Risk Factor: CM
Class: Hormones/ Estrogens
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.
- Shepard TH. Catalog of Teratogenic Agents. 6th ed. Baltimore, MD:Johns Hopkins University Press, 1989:1589.
- 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.
- Dyson JL, Kohler HG, Anencephaly and ovulation stimulation. Lancet 1973;1:12567.
- Field B, Kerr C. Ovulation stimulation and defects of neural tube closure. Lancet 1974;2:1511.
- Sandler B. Anencephaly and ovulation stimulation. Lancet 1973;2:379.
- Biale Y, Leventhal H, Altaras M, Ben-Aderet N. Anencephaly and clomiphene-induced pregnancy. Acta Obstet Gynecol Scand 1978;57:4834.
- Asch RH, Greenblatt RB. Update on the safety and efficacy of clomiphene citrate as a therapeutic agent. J Reprod Med 1976;17:175180.
- Harlap S. Ovulation induction and congenital malformations. Lancet 1976;2:961.
- James WH, Clomiphene, anencephaly, and spina bifida. Lancet 1977;1:603.
- Ahlgren M, Kallen B, Rannevik G. Outcome of pregnancy after clomiphene therapy. Acta Obstet Gynecol Scand 1976;55:3715.
- Elwood JM. Clomiphene and anencephalic births. Lancet 1974;1:31.
- Czeizel A. Ovulation induction and neural tube defects. Lancet 1989;2:167.
- Cuckle H, Wald N. Ovulation induction and neural tube defects. Lancet 1989;2:1281.
- Cornel MC, Ten Kate LP, Graham Dukes MN, De Jong-V D Berg LTW, Meyboom RHB, Garbis H, Peters PWJ. Ovulation induction and neural tube defects. Lancet 1989;1:1386.
- Cornel MC, Ten Kate LP, Te Meerman GJ. Ovulation induction, in-vitro fertilisation, and neural tube defects. Lancet 1989;2:1530.
- Kurachi K, Aono T, Minagawa J, Miyake A. Congenital malformations of newborn infants after clomiphene-induced ovulation. Fertil Steril 1983;40:1879.
- Mills JL, Simpson JL, Rhoads GG, Graubard BI, Hoffman H, Conley MR, Lassman M, Cunningham G. Risk of neural tube defects in relation to maternal fertility and fertility drug use. Lancet 1990;336:1034.
- Rosa F. Ovulation induction and neural tube defects. Lancet 1990;336:1327.
- Mills JL. Clomiphene and neural-tube defects. Lancet 1991;337:853.
- Van Loon K, Besseghir K, Eshkol A. Neural tube defects after infertility treatment: a review. Fertil Steril 1992;58:87584.
- Shoham Z, Zosmer A, Insler V. Early miscarriage and fetal malformations after induction of ovulation (by clomiphene citrate and/or human menotropins), in vitro fertilization, and gamete intrafallopian transfer. Fertil Steril 1991;55:111.
- Werler MM, Louik C, Shapiro S, Mitchell AA. Ovulation induction and risk of neural tube defects. Lancet 1994;344:4456.
- Greenland S, Ackerman DL. Clomiphene citrate and neural tube defects: a pooled analysis of controlled epidemiologic studies and recommendations for future studies. Fertil Steril 1995;64:93641.
- Miles PA, Taylor HB, Hill WC. Hydatidiform mole in a clomiphene related pregnancy: a case report. Obstet Gynecol 1971;37:3589.
- Schneiderman CI, Waxman B. Clomid therapy and subsequent hydatidiform mole formation: a case report. Obstet Gynecol 1972;39:7878.
- Wajntraub G, Kamar R, Pardo Y. Hydatidiform mole after treatment with clomiphene. Fertil Steril 1974;25:9045.
- Berman P. Congenital abnormalities associated with maternal clomiphene ingestion. Lancet 1975;2:878.
- Drew AL. Letter to the editor. Dev Med Child Neurol 1974;16:276.
- Hack M, Brish M, Serr DM, Insler V, Salomy M, Lunenfeld B. Outcome of pregnancy after induced ovulation. Follow-up of pregnancies and children born after clomiphene therapy. JAMA 1972;220:132933.
- Ylikorkala O. Congenital anomalies and clomiphene. Lancet 1975;2:12623.
- Laing IA, Steer CR, Dudgeon J, Brown JK. Clomiphene and congenital retinopathy. Lancet 1981;2:11078.
- Ford WDA, Little KET. Fetal ovarian dysplasia possibly associated with clomiphene. Lancet 1981;2:1107.
- Kistner RW. Induction of ovulation with clomiphene citrate. Obstet Gynecol Surv 1965;20:87399.
- Goldfarb AF, Morales A, Rakoff AE, Protos P. Critical review of 160 clomiphene-related pregnancies. Obstet Gynecol 1968;31:3425.
- Oakely GP, Flynt IW. Increased prevalence of Down’s syndrome (mongolism) among the offspring of women treated with ovulation-inducing agents. Teratology 1972;5:264.
- Singhi M, Singhi S. Possible relationship between clomiphene and neural tube defects. J Pediatr 1978;93:152.
- 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.
- Haring DAJP, Cornel MC, Van Der Linden JC, Van Vugt JMG, Kwee ML. Acardius acephalus after induced ovulation: a case report. Teratology 1993;47:25762.
- Martinez-Roman S, Torres PJ, Puerto B. Acardius acephalus after ovulation induction by clomiphene. Teratology 1995;51:2312.
- 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.
- Melamed I, Bujanover Y, Hammer J, Spirer Z. Hepatoblastoma in an infant born to a mother after hormonal treatment for sterility. N Engl J Med 1982;307:820.
- Product information. Clomid. Hoechst Marion Roussel, 2000.