A large randomized trial has shown that natural ovulation is as effective as hormone treatments for preparing the uterus in frozen embryo transfers during IVF, while posing fewer risks to mothers. The study involved over 4,000 women and highlights potential benefits in reducing complications like pre-eclampsia. Researchers suggest this could influence future IVF protocols for those with regular cycles.
In vitro fertilisation (IVF) has evolved, with frozen embryo transfers now comprising the majority of procedures worldwide, as they may boost success rates for women who produce many eggs. To ready the uterus, patients typically choose between a medicated cycle—using oestrogen and progesterone—or a natural one, monitored via body hormones, if their cycle is regular.
A comprehensive trial led by Daimin Wei at Shandong University in Jinan, China, addressed uncertainties around these methods. Conducted across 24 fertility centres, it included 4,376 women aged 20 to 40 undergoing a single frozen embryo transfer. Participants were randomly split: half followed a medicated protocol, the other half their natural cycle.
Live birth rates were nearly identical, at 41.6 per cent for natural cycles and 40.6 per cent for medicated ones, indicating comparable effectiveness in supporting implantation. However, natural cycles showed clear advantages in safety. Women in this group faced lower risks of pre-eclampsia—a dangerous high blood pressure condition—early pregnancy losses, placental accreta spectrum (where the placenta does not detach properly post-birth), Caesarean sections, and severe postpartum bleeding.
"These risks not only affect maternal and fetal health during pregnancy, but are also associated with long-term health postpartum," Wei noted. The corpus luteum, formed after natural ovulation and producing supportive hormones, may explain the reduced pre-eclampsia risk, according to experts.
"This is the randomised-controlled trial we have been waiting for," said William Buckett of McGill University in Montreal, Canada. Tim Child, from the UK's Human Fertilisation and Embryology Authority, called it "an important new study," confirming prior suspicions of benefits in natural approaches. Wei's team plans to analyse trial blood samples for biomarkers explaining these differences.
The findings, published in The BMJ (DOI: 10.1136/bmj-2025-087045), could guide clinics to favour natural cycles for suitable patients, potentially improving IVF outcomes and safety.
