Higher clomiphene doses may raise IVF pregnancy risks

Clinical takeaway: When using clomiphene citrate for fertility treatment, avoid unnecessary dose escalation and follow recommended dosing limits. Higher cumulative exposure may increase miscarriage and multiple-birth risks without improving the likelihood of live birth.

Clomiphene citrate has been used for decades to induce ovulation and remains one of the most widely prescribed fertility drugs. But repeated or escalating doses may reach a point where additional exposure adds risk without improving the chance of a live birth, according to a large US cohort study.

Researchers analyzed 21,004 fresh autologous IVF embryo transfer cycles involving clomiphene from 2004 through 2021. Compared with cumulative doses below 500 mg, miscarriage risk was 12% higher with 500–749 mg and 38% higher with 750–999 mg after adjustment. Miscarriage rates were 10.3%, 11.8%, and 14.4%, respectively.

Multiple births also became progressively more common as exposure increased. Among live births, the rate rose from 13.2% with less than 500 mg to 17.7% with 500–749 mg, 21.3% with 750–999 mg, and 27.2% with at least 1000 mg. The adjusted risk was nearly twice as high at the highest dose.

Despite the increasing exposure, higher cumulative doses did not significantly improve live-birth rates after adjustment. Stillbirth was more than three times as common at doses of at least 1000 mg compared with less than 500 mg, but the difference was not statistically significant because stillbirths were rare.

The observational findings do not establish that clomiphene caused these outcomes, and the analysis was limited to fresh IVF cycles with available dose information. Still, the combination of increasing risk and no clear live-birth benefit supports avoiding unnecessary escalation and investigating more individualized dosing strategies.

“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,” said lead author Sheree Boulet, DrPH, MPH.

Source: Boulet S, et al. (2026 Aug 7) BMJ Open. Dose-dependent perinatal risks of clomiphene citrate in US IVF cycles: a national cohort study, 2004–2021