A widely used fertility drug may carry a hidden tradeoff: as treatment adds up, the risks may rise without improving the odds of a live birth.
Researchers found that women exposed to higher cumulative doses of clomiphene citrate had progressively greater risks of miscarriage and multiple births, yet no corresponding improvement in the chance of having a live birth. The findings suggest that beyond a certain level of exposure, additional treatment may offer little benefit while adding unnecessary risk.
Clomiphene citrate has been used to stimulate ovulation since 1967. It remains one of the world’s best-known fertility medications and is recognized as an essential medicine by the World Health Organization. Infertility itself is extremely common, affecting about one in six people of reproductive age at some point in their lives.
The drug is intended for women who do not ovulate normally. By altering estrogen signaling, clomiphene triggers hormonal changes that encourage ovarian follicles to develop and eventually release an egg.
For many patients, relatively modest doses are enough. Others may not initially respond, leading to additional cycles or larger doses and therefore greater total exposure over time.
That cumulative exposure is the focus of a new study led by researchers associated with Adelaide University.
Higher Doses, Higher Miscarriage Risk
Supported by the NHMRC and conducted in collaboration with Boston University and the Centers for Disease Control and Prevention, the researchers analyzed 21,004 IVF embryo transfer cycles in the United States.
Women who had received a cumulative 500 to 749 mg of clomiphene citrate had a 12% higher risk of miscarriage. At cumulative doses of 750 to 999 mg, the risk was 38% higher.
The pattern extended beyond miscarriage. Women exposed to at least 750 mg were more than twice as likely to have twins or another multiple birth.
The aim of fertility treatment is not simply to achieve pregnancy. Specialists increasingly emphasize achieving one healthy birth at a time, since multiple pregnancies carry substantially greater health risks for mothers and babies. The American Society for Reproductive Medicine recommends strategies that specifically limit multiple gestation during infertility treatment.
When More Treatment Stops Helping
The new results suggest that increasing exposure to clomiphene may reach a point of diminishing returns. Higher cumulative doses did not significantly raise the likelihood of a live birth, even as some adverse outcomes became more common.
Lead author Associate Professor Sheree Boulet said the study revealed a clear relationship between increasing exposure and risk.
“Women who received higher cumulative doses of clomiphene citrate experienced progressively greater risks of adverse pregnancy outcomes,” Assoc. Prof. Boulet said.
“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.”
Pregnancy Loss and Stillbirth Concerns
The researchers also saw spontaneous abortion become more common as the cumulative dose increased.
At the highest exposure level, stillbirth was more than three times as common. However, the researchers cautioned against drawing firm conclusions from that result because so few women received doses in this category that the finding was not statistically significant. Larger studies will be needed to determine whether the apparent association reflects a true increase in risk.
The observation fits a broader pattern emerging from Adelaide University research. An earlier study reported a doubling of neonatal death among pregnancies involving clomiphene citrate.
The latest findings are also part of a longer research program at Adelaide University’s Robinson Research Institute examining possible links between the drug and pregnancy loss, stillbirth, perinatal death, and certain birth defects.
What Clomiphene Dosing Guidelines Say
Animal research has pointed in a similar direction. In experiments in mice, higher clomiphene doses were associated with fewer successful pregnancies, greater pregnancy loss, poorer fetal growth, and developmental abnormalities.
Clomiphene treatment is already intended to be limited rather than continued indefinitely.
Current U.S. prescribing information recommends beginning with 50 mg a day for five days and increasing the dose only when ovulation does not occur. It also states that increasing treatment beyond 100 mg a day for five days is not recommended and that long-term cyclic treatment should generally not extend beyond about six cycles.
The label also notes that once a woman ovulates at a given dose, increasing that dose in later cycles offers no advantage.
The Case for More Personalized Fertility Treatment
Those recommendations make the new results especially relevant to situations in which treatment accumulates across repeated attempts.
Senior researcher Professor Michael Davies, a co-author of the studies, said the work extends more than two decades of Adelaide-led research into fertility treatment safety.
“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.”
Reference: “Dose-dependent perinatal risks of clomiphene citrate in US IVF cycles: a national cohort study, 2004–2021” by Sheree Boulet, Yujia Zhang, Dmitry Kissin and Michael Davies, 1 August 2026, BMJ Open.
DOI: 10.1136/bmjopen-2025-115285
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