Natural pregnancy and delivery after allogeneic bone marrow transplantation in a Fanconi anaemia patient

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Most conditioning regimens for stem cell transplantation (SCT) can cause germ cell injury and infertility. In female transplanted patients, pregnancies are also at high risk for maternal and fetal complications (Salooja et al, 2001). Although allogeneic SCT (allo-SCT) is the only curative treatment for the haematological complications in Fanconi anaemia (FA), the post-transplant fertility rate is extremely low because of their menstrual irregularity, early menopause (Alter et al, 1991) and germ cell hypersensitivity to DNA damaging agents. In fact, there have been no reports of natural pregnancy and delivery in FA patients after allo-SCT. We report a Japanese FA female with myelodysplastic syndrome (MDS) who conceived and delivered a healthy child without complications after allo-SCT.

The patient was diagnosed with FA, based on pancytopenia and polydactyly, but with no other physical abnormalities, when she was 10 years old. In July 1996, at 19 years of age, she was referred to our hospital with persistent menorrhagia. Laboratory tests revealed pancytopenia (haemoglobin 7·6 g/dl, platelet count 1·0 × 109/l, and white blood cell count 2·0 × 109/l). The bone marrow (BM) aspirate smear showed dysplastic features in trilineage cells without an increase in blast cells. Cytogenetic study of BM cells identified add(1)(q32) and add(11)(q23) in 20 of 20 cells examined, and the chromosome fragility test using mitomycin C was positive, leading to the diagnosis of FA with MDS. Menorrhagia gradually subsided and stopped after administration of an oral contraceptive and subcutaneous injection of gonadotropin-releasing hormone (GnRH) analogue. The second GnRH analogue was administered after a 4-week interval. In September, she received a BM transplant (BMT) from a human leucocyte antigen-matched younger sister, who was negative for the chromosome fragility test. A total of 6·7 × 108/kg of nucleated BM cells were infused following a conditioning regimen of total body irradiation (TBI; 600 cGy) with eyes, lungs and ovaries shielded, cyclophosphamide (CY; 20 mg/kg), horse anti-human thymocyte globulin (ATG; 40 mg/kg), and cytarabine (24 g/m2). Prophylaxis for graft-versus-host disease consisted of ciclosporin A, short-term methotrexate and methylprednisolone. The third GnRH analogue was administered on day 19. Engraftment was consistent, and complete donor chimaerism was confirmed on day 75. Menarche recovered naturally at 6 months and persisted regularly, and her hormonal test results were nearly normal at 15 months. She conceived naturally 48 months after BMT and delivered at 40-week gestation a healthy female baby weighing 3·5 kg, who has grown well without any haematological abnormalities. The patient is alive without any evidence of relapse 119 months after BMT; her menarche is consistently regular and her gonadotrophin levels are normal.

Recently, Dalle et al (2004) reported that an FA patient with secondary amenorrhoea after allo-BMT delivered normal children twice after oocyte donations. Her conditioning regimen included CY (20 mg/kg) + ATG (60 mg/kg) + thoraco-abdominal irradiation (500 cGy) without ovarian shielding. In our patient, despite the aggressive conditioning regimen, including high-dose cytarabine directed against MDS, menstruation recovered spontaneously 6 months after SCT, and she conceived naturally. To our knowledge, this is the first reported FA case of natural pregnancy and delivery after BMT. Gonadal shielding at irradiation, less toxic conditioning regimens, and GnRH co-treatment have been used to decrease ovarian damage (Pereyra Pacheco et al, 2001; Cheng et al, 2005; Nakagawa et al, 2006). Although cells from FA patients have high sensitivity to DNA damaging agents, this case suggests that ovarian shielding during TBI and administration of GnRH analogue could be very effective in protecting ovarian function in FA patients. Further, for FA patients with MDS or leukaemia, the addition of the high-dose anti-metabolic agent, cytarabine, to the standard conditioning regimen is safe and might be effective.

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