TACROLIMUS

Breast Feeding Summary

References Fetal Fisk Summary Tacrolimus (FK506) is a macrolide immunosuppressant agent produced by Streptomyces tsukubaensis that acts similarly to cyclosporine but is a more potent immunosuppressant (1). It is used for the prophylaxis of organ rejection in patients receiving various allogeneic organ transplants, such as kidney, liver, heart, and pancreas.

Reproduction studies have been reported in rats, rabbits, and mice (2,3). In pregnant rabbits, tacrolimus given in oral doses of 0.32 and 1.0 mg/kg (about 0.5–1 and 1.6–3.3 times, respectively, the recommended human dose based on body surface area [RHD]) during organogenesis was associated with maternal toxicity and an increased incidence of abortions (2). At the higher dose, an increased incidence of malformations and developmental variations was also observed (type of defects was not specified). Pregnant rats dosed with 3.2 mg/kg (2.3–4.6 times the RHD) exhibited maternal toxicity and an increase in late resorptions, decreased numbers of live births, and decreased pup weight and viability (2). Oral doses of 1.0 mg/kg (0.7–1.4 times the RHD) and 3.2 mg/kg given after organogenesis and during lactation were associated with reduced pup weight (2).

Mice were treated with IM tacrolimus, 0.17 mg/kg/day or 1.37 mg/kg/day, from day 1 through day 16 of gestation (3). No difference in maternal weight gain was observed in the low-dose group compared with untreated controls or saline controls, but the number of resorptions was significantly increased over the number observed in saline controls. In contrast, none of the 13 pregnancies treated with high-dose tacrolimus was carried to term, and maternal weight gain was significantly less than that of either control group. Except for the embryocidal action, low-dose tacrolimus, compared with untreated and saline controls, had no effect on mean placental or fetal weight and was not associated with an increase in malformations (3).

The molecular weight of tacrolimus (about 804 for the nonhydrated form) is low enough that the drug crosses the human placenta (2,4,5 and 6). In 12 pregnant women with liver transplants who were treated with tacrolimus (mean dose in 11 patients was about 10 mg/day; 1 patient treated with 48–64 mg/day), the mean cord:maternal plasma ratio of tacrolimus was 0.49 (median 0.36) (4). The placentas contained higher drug amounts (mean 4.30 ng/g) than that measured in maternal plasma (about 4 times) or cord plasma (2–56 times) and were thought to indicate a partial placental barrier to passage of the drug (4). A cord:maternal plasma ratio of 0.49 was also reported in another case (see below) (5). In two pregnancies (described below) under tacrolimus immunosuppression, the mothers were taking 15 mg/day and 10 mg/day, respectively (6). At delivery, umbilical cord blood concentrations were 13.2 ng/mL and 5.9 ng/mL, respectively, whereas the maternal venous blood concentrations were 11.8 and 31.2 ng/mL, respectively. The cord:maternal blood ratios were 1.12 and 0.19, respectively.

A number of reports have described the use of tacrolimus during human pregnancy (4,5,6,7,8,9,10,11,12,13 and 14). A 1993 letter reported a case of a woman with a liver transplant who was receiving tacrolimus (0.1 mg/kg/day with a target plasma level of <1.0 ng/mL) and who conceived about a year after her second transplant (5). At 28 weeks' gestation, a threatened acute graft rejection (tacrolimus plasma level <0.05 ng/mL) was successfully treated with bolus corticosteroids and an increase in the tacrolimus dose to 0.15 mg/kg/day. She delivered a healthy, 2860-g male infant at 36 weeks' gestation who was doing well at 12 months of age. The tacrolimus cord blood and maternal plasma concentrations at birth were 0.24 and 0.49 ng/mL, respectively, a ratio of 0.49 (5).

A woman who had received a combined kidney and pancreaticoduodenal graft conceived while receiving tacrolimus (12 mg/day) and prednisolone (7.5 mg/day) (6). She also received furosemide and methyldopa for hypertension that was well controlled throughout gestation. Her pregnancy was complicated by hyperemesis gravidarum, septicemia (Escherichia coli) and endocarditis, and esophagitis. At 38 weeks' gestation, she delivered a normal, 3410-g female infant with Apgar scores of 9 and 9 at 1 and 5 minutes, respectively. At delivery, the tacrolimus cord:maternal blood ratio was 1.12. In a second case, a woman conceived approximately 22 months after her second renal transplant. She received tacrolimus (10 mg/day), azathioprine (75 mg/day), and prednisolone (5 mg/day) for immunosuppression. Nifedipine and methyldopa were used to control her hypertension. Because of a possible placental abruption at 36 weeks' gestation, a normal, 2400-g female infant was delivered by cesarean section. Her Apgar scores were 9 and 9 at 1 and 5 minutes, respectively. The tacrolimus cord:maternal blood ratio was 0.19. Both of the above infants were doing well at 3 months of age (6).

In a 1993 letter, the pregnancy outcomes of nine liver transplant patients who had received tacrolimus (2–64 mg/day) immunosuppression throughout their gestation were detailed (7). Five of the women had also received corticosteroid therapy during pregnancy. None of the newborns was small for gestational age. Complications observed in the newborns included hyperkalemia in five (range 6.1–10.9 mEq/L; potassium levels measured in seven of the nine newborns), hypoxia in one who tested positive for cocaine (mother was taking cocaine), and anuria for 36 hours in one (thought to be secondary to high tacrolimus concentrations in the cord blood due to the mother's renal impairment) who regained normal renal function in 1 week; death after delivery occurred in one at 22 weeks' gestation. In this latter case, the mother had conceived 1 month after transplantation and had cytomegalovirus in her blood and gastrointestinal tract that was being treated with ganciclovir. Of the eight surviving infants, all were alive and developing normally (7).

Some of the cases described in Reference #7 above may have been included in a 1997 abstract that reported the outcomes of 14 pregnancies in 13 liver transplant patients receiving various immunosuppressant agents, including tacrolimus (8). Although the agent used in each of the pregnancies was not specified, the complications included maternal renal insufficiency (N=8), early hypertension (N=5), preeclampsia (N=4), worsening hypertension (N=2), pyelonephritis (N=2), anemia (N=4), prolonged premature rupture of the membranes (N=3), and cytomegalovirus infection (N=3). The mean gestational age at delivery was 32.6 weeks, and the mean birth weight was 1913 g. Three newborns died; all three deaths were associated with cytomegalovirus infection and prematurity. No structural birth defects were mentioned (8).

A third report, from the same medical center as References #7 and #8, was published in 1997 and detailed the outcomes of 27 pregnancies of 21 liver recipients who were treated with tacrolimus before and throughout gestation between October 1990 and April 1996 (4). The mean gestational age at delivery was 36.6 weeks, and the mean birth weight was 2638 g (50.2 percentile). Two infants died from prematurity after delivery at 23 and 24 weeks, respectively. The mean follow-up time of the infants was 39 months, and their mean growth weight percentile was 62. Unilateral nonfunctional cystic renal disease in one newborn was the only congenital anomaly observed in this series. In addition to the retarded growth and premature births in the total series, two other transient complications, noted among the first 13 infants born, were hyperkalemia in 10 and renal impairment in 7. Both adverse effects were thought to be caused by the drug (4).

Successful immunosuppression with tacrolimus following heart transplantation had been maintained for 2 years before conception occurred in a 39-year-old woman (9). She also took prophylactic trimethoprim-sulfamethoxazole before and throughout gestation, and her chronic hypertension was controlled with a long-acting calcium channel blocker (name not specified). Preeclampsia (rising blood pressure, proteinuria, and worsening renal impairment) was manifested between 26 and 31 weeks' gestation. An apparently normal, 2093-g female infant, who had Apgar scores of 9 and 9 at 1 and 5 minutes, respectively, was delivered by repeat cesarean section at 33 weeks. The newborn required, most likely because of prematurity, transient oxygen therapy, theophylline for apnea, and phototherapy for hyperbilirubinemia (9).

A 26-year-old renal transplant patient was treated with tacrolimus (10 mg/day) and prednisolone (10 mg/day) throughout a 33.5-week pregnancy (10). Conception had occurred about 25 months after transplantation. The target blood concentration was 10 ng/mL. Symmetrical intrauterine growth retardation (IUGR) was discovered after 20 weeks' gestation. Because of spontaneous rupture of the membranes and breech presentation, a 1312-g female infant was delivered by cesarean section. A physical and ultrasonic examination found no congenital malformations. Complications other than IUGR noted in the newborn, included mild hyperkalemia and a prolonged course of hyperbilirubinemia. Although not stated, the latter complication may have been secondary to prematurity.

A 1998 case report described the course and outcome of a pregnancy in a 32-year-old woman 17 months after renal transplantation for focal sclerosing glomerulonephritis (11). Tacrolimus, with a target plasma level of 5.0–11.5 ng/mL, was used alone throughout gestation after discontinuance of prednisolone (5 mg/day) early in gestation. Hypertension developed in the 22nd week of gestation and was treated with isradipine. A cesarean section was performed at 31 weeks' gestation because of severe hypertension, a progressive decline in graft function, and an abnormal Doppler assessment of blood velocity in the umbilical artery. No congenital malformations were noted in the 1140-g (3rd percentile) male infant who had Apgar scores of 8, 9, and 9 at 1, 5, and 10 minutes, respectively. The tacrolimus concentration in the umbilical vein was 8.1 ng/mL (maternal level at the time of delivery was not reported). At 2 days of age, the plasma drug level had decreased to 6.4 ng/mL, and at 8 days, the level was <5.0 ng/mL. Complications in the infant included mild hyperkalemia (6.4 mmol/L) on the 2nd day and transient renal impairment (serum creatinine 3.0 mg/dL at birth) that resolved completely over the next few weeks. A renal ultrasound examination was normal. Respiratory distress syndrome and a patent ductus arteriosus were successfully treated, and at a corrected age of 4 months, the healthy infant was developing normally (11).

A study published in 1998 examined the relationship between antenatal complications and various maternal factors in women who had undergone orthotopic liver transplantation (12). Of the 14 pregnancies studied, tacrolimus had been used in 5 (combined with prednisone in 3; with azathioprine and prednisone in 1), cyclosporine in 8 (combined with prednisone in 6; with azathioprine and prednisone in 2), and prednisone only in 1. Three of the complications—preeclampsia, worsening hypertension, and small for gestational age—occurred only in women with renal dysfunction (creatinine ³1.3 mg/dL) at conception. Cyclosporine was more commonly associated (p=0.03) with renal dysfunction than was tacrolimus (12).

A review of pregnancy outcomes after renal transplant was published in 1998 (13). The liveborn incidence among seven cases treated with tacrolimus was 71%.

In a 1999 case report, a woman with a history of renal transplant was treated throughout gestation with tacrolimus (10–12 mg/day), prednisone, amlodipine, and labetalol (14). Azathioprine was also used during the first 10 weeks. Her pregnancy was complicated by worsening renal function, but her hypertension was controlled until shortly before delivery. At 32 weeks' gestation, she delivered twin male infants who developed severe respiratory distress syndrome and congestive heart failure. Echocardiograms showed dilated heart chambers in both infants and only twin B survived. Autopsy of twin A revealed thrombotic cardiomyopathy with degeneration of cardiac muscle. Because animal studies had shown that tacrolimus could cause vasculitis in the cardiac muscle of baboons and dogs, the authors concluded that the cardiomyopathy seen in the twins might have been caused by tacrolimus (14).

In summary, tacrolimus has demonstrated abortifacient properties in three animal species and dose-related teratogenicity in one, but the use of this agent during human pregnancy has not been associated with either of these outcomes, although the number of exposed fetuses is small. Common complications in infants, however, are hyperkalemia, that usually resolves untreated within 24–48 hours, renal toxicity, IUGR, and premature delivery (because of hypertension, preeclampsia, and premature rupture of membranes). A causal association between tacrolimus and cardiomyopathy has not been established. No other reports of this adverse effect in relation to in utero tacrolimus exposure have been located. Based on one report, renal dysfunction is more common with cyclosporine than it is with tacrolimus. Moreover, IUGR and premature delivery are associated with the use of all immunosuppressant agents in pregnant transplant patients. Because of the risk of cytomegalovirus infection in the mother and fetus, two reviews advised waiting at least 6 months before conception is attempted following transplantation and during periods of rejection when high doses of immunosuppressant agents may be used (i.e., the periods when infection with the virus is most likely) (15,16).

Breast Feeding Summary

Tacrolimus is excreted into human breast milk (4). Ten colostrum samples were obtained from six women in the immediate postpartum period (0–3 days) with a mean drug concentration of 0.79 ng/mL (range 0.3–1.9 ng/mL). The median milk:maternal plasma ratio was 0.5. The authors of this study did not mention if the women breast-fed their infants. Because the potential for adverse effects in a nursing infant from exposure to tacrolimus in milk are unknown, breast feeding should be avoided if the mother requires immunosuppressant therapy with tacrolimus.

References

1. Peters DH, Fitton A, Plosker GL, Faulds D. Tacrolimus. A Review of its pharmacology, and therapeutic potential in hepatic and renal transplantation. Drugs 1993;46:746–94.
2. Product information. Prograf. Fujisawa USA, 2000.
3. Farley DE, Shelby J, Alexander D, Scott JR. The effect of two new immunosuppressive agents, FK506 and didemnin B, in murine pregnancy. Transplantation 1991;52:106–10.
4. Jain A, Venkataramanan R, Fung JJ, Gartner JC, Lever J, Balan V, Warty V, Starzl TE. Pregnancy after liver transplantation under tacrolimus. Transplantation 1997;64:559–65.
5. Winkler ME, Niesert S, Ringe B, Pichlmayr R. Successful pregnancy in a patient after liver transplantation maintained on FK 506. Transplantation 1993;56:751–3.
6. Midtvedt K, Hartmann A, Brekke IB, Lyngdal PT, Bentdal O, Haugen G. Successful pregnancies in a combined pancreas and renal allograft recipient and in a renal graft recipient on tacrolimus treatment. Nephrol Dial Transplant 1997;12:2764–5.
7. Jain A, Venkataramanan R, Lever J, Warty V, Fung J, Todo S, Starzl T. FK506 and pregnancy in liver transplant patients. Transplantation 1993;56:751.
8. Casele H, Woelkers D, Laifer S. Pregnancy outcome after liver transplantation (abstract). Am J Obstet Gynecol 1997;176:S23.
9. Laifer SA, Yeagley CJ, Armitage JM. Pregnancy after cardiac transplantation. Am J Perinatol 1994;11:217–9.
10. Yoshimura N, Oka T, Fujiwara Y, Ohmori Y, Yasumura T, Honjo H. A case report of pregnancy in a renal transplant recipient treated with FK506 (tacrolimus). Transplantation 1996;61:1552–3.
11. Resch B, Mache CJ, Windhager T, Holzer H, Leitner G, Muller W. FK 506 and successful pregnancy in a patient after renal transplantation. Transplant Proc 1998;30:163–4.
12. Casele HL, Laifer SA. Association of pregnancy complications and choice of immunosuppressant in liver transplant patients. Transplantation 1998;65:581–3.
13. Armenti VT, McGrory CH, Carter JR, Radomski JS, Moritz MJ. Pregnancy outcomes in female renal transplant recipients. Transplant Proc 1998;30:1732–4.
14. Vyas S, Kumar A, Piecuch S, Hidalgo G, Singh A, Anderson V, Markell MS, Baqi N. Outcome of twin pregnancy in a renal transplant recipient treated with tacrolimus. Transplantation 1999;67:490–2.
15. Laifer SA, Guido RS. Reproductive function and outcome of pregnancy after liver transplantation in women. Mayo Clin Proc 1995;70:388–94.
16. Casele HL, Laifer SA. Pregnancy after liver transplantation. Sem Perinatol 1998;22:149–55.