Natural ovulation the best option before an IVF frozen embryo transfer

Natural ovulation is just as effective as hormone treatment for preparing the uterus for a frozen embryo transfer following in vitro fertilisation (IVF) and carries fewer risks, according to a large, randomised trial.

Emerging evidence suggests that for women who respond well to IVF (by being able to produce lots of eggs), freezing embryos and transferring them in a later cycle may improve success rates. As a result, frozen embryo transfers now account for the majority of embryo transfers globally.

Following IVF, a frozen embryo must be transferred to the uterus at a precise point in the menstrual cycle, when the endometrium – the blood vessel-rich inner lining of the uterus – is thick enough to support implantation.

Women can either choose to use a medicated cycle, where oestrogen and progesterone are taken throughout the month to prepare the uterus, or their natural cycle, if it is regular, which relies on monitoring hormones produced by the body.

Which choice is best has remained somewhat of a mystery, since no previous trial has been large enough to assess complications associated with the different methods.

To address this, Daimin Wei at Shandong University in Jinan, China, and colleagues conducted a large trial involving 4376 women across 24 fertility centres. All the participants were aged 20 to 40 and were planning to undergo a single frozen embryo transfer. Half were assigned a medicated protocol, the other half used their natural cycle.

“This is the randomised-controlled trial we have been waiting for,” says William Buckett at McGill University in Montreal, Canada, who wasn’t involved in the study.

Live birth rates were similar across both groups at 41.6 per cent for the natural cycle and 40.6 per cent in the medicated group, suggesting that natural ovulation is just as effective as hormone treatment for preparing the uterus for implantation.

Clear differences emerged, however, when maternal complications during and after pregnancy were examined.

Women using their natural cycle had a lower risk of pre-eclampsia, a potentially life-threatening condition characterised by high blood pressure, and experienced fewer early pregnancy losses. They were also less likely to develop placental accreta spectrum, a condition where the placenta fails to detach easily after birth. Rates of Caesarean sections and severe bleeding after birth were also lower in this group.

“These risks not only affect maternal and fetal health during pregnancy, but are also associated with long-term health postpartum,” says Wei.

“This is an important new study,” says Tim Child, chair of the UK’s Human Fertilisation and Embryology Authority’s Scientific and Clinical Advances Advisory Committee. Clinics currently advise people with regular cycles that natural and medicated approaches have the same success rate, he says.

But Child adds that there has been some suggestion that natural cycles result in lower rates of pre-eclampsia. This might be because of the presence of a corpus luteum – a temporary structure in the ovary that forms after ovulation and produces hormones that help prepare the uterus for a pregnancy, which could influence pre-eclampsia risk.

“This very large study confirms and extends previous findings and suspicions, in particular the significantly lower rate of pre-eclampsia, early pregnancy loss, placental accreta, C-section and post-partum haemorrhage [with the natural cycle route],” says Child.

Wei’s team now intends to examine blood samples collected during the trial to identify potential biomarkers that might explain the differences in pregnancy complications.