Should any use of artificial cycle regimen for frozen-thawed embryo transfer in women capable of ovulation be abandoned: yes, but what's next for FET cycle practice and research?

Over the past decade, the use of frozen-thawed embryo transfer (FET) treatment cycles has increased substantially. The artificial ('programmed') cycle regimen, which suppresses ovulation, is widely used for that purpose, also in ovulatory women or women capable of ovulation, under the assumption of equivalent efficacy in terms of pregnancy achievement as compared to a natural cycle or modified natural cycle. The advantage of the artificial cycle is the easy alignment of the time point of thawing and transferring embryos with organizational necessities of the IVF laboratory, the treating doctors and the patient. However, recent data indicate that pregnancy establishment under absence of a corpus luteum as a consequence of anovulation may cause relevant maternal and fetal risks. Herein, we argue that randomized controlled trials (RCTs) are not needed to aid in the clinical decision for or against routine artificial cycle regimen use in ovulatory women. We also argue that RCTs are unlikely to answer the most burning questions of interest in that context, mostly because of lack of power and precision in detecting rare but decisive adverse outcomes (e.g. pre-eclampsia risk or long-term neonatal health outcomes). We pinpoint that, instead, large-scale observational data are better suited for that purpose. Eventually, we propose that the existing understanding and evidence is sufficient already to discourage the use of artificial cycle regimens for FET in ovulatory women or women capable of ovulation, as these may cause a strong deviation from physiology, thereby putting patient and fetus at avoidable health risk, without any apparent health benefit.