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Neurodevelopment of Children Exposed in-Utero to Chemotherapy for Maternal Breast Cancer (Dr. I Nulman)
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Cancer in Pregnancy: 6-Mercaptopurine
6-Mercaptopurine (6MP): antimetabolite used in the treatment of leukemia that inhibits DNA synthesis.
|Animal studies *||Rats||31 to 125 mg / kg||Central nervous system, eye and limb defects|
|Mice||400 to 900 mg /kg||Central nervous system, jaw and limb defects; chromosome breaks|
|Rabbits||25 to 250 mg/kg||Central nervous system and limb defects|
|Human studies||Case reports||1st trim exposure||There are around 80 reports of women exposed to 6 MP during pregnancy. Only the following malformed infants out of more than thirty pregnancies were reported after 1st trimester exposure, suggesting a relatively small teratogenic risk:|
|combination with busulfan||A baby with cleft palate, stunted growth, corneal opacity and microphtalmia, external genitalia poorly developed, death within 10 days2. The anomalies were attributed to busulfan.Obs: another malformed baby was reported in a case series3 (see details below).|
|2nd and 3rd trim exposures||Neonatal toxicity due to combination therapy was described in three children including pancytopenia4 (details below);microangiopathic hemolytic anemia 5 and transient severe bone marrow hypoplasia 6
Chromosomal abnormalities (46 chromosomes with the presence of gaps and a ring chromosome) were described in one case after 2nd trimester exposure to 6MP: a healthy girl born from a woman who received combination therapy including 6MP for acute lymphoblastic leukemia, from 22nd week to term. The clinical significance of this finding is still unknown but it can represent an risk of cancer as well as a risk of genetic damage in the next generation 7
Fetal wastage has been reported after 6MP exposure in all trimesters 8,9
epidemiological studies of congenital anomalies among infants of women
treated with 6MP during pregnancy exist. We located the following case
1. No congenital anomalies were observed in one series among 6 children born to women treated during pregnancy with cancer chemotherapeutic regimens that included 6MP. Four of these women were treated during the first trimester 10. Their growth, intellectual development and cytogenetic analysis were normal in ages ranging from 3-19 years at the time of the follow-up.
2. In a series of 9 patients with acute leukemia during pregnancy, 5 of them with the use of 6MP during the first trimester, no one was born with congenital malformations4, but 4 were of subnormal birth weight. One of them had severe pancytopenia and low birth weight. The mother of this patient received combination chemotherapy (cytosine arabinoside, prednisone, 6-mercaptorurine, methotrexate andvincristine) during 1st, 2nd and 3rd trimesters
3. In a series of 26 pregnancies of women receiving chemotherapy for cancer there was one stillborn baby (abruptio placentae) with intra-utero exposure to mercaptopurine from week 6 and cyclophosphamide from week 8. The baby had polydactyly3.
|Pre-pregnancy, man and women||A study of 445 long-term survivors treated with chemoterapy for gestational tumors including 6-MP did not showed any increased incidence of congenital malformation in their children 11. Another study following 202 pregnancies from 100 patients who received chemotherapy for cancer in childhood and adolescence including 6MP also did not detect any increase in the incidence of birth defects in their children 12. Other studies also presented successful pregnancies after pre-conceptional chemotherapy 13|
- Shepard TH. Catalog of Teratogenic Agents. TheJohns Hopkins University Press, Baltimore 1993, p.106.
- Diamond I, Anderson MM, McCreadie SR. Transplacental transmission of busulfan in a mother with leukemia. Pediatrics 25:85-90, 1960.
- Mulvihill JJ, McKeen EA, Rosner F,Zarrabi MH. Pregnancy outcome in cancer patients. Experience in a large cooperative group. Cancer 60:1143-1150, 1987.
- Pizzuto J, Aviles A, Noriega L, et al. Treatment of acute leukemia during pregnancy: Presentation of nine cases. Cancer Treat Rep 64:679-683, 1880.
- McConnel JF, Bhoola R. A neonatal complication of maternal leukemia treated with 6-mercaptopurine. Postgrad Med J 49:211-213, 1973.
- Okun DB, Groncy PK, Sieger L, Tanaka KR.Acute leukemia in pregnancy: Transient neonatal myelosuppression after combination chemotherapy in mother. Med Pediatr Oncol 7:315-319,1979.
- Schleuning M, Clemm C. Chromosomal aberrations in a newborn whose mother received cytotoxic treatment during pregnancy. N Engl J Med 317: 1666-1667, 1987.
- Caligiuri MA, Mayer RJ. Pregnancy and leukemia. Semin Oncol. 16(5): 388-396, 1989.
- Nicholson: Cytotoxic drugs in pregnancy: review of reported cases. J Obstet Gynaecol Br Commonw 75:307-12, 1968.
- Aviles A, Diaz-Maqueo JC, Talavera A, et al.Growth and development of children of mothers treated with chemotherapy during pregnancy. Current status of 43 children. Am J Hematol. 36:243-248, 1991.
- Rustin GJS, Booth M. Dent J et al: Pregnancy after cytotoxic chemotherapy for gestational trophoblastic tumors. BrMed J 288: 103-6, 1984.
- Green DM , Zevon MA, Lowrie G et al: Congenital anomalies in children of patients who received chemotherapy for cancer in childhood and adolescence. N Engl J Med 325: 141-6, 1991.
- Blatt J, Mulvihill JJ, Ziegler JL et al:Pregnancy outcome following cancer chemotherapy. Am J Med 69:828-32,1980.