Tacrolimus is a macrolide obtained from Streptomyces, and is widely used as an immunosuppressant in transplant medicine. Skin diseases such as neurodermatitis are another indication; this will be discussed elsewhere (see Chapter 2.17). Certain advantages and disadvantages of tacrolimus in pregnancy are discussed compared to cyclosporine: rejection and hypertension are less common with tacrolimus, and the necessary dosage of prednisolone is lower. On the other hand, gestational diabetes occurs more often, as does transient hyperkalemia and transient reduction of kidney function in the newborn. Jain (1997) even reported on a newborn with anuria which lasted 36 hours. As with other immunosuppressant drugs, pre-eclampsia, prematurity, low birth weight, and cesarian births were seen at greater incidence.
More than 200 exposed pregnancies are documented, where tacrolimus was given together with prednisolone or other immunosuppressants. This is based on retrospectively ascertained case reports or case series (Jabiry-Zieniewicz 2006, Garcia-Donaire 2005, Jain 2004, Rayes 1998), on a small prospective study (Jain 2003), and on the National Transplantation Registry (Armenti 2003), which was started by the pharmaceutical industry in 1991.
In the prospective study, the outcome of 49 children of 37 liver-transplanted mothers was analyzed (Jain 2003). Two premature babies and one child with multiple anomalies died; one newborn had a unilateral cystic kidney without urine production. In a retrospective analysis of 100 pregnancies with 68 live-born children, there were four with different malformations (Kainz 2000). Retrospective cases report premature twins of 32 weeks' gestation. Both suffered from cardiomyopathy, of which one of them died (Vyas 1999). Among nine tacrolimus-exposed pregnancies, there were two with a small ventricular septal defect (Nagy 2003). An otherwise healthy premature baby who was exposed in utero to tacrolimus and mycophenolate mofetil demonstrated hypoplastic fingernails and short fifth fingers on both hands (Pergola 2001). There are rare case reports on the use of tacrolimus during pregnancy for other indications, such as refractory inflammatory bowel disease (Baumgart 2005).
No substantial teratogenic risk can be concluded from this data. Note that the above-mentioned adverse effects have been reported by almost all authors.
For tacrolimus as an ointment, see Chapter 2.17.
The macrolide sirolimus inhibits the proliferation of T-cells. Information on its use in human pregnancy is limited to a few case reports (Guardia 2006, Armenti 2003). Everolimus has not been evaluated for its use during pregnancy. Pitnecrolimus is only available for dermatic use (sec Chapter 2.17).
Mycophenolate mofetil (MMF) increases birth defects in experimental animal studies. In the National Transplantation Registry (Armenti 2003), no teratogenic effects have been reported in approximately 20 pregnancies. On the other hand, there is one ease report of multiple congenital anomalies in a fetus which was exposed to MMF, tacrolimus, and prednisone (le Ray 2004); another child of a liver transplanted mother was born with atresia of the esophagus, and malformations of the heart and iris (Kalien 2005). The premature baby with hypoplastic fingernails and short fifth fingers (Pergola 2001) is already mentioned above.
Recommendation. The occurrence of gestational diabetes should be considered with tacrolimus therapy. In cases involving long-term prenatal therapy in the second and/or third trimesters, the newborn should be monitored for transient renal insufficiency and hyperkalemia. This applies to tacrolimus, everolimus, and sirolimus. There are insufficient data concerning the safety of first-trimester use of sirolimus, everolimus, and mycophenolate mofetil. From the 200 pregnancies exposed to tacrolimus no substantial teratogenic risk can be concluded. However, the use of these drugs does not require termination of pregnancy. A detailed fetal ultrasound examination should be offered to confirm normal morphologic development in cases of first-trimester exposure. Whether the immunosuppressant therapy of a transplanted woman who Is stable on her medication should be changed is a question of risk-benefit assessment, because there is little experience in human pregnancies.
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