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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: Hydroxyurea
Hydroxyurea (Hydrea) is an antineoplastic drug that reduces the synthesis of deoxyribonucleic acid (DNA). 1
|In vitro studies||rabbit embryos||The formation of reactive free radicals by hydroxyurea seems to be an important part of the embryonic cytotoxicity of this agent. The co-administration of the antioxidant, propyl gallate 2, or the free radical scavenger, mannitol 3, can decrease the rapid cell death and the subsequent incidence of malformations that would otherwise occur after the administration of hydroxyurea.|
|rat embryos||maternal administration of 750 mg per kg.||Scott et al. (1971) showed that DNA synthesis is depressed by the presence of hydroxyurea in the embryo 4. Extensive cell death in the limb buds and central nervous system was noted.
Soukup et al. (1967) found no chromosome changes in embryos after the rat was treated with 750 mg per kg on the 13th day 5.
|Animal studies *||rats||5-67 times the usual human dose||In animals, hydroxyurea has produced an increase in congenital anomalies in all species tested.
Fetal death, fetal growth retardation, and increased frequencies of malformations of the central nervous system, eyes, heart, face, and limbs have been observed among the offspring of rats treated during pregnancy with hydroxyurea 6-11.
|185 -1000 mg /kg||In rats,
treatment during the 9th through 12th gestational days produced defects
of the central nervous system, palate, and skeleton 6.
Alterations have been observed among the offspring of rats treated during pregnancy with 12-67 times the usual human dose of hydroxyurea 12-15. A decrease in performance was found along with body and brain growth reduction.
|monkeys, dogs, cats, rabbits, hamsters, and mice||Behavioural studies with 1 or 2g/kg||Increased frequencies of congenital anomalies have been reported among the offspring of rhesus monkeys, dogs, cats, rabbits, hamsters, and mice treated during pregnancy with hydroxyurea in doses 2-25 times those used in humans 16-23. Fetal growth retardation and a variety of congenital anomalies are seen in each species. Defects of the central nervous system, eyes, face, and limbs often occur.|
|Human studies||Case reports||Hydroxyurea administration during nine human pregnancies has been reported 24-30. Adverse effects have not been observed in any of seven exposed newborns. One apparently normal fetus was electively aborted and one woman delivered a stillborn male infant without gross abnormalities. Although these reports do not demonstrate the safety of hydroxyurea during gestation, some authors have commented that the risk of teratogenicity is not as high as the reports from animal experiments would suggest 26.|
|up to 3 grams/day||A case report reported one normal offspring after treatment throughout pregnancy and cited four other cases from the literature. Among the four cases there was one premature delivery but no congenital defects 28.|
|Survey||Use of hydroxyurea prior to pregnancy has been studied in one report that included 69 women exposed to hydroxyurea prior to pregnancy 31. Of these 69 women, 14 had at least one live birth, three had no live births, three failed to conceive, and 49 did not try to conceive 31. The incidence and distribution of congenital abnormalities in this population did not differ from what would be found in women not exposed to chemotherapy.|
|Breast feeding||Case reports||Based on milk samples derived from one woman, hydroxyurea appears to be excreted in breast milk in small amounts 32. A suckling infant would ingest in a day at maximum 5.0% of the weight -adjusted maternal daily dose 33. Possible adverse effects on the offspring have not been investigated.|
- Kennedy BJ, Yarbro JW: Metabolic and therapeutic effects of hydroxyurea in chronic myeloid leukemia. JAMA195:1038-1043, 1966.
- DeSesso JM, Goeringer GC: The nature of the embryo-protective interaction of propyl gallate with hydroxyurea. Reprod Toxicol 4:145-52,1990.
- DeSesso JM, Goeringer GC: Hydroxyurea developmentaltoxicity in rabbit embryos is ameliorated D-mannitol, a specific scavenger for hydroxyl free radicals. Teratology 41:550, 1990.
- Scott, W.J.; Ritter, E.J. and Wilson, J.G.: DNA synthesis inhibition and cell death associated with hydroxyurea teratogenesis in rat embryos. Dev. Biol. 26:306-315, 1971.
- Soukup, S.; Takas, E. and Warkany, J.: Chromosome changes in embryos treated with various teratogens. J. Embryol. Exp. Morphol.18:215-226, 1967.
- Murphy ML, Chaube S: Hydroxyurea (NSC-32065) as a teratogen. Cancer Chemother Rep 40:1-7, 1964.
- Chaube S, Murphy ML: The effects of hydroxyurea and related compounds on the rat fetus. Cancer Res 26:1448-57, 1966.
- Wilson JG, Scott WJ, Ritter EJ, Fradkin R: Comparative distribution and embryotoxicity of hydroxyurea in pregnant rats and rhesus monkeys. Teratology 11:169-178, 1975.
- Brunner RL, McLean M, Vorhees CV, Butcher RE: A comparison of behavioral and anatomical measures of hydroxyurea induced abnormalities.Teratology 18:379-384, 1978.
- Aliverti V, Bonanomi L, Giavini E: Hydroxyurea as a reference standard interatological screening: Comparison of the embryotoxic and teratogenic effects following single intraperitoneal or repeated oral administrations to pregnant rats. Arch Toxicol (Suppl 4):239-247, 1980.
- Barr Jr M, Beaudoin AR: An exploration of the role of hydroxyurea injection time in fetal growth and teratogenesis in rats. Teratology24:163-167, 1981.
- Butcher RE, Hawver K, Kazmaier K, Scott W: Postnatal behavioral effects from prenatal exposure to teratogens. In: Morselli PL, Garattini S, SereniF (eds). Basic and Therapeutic Aspects of Perinatal Pharmacology. NewYork: Raven Press, 1975, pp 171-176.
- Adlard BPF, Dobbing J: Maze learning by adult rats after inhibition of neuronal multiplication in utero. Pediatr Res 9:139-142,1975.
- Brunner RL, Vorhees CV, Kinney L, Butcher RE: Aspartame:Assessment of developmental psychotoxicity of a new artificial sweetener. Neurobehav Toxicol 1:79-86, 1979.
- Vorhees CV, Butcher RE, Brunner RL, Sobotka TJ: A developmental test battery for neurobehavioral toxicity in rats: A preliminary analysis using monosodium glutamate calcium carrageenan, and hydroxyurea. ToxicolAppl Pharmacol 50:267-282, 1979.
- Wilson JG: Teratologic causation in man and its evaluation in non-human primates. Excerpta Med Int Congr Ser 310:191-203, 1974.
- Earl FL, Miller E, Van Loon EJ: Teratogenic research in beagle dogs and miniature swine. Lab Anim Drug Test Symp Int Comm Lab Anim5:233-247, 1972.
- Ferm VH: Severe developmental malformations. Malformations induced by urethane and hydroxyurea in the hamster. Arch Pathol 81:174-177, 1966.
- DeSesso JM, Jordan RL: Drug-induced limb dysplasias in fetal rabbits. Teratology 15:199-212, 1977.
- DeSesso JM, Goeringer GC: Ethoxyquin and nordihydroguaiaretic acid reduce hydroxyurea developmental toxicity. Reprod Toxicol 4:267-275,1990.
- DeSesso JM, Scialli AR, Goeringer GC: D-mannitol, a specific hydroxyl free radical scavenger, reduces the developmental toxicity of hydroxyurea in rabbits.
- Khera KS: A teratogenicity study on hydroxyurea and diphenylhydantoin in cats. Teratology 20:447-452, 1979.
- Warner CW, Sadler TW, Shockey J, Smith MK: A comparison of the in vivo and in vitro response mammalian embryos to a teratogenic insult.Toxicology 28:271-282, 1983.
- Doney KC, Kraemer KG, Shepard TH: Combination chemotherapy for acute myelocytic leukemia during pregnancy: three case reports. CancerTreat Rep 63:369-71, 1979.
- Patel M, Dukes IAF, Hull JC: Use of hydroxyurea in chronic myeloid leukemia during pregnancy: a case report. Am J Obstet Gynecol165:565-6, 1991.
- Tertian G, Tchernia G, Papiernik E, Elefant E: Hydroxyurea and pregnancy. Am J Obstet Gynecol 166:1868, 1992.
- Delmer A, Rio B, Bauduer F et al: Pregnancy during myelosuppressive treatment for chronic myelogenous leukaemia. Br J Haematol82:783-4, 1992.
- Jackson N, Shukri A, Ali K: Hydroxyurea treatment for chronic myeloid leukaemia during pregnancy. Br J Haematol 85:203-4, 1993.
- Fitzgerald JM, McCann SR: the combination of hydroxyurea and leucapheresis in the treatment of chronic myeloid leukaemia in pregnancy. Clin Lab Haematol 15:63-5, 1993.
- Pajor A, Zimonyi L, Koos R, Lehoczky D, Ambrus C: Pregnancies and offspring in survivors of acute lymphoid leukemia and lymphoma. Eur JObstet Gynecol Reprod Biol 40:1-5, 1991.
- Rustin GJS, Booth M, Dent J et al: Pregnancy after cytotoxic chemotherapy for gestational trophoblastic tumours. Br Med J 288:103-6,1984.
- Sylvester RK, Lobell M, Teresi ME, Brundage D, Dubowy R: Excretion of hydroxyurea into milk. Cancer 60:2177-8, 1987.
- Bennet P.N. Drugs and Human Lactation. Elsevier 2nd ED. Amsterdam, 1996, pp. 278-9.