Follow-Up of Tacrolimus Breastfed Babies

Abstract

Tacrolimus is a calcineurin inhibitor immunosuppressant approved in the prevention of organ allograft rejection or in the treatment of acute graft rejection. The human experience of tacrolimus during pregnancy is reassuring with no specific pattern of neonatal complications, except possible transient hyperkalemia (1). Although the available data on human milk transfer indicate that only very limited amounts of tacrolimus are excreted into breast milk (2), clinical data on the safety of breast-feeding for the newborn of tacrolimus-treated patients are still very scarce. As a member of the European Network of Teratogen Information Services, our center provides advice on the safety and risk of medications for pregnant and lactating women. We report our experience regarding the safety of tacrolimus for newborns whose mother opted for breast-feeding after delivery. Since 2003, we have received advice queries concerning 14 women treated with tacrolimus. After individual assessment including the maternal treatment, dose, comedications, indication, characteristics of the neonate, and the expected type of breast-feeding (exclusive or not), clinical and biologic follow-up of the infant was systematically proposed if the mother decided to breast-feed. After oral consent, the clinical follow-up consisted of a standardized questionnaire filled during telephone interviews of the patient during and after the period of breast-feeding. To monitor the infant’s exposure to tacrolimus through breast-feeding, measurement of whole-blood tacrolimus concentration was also proposed within 2 to 3 weeks after starting breast-feeding to avoid any residual presence of tacrolimus in the newborn caused by transplacental passage and tacrolimus long half-life (up to 43 hr in healthy adults). No immunologic monitoring was proposed. Among these 14 patients, breast-feeding was initiated in 9, but 3 discontinued within 5 to 15 days (2 because of breast-feeding difficulties and 1 because of mycophenolate mofetil initiation), and they were not included in the follow-up. Data from Table 1 provide details on the mothers, the infant’s characteristics at birth, medication exposure, and follow-up of children for the remaining evaluable six patients. All six women (mean age, 32 years) had received tacrolimus throughout pregnancy for the prophylaxis of solid organ rejection. The mean daily dose was 9.6 mg/d (4.5–15 mg/d). Concomitant drugs included azathioprine in four women, diltiazem in one, and prednisolone and low-dose aspirin in one. The mean gestational age at delivery was 37.1 weeks, and four of six newborns were moderately premature (34–36 weeks). Breast-feeding was exclusive in four patients and partial in two. The median duration of breast-feeding was 3 months (range, 1.5–6 months), and the median duration of infant follow-up was 8.5 months (range, 2–30 months). Whole-blood tacrolimus concentration measured in four neonates between day 15 and day 27 after delivery were undetectable (lower limit of detection <1.9 μg/L, antibody-conjugated magnetic immunoassay; Siemens Healthcare Diagnostics, Tarrytown, NY). Clinical follow-up of the infants did not identify any adverse outcome that might be related to tacrolimus maternal treatment, and developmental milestones were within the expected ranges. In particular, no specific pattern of infection was observed. A longer follow-up of these infants is expected.TABLE 1: Details on mothers and child exposureOnly four previous reports have provided data on tacrolimus exposure of infants through breast-feeding. Jain et al. (2) measured tacrolimus concentrations in 10 colostrum samples from six mothers treated with tacrolimus during pregnancy. The highest tacrolimus concentration was 1.9 μg/L, corresponding to a maximal dose of 0.29 μg/kg per day delivered from milk to the neonate, that is, 0.1% of the lowest pediatric dose (based on an infant milk ingestion of 150mL/kg/d). None of these mothers had breast-fed. The very low tacrolimus exposure of infants during breast-feeding was documented by two other reports that included the measurement of tacrolimus levels in mature milk and, respectively, found a mean tacrolimus concentration of 0.6 and 1.8 μg/L in milk (3, 4). Chusney et al. (5) showed a similarly quick postpartum decrease in tacrolimus serum levels in neonates exposed throughout pregnancy, whether or not subsequently breast-fed, suggesting higher exposure in utero than through human milk. Finally, only one report included the clinical follow-up of an exclusively breast-fed neonate with normal physical and neurologic development at 2.5 months of age (3). To the best of our knowledge, the present study is the first one to provide relatively long-term follow-up in infants exposed to tacrolimus through breast-feeding. These results confirm previous analytical data suggesting that tacrolimus exposure in breast-fed babies is negligible and probably safe even in case of prematurity, therefore allowing the mother to breast-feed. Until more data are available, particularly regarding long-term safety, careful infant monitoring is required, especially in patients on a multiple immunosuppressant regimen. Aurore Gouraud Nathalie Bernard Anne Millaret Méri Bruel Nathalie Paret Jacques Descotes Thierry Vial Poison Center and Pharmacovigilance Department Lyon University Hospitals Lyon, France