Pregnancy after stem cell transplantation

Abstract

QUESTION

A married woman under my care underwent successful bone marrow transplantation as part of treatment for a malignancy. She wishes to start a family. What are her chances? Are there risks?

ANSWER

Success in becoming pregnant after stem cell transplantation depends on such factors as cumulative doses of chemotherapy and radiation and mother’s age at time of transplant. There is increased risk of prematurity, low birth weight, and spontaneous abortion. Pregnancy should be managed as high risk.

An increasing number of young women suffering from leukemia and other malignant and non-malignant disorders are being cured by stem cell transplantation (SCT). Improved survival introduces the long-term consequences of SCT, including fertility issues.

Pregnancies following SCT are still rare. The options for conceiving include spontaneous conception and in vitro fertilization with donated or the mother’s own eggs (with embryo cryopreservation before or after chemotherapy).¹ Harvesting and freezing unfertilized eggs is technically difficult and frequently unavailable.¹

Most pretransplant conditioning protocols for SCT include alkylating agents, irradiation, or both. Either of these options can injure germ cells and cause infertility. Thus, almost all women become infertile immediately after SCT due to damage to the ovaries.²

Some women become permanently infertile; others recover fertility. Recovery of ovarian function and fertility has been shown to depend on several factors. The most important risk factors for development of ovarian failure are advanced age at time of first treatment and the number of cycles with alkylating agents and irradiation.³

All alkylating agents have toxic effects on the ovaries. These effects have been mostly documented with cyclophosphamide.⁴ Irradiation doses as low as 4 Gy destroy about 50% of oocytes.⁵ Use of alkylating agents combined with irradiation below the diaphragm causes more pronounced damage.^6-8 Women more often recover fertility if their irradiation regimens do not affect the whole body and if they are younger than 25 years.¹

In allogeneic SCT, recovery of ovarian function ranges from 14% to 24%,^9-11 and the interval from SCT to first spontaneous menstruation ranges from 21 to 87 months (median 49 months).¹² Recovery rates as high as 84% have been reported among patients with favourable predictors. These patients were young, and none received total body irradiation as part of transplant conditioning.¹⁰ Rates of recovery of ovarian function after autologous SCT are expected to be higher than after allotransplantation, because autologous SCT does not require subsequent immunosuppressive therapy, and recipients do not experience graft-versus-host disease. A study of 17 women who underwent autologous SCT showed that five (29%) recovered their ovarian function and that the recovery rate for women younger than 25 years was 79%.²

In a larger study, 32 out of 110 women who recovered ovarian function became pregnant at a median of 8.5 years after allotransplantation.¹³ Another study found that pregnancy can occasionally be achieved in women with non-Hodgkin lymphoma, whether or not they have undergone high-dose therapy with autologous SCT.¹⁴ The pregnancy rate was not lower among women treated with high-dose chemotherapy, despite a cumulative dose of cyclophosphamide of 10 800 mg/m². Only the youngest patients became pregnant; no pregnancy was observed among women who were older than 29 years when diagnosed with a non-Hodgkin lymphoma.¹⁴

A recent study evaluated pregnancy outcome among 113 women after SCT¹⁵ and found that 85% of pregnancies resulted in live births. Only 0.82% of the children had severe anomalies, a rate not higher than that reported in the general population. Among allograft recipients, 42% had cesarean sections (compared with 16% in the general population), 20% had preterm deliveries (compared with 6% in the general population), and 23% had low birth weight infants (compared with 6% in the general population). The authors recommended that pregnancies in patients who received allografts and total body irradiation should be treated as high risk.¹⁵ Other researchers reported an increased risk of spontaneous abortion in women treated with SCT and total body irradiation.¹³

An important association was found between pregnancy and a relatively high rate of relapse of chronic myeloid leukemia after SCT. Suppression of the graft-versus-leukemia effect during pregnancy was suggested as the mechanism of relapse.^16,17

In the future, alternative chemotherapeutic regimens with lower doses of alkylating agents need to be investigated for women who wish to become pregnant after SCT, at least until oocyte or ovarian cryopreservation becomes routinely available.

Motherisk questions are prepared by the Motherisk Team at the Hospital for Sick Children in Toronto, Ont. Drs Schechter and Finkelstein are members and Dr Koren is Director of the Motherisk Program. Dr Doyle is Director of the Bone Marrow Transplant Unit at the Hospital for Sick Children. Dr Koren, a Senior Scientist at the Canadian Institutes of Health Research, is supported by the Research Leadership for Better Pharmacotherapy during Pregnancy and Lactation and holds the Ivey Chair in Molecular Toxicology at The University of Western Ontario.