Discussion
This study aimed to evaluate the success rates of two consecutive SETs
in patients with a good prognosis compared with the transfer of two
embryos in one frozen-thawed cycle, and demonstrated that the first
approach is superior in terms of ongoing PRs. The strategy of
transferring embryos one by one results in higher ongoing PRs with the
advantage of avoiding multiple gestation. Although the use of a
freeze-only strategy in patients at a risk for OHSS has been described
(5, 25-27), studies on the freeze-only strategy have compared the method
with fresh transfers, and no consensus has been reached thus far (8, 9,
28, 29).
The association of the freeze-only strategy with subsequent consecutive
frozen-thawed SETs has not been extensively studied. A study evaluating
the association between the freeze-only strategy and SET in women with
hypogonadotropic hypogonadism showed that SET is an effective strategy
for decreasing the incidence of multiple conceptions while maintaining
satisfactory live birth rates (50.5%) (30). He and colleagues compared
single and double frozen-thawed blastocyst transfers after a freeze-only
strategy and found similar cumulative PRs (31). Our study found fewer
multiple pregnancies with eSET, as expected; however, we also observed
that two consecutive frozen-thawed SETs resulted in higher ongoing PRs
than the transfer of two blastocysts in one frozen-thawed cycle. The
regression model also confirmed an association of two consecutive SETs
with a higher chance of implantation, which may indicate that
transferring blastocysts one by one in a freeze-only strategy is better
than transferring two blastocysts together.
A number of variables are associated with the embryo implantation
potential, and they have been the focus of several studies. Not only the
embryo quality evaluated using conventional morphology, time-lapse
morphokinetics, or preimplantation genetic test (32) but also the
endometrium status (33) and embryo-endometrial synchrony are crucial
factors for a successful implantation (34). Studies from Simon and
collaborators have investigated the progesterone action, endometrium
gene, receptors, and protein expression based on data from the
endometrial receptivity array (35-39). More recently, the endometrium
microbiome and its association with embryo implantation have been
studied by the same research group (40-42). Although the association of
endometrium gene expression or microbiome with the implantation rates is
controversial in the literature (43), it is clear that there is a
variability in the endometrial condition between cycles according to the
patient’s clinical condition or changes in the treatment approaches.
These variations justify the greater chance of implantation when
performing consecutive SETs compared with one DET. However, the large
diversity of variables involved in embryo implantation, with respect to
both the embryo and endometrium, makes the complete elucidation of that
process impossible.
The vitrification technique is able to maintain the embryo implantation
potential (44, 45), which, in turn, allows the performance of a
freeze-only strategy and endometrium preparation for embryo transfer in
natural or hormone replacement cycles. This was confirmed by an
extensive study evaluating > 20,000 freeze-only cycles and
FETs, in which all embryos transferred from that stimulation cycle were
considered. The study demonstrated that the mean cumulative live birth
rate was 50.0% and dependent on the number of oocytes collected and the
patient’s age, suggesting the applicability of the freeze-only strategy
for the general population (46). However, that study did not consider
the number of embryos transferred, which allowed us to evaluate the
association of the freeze-only strategy with SET. Also confirming our
hypothesis of better clinical outcomes after a freeze-only strategy plus
SET, the American Society for Reproductive Medicine and the Society for
Assisted Reproductive Technology (ASRM/SART) recommended SET for
patients with a good prognosis aged < 38 years, except in
cases in which the patient had previously experienced several cycle
failures and for whom DET was suggested (47).
Another study evaluated retrospective data about clinical PRs before and
after the ASRM/SART guidelines, as their clinic policy is to transfer no
more than the recommended number of embryos. The study assessed patients
< 38 years old using their own eggs and without
preimplantation genetic testing, before (mean of 1.3 embryos transferred
per patient) and after (all embryos transfers were single) guideline
revision. The outcomes showed that SET was very efficient in this
population, as the overall live birth rates were maintained at around
50% after the reduction in the number of embryos transferred, and the
twin PR decreased from 14.2% to 2.5% (48). This study also supported
our hypothesis of the considerable advantages of transferring single
embryos, highlighting the absence of reduction in PRs in SET and
avoiding multiple pregnancies after a reduction in the number of embryos
transferred.
Owing to the retrospective nature of our study, we adjusted our
statistical analysis for confounders. However, we cannot exclude the
possibility of residual interfering factors such as endometrium status
or embryo ploidy, as these conditions were not evaluated in the cycles
included in our study. A limitation of our study lies in the fact that
not all patients who had failed eSET in the first transfer proceeded to
a second SET cycle. Nevertheless, the calculation used in our study
estimated the cumulative ongoing PRs as if all women who had a failed
first SET had a second SET, confirming a clear advantage of transferring
consecutive embryos one by one over DET. Another point to consider is
that the decision about the number of embryos to be transferred and the
embryo quality were not controlled. As a clinical routine, the number of
embryos transferred was determined in a shared decision-making process
between patients and doctors, after explaining the advantages and
disadvantages of each situation. Thus, the choice of the number of
embryos to be transferred could have been influenced by the quality of
the blastocysts available and the couple’s preferences. Although our
practice prioritizes transferring the best-quality frozen-thawed
blastocysts available, data on the quality of embryos transferred were
not available for the analysis. All cycles included were elective (with
at least one surplus frozen blastocyst) and the demographic
characteristics of our study groups were similar, which made the
comparisons possible.