Researchers have warned that high cumulative doses of clomiphene citrate, a drug widely used to treat infertility, may increase the risk of pregnancy loss and other complications, without improving the chances of a live birth.
In the study published in the journal BMJ Open, researchers from the University of Adelaide, in collaboration with Boston University and the Centers for Disease Control and Prevention (CDC), analyzed more than 21,000 embryo transfer cycles in the United States.
They found that women who received cumulative doses of 500-749 mg of the drug were 12% more likely to miscarry, while the risk increased to 38% for those who received 750-999 mg. Women who took 750 mg or more were also twice as likely to have twins or multiple births.
Despite the higher rates of spontaneous abortion with increased dose, researchers warn that the more than threefold increase in the risk of stillbirth at the highest dose was not statistically significant due to its infrequent use, calling for larger studies to confirm this relationship.
These findings are consistent with a previous study from the University of Adelaide that showed a doubling of neonatal deaths in pregnancies associated with the drug. Crucially, higher doses did not improve the chance of a live birth; instead, they increased the incidence of twin pregnancies, which are associated with health risks for both mother and child.
Clomiphene citrate is one of the most commonly prescribed fertility drugs in the world, used by millions of women since 1967, and remains a recommended first-line treatment for ovulation induction. The drug, which is on the World Health Organization's List of Essential Medicines, works by stimulating the ovaries to release eggs. However, women who do not respond to lower doses or require multiple cycles may receive progressively higher, cumulative doses.
Lead author Dr. Sheri Polley, Associate Professor, said the results show a clear dose-response relationship, with women receiving higher doses experiencing an increased risk of adverse outcomes, without any significant improvement in their chances of a live birth. She added that there is a point where increasing the dose may not provide any benefit and may even increase the risks, highlighting the need for a careful balance between efficacy and safety.
The study builds on previous research from the Robinson Research Institute at the University of Adelaide, which linked the drug to an increased risk of pregnancy loss, stillbirth, perinatal mortality, and certain birth defects. Experiments in mice also supported these findings, showing that higher doses were associated with pregnancy loss, impaired fetal growth, and developmental abnormalities.
Professor Michael Davies, the lead researcher, emphasized that this study builds upon more than two decades of research on the safety of fertility treatments. He noted that the drug, despite being available since 1967, has not been comprehensively evaluated in large clinical trials, and that women respond to it differently. This necessitates a better understanding of the dose-response relationship and the possibility of tailoring doses to improve safety. He urged physicians to strictly adhere to safety recommendations and avoid unnecessary cumulative doses, adding that any shift to newer medications must be based on strong evidence, not assumptions.
