Infertility affects approximately one in six people worldwide, and irregular or absent ovulation remains one of its most common causes. For decades, clomiphene citrate has been a standard treatment for stimulating ovulation, helping millions of women release eggs and improve their chances of conception. Now, a large study of fertility treatment cycles has raised new concerns about whether repeated exposure to high cumulative doses may increase the risk of pregnancy loss without improving the likelihood of a live birth.
Published in BMJ Open, the study analysed 21,004 embryo-transfer cycles recorded in the United States between 2004 and 2021. Researchers from Adelaide University, Boston University and the US Centers for Disease Control and Prevention examined pregnancy outcomes according to the total amount of clomiphene citrate received across multiple treatment cycles. Their analysis identified a dose-response pattern: as cumulative exposure increased, the risk of miscarriage and multiple pregnancy also rose.
Women who received between 500 and 749 milligrams of clomiphene citrate had a 12 percent higher risk of miscarriage compared with women exposed to lower cumulative amounts. Among those who received between 750 and 999 milligrams, the risk was 38 percent higher. The findings do not prove that clomiphene directly caused the pregnancy losses, because the study was observational and could not account for every factor influencing fertility treatment outcomes. However, the progressive increase in risk across dose categories strengthened the researchers’ concern about a possible biological relationship.
Clomiphene citrate belongs to a class of medicines known as selective estrogen receptor modulators. It acts mainly by interfering with estrogen feedback in the hypothalamus, a region of the brain that regulates reproductive hormones. This stimulates the release of gonadotropin-releasing hormone, which prompts the pituitary gland to produce follicle-stimulating hormone and luteinizing hormone. The resulting hormonal surge can encourage the ovaries to mature and release one or more eggs. In some patients, however, stronger ovarian stimulation can also increase the chance of developing multiple follicles.
The study found that women receiving cumulative doses of 750 milligrams or more were more than twice as likely to have twins or other multiple births. Multiple pregnancies are associated with substantially higher risks for both mothers and babies, including preterm birth, low birth weight, hypertensive disorders of pregnancy and neonatal complications. The researchers said the higher doses did not significantly improve the chance of a live birth, suggesting that escalating treatment may eventually produce more risk without delivering a corresponding benefit.
Spontaneous abortion rates increased as cumulative exposure rose. The researchers also observed more than a threefold increase in stillbirth at the highest dose, although that result was not statistically significant because relatively few women received such large cumulative amounts. A statistically non-significant finding cannot reliably distinguish a true association from random variation, and the authors stressed that larger studies will be required to determine whether the apparent stillbirth signal is real.
The new analysis adds to a series of studies led by researchers at Adelaide University’s Robinson Research Institute. Earlier work reported associations between clomiphene citrate exposure and pregnancy loss, stillbirth, perinatal death and certain birth defects. Experimental research in mice has provided additional biological context, with higher doses linked to fewer successful pregnancies, fetal growth restriction and developmental abnormalities. Animal studies cannot establish what happens in humans, but they can help identify mechanisms that warrant further investigation.
Associate Professor Sheree Boulet, the study’s lead author, said the results showed a progressively greater risk of adverse pregnancy outcomes at higher cumulative doses. “Increasing the dose did not significantly improve the chance of a live birth,” Boulet said, adding that treatment decisions should balance effectiveness against safety. Professor Michael Davies, a senior researcher and co-author of the study, said women appear to respond differently to clomiphene citrate and that personalised dosing strategies may eventually help reduce unnecessary exposure.
Clomiphene citrate remains a World Health Organization essential medicine and is still recommended as a first-line option for ovulation induction in many settings. Its long history of use and low cost have made it especially important in fertility care worldwide. The findings do not mean patients should stop treatment or change their medication without medical advice. Instead, the researchers are calling for clinicians to follow manufacturer safety recommendations, review cumulative exposure carefully and avoid increasing doses when there is little evidence of additional benefit. They also warn that newer ovulation-inducing drugs should be evaluated with the same scientific scrutiny rather than being assumed to be safer simply because they are more modern.
Subject of Research: Cells
Article Title: Dose-dependent perinatal risks of clomiphene citrate in US IVF cycles: a national cohort study, 2004–2021
News Publication Date: 7-Aug-2026
Web References: https://bmjopen.bmj.com/content/16/8/e115285; https://adelaide.edu.au/; https://researchers.adelaide.edu.au/profile/michael.davies; https://www.who.int/news-room/fact-sheets/detail/infertility
References: https://doi.org/10.1136/bmjopen-2025-115285
Keywords: Clomiphene citrate, infertility, ovulation induction, IVF, pregnancy loss, miscarriage, stillbirth, multiple births, reproductive biology, drug safety, fertility treatment, dose response
