Fetal Risk Summary
Clomiphene is used to induce ovulation and is contraindicated after conception has occurred. Multiple pregnancies, most often twins, may be a complication of ovulation induction with clomiphene (1).
Shepard reviewed five animal reproduction studies involving the use of clomiphene in mice, rats, and monkeys (2). Hydramnios, cataracts, dose-related fetal mortality, and multiple abnormalities of the genital tract were observed in fetal mice and rats, but no congenital anomalies resulted after exposure of monkeys during the embryonic period. In mice, preovulatory administration of clomiphene produced a decrease in implantation rates, and growth retardation and an increased incidence of exencephaly in surviving fetuses (3). The decreased rate of implantation and growth retardation, which were most pronounced when the drug was given immediately before ovulation, apparently were caused by impairment of uterine function, rather than by a direct effect on the embryo itself (3).
Several case reports of neural tube defects have been reported after stimulating ovulation with clomiphene (4,5,6,7 and 8). However, an association between the drug and these defects has not been established (9,10,11,12,13,14,15,16 and 17). In one review, the percentage of congenital anomalies after clomiphene use was no greater than in the normal population (9). Similarly, another study involving 1,034 pregnancies after clomiphene-induced ovulation found no association with the incidence or type of malformation (18). Recent studies have also failed to find an association between ovulation induction with clomiphene and neural tube defects (19,20,21,22,23,24 and 25) or any defects (19,23). Congenital malformations reported in patients who received clomiphene before conception include the following (8,9,26,27,28,29,30,31,32,33,34,35,36,37,38,39 and 40): Hydatidiform mole Retinal aplasia Syndactyly Clubfoot Pigmentation defects Microcephaly Congenital heart defects Cleft lip/palate Down’s syndrome Ovarian dysplasia Hypospadias Polydactyly Hemangioma Anencephaly Persistent hyperplastic primary vitreous A 1996 prospective study examined the possible relationship between clomiphene and spontaneous abortions (41). The outcomes of 1,744 clomiphene-induced pregnancies were compared with the outcomes of 3,245 spontaneous pregnancies. The incidence of spontaneous abortion (clinical and preclinical) was higher in clomiphene-induced pregnancies compared to spontaneous pregnancies (23.7% vs 20.4%, p
Acardius acephalus in a monozygotic twin was observed in a pregnancy occurring after ovulation induced with clomiphene (42). Because monozygotic twining is associated with an increased incidence of congenital defects, and because clomiphene-induced ovulation increases the incidence of multiple gestation and possibly of monozygotic twins, the investigators thought that the drug may have had a causative role, either directly or indirectly, in the defect. Another case of acardius acephalus similar to the one above was published in 1995 (43). The authors also mentioned a third case that had been published in 1990 (44). However, they concluded that there was insufficient evidence to establish a relationship between clomiphene and acardiac twinning (43).
A single case of hepatoblastoma in a 15-month-old female was thought to be caused by the use of clomiphene and follicle-stimulating/luteinizing hormone prior to conception (45).
Inadvertent use of clomiphene early in the 1st trimester has been reported in two patients (32,38). A ruptured lumbosacral meningomyelocele was observed in one infant exposed during the 4th week of gestation (32). There was no evidence of neurologic defect in the lower limbs or of hydrocephalus. The second infant was delivered with esophageal atresia with fistula, congenital heart defects, hypospadias, and absent left kidney (38). The mother also took methyldopa throughout pregnancy for mild hypertension.
In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 41 newborns may have been exposed to clomiphene during the 1st trimester (F. Rosa, personal communication, FDA, 1993). Three (7.3%) (two expected) major birth defects were observed, one of which was a cardiovascular defect (0.5 expected). No anomalies were observed in five other categories of defects (oral clefts, spina bifida, polydactyly, limb reduction defects, and hypospadias) for which specific data were available. Although the number of exposures is small, these data do not support an association between the drug and congenital defects.
Patients requiring the use of clomiphene should be cautioned that each new course of the drug should be started only after pregnancy has been excluded.
Breast Feeding Summary
No reports describing the use of clomiphene during lactation have been located. The drug may reduce lactation in some patients (46).
- Product information. Serophene. Serono Laboratories, 1993.
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- Dziadek M. Preovulatory administration of clomiphene citrate to mice causes fetal growth retardation and neural tube defects (exencephaly) by an indirect maternal effect. Teratology 1993;47:26373.
- Barrett C, Hakim C. Anencephaly, ovulation stimulation, subfertility, and illegitimacy. Lancet 1973;2:9167.
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- Goldfarb AF, Morales A, Rakoff AE, Protos P. Critical review of 160 clomiphene-related pregnancies. Obstet Gynecol 1968;31:3425.
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- Mor-Joseph S, Anteby SO, Granat M, Brzezinsky A, Evron S. Recurrent molar pregnancies associated with clomiphene citrate and human gonadotropins. Am J Obstet Gynecol 1985;151:10856.
- Bishai R, Arbour L, Lyons C, Koren G. Intrauterine exposure to clomiphene and neonatal persistent hyperplastic primary vitreous. Teratology 1999;60:1435.
- Dickey RP, Taylor SN, Curole DN, Rye PH, Pyrzak R. Incidence of spontaneous abortion in clomiphene pregnancies. Hum Reprod 1996;11:26238.
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- Sceusa DK, Klein PE. Ultrasound diagnosis of an acardius acephalic monster in a quintuplet pregnancy. JDMS 1990;2:10912. As cited by Martinez-Roman S, Torres PJ, Puerto B. Acardius acephalus after ovulation induction by clomiphene. Teratology 1995;51:2312.
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- Product information. Clomid. Hoechst Marion Roussel, 2000.