Cancer in Pregnancy: Cyclophosphamide

Cyclophosphamide (Cytoxan) is an alkylating antineoplastic and immunosuppresant agent. It is metabolized to phosporamide mustard and acrolein, which are believed to be the ultimate teratogenic compounds.

	Setting	Treatment	Outcomes
	Species studied
Animal studies *			This agent has been found to be teratogenic in all animal species tested. The most consistent pattern of defects involves facial clefts and limb reduction defects.
	rats	7 to 10 mg/kg	Skeletal defects, cleft palate, exencephaly, encephalocele ¹
		up to 5.1 mg/kg daily before mating	Cyclophosphamide was shown to be readily transferred from the plasma to the seminal fluid. Male rats treated before mating with untreated females: malformations, growth retardation, increase in resorptions and fetal death and behavioral abnormalities in the offspring ^2,3 This phenomenon could be mediated by selective expression of paternal genes in the extraembryonic tissues.
	mice	30 mg/kg IV	Central nervous system, limb and digit defects ⁴
	rabbits	10 mg/kg	Cleft lip and/or palate, limb reduction defects ⁵
	rhesus monkeys		Facial clefts, meningoencephalocele, craniofacial dysmorphisms in late exposures ⁶
	Study design
Human studies	Case series		No epidemiological studies of congenital anomalies among the infants of women treated with cyclophosphamide during pregnancy were found. No congenital anomalies were observed in one series among 21 children born to women treated with cyclophosphamide during pregnancy with cancer chemotherapeutic regimens that included cyclophosphamide. Eleven of these women were treated during the first trimester ⁷. In a series of nine patients with acute leukemia during pregnancy, three were treated with cyclophosphamide during the first trimester, and no fetus was born with congenital malformation. One of them had severe pancytopenia and low birth weight. The mother of this patient received combined chemotherapy during 1st, 2nd and 3rd trimesters. ⁸
	Case reports	1st trim exposure	Most of the case reports involve the concomitant use of other chemotherapeutic agents or irradiation. The following malformed children were reported:
		4th to 11th wk (IV) and oral to term	1. Livebirth, 1,900g, absent big toes in both feet, flattening of nasal bridge, hypoplastic 5th finger, bilateral inguinal hernia ⁹
		co-exposure to 5 to 25 rad	2. Stillbirth (interrupted pregnancy)with absence of all toes and single left coronary artery ¹⁰
			3. Hemangioma, umbilical hernia ¹¹
		(+ doxorubicin) 2100 mg total dose	4. Growth retardation, imperforate anus, retovaginal fistula ¹²
		(+ prednisone) two IV doses of 200 mg between days 15 and 45.	5. Dysmorphic facies, cleft palate, multiple eye defects (blepharophimosis and microphtalmos), abnormal shaped and low set ears, absent thumbs. Borderline microcephaly, hypotonia and developmental delay at 10 months of age.¹³
		200 mg/day orally prior to conception until 4 weeks prior to delivery	6. Twins, one normal and the other with multiple malformations: Madelung deformity, esophageal atresia, abnormal inferior vena cava, abnormal renal collecting system, and radial anomaly with abnormal thumb, cryptorchidism with rudimental left testicle. Low IQ at 11 years and diagnosed with papillary thyroid cancer. ¹⁴
		2nd and 3rd trim	There are many cases of 2nd or 3rd trimester exposure to cyclophosphamide without adverse effects to the fetus. In few cases long term follow up showed normal growth and mental development of the children. Low birth weight seems to be a common side effect of exposure to anticancer drugs during pregnancy ¹⁵ Pancytopenia occurred in two infants exposed to cyclophosphamide and other antineoplastics during the 3rd trimester of pregnancy ^8,16
	occupational exposure (case-control study)	124 nurses preparing antineoplastic chemotherapy	Exposure to cyclophosphamide was significantly associated with early fetal loss (odds ratio of 2.66, 95% confidence interval of 1.25 to 5.71) ¹⁷

* - None of the animal studies reported in this table were conducted at The Hospital for Sick Children, Toronto, or by Motherisk.

References

Chaube et al: Teratogenic effects of cyclophosphamide (NCA-26271) in the rat. Cancer Chemother. Rep. 51:363-76, 1967.
Trasler& Robaire: Paternal cyclophosphamide treatment of rats causes fetal loss and malformations without affecting male fertility. Nature 316: 144-6, 1985.
Adams et al: Cyclophosphamide-induced spermatogenic effects detected in the F1 generation by behavioral testing. Science 211,80-2, 1981.
Gibson & Becker: Teratogenicity of cyclophosphamide in mice. Cancer Res. 28:475-80, 1968.
Fritz & Hess: Effects of cyclophosphamide on embryonic development in the rabbit. Agents and actions 2:83-6, 1971.
Wilk et al: Induction of craniofacial malformations in the rhesus monkey with cyclophosphamide. Teratology 45:329, 1992.
Aviles et al: Growth and development of children of mothers treated with chemotherapy during pregnancy: current status of 43 children. Am J Hematol 36:243-8, 1991.
Pizzuto et al: Treatment of acute leukemia during pregnancy:presentation of nine cases. Cancer Treat Rep 64:679-83,1980.
Greenberg & Tanaka: Congenital anomalies probably induced by cyclophosphamide. JAMA 188:423-6, 1964.
Toledo et al: Fetal effects during cyclophosphamide and irradiation therapy. Ann Int Med 74:87-91, 1971.
Coates: Cyclophosphamide in pregnancy. Aust NZ J ObstetGynecol 10:33-4, 1970.
Murray et al: Multimodal cancer therapy for breast cancer in the first trimester of pregnancy. JAMA 252: 2607-8, 1984.
Kirshon et al: Teratogenic effects of first trimester cyclophosphamide therapy. Obstet Gynecol 72: 462-4, 1988.
Zemlickis et al: Teratogenicity and carcinogenicity in a twin exposed in utero to cyclophosphamide. Teratogenesis Carcinog Mutagen13:139-43, 1993.
Nicholson: Cytotoxic drugs in pregnancy: review of reported cases. J Obstet Gynaecol Br Commonw 75:307-12, 1968.
Okun et al: Acute leukemia in pregnancy: transient neonatal myelosupression after combination therapy in the mother. Med PediatrOncol 7:315-9, 1979.
Selevan et al: A study of occupational exposure to antineoplastic drugs and fetal loss in nurses. N Engl J Med 313:1173-8, 1985.

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