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Cancer in Pregnancy: Fertility of children exposed in utero to chemotherapy

Professional Summary
Despite the limited data, it appears that in utero exposure to chemotherapy is not associated with significant gonadal dysfunction. Secondary sexual development signs in different cohorts and direct evidence of normal fertility in a few cases indicate that there are no adverse effects of exposure to chemotherapy during fetal life on fertility later during adolescence. Long-term follow up studies with specific gonadal function evaluation are still needed to establish the safety of chemotherapy during pregnancy with respect to fertility of the offsprings.

The accumulation of data regarding the safety of chemotherapy agents during pregnancy focuses attention on the long-term sequelae of cancer therapy during gestation. The concerns regarding the effects of chemotherapy on gonadal function stem mainly from different reports of germ cell depletion after administration of alkylating agents. However, as most of these studies have focused on adults it was unclear whether exposure to chemotherapy during childhood and especially in utero is associated later with gonadal dysfunction.

Blatt et al. studied gonadal functions in 14 boys with acute leukemia who had been treated with combination chemotherapy that included prednisone, vincristine, methotrexate and 6-mercaptopurine. The time interval between the last chemotherapy cycle and the most recent endocrine evaluation ranged from 2 months to 8 years. All the children/adolescents demonstrated normal testicular function as determined by Tanner staging, physical examination serum gonadotropin and testosterone concentrations. Importantly, these data cannot necessarily be extrapolated to in utero exposure to chemotherapy especially during the period of gonads formation (weeks 4-8).

The information regarding fertility of adolescents and young adults who have been exposed in utero to chemotherapy is scare. This is mainly due to the relative rarity of such cases and the obvious difficulties of a long-term follow up.

Aviles et al. reported long-term follow up of 43 children born to mothers with hematological malignancies. Nineteen out of these 43 were exposed to chemotherapy during the first trimester of pregnancy while the others in later stages of gestation. The children aged 3-19 years have demonstrated normal growth and development according to height and weight developmental tables. Sexual characteristics demonstrated normal development in the adolescents and young adults although the authors do not mention how sexual development was evaluated.

A different study by Aviles et al. reported long-term follow up of 17 children born to mother with acute leukemia who received chemotherapy during pregnancy. Eleven of 17 children received chemotherapy during organogenesis. The children aged 4-22 years have had normal growth and height development. Two girls (ages 13 and 22) started normal menses. Physical and sexual examination of these individuals were considered normal. The 22 year old subject gave birth to a normal baby girl.

Similar findings were reported by Blatt et al. who have reported normal growth and development in 448 children exposed in utero to chemotherapy. However, specific evaluation of gonadal function was not done.

References

  1. Zemlickis D, Lishner M, Degendorfer P, Panzarella T, Sutcliffe SB, Koren G. Fetal outcome after in utero exposure to cancer chemotherapy. Arch Intern Med 1992; 152: 573-576.
  2. Blatt J, Mulvihill JJ, Ziegler JL, Young RC, Poplack DG. Pregnancy outcome following cancer chemotherapy. Am J Med 1980; 69 (9): 828-832.
  3. Sherins RJ, DeVita VT Jr. Effects of drug treatment for lymphoma on male reproductive capacity: studies of men in remission after therapy. Ann Intern Med 1973; 79 : 216-220.
  4. Richter P, Calamera JC, Morgenfeld Jc et al. Effect of chlorambucil on spermatogenesis in the human with malignant lymphoma. Cancer 1970; 25: 1026-1030.
  5. Miller DG. Alkylating agents and human spermatogenesis. JAMA 1971; 217: 1662-1665.
  6. Fairley KF, Barrie JU, Johnson W. Sterility and testicular atrophy related to cyclophosphamide therapy. Lancet 1972; 1: 568-569.
  7. Sieber SM, Adamson RH. Toxicity of antineoplastic agents in man: chromosomal aberrations, antifertility effects, congenital malformations and carcinogenic potential. Adv Cancer Res 1975; 22: 57-155.
  8. Chapman RM, Sutcliffe SB, Malpas JS. Cytotoxic-induced ovarian failure in women with Hodgkin's disease I. Hormone function. JAMA 1979; 242: 1877-1881.
  9. Blatt J, Poplack DG, Sherins RJ. Testicular function in boys after chemotherapy for acute lymphoblastic leukemia. N Engl J Med 1981; 304: 1121-1124
  10. Aviles A, Diaz-Marqueo JC, Terras V, Garcia EL. Non-Hodgkin's lymphoma and pregnancy. Gynecology 1990; 37: 335-337.
  11. Aviles A, Niz J. Long-term follow up of children born to mothers with acute leukemia during pregnancy. Med Ped Oncol 1988; 16: 3-6.
  12. Aviles A, Diaz-Marqueo JC, Talavera A, Gurman R, Garcia EL. Growth and development of children of mothers treated with chemotherapy during pregnancy: current status of 43 children. American Journal of Hematology 1991; 36: 243-248.
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