- Email: [email protected]
Pregnancy Outcomes Among Female Recipients After Liver Transplantation: Further Experience
Pregnancy Outcomes Among Female Recipients After Liver Transplantation: Further Experience Z. Jabiry-Zieniewicz, M. Szpotanska-Sikorska, B. Pietrzak, B. Kociszewska-Najman, B. Foroncewicz, K. Mucha, K. Zieniewicz, M. Krawczyk, and M. Wielgos ABSTRACT Introduction. Liver transplantations give female recipients an ability to carry pregnancies successfully. However, solid organ transplantations exacerbate the pregnancy including maternal and neonatal outcomes. The aim of our study was to evaluate and identify the obstetric outcomes in women with a prior liver transplantation. Methods. We analyzed all pregnant woman who had undergone a prior liver transplantation and afterward delivered from 2001 to 2011. Complete data were assessed in 39 deliveries and 40 live births. Three women were pregnant twice after liver transplantation. Results. The mean gestational age at birth measured 37.2 ⫾ 2.2 weeks. The most common obstetric complications were premature labor (12/39,30.8%), hypertension (10/39, 25.6%), and symptomatic urinary tract infections (7/39, 18%). Other complications were pregestational diabetes (n ⫽ 1), cholestasis (n ⫽ 3), and of severe anemia treated with blood transfusions (n ⫽ 2). The mean time from organ transplantation to delivery was 67.6 ⫾ 47.2 months. Acute graft rejections occurred among pregnant women 7.7% (3/39) of studied. Only 8 (20.5%) deliveries were finished vaginally. Infants small for gestational age were diagnosed in 20% (8/40). One case displayed a congenital urinary tract malformation. None of the neonates died neonatally. Conclusions. Pregnancies are possible after liver transplantation and likely end with successful maternal and newborn outcomes. Some cases experience an increased risk of obstetric complications. Therefore, posttransplant pregnancies must be regularly monitored with a multidisciplinary approach. OWADAYS ORGAN TRANSPLANTATION is the universally approved management of the end-stage liver failure. The first liver transplantation was performed in 1963; 15 years later, the first delivery was reported by a woman after liver transplantation. Great progress in transplantation has been related to new surgical techniques, better anesthetic care, and improved immunologic and pharmacological treatments. Currently, the number of organ transplantations has increased with better management of early and late rejection, improving the chances for a successful procedure and better quality of life. Women with end-stage liver failure usually experience irregular menstrual cycles, which are caused mainly by inappropriate metabolism of hormones from the hypothalamicpituitary-ovary axis. Almost 50% of female recipients suffer amenorrhea. Solid organ transplantation reestablishes regular ovulatory cycles within 1 year. Therefore, women of
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reproductive age meet the challenge of a new life role becoming pregnant and subsequently, a mother. According to the European Liver Transplant Registry, almost 75% of liver transplanted women are in the reproductive age, thus in the nearest future we may expect increasing numbers of pregnancies.
From the 1st Department of Obstetrics and Gynaecology (Z.J.-Z., M.S.-S., B.P., B.K.-N., M.W.), Transplantation Institute, Department of Immunology, Transplantology and Internal Medicine (B.F., K.M.), and Department of General, Transplant & Liver Surgery (K.Z., M.K.), Medical University of Warsaw, Warsaw, Poland. Address reprint requests to Zoulikha Jabiry-Zieniewicz, 1st Department of Obstetrics and Gynaecology, Medical University of Warsaw, Warsaw, Poland. E-mail: [email protected]
© 2011 Published by Elsevier Inc. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/–see front matter doi:10.1016/j.transproceed.2011.08.070
Transplantation Proceedings, 43, 3043–3047 (2011)
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The uneventful pregnancy course and delivery a healthy newborn at term is determined by stable graft function, an essential condition. Therefore, hepatic as well as renal parameters must be closely monitored. Pregnancies in graft recipients may also require modification of immunosuppressive management. It is strongly advised to start conception at least 12 months posttransplantation.
JABIRY-ZIENIEWICZ, SPZOTANSKA-SIKORSKA, PIETRZAK ET AL Table 1. Characteristic of Primary Liver Diseases and Immunosuppressive Regimens
Primary Liver Disease
Autoimmune hepatitis Wilson’s disease
MATERIALS AND METHODS The aim of our study was to assess pregnancy risks and births in liver transplanted women. We identified 45 labors among 39 recipients, who had delivered between 2001 and 2011. Complete data for retrospective analysis were obtained from 39 deliveries in 36 pregnant women. Three cases became pregnant twice after liver transplantation. Each of the following maternal and obstetric parameters before and during pregnancy were assessed: the primary liver disease, immunosuppressive regimen, age at conception, time interval between transplantation and delivery, mode of delivery, and presumptive indications for cesarean section. We also identified the pregnancy complications of: preterm birth (defined as a delivery before 37 weeks of gestation); premature rupture of the membranes (PROM); new-onset as well as chronic hypertension; preeclampsia; gestational diabetes; cholestasis; anemia; urinary tract infections; and graft rejection. The analysis examined neonatal outcomes in particular: birth weight, incidence of hypotrophy, infant survival, and general condition measured at 5 minutes after delivery with the use of the Apgar score. Birth weight was interpreted with regard to the gestational age using growth percentile charts. Hypotrophic newborns were diagnosed when the birth weight measured less than the 10th percentile for gestational age. All of the obtained results were presented as mean values with standard deviations or as percentages.
RESULTS
We identified 39 deliveries in 36 pregnant liver recipients, who regularly attended obstetric visits. There were 40 live births among 39 deliveries, including one twin labor. Five women (5/35, 14.3%) gave birth twice during this period. Each pregnant woman was closely monitored with multidisciplinary care. Obstetric consultations were performed every 2 weeks to the 28th week of gestation and afterward, once a week. Despite the standard obstetricprocedures, liver function was assessed every 2 weeks. Each month we performed more specific tests to detect contagious liver infections. The mean maternal age at delivery was 28.8 ⫾ 4.7 years. None of the pregnant liver recipients had delivered before liver transplantation. The mean time between organ transplantation and birth was 67.6 ⫾ 47.2 months. Six (15.4%) women delivered by the end of 2 years posttransplantation. The most common cause of primary liver insufficiency was autoimmune hepatitis, which was diagnosed in 12/36 studied women (Table 1). The vast majority of pregnant women after liver transplantation were treated with an immunosuppressive regimen based on tacrolimus (29/39); the most common combination was tacrolimus with prednisone (19/39). In two cases, the combined therapy included
Chronic hepatitis
PSC Budd-Chiari syndrome Unknown Other
Number of Women (%) (n ⫽ 35)
Immunosuppressive Regimen
12 (34.4) Tacrolimus and prednisone 6 (17.1) Tacrolimus and mycophenolate mofetil 6 (17.1) Tacrolimus and mycophenolate mofetil and prednisone 2 (5.7) Tacrolimus 2 (5.7) Cyclosporine and prednisone 3 (8.6) Cyclosporine and azathioprine 4 (11.4) Cyclosporine
Number of Pregnancies (%) (n ⫽ 39)
19 (48.7) 3 (7.7) 2 (5.1)
5 (12.8) 6 (15.3) 1 (2.6) 3 (7.7)
three immunosuppressants, in contradistinction to eight women, who required only one drug, usually tacrolimus. Immunosuppressant doses were closely monitored and adjusted as shown in Table 1. The obstetric complications included mainly preterm labor, hypertension, cholestasis, and urinary tract infections. The mean gestational age at birth was 37.2 ⫾ 2.2 weeks. We identified 12 (30.8%) premature deliveries before 37 weeks of gestation. The earliest labors occurred in three pregnancies at 33 weeks of gestation. One twin pregnancy was diagnosed with PROM, which was additionally complicated with preeclampsia, cholestasis, severe anemia treated with blood transfusions, and twin-to-twin transfusion syndrome. The pregnancy was finished by a premature cesarean section at 33 weeks of gestation. The second case of early preterm birth involved a pregnant liver recipient at 33 weeks of gestation, who complained of PROM and contractions. A cesarean section was performed due to a prolonged first stage of labor. In the third case, the presence of fetal distress and imminent intrauterine infection were represented the indication to finish pregnancy early at 33 weeks of gestation. Figure 1 illustrates the distribution of deliveries according to gestational age. Hypertension occurred in 1/4 of studied pregnancies. All women but one suffered gestational hypertension. Three pregnancies were complicated by preeclampsia: the first was the twin pregnancy, mentioned earlier. The other preeclampsia cases were diagnosed at 36 weeks of gestation. In one case, it additionally complicated a pregnancy in a woman, who had a threatening acute graft rejection successfully treated in the second trimester. High blood pressure and increasing gestational proteinuria necessitated cesarean deliveries. The one case of pregestational diabetes was treated with insulin therapy. None of the women became diabetic during pregnancy. The total incidence of cholestasis was approximately 8%. One of the most common complications among pregnant organ recipients
PREGNANCY OUTCOME
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the neonate had chronically received combined therapy with three immunosuppressants: azathioprine, cyclosporine, and prednisone. No infant died neonatally (Figs 2 and 3). DISCUSSION
Fig 1.
Distribution of deliveries according to gestational age.
treated with long-term immunosuppressive therapy was symptomatic urinary tract infections, which occurred in 18% of participants. We also analyzed the frequency of anemia, which was defined as a hemoglobin less than 11 g/dL, which complicated approximately 36% (14/39) of pregnancies. Treatment with blood transfusions was necessary in two cases. Among the entire study group, three pregnancies were complicated by acute graft rejection episodes, which in all cases were successfully managed with intravenous pulses of methylprednisolone. The first woman delivered before 24 months posttransplantation; the second, at less than 12 months and the third, at more than 2 years after organ transplantation (Table 2). Among the analyzed group, 8 (20.5%) deliveries were finished vaginally; the rest, via cesarean section (79.5%). Among the preterm labors, 3 (25%) infants were born vaginally. Obstetric complications were the main reason for cesarean sections, namely fetal distress, prolonged labor, and previous cesarean section (Figure 2). Pregnant women, who were short-listed for cesarean section received preoperative antibiotic prophylaxis as well as perioperative steroid coverage. We did not observe any postoperative complications. Seven procedures were performed electively and 24, during labor or pregnancy period. All newborn babies were delivered in good general condition; the total Apgar score at 5 minutes after birth ranged from 8 to 10. The 12 neonates (30%) born before 37 weeks of gestation presented characteristics of prematurity. This group was mainly composed of late-preterm infants (8/12) whereas only four neonates (33.3%) were born at 33 weeks of gestation. The mean birth weight measured 2877.4 ⫾ 633 g. Eight of 40 neonates (20%) demonstrated low birth weights, which were defined as less than 2500 g. The lowest birth weight occurred in a donor-twin measuring 1420 g, who was hypotrophic at the 5th percentile, whereas the recipient-twin baby weighed 2514 g (85th percentile). The marked difference in weights was a consequence of twin-totwin transfusion syndrome. A similar incidence of low birth weight (20%) was reported among infants who were small for gestational age. One neonate was diagnosed with a congenital malformation, which included a urinary tract defect with a doubled pyelocalyceal system. The mother of
The vast majority of women suffering end-stage liver disease have irregular menstrual cycles, often leading to amenorrhea. Therefore, they have a poor chance to conceive. Organ transplantation enables female liver recipients to become mothers. Organ transplantation leads to a fast return of libido as well as fertility even within 6 weeks posttransplantation. After 1 year, almost 90% of female liver recipients menstruate regularly.1,2 Current studies suggest that organ recipients can be optimistic about pregnancies, if graft function remains stable and the woman remains under close follow-up provided by a multidisciplinary team. It is preferable and recommended to delay pregnancy until 1 or even better 2 years posttransplantation. Conception during the first year posttransplantation is encumbered by a greater risk of prematurity and graft rejection. However, almost 30% of pregnancies are diagnosed within 24 months after organ transplantation.3 In the present study, more than 15% of women delivered within 24 months posttransplantation. The NTPR registry published in 2006 reported a 7% rate of acute graft rejection episodes during pregnancy and 8% graft loss within 2 years after delivery.4 Other studies have noted a wide range of graft rejections from 0% to 17%.5–10 In our study, acute liver rejection episodes were diagnosed in three cases (7.7%); none of these women experienced graft loss within 2 years after delivery. However, it is worth mentioning that 10 women remain in 2-year follow-up. Furthermore, liver transplanted women are at high risk of pregnancy complications, most of all involving postpartum hemorrhage, need for blood transfusions, and gestational hypertension. Hematologic findings are related to both: chronic immunosuppressive therapy and physiological changes of pregnancy. Anemia is one of the most common complications among pregnant liver transplanted women.11 Some data suggest that anemia constitutes an important indication for antepartum admission, which is estimated to Table 2. Pregnancy Complications in Female Liver Recipients Category
Number of Pregnancies (%) (n ⫽ 39)
Premature labor (⬍37 wk of gestation) Hypertension Preeclampsia Gestational diabetes Pregestational diabetes PROM Urinary tract infections Cholestasis Severe anaemia Acute graft rejection
12 (30.8) 10 (25.6) 3 (7.7) 0 1 (2.6) 3 (7.7) 7 (18.0) 3 (7.7) 2 (5.1) 3 (7.7)
PROM, premature rupture of membranes.
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JABIRY-ZIENIEWICZ, SPZOTANSKA-SIKORSKA, PIETRZAK ET AL
Fig 2. Indications for cesarean section.
be approximately 5%.6,8 In the studied group, anemia occurred in more than one per three women. In two cases (6.7%), blood transfusions were necessary. Hypertension was diagnosed in 25% of cases, which is similar to other published reports.4,5,8,10,12,13 The incidence of preeclampsia was 7.7%, which was also comparable to data from the literature.10 Few reports suggest that the vasoconstrictive effect of immunosuppressive therapy, especially calcineurin inhibitors, may induce hypertension among pregnant liver female recipients.13,14 These drugs have also a hyperglycemic influence, although we did not observe a higher incidence of gestational nor pregestational diabetes.15 Cholestasis complicating liver posttransplant pregnancies is quite difficult to distinguish from graft deterioration. A few reports have suggested a higher prevalence of this disorder, albeit larger studies did not confirm these findings.16,17 In our study, cholestasis was diagnosed among 7.7% of pregnancies. Further analysis resulted in additional findings concerning fetal and neonatal outcomes. The data available in the literature suggest adverse neonatal outcomes including a greater incidence of prematurity, intrauterine growth restriction, and fetal distress.5,6,8,9 Results of our study were consistent with previous reports, namely, 30%, 20%, and
15.4% respectively. We did not observe a higher incidence of congenital malformations. Our study was limited by the small group of participants, making detection of congenital abnormalities difficult; however, it may suggest safe immunosuppressive management. Nowadays, the number of cesarean sections is generally increasing. The same situation is observed among posttransplant pregnancies, wherein the frequency of cesarean sections has changed from 20% to 32% in the 1990s to 46% to 48% in the last decade.7–9,12,18 Despite the majority of cesarean sections in the analyzed group to be performed for obstetric indications, the frequency was 79%, which was close to previous years19,20 due to the mothers being encumbered with medical histories wanting to deliver a healthy neonate. In conclusion, pregnancies after liver transplantation are possible and may complete successfully. Although the majority of pregnancies ended uneventfully, there was an increased risk of obstetric and neonatal complications. Therefore, this group of women and their newborns ought to be regularly monitored by a multidisciplinary approach. There is still a need to assess long-term outcomes of pregnant liver recipients and their neonates.
Fig 3. Distribution of neonatal birth weight (percentile).
PREGNANCY OUTCOME
REFERENCES 1. Armenti VT, Radomsky JS, Moritz MJ, et al: Report from the national Transplantation pregnancy Registry (NTPR): outcomes of pregnancy after transplantation. Clin Transpl 123, 2000 2. Armenti VT, Radomsky JS, Moritz MJ, et al: Report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation. Clin Transpl 103, 2004 3. Fischer T, Neumayer HH, Fischer R, et al: Effect of pregnancy on long-term kidney function in renal transplant recipients treated with cyclosporine and with azathioprine. Am J Transplant 5:2732, 2005 4. Armenti VT, Daller JA, Constantinescu S, et al: Report from the National Transplantation Pregnancy Registry: outcomes of pregnancy after transplantation. Clin Transpl 57, 2006 5. Coffin CS, Shaheen AA, Burak KW, et al: Pregnancy outcomes among liver transplant recipients in the United States: a nationwide case-control analysis. Liver Transpl 16:56, 2010 6. Scantlebury V, Gordon R, Tzakis A, et al: Childbearing after liver transplantation. Transplantation 49:317, 1990 7. Patapis P, Irani S, Mirza DF, et al: Outcome of graft function and pregnancy following liver transplantation. Transplant Proc 29:1565, 1997 8. Nagy S, Bush MC, Berkowitz R: Pregnancy outcome in liver transplant recipients. Obstet Gynecol 102:121, 2003 9. Wu A, Nashan B, Messner U, et al: Outcome of 22 successful pregnancies after liver transplantation. Clin Transplant 12:454, 1998
3047 10. Christopher V, Al-Chalabi T, Richardson PD, et al: Pregnancy outcome after liver transplantation: a single-center experience of 71 pregnancies in 45 recipients. Liver Transpl 12:1138, 2006 11. Maheshwari A, Mishra R, Thuluvath PJ: Post-liver-transplant anemia: etiology and management. Liver Transpl 10:165, 2004 12. Jain AB, Reyes J, Marcos A, et al: Pregnancy after liver transplantation with tacrolimus immunosuppression: a single center’s experience update at 13 years. Transplantation 76:827, 2003 13. Textor SC, Taler SJ, Canzanello VJ, et al: Posttransplantation hypertension related to calcineurin inhibitors. Liver Transpl 6:521, 2000 14. Gardiner SM, March JE, Kemp PA, et al: Regional haemodynamic effects of cyclosporine A, tacrolimus and sirolimus in conscious rats. Br J Pharmacol 141:634, 2004 15. Araki M, Flechner SM, Ismail HR, et al: Posttransplant diabetes mellitus in kidney transplant recipients receiving calcineurin or mTOR inhibitor drugs. Transplantation 81:335, 2006 16. Pruvot FR, Declerck N, Valat-Rigot AS, et al: Pregnancy after liver transplantation: focusing on risks to the mother. Transplant Proc 29:2470, 1997 17. Morton A: Liver transplantation and pregnancy. Aust N Z J Obstet Gynaecol 43:236, 2003 18. Raakow R, Neuhaus R, Buscher U, et al: Parenthood following liver transplantation. Transplant Proc 33:1450, 2001 19. Jabiry-Zieniewicz Z, Cyganek A, Luterek K, et al: Pregnancy and delivery after liver transplantation. Transplant Proc 37:1197, 2005 20. Jabiry-Zieniewicz Z, Bobrowska K, Pietrzak B, et al: Mode of delivery in women after liver transplantation. Transplant Proc 39:2796, 2007
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reproductive age meet the challenge of a new life role becoming pregnant and subsequently, a mother. According to the European Liver Transplant Registry, almost 75% of liver transplanted women are in the reproductive age, thus in the nearest future we may expect increasing numbers of pregnancies.
From the 1st Department of Obstetrics and Gynaecology (Z.J.-Z., M.S.-S., B.P., B.K.-N., M.W.), Transplantation Institute, Department of Immunology, Transplantology and Internal Medicine (B.F., K.M.), and Department of General, Transplant & Liver Surgery (K.Z., M.K.), Medical University of Warsaw, Warsaw, Poland. Address reprint requests to Zoulikha Jabiry-Zieniewicz, 1st Department of Obstetrics and Gynaecology, Medical University of Warsaw, Warsaw, Poland. E-mail: [email protected]
© 2011 Published by Elsevier Inc. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/–see front matter doi:10.1016/j.transproceed.2011.08.070
Transplantation Proceedings, 43, 3043–3047 (2011)
3043
3044
The uneventful pregnancy course and delivery a healthy newborn at term is determined by stable graft function, an essential condition. Therefore, hepatic as well as renal parameters must be closely monitored. Pregnancies in graft recipients may also require modification of immunosuppressive management. It is strongly advised to start conception at least 12 months posttransplantation.
JABIRY-ZIENIEWICZ, SPZOTANSKA-SIKORSKA, PIETRZAK ET AL Table 1. Characteristic of Primary Liver Diseases and Immunosuppressive Regimens
Primary Liver Disease
Autoimmune hepatitis Wilson’s disease
MATERIALS AND METHODS The aim of our study was to assess pregnancy risks and births in liver transplanted women. We identified 45 labors among 39 recipients, who had delivered between 2001 and 2011. Complete data for retrospective analysis were obtained from 39 deliveries in 36 pregnant women. Three cases became pregnant twice after liver transplantation. Each of the following maternal and obstetric parameters before and during pregnancy were assessed: the primary liver disease, immunosuppressive regimen, age at conception, time interval between transplantation and delivery, mode of delivery, and presumptive indications for cesarean section. We also identified the pregnancy complications of: preterm birth (defined as a delivery before 37 weeks of gestation); premature rupture of the membranes (PROM); new-onset as well as chronic hypertension; preeclampsia; gestational diabetes; cholestasis; anemia; urinary tract infections; and graft rejection. The analysis examined neonatal outcomes in particular: birth weight, incidence of hypotrophy, infant survival, and general condition measured at 5 minutes after delivery with the use of the Apgar score. Birth weight was interpreted with regard to the gestational age using growth percentile charts. Hypotrophic newborns were diagnosed when the birth weight measured less than the 10th percentile for gestational age. All of the obtained results were presented as mean values with standard deviations or as percentages.
RESULTS
We identified 39 deliveries in 36 pregnant liver recipients, who regularly attended obstetric visits. There were 40 live births among 39 deliveries, including one twin labor. Five women (5/35, 14.3%) gave birth twice during this period. Each pregnant woman was closely monitored with multidisciplinary care. Obstetric consultations were performed every 2 weeks to the 28th week of gestation and afterward, once a week. Despite the standard obstetricprocedures, liver function was assessed every 2 weeks. Each month we performed more specific tests to detect contagious liver infections. The mean maternal age at delivery was 28.8 ⫾ 4.7 years. None of the pregnant liver recipients had delivered before liver transplantation. The mean time between organ transplantation and birth was 67.6 ⫾ 47.2 months. Six (15.4%) women delivered by the end of 2 years posttransplantation. The most common cause of primary liver insufficiency was autoimmune hepatitis, which was diagnosed in 12/36 studied women (Table 1). The vast majority of pregnant women after liver transplantation were treated with an immunosuppressive regimen based on tacrolimus (29/39); the most common combination was tacrolimus with prednisone (19/39). In two cases, the combined therapy included
Chronic hepatitis
PSC Budd-Chiari syndrome Unknown Other
Number of Women (%) (n ⫽ 35)
Immunosuppressive Regimen
12 (34.4) Tacrolimus and prednisone 6 (17.1) Tacrolimus and mycophenolate mofetil 6 (17.1) Tacrolimus and mycophenolate mofetil and prednisone 2 (5.7) Tacrolimus 2 (5.7) Cyclosporine and prednisone 3 (8.6) Cyclosporine and azathioprine 4 (11.4) Cyclosporine
Number of Pregnancies (%) (n ⫽ 39)
19 (48.7) 3 (7.7) 2 (5.1)
5 (12.8) 6 (15.3) 1 (2.6) 3 (7.7)
three immunosuppressants, in contradistinction to eight women, who required only one drug, usually tacrolimus. Immunosuppressant doses were closely monitored and adjusted as shown in Table 1. The obstetric complications included mainly preterm labor, hypertension, cholestasis, and urinary tract infections. The mean gestational age at birth was 37.2 ⫾ 2.2 weeks. We identified 12 (30.8%) premature deliveries before 37 weeks of gestation. The earliest labors occurred in three pregnancies at 33 weeks of gestation. One twin pregnancy was diagnosed with PROM, which was additionally complicated with preeclampsia, cholestasis, severe anemia treated with blood transfusions, and twin-to-twin transfusion syndrome. The pregnancy was finished by a premature cesarean section at 33 weeks of gestation. The second case of early preterm birth involved a pregnant liver recipient at 33 weeks of gestation, who complained of PROM and contractions. A cesarean section was performed due to a prolonged first stage of labor. In the third case, the presence of fetal distress and imminent intrauterine infection were represented the indication to finish pregnancy early at 33 weeks of gestation. Figure 1 illustrates the distribution of deliveries according to gestational age. Hypertension occurred in 1/4 of studied pregnancies. All women but one suffered gestational hypertension. Three pregnancies were complicated by preeclampsia: the first was the twin pregnancy, mentioned earlier. The other preeclampsia cases were diagnosed at 36 weeks of gestation. In one case, it additionally complicated a pregnancy in a woman, who had a threatening acute graft rejection successfully treated in the second trimester. High blood pressure and increasing gestational proteinuria necessitated cesarean deliveries. The one case of pregestational diabetes was treated with insulin therapy. None of the women became diabetic during pregnancy. The total incidence of cholestasis was approximately 8%. One of the most common complications among pregnant organ recipients
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3045
the neonate had chronically received combined therapy with three immunosuppressants: azathioprine, cyclosporine, and prednisone. No infant died neonatally (Figs 2 and 3). DISCUSSION
Fig 1.
Distribution of deliveries according to gestational age.
treated with long-term immunosuppressive therapy was symptomatic urinary tract infections, which occurred in 18% of participants. We also analyzed the frequency of anemia, which was defined as a hemoglobin less than 11 g/dL, which complicated approximately 36% (14/39) of pregnancies. Treatment with blood transfusions was necessary in two cases. Among the entire study group, three pregnancies were complicated by acute graft rejection episodes, which in all cases were successfully managed with intravenous pulses of methylprednisolone. The first woman delivered before 24 months posttransplantation; the second, at less than 12 months and the third, at more than 2 years after organ transplantation (Table 2). Among the analyzed group, 8 (20.5%) deliveries were finished vaginally; the rest, via cesarean section (79.5%). Among the preterm labors, 3 (25%) infants were born vaginally. Obstetric complications were the main reason for cesarean sections, namely fetal distress, prolonged labor, and previous cesarean section (Figure 2). Pregnant women, who were short-listed for cesarean section received preoperative antibiotic prophylaxis as well as perioperative steroid coverage. We did not observe any postoperative complications. Seven procedures were performed electively and 24, during labor or pregnancy period. All newborn babies were delivered in good general condition; the total Apgar score at 5 minutes after birth ranged from 8 to 10. The 12 neonates (30%) born before 37 weeks of gestation presented characteristics of prematurity. This group was mainly composed of late-preterm infants (8/12) whereas only four neonates (33.3%) were born at 33 weeks of gestation. The mean birth weight measured 2877.4 ⫾ 633 g. Eight of 40 neonates (20%) demonstrated low birth weights, which were defined as less than 2500 g. The lowest birth weight occurred in a donor-twin measuring 1420 g, who was hypotrophic at the 5th percentile, whereas the recipient-twin baby weighed 2514 g (85th percentile). The marked difference in weights was a consequence of twin-totwin transfusion syndrome. A similar incidence of low birth weight (20%) was reported among infants who were small for gestational age. One neonate was diagnosed with a congenital malformation, which included a urinary tract defect with a doubled pyelocalyceal system. The mother of
The vast majority of women suffering end-stage liver disease have irregular menstrual cycles, often leading to amenorrhea. Therefore, they have a poor chance to conceive. Organ transplantation enables female liver recipients to become mothers. Organ transplantation leads to a fast return of libido as well as fertility even within 6 weeks posttransplantation. After 1 year, almost 90% of female liver recipients menstruate regularly.1,2 Current studies suggest that organ recipients can be optimistic about pregnancies, if graft function remains stable and the woman remains under close follow-up provided by a multidisciplinary team. It is preferable and recommended to delay pregnancy until 1 or even better 2 years posttransplantation. Conception during the first year posttransplantation is encumbered by a greater risk of prematurity and graft rejection. However, almost 30% of pregnancies are diagnosed within 24 months after organ transplantation.3 In the present study, more than 15% of women delivered within 24 months posttransplantation. The NTPR registry published in 2006 reported a 7% rate of acute graft rejection episodes during pregnancy and 8% graft loss within 2 years after delivery.4 Other studies have noted a wide range of graft rejections from 0% to 17%.5–10 In our study, acute liver rejection episodes were diagnosed in three cases (7.7%); none of these women experienced graft loss within 2 years after delivery. However, it is worth mentioning that 10 women remain in 2-year follow-up. Furthermore, liver transplanted women are at high risk of pregnancy complications, most of all involving postpartum hemorrhage, need for blood transfusions, and gestational hypertension. Hematologic findings are related to both: chronic immunosuppressive therapy and physiological changes of pregnancy. Anemia is one of the most common complications among pregnant liver transplanted women.11 Some data suggest that anemia constitutes an important indication for antepartum admission, which is estimated to Table 2. Pregnancy Complications in Female Liver Recipients Category
Number of Pregnancies (%) (n ⫽ 39)
Premature labor (⬍37 wk of gestation) Hypertension Preeclampsia Gestational diabetes Pregestational diabetes PROM Urinary tract infections Cholestasis Severe anaemia Acute graft rejection
12 (30.8) 10 (25.6) 3 (7.7) 0 1 (2.6) 3 (7.7) 7 (18.0) 3 (7.7) 2 (5.1) 3 (7.7)
PROM, premature rupture of membranes.
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JABIRY-ZIENIEWICZ, SPZOTANSKA-SIKORSKA, PIETRZAK ET AL
Fig 2. Indications for cesarean section.
be approximately 5%.6,8 In the studied group, anemia occurred in more than one per three women. In two cases (6.7%), blood transfusions were necessary. Hypertension was diagnosed in 25% of cases, which is similar to other published reports.4,5,8,10,12,13 The incidence of preeclampsia was 7.7%, which was also comparable to data from the literature.10 Few reports suggest that the vasoconstrictive effect of immunosuppressive therapy, especially calcineurin inhibitors, may induce hypertension among pregnant liver female recipients.13,14 These drugs have also a hyperglycemic influence, although we did not observe a higher incidence of gestational nor pregestational diabetes.15 Cholestasis complicating liver posttransplant pregnancies is quite difficult to distinguish from graft deterioration. A few reports have suggested a higher prevalence of this disorder, albeit larger studies did not confirm these findings.16,17 In our study, cholestasis was diagnosed among 7.7% of pregnancies. Further analysis resulted in additional findings concerning fetal and neonatal outcomes. The data available in the literature suggest adverse neonatal outcomes including a greater incidence of prematurity, intrauterine growth restriction, and fetal distress.5,6,8,9 Results of our study were consistent with previous reports, namely, 30%, 20%, and
15.4% respectively. We did not observe a higher incidence of congenital malformations. Our study was limited by the small group of participants, making detection of congenital abnormalities difficult; however, it may suggest safe immunosuppressive management. Nowadays, the number of cesarean sections is generally increasing. The same situation is observed among posttransplant pregnancies, wherein the frequency of cesarean sections has changed from 20% to 32% in the 1990s to 46% to 48% in the last decade.7–9,12,18 Despite the majority of cesarean sections in the analyzed group to be performed for obstetric indications, the frequency was 79%, which was close to previous years19,20 due to the mothers being encumbered with medical histories wanting to deliver a healthy neonate. In conclusion, pregnancies after liver transplantation are possible and may complete successfully. Although the majority of pregnancies ended uneventfully, there was an increased risk of obstetric and neonatal complications. Therefore, this group of women and their newborns ought to be regularly monitored by a multidisciplinary approach. There is still a need to assess long-term outcomes of pregnant liver recipients and their neonates.
Fig 3. Distribution of neonatal birth weight (percentile).
PREGNANCY OUTCOME
REFERENCES 1. Armenti VT, Radomsky JS, Moritz MJ, et al: Report from the national Transplantation pregnancy Registry (NTPR): outcomes of pregnancy after transplantation. Clin Transpl 123, 2000 2. Armenti VT, Radomsky JS, Moritz MJ, et al: Report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation. Clin Transpl 103, 2004 3. Fischer T, Neumayer HH, Fischer R, et al: Effect of pregnancy on long-term kidney function in renal transplant recipients treated with cyclosporine and with azathioprine. Am J Transplant 5:2732, 2005 4. Armenti VT, Daller JA, Constantinescu S, et al: Report from the National Transplantation Pregnancy Registry: outcomes of pregnancy after transplantation. Clin Transpl 57, 2006 5. Coffin CS, Shaheen AA, Burak KW, et al: Pregnancy outcomes among liver transplant recipients in the United States: a nationwide case-control analysis. Liver Transpl 16:56, 2010 6. Scantlebury V, Gordon R, Tzakis A, et al: Childbearing after liver transplantation. Transplantation 49:317, 1990 7. Patapis P, Irani S, Mirza DF, et al: Outcome of graft function and pregnancy following liver transplantation. Transplant Proc 29:1565, 1997 8. Nagy S, Bush MC, Berkowitz R: Pregnancy outcome in liver transplant recipients. Obstet Gynecol 102:121, 2003 9. Wu A, Nashan B, Messner U, et al: Outcome of 22 successful pregnancies after liver transplantation. Clin Transplant 12:454, 1998
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