Risk Factor: C
Class: Keratolytic agents
Fetal Risk Summary
Podophyllum is the dried rhizomes and roots of Podophyllum peltatum (American mandrake, May apple) (1). Podophyllum resin is the dried mixture of resins extracted from podophyllum (1). Podophyllotoxin (podofilox), the major active compound in podophyllum resin, and podophyllum are keratolytic agents whose caustic action is thought to be caused by the arrest of mitosis in metaphase. In addition to its antimitotic effect, podophyllum also has cathartic action, but should not be used for this purpose because of the potential for severe drug-induced toxicity (2).
Three reproductive studies in rats and mice with podophyllum or podophyllotoxin found no teratogenic effects, but resorptions occurred when the agents were used early in gestation (3,4 and 5). A 1952 study observed no teratogenic changes in mice, rats, and rabbits with podophyllotoxin (6). Two other studies involving podophyllum reported embryotoxicity, but not teratogenicity, in mice (7) and only minor skeletal changes in rats (8). Another agent derived from P. peltatum that is present in podophyllum resin, peltatin (a and b forms), was not teratogenic in mice (9).
The first report of human teratogenicity related to podophyllum appeared in 1962 (10). A 24-year-old woman took herbal slimming tablets, containing podophyllum and other extracts, from the 5th to 9th weeks of gestation, a total of 3.5 weeks. The estimated daily dose of podophyllum was 180 mg. The term, female infant had multiple anomalies, including an absent right thumb and radius, a supernumerary left thumb, a probable septal defect of the heart, a defect of the right external ear, and skin tags. The malformations were attributed to the antimitotic action of podophyllum (10).
In contrast to the above outcome, a woman at 26 weeks’ gestation was treated with multiple applications of 20% podophyllum resin in compound benzoin tincture for condylomata acuminata (genital human papillomavirus infection) that covered the entire vulva, the minor and major labia, and a portion of the vagina (11). In addition, the woman was accidentally given 5 mL of the preparation orally, a potentially fatal dose. Toxic symptoms in the mother included persistent, severe coughing, nausea and vomiting, and hypotension, all of which had resolved within 72 hours. Three months later, the mother delivered a normal, 3560-g, male infant who was doing well.
A 1972 report described severe peripheral neuropathy and intrauterine fetal death in a woman at either 32 or 34 weeks’ (both dates were used) gestation following the administration of 7.5 mL (1.88 g of podophyllum) of 25% podophyllum resin to florid vulval warts that were friable and bled easily (12). General anesthesia (nitrous oxide and oxygen) was used during application of podophyllum. Fetal heart sounds were lost 2 days after the application of podophyllum, and 10 days later a stillborn female infant was delivered. The woman’s symptoms and death of her fetus were attributed to podophyllum poisoning, apparently from systemic absorption of the drug. She eventually recovered and within a year or two she had an uneventful pregnancy and normal infant.
Minor congenital malformations consisting of a simian crease on the left hand and a preauricular skin tag were observed in a newborn whose mother had been treated with five applications of 25% podophyllum resin between the 23rd and 29th weeks of pregnancy for condyloma acuminata (13). Although the authors attributed the skin tag to the drug, podophyllum was not related to either anomaly because of the late timing of exposure (14).
The Collaborative Perinatal Project recorded 14 1st trimester exposures to podophyllum (presumably oral) among 50 mothers who had used a group of miscellaneous gastrointestinal drugs (15). From this group, 1 (2%) infant with an unspecified congenital malformation was observed (standardized relative risk 0.27). It was not stated whether podophyllum was taken by the mother of the affected infant.
In summary, although it is uncertain whether podophyllum is a human teratogen, products containing this drug should not be used during pregnancy for the treatment of genital warts (human papillomavirus infections) because of the potential severe myelotoxicity and neurotoxicity in the mother. Although one author believes the topical application of podophyllum resin is safe during pregnancy (16), most other sources consider it a dangerous agent to use during this period, especially because of the availability of alternative, safer treatments. The American College of Obstetricians and Gynecologists (17) and other reviews (18) and Reference sources (1) all state that the drug is contraindicated during pregnancy. The contraindication to the use of podophyllum agents includes the use of podophyllotoxin (i.e., podofilox) during pregnancy and on the vagina or cervix at any time (17).
Breast Feeding Summary
No data are available.
- American Hospital Formulary Service. Drug Information 1997. Bethesda, MD: American Society of Health-System Pharmacists, 1997:27545.
- Rosenstein G, Rosenstein H, Freeman M, Weston N. Podophylluma dangerous laxative. Pediatrics 1976;57:41921.
- Wiesner BP, Yudkin J. Control of fertility by antimitotic agents. Nature (London) 1955;176:24950. As cited in Shepard TH. Catalog of Teratogenic Agents. 7th ed. Baltimore, MD: Johns Hopkins University Press, 1992:322.
- Thiersch JB. Effects of podophyllin (P) and podophyllotoxin (PT) on the rat litter in utero. Proc Soc Exp Biol Med 1963;113:1247. As cited in Shepard TH. Catalog of Teratogenic Agents. 7th ed. Baltimore, MD: Johns Hopkins University Press, 1992:322.
- Chaube S, Murphy ML. The teratogenic effects of the recent drugs active in cancer chemotherapy. In Woollam DHM, ed. Advances in Teratology. New York, NY: Logos and Academic Press, 1968;3:181237. As cited in Shepard TH. Catalog of Teratogenic Agents. 7th ed. Baltimore, MD: Johns Hopkins University Press, 1992:322.
- Didcock KA, Picard CW, Robson JM. The action of podophyllotoxin on pregnancy. J Physiol (London) 1952;117:65P6P. As cited in Schardein JL. Chemically Induced Birth Defects. 2nd ed. New York, NY: Marcel Dekker, 1993:491.
- Joneja MG, LeLiever WC. Effects of vinblastine and podophyllin on DBA mouse fetuses. Toxicol Appl Pharmacol 1974;27:40814. As cited in Schardein JL. Chemically Induced Birth Defects. 2nd ed. New York, NY: Marcel Dekker, 1993:446.
- Dwornik JJ, Moore KL. Congenital anomalies produced in the rat by podophyllin. Anat Rec 1967;157:237. As cited in Schardein JL. Chemically Induced Birth Defects. 2nd ed. New York, NY: Marcel Dekker, 1993:446.
- Wiesner BP, Wolfe M, Yudkin J. The effects of some antimitotic compounds on pregnancy in the mouse. Stud Fertil 1958;9:12936. As cited in Schardein JL. Chemically Induced Birth Defects. 2nd ed. New York, NY: Marcel Dekker, 1993:805.
- Cullis JE. Congenital deformities and herbal slimming tablets. Lancet 1962;2:5112.
- Balucani M, Zellers DD. Podophyllum resin poisoning with complete recovery. JAMA 1964;189:63940.
- Chamberlain MJ, Reynolds AL, Yeoman WB. Toxic effect of podophyllum application in pregnancy. Br Med J 1972;3:3912.
- Karol MD, Conner CS, Watanabe AS, Murphrey KJ. Podophyllum: suspected teratogenicity from topical application. Clin Toxicol 1980;16:2836.
- Fraser FC. Letter to the editor. Mod Med Canada 1981;36:1508.
- Heinonen OP, Slone D, Shapiro S. Birth Defects and Drugs in Pregnancy. Littleton, MA: Publishing Sciences Group, 1977:385.
- Bargman H. Is podophyllin a safe drug to use and can it be used during pregnancy? Arch Dermatol 1988;124:171820.
- American College of Obstetricians and Gynecologists. Genital human papillomavirus infections. Technical Bulletin, No. 193, June 1994.
- Patsner B, Baker DA, Orr JW Jr. Human papillomavirus genital tract infections during pregnancy. Clin Obstet Gynecol 1990;33:25867.