are the most important aspect of LT recipients’ pregnancies. The most frequently reported maternal complication in this patient population is PIH. The incidence of PIH was reported to be w27% in the meta-analysis of Deshpande et al [1]. PIH, which was observed in 16.6% of patients, was the most common complication in the present study as well. Deshpande et al reported the incidence of preeclampsia as 21.9%, which was w6 times higher than in the general US population (22% vs 3.8%). In the present study, preeclampsia was observed in 2 (11%) patients. Gestational diabetes mellitus was reported in 5% of patients by Deshpande et al. Gestational diabetes mellitus was observed in 2 patients (11%) in the present study. To date, only 50 cases of HCC complicating pregnancy have been reported worldwide. The outcome of these cases was invariably poor, with few maternal survivals, which is attributed to estrogen stimulation of HCC growth and pregnancy-related immunotolerance. Estrogen was shown to increase hepatocyte mitosis, hypervascularity, free radicals, and HBV reactivation and to decrease humoral immunity [9]. Although there is not enough data to predict the outcomes of LT recipients with HCC who become pregnant, we advise our patients not to conceive for at least 3 years after transplantation. Nevertheless, we observed HCC recurrence in 1 patient, who conceived w40 months after transplantation. Pregnancy is a hypercoagulable state with increased serum clotting factors [10], which may result in an increased chance of re-developing thrombosis within the hepatic venous outflow in patients with BCS undergoing LT. In our study, the indication of LT was BCS in 4 patients. We observed no recurrence in these patients during the pregnancy period. Acetylsalicylic acid in the first 2 trimesters and low-molecular-weight heparins with regular monitoring of anti-FXa in the third trimester were the preferred anticoagulation methods in these patients. In our study, all of the patients were taking tacrolimus, and we could therefore not perform any comparisons between immunosuppressive regimens. Tacrolimus and cyclosporine were compared in terms of delivery outcomes and obstetric complications by Christopher et al [11]; there were no statistically significant differences. However, data from the NTPR propose that cyclosporine is related to higher rates of hypertension and preeclampsia compared with tacrolimus [12]. Also, renal dysfunctions were reportedly more common in patients treated with cyclosporine vs patients treated with tacrolimus [3]. In the 2009 NTPR report, the rates of rejection during pregnancy and graft loss within 2 years were stratified in terms of immunosuppressive regimens [12]. Rejection and graft loss rates were 5% and 6% in patients taking tacrolimus, 8% and 10% in those taking cyclosporine, and 2% and 8% in those taking cyclosporine, respectively. Christopher et al [11] reported 12 cases (17%) of acute cellular rejection
1878
during pregnancy and re-transplantation in 7 patients >1 year after birth. Acute rejection rate during pregnancy was reported to be 10% in a review performed by Dei Malatesta et al [13]. Nagy et al [3] reported a total rejection rate in 4 of 24 live births but no cases of graft loss. Despite all these data, the correlation between pregnancy and rejection has not been fully elucidated. In our study, graft rejection during pregnancy was observed in 1 patient (5.6%) who had chronic characteristics; this patient died 2 years after delivery. Prematurity is the most frequently reported fetal complication in LT recipient pregnancies, which affects w40% of live births. The mean reported gestational age at delivery is w36.5 weeks, whereas the mean birth weight is w14% less than in the general population [1,14]. In our study, the prematurity rate was w35%, and the mean gestational age at delivery was 37.4 weeks, whereas the mean birth weight was 3147 g. In our study, no major congenital malformations were observed; however, in the 2009 NTPR report, 5 birth defects among 57 LT recipients were reported (1 with a total anomalous pulmonary venous, 1 with pyloric stenosis, 1 with hypospadias, and 2 with multiple anomalies) [12]. Jain et al [15] reported 1 infant with a tracheoesophageal fistula and valvular heart disease and another infant with a nonfunctional unilateral cystic kidney and accessory nipple. Nagy et al 3] reported 2 neonates with small membranous ventricular septal defects and 1 neonate with bilateral hydrocele from the mothers taking tacrolimus. One other mother taking cyclosporine had a neonate with hypospadias. In our study, cesarean sections were performed in 9 deliveries (52.9%). There were no differences in obstetric outcomes in terms of delivery methods. Our results support the theory that there is no evidence of a contraindication to vaginal delivery in LT recipients [11]. CONCLUSIONS
Despite advances in immunosuppressive therapy and increasing experience in the management of these patients, pregnancies in LT recipients are still more risky than in the general population for both the mother and the fetus. Thus, the issues related to fertility should be comprehensively discussed with the patients and their partners, preferably before transplantation, and pregnancies in LT recipients should be followed up more carefully by a multidisciplinary team.
BASKIRAN, KARAKAS, INCE ET AL
REFERENCES [1] Deshpande NA, James NT, Kucirka LM, et al. Pregnancy outcomes of liver transplant recipients: a systematic review and meta-analysis. Liver Transpl 2012;18:621e9. [2] Walcott WO, Derick DE, Jolley JJ, Snyder DL. Successful pregnancy in a liver transplant patient. Am J Obstet Gynecol 1978;132:340e1. [3] Nagy S, Bush MC, Berkowitz R, Fishbein TM, GomezLobo V. Pregnancy outcome in liver transplant recipients. Obstet Gynecol 2003;102:121e8. [4] Maddukuri VC, Stephenson CD, Eskind L, Ahrens WA, Purdum P, Russo MW. Liver transplantation for acute liver failure at 11-week gestation with successful maternal and fetal outcome. Case Rep Transplant 2012;2012:484080. [5] Cardonick E, Moritz M, Armenti V. Pregnancy in patients with organ transplantation: a review. Obstet Gynecol Surv 2004;59: 214e22. [6] Armenti VT, Radomski JS, Moritz MJ, Gaughan WJ, Hecker WP, Lavelanet A, et al. Report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation. Clin Transplant 2004:103e14. [7] Fischer T, Neumayer HH, Fischer R, Barenbrock M, Schobel HP, Lattrell BC, et al. Effect of pregnancy on long-term kidney function in renal transplant recipients treated with cyclosporine and with azathioprine. Am J Transplant 2005;5:2732e9. [8] Armenti VT, Daller JA, Constantinescu S, Silva P, Radomski JS, Moritz MJ, et al. Report from the National Transplantation Pregnancy Registry: outcomes of pregnancy after transplantation. Clin Transpl 2006:57e70. [9] De Maria N, Manno M, Villa E. Sex hormones and liver cancer. Mol Cell Endocrinol 2002;193:59e63. [10] Franchini M. Haemostasis and pregnancy. Thromb Haemost 2006;95:401e13. [11] Christopher V, Al-Chalabi T, Richardson PD, Muiesan P, Rela M, Heaton ND, et al. Pregnancy outcome after liver transplantation: a single-center experience of 71 pregnancies in 45 recipients. Liver Transpl 2006;12:1138e43. [12] Coscia LA, Constantinescu S, Moritz MJ, Frank A, Ramirez CB, Maley WL, et al. Report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation. Clin Transplant 2009:103e22. [13] Dei Malatesta MF, Rossi M, Rocca B, Iappelli M, Giorno MP, Berloco P, et al. Pregnancy after liver transplantation: report of 8 new cases and review of the literature. Transpl Immunol 2006;15:297e302. [14] 2004 Annual Report of the U.S. Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients: Transplant Data 1994-2003.
ABSTRACT Objective. The aim of this study was to evaluate the outcomes of liver transplant recipients who became pregnant after transplantation. Methods. The clinical data of all patients who underwent liver transplantation between January 2007 and December 2016 in our liver transplantation institute were reviewed. The following data were analyzed: indications for transplantation, recipient age at the beginning of pregnancy, the interval between transplantation and pregnancy, maternal and fetal complications, type of delivery, the health condition of neonates, and modifications in immunosuppressive therapy. Results. During the study period, 1890 patients underwent liver transplantation. There were 185 women (9.8%) in childbearing age (15e45 years old), and 18 (9.7%) of them became pregnant during the study period. There were a total of 26 pregnancies. The mean age of patients at the time of operation was 25.3 5.2 years, and the mean interval between operation and conception was 32.7 15.3 months. Seventeen pregnancies (65.4%) ended in a live birth in the study. Six pregnancies (23%) resulted with no maternal or fetal complications. The most frequent maternal complication during pregnancy was pregnancyinduced hypertension (n ¼ 3; 16.6%). Conclusions. Despite advances in immunosuppressive therapy and increasing experience in the management of these patients, pregnancies in liver transplant recipients are still more risky than in the general population for both the mother and the fetus. Thus, the issues related to fertility should be comprehensively discussed with the patients and their partners, preferably before transplantation, and pregnancies in liver transplant recipients should be followed up more carefully by a multidisciplinary team.
L
IVER transplantation (LT) continues to be the only effective treatment method for end-stage liver failure, which can affect people from all age groups, including women of childbearing age. Thus, there will be a group of women who want to become pregnant after transplantation. Furthermore, infertility often seen in women with end-stage liver disease is usually treated with transplantation, with the goal of restoring reproductive endocrine functions. In the United States, w1000 women of childbearing age undergo LT each year [1]. The first successful pregnancy after LT was reported in 1978, w15 years after the first successful LT [2]. Today, pregnancy is a relatively common occurrence after LT. ª 2017 Elsevier Inc. All rights reserved. 230 Park Avenue, New York, NY 10169
Transplantation Proceedings, 49, 1875e1878 (2017)
Despite advances in immunosuppressive therapy and increasing experience in the management of these patients, pregnancies in LT recipients are still more risky than in the general population for both the mother and the fetus, and they need to be carefully followed up in specialized centers by a multidisciplinary team. These teams include an obstetrician experienced in high-risk pregnancies, a perinatologist, a transplant surgeon, and a transplant
*Address correspondence to Adil Baskiran, Liver Transplantation Institute of Inonu University, Malatya, 44280 Turkey. E-mail: [email protected] 0041-1345/17 http://dx.doi.org/10.1016/j.transproceed.2017.04.023
1875
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BASKIRAN, KARAKAS, INCE ET AL Table 1. Delivery Data of the Patients Parameter
Value
Mean interval between operation and conception, mo Pregnancy outcomes (live birth/ stillbirth/miscarriage) Mean gestational age at delivery in live births Mean birth weight in live births, g Vaginal delivery/cesarean sections in live births
32.7 15.3 17/3/6 (65.4%/11.5%/23.1%) 37.4 1.7 3147 658 8/9 (47.1%/52.9%)
hepatologist [3]. Thus, issues related to fertility should be comprehensively discussed with the patients and their partners, preferably before transplantation, and the timing of pregnancy should be well planned. The most frequently reported complications in the fertile, prenatal, and postnatal periods of the pregnant LT recipient include anemia, pregnancy-induced hypertension (PIH), preeclampsia, intrauterine infections, cholestasis, pyelonephritis, congenital cytomegalovirus infection, perinatal infection with hepatitis B virus (HBV) and hepatitis C virus, prematurity (w40%), prenatal infections, intrauterine growth restriction (w20%), birth defects, and immune suppression [1,3e5]. The aim of the present study was to evaluate the outcomes of LT recipients who became pregnant after transplantation.
(range, 21e35 years), and the mean interval between operation and conception was 32.7 15.3 months (range, 7e76 months). Indications for LT
The etiology of end-stage liver disease was as follows in these study patients: HBV in 8 patients (44.4%), BuddChiari syndrome (BCS) in 4 patients (22.2%), hepatocellular carcinoma (HCC) in 2 patients (11.1%), cryptogenic chronic hepatitis in 2 patients (11.1%), fulminant hepatitis A in 1 patient (5.6%), and a1-antitrypsin deficiency in 1 patient (5.6%). Delivery Outcomes
Seventeen pregnancies (65.4%) ended in a live birth in this study. In the live births, the mean gestational age at delivery was 37.4 1.7 weeks (range, 32e40 weeks), and there were 6 (35.3%) preterm deliveries. The mean birth weight was 3147 658 g (range, 2200e4800). Four neonates (25%) were born at low birth weight. Cesarean sections were performed in 9 deliveries (52.9%). There were no differences in obstetric outcomes in terms of delivery methods (Table 1). Miscarriage and stillbirth occurred in 6 (23.1%) and 3 (11.5%) pregnancies, respectively. The miscarriages and stillbirths occurred at a mean of 10.2 2.8 weeks and 31.3 4.1 weeks. No congenital abnormalities were diagnosed in this study.
PATIENTS AND METHODS
Maternal Complications
Clinical data of all patients who underwent LT between January 2007 and December 2016 in our LT institute were reviewed. Data were obtained from a prospectively maintained database. Data of the patients who became pregnant during the follow-up period after LT were analyzed. The following data were analyzed: indications for transplantation, recipient age at the beginning of pregnancy, the interval between transplantation and pregnancy, maternal and fetal complications, type of delivery, the health condition of neonates, and modifications in immunosuppressive therapy. All data management and statistical analyses were performed by using IBM SPSS version 20.0 (IBM SPSS Statistics, IBM Corporation, Armonk, NY, United States). Means are reported with standard deviations. Continuous variables were compared with Student t tests or Mann-Whitney tests (for nonnormal data), and categorical data were compared with c2 tests.
Tacrolimus was the preferred immunosuppressive drug in all patients during the study period. Dosage adjustments of tacrolimus were required in 5 patients (27.8%) during pregnancy. Mycophenolate mofetil was additionally used in 1 patient (11.1%). Maternal complications during pregnancy were as follows: PIH in 3 patients (16.6%), preeclampsia in 2 patients (11.1%), gestational diabetes mellitus in 2 patients (11.1%), thrombocytopenia in 2 patients (11.1%), various infections in 2 patients (11.1), viral reactivation in 1 patient (11.1% of patients with HBV), chronic rejection in 1 patient (11.1%), and recurrence of HCC in 1 patient (50% of HCC patients) (Table 2). Table 2. Maternal Complications
RESULTS Patients
A total of 1890 patients underwent LT during the study period. There were 185 women (9.8%) in childbearing age (15e45 years old), and 18 of them (9.7%) became pregnant during the study period. Six patients (2.7%) had multiple pregnancies (2 in 4 patients, 3 in 2 patients), and there were a total of 26 pregnancies. All of the 18 patients received an adult-to-adult living donor LT in our study. The mean age of the patients at the time of operation was 25.3 5.2 years
Complication
No. (%)
No complication Hypertension Preeclampsia Gestational diabetes mellitus Thrombocytopenia Infections Viral reactivation HCC recurrence
6 (23) 3 (16.6) 2 (11.1) 2 (11.1) 2 (11.1) 2 (11.1) 1 (11.1 of patients with HBV) 1 (50 of patients with HCC)
Abbreviations: HBV, hepatitis B virus; HCC, hepatocellular carcinoma.
PREGNANCY AFTER LIVER TRANSPLANTATION
Six pregnancies (23%) occurred with no maternal or fetal complications. The mean interval between operation and conception was 49.3 13.7 months in the uncomplicated pregnancies and significantly higher than the complicated pregnancies (27.7 12 months; P < .01). There were no maternal deaths during pregnancy or in the early postpartum period. In the follow-up period, 2 patients (11.1%) died of HCC recurrence and chronic rejection, respectively. DISCUSSION
Approximately 15,000 female LT recipients of childbearing age are currently living in the United States, and an additional 500 women will undergo LT annually [1]. Although experiences in pregnancies of LT recipients have gradually increased, the rate of complications in these pregnancies is still relatively high. The mother, fetus, and allograft are at high risk of complications. Thus, they should be assigned to high-risk pregnancy groups and need to be monitored carefully by a multidisciplinary team. In addition to routine pregnancy checkups, close monitoring of allograft function parameters is also necessary. Bilirubin, international normalized ratio, lactate dehydrogenase, aspartate and alanine aminotransferase levels, and platelet counts should be frequently assessed even if the patient does not have any clinical signs. Although most LT recipients resume their menstrual cycle and are capable of conception within 1 year after LT, there is no proven optimal interval between LT and pregnancy. Currently, the American Society of Transplantation advises that LT recipients postpone pregnancy at least 1 year to stabilize graft functions and immunosuppression dosage [1]. Also, numerous reports have confirmed that the longer the interval between transplantation and conception, the lesser the risk of pregnancy complications [6e8]. In our study, the mean interval between operation and conception was w49 months in the uncomplicated pregnancies and significantly higher than the complicated pregnancies (w28 months), in accordance with the literature. A comprehensive meta-analysis and systematic review study analyzing the US National Transplantation Pregnancy Registry (NTPR) data and several hundred unique reports have been published by Deshpande et al [1]. In this metaanalysis, they reported 450 pregnancies of 306 LT recipients, which resulted in live births in 77%. This finding indicates a marked improvement over a 2006 study published by NTPR, in which only 58% of 202 pregnancies in 121 LT recipients resulted in live births [6]. Interestingly, the live birth rate was higher for LT recipients vs the general population (77% vs 67% in the United States) in the United States, the United Kingdom, and European countries. Correspondingly, they only reported 28 abortions (6.2%) and 4 stillbirths (0.9%), which is significantly less than the 39% reported by NTPR in 2006 [1,8]. Moreover, the miscarriage rate was lower for LT recipients vs the general population (15.6% vs 17.1%). In the present study, 65.3% of
1877
pregnancies ended in a live birth, and the miscarriage and stillbirth rates were 23.1% and 11.5%, respectively. Concerns about complications that may arise in patients undergoing immunosuppression are the most important aspect of LT recipients’ pregnancies. The most frequently reported maternal complication in this patient population is PIH. The incidence of PIH was reported to be w27% in the meta-analysis of Deshpande et al [1]. PIH, which was observed in 16.6% of patients, was the most common complication in the present study as well. Deshpande et al reported the incidence of preeclampsia as 21.9%, which was w6 times higher than in the general US population (22% vs 3.8%). In the present study, preeclampsia was observed in 2 (11%) patients. Gestational diabetes mellitus was reported in 5% of patients by Deshpande et al. Gestational diabetes mellitus was observed in 2 patients (11%) in the present study. To date, only 50 cases of HCC complicating pregnancy have been reported worldwide. The outcome of these cases was invariably poor, with few maternal survivals, which is attributed to estrogen stimulation of HCC growth and pregnancy-related immunotolerance. Estrogen was shown to increase hepatocyte mitosis, hypervascularity, free radicals, and HBV reactivation and to decrease humoral immunity [9]. Although there is not enough data to predict the outcomes of LT recipients with HCC who become pregnant, we advise our patients not to conceive for at least 3 years after transplantation. Nevertheless, we observed HCC recurrence in 1 patient, who conceived w40 months after transplantation. Pregnancy is a hypercoagulable state with increased serum clotting factors [10], which may result in an increased chance of re-developing thrombosis within the hepatic venous outflow in patients with BCS undergoing LT. In our study, the indication of LT was BCS in 4 patients. We observed no recurrence in these patients during the pregnancy period. Acetylsalicylic acid in the first 2 trimesters and low-molecular-weight heparins with regular monitoring of anti-FXa in the third trimester were the preferred anticoagulation methods in these patients. In our study, all of the patients were taking tacrolimus, and we could therefore not perform any comparisons between immunosuppressive regimens. Tacrolimus and cyclosporine were compared in terms of delivery outcomes and obstetric complications by Christopher et al [11]; there were no statistically significant differences. However, data from the NTPR propose that cyclosporine is related to higher rates of hypertension and preeclampsia compared with tacrolimus [12]. Also, renal dysfunctions were reportedly more common in patients treated with cyclosporine vs patients treated with tacrolimus [3]. In the 2009 NTPR report, the rates of rejection during pregnancy and graft loss within 2 years were stratified in terms of immunosuppressive regimens [12]. Rejection and graft loss rates were 5% and 6% in patients taking tacrolimus, 8% and 10% in those taking cyclosporine, and 2% and 8% in those taking cyclosporine, respectively. Christopher et al [11] reported 12 cases (17%) of acute cellular rejection
1878
during pregnancy and re-transplantation in 7 patients >1 year after birth. Acute rejection rate during pregnancy was reported to be 10% in a review performed by Dei Malatesta et al [13]. Nagy et al [3] reported a total rejection rate in 4 of 24 live births but no cases of graft loss. Despite all these data, the correlation between pregnancy and rejection has not been fully elucidated. In our study, graft rejection during pregnancy was observed in 1 patient (5.6%) who had chronic characteristics; this patient died 2 years after delivery. Prematurity is the most frequently reported fetal complication in LT recipient pregnancies, which affects w40% of live births. The mean reported gestational age at delivery is w36.5 weeks, whereas the mean birth weight is w14% less than in the general population [1,14]. In our study, the prematurity rate was w35%, and the mean gestational age at delivery was 37.4 weeks, whereas the mean birth weight was 3147 g. In our study, no major congenital malformations were observed; however, in the 2009 NTPR report, 5 birth defects among 57 LT recipients were reported (1 with a total anomalous pulmonary venous, 1 with pyloric stenosis, 1 with hypospadias, and 2 with multiple anomalies) [12]. Jain et al [15] reported 1 infant with a tracheoesophageal fistula and valvular heart disease and another infant with a nonfunctional unilateral cystic kidney and accessory nipple. Nagy et al 3] reported 2 neonates with small membranous ventricular septal defects and 1 neonate with bilateral hydrocele from the mothers taking tacrolimus. One other mother taking cyclosporine had a neonate with hypospadias. In our study, cesarean sections were performed in 9 deliveries (52.9%). There were no differences in obstetric outcomes in terms of delivery methods. Our results support the theory that there is no evidence of a contraindication to vaginal delivery in LT recipients [11]. CONCLUSIONS
Despite advances in immunosuppressive therapy and increasing experience in the management of these patients, pregnancies in LT recipients are still more risky than in the general population for both the mother and the fetus. Thus, the issues related to fertility should be comprehensively discussed with the patients and their partners, preferably before transplantation, and pregnancies in LT recipients should be followed up more carefully by a multidisciplinary team.
BASKIRAN, KARAKAS, INCE ET AL
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