Risk Factor: CM
Fetal Risk Summary
Cisplatin is an antineoplastic used in the treatment of various cancers. This agent is mutagenic in bacteria, produces chromosomal aberrations in animal cells in tissue culture, and is teratogenic and embryotoxic in mice (1). Cisplatin is also a transplacental carcinogen in rats, producing tumors in the liver, lung, nervous system, and kidneys of adult offspring (2). The mechanism for the production of these tumors is probably the result of DNA damage in fetal rat tissues (3). A 1994 review also reviewed the animal teratogenicity of cisplatin (4).
Only seven cases of cisplatin usage during pregnancy have been located (5,6,7,8,9,10 and 11). In one case, the mother, in her 10th week of gestation, received a single intravenous dose of 50 mg/kg for carcinoma of the uterine cervix (5). Two weeks later, a radical hysterectomy was performed. The male fetus was morphologically normal for its developmental age.
A 25-year-old woman underwent surgery at 25 weeks’ gestation for an endodermal sinus tumor of the ovary (6). The chemotherapy cycle consisting of cisplatin (75 mg/m2), vinblastine (0.25 mg/kg), and bleomycin (50 mg) was started 9 days later. Approximately 3 weeks later she received a second cycle of therapy. A normal, healthy 1900-g male infant was delivered by scheduled cesarean section at 32 weeks’ gestation. The infant was alive and growing normally at the time of the report.
A 1989 case report described the effect of maternal chemotherapy on a premature newborn delivered at approximately 27 weeks’ gestation (7). The mother had been treated with cisplatin (55 mg), bleomycin (30 mg), and etoposide (165 mg) (all given daily for 3 days), 1 week prior to delivery, for an unknown primary cancer with metastases to the eye and liver. The mother developed profound neutropenia just prior to delivery. On the 3rd day after birth, the 1190-g female infant also developed a profound leukopenia with neutropenia, 10 days after in utero exposure to the antineoplastic agents. The condition resolved after 10 days. At 10 days of age, the infant began losing her scalp hair along with a rapid loss of lanugo. Etoposide was thought to be the most likely cause of the neutropenia and the alopecia (7). By 12 weeks of age, substantial hair regrowth had occurred, and at 1 year follow-up, the child was developing normally except for moderate bilateral hearing loss. The investigators could not determine whether the sensorineural deafness was due to the maternal and/or neonatal gentamicin therapy or to the maternal cisplatin chemotherapy (7).
A third case of cisplatin usage during pregnancy involved a 28-year-old woman with advanced epithelial ovarian carcinoma (8). Following surgical treatment at 16 weeks’ gestation, the patient was treated with cisplatin, 50 mg/m2, and cyclophosphamide, 750 mg/m2, every 21 days for seven cycles. 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 percentile. No abnormalities of the kidney, liver, bone-marrow, or auditory-evoked potential were found at birth and the infant’s physical and neurologic growth was normal at 19 months of age.
In a report similar to that above, a 24-year-old woman was treated during the 2nd trimester of pregnancy for epithelial ovarian carcinoma (9). Surgery was performed at 15.5 weeks’ gestation, followed by five courses of chemotherapy consisting of cisplatin (100 mg/m2) and cyclophosphamide (600 mg/m2 2, 1000 mg/m2 3). Spontaneous rupture of membranes occurred just prior to the sixth course of chemotherapy at 36.5 weeks’ gestation, and she delivered a normal-appearing, 3060-g male infant who, except for initial mild respiratory distress, has developed normally as of 28 months of age.
A 21-year-old woman with a dysgerminoma was treated surgically at 26 weeks’ gestation, followed approximately 1 week later with cisplatin, 20 mg/m2, and etoposide, 100 mg/m2, daily for 5 days at 34 week intervals (10). A healthy, 2320-g female infant was delivered at 38 weeks. The infant is developing normally at 9 months of age.
Three treatments of cisplatin (75 mg/m2; total dose 330 mg) were administered at 22, 25, and 28 weeks’ gestation to a 34-year-old woman with a rapidly progressing cervical cancer (11). A cesarean section was performed at 32 weeks’ with delivery of a normal, 2120-g male infant, who was doing well at 12 months of age.
The long-term effects of cisplatin and other antineoplastic agents on menstrual function in females and reproductive function in females and males after treatment of various cancers have been described (12,13 and 14). Of the 76 women studied, cisplatin was used in 9 and in 25 men, cisplatin had been given to 4. The results of one of these studies (12) have been discussed in the monograph for cyclophosphamide (see Cyclophosphamide). In the second report, a normal term infant was delivered from a woman treated with cisplatin, etoposide, dactinomycin, and intrathecal methotrexate 2 years prior to conception for choriocarcinoma (13). Similarly, no congenital malformations were observed in seven liveborn offspring of four males and two females treated with cisplatin during childhood or adolescence (14).
A 1996 report described successful pregnancy outcomes in 14 women who had been treated prior to conception for ovarian germ cell tumors with a chemotherapy regimen (POMB/ACE) consisting of cisplatin (120 mg/m2), vincristine, methotrexate, bleomycin, dactinomycin, cyclophosphamide, and etoposide (15). No congenital malformations were observed.
Reversible azoospermia occurred in a male treated for teratoma of the testis with cisplatin, vinblastine, bleomycin, surgery, and radiation (16). Fifteen months after the end of therapy, the sperm count was
A significant reduction in reproductive organ weights, sperm counts, sperm motility, fertility, and levels of testosterone, LH and FSH occurred in male rats treated with cisplatin 1 week prior to mating (17). After mating, a significant preimplantation loss and lower fetal weights in comparison to controls were observed.
Occupational exposure of the mother to antineoplastic agents during pregnancy may present a risk to the fetus. A position statement from the National Study Commission on Cytotoxic Exposure and a research article involving some antineoplastic agents are presented in the monograph for cyclophosphamide (see Cyclophosphamide).
Breast Feeding Summary
Three studies, two with opposite results from the third, have examined the excretion of cisplatin into human milk. In a 1985 study, a 31-year-old woman, 7 months postpartum with ovarian cancer, was treated with doxorubicin and cisplatin (18). Doxorubicin (90 mg) was given intravenously over 15 minutes followed by intravenous cisplatin (130 mg, 100 mg/m2) infused over 26 hours. Blood and milk samples were collected frequently for cisplatin determination from 0.2571.25 hours after the start of the infusion. Peak plasma concentrations of platinum reached 2.99 g/mL, but platinum was undetectable (sensitivity 0.1 g/mL) in the milk.
Opposite results were obtained in a 1989 study (19). A 24-year-old woman with an entodermal sinus tumor of the left ovary was treated with cisplatin, 30 mg/m2 IV for 4 hours daily, for 5 consecutive days. Etoposide and bleomycin were also administered during this time. On the 3rd day of therapy, milk and serum samples were collected 30 minutes before the cisplatin dose was administered. Cisplatin concentrations in the milk and plasma were 0.9 and 0.8 g/mL, respectively, a milk:plasma ratio of 1.1. The infant was not allowed to breast-feed.
In the third study, cisplatin was measured in breast milk in the range of 0.10.15 g/mL (over 2 hours), with a milk:plasma ratio of about 0.1 over an 18-hour sampling period (20). The woman, who was still lactating 2 years after her last deliver, was treated with six courses of cisplatin (100 mg/course) and cyclophosphamide (1600 mg/course) for ovarian cancer.
The American Academy of Pediatrics did not cite either of these latter two studies and classifies cisplatin as compatible with breast feeding (21). However, based on the two reports, breast feeding during cisplatin therapy should be considered contraindicated.
- Product information. Platinol. Bristol-Myers Squibb Oncology/Immunology Division, 1997.
- Diwan BA, Anderson LM, Ward JM, Henneman JR, Rice JM. Transplacental carcinogenesis by cisplatin in F344/NCr rats: promotion of kidney tumors by postnatal administration of sodium barbital. Toxicol Appl Pharmacol 1995;132:11521.
- Giurgiovich AJ, Diwan BA, Lee KB, Anderson LM, Rice JM, Poirier MC. Cisplatin-DNA adduct formation in maternal and fetal rat tissues after transplacental cisplatin exposure. Carcinogenesis 1996;17:16659.
- Wiebe VJ, Sipila PEH. Pharmacology of antineoplastic agents in pregnancy. Crit Rev Oncol Hematol 1994;16:75112.
- Jacobs AJ, Marchevsky A, Gordon RE, Deppe G, Cohen CJ. Oat cell carcinoma of the uterine cervix in a pregnant woman treated with cis-iamminedichloroplatinum. Gynecol Oncol 1980;9:40510.
- Malone JM, Gershenson DM, Creasy RK, Kavanagh JJ, Silva EG, Stringer CA. Endodermal sinus tumor of the ovary associated with pregnancy. Obstet Gynecol 1986;68(Suppl):86S9S.
- Raffles A, Williams J, Costeloe K, Clark P. Transplacental effects of maternal cancer chemotherapy: case report. Br J Obstet Gynaecol 1989;96:10991100.
- Malfetano JH, Goldkrand JW. Cis-platinum combination chemotherapy during pregnancy for advanced epithelial ovarian carcinoma. Obstet Gynecol 1990;75:5457.
- King LA, Nevin PC, Williams PP, Carson LF. Treatment of advanced epithelial ovarian carcinoma in pregnancy with cisplatin-based chemotherapy. Gynecol Oncol 1991;41:7880.
- Buller RE, Darrow V, Manetta A, Porto M, DiSaia PJ. Conservative surgical management of dysgerminoma concomitant with pregnancy. Obstet Gynecol 1992;79:88790.
- Giacalone P-L, Laffargue F, Benos P, Rousseau O, Hedon B. Cis-platinum neoadjuvant chemotherapy in a pregnant woman with invasive carcinoma of the uterine cervix. Br J Obstet Gynaecol 1996;103:9324.
- Gershenson DM. Menstrual and reproductive function after treatment with combination chemotherapy for malignant ovarian germ cell tumors. J Clin Oncol 1988;6:2705.
- Bakri Y, Pedersen P, Nassar M. Normal pregnancy after curative multiagent chemotherapy for choriocarcinoma with brain metastases. Acta Obstet Gynecol Scand 1991;70:6113.
- Green DM, Zevon MA, Lowrie G, Seigelstein N, Hall B. Congenital anomalies in children of patients who received chemotherapy for cancer in childhood and adolescence. N Engl J Med 1991;325:1416.
- Bower, M, Fife K, Holden L, Paradinas FJ, Rustin GJS, Newlands ES. Chemotherapy for ovarian germ cell tumours. Eur J Cancer 1996;32A:5937.
- Rubery ED. Return of fertility after curative chemotherapy for disseminated teratoma of testis. Lancet 1983;1:186.
- Kinkead T, Flores C, Carboni AA, Menon M, Seethalakshmi L. Short term effects of cis-platinum on male reproduction, fertility and pregnancy outcome. J Urol 1992;147:2016.
- Egan PC, Costanza ME, Dodion P, Egorin MJ, Bachur NR. Doxorubicin and cisplatin excretion into human milk. Cancer Treat Rep 1985;69:13879.
- De Vries EGE, Van Der Zee AGJ, Uges DRA, Sleijfer DTH. Excretion of platinum into breast milk. Lancet 1989;1:497.
- Ben-Baruch G, Menczer J, Goshen R, Kaufman B, Gorodetsky R. Cisplatin excretion in human milk. J Natl Cancer Inst 1992;84:4512.
- Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:13750.