21517 Mifepristone RU486

Pharmacology and toxicology

Mifepristone is a progesterone and glucocorticoid antagonist. It has been the subject of intense study and health policy discussion as an "abortion pill", and it has been approved as an abortifacient in several countries. A dose of 600 mg is required for the interruption of early pregnancy; however, in combination with a prostaglandin preparation (e.g. misoprostol) 200 mg is just as effective (Peyron 1995).

Among the pharmacologic effects of mifepristone are a lowering of luteinizing hormone (LH) secretion, more rapid corpus luteum regression, and an increased contractility of the uterine muscles. Effects on the placental production of progesterone, chorionic gonadotrophin (hCG), and lactogen (hPL) have also been observed (Das 1987).

As a result of its progesterone antagonism, mifepristone has also been tried as an "interceptlve" medication to be taken monthly. In contrast to a contraceptive, it is effective after conception. However, mifepristone is unreliable for interception and for medical treatment of ectopic pregnancy. Mifepristone administration for ripening of the cervix and labor induction, as well as for endometriosis and uterus myomatosis, is also a topic of discussion (Mazouni 2006, Sitruk-Ware 2006, Fedele 2004, Jiang 2001).

Mifepristone crosses the placenta but, according to animal experiments, does not influence the concentrations of fetal progesterone, estradiol or Cortisol. Only aldosterone concentration seems to increase.

Case reports have mainly cited normal babies born after treatment with mifepristone in early pregnancy (Pons 1991, Lim 1990), In a series of 71 pregnancies that continued after a failed attempt at early termination with mifepristone alone or in combination with a prostaglandin, 8 fetuses or infants with different anomalies were observed; among these were four with talipes equinovarus (Sitruk-Ware 1998). There is no controlled experience with which to predict the magnitude of developmental risk.

Recommendation. If a pregnancy is continued after the accidental use of mifepristone, a detailed ultrasound diagnosis can be used to assess fetal development.

2.15.18 Clomiphene

Pharmacology and toxicology

Clomiphene has been in use for many years for ovulation induction. Among the undesirable side effects are increased rates of twinning, and ovarian hyperstimulation. The mechanism of ovulation induction is based on competitive inhibition of the estrogen receptor in the pituitary and hypothalamus, which in turn leads to increased follicle stimulating hormone (FSH) secretion. Clomiphene has a half-life of about 5 days, although its metabolites have been found in feces up to 6 weeks after administration. That is why fetal exposure cannot be totally eliminated in mothers treated with this drug before pregnancy.

The suspicion that ovulation induction with clomiphene increases the risk of birth defects such as neural tube defects (NTD) continues (van Loon 1992). A large population-based study found no increased risk of NTD after fertility treatments, where clomiphcne citrate was the most commonly used drug (Whiteman 2000). One case report of iniencephaly, a rare type of NTD. has been described from a mother exposed to clomiphene for two consecutive cycles (Bhambhani 2004). Nevertheless, a cause-effect relationship can not be established.

Hypospadias has been also investigated in relation to clomiphene exposure. A population-based case-control study on a sample of 319 cases of hypospadias showed no increased risk of this defect in women exposed to clomiphene during the first trimester and 90 days before conception {Sorensen 2005). Nevertheless, a retrospective case-control study found a significantly increased risk for penoscrotal hypospadias (OR = 6.08; 95% CI 1.40-26.33), but not for the mild or moderate forms of this defect. The authors stress the importance of a detailed clinical definition in birth-defect studies (Meijer 2006). More studies arc necessary to confirm the relationship between clomiphene and hypospadias. Moreover, a relationship between craniosynostosis and fertility treatments (specifically clomiphene citratc) has been described (OR - 3.8; 95% CI 1.1-12.3) in a small study covering 20 pregnant women; this also needs to be confirmed in further studies (Reefhuis 2003). One case report, referring to ocular effects in women, described a child with persistent hyperplastic primary vitreous whose mother took 100 mg clomiphene up to approximately week 6 of pregnancy (Bishai 1999).

If there are any teratogenic effects at all, they arc slight. In Japan, 1034 pregnancies following clomiphene-induced ovulation were observed over 5 years. Of the 935 live-bom children, 2.3% had identifiable birth defects. This was not significantly different from a control group (30 000 births with a 1.7% birth-defect rate) (Kurachi 1983). Cases collected by one manufacturer indicated 58 birth defects (2.4%) among 2379 clomiphene patients. In 158 women, clomiphene was also taken after conception. In this group, 8 chil dren (5.1%) had birth defects.

Recommendation. Clomiphene may be prescribed to induce ovulation in patients who have been informed about the still not fully dismissed suspicion of organ-developmental disorders, and who accept the significantly increased incidence of multiple pregnancies. It is also important to note that a woman who is going to undergo fertility treatment should be informed about the possibility of an increased risk of congenital disorders because of her inherent fertility problem. Before starting treatment with clomiphene, any already existing pregnancy should be excluded.

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