Immunologic Agent (Immunosuppressant)
PREGNANCY RECOMMENDATION: Human Data Suggest Low Risk
BREASTFEEDING RECOMMENDATION: Limited Human Data—Probably Compatible
PREGNANCY 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. The available human pregnancy experience continues to suggest that the embryo–fetal risk for congenital malformations is low. Common complications in infants, however, are hyperkalemia, which usually resolves untreated within 24–48 hours, renal toxicity, intrauterine growth restriction (IUGR), and premature delivery (because of hypertension, preeclampsia, and premature rupture of membranes). 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 recipients. 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) (1,2). Another report suggested waiting for 1 year to lower the risk of low birth weight and prematurity (3). Nevertheless, recent data suggest that the overall risk to the embryo–fetus is low. However, the long-term consequences of in utero exposure to tacrolimus, such as functional and/or neurobehavioral deficits, have not been studied.
FETAL FISK SUMMARY
Tacrolimus (FK506) is a macrolide immunosuppressant agent produced by Streptomyces tsukubaensis that acts similar to cyclosporine but is a more potent immunosuppressant. It is used either orally or IV for the prophylaxis of organ rejection in patients receiving various allogeneic organ transplants, such as kidney, liver, heart, and pancreas. The ointment is used for atopic dermatitis (4).
Reproduction studies have been reported in rats, rabbits, and mice (5,6). In pregnant rabbits, tacrolimus given in oral doses about 0.5–1 and 1.6–3.3 times the recommended human dose based on BSA (RHD) during organogenesis was associated with maternal toxicity and an increased incidence of abortions (5). At the higher dose, an increased incidence of malformations and developmental variations was also observed (type of defects was not specified). Pregnant rats dosed at 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. Oral doses 0.7–1.4 and 2.3–4.6 times the RHD given after organogenesis and during lactation were associated with reduced pup weight (5).
Mice were treated with IM tacrolimus (0.17 or 1.37 mg/kg/day; relationship to human dose not specified), from day 1 through day 16 of gestation (6). No effects on maternal weight gain were observed in the low-dose group, but the number of resorptions was significantly increased over the number observed in 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 controls. 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 (6).
The molecular weight of tacrolimus (about 804) is low enough that the drug crosses the human placenta (5,7–9). 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 was 0.49 (7). 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 (7). A cord:maternal plasma ratio of 0.49 also was reported in another case (see below) (8). In two pregnancies (described below) under tacrolimus immunosuppression, the mothers were taking 15 and 10 mg/day, respectively (9). At delivery, umbilical cord blood concentrations were 13.2 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. 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 (8). 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 that 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 (8).
A woman who had received a combined kidney and pancreaticoduodenal graft conceived while receiving tacrolimus (12 mg/day) and prednisolone (7.5 mg/day) (9). She also received furosemide and methyldopa for hypertension that was well controlled throughout gestation. Her pregnancy was complicated by hyperemesis gravidarum, septicemia (Escherichia coli), 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 (9).
In a 1993 letter, the pregnancy outcomes of nine liver transplant recipients who had received tacrolimus (2–64 mg/day) immunosuppression throughout their gestation were detailed (10). 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 (10).
Some of the cases described in reference 10 above may have been included in a 1997 abstract that reported the outcomes of 14 pregnancies in 13 liver transplant recipients receiving various immunosuppressant agents, including tacrolimus (11). 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 (11).
A 1997 report detailed the outcomes of 27 pregnancies of 21 liver recipients who were treated with tacrolimus before and throughout gestation (7). 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 restricted 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 (7).
Successful immunosuppression with tacrolimus following heart transplantation had been maintained for 2 years before conception occurred in a 39-year-old woman (12). 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 cesarean section at 33 weeks (12).
A 26-year-old renal transplant recipient was treated with tacrolimus (10 mg/day) and prednisolone (10 mg/day) throughout a 33.5-week pregnancy (13). Conception had occurred about 25 months after transplantation. The target blood concentration was 10 ng/mL. Symmetrical 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 (13).
A 1998 case report described the course and outcome of a pregnancy in a 32-year-old woman after renal transplantation (14). 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 which 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 (14).
A 1998 study examined the relationship between antenatal complications and various maternal factors in women who had undergone orthotopic liver transplantation (15). 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 ≥1.3 mg/dL) at conception. Cyclosporine was more commonly associated (p = 0.03) with renal dysfunction than was tacrolimus (15).
A review of pregnancy outcomes after renal transplant was published in 1998 (16). The liveborn incidence among seven cases treated with tacrolimus was 71% (16).
In a 1998 report from the National Transplantation Pregnancy Registry (NTPR), the pregnancy outcomes of six women who were recipients of a lung transplant were described, one of whom was treated with tacrolimus (13–15 mg/day) throughout gestation (17). Her pregnancy was complicated by preterm labor at 24 weeks’ gestation and a 1616-g infant (sex not specified) was delivered by cesarean section at 30 weeks’. The infant was successfully treated for respiratory distress syndrome and was healthy and doing well at 15 months of age (17). An updated report from the NTPR was published in 2005 (18). A total of 18 pregnancy outcomes were described from women who were recipients of kidney, liver, or heart transplants. In addition, two 2008 references (19,20) described the pregnancy outcomes of transplant recipients receiving tacrolimus in combination with mycophenolate (see Mycophenolate for details, in references 18–20).
In a 1999 case report, a woman who had a renal transplant was treated throughout gestation with tacrolimus (10–12 mg/day), prednisone, amlodipine, and labetalol (21). Azathioprine was also used during the first 10 weeks. 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 (21).
A 2000 reference described the outcomes of 100 pregnancies in 84 women who were receiving tacrolimus for autoimmune disease (Behcet’s disease) (N = 1) or solid organ transplants (liver [N = 55], kidney [N = 22], heart [N = 3], kidney–pancreas [N = 1], pancreas [N = 1], and lung [N = 1]) (22). During pregnancy, the mean daily tacrolimus dose was 12.1–12.8 mg/day (range 1.0–64 mg/day). The outcomes of the pregnancies were 70 live births (2 neonates died in the perinatal period), 12 spontaneous abortions (SABs), 12 elective abortions (EABs), 1 stillbirth, 2 pregnancies ongoing, and 3 lost to follow-up. Gestational age at birth was known in 63 neonates, 37 (59%) of whom were premature. The birth weight was known in 64 cases with a mean weight of 2573 g (range 886–4346 g). The weight was appropriate for gestational age in 58 cases (90%). There were no malformations observed in the 24 aborted fetuses. However, four of the live births, all exposed to tacrolimus throughout the 1st trimester, had structural anomalies, one of which was alcoholic embryopathy. There was no pattern among the remaining three anomalies that suggested a single cause. The defects were meningocele, urogenital defects, and umbilical hernia; ear defect, cleft palate, and hypospadia; and multicystic dysplastic kidney and dimple without areola. The most common complications in the infants at birth were hypoxia, hyperkalemia, and renal dysfunction (22).
Two case reports, one in 2001 and the other in 2004, detailed the use of tacrolimus and mycophenolate during pregnancies that involved adverse outcomes (see Mycophenolate). A 2003 retrospective review detailed the outcomes of 38 pregnancies in 29 women who had undergone liver transplantation before pregnancy (23). Sixteen pregnancies (nine live births, seven elective abortions) had been exposed to tacrolimus combined with other agents. There were no fetal or neonatal deaths. Two tacrolimus-exposed infants had small membranous ventricular septal defects (23).
Another 2003 report described the pregnancy outcomes of 37 women, all after liver transplantation, who delivered 49 infants (all single gestations) (24). All mothers were treated with tacrolimus that was, in some cases, combined with other agents. In 47 infants, the mean gestational age was 36.4 weeks, but 2 infants were born at 23 and 24 weeks’ gestation, respectively. Both of the very premature infants died, as did one infant from a mother with Alagille syndrome. The latter infant had a tracheoesophageal fistula and valvular heart disease. One of the surviving infants had a nonfunctional unilateral cystic kidney. The mean birth weight was 2797 g, with 78% of the infants weighing more than 2000 g (24).
The pregnancies of 38 renal allograft recipients were reported in a 2003 study (25). Four of the patients were treated with tacrolimus in combination with other agents. The outcomes of 73 pregnancies (48 live births) in the group were compared with 59 pregnancies (41 women; 48 live births) with primary renal disease not treated with immunosuppressive drugs. The study group had significantly more preterm deliveries, infants with intrauterine growth restriction, and infants requiring hospitalization in neonatal intensive care units. However, there was no statistical difference in the incidence of major (4.2% vs. 4.2%) and minor malformations (20.8% vs. 16.6%) (25).
In a 2004 report, the pregnancy outcomes of 13 mothers (19 babies) after kidney transplantation and 2 mothers (3 babies) after kidney–pancreas implantation, all under tacrolimus immunosuppression, were described (26). One mother had a stillborn secondary to amniotic fluid leak and a small, ischemic placenta. The mean gestational age of the infants and their birth weight were 34.4 weeks and 2373 g, respectively. No congenital defects were detected (26).
A brief 2005 communication reported 16 women with 19 pregnancies after renal transplantation under tacrolimus (27). Appropriate birth weights and no malformations were observed in 10 successful pregnancies. The outcomes of the other nine cases were four SABs and five (EABs) (27).
There were 71 pregnancies among 45 women with liver transplantation in a 2006 report (3). Tacrolimus and cyclosporine were used in 42 and 29 of the pregnancies, respectively. The outcomes of the pregnancies were live births (29 vs. 21), SABs (7 vs. 6), EABs (5 vs. 1), molar pregnancy (1 vs. 0), and intrauterine death (0 vs. 1) (all ns). The median gestational age and birth weight were 37.5 vs. 37 weeks and 2660 vs. 2951 g, respectively (all ns). Pregnancies occurring within 1 year of transplantation had the highest incidence of prematurity and lowest birth weight. No congenital anomalies were observed (3).
Four successful pregnancies under tacrolimus in women with liver transplants were described in 2006 (28). The mean gestational age and birth weight were 34.4 weeks and 2302 g, respectively. No birth defects were detected in the infants.
A 2005 case report described the use of tacrolimus throughout pregnancy in a woman with refractory ulcerative colitis (29). She delivered a healthy 3500-g, height 51 cm, baby girl at 40 weeks’ gestation with Apgar scores of 9, 10, and 10.
A 2007 short communication described the pregnancy outcome of a 35-year-old woman treated with tacrolimus after a liver transplant (30). The woman conceived 5 years after the transplant and remained on tacrolimus throughout the pregnancy. Except for hypertension (treated with methyldopa) and suspected chorioamnionitis, the pregnancy was uncomplicated. A cesarean section in the 38th week delivered a healthy 2780-g female infant. No additional information on the infant was provided (30).
Another 2007 reference described the outcomes of 16 pregnancies in renal transplant recipients that were exposed to tacrolimus combined with other immunosuppressive agents (13 with azathioprine and prednisone, 1 with azathioprine, and 2 with prednisone) (31). An additional 33 pregnancies (all in women after renal transplants) were treated with cyclosporine with azathioprine and/or prednisone and 3 pregnancies were treated with azathioprine and prednisone alone. The mean patient age was 26.5 years (range 17–38 years). In the 52 pregnancies, preterm delivery occurred in 20 (38%) and fetal growth restriction in 16 (31%) (outcomes by specific drug exposure not provided). There was one fetal death due to extreme prematurity (26 weeks’). No congenital malformations in the offspring were observed (31).
In a 2007 case report, a 28-year-old woman became pregnant while taking tacrolimus (5 mg/day) and prednisolone (15 mg/day), 1.5 years after her second renal transplant (32). The pregnancy was uneventful and she gave birth vaginally to a healthy 3535-g male infant at term with Apgar scores of 9 and 10.
A 2012 case report described the use of tacrolimus (12 mg/day) throughout pregnancy in a woman with an intestinal transplant (33). Other medications used were prednisone (5 mg/day), esomeprazole (40 mg/day), diphenoxylate-atropine (2 tablets/day), tacrolimus (12 mg/day), ferrous sulfate (650 mg/day), ascorbic acid (1 g/day), prenatal vitamins (1/day), and magnesium supplementation. At 39 3/7 weeks, labor was induced and she had a spontaneous vaginal delivery of a healthy female infant (33).
BREASTFEEDING SUMMARY
Tacrolimus is excreted into breast milk. 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) (7). The median milk: maternal plasma ratio was 0.5. The authors of this study did not mention if the women breastfed their infants.
In a 2003 report, a mother who had taken tacrolimus (0.1 mg/kg/day) throughout pregnancy because of liver transplantation continued the drug while breastfeeding her infant (34). From manually expressed samples, the highest and mean drug concentrations were 0.57 and 0.429 ng/mL, respectively. The milk:blood ratios before a dose and 1-hour postdose were 0.08 and 0.9, respectively. The estimated half-life, calculated on limited data, in milk was 12.85 hours. The estimated maximum dose the infant would absorb was 0.02% of the mother’s weight-adjusted dose. The infant was developing normally at 2.5 months of age (34).
In a second case, a mother with a renal transplant was taking tacrolimus (4 mg/day) while exclusively breastfeeding her 3-month-old infant (35). The milk:blood ratio was 0.23, whereas the average tacrolimus milk concentration was 1.8 mcg/L (1.8 ng/mL). The estimated infant dose was 0.5% of the mother’s weight-adjusted dose (35).
In a case described above, a mother took tacrolimus throughout pregnancy and continued the drug while breastfeeding her infant (33). The infant’s tacrolimus level was <1.0 ng/mL at 1 week of age.
The absolute oral bioavailability of tacrolimus in healthy adults is 18%, but food, especially fat, markedly decreases the bioavailability (5). Based on the two cases above, breastfeeding during tacrolimus therapy does not appear to represent a significant risk to the infant. However, monitoring infant plasma levels is an option.
References
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