Chronic liver disease can lead to amenorrhea in women, and pregnancy is often not possible in women of childbearing age. There are reports after liver transplantation (LTx) indicating that the normal menstrual cycle is restored, and that childbearing is possible. There are also reports of pregnancy during which azathioprine (Aza) and cyclosporine A (CsA)-based (1–3) immunosuppression is administered. Tacrolimus was introduced in clinical trials at our center 13 years ago and has been used by many other centers during the last 10 years. During the last 5 to 10 years, we have published our initial reports on successful pregnancies after LTx with tacrolimus-based immunosuppression (4,5).
This report updates our center’s experience and examines the outcome of pregnancies after LTx with tacrolimus-based immunosuppression during the last 13 years from a single center.
PATIENTS AND METHODS
All pregnancies with tacrolimus-based immunosuppression after LTx were examined prospectively. The course of the pregnancy in the mother, changes in allograft function, complication in the mother, and immunosuppression were examined. Gestational period, type of delivery, birth weight, intrauterine development of the fetus, and congenital defect in the fetus were recorded. Intrauterine growth of the fetus was determined by calculating birth weight percentile using the scatter gram from Lubchenco, Hansman, and Boyd (6).
RESULTS
Overall, 37 mothers delivered 49 babies. Three mothers delivered three times (cases 2, 11, and 35), and six mothers delivered two times (cases 1, 5, 9, 10, 14, and 16). The primary diagnosis of end-stage liver failure is given in Table 1. Eight mothers underwent two transplants and three mothers underwent three transplants before pregnancy. Seven mothers (18.9%) had undergone LTx at the age of 12 years or less; the youngest patients were 6 (case 32) and 8 years (case 31) at the time of LTx. The mean age of the mother at the time of delivery was 29.1±6.3 years (median 27.5; range 18.3–43.4 years). The mean interval from LTx to delivery was 70.2±51.8 months (median 48; range 8–163 months). All mothers received tacrolimus for the entire gestational period. A total of 20 mothers received tacrolimus from the outset after LTx, and 17 mothers originally received CsA and were converted to tacrolimus for ongoing rejection. They were converted to tacrolimus before pregnancy. The mean time they received tacrolimus before delivery was 49.9±40.8 months (median 31.2; range 5.8–114.8 months).
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Table 1: Demographics
Survival
Mothers.
Thirty-six mothers (92.3%) survived the pregnancy. One mother (case 32) underwent two LTxs; primipara at age 40 years, her infra-renal aortic graft clotted during labor. She developed liver failure 2 days later and died of fulminant gangrene of the allograft on transfer to our center before retransplantation could be accomplished. However, the newborn baby survived. Of the remaining 36 mothers, three died during the subsequent follow-up period. One mother (case 3) had a documented history of noncompliance with substance abuse and died as a result of liver failure from chronic rejection 67 months postdelivery and 101 months post-LTx. Another mother (case 12) was also noncompliant and died of liver failure from recurrent hepatitis B virus infection and chronic rejection 40 months after delivery and 84 months post-LTx. A third mother (case 7) underwent retransplantation 30 months postdelivery for de novo hepatitis C virus infection. Postoperatively, she sustained ischemic brain injury from respiratory failure and died 34 months postdelivery.
Liver Allograft.
All mothers maintained liver allograft function during the pregnancy except case 32 (described previously), who experienced ischemic graft injury during labor. After delivery, one mother (case 11) lost the liver allograft from recurrent autoimmune hepatitis and chronic rejection. After two successful pregnancies, she underwent combined liver and kidney transplantation 46 and 19 months after delivery after the first and second babies, respectively. She subsequently delivered for the third time 69 months after kidney and liver retransplantation. The rest of the surviving mothers have kept their original graft from the time of pregnancy.
Newborn Babies.
Twenty-seven babies (55%) were delivered vaginally, and 22 babies (46.9%) were delivered by caesarean section. The reasons for caesarean section are given in Table 1.
Of 49 live babies, two were premature and died soon after delivery (cases 5 and 10a); both mothers conceived soon after transplantation and are described in our previous report. Of the remaining 47 live babies, one baby (case 35) was born to a mother who underwent transplantation for Alagille syndrome and died 4 months later from multiple congenital birth defects of cardiopulmonary and esophageal origin. The mother subsequently remarried and has two viable babies (cases 35b and 35c) from the second marriage. The remaining 46 babies (25 boys and 21 girls) were alive and well at the last follow-up.
Gestational Period.
The mean gestational period for the viable babies was 36.4±3.2 weeks (excluding the two premature babies; range 28–40, median 37 weeks).
Thirty-two babies (68%) had gestational periods of 36 weeks or more, 12 babies (26%) had gestational periods ranging from 32 to 36 weeks, and the remaining three babies (6%) had gestational periods of less than 32 weeks.
Birth Weight
The mean birth weight was 2,697±775 g (median 2,652; range 924–2,346 g). Thirty-eight babies (78%) weighed more than 2,000 g, excluding two premature babies.
Birth Weight Percentile for Gestational Period.
The mean birth weight percentile was 54±27 (range <10–>90; median=50). Four babies (8.5%) had a birth weight percentile of less than 25, 15 babies (31.9%) had a birth weight percentile of 25 to 50, and the remaining 28 babies (59.6%) had a birth weight percentile of 50 or greater.
Congenital Anomaly
There was a multiple congenital defect in case 35a consisting of a tracheoesophageal fistula and valvular heart disease. There was a nonfunctional unilateral cystic kidney in case 14a. The baby also had an accessory nipple on the right side. The mother had a history of a similar abnormality in two sons with one extra nipple and one son with two extra nipples before LTx. She did not inform us initially, because she felt it was a familial condition. No other congenital anomaly was detected.
Renal Function
Overall, renal function before conception, during the first, second, and third trimesters, and after delivery remained stable. There was a slight improvement in mean serum creatinine during the pregnancy, but this returned to baseline after delivery. The details of mean blood urea nitrogen and serum creatinine are given in Table 2. During the follow-up period, one patient (case 11) underwent kidney transplantation (with retransplantation of liver described earlier in the present report) 19 months after the second delivery. Also, one patient (case 30) developed end-stage renal failure 28 months postdelivery and is currently on hemodialysis. She had a longstanding history of diabetes and hypertension. One patient (case 36) passed kidney stones during the pregnancy.
Table 2: Liver and renal function with tacrolimus dose and concentration
Liver Function
Twelve pregnancies (24.5%) were associated with an increase in liver enzymes without jaundice (six during pregnancy and six in the postpartum period). These were usually treated with an augmentation of baseline immunosuppression or a steroid bolus or both. None of the grafts were lost for immunologic reasons.
Hypertension and Toxemia of Pregnancy
Four mothers (cases 8, 10, 22, and 30) were hypertensive before pregnancy, which required treatment. Calcium channel blocker has been the antihypertensive agent of choice at our center, and usually single agent was adequate. They remained stable during the pregnancy, except in case 10a in which emergency cesarean section was required. Their gestation periods were 35, 32, 38, and 38 weeks with birth weights of 2,594, 1,565, 2,430, and 2,585 g and birth weight percentiles for gestational periods of 75, 50, 25, and 25, respectively.
FIGURE
Figure 1: Gestation period in weeks for each pregnancy (top); birth weight for each newborn baby (middle); birth weight percentile based on gestation period for each newborn baby (bottom).
Insulin-Dependent Diabetes Mellitus
Three mothers (cases 4, 29, and 30) were receiving insulin before and during the viable pregnancy. The mean gestational periods in these three mothers were 33, 35.5, and 38 weeks with birth weight percentiles of 40, 80, and 20, respectively.
Immunosuppression
All patients received tacrolimus during the entire pregnancy period. Seventeen of the 37 mothers initially received CsA but were converted to tacrolimus before pregnancy. The mean tacrolimus dose and tacrolimus trough concentration before, during, and after pregnancy are given in Table 2. Three patients received Aza (cases 6, 11, 11c, and 36). In one mother (case 6), Aza was discontinued during the first trimester; the other two mothers continued to take Aza during the pregnancy (75 and 50 mg/day), respectively.
Prednisone
Twelve mothers (27%) received prednisone (5–10 mg/day) before and at the time of conception. In two of them, the prednisone was discontinued during the pregnancy without any ill effects.
Fludrocortisone
Nine of the 37 mothers (25%) received fludrocortisone (0.1 mg/day) to control hyperkalemia.
DISCUSSION
Tacrolimus has proven to be a potent immunosuppressive agent (7–11). It was first used in clinical trials 13 years ago at our center, and many other centers have confirmed our initial findings of safety and efficacy of the drug in clinical LTx (12). Its safety in pregnancy has been similarly described by us (5) and others (13–16). It is important to note that this is a case series with only 39 mothers and 49 babies, and that it is premature to draw a firm conclusion.
In our previous report, we showed that the drug is transmitted transplacentally and also is excreted in the breast milk (5); we therefore advise mothers not to breast-feed their babies. We also reported transient hyperkalemia and slight impaired renal function in the babies; this is still not a major problem. In addition, congenital anomalies are rare. One patient (case 9) with a unilateral renal cyst with an accessory nipple was probably familial. In patients with Alagille syndrome, congenital multiple defects are well documented. Although LTx offers the phenotypic correction of liver function in Alagille syndrome, the genetic defect continues to persist with the risk of transmission of the defective genome to the offspring. One mother, who had lost her first baby as the result of multiple esophageal and cardiovascular pulmonary abnormalities, delivered two viable and healthy babies with a different male partner after her second marriage. Both babies were tested by genetic counseling and were healthy, indicating that the previous anomalies, in all probability, were not related to tacrolimus. Two premature babies conceived soon after LTx died. The general recommendation for women wanting to conceive post-LTx is to wait 1 to 2 years until overall immunosuppression is lower and graft function is stable.
The cesarean section rate has remained high for a variety of reasons. As is the case with CsA, preterm delivery remains a common occurrence without any long-term consequences.(1–3,14,17–19). No risk factors in particular were identified in the present series. The rate of preeclampsia, deterioration in renal function, development of hypertension, and rate of rejection are also reported in kidney transplantation with CsA (20,21). Preterm births continue to be a factor reported in all of organ transplantation without any long-term consequences. The median birth weight percentile is 50, although 10% of babies still have a birth weight percentile less than 25, and 32% of babies are born before 36 weeks of the gestational period. Graft loss and mothers’ deaths are consistent with the rest of the LTx population with a 3% to 4% loss beyond 2-year survival (12). One death as the result of clotting of the infra-renal aortic graft by external compression from the gravid uterus has not been reported and should be kept in mind by both transplant surgeons and obstetricians. Fortunately, renal function and liver function is generally well preserved in this series, compared with other reports of solid-organ transplantation with CsA (22–24). All pregnancies in mothers post-LTx should be considered high-risk and followed carefully by transplant clinicians and obstetricians.
CONCLUSION
Preterm delivery, low birth weight, and the high rate of cesarean section with relatively lower rates of toxemia of pregnancy reconfirm our initial observation of the safety of tacrolimus use during pregnancy post-LTx. Late incidence of graft loss and death are comparable to that in other transplant patients. Patients with infra-aortic grafts for hepatic arterial flow may need to be monitored with color Doppler ultrasonography during labor.
Acknowledgments.
We thank Ron Shapiro, M.D., and Judy Canelos, M.A., for help in editing this manuscript.
FOOTNOTES
1 This article was presented in part at the XIX International Congress of The Transplantation Society, Miami, Florida, August 25 to 30, 2002.
REFERENCES
1. Laifer SA, Darby MJ, Scantlebury VP, et al. Pregnancy and liver transplantation. Obstet Gynecol 1990; 76 ( 6): 1083.
2. Penn I, Makowski EL, Harris P. Parenthood following renal and hepatic transplantation. Transplantation 1980; 30 ( 6): 397.
3. Scantlebury V, Gordon R, Tzakis A, et al. Childbearing after liver transplantation. Transplantation 1990; 49 ( 2): 317.
4. Jain A, Venkataramanan R, Lever J, et al. FK506 and pregnancy in liver transplant patients. Transplantation 1993; 56 ( 6): 1588.
5. Jain A, Venkataramanan R, Fung JJ, et al. Pregnancy after liver transplantation under tacrolimus. Transplantation 1997; 64 ( 4): 559.
6. Lubchenco LO, Hansman C, Boyd E. Intrauterine growth in length and head circumference as estimated from live births at gestational ages from 26 to 42 weeks. Pediatrics 1966; 37 ( 3): 403.
7. Fung JJ, Eliasziw M, Todo S, et al. The Pittsburgh randomized trial of tacrolimus compared to cyclosporine for hepatic transplantation. J Am Coll Surg 1996; 183 ( 2): 117.
8. Randomised trial comparing tacrolimus (FK506) and cyclosporin in prevention of liver allograft rejection. European FK506 Multicentre Liver Study Group. Lancet 1994; 344(8920): 423.
9. A comparison of tacrolimus (FK 506) and cyclosporine for immunosuppression in liver transplantation. The U.S. Multicenter FK506 Liver Study Group. N Engl J Med 1994; 331(17): 1110.
10. Jain AB, Fung JJ, Todo S, et al. Incidence and treatment of rejection episodes in primary orthotopic liver transplantation under FK 506. Transplant Proc 1991; 23 ( 1 Pt 2): 928.
11. Starzl TE, Donner A, Eliasziw M, et al. Randomised trialomania? The multicentre liver transplant trials of tacrolimus. Lancet 1995; 346 ( 8986): 1346.
12. Jain A, Reyes J, Kashyap R, et al. What have we learned about primary liver transplantation under tacrolimus immunosuppression? Long-term follow-up of the first 1000 patients. Ann Surg 1999; 230 ( 3): 441.
13. Kainz A, Harabacz I, Cowlrick IS, et al. Analysis of 100 pregnancy outcomes in women treated systemically with tacrolimus. Transpl Int 2000; 13 (Suppl 1): S299.
14. Armenti VT, Coscia LA, McGrory CH, et al. National Transplantation Pregnancy Registry looks at outcomes with Neoral and tacrolimus. Nephrol News Issues 2000; 14 ( 9): S11.
15. Prevot A, Martini S, Guignard JP. In utero exposure to immunosuppressive drugs. Biol Neonate 2002; 81 ( 2): 73.
16. Winkler ME, Niesert S, Ringe B, et al. Successful pregnancy in a patient after liver transplantation maintained on FK 506. Transplantation 1993; 56 ( 6): 1589.
17. Rayes N, Neuhaus R, David M, et al. Pregnancies following liver transplantation—how safe are they? A report of 19 cases under cyclosporine A and tacrolimus. Clin Transplant 1998; 12 ( 5): 396.
18. Wu A, Nashan B, Messner U, et al. Outcome of 22 successful pregnancies after liver transplantation. Clin Transplant 1998; 12 ( 5): 454.
19. Armenti VT, Ahlswede KM, Ahlswede BA, et al. National Transplantation Pregnancy Registry—outcomes of 154 pregnancies in cyclosporine-treated female kidney transplant recipients. Transplantation 1994; 57 ( 4): 502.
20. Armenti VT, Ahlswede KM, Ahlswede BA, et al. National Transplantation Pregnancy Registry: analysis of outcome/risks of 394 pregnancies in kidney transplant recipients. Transplant Proc 1994; 26 ( 5): 2535.
21. IV. 10 Pregnancy in renal transplant recipients. Nephrol Dial Transplant 2002; 17(Suppl 4): 50.
22. Klintmalm G, Althoff P, Appleby G, et al. Renal function in a newborn baby delivered of a renal transplant patient taking cyclosporine. Transplantation 1984; 38 ( 2): 198.
23. Armenti VT, Ahlswede KM, Ahlswede BA, et al. Variables affecting birthweight and graft survival in 197 pregnancies in cyclosporine-treated female kidney transplant recipients. Transplantation 1995; 59 ( 4): 476.
24. Casele HL, Laifer SA. Association of pregnancy complications and choice of immunosuppressant in liver transplant patients. Transplantation 1998; 65 ( 4): 581.
