Freeze-only versus fresh embryo transfer in a multicenter matched cohort study: contribution of progesterone and maternal age to success rates

In this multi-center matched cohort study, freeze-only cycles were associated with significantly higher pregnancy rates compared with fresh cycles, particularly for patients with progesterone concentration > 1.0 ng/mL at trigger.

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Volume 108, Issue 2, Pages 254–261.e4

Authors:

Ange Wang, M.D., Anthony Santistevan, M.S., Karen Hunter Cohn, Ph.D., Alan Copperman, M.D., John Nulsen, M.D., Brad T. Miller, M.D., Eric Widra, M.D., Lynn M. Westphal, M.D., Piraye Yurttas Beim, Ph.D.

Abstract:

Objective

To compare implantation and ongoing pregnancy rates in freeze-only versus fresh transfer cycles.

Design

Retrospective matched cohort study.

Setting

Not applicable.

Patient(s)

Women selected using a matching algorithm for similar distributions of clinical characteristics for a total of 2,910 cycles (1,455 fresh cohort and 1,455 freeze-only cohort).

Intervention(s)

None.

Main Outcome Measure(s)

Implantation and ongoing pregnancy rates.

Result(s)

Implantation and ongoing pregnancy rates were statistically significantly higher in the freeze-only transfer cohort than in the matched fresh transfer cohort: ongoing pregnancy rate for freeze-only was 52.0% (95% confidence interval [CI], 49.4–54.6) and for fresh was 45.3% (95% CI, 42.7–47.9), odds ratio (OR) 1.31 (95% CI, 1.13–1.51). In a stratified analysis, the odds of ongoing pregnancy after freeze-only transfer were statistically significantly higher for women both above and below age 35 with progesterone concentration >1.0 ng/mL (age ≤35: OR 1.38 [1.11–1.71]; age >35: OR 1.73 [1.34–2.24]). For women with progesterone concentration ≤1.0 ng/mL, no statistically significant difference in freeze-only odds of ongoing pregnancy was observed in either age group. The sensitivity analysis revealed that increasing maternal age alone (regardless of progesterone) trended toward a more beneficial effect of freeze-only cycles. A lower progesterone concentration was associated with statistically significantly higher ongoing pregnancy odds for fresh but not freeze-only cycles.

Conclusion(s)

Freeze-only transfer protocols are associated with statistically significantly higher ongoing implantation and pregnancy rates compared with fresh transfer cycles. This effect is most pronounced for cycles with progesterone >1.0 ng/mL at trigger and may also be stronger for older patients.


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Editorial Office, American Society for Reproductive Medicine

Fertility and Sterility® is an international journal for obstetricians, gynecologists, reproductive endocrinologists, urologists, basic scientists and others who treat and investigate problems of infertility and human reproductive disorders. The journal publishes juried original scientific articles in clinical and laboratory research relevant to reproductive endocrinology, urology, andrology, physiology, immunology, genetics, contraception, and menopause. Fertility and Sterility® encourages and supports meaningful basic and clinical research, and facilitates and promotes excellence in professional education, in the field of reproductive medicine.

3 Comments

Go to the profile of Micah J Hill
Micah J Hill 4 months ago

Thank you for this interesting paper!  Its great to see further data supporting better outcomes in FET cycle with elevated P in the fresh cycle, this time in freeze all FET cycles.

In our data sets, using ROC curves to define the P threshold, we found a cutoff of 1.04, which identical to yours.  In our data set, that would classify 39% of patients as having a positive test.  Is that percent similar to yours?

We also find similar low AUC for P in predicting live birth.  Which is always interesting to me given the strong effect of P is in regression and GEE models on live birth.  Just goes to show how multifactorial live birth as an outcome is. Even very important predictors like age, stage of transfer, quality of embryo, and P have what would be consider poor AUCs by conventional classification.

Go to the profile of Piraye Yurttas Beim, PhD

Thank you! We are prospectively tracking data trends across multiple clinics in the US, and one major shift in protocols that we saw was that more and more clinics are moving to freeze-only cycles. We thought it was important to understand and report the implications for patient outcomes. It’s interesting that you found an identical P threshold in your data analysis as well. Not sure we can give you an apples-to-apples comparison on the question about percentage of patients that have a positive test. The data set that is included in this study was generated using a propensity score matching algorithm to create a matched fresh cohort for comparison to the freeze-only cohort. Accordingly, 66% of the cohort have P greater than 1 ng/mL, which reflects the fact that a freeze-only strategy is utilized more frequently with patients that have elevated P. When we look at the full data set of IVF cycles prior to matching, we see that overall 43% of patients who had P measured during their cycle had P greater than 1 ng/mL. This varies by center with rates ranging from 30% to 60%, possibly due to differences in testing platforms and/or patient selection for testing, as the proportion of patients at a clinic that had P tested at trigger ranged from <10% to nearly all patients. This variability highlights the importance of clinic-based evaluation and calibration of these thresholds.


We completely agree with your comments about low AUC for P in predicting live birth and the multifactorial nature of live birth. It is one of the reasons that we feel that physicians should increasingly become comfortable leveraging multi-variable predictive models in their clinical decision making and patient counseling. So many patients are still counseled based primarily on age or a handful of predictors, like the ones you mention. Thanks again for your comments. If you feel that our Polaris Data Network could be helpful to serve as an extra layer of independent validation for any other trends you are studying at your center, please feel free to reach out to us. 

Go to the profile of Alexander Quaas
Alexander Quaas 4 months ago

This study adds new important information for the freeze-only versus fresh transfer debate, providing potential guidance for which patients should be selected for freeze only cycles. 

With the increasing discussion about the efficacy of freeze-only versus fresh cycles, it is always curious to me that there is so much heterogeneity  in FET protocols and methods between centers.


In this study, did the authors find differences in FET  outcomes between centers or according to the FET method used (natural versus medicated, IM versus PV progesterone etc)?