Fetal Risk Summary
Tamoxifen, a triphenylethylene derivative that is structurally related to clomiphene, is a nonsteroidal, antiestrogen agent used in the treatment of breast cancer (1,2). In addition to its antiestrogen properties, it may also produce weak estrogenic and estrogenic-like activity at some sites. Unlabeled uses have included induction of ovulation and treatment of idiopathic oligospermia. Tamoxifen is thought to act by competing with estrogen for binding sites in target tissues (2). The parent drug has an elimination half-life of about 57 days (range 321 days) (1,2), whereas the elimination half-life of the major metabolite, N-desmethyltamoxifen, is approximately 914 days (1). Following prolonged treatment (e.g., 2 to 3 months), clearance of tamoxifen and its metabolites from the system may require 68 weeks (3).
Tamoxifen is carcinogenic, producing ovarian and testicular tumors in immature and mature mice and hepatocellular carcinoma in rats, at all doses tested (5, 20, and 35 mg/kg/day for up to 2 years) (2). The drug is also genotoxic in rat liver cells and in the human lymphoblastoid cell line. Tamoxifen, at a dose of 0.04 mg/kg/day (approximately 1/10th the human dose on a mg/kg basis) for 2 weeks before conception through day 7 of pregnancy, impaired the fertility of female rats causing a decreased number of implantations and 100% fetal mortality (2).
In reproductive studies reported by the manufacturer, no teratogenicity was observed with rats, rabbits, and marmosets, but fetal toxicity was common (2). In rats, however, reversible, nonteratogenic developmental skeletal changes were observed at doses equal to or below the human dose (2). An increased fetal death rate occurred in pregnant rats when tamoxifen, 0.16 mg/kg/day (human dose about 0.40.8 mg/kg/day), was administered from days 7 to 17 (2). When this dose was given from day 17 of pregnancy to 1 day before weaning, an increased number of dead pups were noted and some of the surviving pups demonstrated slower learning behavior. Moreover, in utero growth retardation was evident in some of the pups (2). Tamoxifen, 0.125 mg/kg/day administered to pregnant rabbits during days 6 through 18 of pregnancy, caused abortions and premature delivery (2). Higher doses produced fetal deaths. Abortions were observed in pregnant marmosets given 10 mg/kg/day either during organogenesis or in the last half of pregnancy (2).
A 1976 study administered oral tamoxifen, 2 mg/kg/day, to rabbits starting either at day 10 or day 20 of pregnancy (4). A significant increase in embryonic loss occurred in the first group, whereas treatment later in gestation resulted in premature delivery or abortion.
Several studies have described the effectiveness of tamoxifen as a postcoital contraceptive in animals (5,6,7,8,9,10 and 11). The action of tamoxifen as an antifertility agent appears to be a dose-related, antiestrogen effect that prevents implantation in the uterus. In one report, however, a single, 5-mg/kg dose on day 4 after ovulation in macaques had no effect on fertility (12). No reports describing the use of tamoxifen as a contraceptive in humans have been located.
In rats and guinea pigs, tamoxifen produced significant, dose-related changes in the reproductive tract of the fetus and newborn (13,14,15,16 and 17). These changes, most pronounced in the guinea pig, involved trophic effects on the uterus and vagina similar to those produced by estrogens. Abnormalities in sexual differentiation of female offspring of guinea pigs have also been observed (18).
In a study published in 1987, the estrogenicity and potential teratogenicity of tamoxifen were demonstrated in genital tracts isolated from aborted 4- to 19-week-old human female fetuses grown for 12 months in mice (19). Some mice were used as controls, and others were treated with tamoxifen, clomiphene, or diethylstilbestrol (DES). In comparison with controls, abnormalities observed in the drug-treated mice included proliferation and maturation of the squamous vaginal epithelium, a decrease in the number of endometrial and cervical glands, impaired condensation and segregation of the uterine mesenchyme, and hyperplastic, disorganized epithelium and distorted mucosal plications in the fallopian tube. The abnormalities induced by tamoxifen and clomiphene were, in most instances, comparable to those of DES (19). A study published in 1979 examined the effects of tamoxifen administration on newborn female rats (5 g on days 1, 3, and 5), observing several abnormalities of reproductive development, including early vaginal opening, absence of cycles, atrophic ovaries and uteri, vaginal adenosis, and severe squamous metaplasia of the oviducts (20). Gonad and genitourinary tract abnormalities, including uterine hypoplasia and vaginal adenosis, were also observed in newborn female mice given tamoxifen for 5 days (21). A 1997 report compared the uterotrophic effects of tamoxifen (100 g), DES (1 g), or placebo administered SC daily to newborn female rat pups for 5 days (22). At postnatal day 6, both tamoxifen and DES produced significant epithelial hypertrophy and myometrial thickening, as well as other uterine changes, that led the investigators to conclude that tamoxifen’s estrogenic action on the developing uterus was similar to that produced by DES (22).
The clinical significance of the above studies demonstrating developmental changes in animals, three of which involved neonatal exposure to tamoxifen, is presently unknown, but some of the alterations observed in experiments, especially vaginal adenosis, are similar to those observed in young women following in utero exposure to DES (2). Moreover, too few women have been exposed in utero to tamoxifen and followed long enough (up to 20 years), to determine whether the drug presents a risk of clear-cell adenocarcinoma of the vagina or cervix similar to DES (about 1 in 1000) (2) (see also Diethylstilbestrol). It should also be noted that long-term exposure of nonpregnant, adult humans to tamoxifen has been associated with an increased incidence of endometrial cancer (2).
Data pertaining to human fetal exposure to tamoxifen are limited. A 1993 letter cited a statement made by tamoxifen researchers that 85 women had become pregnant while receiving the drug and that no fetal abnormalities had been reported (23). A 1994 letter, however, citing data (oral and written) reported to the manufacturer, described the outcomes of 50 pregnancies associated with tamoxifen therapy (24). Of the total, there were 19 normal births, 8 elective abortions, 10 with a fetal or neonatal disorder (2 of which were congenital craniofacial defects), and 13 unknown outcomes. Although the number of adverse outcomes is suggestive of human teratogenicity, no mention was made whether the above cases represented prospective or retrospective reporting. The latter type frequently involves biased reporting in that adverse outcomes are much more likely to be communicated. Also included in this letter was the description of a case in which a 35-year-old woman, following breast cancer surgery, took tamoxifen, 20 mg/day, throughout an approximately 27-week pregnancy (24). Because of premature labor, chorioamnionitis, and an abnormal lie, a cesarean section was performed to deliver an 896-g, karyotypically normal infant (sex not specified). Malformations noted in the infant, consistent with a diagnosis of Goldenhar’s syndrome, included right-sided microtia, preauricular skin tags, and hemifacial microsomia (24). Other exposures, in addition to tamoxifen, were cocaine and marijuana smoking (1 or 2 times/week) during the first 6 weeks of gestation and a bone scan performed using technetium-99m medronate. The causal relationship between tamoxifen and the defects in the infant was unknown (24), but in some reports of familial cases, the patterns of inheritance of Goldenhar’s syndrome (oculoauriculovertebral anomaly) have been described as consistent with an autosomal dominant, autosomal recessive, and multifactorial inheritance (25).
Ambiguous genitalia in a female newborn exposed in utero to tamoxifen during the first 20 weeks of pregnancy was reported in 1997 (26). The 35-year-old mother had been treated with tamoxifen, 20 mg daily, for about 1 year for metastatic breast cancer. Because of the mother’s deteriorating condition, the normal 46,XX karyotype, 1360-g infant was delivered at 29 weeks’ gestation. Reproductive malformations included an enlarged, phallic-like clitoris (1.4 0.6 cm), a single perineal opening for the urethra and vagina, and fusion of the posterior portion of the rugated labioscrotal folds without palpable glands. An ultrasound examination revealed a normal uterus and ovaries without identifiable male structures. Congenital adrenal hyperplasia was excluded and a serum testosterone level was normal for a female infant. At 6 months of age, a reduction phalloplasty and vaginal reconstruction were performed without complications (26).
Two reports have described three successful pregnancies following chemotherapy with tamoxifen (27,28). In one of two cases described in a 1986 Reference, a 26-year-old woman with a pituitary microadenoma and primary infertility was successfully treated with tamoxifen 20 mg/day and bromocriptine 10 mg/day (27). Combination therapy was used because she could not tolerate high-dose bromocriptine monotherapy. She ovulated and conceived approximately 7.5 months after combination therapy was begun. Tamoxifen was discontinued when pregnancy was confirmed (exact timing not specified), but bromocriptine was continued until 8 weeks’ gestation. She delivered a normal, 3240-g female infant at term. In the second case, a 25-year-old woman with a pituitary macroadenoma and primary infertility was treated for about 3 months with the same combination therapy as in the first case, again because of intolerance to monotherapy (27). Combination therapy was stopped when pregnancy was confirmed (exact timing not specified) and she delivered a normal, 2600-g female infant at 37 weeks’ gestation. The third pregnancy involved a 31-year-old woman with a diagnosis of well-differentiated adenocarcinoma of the endometrium who elected to receive 6 months of hormonal therapy with tamoxifen 30 mg/day and megestrol acetate 160 mg/day, combined with repeated hysteroscopy and uterine curettage, rather than undergo a hysterectomy (28). She was then placed on combination oral contraceptives for 3 months and conceived 1 month after they were discontinued. She eventually delivered a normal, 3340-g male infant at term.
A number of studies have examined the efficacy of tamoxifen, often in direct comparison with clomiphene, for ovulation induction in infertile women (29,30,31,32,33,34 and 35). Although no fetal anomalies were reported in these pregnancies following tamoxifen induction, a higher than expected occurrence of spontaneous abortion was noted in two studies (29,33). In contrast to clomiphene, however, tamoxifen induction did not appear to increase the frequency of multiple gestations (34).
In males, tamoxifen, like clomiphene, has been used for the treatment of idiopathic oligospermia (36,37,38,39,40 and 41). Tamoxifen appears to improve sperm density and the number of live spermatozoa, but conflicting results have been reported concerning the effect on sperm motility or morphology (37,40,41). A 1987 review, moreover, concluded that there was no convincing evidence that tamoxifen was effective in increasing the conception rate (41).
In summary, tamoxifen is an antiestrogen that has weak estrogenic activity in some tissues. Although tamoxifen is not considered an animal teratogen, it is carcinogenic in rodents and has been associated with intrauterine growth retardation, abortions, and premature delivery in some species. Uterine cancer has been reported in human adults treated with tamoxifen. Moreover, tamoxifen has produced toxic changes in the reproductive tracts of animals. Some of these changes were similar to those observed in humans exposed in utero to DES, but the risk of tamoxifen-induced clear cell adenocarcinoma of the vagina or cervix in exposed offspring is unknown because too few humans have been exposed during pregnancy or followed up long enough. Two adverse outcomes following inadvertent exposure to tamoxifen during gestation have been described. The relationship between tamoxifen and Goldenhar’s syndrome in the first case is unknown, but, in the second case, a causal association between the drug and the ambiguous genitalia noted in the female infant appears to be more certain. In addition, a number of fetal and neonatal disorders and defects have been reported to the manufacturer, but it is not known whether this is the result of retrospective reporting. Because of the various toxicities noted in animals, the increased incidence of abortions noted in some patients when the drug was used for ovulation induction, and the possible human teratogenicity, the best course is to avoid use of tamoxifen during pregnancy. Moreover, because both the parent compound and the major metabolite have prolonged half-lives that may require up to 8 weeks to eliminate, women of child-bearing age should be informed that a pregnancy occurring within 2 months of tamoxifen therapy may expose the embryo and/or fetus to the drug. If an inadvertent pregnancy does occur, the potential fetal and newborn risks must be discussed with the patient. Offspring who have been exposed to tamoxifen during pregnancy require long-term (up to 20 years) follow-up to access the risk of carcinogenicity.
Breast Feeding Summary
Tamoxifen has been shown to inhibit lactation (42,43). In a double-blind, placebo-controlled trial, tamoxifen started within 2 hours after delivery was effective in preventing milk secretion and breast engorgement (42). Two treatment courses were studied: 30 mg twice daily 2 days, then 20 mg twice daily 2 days, then 10 mg twice daily 2 days (N=50); and 10 mg twice daily 14 days (N=42). Two groups of control patients (N=25 and N=23) received similar placebo tablets. The 6-day treatment course was superior (statistical analysis was not done) to the 14-day treatment course with 43 (86%) vs. 31 (74%) of the women having a good response (i.e., either no milk in their breasts or only slight to moderate milk secretion) (42). Only 6 (13%) of the control patients had a good response. No adverse effects or rebound engorgement were observed in the women who had received tamoxifen.
In a second, placebo-controlled, single-blinded study, tamoxifen (N=60, 10 mg 4 times daily) or placebo (N=20) was started within 24 hours of delivery and continued for 5 days (43). Breast stimulation using a mechanical breast pump was used before the first dose, and then on days 3 and 5, followed by blood sampling for serum prolactin. By the 5th day, a significant decrease (compared with baseline) in serum prolactin concentration occurred in the tamoxifen group, but not in controls. Moreover, tamoxifen was effective in inhibiting lactation and preventing breast engorgement, and no rebound lactation was observed (43).
Because tamoxifen inhibits lactation and because of the adverse effects noted in newborn animals and human adults (see Fetal Risk Summary above) given the drug directly, the drug should be considered contraindicated during nursing.
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