Journal of Assisted Reproduction and Genetics

https://doi.org/10.1007/s10815-024-03103-y

ASSISTED REPRODUCTION TECHNOLOGIES

Can serum progesterone concentration direct a fresh or freeze‑all

transfer strategy in the first in vitro fertilisation cycle?
Sarah Hunt1,2,3 · Jing Liu4 · Pulin Luo4 · Ying Zhong4 · Ben W. Mol1,2,5 · Ling Chi4 · Rui Wang1

Received: 29 November 2023 / Accepted: 18 March 2024

© The Author(s) 2024

Abstract
Purpose To examine the interaction between serum progesterone concentration on the trigger day and choice of freeze-all
and fresh transfer strategies on live birth in an unselected population as well as in patients over 35 years old.
Methods We performed a retrospective cohort study of 26,661 patients commencing their first IVF cycle in a large fertility
centre between 2015 and 2019, including 4687 patients over 35 years old. We performed a multivariable fractional polynomial
interaction analysis within a logistic regression model to investigate the interaction between serum progesterone concentra-
tion and the choice of freeze-all or fresh transfer strategy following the first transfer.
Results 15,539 patients underwent a fresh embryo transfer and 11,122 underwent a freeze-all strategy in their first IVF
cycle. The freeze-all group had a higher live birth rate compared to the fresh group (43.9% vs 40.3%). After adjusting for
confounding factors, there was a positive interaction between serum progesterone concentrations and the choice of a freeze-
all versus fresh embryo transfer on live birth (p for interaction 0.0001), with a larger magnitude of effect when progesterone
concentration was higher. Such an interaction was also observed in patients over 35 years old (p for interaction 0.01), but
the treatment effect curve over progesterone concentrations was almost flat.
Conclusions In an unselected population, frozen transfer is associated with greater chances of live birth, especially in patients
with higher serum progesterone concentration. In patients over 35 years old, the benefit of a freeze-all policy appears small
across all serum progesterone concentrations.

Keywords Freeze all · Embryo transfer · IVF · Progesterone · Live birth

Introduction

Historically, most fertility clinics worldwide have prac-

ticed fresh embryo transfer, with frozen transfer of surplus
embryos. Fresh embryo transfer is associated with increased
chances ovarian hyperstimulation and studies suggest that
* Rui Wang there are differences in the resulting pregnancy [1–3]. These
r.wang@monash.edu
differences are thought to potentially reflect differences in
1
Department of Obstetrics and Gynaecology, School placentation which result from the altered hormonal milieu
of Clinical Sciences at Monash Health, Monash University, and endometrial gene expression, characteristic of these
Clayton, Victoria, Australia treatment modalities [4, 5]. This, coupled with the advances
2
Monash Womens, Monash Health, Clayton, Victoria, in vitrification technology, has led to the introduction of
Australia freeze-all embryo transfer to clinical practice. Recognition
3
Monash IVF, Richmond, Victoria, Australia of the potential impacts of transfer strategy on perinatal out-
4
Chengdu Xinan Gynecology Hospital, Chengdu, Sichuan, come as well as a move to a personalised approach to treat-
China ment has led to a shift in practice where frozen transfer is
5
Aberdeen Centre for Women’s Health Research, Institute increasingly performed. Accordingly, the clinical effective-
of Applied Health Sciences, School of Medicine, Medical ness of one transfer strategy over the other has been the sub-
Sciences and Nutrition, University of Aberdeen, Aberdeen, ject of many recent large randomised control studies [6–9].
UK

Vol.:(0123456789)

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A large multicentre trial found that for patients with
polycystic ovary syndrome (PCOS), a freeze-all embryo
transfer in the first cycle of treatment was associated with
increased live birth rates [8]. The same group went on
to report on the outcomes of patients who were normal
ovulatory and found that freeze-all and fresh transfer were
comparable with respect to live birth rate in the first trans-
fer cycle [6]. This finding was confirmed in a second large
study [7]. A subsequent multicentre trial, however, found
that in ovulatory patients with good prognosis, frozen sin-
gle blastocyst transfer was associated with a 10% increase
in pregnancy rate (40% vs 50%) [9]. More recently pub-
lished European studies have yielded similarly conflict-
ing results. Stormlund et al. reported no difference in live
birth rate for ovulatory patients when human chorionic
gonadotrophin (HCG) trigger and fresh transfer was com-
pared with agonist trigger and freeze all [10]. Wong et al.
however reported a significant reduction in cumulative live
birth at 12 months from freeze all as compared to fresh
transfer. The resulting clinical equipoise has led to con-
sideration of cycle specific factors which may effectively
direct transfer strategy [11].
The role of progesterone in preparing the endometrium
for implantation and sustaining early pregnancy is well
established in ART practice [12]. The role of serum pro-
gesterone concentration measurement within ART cycles
in determining the outcome of embryo transfer and as a
guide for clinical decision-making is yet to be defined.
Secondary analysis of four randomised trials showed
inconsistent findings [7, 13]. Vuong et al. found that pro-
gesterone concentration greater than 1.14 ng/mL was
associated with higher live births in the freeze-all group
as compared to the fresh transfer group, which reflects
the findings of previous observational studies [14]. The
other secondary analysis of three large trials demonstrated
frozen transfer associated with higher rates of live birth
irrespective of progesterone concentration on the day of
HCG trigger, with greater differences in live birth rates in
patients with progesterone ≥ 1.14 ng/mL as compared to
those with progesterone < 1.14 [13].
While these secondary studies explored the potential
role of progesterone elevation in IVF cycle outcome, they
have been underpowered for interaction analysis and they
oftern excluded patients with advanced age due the inclu-
sion criteria of the primary trials. Therefore, it would be
important at this stage to use large observational data
to explore such a research question, without restricting
to young patients with good prognosis. This study aims
to determine the potential role of progesterone as a bio-
marker, routinely examined in IVF treatment cycles, in
guiding the selection of fresh or freeze-all embryo transfer
strategy in unselected population as well as in patients
over 35 years old.
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Journal of Assisted Reproduction and Genetics
Methods
This was a single-centre retrospective cohort study con-
ducted in accordance with the Declaration of Helsinki.
Ethics approval for the study was granted by Chengdu
Xinan Hospital Reproductive Medicine Ethics Committee
(2021SZLS001) and Monash University Human Research
Ethics Committee (23120). Informed consent was waived
as it was a retrospective study based on routinely. The
medical records of all patients undergoing IVF/ICSI
treatment at Chengdu Xinan Hospital between January
2015 and September 2019 were reviewed. We included
all patients who commenced their first fresh stimulated
IVF/ICSI cycle using autologous gametes during this
period. We excluded oocyte preservation and oocyte
donation cycles, artificial insemination cycles, preim-
plantation genetic testing (PGT) cycles and donor sperm
cycles. Cycles where oocyte retrieval was cancelled or no
embryos were available for transfer were also excluded
from the final analysis. To avoid confounding by indica-
tion, we also excluded those cycles where a freeze-all
strategy was performed with absolute indication in our
setting, with the serum progesterone on the trigger day ≥
2.0 or ≥ 20 oocytes collected.
Procedures and interventions
Protocols for treatment included both gonadotrophin
releasing hormone (GnRH) agonist and antagonist pro-
tocols. All patients were monitored with ultrasound and
serial hormone studies. Serum progesterone concentration
was routinely measured during controlled ovarian hyper-
stimulation including measurement on the day of trigger.
When 3 follicles were ≥ 18 mm, final oocyte maturation
was triggered with the administration of human chorionic
gonadotrophin (HCG) or GnRH agonist trigger and vagi-
nal oocyte collection was performed 36 h later under seda-
tion with transvaginal ultrasound guidance. Fertilisation
was by conventional IVF or intracytoplasmic sperm injec-
tion (ICSI) depending on semen analysis results. Embryos
were cultured in vitro to cleavage or blastocyst stage.
Luteal-phase support was commenced on the night
of oocyte collection and continued up to the time of a
positive pregnancy test. In patients undergoing frozen
embryo transfer, transfer was performed in a natural cycle
in patients who were normal ovulatory or otherwise in a
hormone replacement (HRT) cycle.
Journal of Assisted Reproduction and Genetics

Outcome measure and definitions
The primary outcome of interest was live birth after
28-week gestation following the first embryo transfer and
expressed as an odds ratio (OR).
Statistical analysis
We used logistic regression to calculate the odds ratio (OR)
with 95% confidence intervals (CI) of live birth in a freeze-
all transfer strategy versus a fresh embryo transfer strategy.
We selected a minimal set of confounding factors to be
adjusted in the analysis, based on clinical knowledge, includ-
ing female age, BMI, the diagnosis of PCOS and the number
of oocytes and serum progesterone levels on the day of hCG
triggering. We did not adjust for any potential mediators,
including the number or stage of embryos transferred, as
is the recommended methodology for statistical analysis in
observational studies [15].
To evaluate whether the treatment effect varied with
serum progesterone concentration, we built a multivari-
able fractional polynomial interaction test within a logistic
regression model. This approach allows the detection of non-
linear associations, in addition to common linear associa-
tions, and the selection of the best-fitting one based on the
smallest Akaike information criterion. This methodology
has been successfully applied in other biomarker interac-
tion analyses in reproductive medicine [16]. We restricted
the analyses to linear and first-degree fractional polyno-
mials for both main effects and interaction due to clinical
plausibility. The p-value for the interaction was based on a
likelihood ratio test. We visualised (1) the treatment effect
at different serum progesterone concentrations and (2) both
the predicted live birth rates in a fresh and a freeze-all
embryo transfer strategies at different serum progesterone
concentrations.
To evaluate the robustness of the findings, we also
divided the cohort into quartiles based on serum progester-
one concentration and performed logistic regression within
each quartile adjusting for the same covariates. We plotted
the ORs and 95% CIs for each group in a forest plot. The
main analysis was performed based on complete cases. We
also performed multiple imputations in a sensitivity analysis
to examine the robustness of the findings.
In addition, we performed sensitivity analyses on the mul-
tivariable fractional polynomial
interaction analysis for a subset of patients over 35 years
old, a subset of patients
with a single embryo transfer and a third subset of
patients with blastocyst transfer. All statistical analyses was
performed in Stata v16.1 (StataCorp, College Station, TX,
USA).
Results
Over the study period, 43,576 patients commenced their first
cycle of treatment. Patients with donor sperm (n = 1340),
preimplantation genetic testing (n = 460), artificial insemi-
nation (n = 1) cycles, for oocyte donation (n = 60), oocyte
cryopreservation (n = 29), no embryo available for transfer
(n = 3297) or oocyte retrieval canceled (n = 1341) were
excluded from the cohort. We then excluded patients not
returning for frozen embryo transfer within the data col-
lection period, with oocyte number ≥ 20, progesterone on
the day of HCG was ≥ 2 nmol/mL or with triple embryo
transfer. This left 26,661 patients included, of which 15,539
underwent fresh embryo transfer strategy and 11 122 under-
went freeze-all embryo transfer strategy (Appendix 1).
The baseline characteristics of unselected patients under-
going fresh or freeze-all embryo transfer in their first cycle
of treatment as displayed in Table 1. There were differences
between the two groups with respect to age, number of

Table 1  Baseline characteristics

Characteristics Freeze all (N = 11,122) Fresh (N = 15,539) p-value

Female age (years) 32.0 (5.1) 30.9 (4.1) < 0.001

Body mass index (BMI) kg/m2 22.0 (3.0) 21.9 (3.0) 0.15
Primary infertility (%) 4770 (42.9%) 7079 (45.6%) < 0.001
Duration of infertility 3 (2–6) 3 (2–5) 0.008
Polycystic ovary syndrome (PCOS) 988 (8.9%) 768 (4.9%) < 0.001
Number of oocytes collected 10 (5–15) 9 (6–12) < 0.001
Serum progesterone concentration on the trigger day (ng/mL) 1.06 (0.75–1.43) 0.98 (0.70–1.29) < 0.001
Serum oestradiol concentration on the trigger day (pg/mL) 3235 (1762, 4854) 2692 (1756, 3851) < 0.001
Serum luteinizing hormone concentration on the trigger day (IU/L) 1.66 (1.09, 2.62) 1.52 (1.02, 2.25) < 0.001

All values are presented as mean and standard deviation where data are normally distributed or median and interquartile range where data are
skewed

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 Journal of Assisted Reproduction and Genetics

oocytes retrived, frequency of PCOS diagnosis and serum a

progesterone concentration with these values all being
higher in the freeze-all group. The proportion of couples
undergoing treatment for primary infertility was higher in
the fresh transfer group.
Compared to the fresh transfer group, the freeze-all
group had more single embryo transfers (21.8% vs 7.5%),
more blastocyst transfers (63.1% vs 13.9%), higher clinical
pregnancy rate (56.4% vs 50.3%) and higher live birth rate
(43.9% vs 40.3%) (Table 2).
In multivariable fractional polynomial interaction anal-
ysis, a linear polynomial (i.e. power=1) was chosed for
progesterone concentration as it had the smallest Akaike
information criterion. After adjusting confounding factors
considering non-linearity (female age (power = 3), BMI
(power = 1), the diagnosis of PCOS (power = 1) and the b
number of oocytes (power = − 0.5)), the multivariable
fractional polynomial interaction analysis showed a posi-
tive interaction between serum progesterone concentrations
and the choice of a freeze-all strategy versus fresh embryo
transfer on live birth (p for interaction 0.0001). The pre-
dicted odds of live birth were greater in the frozen embryo
transfer group at all progesterone concentrations. The dif-
ference in live birth rate between groups was demonstrated
at all progesterone concentrations but the effect was more
pronounced with a progressive increase in progesterone
concentration (Fig. 1a, b). This relationship was maintained
in both unadjusted and adjusted models. When performing
multiple imputation for covariates with missing data, the
interaction effect was still valid (p for interaction < 0.0001). Fig. 1  a Odds ratio of live birth for freeze-all vs frozen transfer at dif-
When further stratify progesterone concentrations into ferent serum progesterone concentrations. b Predicted live birth for
four quartiles, the calculated odds ratios of freeze-all versus freeze-all and fresh embryo transfer by progesterone concentration on
HCG trigger day
fresh transfer on live birth were higher groups with higher
progestereone concentrations (Fig. 2), consistent with find-
ings from multivariable fractional polynomial interaction was still present (Supplementary Figure 1 and 2, p for inter-
analysis in both unadjusted and adjusted models. action = 0.0423 and 0.0025 respectively). For patients over
When repeating the multivariable fractional polyno- 35 years old (n = 4687), the positive interaction between
mial interaction analyses in a subset of patients with single progesterone and treatment effect was also present although
embryo transfer (n = 3586) or blastocyst transfer (n = 9107), the treatment effect curve is almost flat (Fig. 3, p for interac-
the interaction between progesterone and treatment effect tion = 0.01).

Table 2  Outcomes following Outcomes Freeze all (N = 11,122) Fresh (N = 15,539) p-value
freeze-all or fresh embryo
transfer Number of embryos < 0.001
Single embryo transfer 2420 (21.8%) 1168 (7.5%)
Double embryos transfer 8688 (78.2%) 14373 (92.5%)
Stage of embryos < 0.001
Clevage 4101 (36.9%) 13382(86.1%)
Blastocyst 7008 (63.1%) 2157 (13.9%)
Clinical pregnancy 5270 (56.4%) 7817 (50.3%) < 0.001
Live birth 4883 (43.9%) 6256 (40.3%) < 0.001
Multiple birth 1560 (14.0%) 1298 (8.4%) < 0.001

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Journal of Assisted Reproduction and Genetics
Fig. 2  Forest plot for adjusted
odds ratio based on progester-
one concentration (quartile)
Fig. 3  Odds ratios of live birth for freeze-all vs fresh transfer at dif-
ferent serum progesterone concentrations in patients over 35 years old
Discussion
Our results suggest that in an unselected population under-
going IVF/ICSI treatment, there is an increased chance
of pregnancy associated with a freeze-all embryo transfer
strategy at different progesterone concentrations on HCG
trigger day. The effect appears to be dose related with an
increasing magnitude of effect with rising progesterone
concentration. Such an interaction was also observed in
subsets of patients with single embryo transfer, blastocyst
ransfer and patients over 35 years old, but the benefit of a
freeze-all policy appears small in patients over 35 years
old.
The strength of the study includes a large sample size
as well as the exclusion of patients with absolute indica-
tions of freeze-all transfers to minimise indication bias.
Nevertheless, there are a few limitations. Our study was
retrospective in design and limited to a single centre.
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Although the single centre has a large and geographically
varied population, the results may not be readily generalis-
able to all centres and patient populations. While we did
adjust for a minimal set of confounders in the final analy-
sis, one of the inherent limitations of our study design is
the inability to adjust for unknown confounders. At our
centre, vitrification was the preferred method of embryo
cryopreservation and our findings may not, therefore, be
comparable to other programs where methodology other
than vitrification-thaw is used in freeze-all cycles. The
success of freeze-all transfer is defined by an efficient and
well-established freezing program. The pregnancy rate
amongst our freeze-all cycles was 43 percent which is
comparable to large registry data [17, 18].
These limitations notwithstanding, the results we have
presented would suggest that in an unselected patient popu-
lation, a freeze-all approach may be associated with improved
pregnancy outcome as well as significantly reducing the risk
of OHSS and adverse perinatal outcome related to controlled
ovarian hyperstimulation effect on the endometrium and pla-
centation [19, 20]. We did not include cycles in which the
progesterone on the day of trigger was > 2 ng/mL to avoid
confounding by indication but modelling would suggest that
this subgroup of patients would derive greater benefit from
this approach. Our findings are consistent with the previous
large secondary analyses examining the role of progesterone
in fresh and frozen transfer [13]. In comparison to the pri-
mary studies included in Yu et al. which were restricted to
relatively good prognosis populations, we included all cou-
ples undergoing treatment in their first cycle suggesting that
a freeze-all approach would benefit a wider population group.
By comparison, our study population was older, more likely
to have primary infertility and had fewer oocytes collected.
It may be that there is an intrinsic benefit in fresh over frozen
transfer in poorer prognosis populations due to the impact of
cryo-storage on those embryos and a secondary analysis in
couples with female age greater than 35 years is planned to

explore this further. The reduction of benefit in women aged
greater than 35 years may also be representative of an interac-
tion of embryo quality and endometrial receptivity to achieve
a successful pregnancy and a relatively greater impact of
elevated progesterone concentration in women aged less
than 35 where we would assume superior embryo quality.
It is also possible that the effects of supraphysiological sex
steroid levels on the endometrium associated with optimal
ovarian response have an increasingly detrimental effect on
endometrial receptivity in fresh transfer cycles. We would
aim that our study forms a basis for further investigation and
that the hypothesis be tested in future individual participant
data meta-analysis and confirmed in other populations and
settings [21]. Such analyses may be used to explore proges-
terone and other biomarkers which may direct a personal-
ised approach to embryo transfer and other components of
assisted reproductive treatment cycles. More recently, there
have been studies investigating the impact of serum hormone
levels on the day of transfer on fertility outcomes, but the
findings are conflicting [22, 23] and it is unclear whether
these biomarkers on the day of transfer could better guide
the clinical choice on the transfer strategy. Therefore, these
should be further investigated in future studies.
Conclusion
In couples undergoing their first IVF cycles, there is a ben-
efit from a freeze-all transfer strategy as compared to fresh
at all serum progesterone concentrations. The effect on live
births may be of increasing magnitude with increasing pro-
gesterone concentration. In patients over 35 years old, the
benefit of a freeze-all policy appears small. While this study
is hypothesis-generating, it suggests that progesterone may
represent a valuable biomarker to guide clinical decision-
making and optimise outcomes for couples undergoing
assisted reproductive treatment.
Supplementary Information The online version contains supplemen-
tary material available at https://​doi.​org/​10.​1007/​s10815-​024-​03103-y.
Author contributions SH, BWM, LC and RW designed the study. JL,
PL, YZ and LC collected the data. SH, PL, LC and RW contributed
to the data cleaning and analysis. SH, JL, PL, YZ, BWM, LC and RW
interpreted the data. SH and RW drafted the manuscript. JL, PL, YZ,
BWM and LC revising it critically for important intellectual content.
All authors approved the final version to be published.
Funding Open Access funding enabled and organized by CAUL and
its Member Institutions. RW is supported by an NHMRC Emerging
Leadership Investigator Grant (GNT2009767). BWM is supported by
an NHMRC Investigator grant (GNT1176437).
Data availability Data are available from the authors upon reasonable
request and with permission of the research office and ethics committee
at Chengdu Xinan Gynecology Hospital.
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Journal of Assisted Reproduction and Genetics
Declarations
Ethics aproval Ethics approval for the study was granted by
Chengdu Xinan Hospital Reproductive Medicine Ethics Committee
(2021SZLS001) and Monash University Human Research Ethics Com-
mittee (23120).
Competing interests BWM reports consultancy and travel support from
Merck. The other authors do not have competing interests to declare.
Open Access This article is licensed under a Creative Commons Attri-
bution 4.0 International License, which permits use, sharing, adapta-
tion, distribution and reproduction in any medium or format, as long
as you give appropriate credit to the original author(s) and the source,
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LC is no longer affiliated with Chengdu Xinan Gynecology Hospital at
the time of submission.
Publisher’s Note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.
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