Cyclophosphamide

 Risk Factor: DM
 Class: ANTINEOPLASTICS

Contents of this page:

Fetal Risk Summary
Breast Feeding Summary
References
Questions and Answers

Fetal Risk Summary

Cyclophosphamide is an alkylating antineoplastic agent. Both normal and malformed newborns have been reported following the use in pregnancy of cyclophosphamide (1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24, 25,26,27,28,29,30,31,32 and 33). Ten malformed infants have resulted from 1st trimester exposure (1,2,3,4,5,6,7 and 8). Radiation therapy was given to most of the mothers, and at least one patient was treated with other antineoplastics (1,2,4). Defects observed in four of the infants are shown in the list below, and three other infants are described in the text that follows: Flattened nasal bridge, palate defect, skin tag, four toes each foot, hypoplastic middle phalanx fifth finger, bilateral inguinal hernia sacs Toes missing, single coronary artery Hemangioma, umbilical hernia Imperforate anus, rectovaginal fistula, growth retarded A newborn exposed in utero to cyclophosphamide during the 1st trimester presented with multiple anomalies (6). The mother, who was being treated for a severe exacerbation of systemic lupus erythematosus, received two IV doses of 200 mg each between 15 and 46 days' gestation. Except for prednisone, 20 mg daily, no other medication was given during the pregnancy. The 3150-g female infant was delivered at 39 weeks' gestational age with multiple abnormalities, including dysmorphic facies, multiple eye defects including bilateral blepharophimosis with left microphthalmos, abnormally shaped, low-set ears, cleft palate, bilaterally absent thumbs, and dystrophic nails. Borderline microcephaly, hypotonia, and possible developmental delay were observed at 10 months of age.

A 1993 publication reported a 29-year-old woman with twins who was treated for acute lymphocytic leukemia throughout gestation with cyclophosphamide (200 mg/day) and intermittent prednisone (7). Therapy was stopped at 33 weeks' gestation and she delivered 4 weeks later. Both infants recovered from their severe respiratory distress syndromes. The 1250-g female twin has developed normally and is now 22 years of age. Except for strabismus repair at age 9, she has not required any further hospitalizations (7). In contrast, the 1190-g male twin required hospitalization until 10 months of age due to multiple congenital anomalies: dyschondrosteosis (Madelung's deformity) of the right arm, esophageal atresia, abnormal inferior vena cava, abnormal renal collecting system later diagnosed as cross-renal atopia, and a rudimentary left testicle (found later) (7). Chromosomal analysis of the child revealed a normal karyotype (46, XY). Developmental and neurological problems were diagnosed at about 8 years of age and an IQ test performed at 11 years of age was in the low average range (full scale IQ of 81) with even lower verbal skills (7). At 14 years of age, a stage III neuro blastoma arising from the left adrenal gland was diagnosed and was treated with surgery and radiation. At 16 years of age, metastatic papillary thyroid cancer was found and this was treated with surgery. In addition, three courses of radioactive iodine were administered to treat the primary cancer and two recurrences (7). The authors speculated that the different outcomes in the twins may have been due to differences in metabolism, either by the individual placentas or by the hepatic cytochrome P-450 activity of the fetuses (7). In either case, two cyclophosphamide active metabolites, phosphoramide mustard and acrolein, may have actually caused the malformations. Moreover, because of the timing of the two malig nancies in the boy, the authors also thought it was possible that they were the result of in utero exposure to cyclophosphamide (7).

A 23-year-old woman with hypertension and lupus nephritis received four IV doses of cyclophosphamide (20 mg/kg/dose), three of which were given before conception and one during the 6th week of gestation (8). She delivered a female, 1705-g (<5th percentile) infant at 37 weeks' gestation with Apgar scores of 5 and 7 at 1 and 5 minutes, respectively. The infant's length was 46 cm (5th10th percentile) and the head circumference 30.2 cm (<5th percentile). Other medications received throughout gestation were prednisone, nifedipine, atenolol, clonidine, potassium chloride, and aspirin. In addition to respiratory distress syndrome, multiple anomalies were noted, including microbrachycephaly, coronal craniosynostosis, blepharophimosis, shallow orbits, proptosis, hypotelorism, broad, flat nasal bridge, bulbous nasal tip, overfolded small ears, left preauricular pit, microstomia, high-arched palate, micrognathia, hypoplastic thumbs, 5th finger clinodactyly, and absent 4th and 5th toes bilaterally (8). Other malformations were detected in the skeleton and central nervous system during diagnostic workups. Growth delay (<3rd percentile in all growth parameters) and gross motor skills continued to be impaired at age 17.5 months. Based on their comparisons to previous cases of cyclophosphamide-induced congenital defects, the authors concluded that cyclophosphamide was a human teratogen and that a distinct phenotype existed (8).

A case report of a 16-year-old woman with ovarian endodermal sinus tumor presenting in two pregnancies was published in 1979 (19). Conservative surgery, suction curettage to terminate a pregnancy estimated to be at 810 weeks' gestation, and chemotherapy with cyclophosphamide, dactinomycin, and vincristine (VAC) produced a complete clinical response for 12 months. The patient then refused further therapy and presented a second time, 6 months later, with tumor recurrence and a pregnancy estimated at 1820 weeks' gestation. She again refused chemotherapy, but her disease progressed to the point where she allowed VAC chemotherapy to be reinstated 4 weeks later. At 33 weeks' gestation, 2 weeks after her last dose of chemotherapy, she spontaneously delivered a normal 2213-g female infant. The infant was developing normally when last seen at 8 months of age. In a similar case, a woman, treated with surgery and chemotherapy in her 15th week of pregnancy for an ovarian endodermal sinus tumor, delivered a normal 2850-g male infant at 37 weeks' gestation (20). Chemotherapy, begun during the 16th gestational week, included six courses of VAC chemotherapy. The last course was administered 5 days prior to delivery. No information was provided on the subsequent growth and development of the infant.

Following surgical treatment at 16 weeks' gestation, a 28-year-old woman with advanced epithelial ovarian carcinoma was treated with cyclophosphamide, 750 mg/m2, and cisplatin, 50 mg/m2, every 21 days for seven cycles (21). Labor was induced at 3738 weeks' gestation resulting in the delivery of a healthy, 3275-g male infant. Height, weight, and head circumference were in the 75th90th percentiles. No abnormalities of the kidney, liver, bone-marrow, or audiometry-evoked potential were found at birth, and the infant's physical and neurologic growth was normal at 19 months of age.

Pancytopenia occurred in a 1000-g male infant exposed to cyclophosphamide and five other antineoplastic agents in the 3rd trimester (14). In a similar case, maternal treatment for leukemia was begun at 12.5 weeks' gestation and eventually included cyclophosphamide, five other antineoplastic agents, and whole brain radiation (25). A normally developed, premature female infant was delivered at 31 weeks, who subsequently developed transient severe bone marrow hypoplasia in the neonatal period. The myelosuppression was probably due to mercaptopurine therapy.

In a brief 1997 report, three pregnant women with breast cancer were successfully treated with two or three courses of vinorelbine (2030 mg/m2) and fluorouracil (500750 mg/m2) at 24, 28, and 29 weeks' gestation, respectively (33). Delivery occurred at 34, 41, and 37 weeks' gestation, respectively. One patient also required six courses of epidoxorubicin and cyclophosphamide. Her infant developed transient anemia at 21 days of age that resolved spontaneously. No adverse effects were observed in the other two newborns. All three infants were developing normally at about 23 years of age (33).

A 1999 report from France described the outcomes of pregnancies in 20 women with breast cancer who were treated with antineoplastic agents (34). The first cycle of chemotherapy occurred at a mean gestational age of 26 weeks with delivery occurring at a mean 34.7 weeks. A total of 38 cycles were administered during pregnancy with a median of two cycles per woman. None of the women received radiation therapy during pregnancy. The pregnancy outcomes included two spontaneous abortions (SAB) (both exposed in the 1st trimester), one intrauterine death (exposed in the 2nd trimester), and 17 live births, one of whom died at 8 days of age without apparent cause. The 16 surviving children were developing normally at a mean follow-up of 42.3 months (34). Cyclophosphamide (C), in combination with various other agents (doxorubicin [D], epirubicin [E], fluorouracil [F], or mitoxantrone [M]) was administered to 13 of the women at a mean dose of 600 mg/m2 (range 3001200 mg/m2). The outcomes were one SAB (CEF; 1st trimester), one stillbirth (one cycle of CE at 23 weeks'), one neonatal death (one cycle of CEF 32 days before birth), and 11 surviving liveborn infants (one CE, six CEF, two CDF, and two CFM; all in the 3rd trimester). One of the infants, exposed to two cycles of CEF with the last at 25 days before birth, had transient leukopenia and another was growth retarded (1460-g, born at 33 weeks' gestation after two cycles of CFM) (34).

Data from one review indicated that 40% of the patients exposed to anticancer drugs during pregnancy delivered low-birth-weight infants (35). This finding was not related to the timing of exposure. Use of cyclophosphamide in the 2nd and 3rd trimesters does not seem to place the fetus at risk for congenital defects. Except in a few individual cases, long-term studies of growth and mental development in offspring exposed to cyclophosphamide during the 2nd trimester, the period of neuroblast multiplication, have not been conducted (36).

Cyclophosphamide is one of the most common causes of chemotherapy-induced menstrual difficulties and azoospermia (37,38,39,40,41,42,43,44 and 45). Permanent secondary amenorrhea with evidence of primary ovarian damage has been observed after long-term (20 months) use of cyclophosphamide (45). In contrast, successful pregnancies have been reported following high-dose therapy (39,40,46,47,48,49 and 50). Moreover, azoospermia appears to be reversible when the drug is stopped (41,42,43 and 44,51).

One report associated paternal use of cyclophosphamide and three other antineoplastics prior to conception with congenital anomalies in an infant (52). Defects in the infant included syndactyly of the first and second digits of the right foot and tetralogy of Fallot. In a group of men treated over a minimum of 3.5 years with multiple chemotherapy for acute lymphocytic leukemia, one man fathered a normal child while a second fathered two children, one with multiple anomalies (53). Any relationship between these outcomes and paternal use of cyclophosphamide is doubtful because of the lack of experimental evidence and confirming reports.

Cyclophosphamide-induced chromosomal abnormalities are also of doubtful clinical significance but have been described in some patients after use of the drug. A study published in 1974 reported chromosome abnormalities in patients treated with cyclophosphamide for rheumatoid arthritis and scleroderma (54). In contrast, chromosomal studies were normal in a mother and infant treated during the 2nd and 3rd trimesters in another report (16). In another case, a 34-year-old woman with acute lymphoblastic leukemia was treated with multiple antineoplastic agents from 22 weeks' gestation until delivery of a healthy female infant 18 weeks later (22). Cyclophosphamide was administered three times between the 26th and 30th weeks of gestation. Chromosomal analysis of the newborn revealed a normal karyotype (46,XX) but with gaps and a ring chromosome. The clinical significance of these findings is unknown, but since these abnormalities may persist for several years, the potential existed for an increased risk of cancer as well as for a risk of genetic damage in the next generation (22).

The long-term effects of cyclophosphamide on female and male reproductive function have been reported (55,56). In a 1988 publication, 40 women who had been treated with combination chemotherapy for malignant ovarian germ cell tumors (median age at diagnosis 15 years, range 629 years) were evaluated approximately 10 years later (median age 25.5 years, range 1440 years) (55). Cyclophosphamide had been used in 33 (83%) of the women. Menstrual function in these women after chemotherapy was as follows: premenarchal (N=1), regular menses (N=27), irregular menses (N=5), oligomenorrhea (N=2), amenorrhea (N=4), and premature menopause (N =1). Of the 12 women with menstrual difficulties, only 3 were considered serious or persistent. Evaluation of the reproductive status after chemotherapy revealed that 24 had not attempted to become pregnant, 9 had problem-free conceptions, 3 had initial infertility followed by conceptions, and 4 had chronic infertility. Of the 12 women who had conceived on one or more occasions, 1 had an elective abortion at 10 weeks' gestation, and 11 had delivered 22 healthy infants, although 1 had amelogenesis imperfecta.

A study published in 1985 examined 30 men to determine the effect of cyclophosphamide on male hormone levels and spermatogenesis (56). The men had been treated at a mean age of 9.4 years for a mean duration of 280 days. The mean age of the men at the time of the study was 22 years with a mean interval from end of treatment to evaluation of 12.8 years. Four of the men were azoospermic, 9 were oligospermic, and 17 were normospermic. Compared to normal controls, however, the 17 men classified as normospermic had lower ejaculate volumes (3.1 vs. 3.3 mL), lower sperm density (54.5 106 vs. 79 106/mL), decreased sperm motility (42% vs. 61%, p<0.05), and less normal sperm forms (61% vs. 70%, p<0.05). Concentrations of testosterone, dehydroepiandrosterone sulfate, and prolactin were not significantly different between patients and controls. One oligospermic man (sperm density 12 106/mL) had fathered a child.

The effect of occupational exposure to antineoplastic agents on pregnancy outcome was examined in a 1985 case-control study involving 124 nurses in 17 Finnish hospitals compared to 321 matched controls (57). The cases involved nurses working in 1979 and 1980 in hospitals that used at least 100 g of cyclophosphamide (the most commonly administered antineoplastic agent in Finland) per year or at least 200 g of all antineoplastic drugs per year. The average total antineoplastic drug use for all hospitals was 1898 g, but a lower total use, 887 g, occurred for intravenous drugs (58). Moreover, the nurses had to be 40 years of age or younger in 1980 and had to work in patient areas where antineoplastic agents were mixed and administered (57). The agents were prepared without the use of vertical-airflow biologic-safety hoods or protective clothing (58). Exposure to these agents during the 1st trimester was significantly associated with early fetal loss (odds ratio 2.30, 95% CI 1.204.39) (p=0.01) (57). Cyclophosphamide, one of four individual antineoplastic agents to which at least 10 women had been exposed, had an odds ratio for fetal loss of 2.66 (95% CI 1.255.71). Other significant associations were found for doxorubicin (odds ratio 3.96, 95% CI 1.3111.97) and vincristine (odds ratio 2.46, 95% CI 1.135.37). The association between fluorouracil and fetal loss (odds ratio 1.70, 95% CI 0.555.21) was not significant. Based on the results of their study and data from previous studies, the investigators concluded that nursing personnel should exercise caution in handling these agents (57).

Although there is no current consensus on the danger posed to pregnant women from the handling of antineoplastic agents (e.g., the above study generated several letters that questioned the observed association [59,60,61 and 62]), pharmacy and nursing personnel should take precautions to avoid exposure to these potent agents. The National Study Commission on Cytotoxic Exposure published a position statement on this topic in January 1987 (63). Due to the importance of this issue, the statement is quoted in its entirety below: The Handling of Cytotoxic Agents by Women Who Are Pregnant, Attempting to Conceive, or Breast Feeding There are substantial data regarding the mutagenic, teratogenic and abortifacient properties of certain cytotoxic agents both in animals and humans who have received therapeutic doses of these agents. Additionally, the scientific literature suggests a possible association of occupational exposure to certain cytotoxic agents during the first trimester of pregnancy with fetal loss or malformation. These data suggest the need for caution when women who are pregnant or attempting to conceive handle cytotoxic agents. Incidentally, there is no evidence relating male exposure to cytotoxic agents with adverse fetal outcome.

There are no studies which address the possible risk associated with the occupational exposure to cytotoxic agents and the passage of these agents into breast milk. Nevertheless, it is prudent that women who are breast feeding should exercise caution in handling cytotoxic agents.

If all procedures for safe handling, such as those recommended by the Commission are complied with, the potential for exposure will be minimized.

Personnel should be provided with information to make an individual decision. This information should be provided in written form and it is advisable that a statement of understanding be signed.

It is essential to refer to individual state right-to-know laws to insure compliance.

Breast Feeding Summary

Cyclophosphamide is excreted into breast milk (64). Although the concentrations were not specified, the drug was found in milk up to 6 hours after a single 500-mg IV dose. The mother was not nursing. A brief 1977 correspondence from investigators in New Guinea described neutropenia in a breast-fed infant whose mother received weekly injections of 800 mg of cyclophosphamide, 2 mg of vincristine, and 30-mg daily oral doses of prednisolone for 6 weeks (65). Absolute neutropenia was present 9 days after breast feeding had been stopped, which persisted for at least 12 days (65). Serial determinations of the infant's white cell and neutrophil counts were begun 2 days after the last exposure to breast milk. The lowest measured absolute lymphocyte count was 4750/L. Except for the neutropenia and a brief episode of diarrhea, no other adverse effects were observed in the infant.

A 1979 report involved a case of an 18-year-old woman with Burkitt's lymphoma diagnosed in the 26th week of gestation (66). She was treated with a 7-day course of cyclophosphamide, 10 mg/kg IV, as a single daily dose (total dose 3.5 g). Six weeks after the last chemotherapy dose, she delivered a normal, 2160-g male infant. Analysis of the newborn's blood counts was not conducted. The tumor recurred in the postpartum period and treatment with cyclophosphamide, 6 mg/kg/day IV, was started 20 days after delivery. Although she was advised not to nurse her infant, she continued to do so until her sudden death after the third dose of cyclophosphamide. Blood counts were conducted on both the mother and the infant during therapy. Immediately prior to the first dose, the infant's leukocyte and platelet counts were 4800/mm3 (abnormally low for age) and 270,000/mm3, respectively. After the third maternal dose, the infant's counts were 3200/mm3 and 47,000/mm3, respectively. Both counts were interpreted by the investigator as signs of cyclophosphamide-induced toxicity. It was concluded that breast feeding should be stopped during therapy with the agent (66).

The American Academy of Pediatrics considers cyclophosphamide to be contraindicated during breast feeding because of the reported case of neutropenia and because of the potential adverse effects relating to immune suppression, growth, and carcinogenesis (67).

References

1. Greenberg LH, Tanaka KR. Congenital anomalies probably induced by cyclophosphamide. JAMA 1964;188:4236.
2. Toledo TM, Harper RC, Moser RH. Fetal effects during cyclophosphamide and irradiation therapy. Ann Intern Med 1971;74:8791.
3. Coates A. Cyclophosphamide in pregnancy. Aust N-Z J Obstet Gynaecol 1970;10:334.
4. Murray CL, Reichert JA, Anderson J, Twiggs LB. Multimodal cancer therapy for breast cancer in the first trimester of pregnancy. JAMA 1984;252:26078.
5. Sweet DL, Kinzie J. Consequences of radiotherapy and antineoplastic therapy for the fetus. J Reprod Med 1976;17:2416.
6. Kirshon B, Wasserstrum N, Willis R, Herman GE, McCabe ERB. Teratogenic effects of first-trimester cyclophosphamide therapy. Obstet Gynecol 1988;72:4624.
7. Zemlickis D, Lishner M, Erlich R, Koren G. Teratogenicity and carcinogenicity in a twin exposed in utero to cyclophosphamide. Teratogenesis Carcinog Mutagen 1993;13:13943.
8. Enns GM, Roeder E, Chan RT, Catts ZA-K, Cox VA, Golabi M. Apparent cyclophosphamide (Cytoxan) embryopathy: a distinct phenotype? Am J Med Genet 1999;86:23741.
9. Lasher MJ, Geller W. Cyclophosphamide and vinblastine sulfate in Hodgkin's disease during pregnancy. JAMA 1966;195:4868.
10. Lergier JE, Jimenez E, Maldonado N, Veray F. Normal pregnancy in multiple myeloma treated with cyclophosphamide. Cancer 1974;34:101822.
11. Garcia V, San Miguel J, Borrasca AL. Doxorubicin in the first trimester of pregnancy. Ann Intern Med 1981;94:547.
12. Lowenthal RM, Funnell CF, Hope DM, Stewart IG, Humphrey DC. Normal infant after combination chemotherapy including teniposide for Burkitt's lymphoma in pregnancy. Med Pediatr Oncol 1982;10:1659.
13. Daly H, McCann SR, Hanratty TD, Temperley IJ. Successful pregnancy during combination chemotherapy for Hodgkin's disease. Acta Haematol (Basel) 1980;64:1546.
14. Pizzuto J, Aviles A, Noriega L, Niz J, Morales M, Romero F. Treatment of acute leukemia during pregnancy: presentation of nine cases. Cancer Treat Rep 1980;64:67983.
15. Sears HF, Reid J. Granulocytic sarcoma: local presentation of a systemic disease. Cancer 1976;37:180813.
16. Falkson HC, Simson IW, Falkson G. Non-Hodgkin's lymphoma in pregnancy. Cancer 1980;45:167982.
17. Webb GA. The use of hyperalimentation and chemotherapy in pregnancy: a case report. Am J Obstet Gynecol 1980;137:2636.
18. Gililland J, Weinstein L. The effects of cancer chemotherapeutic agents on the developing fetus. Obstet Gynecol Surv 1983;38:613.
19. Weed JC Jr, Roh RA, Mendenhall HW. Recurrent endodermal sinus tumor during pregnancy. Obstet Gynecol 1979;54:6536.
20. Kim DS, Park MI. Maternal and fetal survival following surgery and chemotherapy of endodermal sinus tumor of the ovary during pregnancy: a case report. Obstet Gynecol 1989;73:5037.
21. Malfetano JH, Goldkrand JW. Cis-platinum combination chemotherapy during pregnancy for advanced epithelial ovarian carcinoma. Obstet Gynecol 1990;75:5457.
22. Schleuning M, Clemm C. Chromosomal aberrations in a newborn whose mother received cytotoxic treatment during pregnancy. N Engl J Med 1987;317:16667.
23. Haerr RW, Pratt AT. Multiagent chemotherapy for sarcoma diagnosed during pregnancy. Cancer 1985;56:102833.
24. Turchi JJ, Villasis C. Anthracyclines in the treatment of malignancy in pregnancy. Cancer 1988;61:43540.
25. Okun DB, Groncy PK, Sieger L, Tanaka KR. Acute leukemia in pregnancy: transient neonatal myelosuppression after combination chemotherapy in the mother. Med Pediatr Oncol 1979;7:3159.
26. Ortega J. Multiple agent chemotherapy including bleomycin of non-Hodgkin's lymphoma during pregnancy. Cancer 1977;40:282935.
27. Hardin JA. Cyclophosphamide treatment of lymphoma during third trimester of pregnancy. Obstet Gynecol 1972;39:8501.
28. Khurshid M, Saleem M. Acute leukaemia in pregnancy. Lancet 1978;2:5345.
29. Yankowitz J, Kuller JA, Thomas RL. Pregnancy complicated by Goodpasture syndrome. Obstet Gynecol 1992;79:8068.
30. Barry C, Davis S, Garrard P, Ferguson IT. Churg-Strauss disease: deterioration in a twin pregnancy. Successful outcome following treatment with corticosteroids and cyclophosphamide. Br J Obstet Gynaecol 1997;104:7467.
31. Mavrommatis CG, Daskalakis GJ, Papageorgiou IS, Antsaklis AJ, Michalas SK. Non-Hodgkin's lymphoma during pregnancycase report. Eur J Obstet Gynecol Reprod Biol 1998;79:957.
32. Dayoan ES, Dimen LL, Boylen CT. Successful treatment of Wegener's granulomatosis during pregnancy. A case report and review of the medical literature. Chest 1998;113:8368.
33. Cuvier C, Espie M, Extra JM, Marty M. Vinorelbine in pregnancy. Eur J Cancer 1997;33:1689.
34. Giacalone PL, Laffargue F, Benos P. Chemotherapy for breast carcinoma during pregnancy. Cancer 1999;86:226672.
35. Nicholson HO. Cytotoxic drugs in pregnancy: review of reported cases. J Obstet Gynaecol Br Commonw 1968;75:30712.
36. Dobbing J. Pregnancy and leukaemia. Lancet 1977;1:1155.
37. Schilsky RL, Lewis BJ, Sherins RJ, Young RC. Gonadal dysfunction in patients receiving chemotherapy for cancer. Ann Intern Med 1980;93:10914.
38. Stewart BH. Drugs that cause and cure male infertility. Drug Ther 1975;5:428.
39. Schwartz PE, Vidone RA. Pregnancy following combination chemotherapy for a mixed germ cell tumor of the ovary. Gynecol Oncol 1981;12:3738.
40. Bacon C, Kernahan J. Successful pregnancy in acute leukaemia. Lancet 1975;2:515.
41. Qureshji MA, Pennington JH, Goldsmith HJ, Cox PE. Cyclophosphamide therapy and sterility. Lancet 1972;2:12901.
42. George CRP, Evans RA. Cyclophosphamide and infertility. Lancet 1972;1:8401.
43. Sherins RJ, DeVita VT Jr. Effect of drug treatment for lymphoma on male reproductive capacity. Ann Intern Med 1973;79:21620.
44. Lendon M, Palmer MK, Hann IM, Shalet SM, Jones PHM. Testicular histology after combination chemotherapy in childhood for acute lymphoblastic leukaemia. Lancet 1978;2:43941.
45. Uldall PR, Feest TG, Morley AR, Tomlinson BE, Kerr DNS. Cyclophosphamide therapy in adults with minimal-change nephrotic syndrome. Lancet 1972;2:12503.
46. Card RT, Holmes IH, Sugarman RG, Storb R, Thomas D. Successful pregnancy after high dose chemotherapy and marrow transplantation for treatment of aplastic anemia. Exp Hematol 1980;8:5760.
47. Deeg HJ, Kennedy MS, Sanders JE, Thomas ED, Storb R. Successful pregnancy after marrow transplantation for severe aplastic anemia and immunosuppression with cyclosporine. JAMA 1983;250:647.
48. Javaheri G, Lifchez A, Valle J. Pregnancy following removal of and long-term chemotherapy for ovarian malignant teratoma. Obstet Gynecol 1983;61:8S9S.
49. Rustin GJS, Booth M, Dent J, Salt S, Rustin F, Bagshawe KD. Pregnancy after cytotoxic chemotherapy for gestational trophoblastic tumours. Br Med J 1984;288:1036.
50. Lee RB, Kelly J, Elg SA, Benson WL. Pregnancy following conservative surgery and adjunctive chemotherapy for stage III immature teratoma of the ovary. Obstet Gynecol 1989;73:8535.
51. Hinkes E, Plotkin D. Reversible drug-induced sterility in a patient with acute leukemia. JAMA 1973;223:14901.
52. Russell JA, Powles RL, Oliver RTD. Conception and congenital abnormalities after chemotherapy of acute myelogenous leukaemia in two men. Br Med J 1976;1:1508.
53. Evenson DP, Arlin Z, Welt S, Claps ML, Melamed MR. Male reproductive capacity may recover following drug treatment with the L-10 protocol for acute lymphocytic leukemia. Cancer 1984;53:306.
54. Tolchin SF, Winkelstein A, Rodnan GP, Pan SF, Nankin HR. Chromosome abnormalities from cyclophosphamide therapy in rheumatoid arthritis and progressive systemic sclerosis (scleroderma). Arthritis Rheum 1974;17:37582.
55. Gershenson DM. Menstrual and reproductive function after treatment with combination chemotherapy for malignant ovarian germ cell tumors. J Clin Oncol 1988;6:2705.
56. Watson AR, Rance CP, Bain J. Long term effects of cyclophosphamide on testicular function. Br Med J 1985;291:145760.
57. Selevan SG, Lindbohm M-L, Hornung RW, Hemminki K. A study of occupational exposure to antineoplastic drugs and fetal loss in nurses. N Engl J Med 1985;313:11738.
58. Selevan SG, Hornung RW. Antineoplastic drugs and spontaneous abortion in nurses. N Engl J Med 1986;314:10501.
59. Kalter H. Antineoplastic drugs and spontaneous abortion in nurses. N Engl J Med 1986;314:10489.
60. Mulvihill JJ, Stewart KR. Antineoplastic drugs and spontaneous abortion in nurses. N Engl J Med 1986;314:1049.
61. Chabner BA. Antineoplastic drugs and spontaneous abortion in nurses. N Engl J Med 1986;314:104950.
62. Zellmer WA. Antineoplastic drugs and spontaneous abortion in nurses. N Engl J Med 1986;314:1050.
63. Jeffrey LP, Chairman, National Study Commission on Cytotoxic Exposure. Position statement. The handling of cytotoxic agents by women who are pregnant, attempting to conceive, or breast feeding. January 12, 1987.
64. Wiernik PH, Duncan JH. Cyclophosphamide in human milk. Lancet 1971;1:912.
65. Amato D, Niblett JS. Neutropenia from cyclophosphamide in breast milk. Med J Aust 1977;1:3834.
66. Durodola JI. Administration of cyclophosphamide during late pregnancy and early lactation: a case report. J Natl Med Assoc 1979;71:1656.
67. Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:13750.