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

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