Researchers have found that higher cumulative doses of clomiphene citrate, one of the world's most widely prescribed fertility drugs, significantly increase the risk of pregnancy loss without improving the likelihood of a successful pregnancy. The findings raise important questions about how fertility specialists should dose this medication, which has been used by millions of women since 1967.

What Did the Study Find About Clomiphene Citrate and Pregnancy Loss?

Scientists at Adelaide University, working with Boston University and the US Centers for Disease Control and Prevention, analyzed data from 21,004 IVF embryo transfer cycles in the United States. The research examined how cumulative doses of clomiphene citrate, a drug that stimulates the ovaries to release eggs, affected pregnancy outcomes.

The results showed a clear dose-response relationship. Women who received cumulative doses of 500 to 749 milligrams had a 12% higher risk of miscarriage compared to those on lower doses. Women receiving 750 to 999 milligrams experienced a 38% higher risk of miscarriage. Additionally, women receiving cumulative doses of 750 milligrams or more were more than twice as likely to have twins or other multiple births, which carries its own set of health risks for both mother and baby.

"Women who received higher cumulative doses of clomiphene citrate experienced progressively greater risks of adverse pregnancy outcomes," said Associate Professor Sheree Boulet, lead author of the study. "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."

Associate Professor Sheree Boulet, Adelaide University

Perhaps most concerning, the higher doses did not improve the chance of achieving a live birth, meaning women were accepting greater risks without gaining better odds of success.

Why Does This Matter for Fertility Treatment?

Clomiphene citrate has been a cornerstone of fertility treatment for decades. It is recommended as a first-line treatment for ovulation induction, meaning it is typically the first medication doctors try when women have difficulty releasing eggs naturally. Women who do not respond to lower doses or who require multiple treatment cycles may receive progressively higher cumulative doses over time, which is where the safety concerns emerge.

The research builds on more than two decades of work from Adelaide University's Robinson Research Institute linking clomiphene citrate to 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.

"Clomiphene citrate has been used by many women since 1967, but it has never been comprehensively evaluated in large prospective clinical trials," noted Professor Michael Davies, senior researcher and co-author of all studies. "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."

Professor Michael Davies, Adelaide University

How Should Doctors Approach Clomiphene Citrate Dosing?

The findings suggest that fertility specialists need to carefully balance the potential benefits of higher doses against the documented risks. The research indicates there may be a threshold beyond which increasing the dose offers little additional benefit while exposing women to greater harm.

• Follow manufacturer guidelines: Clinicians should rigorously adhere to manufacturers' safety recommendations and avoid unnecessarily increasing cumulative doses without clear clinical justification.
• Monitor individual response: Women respond differently to clomiphene citrate, so personalized treatment plans that account for individual variation are important rather than automatically escalating doses.
• Evaluate alternatives carefully: Any move away from clomiphene citrate to newer ovulation-inducing medications should be guided by robust evidence rather than assumptions about safety.

Professor Davies emphasized that the same safety questions now being asked of clomiphene citrate should also be applied to newer fertility medications. This suggests a broader need for comprehensive evaluation of how fertility drugs are dosed and monitored across the industry.

The study, published in the journal BMJ Open and supported by the National Health and Medical Research Council, represents one of the largest examinations of clomiphene citrate safety in real-world fertility treatment. For women considering fertility treatment or those already undergoing multiple cycles, these findings underscore the importance of discussing dosing strategies with their fertility specialists and understanding the potential risks associated with cumulative drug exposure.