Higher cumulative doses of common fertility drug clomiphene citrate may increase pregnancy loss risks, according to new research.

Around one in six people experience infertility, with irregular or absent ovulation among the most common causes.

Clomiphene citrate has long been a mainstay of fertility treatment, but Adelaide University research has raised concerns about higher cumulative doses.

The new study found that high doses of clomiphene citrate accumulated over multiple fertility treatment cycles could increase the risk of pregnancy loss.

Lead author associate professor Sheree Boulet said the findings showed a clear dose-response relationship, meaning the risks increased as cumulative exposure rose.

She said: “Women who received higher cumulative doses of clomiphene citrate experienced progressively greater risks of adverse pregnancy outcomes.

“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.”

Supported by the NHMRC and conducted in partnership with Boston University and the Centers for Disease Control and Prevention, researchers analysed 21,004 IVF embryo transfer cycles in the US.

Women receiving cumulative doses of 500mg to 749mg of clomiphene citrate had a 12 per cent higher risk of miscarriage, while those receiving 750mg to 999mg had a 38 per cent higher risk.

Women receiving cumulative doses of 750mg or more were also more than twice as likely to have twins or other multiple births.

Rates of spontaneous abortion, another term for miscarriage, increased as the dose rose.

Researchers also recorded more than a threefold increase in stillbirth at the highest dose, although the finding was not statistically significant because that dose was rare. Larger studies are needed to confirm the association.

The finding is consistent with an earlier Adelaide University study that showed a doubling of neonatal death in pregnancies involving clomiphene citrate. Neonatal death means the death of a baby shortly after birth.

Higher cumulative doses did not improve the chance of a live birth, but did increase twinning, which raises the risk of adverse outcomes for both mother and child.

Clomiphene citrate is one of the world’s most widely prescribed fertility drugs. It has been prescribed to millions of women worldwide since 1967 and remains a recommended first-line treatment for ovulation induction.

The drug is recognised as an essential medicine by the World Health Organization. It works by stimulating the ovaries to release eggs, increasing the chance of pregnancy.

Women who do not respond to lower doses, or who require multiple treatment cycles, may receive progressively higher cumulative doses over time.

The findings build on a series of studies from Adelaide University’s Robinson Research Institute linking clomiphene citrate with increased risks of pregnancy loss, stillbirth, perinatal death and some birth defects.

Experimental studies in mice supported these findings, showing that higher doses reduced successful pregnancies and were associated with pregnancy loss, impaired fetal growth and developmental abnormalities.

Professor Michael Davies, senior researcher and co-author of all the studies, said the latest work builds on more than two decades of Adelaide-led research into the safety of fertility treatments.

He said: “Clomiphene citrate has been used by many women since 1967, but it has never been comprehensively evaluated in large prospective clinical trials.

“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 personalised 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.”

Common IVF preparation techniques used before embryo transfer have no proven effect on pregnancy rates, according to a review.

Researchers said evidence for the widely used practices remains uncertain because available studies are limited and generally of low quality.

Embryo transfer is the final and most vulnerable stage of IVF, when an embryo is placed into the womb. Only around one in three transfers results in pregnancy.

Practice varies between clinics, with some routinely using preparation techniques such as adjusting bladder fullness while others do not consider them necessary.

Dr Ryosuke Akino, practising obstetrician-gynaecologist from Kato Ladies Clinic, said: “To an extent, this is a case of tradition driving practice rather than the evidence.

“Current practices in this area often reflect local protocols, clinician preference, and historical convention rather than strong, high-quality evidence.”

The Cochrane review analysed 11 studies involving 2,524 women undergoing embryo transfer.

Researchers looked at three preparation techniques used by fertility clinics: having women arrive with a full bladder to straighten the angle between the uterus and cervix, removing cervical mucus and using a technique called afterloading.

Afterloading is a technique used to guide the embryo through the cervix.

The review found no reliable evidence that any of the three approaches improved pregnancy rates compared with standard care.

Researchers rated the evidence as low or very low certainty because the trials were small and had methodological weaknesses. They found no grounds to recommend any of the techniques over standard care.

There was also limited information about possible side effects.

The review team, which included methodologists and practising obstetrician-gynaecologists, said full bladder preparation and cervical mucus removal were generally considered safe, with no clear evidence of harm or major complications.

Dr James Brown, obstetrician-gynaecologist from Women’s Health and Research Institute Australia, said: “While these techniques are generally considered safe, it’s still important to test their effectiveness.”

Akino and Brown added: “A full bladder can be uncomfortable, although it may ease catheter insertion in certain uterine positions and reduce procedural difficulty.

“Mucus removal is usually quick, but if done roughly and causes bleeding, it may affect the woman’s experience.

“Overall, the risks are minor and relate mostly to discomfort and procedural factors rather than clinical harm.”

The authors said embryo transfer has changed relatively little despite major advances elsewhere in IVF.

Research has instead focused more heavily on embryo quality and genetic factors, which have a greater bearing on treatment success than transfer technique.

Embryo transfer also depends heavily on the person carrying out the procedure and can be difficult to standardise, making large, rigorous clinical trials harder to design.

Researchers said women may also be reluctant to risk valuable embryos by taking part in randomised studies comparing different transfer techniques.

Dr Noyuri Yamaji from Showa Medical University in Japan said: “Sixteen years of research still haven’t answered a basic IVF technique question.

“This is a critical step in the IVF process and these small changes and techniques have the possibility to make a massive difference, but we won’t know more until more robust, better-quality trials are conducted.”

All the studies assessed were carried out in high-income countries, meaning the findings may not necessarily apply to other healthcare settings and populations.

The authors said further research could be particularly valuable in resource-limited settings, where these procedures are inexpensive and simple to change and basic procedural standardisation could matter more than advanced technical modifications.

Natural Cycles has received its sixth FDA clearance for an updated fertility algorithm designed to personalise digital contraception.

The regulator cleared the company’s next-generation NC° Fertility Algorithm, which combines statistical modelling with machine learning to predict fertile and non-fertile days.

Natural Cycles said the algorithm was trained on tens of millions of real-world fertility data points and adapts to individual cycle patterns.

“People don’t just want effective birth control; they want a method that fits naturally into their lives,” said Dr Elina Berglund Scherwitzl, chief executive and co-founder of Natural Cycles.

“One of the unique advantages of a software-based contraceptive is that it can continue to evolve.

“As our scientific understanding of fertility grows and we continue to learn from more than a decade of real-world data, we can responsibly refine the technology through rigorous research, clinical validation, and FDA review.

“This latest clearance is the result of that work, helping us give many users more flexibility while maintaining the effectiveness they rely on.”

Evidence supporting the FDA clearance showed that the updated system maintained the app’s established safety and effectiveness while giving many users more Green Days.

Green Days are those on which the app confirms that pregnancy protection is not needed.

The birth control app remains 98 per cent effective when used as intended and 93 per cent effective with typical use, according to the company.

Natural Cycles said these rates place it in the same effectiveness category as the combined oral contraceptive pill.

Typical use includes mistakes or inconsistent use, while intended use means following the method correctly.

Digital contraception uses technology and physiological data, such as body temperature, to provide personalised fertility predictions.

Natural Cycles said its updated algorithm can identify fertile and non-fertile days more precisely than traditional fertility awareness methods, which may classify larger parts of the cycle as potentially fertile.

The changes provide more Green Days while maintaining effectiveness, improve performance for people with irregular cycles and better handle lower-quality temperature or biomarker data, the company said.

A biomarker is a measurable biological signal, such as body temperature, that provides information about processes taking place in the body.

Natural Cycles also said the system can personalise its predictions more quickly as a user’s menstrual cycle changes over time.

“Years ago, the question was whether digital contraception could work. Today, Natural Cycles has demonstrated robust clinical and real-world evidence that it can,” said Dr Kerry Krauss, senior medical adviser at Natural Cycles.

“The next chapter for digital contraception is making it more personalised and easier to use while maintaining the same high standard of safety.

“This FDA clearance demonstrates how advances in AI and machine learning can improve the user experience while preserving the scientific rigour expected of a regulated medical device.”

Natural Cycles has filed a patent application covering key innovations in the updated algorithm.

The decision follows the FDA’s first De Novo clearance of the company’s birth control app in 2018.

Later clearances allowed the app to integrate with the Oura Ring in 2021 and Apple Watch in 2023.

In 2024, the FDA cleared a Predetermined Change Control Plan, creating a regulatory pathway for future hardware integrations.

Natural Cycles said the plan has since enabled the launch of its NC° Band and other hardware integrations, including a Garmin connection introduced in March 2026.

A further clearance in 2025 allowed the birth control app to be offered both over the counter and by prescription.

The company has also received regulatory authorisations in more than eight markets worldwide, including Europe, Canada, Brazil, Australia, South Korea and Singapore.