Benefits of progesterone supplementation in natural cycle FET confirmed in new trial

The outcome of FET in a natural cycle was sigificantly improved by progesterone supplementation in the luteal phase.

Published 01 September 2022

At a time when the number of frozen embryo transfers is increasing worldwide, a new RCT in unmedicated cycle FETs found a statistically higher birth rate when supplemented in the luteal phase with vaginal progesterone; such support, write the authors, ‘should be considered for introduction in clinical routine’.

The number of frozen embryo transfer cycles continues to rise in ART. In her report of preliminary European ART data at ESHRE 2022, Christine Wyns, Chair of ESHRE’s EIM consortium, reported almost 300,000 FETs performed in 2019, more than half the sum total of fresh IVFs and ICSI. Similarly, in his presentation of global data on behalf of ICMART, David Adamson reported that FETs represented some 56.8% of all autologous cycles, up from 39% in 2014.

However, the rise in FETs has been accompanied by questions of endometrial preparation and the risk of pre-eclampsia in hormonally primed transfers. In another presentation at ESHRE 2022, Nikolaos Polyzos from the Dexeus Hospital in Barcelona described the increase in FETs as ‘freeze mania’, and concluded that the corpus luteum – absent in artificial cycles – ‘appears to play a special role not only in maintaining early pregnancy but also in maintaining vascular health during early pregnancy’.(1) The solution, suggested Polyzos – at least to avoid the hypertensive risk, however clinically relevant it is – seems to be transfer in a natural cycle.

However, according to new study of luteal support in natural cycle FET, levels of serum progesterone vary considerably between women and may not be reliable in predicting live birth.(2) Indeed, a recent study from the group of Polyzos found that progesterone levels below a low threshold in natural cycle FET (10 ng/ml) was associated with significantly lower LBRs than levels over this threshold.(3) Analysis of progesterone levels at the time of FET, the authors suggested, might indicate the levels of luteal phase support needed. Now, a new RCT has indeed found that progesterone supplementation in natural cycle FET significantly improved LBR ‘and should therefore be considered for introduction in clinical routine’.(2)

In the treatment arm of the trial, in which all subjects received FET in a natural cycle, 243 women were given 100 mg vaginal progesterone tablets twice daily, starting on the day of FET - which continued for six full weeks corresponding to eight weeks of pregnancy. The other half (n = 245) were given no treatment. Blood samples for progesterone measurements were taken from all subjects on the day of FET.

Results revealed a significantly higher LBR in the supplementation group: 34.2% vs 24.1% (OR 1.635). Similarly, both pregnancy rate and clinical PR were higher in the treatment group than in the control group, with no significant differences in miscarriage rate. To avoid statistical anomalies, an intention-to-treat analysis showed similar differences in LBR: 33.5% vs 23.6%.

The authors describe the findings as indicative of ‘the beneficial role of progesterone supplementation’ after FET in a natural cycle, a statistically significant increase of 10%, which ‘strengthens the evidence for luteal phase supplementation with vaginal progesterone’ in such transfers. However, although their results confirm those of two recent meta-analyses, they note conflicting results with at least one retrospective study, and suggest that the starting day of supplementation – which in their trial was the day of transfer – is ‘likely of importance’. While supplementation continued over eight weeks, they note that ‘the optimal length of [luteal phase support] has not been thoroughly studied for embryo transfer in natural cycles’.

The trial took place at two centres in Denmark over five years, a time which saw improvements in outcome from FETs generally attributed to a greater uptake of vitrification and blastocyst transfers. These changes were evident in the trial as well as generally, though not apparently affecting its results.

Also having an apparently neutral effect on results was the progesterone level measured on the day of transfer, which, concede the authors, ‘may not be the perfect predictive marker for successful implantation in natural cycles’ because of the variability among women. Although other studies have found correlations – lower progesterone levels associated with poorer outcomes – this trial could not replicate that association. Nevertheless, in stressing that their results confirm the outcome of previous studies, they conclude that ‘progesterone supplementation favours the number of live birth outcomes after FET in natural cycles’, with a ‘suggestion’ that ‘patients undergoing FET in natural cycles should be offered LPS with progesterone’.

1. See
2. K Wånggren, Dahlgren Granbom M, Iliadis M, et al. Progesterone supplementation in natural cycles improves live birth rates after embryo transfer of frozen-thawed embryos—a randomized controlled trial. Hum Reprod 2022;
3. Gaggiotti-Marre S, Álvarez M, González-Foruria I, et al. Low progesterone levels on the day before natural cycle frozen embryo transfer are negatively associated with live birth rates. Hum Reprod 2020; 35: 1623-1629.

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