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Cancer in Pregnancy: Vincristine
Vincristine is an alkaloid derived from the periwinkle plant used for the treatment of neoplastic disease. It interferes with the mitotic cells arresting the metaphases. It is related to vinblastine.
|Animal studies *||Hamsters 1||0.25 mg/kg intravenously on the 8th gestational day||Fetal death. Increased incidence of skeletal and eye defects, spina bifida and exencephaly.|
|Rats and mice 2,3||6.7 -13 times the doses used in humans||Increased incidence of fetal death and malformations of the central nervous system, skeletal, and of the body wall.|
|Rats 4||1 - 5 times the doses used in humans||Increased incidence of eye defects, microcephaly, neural tube defects and midfacial defects. Many arrested metaphases observed in the treated embryos.|
|Rhesus monkey 5||0.15 to 1.175 mg per kg on the 27th or 29th day, single dose||Encephalocele in one fetus and syndactyly in another.|
|Human studies||Case reports||There are many case reports of normal babies after 1st, 2nd or 3rd trimester exposure to vincristine 6-8|
|1st trim exposure||Two malformed infants were reported after 1st trimester exposure to vincristine:|
|vincristine, vinblastine procarbazine||1. A 1900g male infant delivered at 37 weeks of pregnancy. He died after respiratory distress syndrome and at autopsy a small secundum atrial septal defect was observed 9.|
|vincristine, nitrogen mustard, prednisone, procarbazine||2. A male
fetus electively aborted due to malpositioned kidneys with markedly reduced size. Karyotype performed on amniotic fluid cell culture was normal. 10
OBS: Two other malformed children were reported in case series and described below 11, 12
|2nd or 3rd trimester exposures||The following abnormalities were described:
1. A healthy girl born to a woman who received combination therapy including vincristine for acute lymphoblastic leukemia, from 22nd week to term. Karyotype analysis showed 46 chromosomes with the presence of gaps and a ring chromosome. The clinical significance of this finding is still unknown but it may represent a risk of cancer as well as a risk of genetic damage in the next generation 13.
2. A case of severe myelosupression in an infant exposed to combination therapy during 1st, 2nd and 3rd trim 14 (details below), and another case of transient severe bone marrow suppression most probably attributed to mercaptopurine exposure. 15
3. One case of intrauterine death after combination therapy including vincristine was reported 16.
|Case series||No epidemiological studies of congenital anomalies among the infants of women treated with vincristine during pregnancy exist. The available case series indicates that the risk for teratogenicity is small:
1. No congenital anomalies were observed in one series among 28 children born to women treated during pregnancy with cancer chemotherapeutic regimens that included vincristine. Twelve of these women were treated during the first trimester 17. Their growth, intellectual development and cytogenetic analysis were normal in ages ranging from 3 - 19 years at the moment of the follow-up.
2. In a series of 9 patients with acute leukemia during pregnancy, 5 of them with the use of vincristine during the first trimester , no one was born with congenital malformation. 14 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 and vincristine) during 1st, 2nd and 3rd trimesters
3. In a case series of 7 pregnant patients with acute leukemia, 3 of them with combination therapy including vincristine during the 2nd or 3rd trimester, all were born alive without major malformations or other complications. Their long term follow-up (1 to 11 years) did not show any abnormality in their development 18.
4. In a series of 26 pregnancies of women receiving chemotherapy for cancer, there was one baby with cleft lip and palate who was exposed to lomustine, vincristine, prednisone and procarbazine from week 1-6 and to vinblastine from week 9 to term 11.
5. In a case series of 13 patients with first trimester exposure to cancer chemotherapy, 4 were exposed to combination regimens including vincristine. One pregnancy ended as a normal live birth, one was a spontaneous abortion, one was an electively terminated pregnancy and the last was a baby born with hydrocephalus who died 4 hours after birth 12.
|Pre-pregnancy||A study of 445 long-term survivors treated with chemoterapy for gestational tumors including vincristine did not show any increased incidence of congenital malformation in their children 19. Another study following 202 pregnancies from 100 patients who received chemotherapy for cancer in childhood and adolescence including vincristine also did not detect any increase in the incidence of birth defects in their children 20. Other studies also presented successful pregnancies after pre-conceptional chemotherapy 21|
|Occupational exposure, case-control study||124 nurses preparing antineoplastic chemotherapy||Exposure to vincristine was significantly associated with early fetal loss (odds ratio of 2.46, 95% confidence interval of 1.13 to5.37) 22.|
- Ferm, V.H. Congenital malformations in hamster embryos after treatment with vinblastine and vincristine. Science 141: 426, 1963.
- Demyer, W. Cleft lip and jaw induced in fetal rats by vincristine. Archives of Anatomy 48: 181-186, 1965.
- Joneja MG, LeLiever WC: Effect of vinblastine and podophyllin on DBA mouse fetuses. Toxicol Appl Pharmacol 27:408-414,1974.
- Demyer, W. Vinblastine-induced malformation of face and nervous system in two rat strains. Neurology (Minneap.) 14:806-808, 1964.
- Courtney, K.D.; Valerio, D.A. Teratology in the Macaca mulatta. Teratology 1: 163-172, 1968.
- Caligiuri MA, Mayer RJ. Pregnancy and leukemia. Semin Oncol. 16(5): 388-396, 1989.
- Doll DC, Ringenberg QS & Yarbro JW Antineoplastic agents and pregnancy. Semin Oncol. 16(5): 337-346, 1989.
- Schardein JL. Chemically induced birth defects, Marcel Dekker, NewYork and Basel 1993, p 480.
- Thomas, P.R.M.; Peckham, M.J. The investigation and management of Hodgin's disease in the pregnant patient. Cancer 38: 1443-51, 1976.
- Mennuti, M.T.; Shepard, T.H.; Mellman, W.J.Fetal renal malformation following treatment of Hodgkin's disease during pregnancy. Obstet Gynecol 46: 194-196, 1975.
- Mulvihill JJ et al: Pregnancy outcome in cancer patients. Cancer 60:1143-50, 1987.
- Zemlickis D, Lishner M, Degendorfer P, et al. Fetal outcome after in utero exposure to cancer chemotherapy. Arch Intern Med. 152:573-576, 1992.
- Schleuning & Clemm: Chromosomal aberrations in a newborn whose mother received cytotoxic treatment during pregnancy. New Engl J Med317: 1666-7, 1987.
- Pizzuto J, Aviles A, Noriega L, et al. Treatment of acute leukemia during pregnancy: presentation of nine cases. Cancer Treat Rep.64(4-5): 679-683, 1980.
- 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.
- Karp, G.L.; von Oeyen, P.; Valone, F.; Khetarpal, V.K.; Israel, M.; Mayer, R.J.; Frigoletto, F.D.; Garnick, M.B. Doxorubicin in pregnancy: possible transplacental passage. Cancer Treat Rep67: 773-777, 1983.
- 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.
- Reynoso et al: Acute Leukemia during pregnancy: the Toronto Leukemia Study group experience with long-term follow-up of children exposed in utero to chemotherapeutic agents. J Clin Oncol 5:1098-1106,1987.
- Rustin, G.J.S.; Booth, M.; Dent, J.; Salt,S.; Rustin, F.; Bagshawe, K.D. Pregnancy after cytotoxic chemoterapy for gestational trophoblastic tumors. Br Med J 288: 103-106, 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.
- Selevan, S,G.; Lindbohn M.L.; Hornung, R.W.;Hemminki, K. A study of occupational exposure to antineoplastic drugs and fetal loss in nurses. N Engl J Med 313 (19): 1173-1178,1985.