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Clomiphene citrate for unexplained subfertility in women

  • Review
  • Intervention




The effectiveness of clomiphene citrate is demonstrated in the treatment of subfertility associated with oligo-ovulation. Clomiphene citrate acts as a central estrogen receptor blocker, which results in increased production and secretion of follicle stimulating hormone (FSH). The physiologic effects and clinical benefits in ovulatory women with unexplained subfertility are less clear. The drug is associated with the side effect of 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.


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

Search strategy

We searched the Cochrane Menstrual Disorders and Subfertility Group Specialised Register of trials (searched October 31, 2006), the Cochrane Central Register of Controlled Trials (The Cochrane Library 2006, Issue 3), MEDLINE (1966 to October 2006), EMBASE (1980 to October 2006) and reference lists of articles.

Selection criteria

Randomised controlled trials were included. Quasi-randomised, cross-over designs where data before cross over could not be obtained and cohort studies were excluded.

Data collection and analysis

Thirteen potentially relevant trials were identified of which five were included in this review. All trials were assessed for quality in terms of method of randomisation, completeness of follow up, presence or absence of cross over and co-intervention, and allocation concealment.

Main results

There was no evidence that clomiphene citrate was more effective than no treatment or placebo. The odds ratios for clinical pregnancy per patient was 2.40 with a 95% confidence interval (CI) (CI 0.70 to 8.19;P=0.16) for clomiphene citrate with IUI; 0.99 (CI 0.61 to 1.60; P=0.96) without intrauterine insemination (IUI) and 1.66 (CI 0.56 to 4.80; P=0.35) without IUI and using human chorionic gonadotropin (hCG). It should be noted that the heterogeneity between studies ranged from 33.5% to 57.6% using the I2 statistic.

Authors' conclusions

There does not appear to be any clinical benefit to the use of clomiphene citrate for unexplained fertility although the lack of homogeneity among the studies should be noted. When making this treatment choice, potential side effects should be discussed. These include the increased risk of multiple pregnancy, minor symptoms and the concern that use for more that 12 cycles has been associated with an increased risk of ovarian cancer. Given the extensive use of clomiphene citrate in ovulatory women and recent concerns associated with its long-term use, a definitive trial with adequate power is warranted to establish effectiveness in women with unexplained subfertility.

Plain language summary

Clomiphene citrate for unexplained subfertility in women

Clomiphene citrate is a fertility drug that can increase the number of eggs released for possible fertilisation. It is used by women who do not ovulate regularly and by some who do but still have not become pregnant. Clomiphene citrate does not appear to increase the chance of pregnancy in women who ovulate regularly but have failed to conceive after more than a year of unprotected intercourse. The main risk associated with clomiphene citrate is a 10% chance of multiple pregnancy. The review of trials found that clomiphene does not increase chances of pregnancy in women who ovulate regularly however the results should be taken with caution due to the heterogeneity between the studies.