Mifepristone in Pregnancy and Breastfeeding
Fetal Risk Summary
Mifepristone (RU 38486; RU 486) is an orally active, synthetic antiprogestogen that has been primarily used for the termination of pregnancy. At higher doses, the drug also has antiglucocorticoid effects. The mechanism of action of mifepristone, which exerts its antiprogestogen effect at the level of the receptor, and the physiologic effects it produces in both animals and humans have been studied and reviewed in a number of References (1,2,3,4,5,6,7,8,9,10,11,12,13,14,15 and 16). A 1993 review summarized the drug's antiprogestin and other pharmacologic effects in humans (17).
Mifepristone rapidly crosses the placenta to the fetus in both monkeys (18) and humans (19,20). The fetal:maternal ratio decreased from 0.31 to 0.18 in monkeys between the 2nd and 3rd trimesters (18). In 13 women undergoing 2nd-trimester abortions, a single 100-mg oral dose produced fetal cord blood concentrations of mifepristone ranging from 20 ng/mL (30 minutes) to 400 ng/mL (18 hours) (19). The peak maternal concentration (1500 ng/mL) was attained in 12 hours, and the average fetal:maternal ratio was approximately 0.33. In contrast to a simple diffusion process observed in monkeys (18), an active transport mechanism was suggested because the fetal concentration increased exponentially (19). In the second human study, a lower mean fetal:maternal ratio (0.11) was measured at 17.2 8.6 hours in six women treated with 600 mg of mifepristone for 2nd-trimester abortion (20). Maternal plasma concentrations of aldosterone, progesterone, estradiol, or cortisol did not change significantly 4 hours after mifepristone, but a significant increase in fetal aldosterone occurred at this time, rising from 999 pmol/L to 1699 pmol/L. Mean changes in the fetal levels of the other three steroids were not significant.
A large number of studies have investigated the use of mifepristone as an abortive agent, either when given alone (21,22,23,24,25,26,27,28,29,30,31,32,33,34,35 and 36), or when combined with a prostaglandin analogue (24,30,37,38,39,40,41,42,43,44,45,46,47,48,49,50 and 51). The drug has also been studied for labor induction after 2nd trimester intrauterine death (52,53), as a cervical ripening agent in the 1st trimester (54,55,56,57,58 and 59), in the 2nd trimester (60), and at term (61,62 and 63). Although mifepristone, especially when combined with a prostaglandin analogue, is an effective abortive agent, it has not been effective when used for the termination of ectopic pregnancies (64,65). The use of mifepristone as a postcoital contraceptive or for routine administration during the mid to late luteal phase to prevent a potential early pregnancy by induction of menses (i.e., contragestation) has also been frequently investigated (22,66,67,68,69,70,71,72,73,74,75,76,77,78 and 79).
Mifepristone is teratogenic in rabbits, and the effect is both dose and duration dependent (80). Abnormalities observed included growth retardation, nonfused eyelids and large fontanelle, opened cranial vault with exposure of the meninges and hemorrhagic or necrotic nervous tissue, necrotic destruction of the upper part of the head and brain, and absence of closure of the vertebral canal (80). At doses approximating those used in clinical practice, no evidence of teratogenicity was observed in postimplantation rat embryos exposed to mifepristone in culture (81). Similarly, no teratogenicity was observed after in vitro exposure of monkey embryos to mifepristone (82,83).
In humans, only six cases have been reported of exposure to mifepristone that was not followed by subsequent abortion. Although specific details were not provided, in the United Kingdom Multicenter Trial (gestational age <3669 days from last menstrual period), one woman changed her mind after taking mifepristone and her pregnancy continued until a normal infant was delivered at term (41). In 1989, brief mention was made of fetal malformations discovered after pregnancy termination at 18 weeks' gestation (84). Additional information on this and one other case was published in 1991 (85,86 and 87). A 25-year-old primigravida was treated with 600 mg of mifepristone at 5 weeks' gestation, but then decided not to proceed with termination (85,86). Severe malformations were observed by ultrasound examination at 17 weeks' gestation, consisting of an absence of amniotic sac, stomach, gallbladder, and urinary tract, and the pregnancy was stopped with prostaglandin at 18 weeks (85). The 190-g fetus had typical features of the sirenomelia sequence (sympodia; caudal regression syndrome): fused lower limbs with a single flexed foot containing seven toes, no external genitalia or anal or urethral openings, and absence of internal reproductive organs, lower urinary tract, and kidneys. Other anomalies were hypoplastic lungs, a cleft palate, and a cleft lip. Sirenomelia is thought to date back to the primitive streak stage during the 3rd week of gestation, and, thus, in this case, before exposure to mifepristone (85). However, induction of cleft palate and cleft lip occurs at approximately 36 days of gestation (85) and may have been a consequence of drug exposure.
A normal outcome was achieved in the second case in which a 30-year-old woman was treated with 400 mg of mifepristone 6 weeks after her last menstrual period, but then decided to continue her pregnancy (85). She eventually delivered a healthy, 3030-g male baby at 41 weeks' gestation. Three other normal infants have been described after in utero exposure to mifepristone (59,88). All three were participants in clinical trials who decided to continue their pregnancies after treatment with mifepristone at 8, 8, and 9 weeks' gestation (88). The latter patient vomited 1.5 hours after taking the drug and reported seeing at least one partially digested tablet in the vomit. Delivery occurred at 40 weeks (4150-g male), 39 weeks (3930-g male), and 41 weeks (3585 g-female), respectively. Follow-ups of the infants at 15, 9, and 6 months, respectively, were completely normal.
In summary, mifepristone (RU 486) is a potent antiprogestogen compound that is mainly used for the termination of pregnancy, usually in combination with a prostaglandin agent. It has also been used for cervical ripening before abortion and is currently being studied as an aid in the induction of labor at term. It is teratogenic in one animal species, but not in two others, one of which is a primate species. Data are too limited to determine whether the drug is a human teratogen. Because the incidence of successful abortion after mifepristone is high, but not total, women should be informed of the risk for embryotoxicity if their pregnancy continues after use of this drug.
Breast Feeding Summary
No data have been located on the excretion of mifepristone in breast milk. Since the drug is well absorbed after oral administration, it should not be used during breast feeding because of its potent antihormonal effects. However, as a result of the limited indications for this agent, the opportunities for its use during lactation should be infrequent.
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