Clomiphene

 Risk Factor: CM
 Class: HORMONES / Estrogens

Contents of this page:

Fetal Risk Summary
Breast Feeding Summary
References
Questions and Answers

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<0.01).

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).

References

1. Product information. Serophene. Serono Laboratories, 1993.
2. Shepard TH. Catalog of Teratogenic Agents. 6th ed. Baltimore, MD:Johns Hopkins University Press, 1989:1589.
3. 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.
4. Barrett C, Hakim C. Anencephaly, ovulation stimulation, subfertility, and illegitimacy. Lancet 1973;2:9167.
5. Dyson JL, Kohler HG, Anencephaly and ovulation stimulation. Lancet 1973;1:12567.
6. Field B, Kerr C. Ovulation stimulation and defects of neural tube closure. Lancet 1974;2:1511.
7. Sandler B. Anencephaly and ovulation stimulation. Lancet 1973;2:379.
8. Biale Y, Leventhal H, Altaras M, Ben-Aderet N. Anencephaly and clomiphene-induced pregnancy. Acta Obstet Gynecol Scand 1978;57:4834.
9. Asch RH, Greenblatt RB. Update on the safety and efficacy of clomiphene citrate as a therapeutic agent. J Reprod Med 1976;17:175180.
10. Harlap S. Ovulation induction and congenital malformations. Lancet 1976;2:961.
11. James WH, Clomiphene, anencephaly, and spina bifida. Lancet 1977;1:603.
12. Ahlgren M, Kallen B, Rannevik G. Outcome of pregnancy after clomiphene therapy. Acta Obstet Gynecol Scand 1976;55:3715.
13. Elwood JM. Clomiphene and anencephalic births. Lancet 1974;1:31.
14. Czeizel A. Ovulation induction and neural tube defects. Lancet 1989;2:167.
15. Cuckle H, Wald N. Ovulation induction and neural tube defects. Lancet 1989;2:1281.
16. 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.
17. Cornel MC, Ten Kate LP, Te Meerman GJ. Ovulation induction, in-vitro fertilisation, and neural tube defects. Lancet 1989;2:1530.
18. Kurachi K, Aono T, Minagawa J, Miyake A. Congenital malformations of newborn infants after clomiphene-induced ovulation. Fertil Steril 1983;40:1879.
19. 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.
20. Rosa F. Ovulation induction and neural tube defects. Lancet 1990;336:1327.
21. Mills JL. Clomiphene and neural-tube defects. Lancet 1991;337:853.
22. Van Loon K, Besseghir K, Eshkol A. Neural tube defects after infertility treatment: a review. Fertil Steril 1992;58:87584.
23. 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.
24. Werler MM, Louik C, Shapiro S, Mitchell AA. Ovulation induction and risk of neural tube defects. Lancet 1994;344:4456.
25. 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.
26. Miles PA, Taylor HB, Hill WC. Hydatidiform mole in a clomiphene related pregnancy: a case report. Obstet Gynecol 1971;37:3589.
27. Schneiderman CI, Waxman B. Clomid therapy and subsequent hydatidiform mole formation: a case report. Obstet Gynecol 1972;39:7878.
28. Wajntraub G, Kamar R, Pardo Y. Hydatidiform mole after treatment with clomiphene. Fertil Steril 1974;25:9045.
29. Berman P. Congenital abnormalities associated with maternal clomiphene ingestion. Lancet 1975;2:878.
30. Drew AL. Letter to the editor. Dev Med Child Neurol 1974;16:276.
31. 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.
32. Ylikorkala O. Congenital anomalies and clomiphene. Lancet 1975;2:12623.
33. Laing IA, Steer CR, Dudgeon J, Brown JK. Clomiphene and congenital retinopathy. Lancet 1981;2:11078.
34. Ford WDA, Little KET. Fetal ovarian dysplasia possibly associated with clomiphene. Lancet 1981;2:1107.
35. Kistner RW. Induction of ovulation with clomiphene citrate. Obstet Gynecol Surv 1965;20:87399.
36. Goldfarb AF, Morales A, Rakoff AE, Protos P. Critical review of 160 clomiphene-related pregnancies. Obstet Gynecol 1968;31:3425.
37. 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.
38. Singhi M, Singhi S. Possible relationship between clomiphene and neural tube defects. J Pediatr 1978;93:152.
39. 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.
40. Bishai R, Arbour L, Lyons C, Koren G. Intrauterine exposure to clomiphene and neonatal persistent hyperplastic primary vitreous. Teratology 1999;60:1435.
41. Dickey RP, Taylor SN, Curole DN, Rye PH, Pyrzak R. Incidence of spontaneous abortion in clomiphene pregnancies. Hum Reprod 1996;11:26238.
42. 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.
43. Martinez-Roman S, Torres PJ, Puerto B. Acardius acephalus after ovulation induction by clomiphene. Teratology 1995;51:2312.
44. 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.
45. 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.
46. Product information. Clomid. Hoechst Marion Roussel, 2000.
    
    

Questions and Answers

How long after taking Clomiphene should i get pregnant?

I have been taking it for 2month now ( for a week after each period). I have been trying to get pregnant for 1 year now. Has anyone every taken Clomiphene and it worked and how long should it take to work.

Success Rates with Clomiphene
Of the women who have a withdrawal bleed following to Provera, 70 to 90 percent will ovulate in response to clomiphene citrate; and 40 to 60 percent will conceive within six to twelve cycles. Taking clomiphene will not make you super-fertile. The conception rate approaches that of normal couples: approximately 20 percent per month for women in their twenties. When clomiphene therapy fails, other fertility factors should be examined more closely.

GOD BLESS,
Mieko M

Can I be pregnant after one dose of Clomiphene?

I had a period in November 07, my doctor then instructed me to take three (3) Clomiphene per day on the third day of my period, which I did for 5 days and no period. Now it's January and I am feeling pain in my lower abdomen and spotted pink discharge for two (2) days. Could I be pregnant?

You very well could be but im not the one to say yes or no. you need to get a pregnancy test to know for sure.

How long is it safe to use Clomiphene to become pregnant? does it work?

I want to try to take this, and i want to know how safe it is. Would it make my body screwy. I hate chemicals and I don't take birthcontrol, but i want to get pregant and am older so I need some help maybe.

I used Clomid 100mg and I am now 11wks pg with TWINS. My doctor feels there is a higher risk of misc. and it stays in your system for 6mths after. He doesn't like it, he prefers femara. I got it from the internet.
Good Luck

i'm trying to conceive using clomiphene and i have pregnancy symptoms. AM i pregnant?

i am taking clomiphene in hopes of becoming pregnant this month. i still have a week before my expected period but i have ovulation like cramping and some nausea. i took a pregnancy test but it was negative. is it possible that i still might be pregnant?

Could be you caught it too early so yes, you still may be pregnant. Give it another week and test again.

CLOMIPHENE 50mg and sex what is the best way to have sex to fall pregnant??

Today is the 6 th day of my period and i forgot to take my first clomiphene tablet yesterday the 5th day of my period and i took the first one today.
Would it be ok if i take the second that i was meant to have yesterday?? and have it today as well as todays tablet ??
well it still work?? and not hurt me in any way??

no clue about the question about clomiphene but the best way to have sex is in a position that will help the sperm travel towards your uterus. ie: you on top is probably not the best position...where as missionary with a pillow beneath your hips to tilt your pelvis upward is a great one. I hope this is what you were looking for??

will taking clomiphene help you get pregnant if you ovulate normally?

The truth is if you already ovulate then Clomid CAN be useful in some cases. Doctors will prescribe Clomid to improve your ovulation. They prescribe it on days 3-7 to help you produce more eggs (quantity) or days 5-9 to help you produce better eggs (quality).

So yes, Clomid can help if you already ovulate.

Good luck.

Has anyone used Clomid (clomiphene citrate) to get pregnant?

Just wondering if anyone has used Clomid (clomiphene citrate)
to help with ovulation, and how did it work?

Have used clomid for 4cycles and have ovulated every cycle but still I could not acheive pregnancy,have taken a break this month n will start over again frm next cycle.I must tell u that clomid really helps one to ovulate,its a great med to depend on.All the best if u r on clomid and lots of babydust to u............

i am taking clomiphene citrate 50 gm tablets for getting pregnant..?

i am taking clomiphene citrate 50gm tablets its my 4th day tht i am taking these tablets..can some one tell me that in normal circumstances a women will know that she pregnant or not after 3 weeks or so ..wht about if a women taking these tabs ...is this posible that the indications of getting pregnant came more earlier ?i mean in a week or so.? or the same like after 2 or 3 weeks?

I was taking 100mg, and had no clue that I was preggers til I took the test. I was 7 days late for my period. When I took it. I had been ttc for a very long time and late periods were sometimes the norm for me. So it did come as a complete surprise that it actually worked for me.

if no cervical mucus releases means no ovulation.im on clomiphene trying to get pregnant but still not.?

im having pcos. doc has suggested clomiphene and an injection.today is my day 14.and still no discharge. plz tell me that can a women get pregnant without having this cervical mucus. without its discharge eggs can release to pregnant a women.

I guess for my own curiosity, how do you know you are not experiencing cervical mucus? Alot of times women actually do have the discharge, but it is either very thin that they think it is just urine when they go to the bathroom or they are expecting it to be different than it actually is.

Here is an excerpt from a great site with information on cervical mucus that I will list in the sources:
What is cervical mucus?
There are many different types of vaginal discharge, one of which is cervical mucus. The type of mucus your body produces provides clues to your fertility. You can check your cervical mucus using either your fingers or toilet paper. On days when you're not fertile, the mucus from your cervix is either light or sticky (about the same texture as sticky rice). During the few days leading up to ovulation, when you're most fertile, you'll have more discharge — clear and slippery with the consistency of raw egg white. You are most fertile on the last day you notice cervical mucus of this kind. It usually happens either the day before, or the day of, ovulation. The change in volume and texture of your cervical mucus is due to the increase in estrogen levels that accompanies ovulation.