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Pregnancy in liver transplant recipients: Course and ou tcome in 19 cases
Pregnancy in liver transplant recipients: Course and ou tcome in 19 cases Yves Ville, MD: Herve Fernandez, MD: Didier Samuel, MD,b Henri Bismuth, MD,b and Rene Frydman, MD" Clamart and Villejuif, France OBJECTIVE: Our aim was to evaluate the course and outcome of pregnancy in orthotopic liver transplant recipients. STUDY DESIGN: We report the course and outcome of 19 pregnancies in 19 orthotopic recipients since 1985, out of 775 patients who have undergone liver transplant in our center. Statistical analysis was based on the x 2 test with a 95% confidence interval, when appropriate. RESULTS: There were four spontaneous abortions and three therapeutic abortions for impaired liver function. One current pregnancy is uncomplicated at 19 weeks' gestation. Eleven women have given birth to 11 healthy infants at 38 ± 1.5 weeks' gestation. There were no preterm deliveries. Birth weight was normal for gestational age in 10 of the 11 cases, with a mean value of 2990 ± 370 gm. The main complications in the 11 successful pregnancies were hypertension in three and graft dysfunction at 37 weeks' gestation in another. CONCLUSION: Pregnancy is successful in a large proportion of liver transplant recipients, but it must be planned and managed as a high-risk situation by both an obstetrician and a surgeon. (AM J OBSTET GYNECOL 1993; 168:896-902.)
Key words: Pregnancy, orthotopic liver transplant, pregnancy-induced hypertension, graft rejection, immunosuppression More than 4000 orthotopic liver transplants have been performed since 1967, mostly (3000) in the United States I; between 10% and 30% of recipients are children. The number of orthotopic liver transplants is increasing with the improving 1 (32% in 1979, 80% in 1988) and 5-year survival rates (60% to 70% in 1988).2 More often patients are able to resume a normal lifestyle, and, in spite of concern over the long-term use of immunosuppressive medication, many women are choosing to become pregnant. In contrast to the large number of successful pregnancies in kidney transplant recipients, only 35 pregnancies in orthotopic liver transplant recipients have been described in the literature 3 - 16 since the first report by Walcott et al. 3 In one such case, orthotopic liver transplantation was performed during pregnancy, IS with a successful outcome for both mother and child. We report the outcome of the 19 pregnancies that have occurred among 775 patients who have undergone orthotopic liver transplantation in our center and pro-
From the Service de Gynecologie-Obstetrique, Hopital A. Bec/ere: and the Service de Chirurgie Digestive, Hopital Paul Brousse.' Received for publication May 18, 1992; revised August 17, 1992; accepted September 22, 1992. Reprint requests: Herve Fernandez, MD, Service de GynecologieObstetrique, Hopital A. Bec/ere, 157, Rue de la Porte de Trivaux, 92141 Clamart, France. Copyright © 1993 by Mosby-Year Book, Inc. 0002-9378193 $1.00 + .20 6!1!42868
896
pose specific measures for the management of pregnant liver transplant recipients.
Patients and methods Nineteen patients who received liver grafts in our institution have become pregnant since 1985, 8 to 60 months after transplantation (mean 26.4 ± 13 months), among a total of about 400 female recipients. All 19 patients were of childbearing age at the time of transplant and their mean age at conception was 29.7 ± 6.7 years. Seven of the 19 patients had previously had children, and one had had several abortions. The primary liver disease was primary biliary cirrhosis or autoimmune cirrhosis in 50% of the patients and hepatitis B in 35%. The condition was inherited in 15% of cases (Table I). In our institution healthy pregnant women are seen on alternate months by a midwife and an obstetrician. The mean number of antenatal visits is 6 ± 0.9 and ultrasonographic examination is performed at 12, 22, and 32 weeks' gestation (mean 3.0 ± 0.6), or more often as indicated. Pregnant orthotopic liver transplant recipients are managed as outpatients by an obstetrician and a liver transplantation specialist when the pregnancy is uneventful. The patients in this study were seen at least every 2 weeks up to 28 weeks of gestation and weekly thereafter, and they underwent a complete clinical examination and blood tests for liver function abnormalities on each occasion (Fig. 1). Gestational age is determined by
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Table I. Clinical data Patient No. I 2
3 4 5 6
7
8 9 10 II 12 13 14 15 16 17 18 19
Age at pregnancy (yr)
Gravidity and parity
Diagnosis at orthotopic liver transplantation
28
G2PI G2P2 GIPO G5P4 G3P2 GIPO GIPO G3P2 G6PI G3PI GIPI ? G2PO GIPO G2PI GIPI GIPI G2PI GIPI
Crytogenic cirrhosis Chronic active hepatitis Fulminant hepatitis Primary biliary cirrhosis Primary biliary cirrhosis Fulminant hepatitis Cryptogenic cirrhosis Fulminant hepatitis Primary biliary cirrhosis Secondary biliary cirrhosis Arterioplastic dysplasia· Cryptogenic cirrhosis Fulminant hepatitis Chronic active hepatitis Cryptogenic cirrhosis Cryptogenic cirrhosis Cryptogenic cirrhosis Fulminant hepatitis Primary biliary cirrhosis
38 17 33 33
22
25 39 38 31 33 25
22
32 26 34 33 34 31
Interval from orthotopic liver transplantation to pregnancy (mo)
24
27 18 8 26 36 12 60 36 26 27 12
24
34
24
36 17 27
28
·Alagille's syndrome, dominant inheritance with variable penetrance and expression.
means of an ultrasonographic scan before 12 weeks of amenorrhea, and full information on the potential risks for the mother and fetus is given, Patients with unstable liver function were advised to undergo abortion. Fetal growth was monitored clinically and by means of serial ultrasonographic examinations, whereas the fetal heart rate was assessed weekly from 28 weeks of gestation until delivery. Serologic tests for viral markers (hepatitis B [HBs], cytomegalovirus [CMV], Toxoplasma) and vaginal smear cultures were performed monthly, and human immunodeficiency virus (HIV) testing was performed at the first antenatal visit. One patient was HIV-seropositive, having been contaminated by blood transfusion during liver transplantation. Clinical signs of toxemia were sought at each clinical examination, and blood levels of uric acid, creatinine, and albumin were measured every month, Five mothers who were HBs positive before transplantation received HBs immune globulins throughout pregnancy to prevent the reemergence of HBsAg.'7 Immunosuppressive therapy consisting of cyclosporin A, corticosteroids (prednisone), and azathioprine 'H was maintained throughout pregnancy, at mean of daily doses of 227 ± 124, 11.5 ± 2.5, and 30.5 ± 27 mg, respectively, Graft tolerance and the immunosuppressive regimen during pregnancy are given in Table II. Increased doses of steroids were not necessary during labor. The fetal heart rate was monitored throughout labor and delivery. The detection of graft rejection was based on clinical signs Gaundice, tenderness of the right upper quadrant of the abdomen, obnubilation, and asterixis), biologic parameters (strong increase in aminotransferases, alka-
line phosphatase, and bilirubin and decrease in serum albumin and liver-dependent factors), and histologic findings at biopsy when indicated (lipid accumulation around the vessels, periportal fibrosis, and cholestasis), Statistical analysis was performed by X" analysis with a 95% confidence interval. Results Among a total of 19 pregnancies III 19 orthotopic liver transplant recipients there were four spontaneous abortions in the first trimester, three therapeutic abortions in the first trimester, and 11 live births; one pregnancy is proceeding normally at 19 weeks' gestation (Table III). All 11 neonates were healthy. Eleven pregnancies were unplanned. Spontaneous abortions occurred in four women, one of which was related to CMV infection. This patient was found infected with CMV at the time of the miscarriage; histopathologic examination of the abortus was consistent with viral infection and CMV was isolated from fetal tissues. Three therapeutic abortions were performed, two because of impaired liver function. One of these patients had severe cholestasis and chronic hepatitis before pregnancy, and the other had a recurrence of hepatitis at 7 weeks' gestation. The third patient underwent abortion because she was HIV-seropositive. No ectopic pregnancies occurred. The following results concern the 11 cases in which pregnancy was successful. The women attended 13 ± 5.2 antenatal visits and underwent 9 ± 4.5 ultrasonographic examinations. Ultrasonographic examination (Fig. 1) was performed in every patient at the first antenatal visit for precise determination of gestational
898
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March 1993 Am J Obstet Gynecol
Full information on potential maternal and fetal risks +1genetic conseling
Stable
1
Unstable
~rn'~p,;,"
1
Ultrasound evaluation of gestational age and at 20 weeks
Termination of pregnancy
Serial examinations every two weeks lip to 28 weeks and weekly thereafter:
Complele clinical examinalion Graft rejection~ Liver lunctlon tests Liver biopsy (alkaline. phosphatase. Iransaminase) _ _ _ _~) Severe ~
.M2!l1llh! :
J
ultrasonography Glucose. cholesterol. bilirubin. uric acid and crealinine Blood celi count Viral serology: HBs CMV 619 parvovirus Toxoplasma HIV
impairment"
.
~
oxytocin induction of laborl cesarean section
-"-r""""'" Spontaneous delivery
Fig_ 1. Management of pregnancy in orthotopic liver transplant recipients.
age, at 20 weeks' for detailed morphologic status, and every 3 weeks thereafter for fetal growth. Furthermore, fetal biophysical profile was part of the evaluation of fetal well-being in inpatients with complicated pregnancies (Table III). The overall preterm delivery rate was 10.2% in our institution during the study period, but no preterm deliveries occurred in this small series (mean gestational age at birth 38 ± 1.5 weeks). The overall rate of intrauterine growth retardation at our institution was 8.0% during the study period; this complication arose in one (10%) of the pregnant orthotopic liver transplant recipients in this study and was concomitent with chronic graft rejection. The mean birth weight was 2990 ± 370 gm. The overall rate of chronic graft rejection during the study period was 35% after 1 year and < 10% per year thereafter, although only one of the 19 pregnant recipients developed this complication. The incidence of preeclampsia at < 36 weeks was
3.3% in the overall pregnant population during the study period, whereas three of the 11 (27.3%) successful pregnancies in this series were complicated by severe hypertension at 34 weeks (X 2 = 7.42, 95% confidence interval = 0.05 to 0.45,p < 0.01). The first patient had preeclampsia with consistently elevated blood pressure and biologic parameters (uricemia, 460 mmo1!L; creatininemia, 90 mmo1!L; albuminuria, 3 gm per 24 hours), associated with severe cholestasis and mild cytolysis (Table II). Clinical and biologic examinations revealed no signs of liver failure. The second patient developed toxemia and a marked rise in liver enzyme activities and uric acid levels, together with a low platelet count (Table II). The third patient had preeclampsia; cesarean section was performed because of failure to labor induction. One patient had severe cholestasis and moderate liver function impairment at 25 weeks, reflected by a mild decrease in the prothrombin time and a low level
Volume 168, Number 3, Part I Am J Obstet Gynecol
of accelerin factor (40% of normal), She required increased immunosuppressive treatment (Table II) and was monitored closely until the induction oflabor at 37 weeks' gestation. Alkaline phosphatase values were slightly elevated (260 to 315 lUlL) in four patients but remained within the normal range for pregnancy (up to 340 IU/L in our institution). There was one case of maternal infectious pyelonephritis at 37 weeks' gestation, which was successfully treated with amoxicillin plus clavulanic acid. Five cesarean sections were performed for the following reasons: severe cholestasis and pregnancy-induced hypertension (38 weeks), breech presentation and prior cesarean section (37 weeks), cord prolapse after the induction of labor because of maternal infection (38 weeks' gestation), HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets) (37 weeks), and severe hypertension after failure of induction of labor (37 weeks' gestation). One patient was delivered vaginally at 37 weeks' gestation after induction of labor with oxytocin because of graft impairment. Normal spontaneous vaginal delivery occurred in five cases. The postpartum course was always uneventful. The fetal survival rate was 100% (11/11), and all the children are developing well at 3 months to 5 years of age. All 11 neonates were healthy; there were no congenital abnormalities of birth defects, no adrenal or respiratory insufficiency, and no neonatal lymphopenia. Immunoprophylaxis was initiated at birth in five infants born to HBsAg-seropositive mothers, with combined anti-HBs immune globulins (HBIG) and hepatitis B virus vaccine, although none had detectable serum HBsAg at birth. No rhesus isoimmunization occurred. Comment
Complementing the previous reports of 35 normal pregnancies in 33 orthotopic liver transplant recipients,'-16 we now describe a further 11 successful pregnancies in such women. With regard to the course of pregnancy, spontaneous abortion occurred at the same rate in this series as in our normal hospital population. The incidence of elevated liver enzyme activities, particularly alkaline phosphatase, is about 35% during normal pregnancy, but these abnormalities resolve in 80% of cases during the postpartum period. Liver biopsy was performed because of suspected rejection in three previously reported cases lO during the last trimester; rejection was confirmed in two and hepatitis was diagnosed in one. The annual rate of graft rejection in our overall population of 77 5 patients with liver transplants is 35% during the first year and < 10% thereafter. One patient in our series developed severe cholestasis associated
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with hypertension, but this was probably caused by a coincidental association of preeclampsia and intrahepatic cholestasis of pregnancy, although acute fatty liver of pregnancy could not be ruled out. There were no other suspected or confirmed episodes of graft rejection, suggesting that pregnancy does not increase the risk of this complication. Tn addition, the frequency of graft impairment does not seem to vary with the time elapsing between orthotopic liver transplantation and conception. 3 - 16 The incidence of clinical toxemia in pregnant orthotopic liver transplant recipients is 10% to 20%.3-16 Hypertension before 36 weeks of gestation was significantly more frequent in this series (27.3%) than in the general pregnant population in our institution (3.3%) and in the country (9.3%),19 whereas the overall incidence of hypertension in nonpregnant orthotopic liver transplant recipients is of the order of 30%. Corticosteroids are known to enhance the renin-angiotensinaldosterone system, and in up to 40% of patients taking cyclosporin A, a nephrotoxic drug, hypertension develops during pregnancy.9 In addition, most of our pregnant orthotopic liver transplant recipients were primiparous. Finally, immunosuppressive drug-induced suppression of maternal antibodies that block anti paternal antigen recognition has also been associated with preeclampsia. 20 Orthotopic liver transplant recipients are more susceptible to various infections because of the immunosuppressive regimen!1 CMV infection, a frequent complication of liver transplantation, occurred in one patient in this series and caused a miscarriage. 21 Patients undergoing transplantation before the introduction of screening tests of donor blood were exposed to the risk of HIV infection, which carries a rate of vertical transmission of the order of 20% to 25%. In this series the only HIV-infected woman opted for termination. The risk of mother-to-infant transmission of hepatitis B virus (of the order of 10%22) may be reduced by the use of immunoglobulins weekly throughout pregnancy, together with neonatal immunoprophylaxis 17; indeed, none of the infants born to the HBsAg-seropositive women in this series had evidence of hepatitis B virus infection. Toxoplasma, rubella, and parvovirus infections, which are likely to be reactivated in immunosuppressed patients, were not seen in this study. Although the postpartum course was uneventful in this series, in one reported case lO the mother developed a midgut volvulus involving a prolapse of the small bowel through a defect in the mesentery of the Rouxen-Y extension to the transplanted liver; the volvulus appeared as a painful acute obstructive syndrome immediately after delivery. None of the neonatal complications of immunosup-
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Table II. Immunosuppressive regimen and liver function during pregnancy Patient No.
Prednisone (mg/day) Cyclosporin A (mg/day) Azathioprine (mg/day) Liver function at begining of pregnancy Liver function at end of pregnancy
1
2
3
4
15 140 50 Mild cytolysis (x3) Severe cholestasis
10 240 50 N
14 220 50 N
200 0 N
N
N
10
5
6
9 220 50 N
200 0 N
10
7
8 10
200 50 Cholestasis (Nx5)
10
200 0 N
9
10 200 50 N
N, Normal level.
Table III. Outcome of pregnancy after liver transplantation
Patient No.
Gestational age at delivery (wk)
Mode of delivery
Apgar score 1 min
I 5min
Birth weight (gm)
Complications
38
Cesarean section
9
10
2
37
Cesarean section
8
10
2740 (30th percentile) 3500
3 4 5 6 7
7 10 38 10 8
Spontaneous abortion Elective abortion Cesarean section Spontaneous abortion Elective abortion
6
10
3200
8 9 10
7 7 37
Spontaneous abortion Spontaneous abortion Cesarean section
9
10
2900 «50th percentile)
11
37
9
10
12
37
8
10
2300 « lOth percentile) 2980
13
38
9
10
3000
None
14
37
3300
None
15
38
16
39
17 18
37 8
Normal spontaneous vaginal delivery Normal spontaneous vaginal delivery Normal spontaneous vaginal delivery Normal spontaneous vaginal delivery Normal spontaneous vaginal delivery Normal spontaneous vaginal delivery Cesarean section Elective abortion
19
19
Severe cholestasis, mild cytolysis, preeclampsia Breech presentation, glucose intolerance None Recurrence of hepatitis Maternal fever, cord prolapse CMV infection Severe cholestasis and chronic hepatitis None Failure of tubal sterilization Toxemia, severe rise in liver enzymes and uric acid, low platelet count, graft rejection Graft rejection None
8
10
3000
None
8
10
2900
Pyelonephritis
9
10
2700
Preeclampsia Human immunodeficiency virus positive Ongoing without complication
pressive therapy described in the literature were seen in this series, and the infants are developing well at 9 months to 5 years of age. At all events, fetal respiratory distress, adrenal insufficiency, and neonatal lymphocytopenia are unlikely at the daily doses generally administered in this setting. Theoretically, the fetus should be protected from the effects of azathioprine, a drug first used during pregnancy in 1973.23 Although azathioprine crosses the
placenta in early pregnancy, the fetus lacks the enzyme that converts azathioprine into its active metabolite!' However, anomalies have been reported in seven of 110 babies!8 whose mothers had been taking a significantly higher daily dose of azathioprine than those who had normal babies (2.64 vs 2.02 mg/kg). These are the only cases of birth anomalies among more than 1600 pregnancies; this could be a coincidence. However, doubts remain as to the long-term side effects of aza-
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Patient No. 11
10
10/20 300 50/75 N
Severe cytolysis
(Nx5)
10/25 600 50/100 N
12
13
14
10 300 50 N
20 160 50
0 0 0 N
N
Severe cholestasis
(Nx5)
thioprine, particularly regarding reproductive potential and the risk of malignancy. Cyclosporin A crosses the placenta passively according to Fick's laW!4 but the toxicity of cyclosporin A metabolites is unknown. No large series is available, but isolated anomalies have been reported in the offspring of 116 women who had taken cyclosporin A throughout pregnancy,14 although none were observed more than once. Intrauterine growth retardation has been reported in up to 50% of pregnant orthotopic liver transplant patients, and there has been one reported case of intrauterine death due to cyclosporin-induced vasoconstriction. 10 We have found cyclosporin A levels 10 to 20 times higher in an electively aborted 10-weekold embryo than in the maternal serum,25 whereas others have reported lower levels in the fetus at 33 weeks' gestation. 9 Some of the explanations regarding the high level of cyclosporin A in the fetal kidneys and liver is that these organs are capable of accumulating the drug and are unable to excrete it at lO weeks. Alternatively, these organs could have special receptors for cyclosporin A, and immunologic implications for the fetus need further evaluation. The lower levels found in other studies could be because the cyclosporin A levels were measured later in pregnancy, when placental transfer was already compromised by preeclampsia. Of the 11 viable pregnancies in this study, none gave rise to preterm births, although preterm delivery has been reported in 70% of orthotopic liver transplant recipients (mean 36 weeks)."16 The main causes were interventions because of maternal complications (30%) and untoward events such as premature rupture of membranes or premature labor (40%). One possible explanation for this difference is that the French National Health Service provides for careful management of pregnant women from 22 weeks' gestation. 19 Four cesarean sections were performed for maternal complications, all after 37 weeks' gestation. There were no cases of premature rupture of membranes or preterm labor; the overall preterm birth rate in our hospital is lO.2% and the difference with this series was not sig-
15 5/12 240 50 N Mild cytolysis
16 5/10 180 50
Mild cytolysis
17
18
19
10 140 50 N
10 200 50 N
15 180 50 N
N
nificant. Long-term steroid therapy favors premature rupture of membranes by weakening connective tissue and reducing resistance to local infection. The reported average birth weight of infants born to liver transplant recipients is low (2500 gm) because most deliveries have been preterm. However, in our series it was 2990 gm which is normal according to Lubchenco's curves. The incidence of small-for-gestational-age babies is 8% to 45% in kidney recipients 26 and up to 60% in liver recipients. 3 . 16 Low birth weight is not necessarily related to liver impairment or hypertension because half the mothers of small-for-gestationalage babies have normal blood pressure. Immunogenetic disparity between the conceptus and mother is advantageous, with bigger placentas and fetuses 26 ; nonspecific depression of the maternal immune system by immunosuppressive drugs might thus contribute to fetal growth retardation, as may undiagnosed viral infection of the fetus. Spontaneous vaginal delivery should be the aim. In this series primary cesarean section was necessary only for purely obstetric reasons. The reported rate of 70% (40% in our series) reflects the high rate offetal distress and both maternal and obstetric complications in this setting. Although most congenital or genetic defects primarily affecting the liver (mainly Wilson's disease) are rare,27 couples must be aware that the risk to the fetus is unpredictable given the different modes of transmission and the variable clinical expression of these diseases. Childbearing in orthotopic liver transplant recipients should be planned and managed as a high-risk situation at as early a stage as possible, for two main reasons: 1. Pregnancy is not advised in patients with poor liver function or active viral infection. A 12-month interval from orthotopic liver transplantation to conception is thus recommended. 2. Couples must be fully informed of the risks to the fetus, and genetic counseling should be provided when the primary liver disease is hereditary.
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Posttransplant immunosuppressive therapy should be maintained throughout pregnancy unless liver function impairment occurs. As shown by the results of our study and those reported in the literature, pregnancy is not only feasible but also successful in a large proportion of orthotopic liver transplant recipients.
REFERENCES 1. Starzl TE, Marchioro TL, Van Kaulla KN, Waddell WR. Homotransplantation of the liver in humans. Gynecol Obstet 1963; 117:659-61. 2. Bismuth H, Castaing D, Ericzon BG, et al. Hepatic transplantation in Europe. First report of the European liver transplant registry. Lancet 1987;2:674. 3. Walcott WO, Derick DE, Jolley JT, Snyder DL. Successful patient in a liver transplant patient. AM J OBSTET GYNECOL 1978; 132:340-1. 4. Myers RL, Schmid R, Newton JJ. Childbirth after liver transplantation. Transplantation 1980;29:432-4. 5. Penn I, Makowski EL, Harris P. Parenthood following renal and hepatic transplantation. Transplantation 1980; 30:397-9. 6. Haagsma EB, Visser GHA, Klompmaker I, Verwer R, Sioff MJH. Successful pregnancy after orthotopic liver transplantation. Obstet Gynecol 1989;74:442-3. 7. Newton ER, Turksoy N, Kaplan M, Reinhold R. Pregnancy and liver transplantation. Obstet Gynecol 1988;71 :449-53. 8. Sims C, Porter LB, Knuppel RA. Successful pregnancy after a liver transplant. A\1 J OBsn:! GY:\ECOL 1989; 161: 532-3. 9. Venkataramanan R, Koneru B, Wang CP, Burckart GJ, Caritis SN, Starzl TE. Cyclosporine and its metabolites in mother and baby. Transplantation 1988;46:468-9. 10. Scantelbury V, Gordon R, Tzakis A, Starzl TE. Childbearing after liver transplantation. Transplantation 1990;49: 317-21. 11. Alvin P, Muller J, Houssin D, Prasjude N, Chapuis Y, Courtecuisse V. Grossesse et maternite apres transplantation hepatique pour hepatite active auto-immune terminale avec amenorrhee primaire. Gastroenteroly 1989;13: 1079-81.
J Obstet Gyneco1
12. Cundy TF, O'Grady JG, Williams R. Recovery ofmenstruation and pregnancy after liver transplantation. Gut 1990; 31:337-8. 13. Winter H, MacKenzie WE, Newton JR. Successful pregnancy following liver transplantation in a patient taking cyclosporin. J Obstet Gynaecol 1990;7:396-7. 14. Hutton JD, Wyeth JW. Pregnancy rate liver transplantation: effects of immunosuppressive therapy and abdominal hepatic function. NZJ Obstet Gynecol 1990;30: 130-2. 15. Hill NCW, Morris NH, Shaw RW, Mathur S, Rowes K, Bunoughs AK. Pregnancy after orthotopic liver transplantation. Case report. BrJ Obstet Gynaecol 1991 ;98:719-21. 16. Fair J, Klein AS, Feng T, Merritt WT, Burdick JF. Intrapontum orthotopic liver transplantation with successful outcome of pregnancy. Transplantation 1990;50:534-5. 17. Samuel D, Bismuth A, Mathieu D, et al. Passive immunoprophylaxis after liver transplantation in HBs-Ag-positive patients. Lancet 1991;337:813-5. 18. GugenheimJ, Samuel D, Saliba F, Castaing D, Bismuth H. The use of flexible triple drug immunosuppressive therapy in liver transplantation. Transplant Proc 1987; 19: 3805-7. 19. Rumeau-Rouquette C, du Mazaubrunc, Rabarison Y. Naitre en France, 10 ans d'evolution. In: Doin, ed. Paris: INSERM, 1984:47-72. 20. Wegman TG, Gil 1J. Immunology of reproduction, vol 1. London: Oxford, 1983:147-62. 21. Colonn JO II, Winston DJ, Brill .IE, et al. Infectious complications in liver transplantation. Arch Surg 1988; 123:360-4. 22. Trepo C. Hepatite virale et grossesse. Rev Fr Gynecol 1980; 175: 101-4. 23. Saarikowski S, Seppala M. Immunosuppression during pregnancy: transmission of azathioprine and its metabolites from mother to the fetus. AM .I OBSTET GYNECOL 1973;115:1100-6. 24. Lewis GJ, Lamont CAR, Lee HA, Siapek M. Successful pregnancy in a renal transplant recipient taking cyclosporin A. BMJ 1983;286:603-4. 25. Bourget P, Fernandez H. Accumulation of cydosporine in the conceptus during the first trimester of pregnancy after liver transplantation. Transplantation 1991 ;51: 1306-7. 26. Hamid AH. Pregnancy in renal transplant recipients: a review. Obstet Gynecol Surv 1986;41:264-71. 27. Mc Connell RB. The genetics of gastrointestinal disorders. London: Oxford, 1966: 112-30.
Key words: Pregnancy, orthotopic liver transplant, pregnancy-induced hypertension, graft rejection, immunosuppression More than 4000 orthotopic liver transplants have been performed since 1967, mostly (3000) in the United States I; between 10% and 30% of recipients are children. The number of orthotopic liver transplants is increasing with the improving 1 (32% in 1979, 80% in 1988) and 5-year survival rates (60% to 70% in 1988).2 More often patients are able to resume a normal lifestyle, and, in spite of concern over the long-term use of immunosuppressive medication, many women are choosing to become pregnant. In contrast to the large number of successful pregnancies in kidney transplant recipients, only 35 pregnancies in orthotopic liver transplant recipients have been described in the literature 3 - 16 since the first report by Walcott et al. 3 In one such case, orthotopic liver transplantation was performed during pregnancy, IS with a successful outcome for both mother and child. We report the outcome of the 19 pregnancies that have occurred among 775 patients who have undergone orthotopic liver transplantation in our center and pro-
From the Service de Gynecologie-Obstetrique, Hopital A. Bec/ere: and the Service de Chirurgie Digestive, Hopital Paul Brousse.' Received for publication May 18, 1992; revised August 17, 1992; accepted September 22, 1992. Reprint requests: Herve Fernandez, MD, Service de GynecologieObstetrique, Hopital A. Bec/ere, 157, Rue de la Porte de Trivaux, 92141 Clamart, France. Copyright © 1993 by Mosby-Year Book, Inc. 0002-9378193 $1.00 + .20 6!1!42868
896
pose specific measures for the management of pregnant liver transplant recipients.
Patients and methods Nineteen patients who received liver grafts in our institution have become pregnant since 1985, 8 to 60 months after transplantation (mean 26.4 ± 13 months), among a total of about 400 female recipients. All 19 patients were of childbearing age at the time of transplant and their mean age at conception was 29.7 ± 6.7 years. Seven of the 19 patients had previously had children, and one had had several abortions. The primary liver disease was primary biliary cirrhosis or autoimmune cirrhosis in 50% of the patients and hepatitis B in 35%. The condition was inherited in 15% of cases (Table I). In our institution healthy pregnant women are seen on alternate months by a midwife and an obstetrician. The mean number of antenatal visits is 6 ± 0.9 and ultrasonographic examination is performed at 12, 22, and 32 weeks' gestation (mean 3.0 ± 0.6), or more often as indicated. Pregnant orthotopic liver transplant recipients are managed as outpatients by an obstetrician and a liver transplantation specialist when the pregnancy is uneventful. The patients in this study were seen at least every 2 weeks up to 28 weeks of gestation and weekly thereafter, and they underwent a complete clinical examination and blood tests for liver function abnormalities on each occasion (Fig. 1). Gestational age is determined by
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Table I. Clinical data Patient No. I 2
3 4 5 6
7
8 9 10 II 12 13 14 15 16 17 18 19
Age at pregnancy (yr)
Gravidity and parity
Diagnosis at orthotopic liver transplantation
28
G2PI G2P2 GIPO G5P4 G3P2 GIPO GIPO G3P2 G6PI G3PI GIPI ? G2PO GIPO G2PI GIPI GIPI G2PI GIPI
Crytogenic cirrhosis Chronic active hepatitis Fulminant hepatitis Primary biliary cirrhosis Primary biliary cirrhosis Fulminant hepatitis Cryptogenic cirrhosis Fulminant hepatitis Primary biliary cirrhosis Secondary biliary cirrhosis Arterioplastic dysplasia· Cryptogenic cirrhosis Fulminant hepatitis Chronic active hepatitis Cryptogenic cirrhosis Cryptogenic cirrhosis Cryptogenic cirrhosis Fulminant hepatitis Primary biliary cirrhosis
38 17 33 33
22
25 39 38 31 33 25
22
32 26 34 33 34 31
Interval from orthotopic liver transplantation to pregnancy (mo)
24
27 18 8 26 36 12 60 36 26 27 12
24
34
24
36 17 27
28
·Alagille's syndrome, dominant inheritance with variable penetrance and expression.
means of an ultrasonographic scan before 12 weeks of amenorrhea, and full information on the potential risks for the mother and fetus is given, Patients with unstable liver function were advised to undergo abortion. Fetal growth was monitored clinically and by means of serial ultrasonographic examinations, whereas the fetal heart rate was assessed weekly from 28 weeks of gestation until delivery. Serologic tests for viral markers (hepatitis B [HBs], cytomegalovirus [CMV], Toxoplasma) and vaginal smear cultures were performed monthly, and human immunodeficiency virus (HIV) testing was performed at the first antenatal visit. One patient was HIV-seropositive, having been contaminated by blood transfusion during liver transplantation. Clinical signs of toxemia were sought at each clinical examination, and blood levels of uric acid, creatinine, and albumin were measured every month, Five mothers who were HBs positive before transplantation received HBs immune globulins throughout pregnancy to prevent the reemergence of HBsAg.'7 Immunosuppressive therapy consisting of cyclosporin A, corticosteroids (prednisone), and azathioprine 'H was maintained throughout pregnancy, at mean of daily doses of 227 ± 124, 11.5 ± 2.5, and 30.5 ± 27 mg, respectively, Graft tolerance and the immunosuppressive regimen during pregnancy are given in Table II. Increased doses of steroids were not necessary during labor. The fetal heart rate was monitored throughout labor and delivery. The detection of graft rejection was based on clinical signs Gaundice, tenderness of the right upper quadrant of the abdomen, obnubilation, and asterixis), biologic parameters (strong increase in aminotransferases, alka-
line phosphatase, and bilirubin and decrease in serum albumin and liver-dependent factors), and histologic findings at biopsy when indicated (lipid accumulation around the vessels, periportal fibrosis, and cholestasis), Statistical analysis was performed by X" analysis with a 95% confidence interval. Results Among a total of 19 pregnancies III 19 orthotopic liver transplant recipients there were four spontaneous abortions in the first trimester, three therapeutic abortions in the first trimester, and 11 live births; one pregnancy is proceeding normally at 19 weeks' gestation (Table III). All 11 neonates were healthy. Eleven pregnancies were unplanned. Spontaneous abortions occurred in four women, one of which was related to CMV infection. This patient was found infected with CMV at the time of the miscarriage; histopathologic examination of the abortus was consistent with viral infection and CMV was isolated from fetal tissues. Three therapeutic abortions were performed, two because of impaired liver function. One of these patients had severe cholestasis and chronic hepatitis before pregnancy, and the other had a recurrence of hepatitis at 7 weeks' gestation. The third patient underwent abortion because she was HIV-seropositive. No ectopic pregnancies occurred. The following results concern the 11 cases in which pregnancy was successful. The women attended 13 ± 5.2 antenatal visits and underwent 9 ± 4.5 ultrasonographic examinations. Ultrasonographic examination (Fig. 1) was performed in every patient at the first antenatal visit for precise determination of gestational
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Full information on potential maternal and fetal risks +1genetic conseling
Stable
1
Unstable
~rn'~p,;,"
1
Ultrasound evaluation of gestational age and at 20 weeks
Termination of pregnancy
Serial examinations every two weeks lip to 28 weeks and weekly thereafter:
Complele clinical examinalion Graft rejection~ Liver lunctlon tests Liver biopsy (alkaline. phosphatase. Iransaminase) _ _ _ _~) Severe ~
.M2!l1llh! :
J
ultrasonography Glucose. cholesterol. bilirubin. uric acid and crealinine Blood celi count Viral serology: HBs CMV 619 parvovirus Toxoplasma HIV
impairment"
.
~
oxytocin induction of laborl cesarean section
-"-r""""'" Spontaneous delivery
Fig_ 1. Management of pregnancy in orthotopic liver transplant recipients.
age, at 20 weeks' for detailed morphologic status, and every 3 weeks thereafter for fetal growth. Furthermore, fetal biophysical profile was part of the evaluation of fetal well-being in inpatients with complicated pregnancies (Table III). The overall preterm delivery rate was 10.2% in our institution during the study period, but no preterm deliveries occurred in this small series (mean gestational age at birth 38 ± 1.5 weeks). The overall rate of intrauterine growth retardation at our institution was 8.0% during the study period; this complication arose in one (10%) of the pregnant orthotopic liver transplant recipients in this study and was concomitent with chronic graft rejection. The mean birth weight was 2990 ± 370 gm. The overall rate of chronic graft rejection during the study period was 35% after 1 year and < 10% per year thereafter, although only one of the 19 pregnant recipients developed this complication. The incidence of preeclampsia at < 36 weeks was
3.3% in the overall pregnant population during the study period, whereas three of the 11 (27.3%) successful pregnancies in this series were complicated by severe hypertension at 34 weeks (X 2 = 7.42, 95% confidence interval = 0.05 to 0.45,p < 0.01). The first patient had preeclampsia with consistently elevated blood pressure and biologic parameters (uricemia, 460 mmo1!L; creatininemia, 90 mmo1!L; albuminuria, 3 gm per 24 hours), associated with severe cholestasis and mild cytolysis (Table II). Clinical and biologic examinations revealed no signs of liver failure. The second patient developed toxemia and a marked rise in liver enzyme activities and uric acid levels, together with a low platelet count (Table II). The third patient had preeclampsia; cesarean section was performed because of failure to labor induction. One patient had severe cholestasis and moderate liver function impairment at 25 weeks, reflected by a mild decrease in the prothrombin time and a low level
Volume 168, Number 3, Part I Am J Obstet Gynecol
of accelerin factor (40% of normal), She required increased immunosuppressive treatment (Table II) and was monitored closely until the induction oflabor at 37 weeks' gestation. Alkaline phosphatase values were slightly elevated (260 to 315 lUlL) in four patients but remained within the normal range for pregnancy (up to 340 IU/L in our institution). There was one case of maternal infectious pyelonephritis at 37 weeks' gestation, which was successfully treated with amoxicillin plus clavulanic acid. Five cesarean sections were performed for the following reasons: severe cholestasis and pregnancy-induced hypertension (38 weeks), breech presentation and prior cesarean section (37 weeks), cord prolapse after the induction of labor because of maternal infection (38 weeks' gestation), HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets) (37 weeks), and severe hypertension after failure of induction of labor (37 weeks' gestation). One patient was delivered vaginally at 37 weeks' gestation after induction of labor with oxytocin because of graft impairment. Normal spontaneous vaginal delivery occurred in five cases. The postpartum course was always uneventful. The fetal survival rate was 100% (11/11), and all the children are developing well at 3 months to 5 years of age. All 11 neonates were healthy; there were no congenital abnormalities of birth defects, no adrenal or respiratory insufficiency, and no neonatal lymphopenia. Immunoprophylaxis was initiated at birth in five infants born to HBsAg-seropositive mothers, with combined anti-HBs immune globulins (HBIG) and hepatitis B virus vaccine, although none had detectable serum HBsAg at birth. No rhesus isoimmunization occurred. Comment
Complementing the previous reports of 35 normal pregnancies in 33 orthotopic liver transplant recipients,'-16 we now describe a further 11 successful pregnancies in such women. With regard to the course of pregnancy, spontaneous abortion occurred at the same rate in this series as in our normal hospital population. The incidence of elevated liver enzyme activities, particularly alkaline phosphatase, is about 35% during normal pregnancy, but these abnormalities resolve in 80% of cases during the postpartum period. Liver biopsy was performed because of suspected rejection in three previously reported cases lO during the last trimester; rejection was confirmed in two and hepatitis was diagnosed in one. The annual rate of graft rejection in our overall population of 77 5 patients with liver transplants is 35% during the first year and < 10% thereafter. One patient in our series developed severe cholestasis associated
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with hypertension, but this was probably caused by a coincidental association of preeclampsia and intrahepatic cholestasis of pregnancy, although acute fatty liver of pregnancy could not be ruled out. There were no other suspected or confirmed episodes of graft rejection, suggesting that pregnancy does not increase the risk of this complication. Tn addition, the frequency of graft impairment does not seem to vary with the time elapsing between orthotopic liver transplantation and conception. 3 - 16 The incidence of clinical toxemia in pregnant orthotopic liver transplant recipients is 10% to 20%.3-16 Hypertension before 36 weeks of gestation was significantly more frequent in this series (27.3%) than in the general pregnant population in our institution (3.3%) and in the country (9.3%),19 whereas the overall incidence of hypertension in nonpregnant orthotopic liver transplant recipients is of the order of 30%. Corticosteroids are known to enhance the renin-angiotensinaldosterone system, and in up to 40% of patients taking cyclosporin A, a nephrotoxic drug, hypertension develops during pregnancy.9 In addition, most of our pregnant orthotopic liver transplant recipients were primiparous. Finally, immunosuppressive drug-induced suppression of maternal antibodies that block anti paternal antigen recognition has also been associated with preeclampsia. 20 Orthotopic liver transplant recipients are more susceptible to various infections because of the immunosuppressive regimen!1 CMV infection, a frequent complication of liver transplantation, occurred in one patient in this series and caused a miscarriage. 21 Patients undergoing transplantation before the introduction of screening tests of donor blood were exposed to the risk of HIV infection, which carries a rate of vertical transmission of the order of 20% to 25%. In this series the only HIV-infected woman opted for termination. The risk of mother-to-infant transmission of hepatitis B virus (of the order of 10%22) may be reduced by the use of immunoglobulins weekly throughout pregnancy, together with neonatal immunoprophylaxis 17; indeed, none of the infants born to the HBsAg-seropositive women in this series had evidence of hepatitis B virus infection. Toxoplasma, rubella, and parvovirus infections, which are likely to be reactivated in immunosuppressed patients, were not seen in this study. Although the postpartum course was uneventful in this series, in one reported case lO the mother developed a midgut volvulus involving a prolapse of the small bowel through a defect in the mesentery of the Rouxen-Y extension to the transplanted liver; the volvulus appeared as a painful acute obstructive syndrome immediately after delivery. None of the neonatal complications of immunosup-
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Table II. Immunosuppressive regimen and liver function during pregnancy Patient No.
Prednisone (mg/day) Cyclosporin A (mg/day) Azathioprine (mg/day) Liver function at begining of pregnancy Liver function at end of pregnancy
1
2
3
4
15 140 50 Mild cytolysis (x3) Severe cholestasis
10 240 50 N
14 220 50 N
200 0 N
N
N
10
5
6
9 220 50 N
200 0 N
10
7
8 10
200 50 Cholestasis (Nx5)
10
200 0 N
9
10 200 50 N
N, Normal level.
Table III. Outcome of pregnancy after liver transplantation
Patient No.
Gestational age at delivery (wk)
Mode of delivery
Apgar score 1 min
I 5min
Birth weight (gm)
Complications
38
Cesarean section
9
10
2
37
Cesarean section
8
10
2740 (30th percentile) 3500
3 4 5 6 7
7 10 38 10 8
Spontaneous abortion Elective abortion Cesarean section Spontaneous abortion Elective abortion
6
10
3200
8 9 10
7 7 37
Spontaneous abortion Spontaneous abortion Cesarean section
9
10
2900 «50th percentile)
11
37
9
10
12
37
8
10
2300 « lOth percentile) 2980
13
38
9
10
3000
None
14
37
3300
None
15
38
16
39
17 18
37 8
Normal spontaneous vaginal delivery Normal spontaneous vaginal delivery Normal spontaneous vaginal delivery Normal spontaneous vaginal delivery Normal spontaneous vaginal delivery Normal spontaneous vaginal delivery Cesarean section Elective abortion
19
19
Severe cholestasis, mild cytolysis, preeclampsia Breech presentation, glucose intolerance None Recurrence of hepatitis Maternal fever, cord prolapse CMV infection Severe cholestasis and chronic hepatitis None Failure of tubal sterilization Toxemia, severe rise in liver enzymes and uric acid, low platelet count, graft rejection Graft rejection None
8
10
3000
None
8
10
2900
Pyelonephritis
9
10
2700
Preeclampsia Human immunodeficiency virus positive Ongoing without complication
pressive therapy described in the literature were seen in this series, and the infants are developing well at 9 months to 5 years of age. At all events, fetal respiratory distress, adrenal insufficiency, and neonatal lymphocytopenia are unlikely at the daily doses generally administered in this setting. Theoretically, the fetus should be protected from the effects of azathioprine, a drug first used during pregnancy in 1973.23 Although azathioprine crosses the
placenta in early pregnancy, the fetus lacks the enzyme that converts azathioprine into its active metabolite!' However, anomalies have been reported in seven of 110 babies!8 whose mothers had been taking a significantly higher daily dose of azathioprine than those who had normal babies (2.64 vs 2.02 mg/kg). These are the only cases of birth anomalies among more than 1600 pregnancies; this could be a coincidence. However, doubts remain as to the long-term side effects of aza-
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Patient No. 11
10
10/20 300 50/75 N
Severe cytolysis
(Nx5)
10/25 600 50/100 N
12
13
14
10 300 50 N
20 160 50
0 0 0 N
N
Severe cholestasis
(Nx5)
thioprine, particularly regarding reproductive potential and the risk of malignancy. Cyclosporin A crosses the placenta passively according to Fick's laW!4 but the toxicity of cyclosporin A metabolites is unknown. No large series is available, but isolated anomalies have been reported in the offspring of 116 women who had taken cyclosporin A throughout pregnancy,14 although none were observed more than once. Intrauterine growth retardation has been reported in up to 50% of pregnant orthotopic liver transplant patients, and there has been one reported case of intrauterine death due to cyclosporin-induced vasoconstriction. 10 We have found cyclosporin A levels 10 to 20 times higher in an electively aborted 10-weekold embryo than in the maternal serum,25 whereas others have reported lower levels in the fetus at 33 weeks' gestation. 9 Some of the explanations regarding the high level of cyclosporin A in the fetal kidneys and liver is that these organs are capable of accumulating the drug and are unable to excrete it at lO weeks. Alternatively, these organs could have special receptors for cyclosporin A, and immunologic implications for the fetus need further evaluation. The lower levels found in other studies could be because the cyclosporin A levels were measured later in pregnancy, when placental transfer was already compromised by preeclampsia. Of the 11 viable pregnancies in this study, none gave rise to preterm births, although preterm delivery has been reported in 70% of orthotopic liver transplant recipients (mean 36 weeks)."16 The main causes were interventions because of maternal complications (30%) and untoward events such as premature rupture of membranes or premature labor (40%). One possible explanation for this difference is that the French National Health Service provides for careful management of pregnant women from 22 weeks' gestation. 19 Four cesarean sections were performed for maternal complications, all after 37 weeks' gestation. There were no cases of premature rupture of membranes or preterm labor; the overall preterm birth rate in our hospital is lO.2% and the difference with this series was not sig-
15 5/12 240 50 N Mild cytolysis
16 5/10 180 50
Mild cytolysis
17
18
19
10 140 50 N
10 200 50 N
15 180 50 N
N
nificant. Long-term steroid therapy favors premature rupture of membranes by weakening connective tissue and reducing resistance to local infection. The reported average birth weight of infants born to liver transplant recipients is low (2500 gm) because most deliveries have been preterm. However, in our series it was 2990 gm which is normal according to Lubchenco's curves. The incidence of small-for-gestational-age babies is 8% to 45% in kidney recipients 26 and up to 60% in liver recipients. 3 . 16 Low birth weight is not necessarily related to liver impairment or hypertension because half the mothers of small-for-gestationalage babies have normal blood pressure. Immunogenetic disparity between the conceptus and mother is advantageous, with bigger placentas and fetuses 26 ; nonspecific depression of the maternal immune system by immunosuppressive drugs might thus contribute to fetal growth retardation, as may undiagnosed viral infection of the fetus. Spontaneous vaginal delivery should be the aim. In this series primary cesarean section was necessary only for purely obstetric reasons. The reported rate of 70% (40% in our series) reflects the high rate offetal distress and both maternal and obstetric complications in this setting. Although most congenital or genetic defects primarily affecting the liver (mainly Wilson's disease) are rare,27 couples must be aware that the risk to the fetus is unpredictable given the different modes of transmission and the variable clinical expression of these diseases. Childbearing in orthotopic liver transplant recipients should be planned and managed as a high-risk situation at as early a stage as possible, for two main reasons: 1. Pregnancy is not advised in patients with poor liver function or active viral infection. A 12-month interval from orthotopic liver transplantation to conception is thus recommended. 2. Couples must be fully informed of the risks to the fetus, and genetic counseling should be provided when the primary liver disease is hereditary.
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Posttransplant immunosuppressive therapy should be maintained throughout pregnancy unless liver function impairment occurs. As shown by the results of our study and those reported in the literature, pregnancy is not only feasible but also successful in a large proportion of orthotopic liver transplant recipients.
REFERENCES 1. Starzl TE, Marchioro TL, Van Kaulla KN, Waddell WR. Homotransplantation of the liver in humans. Gynecol Obstet 1963; 117:659-61. 2. Bismuth H, Castaing D, Ericzon BG, et al. Hepatic transplantation in Europe. First report of the European liver transplant registry. Lancet 1987;2:674. 3. Walcott WO, Derick DE, Jolley JT, Snyder DL. Successful patient in a liver transplant patient. AM J OBSTET GYNECOL 1978; 132:340-1. 4. Myers RL, Schmid R, Newton JJ. Childbirth after liver transplantation. Transplantation 1980;29:432-4. 5. Penn I, Makowski EL, Harris P. Parenthood following renal and hepatic transplantation. Transplantation 1980; 30:397-9. 6. Haagsma EB, Visser GHA, Klompmaker I, Verwer R, Sioff MJH. Successful pregnancy after orthotopic liver transplantation. Obstet Gynecol 1989;74:442-3. 7. Newton ER, Turksoy N, Kaplan M, Reinhold R. Pregnancy and liver transplantation. Obstet Gynecol 1988;71 :449-53. 8. Sims C, Porter LB, Knuppel RA. Successful pregnancy after a liver transplant. A\1 J OBsn:! GY:\ECOL 1989; 161: 532-3. 9. Venkataramanan R, Koneru B, Wang CP, Burckart GJ, Caritis SN, Starzl TE. Cyclosporine and its metabolites in mother and baby. Transplantation 1988;46:468-9. 10. Scantelbury V, Gordon R, Tzakis A, Starzl TE. Childbearing after liver transplantation. Transplantation 1990;49: 317-21. 11. Alvin P, Muller J, Houssin D, Prasjude N, Chapuis Y, Courtecuisse V. Grossesse et maternite apres transplantation hepatique pour hepatite active auto-immune terminale avec amenorrhee primaire. Gastroenteroly 1989;13: 1079-81.
J Obstet Gyneco1
12. Cundy TF, O'Grady JG, Williams R. Recovery ofmenstruation and pregnancy after liver transplantation. Gut 1990; 31:337-8. 13. Winter H, MacKenzie WE, Newton JR. Successful pregnancy following liver transplantation in a patient taking cyclosporin. J Obstet Gynaecol 1990;7:396-7. 14. Hutton JD, Wyeth JW. Pregnancy rate liver transplantation: effects of immunosuppressive therapy and abdominal hepatic function. NZJ Obstet Gynecol 1990;30: 130-2. 15. Hill NCW, Morris NH, Shaw RW, Mathur S, Rowes K, Bunoughs AK. Pregnancy after orthotopic liver transplantation. Case report. BrJ Obstet Gynaecol 1991 ;98:719-21. 16. Fair J, Klein AS, Feng T, Merritt WT, Burdick JF. Intrapontum orthotopic liver transplantation with successful outcome of pregnancy. Transplantation 1990;50:534-5. 17. Samuel D, Bismuth A, Mathieu D, et al. Passive immunoprophylaxis after liver transplantation in HBs-Ag-positive patients. Lancet 1991;337:813-5. 18. GugenheimJ, Samuel D, Saliba F, Castaing D, Bismuth H. The use of flexible triple drug immunosuppressive therapy in liver transplantation. Transplant Proc 1987; 19: 3805-7. 19. Rumeau-Rouquette C, du Mazaubrunc, Rabarison Y. Naitre en France, 10 ans d'evolution. In: Doin, ed. Paris: INSERM, 1984:47-72. 20. Wegman TG, Gil 1J. Immunology of reproduction, vol 1. London: Oxford, 1983:147-62. 21. Colonn JO II, Winston DJ, Brill .IE, et al. Infectious complications in liver transplantation. Arch Surg 1988; 123:360-4. 22. Trepo C. Hepatite virale et grossesse. Rev Fr Gynecol 1980; 175: 101-4. 23. Saarikowski S, Seppala M. Immunosuppression during pregnancy: transmission of azathioprine and its metabolites from mother to the fetus. AM .I OBSTET GYNECOL 1973;115:1100-6. 24. Lewis GJ, Lamont CAR, Lee HA, Siapek M. Successful pregnancy in a renal transplant recipient taking cyclosporin A. BMJ 1983;286:603-4. 25. Bourget P, Fernandez H. Accumulation of cydosporine in the conceptus during the first trimester of pregnancy after liver transplantation. Transplantation 1991 ;51: 1306-7. 26. Hamid AH. Pregnancy in renal transplant recipients: a review. Obstet Gynecol Surv 1986;41:264-71. 27. Mc Connell RB. The genetics of gastrointestinal disorders. London: Oxford, 1966: 112-30.