Around one in six people experience infertility, with irregular or absent ovulation among the most common causes. The drug clomiphene citrate has long been a mainstay of fertility treatment, but a growing body of Adelaide University research is raising safety concerns about higher cumulative doses.

In a newly published study, researchers found that high doses of clomiphene citrate – accumulated over multiple fertility treatment cycles – could increase the risk of pregnancy loss.

Supported by the NHMRC and conducted in partnership with Boston University and the Centers for Disease Control and Prevention, the study analyzed 21,004 IVF embryo transfer cycles in the United States, finding that women receiving cumulative doses of 500-749 mg clomiphene citrate had a 12% higher risk of miscarriage; while women who received 750-999 mg had a 38% higher risk of miscarriage.

Women receiving cumulative doses of 750 mg or more were also more than twice as likely to have twins or other multiple births.

Spontaneous abortion rates increased as dose increased, but the researchers caution that the greater than tripling of stillbirth at the highest dose was not statistically significant as the dose was rare, and larger studies are needed to confirm the association. The observation is, however, consistent with a previous publication from Adelaide University showing a doubling of neonatal death in pregnancies involving clomiphene citrate.

Importantly for the new study, higher cumulative doses of the drug did not improve the chance of a live birth, but did increase twinning, which increases the risk of adverse outcomes for both mother and child.

Clomiphene citrate is one of the world’s most widely prescribed fertility drugs. It has been prescribed to millions of women worldwide since 1967 and remains a recommended first-line treatment for ovulation induction.

Recognized as an essential medicine by the World Health Organization, clomiphene citrate works by stimulating the ovaries to release eggs, thereby increasing the chance of pregnancy.

Women who do not respond to lower doses, or who require multiple treatment cycles, may receive progressively higher cumulative doses over time.

Lead author Associate Professor Sheree Boulet said the findings demonstrated a clear dose-response relationship.

Women who received higher cumulative doses of clomiphene citrate experienced progressively greater risks of adverse pregnancy outcomes.”

Sheree Boulet, Lead Author and Associate Professor, Adelaide University 

“We examined more than 21,000 embryo transfer cycles across four cumulative dose categories and found that increasing the dose did not significantly improve the chance of a live birth.

“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.”

The findings build on a series of studies from Adelaide University’s Robinson Research Institute that linked clomiphene citrate with increased risks of pregnancy loss, stillbirth, perinatal death and some birth defects.

Experimental studies in mice supported these findings, showing that higher doses reduced successful pregnancies and were associated with pregnancy loss, impaired fetal growth and developmental abnormalities.

Senior researcher and co-author of all studies, Professor Michael Davies, said the study builds on more than two decades of Adelaide-led research examining the safety of fertility treatments.

“Clomiphene citrate has been used by many women since 1967, but it has never been comprehensively evaluated in large prospective clinical trials,” Prof Davies said.

“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.

“The findings confirm and extend our previous studies in both human and mouse models which highlight the need to better understand the dose-response relationship and whether more personalized dosing strategies could improve safety.

“Until we can better understand these differences, it remains important that clinicians rigorously follow manufacturer’s safety recommendations and avoid unnecessarily increasing cumulative doses.

“The same questions are now being asked of newer ovulation-inducing medications, so any move away from clomiphene citrate should also be guided by robust evidence rather than assumptions about safety.”