Publication

Abstract : Imatinib mesylate has become an important therapy in the management of chronic myeloid leukemia (CML). It has an excellent safety profile, but animal studies have shown that it is potentially teratogenic. This drug is not recommended for use during pregnancy or if the patient plans to conceive. There are very few reports of outcome of pregnancy conceived while on imatinib. We report one case of successive two pregnancies that were conceived while the patient was on imatinib, and the patients continued imatinib till term. A 34-year-old female was diagnosed as having CML in chronic phase in January 2005. She had no significant past medical history and was nulliparous. Examination revealed spleen palpable 13 cm below costal margin. Hematological parameters (hemoglobin 8.2 g/dl, white blood cell count 16.8 × 109/L and platelet count 270 × 109/L) and RT–PCR revealed positive BCR-ABL translocation. Her biochemical parameters, including liver, renal functions and uric acid, were within normal limits. Therapy was started with imatinib (Glivec; Novartis, Basel, Switzerland) 400 mg/day as part of a GIPAP (Glivec International Patient Assistance Program) where the drug was provided free. She was counseled to avoid pregnancy. Complete hematological remission was achieved at the end of 2 months and molecular remission after 5 months. Imatinib was continued at the same dosage. The patient reported to the clinic with history of amenorrhea of 4 months duration in November 2005 and a pregnancy test was positive. After counseling, she declined termination of pregnancy, but imatinib was stopped. As the patient could not afford interferon, hydroxyurea was administered to control the blood counts and symptoms. Repeated ultrasound abdomen was revealed normal fetus. She delivered a healthy baby (Apgar 9/10 and weight 3.12 kg) at 37th week's (May 2006) gestation. There was no birth defect. The total blood count of the newborn was normal. She was restarted on imatinib with further advice for strict contraception and to stop the drug before any planned pregnancy. After delivery, routine examination revealed spleen of 4 cm palpable below costal margin and hematological parameters (hemoglobin 7.2 g/dl, white blood cell count 14.3 × 109/L and platelet count 60 × 109/L), bone marrow aspiration (basophil 23%, myelocyte 15%, metamyelocyte 9%, promyelocyte 8% and blast 14%) and biopsy suggest accelerated phase of CML. RT–PCR revealed positive BCR-ABL translocation. Imatinib was started with the dose of 800 mg/day. Complete hematological remission was achieved at the end of 1 month and she was lost to follow up. She came again at 36th week (October 2007) of her second gestation; (while on 800 mg of imatinib) on quarries found she conceives her 2nd pregnancy on February 2007 (9 months after delivery of 1st child). She delivered vaginally a healthy baby (Apgar 10/10 and weight 2.98 kg) at 37th week's gestation. There was no birth defect and the total blood count of the newborn was also normal. Post-delivery blood counts were normal, QPCR BCR-ABL was negative and she was on 400 mg imatinib till now. There was apparently no late side-effect, the older child being now 26 months old and the younger 9 months old. Imatinib, an inhibitor of abl-tyrosine kinase, is teratogenic in mouse and rats when administered during organogenesis at doses of >100 mg/kg, causing exencephaly or encephalocele, and absent or reduced frontal and absent parietal bones [1]. The most critical period for teratogenicity is the first trimester as this period correlates with active organogenesis. Choudhary et al. had reported from our center with fatal meningocele with use of imatinib during fist trimester of pregnancy [2]. However, the limited published literature suggests that imatinib is safe in pregnancy [3], [4], [5], [6], [7], [8], [9], [10], [11]. However, animal experiments suggest it is unsafe. Pregnancy does not affect the course of CML as was observed in our case. In our case, 400 mg imatinib was taken during organogenesis period and deliver normal fetus. In second pregnancy, she took 800 mg imatinib throughout the course of pregnancy and also deliver normal fetus. So from our case both 400 mg and 800 mg imatinib was safe during pregnancy. However, these apparently normal children need to be followed up to look for any long-term side-effects if any. We recommend effective contraception for all patients who are on imatinib. More data are needed to address this issue.