Higher Clomiphene Doses Linked to Adverse IVF Outcomes

HIGHER cumulative doses of clomiphene citrate during in vitro fertilisation (IVF) may be associated with an increased risk of adverse perinatal outcomes, new research suggests. 

The US national cohort study found evidence of a dose-dependent relationship between clomiphene citrate exposure and several adverse outcomes, including spontaneous abortion and multiple birth, raising questions about the potential effects of repeated or higher-dose treatment during IVF. 

Investigating Clomiphene Dose in IVF 

Clomiphene citrate is widely used to induce ovulation and may be incorporated into IVF stimulation protocols to reduce the need for hormonal injections and to lower treatment costs. However, the relationship between cumulative exposure and reproductive outcomes remains poorly understood. 

Researchers analysed data from the US National Assisted Reproductive Technology Surveillance System, examining fresh autologous IVF cycles performed between 2004 and 2021. 

The final analysis included 21,004 embryo transfer cycles involving clomiphene citrate. Participants were grouped according to cumulative dose: less than 500  mg, 500-749  mg, 750-999 mg, and 1,000 mg or more. 

Most cycles (67.8%) involved doses of 500-749 mg, while 21.3% involved less than 500mg. Researchers also observed that the mean total clomiphene dose increased over the study period, from 510.5 mg in 2004 to 621.8 mg in 2021. 

Higher Doses Associated with Pregnancy Loss 

Rates of spontaneous abortion increased from 10.3% amongst those receiving less than 500 mg to 11.8% recieiving 500-749 mg, and 14.4% receiving 750-999 mg. 

After adjusting for factors including age, parity, previous assisted reproductive technology cycles, infertility diagnosis, race and ethnicity, and BMI, the 500-749 mg group had a 12% greater risk of spontaneous abortion compared with the lowest-dose group. Risk was 38% higher amongst those receiving 750-999 mg. 

Similar associations were observed when researchers restricted the analysis to singleton pregnancies. 

Stillbirth rates also increased across the dose categories, reaching 0.7% amongst those receiving at least 1,000 mg compared with 0.2% in the lowest-dose group. The adjusted risk was more than three times higher, however, the researchers stressed that the estimate was imprecise due to the small number of stillbirths and was not statistically significant. 

Multiple birth risk was also significantly higher across all three higher-dose categories compared with doses below 500 mg, supporting evidence of a dose-response relationship. 

Findings May Support Closer Monitoring 

No significant adjusted association was observed between clomiphene dose and clinical pregnancy or live birth rates. This suggests that higher cumulative doses may not necessarily improve the likelihood of a successful live birth despite their associations with some adverse outcomes. 

The researchers, however, noted several limitations of the study. Clomiphene was used in only a small proportion of all fresh autologous IVF cycles, and information on factors including ovarian reserve, endometrial thickness, other medications, and embryo stage at transfer was unavailable. Some outcomes, particularly stillbirth, were also rare, resulting in uncertain estimates. 

As an observational study, the findings cannot demonstrate that higher clomiphene doses directly cause adverse pregnancy outcomes. Nevertheless, the combination of increasing cumulative doses over time and observed dose-dependent associations suggests that continued monitoring of clomiphene use during IVF may be warranted. 

The authors conclude that further research is needed to clarify the potential effects of cumulative clomiphene exposure and identify dosing approaches that balance effective ovarian stimulation with maternal and perinatal safety. 

Reference 

Boulet S et al. Dose-dependent perinatal risks of clomiphene citrate in US IVF cycles: a national cohort study, 2004–2021. BMJ Open. 2026;16. 

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