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Meta-Analysis
. 2010 Jan 20;2010(1):CD000057.
doi: 10.1002/14651858.CD000057.pub2.

Clomiphene citrate for unexplained subfertility in women

Edward Hughes  1 , Julie Brown, John J Collins, Patrick Vanderkerchove
Affiliations
Meta-Analysis

Clomiphene citrate for unexplained subfertility in women

Edward Hughes et al. Cochrane Database Syst Rev. .

Abstract

Background: The effectiveness of clomiphene citrate has been demonstrated in the treatment of subfertility associated with infrequent or irregular ovulation. The physiologic effects and clinical benefits in ovulatory women with unexplained subfertility are less clear. The drug is associated with an increased risk of multiple pregnancy and a suggestion of potentially increased ovarian cancer risks. In light of these concerns, defining the effectiveness of clomiphene citrate for ovulatory women with unexplained subfertility is extremely important.

Objectives: To determine the effectiveness of clomiphene citrate in improving pregnancy outcomes in women with unexplained subfertility, used in a dose range of 50 to 250 mg for up to 10 days. The primary outcome was live births.

Search strategy: We searched the Cochrane Menstrual Disorders and Subfertility Group Specialised Register (June 2009), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2009, Issue 2), MEDLINE (1966 to June 2009), EMBASE (1980 to June 2009) and reference lists of articles.

Selection criteria: Only randomised controlled trials were included. Quasi-randomised designs were excluded.

Data collection and analysis: Fourteen potentially relevant trials were identified of which seven were included in this review. All trials were assessed for risk of bias using standardised Menstrual Disorders and Subfertility Group methodology.

Main results: Data relating to 1159 participants from seven trials were collated. There was no evidence that clomiphene citrate was more effective than no treatment or placebo for live birth (odds ratio (OR) 0.79, 95% CI 0.45 to 1.38; P = 0.41) or for clinical pregnancy per woman randomised both with intrauterine insemination (IUI) (OR 2.40, 95% CI 0.70 to 8.19; P = 0.16), without IUI (OR 1.03, 95% CI 0.64 to 1.66; P = 0.91) and without IUI but using human chorionic gonadotropin (hCG) (OR 1.66, 95% CI 0.56 to 4.80; P = 0.35). It should be noted that heterogeneity between studies ranged from 34% to 58% using the I(2) statistic.

Authors' conclusions: There is no evidence of clinical benefit of clomiphene citrate for unexplained fertility. When making this treatment choice, potential side effects should be discussed. These include the increased risk of multiple pregnancy and the concern that use for more that 12 cycles has been associated with a three-fold increase in risk of ovarian cancer.

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Conflict of interest statement

None known

Figures

1
1
Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.
2
2
Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
3
3
Forest plot of comparison: 1 Clomiphene versus placebo or no treatment in unexplained subfertility, outcome: 1.1 Live birth per woman randomised.
4
4
Forest plot of comparison: 1 Clomiphene versus placebo or no treatment in unexplained subfertility, outcome: 1.2 Pregnancy per woman randomised.
5
5
Forest plot of comparison: 1 Clomiphene versus placebo or no treatment in unexplained subfertility, outcome: 1.3 Miscarriage per woman randomised.
6
6
Forest plot of comparison: 1 Clomiphene versus placebo or no treatment in unexplained subfertility, outcome: 1.6 Adverse effects.
1.1
1.1. Analysis
Comparison 1 Clomiphene versus placebo or no treatment in unexplained subfertility, Outcome 1 Live birth per woman randomised.
1.2
1.2. Analysis
Comparison 1 Clomiphene versus placebo or no treatment in unexplained subfertility, Outcome 2 Pregnancy per woman randomised.
1.3
1.3. Analysis
Comparison 1 Clomiphene versus placebo or no treatment in unexplained subfertility, Outcome 3 Miscarriage per woman randomised.
1.4
1.4. Analysis
Comparison 1 Clomiphene versus placebo or no treatment in unexplained subfertility, Outcome 4 Multiple pregnancies.
1.5
1.5. Analysis
Comparison 1 Clomiphene versus placebo or no treatment in unexplained subfertility, Outcome 5 Ectopic pregnancy per woman randomised.
1.6
1.6. Analysis
Comparison 1 Clomiphene versus placebo or no treatment in unexplained subfertility, Outcome 6 Adverse effects.
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References

References to studies included in this review

Arici 1994 {published data only}
    1. Arici A, Byrd W, Bradshaw K, Kutteh W, Marshburn P, Carr B. Evaluation of clomiphene citrate and human chorionic gonadotropin treatment: a prospective, randomized, crossover study during intrauterine insemination cycles. Fertility and Sterility 1994;61:314‐8. - PubMed
Battacharya 2008 {published data only}
    1. Battacharya S, Harrild K, Mollison J, Wordsworth S, Tay C, Harrold A, et al. Clomifene citrate or unstimulated intrauterine insemination compared with expectant management for unexplained fertility: pragmatic randomised controlled trial. BMJ 2008;337:a716. [DOI: 10.1136/bmj.a716] - DOI - PMC - PubMed
Deaton 1990 {published data only}
    1. Deaton J, Gibson M, Blackmer K, Nakajima S, Badger G, Brumsted J. A randomized, controlled trial of clomiphene citrate and intrauterine insemination in couples with unexplained infertility or surgically corrected endometriosis. Fertility and Sterility 1990;54:1083‐8. - PubMed
Fisch 1989 {published data only}
    1. Fisch P, Casper R, Brown S, Wrixon W, Collins J, Reid R, Simpson C. Unexplained infertility: evaluation of treatment with clomiphene citrate and human chorionic gonadotropin. Fertility and Sterility 1989;51(5):828‐32. - PubMed
Glazener 1990 {published data only}
    1. Glazener CMA, Coulson C, Lambert PA, Watt E, Hinton RA, Kelly NG, Hull MGR. Clomiphene treatment for women with unexplained infertility: placebo‐controlled study of hormonal responses and conception rates. Gynecological Endocrinology 1990;4:75‐83. - PubMed
Harrison 1983 {published data only}
    1. Harrison RF, O'Moore R. The use of clomiphene citrate with and without human chorionic gonadotropin. Irish Medical Journal 1983;76(6):273‐4. - PubMed
Melis 1987 {published data only}
    1. Melis G, Paoletti A, Strigini F, Fabris F, Canale D, Fiorette P. Pharmacologic induction of multiple follicular development improves the success rate of artificial insemination with husband's semen in couples with male‐related or unexplained infertility. Fertility and Sterility 1987;47:441‐5. - PubMed

References to studies excluded from this review

Agarwal 2004 {published data only}
    1. Agarwal S, Mittal S. A randomised prospective trial of intrauterine insemination versus timed intercourse in superovulated cycles with clomiphene. The Indian Journal of Medical Research 2004;120(6):519‐22. [MEDLINE: ] - PubMed
Battacharya 2006 {published and unpublished data}
    1. Battacharya S, Harrild K, Harrold A, Lyall H, McQueen D, Tay C. A randomised trial of expectant management, clomiphene and intrauterine insemination (IUI) in the treatment of infertility. Fertility and Sterility 2006;86 Suppl 1(3):43.
Check 1992 {published data only}
    1. Check J, Davies E, Adelson H. A randomized prospective study comparing pregnancy rates following clomiphene citrate and human menopausal gonadotrophin therapy. Human Reproduction 1992;7:801‐5. - PubMed
Fujii 1997 {published data only}
    1. Fuji S, Fukui A, Fukushi Y, Kagiya A, Sato S, Saito Y. The effects of clomiphene citrate on normally ovulating women. Fertility and Sterility 1997;68(6):997‐9. - PubMed
Karlstrom 1993 {published data only}
    1. Karlstrom P, Bergh T, Lundkvist O. A prospective randomized trial of artificial insemination versus intercourse in cycles stimulated with human menopausal gonadotropin or clomiphene citrate. Fertility and Sterility 1993;59:554‐9. - PubMed
Martinez 1990 {published data only}
    1. Martinez AR, Bernardus RE, Voorhorst FJ, Vermeiden JPW, Schoemaker J. Intrauterine insemination does and clomiphene citrate does not improve fecundity in couples with infertility due to male or idiopathic factors: A prospective, randomized, controlled study. Fertility and Sterility 1990;53(5):847‐53. - PubMed
Parker 1992 {published data only}
    1. Parker JA, Kaplan BR, Nisker JA, Tummon IS, Powers SD, Yuzpe AA. Empiric administration of clomiphene citrate to women with normal ovulatory cycles in a therapeutic donor insemination program (abstract). Fertility and Sterility 1992:97.

Additional references

Collins 1991
    1. Collins JA, Milner RA. The effect of treatment on pregnancy among couples with unexplained infertility. International Journal of Fertility 1991;36(3):140‐52. - PubMed
Compendium 1998
    1. Canadian Pharmacists Association. Compendium of Pharmaceuticals and Specialties. Thirty‐third. Canada: Canadian Pharmacists Association, 1998:332‐3.
Hughes 1996
    1. Hughes E, Collins J, Vandekerckhove P. Clomiphene citrate vs placebo for ovulation induction in oligo‐amenorrhoeic women. Cochrane Database of Systematic Reviews 1996, Issue 2. - PMC - PubMed
Maxson 1984
    1. Maxson WS, Pittaway DE, Herbert CM, Garner CH, Wentz AC. Antiestrogenic effect of clomiphene citrate: correlation with serum estradiol concentrations. Fertility and Sterility 1984;42:356‐9. - PubMed
Peto 1987
    1. Peto R. Why do we need systematic overviews of randomized trials. Statistics in Medicine 1987;6:233‐40. - PubMed
Randall 1991
    1. Randall JM, Templeton AA. Transvaginal sonographic assessment of follicular and endometrial growth in spontaneous and clomiphene citrate cycles. Fertility and Sterility 1991;56:208‐12. - PubMed
Rossing 1994
    1. Rossing MA, Weiss NS. Ovarian tumours in a cohort of infertile women. New England Journal of Medicine 1994;331:771‐6. - PubMed
Whittemore 1992
    1. Whittemore AS, Harris R, Itnyre J. Characteristics relating to ovarian cancer risk: Collaborative analysis of 12 U.S. case controlled studies. American Journal of Epidemiology 1992;136:1184‐203. - PubMed