Higher doses of common fertility drug may increase pregnancy risks

Higher cumulative doses of common fertility drug clomiphene citrate may increase pregnancy loss risks, according to new research.

Around one in six people experience infertility, with irregular or absent ovulation among the most common causes.

Clomiphene citrate has long been a mainstay of fertility treatment, but Adelaide University research has raised concerns about higher cumulative doses.

The new study found that high doses of clomiphene citrate accumulated over multiple fertility treatment cycles could increase the risk of pregnancy loss.

Lead author associate professor Sheree Boulet said the findings showed a clear dose-response relationship, meaning the risks increased as cumulative exposure rose.

She said: “Women who received higher cumulative doses of clomiphene citrate experienced progressively greater risks of adverse pregnancy outcomes.

“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.”

Supported by the NHMRC and conducted in partnership with Boston University and the Centers for Disease Control and Prevention, researchers analysed 21,004 IVF embryo transfer cycles in the US.

Women receiving cumulative doses of 500mg to 749mg of clomiphene citrate had a 12 per cent higher risk of miscarriage, while those receiving 750mg to 999mg had a 38 per cent higher risk.

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

Rates of spontaneous abortion, another term for miscarriage, increased as the dose rose.

Researchers also recorded more than a threefold increase in stillbirth at the highest dose, although the finding was not statistically significant because that dose was rare. Larger studies are needed to confirm the association.

The finding is consistent with an earlier Adelaide University study that showed a doubling of neonatal death in pregnancies involving clomiphene citrate. Neonatal death means the death of a baby shortly after birth.

Higher cumulative doses did not improve the chance of a live birth, but did increase twinning, which raises 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.

The drug is recognised as an essential medicine by the World Health Organization. It works by stimulating the ovaries to release eggs, 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.

The findings build on a series of studies from Adelaide University’s Robinson Research Institute linking 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.

Professor Michael Davies, senior researcher and co-author of all the studies, said the latest work builds on more than two decades of Adelaide-led research into the safety of fertility treatments.

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

“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 personalised 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.”