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Pregnancy after liver transplantation
Pregnancy After Liver Transplantation Holly L. Casele and Steven A. Laifer
This article reviews the reported experience with pregnancy after liver transplantation and describes obstetric risks and medical issues that the maternal fetal medicine specialist has a reference for managing these pregnancies and for providing appropriate preconception counseling. Women who undergo liver transplantations have a higher risk of preeclampsia, worsening hypertension, preterm premature rupture of membranes, anemia, small for gestational age, preterm delivery, and cesarean section than the normal obstetric population. Women with preconcepllonal renal dysfunction appear to be at greatest risk for pregnancy complications. Women who conceived within 6 months of transplant had a high risk of rejection. Reproductive-aged recipients of liver allograft should receive contraception and preconception counseling. In an appropriately timed and planned pregnancy, women who undergo liver transplantations can have successful pregnancies with little risk to their allograft function. Copyright 9 1998 by W.B. Saunders Company
transplantation has been p e r f o r m e d for L iver over three decades and is an acceptable therapy for many congenital and acquired conditions. 1 Approximately 11% of patients who receive transplants are women of child-bearing age and another 15% are female pediatric patients who have greater than 70% chance of surviving into and beyond the reproductive years. 2 Although the first liver transplant was p e r f o r m e d in 1963, 1-year survival rates were p o o r until the 1980s, and thus, experience with pregnancy after liver transplantation is limited, s In this chapter, we review the reported experience with pregnancy after liver transplantation and delineate salient medical and obstetric issues in managing these pregnancies. We review obstetric risks and pregnancy outcome. We also discuss preconception counseling, contraception, and the use of immunosuppressants in pregnancy. Finally, we describe the protocol used at Magee-Womens Hospital for managing these pregnancies.
Preconception Counseling In the reproductive-aged woman who has undergone a liver transplant, obstetric care ideally should begin before conception. Abnormal menstrual function commonly occurs in women with chronic hepatic dysfunction. These women should be counseled that menstrual function normalizes soon after transplantation because of restoration o f normal hepatic function and that contraception is necessary to avoid u n i n t e n d e d
pregnancies. 4'5 In a series o f 44 women who had u n d e r g o n e liver transplantation, Cundy et al 4 demonstrated that 90% o f patients resumed normal menstruation within 7 months of transplantation. In our series, conception occurred in one patient just 3 weeks after transplantation.6 T h e optimal timing of conception after transplantation is an important issue in preconception counseling for these women. Because of the n e e d for chronic immunosuppression, infection is a major cause o f morbidity and mortality in recipients of all organ transplants. 7 Infections caused by herpesviruses, specifically cytomegalovirus (CMV), are extremely c o m m o n and are associated with a high incidence of graft failure and patient mortality. 8 Maternal CMV infection may also lead to fetal CMV infection with devastating consequences. All of the neonatal deaths in o u r series were secondary to CMV infection. 9 Active CMV infection occurs primarily within the first several months after transplantation and coincides with the period of maximal immunosuppression. For this reason we strongly advocate delaying contraception for at least the first 6 months after transplantation. We feel that pregnancy can be safely considered when graft From the Division of Maternal FetalMedicine, Northwestern University Medical Sehoo~ Evanston Hospita~ Evanston, IL and Bridgeport Hospital, Yale New Haven Health Center, Bridgeport, CT. Address reprint requests to Holly L. Casele, MD, Division of Maternal Fetal Medicine, Evanston Hospita~ 2650 Ridge Ave Suite 1600 WH, Evanston, IL 60201. Cop~ght 9 1998 by W.B. Saunders Company 0146-0005/98/2202-00081;08.00/0
Seminars in Perinatology, Vol 22, No 2 (April), 1998: pp 149-155
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function is stable and there is no evidence of rejection, when immunosuppressants are at maintenance levels, and when associated medical conditions such as hypertension or diabetes are well controlled. The appropriate interval will vary in individual patients. Preconception counseling also should include reviewing the various maternal and fetal risks of pregnancies in transplant recipients, the effects of immunosuppressant medications on the fetus, and the specialized management and monitoring required during pregnancy. After counseling the patient, she should be able to make an informed decision about attempting or avoiding conception.
lmmunosuppressants in Pregnancy Outcomes for recipients of solid-organ allografts have improved dramatically in recent years largely because of improved means of suppressing the immune system of the recipient to avoid rejection. Newer immunosuppressant agents combine greater specificity and potency with reduced toxicity to the recipient. Prototype immunosuppressants such as corticosteroids and azathioprine are highly nonspecific and inhibit all elements of the immune system, whereas newer agents such as cyclosporine, tacrolimus (FK 506) and mycophenolic acid, have more immunologic specificity. Many of the important considerations about pregnancy after liver transplantation are directly related to the use of immunosuppressant medications during pregnancy. Here we review the commonly used immunosuppressants, their putative mechanism of action, maternal and fetal side effects, and other considerations regarding their use in pregnancy.
Corticosteroids Corticosteroids have been used in pregnancy to treat a variety of conditions (ie, asthma, connective tissue disorders) in addition to immunosuppression for organ transplantation, and considerable literature exists describing the effects of these agents in pregnancy. ~~ Corticosteroids, most commonly prednisone, are used for both prophylaxis and treatment of acute rejection. Corticosteroids prevent rejection by sequestering circulating lymphocytes and monocytes in
lymphoid tissue and by blocking the production of interleukin 1 OLd) and IL-2.1~ Maternal side effects relevant to pregnancy include poor wound healing, increased susceptibility to infection, hypertension, weight gain, gastric ulceration, osteoporosis, and carbohydrate intolerance. lzls Although corticosteroids have been associated with cleft lip and palate in animals, teratogenicity has not been confirmed in human pregnancy in any controlled studies. 14 Prednisone also has been associated with fetal growth restriction, suppression of the fetal adrenal axis, and premature rupture of the membranes, presumably by altering vaginal flora. 14 Because of metabolism in the placenta, umbilical cord levels of maternally administered prednisone and prenisolone are 10-fold lower than maternal concentrations. 15 Similarly, less than 10% of active drug is secreted into breast milk, and thus breast feeding while taking prednisone is considered safer 6A7
Azathioprine Like prednisone, azathioprine has been used to treat a variety of conditions, and thus there is considerable accumulated experience with azathioprine use in pregnancy.~7 Azathioprine, a pufine synthesis inhibitor, is used primarily as prophylaxis against rejection. After metabolism in the liver to 6-mercaptopurine, it interferes with purine biosynthesis and thus inhibits clonal proliferation of T and B lymphocytes.12 Maternal side effects include increased susceptibility to infection, alopecia, stomatitis, hepatotoxicity, fever, nausea, vomiting, pancreatitis, leukopenia, thrombocytopenia, and macrocytic anemia, lz14 Although azathioprine crosses the placenta, teratogenicity has not been reported. However, azathioprine has been associated with fetal growth restriction, preterm delivery, neonatal bone marrow suppression, and possibly chromosomal aberrations, is Neonatal bone marrow suppression appears to correlate with maternal leukopenia and when maternal leukopenia is avoided, neonatal bone marrow suppression usually is not observed. Is Whether intrauterine exposure to azathioprine will affect germ cell lines of offspring and affect future fertility remains a theoretical but unanswered question. Finally, although azathioprine does not cross into breast milk in significant concentrations, patients still should be
Pregnancy After Liver Transplantation
counseled regarding the possible risk of neonatal immunosuppression from nursing. 16 Cyclosporine Cyclosporine has been the mainstay of immunosuppression for organ transplant recipients since its introduction in ]978. Cyclosporine is a lipophilic, cyclic decapeptide derived from soil fungus, and it is dosed to achieve trough whole blood levels in the range of 250 to 400 ng/mL. 19 Because it is metabolized by the p-450 o/tochrome in the liver, caution should be used when coadministering drugs that interact with this cytochrome. Cyclosporine inhibits T cell clonal expansion by interfering with production of IL-2 and gamma interferon. ~9'~~Maternal side effects include hypertension, nephrotoxicty, neurotoxicity, hyperkalemia, tremor, hirsutism, hypomagnesemia, and glucose intolerance. 19 Cyclosporine readily crosses the placenta with fetal/neonatal concentration of 37% to 64% of maternal concentrations.2~ It is also secreted in high concentrations in breast milk, and thus breast feeding is not recommended. Although not teratogenic, cyclosporine has been associated with intrauterine growth restriction.~9 A theoretic concern about the use of cyclosporine in pregnancy is fetal or neonatal nephrotoxicty; however, this has not been observed (mean follow-up 39 months), m Cyclosporine is highly bound to erythrocytes. Because plasma volume expansion exceeds red cell volume expansion during pregnancy, whole blood levels will be lower than plasma levels. Consequently, plasma levels should be monitored preferentially.16 Sex steroids can inhibit hepatic microsomal enzymes and decrease requirements, whereas increased plasma volume in pregnancy can actually increase dosage requirements. 16 Because normal physiological changes in pregnancy can alter metabolism and clearance unpredictably, plasma levels must be monitored to adjust dosing and maintain patients in a therapeutic range. Our clinical experience is that, in general, cyclosporine requirements increase with gestational age.
Tacrolimus Tacrolimus (FK 506) is a comparably more potent macrolide immunosuppressant also of fungal origin. This drug has a relatively narrow ther-
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apeutic window and typically 7.5 to 15 mg is given daily in two divided doses to maintain a trough plasma level of 5 to 15 ng/mL. ~9 Although structurally different from cyclosporine, it also exerts its immunosuppressant action by inhibiting IL-2 production. 19 Adverse effects of tacrolimus include nephrotoxicity, neurotoxicity, glucose intolerance, hyperkalemia, diarrhea, and headache. 19 Because cyclosporine can also be nephrotoxic, tacrolimus and cyclosporine are not used concurrently. A possible advantage of tacrolimus is that many patients do not require co-therapy with corticosteroids. 19 The use of tacrolimus in pregnancy has been studied prospectively in 27 pregnancies in 21 patients by the group at the University of Pittsburgh. 23'24 One newborn had a unilateral cystic kidney; other congenital anomalies and growth restriction were not observed. 23'24 Transient (24 to 48 hour) neonatal hyperkalemia was noted in 36% of infants. 24 Tacrolimus does cross the placenta and is found in fetal blood and breast milk in significant concentrations (cord plasma/ maternal plasma concentration of 36%; breast milk/maternal plasma concentration of 50%). ~4
Mycophenolate Mofetil Mycophenolate mofetil is a new purine synthesis inhibitor that has been approved for rejection prevention and rescue therapy in recipients of kidney transplants and has recently been used in recipients of liver transplants. ~5"27Mycophenolate mofetil is administered orally and is rapidly hydrolyzed to mycophenolic acid (MPA), the active moiety.~9 The maximum plasma concentration occurs at 2 hours, and MPA is 94% bioavailable. 2s By inhibiting de novo purine synthesis, MPA is cytostatic to both B and T lymphocytes.19 MPA also inhibits T and B cell proliferation to allogenic stimulation as well as antibody formation by B lymphocytes. Side effects include diarrhea, leukopenia, urinary tract infection, respiratory infection, abdominal pain, edema, and anemia, t9 Currently, there are no reports of the use of this agent in human pregnancy. Animal studies suggest that MPA may result in premature meiotic maturation that would result in compromised development. 29
Pregnancy Outcome Maternal Outcome Pregnancy after liver transplantation is associated with increased risks of worsening hyperten-
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sion, preeclampsia, preterm premature rupture of membranes, anemia, small for gestational age fetuses, cesarean delivery, infection, and first trimester abortion. These risks have been repeatedly observed and confirmed in our series of patients.2,4,6,9,3~50 In our series, we observed that the complications of preeclampsia, worsening hypertension, and intrauterine growth restriction (IUGR) only occurred in women whose baseline serum creatinine was greater than or equal to 1.3 mg/dL, a well-recognized risk factor for these complications. We also observed that mild renal dysfunction (creatinine ---1.3 m g / d L ) was more commonly associated with cyclosporine (six of seven) than tacrolimus (one of seven) use) 1 Other groups have made similar observations. Tacrolimus appears to cause a lower incidence of preeclampsia in pregnant transplant recipients than cyclosporine.52 We speculate that the renal dysfunction caused by longterm exposure to cyclosporine is the factor that predisposes transplant recipients to preeclampsia. In their series of five liver transplant patients, Pruvotet aP 3 also observed that the risk of preeclampsia is mainly related to prepregnancy renal function. Alternatively, the immunosuppressants themselves may be directly responsible for the observed increased risk of preeclampsia. Both tacrolimus and cyclosporine decrease endogenous nitric oxide production. 54 If nitric oxide is a mediator of smooth muscle relaxation, interference with its production may enhance hypersensitivity to vasoconstrictors and therefore predispose to preeclampsia. More than one half of women who have undergone liver transplants undergo cesarean section. Preterm gestations contributed disproportionately to the number of cesarean deliveries. Except for one pregnancy that was induced at 36 weeks for recurrent pyelonephritis, one pregnancy that delivered precipitously because of abruption at 27 weeks, 26 and two 23-week gestations, all preterm gestations were delivered by cesarean section. In our series, cesarean sections were performed only for standard obstetric indications. In two other larger series, the investigators state that the indication for some of the cesarean sections was preeclampsia or preterm premature rupture of membranes (PPROM), but not enough detail is given to discern whether there were specific obstetric indications for cesarean delivery.2'3~
Pregnancy does not appear to alter hepatic allograft function. Only one patient in our series and two patients in the 63 other reported cases who continued their pregnancies past 20 weeks' gestation experienced acute rejection. 9'41'44In all three cases, acute rejection was successfully managed with adjustments in the immunosuppressant regimen. Mild or moderate elevation of liver enzymes, which antedate conception and remain stable during pregnancy, is common and does n o t require aggressive evaluation or change in the immunosuppressive regimen. In contrast, new onset elevation of liver enzymes does require aggressive evaluation for allograft rejection. Pregnancy should not be considered a contraindication to liver biopsy if rejection is suspected. Fetal and Neonatal O u t c o m e
Fetal and neonatal outcome has been good after pregnancies in recipients of liver transplants. An increased risk of congenital anomalies has n o t been identified. Although data on long term outcome of offspring born to liver transplant recipients are not available, long-term outcome of offspring born to women with renal transplants has been favorable. In the series of 14 pregnancies in 13 women followed at Magee-Womens Hospital, there were three neonatal deaths, and all were secondary to congenital cytomegalovirus infection. 5m~ Two of these fetuses had n o n i m m u n e hydrops, and both died after preterm spontaneous delivery at 2B weeks' gestation. The third neonate was delivered preterm because of severe preeclampsia and died of CMV sepsis at 12 days of age. Intrauterine CMV was suspected in this case and was supported by recovery of CMV DNA from the placenta with polymerase chain reaction (PCR) techniques. Two of these patients conceived shortly after transplantation (3 weeks, 2 months), and the third patient was receiving high doses of immunosuppression because of chronic rejection. These cases of congenital CMV underscore the importance of avoiding conception during periods of increased susceptibility, ie, for the first 6 months after transplantation, and during periods of organ rejection. Pregnancy Management
The optimal management of pregnancy in liver transplant recipients requires a coordinated ef-
Pregnancy After Liver Transplantation
fort between maternal-fetal medicine and surgical transplantation specialists. All patients undergo baseline and serial assessment of complete blood count, electrolytes, CMV serostatus, and renal and liver function. Immunosuppressive medications are continued and dosages of cyclosporine and tacrolimus (FK 506) are adjusted as needed based on serial monitoring. Because of a higher risk of cervical neoplasia in immunocompromised patients, all women should be screened with cervical cytology. All patients are offered a targeted anatomy ultrasound examination at 18 to 20 weeks. Growth scans are performed every 4 to 6 weeks after 24 weeks' gestation, and weekly fetal surveillance with either biophysical profile or nonstress test is started at 26 weeks' gestation. Because of an increased risk of carbohydrate intolerance, patients who are on tacrolimus, cyclosporine, or high doses of corticosteroids are screened in the first trimester with a 1-hour, 50-g, nonfasting, glucose tolerance test. All patients, regardless of whether they were screened in the first trimester, are screened for gestadonal diabetes at 24 to 26 weeks. Minor symptoms such as nausea, vomiting, and diarrhea may signify cytomegalovirus infection and should not be ignored. T h e m o t h e r may n e e d to be evaluated with endoscopy, biopsy, quantitative serology, or viral culture. If acute CMV infection is suspected, the fetus can be evaluated by ultrasound scan and amniotic fluid analysis. Suspected graft rejection can usually be managed with adjustment in the immunosuppressant regimen and should be confirmed by liver biopsy. Standard obstetric indications determine route of delivery. T o minimize continued fetal exposure to immunosuppressants, our patients undergo delivery when the fetal lung is mature or by 40 weeks' gestation. Patients on prednisone receive stress dose steroids for labor and delivery. Previously, we have r e c o m m e n d e d low-dose aspirin prophylaxis because o f the increased risk o f preeclampsia. 6 However, a recent multicenter trial failed to show a benefit o f low-dose aspirin in preventing preeclampsia in high-risk women, thus we no longer r e c o m m e n d low-dose aspirin prophylaxis in these patients. 56 Because patients are on immunosuppressants, we use antibiotic prophylaxis for delivery and discourage breast feeding for all patients except those on prednisone as monotherapy.
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Contraception T h e ideal m e t h o d of contracepdon for liver transplant recipients is unknown and should be individualized. Barrier contraception is probably the safest m e t h o d but may be less effective than other approaches. Intrauterine devices may be less effective in patients receiving immunosuppressive medications and should be avoided entirely in patients who are at increased risk of infection. 57 Combined oral contraceptives may be considered but should be used cautiously in patients with hypertension or active hepatic disease. For women using cyclosporine, oral contraceptives can decrease cyclosporine metabolism and potentiate hepatotoxicity. 5a T o minimize the effects o f cyclical h o r m o n a l withdrawal on immunosuppressant metabolism, oral contraceptives can be administered continuously (ie, deleting the placebo week). We have used progestin-only contraception in several patients without adverse sequelae. Progestin-only methods are appealing because they may be used in the setting of hypertension and thromboembolic disease. We would r e c o m m e n d careful monitoring o f immunosuppressant concentrations with any h o r m o n a l method. Finally, sterilization should be seriously considered when pregnancy is no longer desired.
Liver Transplantation During Pregnancy and Puerperium Although u n c o m m o n , hepatic failure may occur during pregnancy or the puerperium, and liver transplantation may be lifesaving. 59 Hepatic failure may occur secondary to deterioration in chronic liver disease that antedated pregnancy, secondary to coincidental fulminant liver disease, or from a pregnancy-induced liver disorder. When deciding whether to perform a liver transplantation in a pregnant patient without delivering the fetus, there are several important considerations. First, pregnancy termination may pose a significant risk (ie, hemorrhage, infection) to a woman with hepatic failure. Second, the pregnancy may interfere with optimal surgical, anesthetic, and postoperative treatment of the patient. Finally, the fetus should be at a previable or periviable gestational age. If the fetus is at a viable gestational age, delivery o f the fetus immediately before transplantation may be
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life saving to the fetus without imposing excessive risks to the mother. In the limited n u m b e r of cases reported, the ratio of maternal survival to hospital discharge of patients undergoing transplant in pregnancy or the p u e r p e r i u m is 94% (17 o f 18). ~176 When caring for pregnant women with hepatic failure, consultation with hepatology and surgery should be sought early and transfer o f the patient to a liver transplant center may be necessary.
Summary For most liver transplant recipients, successful pregnancies are likely to occur with optimal management. W o m e n with liver allografts appear to have a higher risk of preeclampsia, worsening hypertension, PPROM, anemia, IUGR, p r e t e r m delivery, and cesarean section than the normal obstetric population. We observed that renal dysfunction, a direct consequence o f immunosuppressant medications, confers an increased risk for these complications and that women with normal renal function may not be at increased risk. Renal dysfunction was m o r e often associated with cyclosporine than tacrolimus use. Although experience with tacrolimus in pregnancy is still limited, we observed no adverse fetal effects and believe that, if possible, this may be the immunosuppressant of choice for reproductive-age women. Preconception and pretransplant counseling o f reproductive-age women should incorporate explanation of these risks and stress the importance of delaying pregnancy for at least 6 months after transplant.
Acknowledgment T h e d a t a p r e s e n t e d i n this m a n u s c r i p t were collected while t h e a u t h o r s were at M a g e e - W o m e n s Hospital a n d t h e University o f P i t t s b u r g h S c h o o l o f Medicine.
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References 22. 1. Keefe EB: Selection of patients for liver transplantation, in Maddrey WC, Sorrell MR (eds): Transplantation of the Liver (ed 2). Norwalk, CT, Appleton & Lange, 1995, p 13 2. Scantlebury VP, Gordon R, Tzakis A, et al: Childbearing after liver transplantation. Transplantation 49:31%321, 1990 3. Starzl TE, Marchioro TL, Von Kaulla KN, et al: Homo-
23.
24.
transplantation of the liver in humans. Surg Gynecol Obstet 117:658, 1963 Cundy TF, O'GradyJG, Williams R: Recovery of menstruation and pregnancy after liver transplantation. Gut 31:337-338, 1990 de Konig ND, Haagsma EB: Normalization of menstrual pattern after liver transplantation: Consequences for contraception. Digestion 46:239-241, 1990 Laifer SA, Guido R: Reproductive function and outcome of pregnancy after liver transplantation in women. Mayo Clin Proc 70:388-394, 1995 Brayman K, Stephanian E, Matas AJ, et al: Analysis of infectious complications occurring after solid-organ transplantation. Arch Surg 127:3848, 1992 Dunn DL, NajarianJS: New approaches to the diagnosis, prevention, and treatment of cytomegaiovirus infection after transplantation. Am J Surg 161:25-55, 1991 Laifer SA, Darby MJ, Scantlebury VP, et al: Pregnancy and liver transplantation. Obstet Gynecol 76:1083-1088, 1990 Yackel DB, Kempers RD, McConahey WM: Adrenocorticosteroid therapy in pregnancy. Am J Obstet Gynecol 96:985, 1966 Sato H: Effect of adrenocorticoids during pregnancy. Lancet 2:1235, 1963 Council on Scientific Affairs: Introduction to the management of immunosuppression. JAMA 257:1781-1785, 1987 Laifer SA: Pregnancy after transplantation, in Lee RV, (ed.): Current Obstetric Medicine. Vol 2. St. Louis, MO, Mosby, 1993, pp 1-23 Beitinis IZ, Bayard F, Ances IG, et al: The transplacental passage of prednisone in pregnancy near term. J Pediatr 81:936-945, 1972 Committe on Drugs, American Academy of Pediatrics: The transfer of drugs and other chemicals into human breast milk. Pediatrics 84:924-936, 1989 Ross WB, Richards T, Williams GL, et al: Cyclosporine and pregnancy. Transplantation 45:1142, 1988 Bermas BL, HiI1JA: Effects of immunosuppressive drugs during pregnancy. Arthr Rheum 38:1722-1732, 1995 Davison JM, Dellagrammatikas H, Parkin JM: Maternal azathioprine therapy and depressed haemopoiesis in the babies of renal allograft patients. Br J Obstet Gynecol 92:233-239, 1985 Munoz SJ: Long-term management of the liver transplant recipient. Med Clin North Am 80:1103-1120, 1996 Calne R, White D, Thiru S, et al: Cyclosporin A in patients receiving renal alloga'afts from cadaver donors. Lancet 2:1323, 1978 Venkataramanan R, Koneru B, Wang CP, et al: Cyclosporine and its metabolites in mother and baby. Transplantation 46:468-469, 1988 Shaheen FAM, Al-Sulaiman MH, Al-Khader AA: Longterm nephrotoxicty after exposure to cyclosporine in utero. Transplantation 56:224-225, 1993 Winkler ME, Niesert S, Ringe B, et al: Successful pregnancy in a patient after liver transplanatation maintained on FK 506. Transplantation 56:1589-1590, 1993 Jain A, Venkataramanan R, Lever J, et al: FK 506 and pregnancy in liver transplant patients. Transplantation 56:1588-1589, 1993
Pregnancy After Liver Transplantation
25. Klupp J, Bechstein WO, Platz KP, et al: Mycophenolate mofetil added to immunosuppression after liver transplantation-First results. Transplant Int 10:223-228, 1997 26. Gavlik A, Goldberg MG, Tsaroucha A, et al: Mycophenc~ late mofetil rescue therapy in liver transplant patients. Transplant Proc 29:549-552, 1997 27. McDiarmid SV: Mycophenolate mofetil in liver transplantation. Clin Transplant 10:140-145, 1996 28. Hood KA, Zarembski DG: Mycophenolate mofetil: A unique immunosuppressive agent. American Journal of Health-System Pharmacy 54:285-294, 1997 29. Downs SM: Induction of meiotic maturation in vivo in the mouse by IMP dehydrogenase inhibitors: Effetcs on the developmental capacity of ova. Mol Reprod Dev 38:293-302, 1994 30. Viile Y, Fernandez, Samuel D, et al: Pregnancy in liver transplant recipients: Course and outcome in 19 cases, Am J Obstet Gynecol 168:896-902, 1993 31. Baruch Y, Weiner Z, Enat R, et al: Pregnancy after liver transplantation. IntJ Gynecol Obstet 41:273-276, 1993 32. HuttonJD, Wyeth JW: Pregnancy after liver transplantation: Effects of immunosuppressive therapy and abnormal hepatic function. Aust NZ J Obstet Gynaecol 30:130, 1990 33. Newton ER, Turksoy N, Kaplan M, et al: Pregnancy and liver transplantation. Obstet Gynecol 71:499, 1988 34. Sims CJ, Porter KB, Knuppel RA: Successful pregnancy after liver transplant. AmJ Obstet Gynecol 161:532-533, 1989 35. Hill NCW, Morris NH, Shaw RW, et ai: Pregnancy after orthotopic liver transplantation. Br J Obstet Gynecol 98:719-721, 1991 36. Haagsma EB, Visser GHA, Klompmaker IJ, et al: Success, ful pregnancy after orthotopic liver transplantation. Obstet Gynecol 74:442, 1989 37. Paternoster DM, Floreani A, Burra P: Liver transplantation and pregnancy. Int J Gynecol Obstet 50:199-200, 1995 38. Myer RL, Schmid R, NewtonJJ: Chilbirth after liver transplantation. Transplantation 29:432, 1980 39. Venkataramanan R, Konern B, Wang CC, et al: Cyclosporine and its metabolites in mother and baby. Transplantation 46:468, 1988 40. Walcott WO, Derick DE, JolleyJJ, et al: Successful pregnancy in a liver transplant patient. AmJ Obstet Gynecol 132:340, 1978 41. Roberts M, Brown ASM, James OFW, et al: Interpretation of cyclosporin A levels in pregnancy following orthotopic liver transplantation. Br J Obstet Gynecol 102:570-572, 1995 42. Winter H, MacKenzie WE, Newton JR= Successful pregnancy following liver transplantation in a patient taking cyclosporin. J Obstet Gynecol 10:396-397, 1990 43. Winkler ME, Niesert S, Ringe B, et al: Successful preg-
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nancy in a patient after liver transplantation maintained on FK 506. Transplantation 56:1589-1590, 1993 44. Pagnoni B, Mariconti P, Bedoni M: Gravidanza e maternita' dopo trapianto di fegato. Minerva Anestes 57:745-746, 1991 45. Gunter HH, Mauz S, Ringe B, et al: Schwangerschaft nach lebertransplantation und unter immunosuppression mit ciclosprin. Dtsch Med Wschr 115:740-742, 1990 46. HanfV, Viebahn R, Lauchart W, et al: Schwangerschaft und enthindung nach lebertransplantation. Gebursh Frauenheilk 50:813815, 1990 47. Kreuzpainmer G, Ringe B, Niesert S, et al: Zwillingsschwangerschaft nach lebertransplantation. Dtsch Med Wschr 115:895-898, 1990 48. Grow DR, Simon NV, LissJ, et al: Twin pregnancy after orthotopic liver transplantation with exacerbation of chronic graft rejection. Am J Perinatol 8:135-138, 1991 49. Alvin P, Muller J, Houssin D, et al: Grossesse et maternite apres transplantation hepatique pur hepatite active autoimmune terminale avec amenorrhee primaire. Gastroenterol Clin Biol 13:1079-1081, 1989 50. Fair J, Klein AS, Feng T, et al: Intrapontum orthotopic liver transplantation with successful outcome of pregnancy. Transplantation 50:534-535, 1990 51. Casele HL, Woelkers DA, Laifer SA: Pregnancy after Liver Transplantation. Am J Obstet Gynecoi 176:$23, 1997 52. Jain A, Venkataramanan R, Fung.IJ, et al: Pregnancy after liver transplantation under tacrolimus. Transplantation 64:559-565, 1997 53. Prnvot FR, Declerck N, Valat-Rigot AS, et al: Pregnancy after liver transplantation: Focusing on risks to the mother. Transpl Proc 29:2470-2471, 1997 54. Conde M, Andrde J, Bedoya FJ, et al: Inhibitory effect of cyclosporin A and FK506 on nitric oxide production by cultured macrophages. Evidence of a direct effect on nitric oxide synthase activity. Immunology 84:476-481, 1995 55. Laifer SA, Ehrlich GD, Huff DS, et al: Congenital cytomegalovirns infection in offspring of liver transplant recipients. Clin Infect Dis 20:52-55, 1995 56. Caritis SN, NICHD MFMU Network: Low dose aspirin does not prevent preeclampsia in high risk women. Am J Obstet Gynecol 176:$3, 1997 57. ZernerJ, Doll KL, DrewryJ, et al: Intrauterine contraceptive device failures in renal transplant patients. J Reprod Med 26:99-102, 1981 58. ScottJP, Higenbottam TW: Adverse reactions and interactions of cyciosporin. Med Toxicol 3:107-127, 1988 59. Laifer SA, Abu-Elmagd K, F u n g i : Hepatic transplantation during pregnancy and the puerperium. Journal of Maternal-Fetal Medicine 6:40-44, 1997 60. Salha D, Campbell DS, Pollard S: Budd-Chiari syndrome in pregnancy treated by cesarean section and liver transplant. BrJ Obstet Gynecol 103:1254-1256, 1996
This article reviews the reported experience with pregnancy after liver transplantation and describes obstetric risks and medical issues that the maternal fetal medicine specialist has a reference for managing these pregnancies and for providing appropriate preconception counseling. Women who undergo liver transplantations have a higher risk of preeclampsia, worsening hypertension, preterm premature rupture of membranes, anemia, small for gestational age, preterm delivery, and cesarean section than the normal obstetric population. Women with preconcepllonal renal dysfunction appear to be at greatest risk for pregnancy complications. Women who conceived within 6 months of transplant had a high risk of rejection. Reproductive-aged recipients of liver allograft should receive contraception and preconception counseling. In an appropriately timed and planned pregnancy, women who undergo liver transplantations can have successful pregnancies with little risk to their allograft function. Copyright 9 1998 by W.B. Saunders Company
transplantation has been p e r f o r m e d for L iver over three decades and is an acceptable therapy for many congenital and acquired conditions. 1 Approximately 11% of patients who receive transplants are women of child-bearing age and another 15% are female pediatric patients who have greater than 70% chance of surviving into and beyond the reproductive years. 2 Although the first liver transplant was p e r f o r m e d in 1963, 1-year survival rates were p o o r until the 1980s, and thus, experience with pregnancy after liver transplantation is limited, s In this chapter, we review the reported experience with pregnancy after liver transplantation and delineate salient medical and obstetric issues in managing these pregnancies. We review obstetric risks and pregnancy outcome. We also discuss preconception counseling, contraception, and the use of immunosuppressants in pregnancy. Finally, we describe the protocol used at Magee-Womens Hospital for managing these pregnancies.
Preconception Counseling In the reproductive-aged woman who has undergone a liver transplant, obstetric care ideally should begin before conception. Abnormal menstrual function commonly occurs in women with chronic hepatic dysfunction. These women should be counseled that menstrual function normalizes soon after transplantation because of restoration o f normal hepatic function and that contraception is necessary to avoid u n i n t e n d e d
pregnancies. 4'5 In a series o f 44 women who had u n d e r g o n e liver transplantation, Cundy et al 4 demonstrated that 90% o f patients resumed normal menstruation within 7 months of transplantation. In our series, conception occurred in one patient just 3 weeks after transplantation.6 T h e optimal timing of conception after transplantation is an important issue in preconception counseling for these women. Because of the n e e d for chronic immunosuppression, infection is a major cause o f morbidity and mortality in recipients of all organ transplants. 7 Infections caused by herpesviruses, specifically cytomegalovirus (CMV), are extremely c o m m o n and are associated with a high incidence of graft failure and patient mortality. 8 Maternal CMV infection may also lead to fetal CMV infection with devastating consequences. All of the neonatal deaths in o u r series were secondary to CMV infection. 9 Active CMV infection occurs primarily within the first several months after transplantation and coincides with the period of maximal immunosuppression. For this reason we strongly advocate delaying contraception for at least the first 6 months after transplantation. We feel that pregnancy can be safely considered when graft From the Division of Maternal FetalMedicine, Northwestern University Medical Sehoo~ Evanston Hospita~ Evanston, IL and Bridgeport Hospital, Yale New Haven Health Center, Bridgeport, CT. Address reprint requests to Holly L. Casele, MD, Division of Maternal Fetal Medicine, Evanston Hospita~ 2650 Ridge Ave Suite 1600 WH, Evanston, IL 60201. Cop~ght 9 1998 by W.B. Saunders Company 0146-0005/98/2202-00081;08.00/0
Seminars in Perinatology, Vol 22, No 2 (April), 1998: pp 149-155
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function is stable and there is no evidence of rejection, when immunosuppressants are at maintenance levels, and when associated medical conditions such as hypertension or diabetes are well controlled. The appropriate interval will vary in individual patients. Preconception counseling also should include reviewing the various maternal and fetal risks of pregnancies in transplant recipients, the effects of immunosuppressant medications on the fetus, and the specialized management and monitoring required during pregnancy. After counseling the patient, she should be able to make an informed decision about attempting or avoiding conception.
lmmunosuppressants in Pregnancy Outcomes for recipients of solid-organ allografts have improved dramatically in recent years largely because of improved means of suppressing the immune system of the recipient to avoid rejection. Newer immunosuppressant agents combine greater specificity and potency with reduced toxicity to the recipient. Prototype immunosuppressants such as corticosteroids and azathioprine are highly nonspecific and inhibit all elements of the immune system, whereas newer agents such as cyclosporine, tacrolimus (FK 506) and mycophenolic acid, have more immunologic specificity. Many of the important considerations about pregnancy after liver transplantation are directly related to the use of immunosuppressant medications during pregnancy. Here we review the commonly used immunosuppressants, their putative mechanism of action, maternal and fetal side effects, and other considerations regarding their use in pregnancy.
Corticosteroids Corticosteroids have been used in pregnancy to treat a variety of conditions (ie, asthma, connective tissue disorders) in addition to immunosuppression for organ transplantation, and considerable literature exists describing the effects of these agents in pregnancy. ~~ Corticosteroids, most commonly prednisone, are used for both prophylaxis and treatment of acute rejection. Corticosteroids prevent rejection by sequestering circulating lymphocytes and monocytes in
lymphoid tissue and by blocking the production of interleukin 1 OLd) and IL-2.1~ Maternal side effects relevant to pregnancy include poor wound healing, increased susceptibility to infection, hypertension, weight gain, gastric ulceration, osteoporosis, and carbohydrate intolerance. lzls Although corticosteroids have been associated with cleft lip and palate in animals, teratogenicity has not been confirmed in human pregnancy in any controlled studies. 14 Prednisone also has been associated with fetal growth restriction, suppression of the fetal adrenal axis, and premature rupture of the membranes, presumably by altering vaginal flora. 14 Because of metabolism in the placenta, umbilical cord levels of maternally administered prednisone and prenisolone are 10-fold lower than maternal concentrations. 15 Similarly, less than 10% of active drug is secreted into breast milk, and thus breast feeding while taking prednisone is considered safer 6A7
Azathioprine Like prednisone, azathioprine has been used to treat a variety of conditions, and thus there is considerable accumulated experience with azathioprine use in pregnancy.~7 Azathioprine, a pufine synthesis inhibitor, is used primarily as prophylaxis against rejection. After metabolism in the liver to 6-mercaptopurine, it interferes with purine biosynthesis and thus inhibits clonal proliferation of T and B lymphocytes.12 Maternal side effects include increased susceptibility to infection, alopecia, stomatitis, hepatotoxicity, fever, nausea, vomiting, pancreatitis, leukopenia, thrombocytopenia, and macrocytic anemia, lz14 Although azathioprine crosses the placenta, teratogenicity has not been reported. However, azathioprine has been associated with fetal growth restriction, preterm delivery, neonatal bone marrow suppression, and possibly chromosomal aberrations, is Neonatal bone marrow suppression appears to correlate with maternal leukopenia and when maternal leukopenia is avoided, neonatal bone marrow suppression usually is not observed. Is Whether intrauterine exposure to azathioprine will affect germ cell lines of offspring and affect future fertility remains a theoretical but unanswered question. Finally, although azathioprine does not cross into breast milk in significant concentrations, patients still should be
Pregnancy After Liver Transplantation
counseled regarding the possible risk of neonatal immunosuppression from nursing. 16 Cyclosporine Cyclosporine has been the mainstay of immunosuppression for organ transplant recipients since its introduction in ]978. Cyclosporine is a lipophilic, cyclic decapeptide derived from soil fungus, and it is dosed to achieve trough whole blood levels in the range of 250 to 400 ng/mL. 19 Because it is metabolized by the p-450 o/tochrome in the liver, caution should be used when coadministering drugs that interact with this cytochrome. Cyclosporine inhibits T cell clonal expansion by interfering with production of IL-2 and gamma interferon. ~9'~~Maternal side effects include hypertension, nephrotoxicty, neurotoxicity, hyperkalemia, tremor, hirsutism, hypomagnesemia, and glucose intolerance. 19 Cyclosporine readily crosses the placenta with fetal/neonatal concentration of 37% to 64% of maternal concentrations.2~ It is also secreted in high concentrations in breast milk, and thus breast feeding is not recommended. Although not teratogenic, cyclosporine has been associated with intrauterine growth restriction.~9 A theoretic concern about the use of cyclosporine in pregnancy is fetal or neonatal nephrotoxicty; however, this has not been observed (mean follow-up 39 months), m Cyclosporine is highly bound to erythrocytes. Because plasma volume expansion exceeds red cell volume expansion during pregnancy, whole blood levels will be lower than plasma levels. Consequently, plasma levels should be monitored preferentially.16 Sex steroids can inhibit hepatic microsomal enzymes and decrease requirements, whereas increased plasma volume in pregnancy can actually increase dosage requirements. 16 Because normal physiological changes in pregnancy can alter metabolism and clearance unpredictably, plasma levels must be monitored to adjust dosing and maintain patients in a therapeutic range. Our clinical experience is that, in general, cyclosporine requirements increase with gestational age.
Tacrolimus Tacrolimus (FK 506) is a comparably more potent macrolide immunosuppressant also of fungal origin. This drug has a relatively narrow ther-
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apeutic window and typically 7.5 to 15 mg is given daily in two divided doses to maintain a trough plasma level of 5 to 15 ng/mL. ~9 Although structurally different from cyclosporine, it also exerts its immunosuppressant action by inhibiting IL-2 production. 19 Adverse effects of tacrolimus include nephrotoxicity, neurotoxicity, glucose intolerance, hyperkalemia, diarrhea, and headache. 19 Because cyclosporine can also be nephrotoxic, tacrolimus and cyclosporine are not used concurrently. A possible advantage of tacrolimus is that many patients do not require co-therapy with corticosteroids. 19 The use of tacrolimus in pregnancy has been studied prospectively in 27 pregnancies in 21 patients by the group at the University of Pittsburgh. 23'24 One newborn had a unilateral cystic kidney; other congenital anomalies and growth restriction were not observed. 23'24 Transient (24 to 48 hour) neonatal hyperkalemia was noted in 36% of infants. 24 Tacrolimus does cross the placenta and is found in fetal blood and breast milk in significant concentrations (cord plasma/ maternal plasma concentration of 36%; breast milk/maternal plasma concentration of 50%). ~4
Mycophenolate Mofetil Mycophenolate mofetil is a new purine synthesis inhibitor that has been approved for rejection prevention and rescue therapy in recipients of kidney transplants and has recently been used in recipients of liver transplants. ~5"27Mycophenolate mofetil is administered orally and is rapidly hydrolyzed to mycophenolic acid (MPA), the active moiety.~9 The maximum plasma concentration occurs at 2 hours, and MPA is 94% bioavailable. 2s By inhibiting de novo purine synthesis, MPA is cytostatic to both B and T lymphocytes.19 MPA also inhibits T and B cell proliferation to allogenic stimulation as well as antibody formation by B lymphocytes. Side effects include diarrhea, leukopenia, urinary tract infection, respiratory infection, abdominal pain, edema, and anemia, t9 Currently, there are no reports of the use of this agent in human pregnancy. Animal studies suggest that MPA may result in premature meiotic maturation that would result in compromised development. 29
Pregnancy Outcome Maternal Outcome Pregnancy after liver transplantation is associated with increased risks of worsening hyperten-
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sion, preeclampsia, preterm premature rupture of membranes, anemia, small for gestational age fetuses, cesarean delivery, infection, and first trimester abortion. These risks have been repeatedly observed and confirmed in our series of patients.2,4,6,9,3~50 In our series, we observed that the complications of preeclampsia, worsening hypertension, and intrauterine growth restriction (IUGR) only occurred in women whose baseline serum creatinine was greater than or equal to 1.3 mg/dL, a well-recognized risk factor for these complications. We also observed that mild renal dysfunction (creatinine ---1.3 m g / d L ) was more commonly associated with cyclosporine (six of seven) than tacrolimus (one of seven) use) 1 Other groups have made similar observations. Tacrolimus appears to cause a lower incidence of preeclampsia in pregnant transplant recipients than cyclosporine.52 We speculate that the renal dysfunction caused by longterm exposure to cyclosporine is the factor that predisposes transplant recipients to preeclampsia. In their series of five liver transplant patients, Pruvotet aP 3 also observed that the risk of preeclampsia is mainly related to prepregnancy renal function. Alternatively, the immunosuppressants themselves may be directly responsible for the observed increased risk of preeclampsia. Both tacrolimus and cyclosporine decrease endogenous nitric oxide production. 54 If nitric oxide is a mediator of smooth muscle relaxation, interference with its production may enhance hypersensitivity to vasoconstrictors and therefore predispose to preeclampsia. More than one half of women who have undergone liver transplants undergo cesarean section. Preterm gestations contributed disproportionately to the number of cesarean deliveries. Except for one pregnancy that was induced at 36 weeks for recurrent pyelonephritis, one pregnancy that delivered precipitously because of abruption at 27 weeks, 26 and two 23-week gestations, all preterm gestations were delivered by cesarean section. In our series, cesarean sections were performed only for standard obstetric indications. In two other larger series, the investigators state that the indication for some of the cesarean sections was preeclampsia or preterm premature rupture of membranes (PPROM), but not enough detail is given to discern whether there were specific obstetric indications for cesarean delivery.2'3~
Pregnancy does not appear to alter hepatic allograft function. Only one patient in our series and two patients in the 63 other reported cases who continued their pregnancies past 20 weeks' gestation experienced acute rejection. 9'41'44In all three cases, acute rejection was successfully managed with adjustments in the immunosuppressant regimen. Mild or moderate elevation of liver enzymes, which antedate conception and remain stable during pregnancy, is common and does n o t require aggressive evaluation or change in the immunosuppressive regimen. In contrast, new onset elevation of liver enzymes does require aggressive evaluation for allograft rejection. Pregnancy should not be considered a contraindication to liver biopsy if rejection is suspected. Fetal and Neonatal O u t c o m e
Fetal and neonatal outcome has been good after pregnancies in recipients of liver transplants. An increased risk of congenital anomalies has n o t been identified. Although data on long term outcome of offspring born to liver transplant recipients are not available, long-term outcome of offspring born to women with renal transplants has been favorable. In the series of 14 pregnancies in 13 women followed at Magee-Womens Hospital, there were three neonatal deaths, and all were secondary to congenital cytomegalovirus infection. 5m~ Two of these fetuses had n o n i m m u n e hydrops, and both died after preterm spontaneous delivery at 2B weeks' gestation. The third neonate was delivered preterm because of severe preeclampsia and died of CMV sepsis at 12 days of age. Intrauterine CMV was suspected in this case and was supported by recovery of CMV DNA from the placenta with polymerase chain reaction (PCR) techniques. Two of these patients conceived shortly after transplantation (3 weeks, 2 months), and the third patient was receiving high doses of immunosuppression because of chronic rejection. These cases of congenital CMV underscore the importance of avoiding conception during periods of increased susceptibility, ie, for the first 6 months after transplantation, and during periods of organ rejection. Pregnancy Management
The optimal management of pregnancy in liver transplant recipients requires a coordinated ef-
Pregnancy After Liver Transplantation
fort between maternal-fetal medicine and surgical transplantation specialists. All patients undergo baseline and serial assessment of complete blood count, electrolytes, CMV serostatus, and renal and liver function. Immunosuppressive medications are continued and dosages of cyclosporine and tacrolimus (FK 506) are adjusted as needed based on serial monitoring. Because of a higher risk of cervical neoplasia in immunocompromised patients, all women should be screened with cervical cytology. All patients are offered a targeted anatomy ultrasound examination at 18 to 20 weeks. Growth scans are performed every 4 to 6 weeks after 24 weeks' gestation, and weekly fetal surveillance with either biophysical profile or nonstress test is started at 26 weeks' gestation. Because of an increased risk of carbohydrate intolerance, patients who are on tacrolimus, cyclosporine, or high doses of corticosteroids are screened in the first trimester with a 1-hour, 50-g, nonfasting, glucose tolerance test. All patients, regardless of whether they were screened in the first trimester, are screened for gestadonal diabetes at 24 to 26 weeks. Minor symptoms such as nausea, vomiting, and diarrhea may signify cytomegalovirus infection and should not be ignored. T h e m o t h e r may n e e d to be evaluated with endoscopy, biopsy, quantitative serology, or viral culture. If acute CMV infection is suspected, the fetus can be evaluated by ultrasound scan and amniotic fluid analysis. Suspected graft rejection can usually be managed with adjustment in the immunosuppressant regimen and should be confirmed by liver biopsy. Standard obstetric indications determine route of delivery. T o minimize continued fetal exposure to immunosuppressants, our patients undergo delivery when the fetal lung is mature or by 40 weeks' gestation. Patients on prednisone receive stress dose steroids for labor and delivery. Previously, we have r e c o m m e n d e d low-dose aspirin prophylaxis because o f the increased risk o f preeclampsia. 6 However, a recent multicenter trial failed to show a benefit o f low-dose aspirin in preventing preeclampsia in high-risk women, thus we no longer r e c o m m e n d low-dose aspirin prophylaxis in these patients. 56 Because patients are on immunosuppressants, we use antibiotic prophylaxis for delivery and discourage breast feeding for all patients except those on prednisone as monotherapy.
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Contraception T h e ideal m e t h o d of contracepdon for liver transplant recipients is unknown and should be individualized. Barrier contraception is probably the safest m e t h o d but may be less effective than other approaches. Intrauterine devices may be less effective in patients receiving immunosuppressive medications and should be avoided entirely in patients who are at increased risk of infection. 57 Combined oral contraceptives may be considered but should be used cautiously in patients with hypertension or active hepatic disease. For women using cyclosporine, oral contraceptives can decrease cyclosporine metabolism and potentiate hepatotoxicity. 5a T o minimize the effects o f cyclical h o r m o n a l withdrawal on immunosuppressant metabolism, oral contraceptives can be administered continuously (ie, deleting the placebo week). We have used progestin-only contraception in several patients without adverse sequelae. Progestin-only methods are appealing because they may be used in the setting of hypertension and thromboembolic disease. We would r e c o m m e n d careful monitoring o f immunosuppressant concentrations with any h o r m o n a l method. Finally, sterilization should be seriously considered when pregnancy is no longer desired.
Liver Transplantation During Pregnancy and Puerperium Although u n c o m m o n , hepatic failure may occur during pregnancy or the puerperium, and liver transplantation may be lifesaving. 59 Hepatic failure may occur secondary to deterioration in chronic liver disease that antedated pregnancy, secondary to coincidental fulminant liver disease, or from a pregnancy-induced liver disorder. When deciding whether to perform a liver transplantation in a pregnant patient without delivering the fetus, there are several important considerations. First, pregnancy termination may pose a significant risk (ie, hemorrhage, infection) to a woman with hepatic failure. Second, the pregnancy may interfere with optimal surgical, anesthetic, and postoperative treatment of the patient. Finally, the fetus should be at a previable or periviable gestational age. If the fetus is at a viable gestational age, delivery o f the fetus immediately before transplantation may be
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life saving to the fetus without imposing excessive risks to the mother. In the limited n u m b e r of cases reported, the ratio of maternal survival to hospital discharge of patients undergoing transplant in pregnancy or the p u e r p e r i u m is 94% (17 o f 18). ~176 When caring for pregnant women with hepatic failure, consultation with hepatology and surgery should be sought early and transfer o f the patient to a liver transplant center may be necessary.
Summary For most liver transplant recipients, successful pregnancies are likely to occur with optimal management. W o m e n with liver allografts appear to have a higher risk of preeclampsia, worsening hypertension, PPROM, anemia, IUGR, p r e t e r m delivery, and cesarean section than the normal obstetric population. We observed that renal dysfunction, a direct consequence o f immunosuppressant medications, confers an increased risk for these complications and that women with normal renal function may not be at increased risk. Renal dysfunction was m o r e often associated with cyclosporine than tacrolimus use. Although experience with tacrolimus in pregnancy is still limited, we observed no adverse fetal effects and believe that, if possible, this may be the immunosuppressant of choice for reproductive-age women. Preconception and pretransplant counseling o f reproductive-age women should incorporate explanation of these risks and stress the importance of delaying pregnancy for at least 6 months after transplant.
Acknowledgment T h e d a t a p r e s e n t e d i n this m a n u s c r i p t were collected while t h e a u t h o r s were at M a g e e - W o m e n s Hospital a n d t h e University o f P i t t s b u r g h S c h o o l o f Medicine.
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References 22. 1. Keefe EB: Selection of patients for liver transplantation, in Maddrey WC, Sorrell MR (eds): Transplantation of the Liver (ed 2). Norwalk, CT, Appleton & Lange, 1995, p 13 2. Scantlebury VP, Gordon R, Tzakis A, et al: Childbearing after liver transplantation. Transplantation 49:31%321, 1990 3. Starzl TE, Marchioro TL, Von Kaulla KN, et al: Homo-
23.
24.
transplantation of the liver in humans. Surg Gynecol Obstet 117:658, 1963 Cundy TF, O'GradyJG, Williams R: Recovery of menstruation and pregnancy after liver transplantation. Gut 31:337-338, 1990 de Konig ND, Haagsma EB: Normalization of menstrual pattern after liver transplantation: Consequences for contraception. Digestion 46:239-241, 1990 Laifer SA, Guido R: Reproductive function and outcome of pregnancy after liver transplantation in women. Mayo Clin Proc 70:388-394, 1995 Brayman K, Stephanian E, Matas AJ, et al: Analysis of infectious complications occurring after solid-organ transplantation. Arch Surg 127:3848, 1992 Dunn DL, NajarianJS: New approaches to the diagnosis, prevention, and treatment of cytomegaiovirus infection after transplantation. Am J Surg 161:25-55, 1991 Laifer SA, Darby MJ, Scantlebury VP, et al: Pregnancy and liver transplantation. Obstet Gynecol 76:1083-1088, 1990 Yackel DB, Kempers RD, McConahey WM: Adrenocorticosteroid therapy in pregnancy. Am J Obstet Gynecol 96:985, 1966 Sato H: Effect of adrenocorticoids during pregnancy. Lancet 2:1235, 1963 Council on Scientific Affairs: Introduction to the management of immunosuppression. JAMA 257:1781-1785, 1987 Laifer SA: Pregnancy after transplantation, in Lee RV, (ed.): Current Obstetric Medicine. Vol 2. St. Louis, MO, Mosby, 1993, pp 1-23 Beitinis IZ, Bayard F, Ances IG, et al: The transplacental passage of prednisone in pregnancy near term. J Pediatr 81:936-945, 1972 Committe on Drugs, American Academy of Pediatrics: The transfer of drugs and other chemicals into human breast milk. Pediatrics 84:924-936, 1989 Ross WB, Richards T, Williams GL, et al: Cyclosporine and pregnancy. Transplantation 45:1142, 1988 Bermas BL, HiI1JA: Effects of immunosuppressive drugs during pregnancy. Arthr Rheum 38:1722-1732, 1995 Davison JM, Dellagrammatikas H, Parkin JM: Maternal azathioprine therapy and depressed haemopoiesis in the babies of renal allograft patients. Br J Obstet Gynecol 92:233-239, 1985 Munoz SJ: Long-term management of the liver transplant recipient. Med Clin North Am 80:1103-1120, 1996 Calne R, White D, Thiru S, et al: Cyclosporin A in patients receiving renal alloga'afts from cadaver donors. Lancet 2:1323, 1978 Venkataramanan R, Koneru B, Wang CP, et al: Cyclosporine and its metabolites in mother and baby. Transplantation 46:468-469, 1988 Shaheen FAM, Al-Sulaiman MH, Al-Khader AA: Longterm nephrotoxicty after exposure to cyclosporine in utero. Transplantation 56:224-225, 1993 Winkler ME, Niesert S, Ringe B, et al: Successful pregnancy in a patient after liver transplanatation maintained on FK 506. Transplantation 56:1589-1590, 1993 Jain A, Venkataramanan R, Lever J, et al: FK 506 and pregnancy in liver transplant patients. Transplantation 56:1588-1589, 1993
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25. Klupp J, Bechstein WO, Platz KP, et al: Mycophenolate mofetil added to immunosuppression after liver transplantation-First results. Transplant Int 10:223-228, 1997 26. Gavlik A, Goldberg MG, Tsaroucha A, et al: Mycophenc~ late mofetil rescue therapy in liver transplant patients. Transplant Proc 29:549-552, 1997 27. McDiarmid SV: Mycophenolate mofetil in liver transplantation. Clin Transplant 10:140-145, 1996 28. Hood KA, Zarembski DG: Mycophenolate mofetil: A unique immunosuppressive agent. American Journal of Health-System Pharmacy 54:285-294, 1997 29. Downs SM: Induction of meiotic maturation in vivo in the mouse by IMP dehydrogenase inhibitors: Effetcs on the developmental capacity of ova. Mol Reprod Dev 38:293-302, 1994 30. Viile Y, Fernandez, Samuel D, et al: Pregnancy in liver transplant recipients: Course and outcome in 19 cases, Am J Obstet Gynecol 168:896-902, 1993 31. Baruch Y, Weiner Z, Enat R, et al: Pregnancy after liver transplantation. IntJ Gynecol Obstet 41:273-276, 1993 32. HuttonJD, Wyeth JW: Pregnancy after liver transplantation: Effects of immunosuppressive therapy and abnormal hepatic function. Aust NZ J Obstet Gynaecol 30:130, 1990 33. Newton ER, Turksoy N, Kaplan M, et al: Pregnancy and liver transplantation. Obstet Gynecol 71:499, 1988 34. Sims CJ, Porter KB, Knuppel RA: Successful pregnancy after liver transplant. AmJ Obstet Gynecol 161:532-533, 1989 35. Hill NCW, Morris NH, Shaw RW, et ai: Pregnancy after orthotopic liver transplantation. Br J Obstet Gynecol 98:719-721, 1991 36. Haagsma EB, Visser GHA, Klompmaker IJ, et al: Success, ful pregnancy after orthotopic liver transplantation. Obstet Gynecol 74:442, 1989 37. Paternoster DM, Floreani A, Burra P: Liver transplantation and pregnancy. Int J Gynecol Obstet 50:199-200, 1995 38. Myer RL, Schmid R, NewtonJJ: Chilbirth after liver transplantation. Transplantation 29:432, 1980 39. Venkataramanan R, Konern B, Wang CC, et al: Cyclosporine and its metabolites in mother and baby. Transplantation 46:468, 1988 40. Walcott WO, Derick DE, JolleyJJ, et al: Successful pregnancy in a liver transplant patient. AmJ Obstet Gynecol 132:340, 1978 41. Roberts M, Brown ASM, James OFW, et al: Interpretation of cyclosporin A levels in pregnancy following orthotopic liver transplantation. Br J Obstet Gynecol 102:570-572, 1995 42. Winter H, MacKenzie WE, Newton JR= Successful pregnancy following liver transplantation in a patient taking cyclosporin. J Obstet Gynecol 10:396-397, 1990 43. Winkler ME, Niesert S, Ringe B, et al: Successful preg-
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nancy in a patient after liver transplantation maintained on FK 506. Transplantation 56:1589-1590, 1993 44. Pagnoni B, Mariconti P, Bedoni M: Gravidanza e maternita' dopo trapianto di fegato. Minerva Anestes 57:745-746, 1991 45. Gunter HH, Mauz S, Ringe B, et al: Schwangerschaft nach lebertransplantation und unter immunosuppression mit ciclosprin. Dtsch Med Wschr 115:740-742, 1990 46. HanfV, Viebahn R, Lauchart W, et al: Schwangerschaft und enthindung nach lebertransplantation. Gebursh Frauenheilk 50:813815, 1990 47. Kreuzpainmer G, Ringe B, Niesert S, et al: Zwillingsschwangerschaft nach lebertransplantation. Dtsch Med Wschr 115:895-898, 1990 48. Grow DR, Simon NV, LissJ, et al: Twin pregnancy after orthotopic liver transplantation with exacerbation of chronic graft rejection. Am J Perinatol 8:135-138, 1991 49. Alvin P, Muller J, Houssin D, et al: Grossesse et maternite apres transplantation hepatique pur hepatite active autoimmune terminale avec amenorrhee primaire. Gastroenterol Clin Biol 13:1079-1081, 1989 50. Fair J, Klein AS, Feng T, et al: Intrapontum orthotopic liver transplantation with successful outcome of pregnancy. Transplantation 50:534-535, 1990 51. Casele HL, Woelkers DA, Laifer SA: Pregnancy after Liver Transplantation. Am J Obstet Gynecoi 176:$23, 1997 52. Jain A, Venkataramanan R, Fung.IJ, et al: Pregnancy after liver transplantation under tacrolimus. Transplantation 64:559-565, 1997 53. Prnvot FR, Declerck N, Valat-Rigot AS, et al: Pregnancy after liver transplantation: Focusing on risks to the mother. Transpl Proc 29:2470-2471, 1997 54. Conde M, Andrde J, Bedoya FJ, et al: Inhibitory effect of cyclosporin A and FK506 on nitric oxide production by cultured macrophages. Evidence of a direct effect on nitric oxide synthase activity. Immunology 84:476-481, 1995 55. Laifer SA, Ehrlich GD, Huff DS, et al: Congenital cytomegalovirns infection in offspring of liver transplant recipients. Clin Infect Dis 20:52-55, 1995 56. Caritis SN, NICHD MFMU Network: Low dose aspirin does not prevent preeclampsia in high risk women. Am J Obstet Gynecol 176:$3, 1997 57. ZernerJ, Doll KL, DrewryJ, et al: Intrauterine contraceptive device failures in renal transplant patients. J Reprod Med 26:99-102, 1981 58. ScottJP, Higenbottam TW: Adverse reactions and interactions of cyciosporin. Med Toxicol 3:107-127, 1988 59. Laifer SA, Abu-Elmagd K, F u n g i : Hepatic transplantation during pregnancy and the puerperium. Journal of Maternal-Fetal Medicine 6:40-44, 1997 60. Salha D, Campbell DS, Pollard S: Budd-Chiari syndrome in pregnancy treated by cesarean section and liver transplant. BrJ Obstet Gynecol 103:1254-1256, 1996