Danazol in Pregnancy and Breastfeeding

Risk Factor: XM
Class: Hormones / Androgen

Contents of this page:
Fetal Risk Summary
Breast Feeding Summary
Questions and Answers

Fetal Risk Summary

Danazol is a synthetic androgen derived from ethisterone that is used in the treatment of various conditions, such as endometriosis, fibrocystic breast disease, and hereditary angioedema. No fetal harm was observed in reproduction studies with pregnant rats at doses 7 to 15 times the human dose, but fetal development was inhibited in rabbits at doses 2 to 4 times the human dose (1).

Early studies with this agent had examined its potential as an oral contraceptive (2,3 and 4). This use was abandoned, however, because low doses (e.g., 50100 mg/day) were associated with pregnancy rates up to 10% and higher doses were unacceptable to the patient due to adverse effects (2,4).

In experimental animals, danazol crosses the placenta to the fetus, but human data are lacking. However, it is reasonable to assume that it does reach the human fetus. Because danazol is used to treat endometriosis, frequently in an infertile woman, a barrier (nonhormonal) contraception method is recommended to prevent accidental use during pregnancy.

A number of reports have described the inadvertent use of danazol during human gestation resulting in female pseudohermaphroditism (5,6,7,8,9,10,11,12,13 and 14). This teratogenic condition is characterized by a normal XX karyotype and internal female reproductive organs, but ambiguous external genitalia. No adverse effects in male fetuses have been associated with danazol.

The first published report of female pseudohermaphroditism appeared in 1981 (5). A woman was treated for endometriosis with a total danazol dose of 81 g divided over 101 days. Subsequent evaluation revealed that the treatment period corresponded to approximately the first 14 weeks of pregnancy. The female infant, whose length and weight were at the 5th percentile, had mild clitoral enlargement and a urogenital sinus evident at birth. Physical findings at 2 years of age were normal except for clitoromegaly, empty, darkened, rugated labia majora, and a complete urogenital sinus formation. Studies indicated the child had a normal vagina, cervix, fallopian tubes, and ovaries. The mother had no evidence of virilization.

A second case reported in 1981 involved a woman with endometriosis who was inadvertently treated with danazol, 800 mg/day, during the first 20 weeks of gestation (6). The mother went into premature labor at 27 weeks and delivered a female infant with a birth weight of 980 g. Ambiguous genitalia were evident at birth, consisting of marked clitoromegaly with fusion of the labia scrotal folds. A urogenital sinus, with well-developed vagina and uterus, was noted on genitogram. Bilateral inguinal hernias with palpable gonads were also present. At 4 days of age, clinical and laboratory findings compatible with a salt-losing congenital adrenal hyperplasia were observed. The infant was successfully treated for this complication, which was thought to be due to a transitory block of the steroid 21- and 11b-monooxygenases (6). At 1 year of age, the infant was asymptomatic, and no signs of progressive virilization were observed.

The authors of the above report cited knowledge of 27 other pregnancies in which danazol had been accidentally used (6). Seven of these pregnancies were terminated by abortion. Of the remaining 20 pregnancies, 14 delivered female infants and 5 (36%) of these had evidence of virilization with ambiguous genitalia.

A 1982 case report described female pseudohermaphroditism in an infant exposed to a total danazol dose of 96 g administered over 120 days, corresponding to approximately the first 16 weeks of gestation (7). The infant, weighing 3100 g (5th percentile) with a length of 53.5 cm (25th50th percentile), had fused labia with coarse rugations, mild clitoromegaly, and a urogenital sinus opening below the clitoris. An 8-cm mass, eventually shown to be a hydrometrocolpos, was surgically drained because of progressive obstructive uropathy. A balanced somatic chromosomal translocation was an incidental finding in this case, most likely inherited from the mother. Growth and development were normal at 6 months of age with no further masculinization.

Two brief 1982 communications described infants exposed in utero to danazol (8,9). In one, a 2400-g term female infant with ambiguous genitalia had been exposed to danazol (dose not specified) during the first 4 months of pregnancy (8). The infant's phallus measured 0.75 cm and complete posterior labial fusion was observed. The second case involved a woman treated with danazol, 200 mg/day, during the first 6 weeks of gestation, who eventually delivered a female infant with normal external genitalia (9). The absence of virilization of the infant's genitalia, as evidenced by a normal clitoris and no labial fusion, indicates the drug was stopped prior to the onset of fetal sensitivity to androgens.

British investigators reported virilization of the external genitalia consisting of clitoromegaly, a fused, scrotalized labia with a prominent median raphe, and a urogenital sinus in a female infant exposed in utero to danazol, 400 mg/day, during the first 18 weeks of pregnancy (10). The mother showed no signs of virilization.

A summary of known cases of danazol exposure during pregnancy was reported in 1984 by Rosa, an investigator from the Epidemiology Branch of the Food and Drug Administration (FDA) (11). A total of 44 cases of pregnancy exposure, all to 800 mg/day, were known as of this date, but this number was considered to be understated since normal outcomes were unlikely to be reported (11). Each of the cases of exposure was thought to have occurred after conception had taken place. Of the 44 cases, 7 (16%) aborted and the outcome in 14 others was unknown. Seven males and 15 females resulted from the 22 pregnancies that had been completed. Ten (67%) of the females had virilization and one male infant had multiple congenital abnormalities (details not given). No cases of virilization were observed when the drug was discontinued prior to the 8th gestational week, the onset of androgen receptor sensitivity (11).

An Australian case of an infant with masculinized external genitalia secondary to danazol was reported in 1985 (12). The mother had been treated with 400 mg/day, without evidence of virilization, until the 19th week of gestation. The infant was developing normally at 6 months of age except for a minimally enlarged clitoris, rugose and fused labia with a thick median raphe, and a urogenital sinus opening at the base of the phallus.

A 1985 case report described a female fetus exposed in utero to 800 mg/day of danazol until pregnancy was terminated at 20 weeks' gestation (13). A urogenital sinus was identified in the aborted fetus, but the external genitalia were normal except for a single opening in the vulva. Citing a personal communication from the manufacturer, the authors noted a total of 74 cases of danazol exposure during pregnancy (13). Among these cases were 29 term females, 9 (31%) of whom had clitoromegaly and labial fusion.

A retrospective review of fetal exposure to danazol included cases gathered from multiple sources, including individual case reports, data from the Australian Drug Reactions Advisory Committee, the FDA, and direct reports to the manufacturers (14). Of the 129 total pregnancies that were exposed to danazol, 23 were electively terminated and 12 miscarried. Among the 94 completed pregnancies there were 37 normal males, 34 nonvirilized females, and 23 virilized females. All of the virilized female offspring were exposed beyond 8 weeks' gestation. The lowest daily dose that resulted in virilization was 200 mg.

In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 10 newborns had been exposed to danazol during the 1st trimester (F. Rosa, personal communication, FDA, 1993). No major birth defects were observed.

There is no conclusive evidence of fetal harm when conception occurs in a menstrual cycle shortly after cessation of danazol therapy (15,16 and 17). A 1978 publication noted 4 intrauterine fetal deaths occurring from a total of 39 pregnancies following danazol treatment, presumably after elimination of the drug from the mother (18). The stillbirths, two each in the 2nd and 3rd trimesters, occurred in women who had conceived within 03 cycles of stopping danazol. However, one of the fetal deaths was due to cord torsion and a second death in a twin was due to placental insufficiency, neither of which can be attributed to danazol.

No long-term follow-up studies of children exposed in utero to danazol have been located. A 1982 Reference, however, did describe this type of evaluation in 12 young women, aged 1627 years, who had been exposed to in utero synthetic androgenic progestins resulting in the virilization of the external genitalia in 11 of them (19). Despite possible virilization of early behavior with characterization as tomboys (e.g., increased amounts of rough-and-tumble play and an avid interest in high school sports), all of the women eventually displayed stereotypically feminine sexual behavior without any suggestion of behavior abnormalities (19).

Breast Feeding Summary

No reports describing the use of danazol during lactation have been located. Because of the potential for severe adverse effects in a nursing infant, women taking this drug should not breast-feed.


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