Higher cumulative doses of the widely used fertility drug clomiphene citrate may increase the risk of miscarriage and multiple pregnancies without improving the chances of a live birth, according to new research involving more than 21,000 IVF embryo transfer cycles in the United States.
The study, led by researchers from the University of Adelaide in partnership with Boston University and the US Centers for Disease Control and Prevention, found a dose-related increase in adverse pregnancy outcomes among women receiving higher cumulative doses of clomiphene citrate across multiple treatment cycles.
Researchers analysed 21,004 IVF embryo transfer cycles and found that women who received cumulative doses of 500 to 749 mg had a 12 per cent higher risk of miscarriage. Those who received 750 to 999 mg had a 38 per cent higher risk compared with women receiving lower doses.
Women whose cumulative dose reached 750 mg or more were also more than twice as likely to have twins or other multiple births. Multiple pregnancies are associated with higher risks for both mothers and babies, including premature birth and other complications.
The findings were published in BMJ Open and were supported by Australia’s National Health and Medical Research Council.
Clomiphene citrate has been prescribed since 1967 and remains one of the world’s most commonly used fertility medicines. It is recommended as a first line treatment for women with irregular or absent ovulation, a common cause of infertility.
The researchers found that while miscarriage rates increased as cumulative dose increased, higher doses did not improve the likelihood of a live birth.
Lead author Associate Professor Sheree Boulet said the results suggested there may be a limit to the benefits of increasing the dose.
“Our findings suggest there may be a point where increasing the dose offers little additional benefit while exposing women to greater risk, highlighting the importance of carefully balancing effectiveness with safety when making treatment decisions,” she said.
The study also observed a higher rate of stillbirth among women receiving the highest cumulative doses, although the researchers said this result was not statistically significant because relatively few women fell into that category. They said larger studies would be needed to determine whether the association is genuine.
The research builds on earlier studies from the University of Adelaide’s Robinson Research Institute that reported links between clomiphene citrate and pregnancy loss, stillbirth, perinatal death and some birth defects. Experimental studies in mice have produced findings consistent with those observed in humans, including reduced pregnancy success and impaired fetal development at higher doses.
Senior researcher Professor Michael Davies said women appear to respond differently to clomiphene citrate, raising questions about whether treatment could be tailored more effectively.
“Our studies indicate that women respond differently to clomiphene citrate and that increasing cumulative doses may increase the risk of adverse pregnancy outcomes without improving the likelihood of a live birth,” he said.
He said clinicians should continue to follow manufacturer safety recommendations and avoid unnecessarily increasing cumulative doses until more evidence becomes available.
The researchers also noted that similar questions are now being examined for newer ovulation inducing medications, and they cautioned that decisions about alternative treatments should be based on evidence rather than assumptions about safety.
The study does not suggest that clomiphene citrate should no longer be used, but it adds to the evidence that the amount taken over multiple treatment cycles may matter. For patients undergoing fertility treatment, the findings may encourage discussions with their specialist about how treatment is monitored and when dose increases are warranted.
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