Natural cycle and modified natural cycle: protocols of choice for FET cycles in ovulatory women.

Despite the fact that artificial cycle protocols were initially developed for frozen-thawed embryo transfer (FET) cycles in anovulatory women, soon dominated clinical practice, ranking first among various protocols for endometrial preparation. Ease of scheduling and flexibility for the IVF lab, the treating physicians and the patients themselves, resulted in the wide application of artificial cycles in FET cycles.

However, artificial cycles have been associated with increased risks for both mother and the embryo, compared to natural cycles, as various observational studies have shown so far. The risk of hypertensive disorders in pregnancy and pre-eclampsia increases, while the risk of large for dates and fetal macrosomia with long term health consequences appears to increase as well.

So, despite the absence of evidence from large-size randomised controlled (RCT) studies, an argument is made in favour of the use of natural cycle and modified natural cycle in all ovulatory women undergoing endometrial preparation for a FET cycle, based on current evidence from a large number of observational data. It was recently proposed that it is rather unrealistic to wait for RCTs to further support the initial argument, mainly due to a large sample required to detect significant differences in obstetric outcomes, as well as ethical issues in enrolling women in testing medical interventions that are not required (1).

However, the choice of natural cycle in ovulatory women undergoing endometrial preparation for a FET cycle requires further considerations. First, we need more data comparing the natural cycle with the modified natural cycle, both in terms of efficacy and cancellation rates. Second, the timing of embryotransfer and luteal support protocol needs further research (2). In particular, previous research suggested that age-related changes are present in the function of bovine corpus luteum, affecting endogenous progesterone production, therefore, maternal age should be taken into consideration when deciding luteal support length and regimen (3).

Last, an effort should be made where ovulation disorders are amenable to ovulation induction, or modified natural cycle protocols, to support ovulation so that the presence of a corpus luteum is secured. It is likely that through the various physiological functions of the corpus luteum early placentation takes place without deviations, such as those previously mentioned, hypertensive disorders and fetal growth disorders.

References

  1. 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? Frauke von Versen-Hoynck, et al. Human Reproduction, Vol.37, No.8, pp. 1697–1703, 2022
  2. Preparation of the endometrium and timing of blastocyst transfer in modified natural cycle frozen-thawed embryo transfers (mNC-FET): a study protocol for a randomised controlled multicentre trial. Saupstad M, et al. BMJ Open 2019;9:e031811. doi:10.1136/bmjopen-2019-031811
  3. Age-related changes in the bovine corpus luteum function and progesterone secretion. K Hori et al. Reproduction in Domestic Animals, 7 August 2018, doi.org/10.1111/rda.13303

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