P-416 Good and bad news regarding low luteal-phase progesterone during natural cycle frozen embryo transfer: it’s rare, but rescue-therapy may not be enough to fix it
Authors: Godinho C  M , Costa Vieira I , Semenova T , Neves A , Reis-Soares S , Santos-Ribeiro S 
Published: July 2024

Study question

Do low circulating luteal-phase progesterone levels during natural cycle frozen embryo transfer (NC-FET) affect live birth rates (LBR) and can rescue-therapy advert possible detrimental outcomes?

Summary answer

Low luteal-phase progesterone occurred in only approximately 3% of all FETs. However, when it occurred, LBR were lower despite the use of additional rescue-strategy.

What is known already

Low serum progesterone on the day of FET is known to be associated with a reduction in pregnancy rates and rescue-therapy (i.e. the increase and/or change in the route of administration of exogenous progesterone) has been shown to be useful in reducing its potential hindering effects. However, these findings are mostly limited to studies assessing artificial FET cycles. Following NC-FET, the data is not only scarce but also less clear regarding both the incidence of such low circulating levels and whether rescue-therapy may be useful in such cases or not.

Study design, size, duration

A total of 2292 patients (32.5% did an IVF with egg donation and 10,4% did an IVF with PGT-a) who underwent a NC-FET at blastocyst stage in a single infertility center between 2014 and 2021 were included in this retrospective cohort study. The cycles were subdivided into three groups of progesterone levels the day of FET: &lt;10ng/ml, 10-20ng/ml and &gt;20ng/ml. The primary outcome was LBR, with secondary outcomes including miscarriage and neonatal outcomes.

Participants/materials, setting, methods

Patients underwent endometrial preparation in either a true, modified or natural proliferative phase (NPP) NC-FET. Luteal-phase support was routinely provided using micronized vaginal progesterone. Rescue intramuscular progesterone was systematically administered whenever low midluteal progesterone (below 1 standard deviation of the center’s mean) levels were detected. Maternal age and body mass index (BMI), year of treatment, ovarian response, endometrial thickness, cause of infertility and embryo quality were controlled by means of a multivariable logistic regression.

Main results and the role of chance

The mean age (± standard deviation) of patients was 38.3±4.5 years, while mean weight and BMI were 62.6±10.7 kg and 23.3±3.7kg/m2, respectively. Only 72 (3.1%) cycles had FET day circulating progesterone below 10 ng/mL, while 1084 (47.3%) and 1136 (49.6%) had 10-20 ng/mL and &gt;20 ng/mL, respectively. The unadjusted LBRs in the subgroup with progesterone &lt;10ng/ml, 10-20ng/ml and &gt;20ng/ml were, respectively, 43.5%, 52.7% and 49.6%, differences that were not statistically significant in this non-adjusted analysis (p = 0.151). However, following confounder adjustment using multivariable logistic regression, progesterone &lt;10ng/ml was associated with a lower LBR (adjusted odds-ratio 0.568; 95% confidence interval 0.330-0.977), a finding that occurred despite the aforementioned use of rescue progesterone therapy in this subgroup. The miscarriage rate, in the &lt;10ng/ml subgroup was higher (26.1%), but without statistically significance, comparing to other subgroups (19% and 20.5% respectively).

Limitations, reasons for caution

This study is limited by its retrospective design. Moreover, as different NC-FET protocols were included, further research should be performed to assess whether this effects differs according to each protocol. Also the number of embryos transfered varied also affecting the final conclusion.

Wider implications of the findings

This study raises the hypothesis that low midluteal progesterone may be rare in NC-FETs. However, to our knowledge, it is also the first to posit that rescue-therapy may be insufficient to restore adequate endometrial function. Further research should assess eventual pathophysiological differences between artificial and NCs to justify such findings.

Trial registration number

not applicable