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Tacrolimus is currently approved only in patients receiving allogeneic liver or kidney transplants.1 We and others have demonstrated its successful use in refractory colitis.2,3 Here we report the first patient who was successfully maintained in remission during pregnancy and delivered a healthy baby.
Our patient was diagnosed with ulcerative colitis at the age of 25 years. Her first baby was delivered by Caesarean section prematurely at 29 weeks’ gestation. Frequent flare ups of her pancolitis required repeated steroid rescue and she was soon started on azathioprine. Unfortunately, she was unable to tolerate purine analogues due to heterozygous thiopurine methyltransferase deficiency causing severe pancytopenia and life threatening sepsis.
Discussing the remaining therapeutic options, the patient refused proctocolectomy and ileoanal pouch anastomosis and chose a trial on oral tacrolimus. She was started on 0.1 mg/kg body weight oral tacrolimus, divided into two daily doses. The dose was adjusted aiming for serum trough levels of 4–6 ng/ml. Her condition improved quickly within the following weeks and complete remission was achieved. The patient was discouraged from conceiving while on tacrolimus. When weaning off tacrolimus resulted in repeated disease flare ups, she underwent granulocyte aphaeresis (Adacolumn) at age 27 years but was unable to attain prolonged remission without tacrolimus.
At the age of 31 years she became intentionally pregnant with her second child. Sonographic malformation screening during the second trimester did not detect any fetal abnormalities. She spontaneously delivered a healthy baby girl (Apgar score 9/10/10; birth weight 3500 g; height 51 cm) at 40 weeks’ gestation. She was continued on tacrolimus throughout the pregnancy and following delivery, aiming for serum trough levels of 4–6 ng/ml, and maintained a stable remission. To date she is 33 years old and still in remission. Because of the unknown immediate and long term side effects of tacrolimus in the newborn, we recommended refraining from breastfeeding. There is no evidence of any functional impairment or developmental delay in her now two year old daughter.
This case is the first report of tacrolimus use during pregnancy for refractory ulcerative colitis. Most experience with tacrolimus in pregnancy exists with transplant patients. In a recent study, 37 female liver transplant recipients who delivered 49 babies were reported. Thirty six mothers (97%) survived the pregnancy. One patient who clotted an infra-aortic arterial graft during labour died. The mean gestational period was 36.4±3.2 weeks, excluding two premature deliveries at 23 and 24 weeks’ gestation. Twenty two babies (46.9%) were delivered by Caesarean section. One baby, who was born to a mother with Alagille syndrome, died from congenital birth defects. Preterm delivery and low birth weight were in the same range as seen in all solid organ transplant patients under any form of immunosuppression.4 The results for 15 kidney transplant and simultaneous kidney-pancreas transplant mothers were similar.5
In an older survey of 100 pregnancies in 84 mothers from multiple centres, 71 pregnancies progressed to delivery (68 live births, two neonatal deaths, and one stillbirth), 24 were terminated (12 spontaneous and 12 induced), two pregnancies were ongoing, and three were lost to follow up. Preterm delivery occurred in 41% and low birth weight in 10% of patients. Four neonates presented with malformations without any consistent pattern.6
As tacrolimus is excreted into human milk, nursing is discouraged because of potential short term and long term toxicity due to immature metabolism of tacrolimus in the neonate. However, one uncomplicated case with breastfeeding under tacrolimus has been published.7
Based on the experience in the transplant population and this case, the use of tacrolimus in pregnancy may be justified under special circumstances in carefully selected non-transplant patients. Unlike in her first pregnancy, our patient was able to deliver a full term healthy baby girl vaginally after an uneventful pregnancy, maintaining sustained remission of her ulcerative colitis.