| 1. |
- Ahlström, Aisling, 1976, et al.
(författare)
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A double-blind randomized controlled trial investigating a time-lapse algorithm for selecting Day 5 blastocysts for transfer
- 2022
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Ingår i: Human Reproduction. - : Oxford University Press (OUP). - 0268-1161 .- 1460-2350. ; 37:4, s. 708-717
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Tidskriftsartikel (refereegranskat)abstract
- STUDY QUESTION Can use of a commercially available time-lapse algorithm for Day 5 blastocyst selection improve pregnancy rates compared with morphology alone? SUMMARY ANSWER The use of a time-lapse selection model to choose blastocysts for fresh single embryo transfer on Day 5 did not improve ongoing pregnancy rate compared to morphology alone. WHAT IS KNOWN ALREADY Evidence from time-lapse monitoring suggests correlations between timing of key developmental events and embryo viability. No good quality evidence exists to support improved pregnancy rates following time-lapse selection. STUDY DESIGN, SIZE, DURATION A prospective multicenter randomized controlled trial including 776 randomized patients was performed between 2018 and 2021. Patients with at least two good quality blastocysts on Day 5 were allocated by a computer randomization program in a proportion of 1:1 into either the control group, whereby single blastocysts were selected for transfer by morphology alone, or the intervention group whereby final selection was decided by a commercially available time-lapse model. The embryologists at the time of blastocyst morphological scoring were blinded to which study group the patients would be randomized, and the physician and patients were blind to which group they were allocated until after the primary outcome was known. The primary outcome was number of ongoing pregnancies in the two groups. PARTICIPANTS/MATERIALS, SETTING, METHODS From 10 Nordic IVF clinics, 776 patients with a minimum of two good quality blastocysts on Day 5 (D5) were randomized into one of the two study groups. A commercial time-lapse model decided the final selection of blastocysts for 387 patients in the intervention (time-lapse) group, and blastocysts with the highest morphological score were transferred for 389 patients in the control group. Only single embryo transfers in fresh cycles were performed. MAIN RESULTS AND THE ROLE OF CHANCE In the full analysis set, the ongoing pregnancy rate for the time-lapse group was 47.4% (175/369) and 48.1% (181/376) in the control group. No statistically significant difference was found between the two groups: mean difference -0.7% (95% CI -8.2, 6.7, P = 0.90). Pregnancy rate (60.2% versus 59.0%, mean difference 1.1%, 95% CI -6.2, 8.4, P = 0.81) and early pregnancy loss (21.2% versus 18.5%, mean difference 2.7%, 95% CI -5.2, 10.6, P = 0.55) were the same for the time-lapse and the control group. Subgroup analyses showed that patient and treatment characteristics did not significantly affect the commercial time-lapse model D5 performance. In the time-lapse group, the choice of best blastocyst changed on 42% of occasions (154/369, 95% CI 36.9, 47.2) after the algorithm was applied, and this rate was similar for most treatment clinics. LIMITATIONS, REASONS FOR CAUTION During 2020, the patient recruitment rate slowed down at participating clinics owing to coronavirus disease-19 restrictions, so the target sample size was not achieved as planned and it was decided to stop the trial prematurely. The study only investigated embryo selection at the blastocyst stage on D5 in fresh IVF transfer cycles. In addition, only blastocysts of good morphological quality were considered for transfer, limiting the number of embryos for selection in both groups: also, it could be argued that this manual preselection of blastocysts limits the theoretical selection power of time-lapse, as well as restricting the results mainly to a good prognosis patient group. Most patients were aimed for blastocyst stage transfer when a minimum of five zygotes were available for extended culture. Finally, the primary clinical outcome evaluated was pregnancy to only 6-8 weeks. WIDER IMPLICATIONS OF THE FINDINGS The study suggests that time-lapse selection with a commercially available time-lapse model does not increase chance of ongoing pregnancy after single blastocyst transfer on Day 5 compared to morphology alone. STUDY FUNDING/COMPETING INTEREST(S) The study was financed by a grant from the Swedish state under the ALF-agreement between the Swedish government and the county councils (ALFGBG-723141). Vitrolife supported the study with embryo culture dishes and culture media. During the study period, T.H. changed his employment from Livio AB to Vitrolife AB. All other authors have no conflicts of interests to disclose. DATE OF FIRST PATIENT'S ENROLMENT 11 June 2018.
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| 2. |
- Ahlström, Aisling, 1976, et al.
(författare)
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Conventional morphology performs better than morphokinetics for prediction of live birth after day 2 transfer
- 2016
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Ingår i: Reproductive Biomedicine Online. - : Elsevier BV. - 1472-6483. ; 33:1, s. 61-70
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Tidskriftsartikel (refereegranskat)abstract
- Numerous studies have reported on the potential value of time-lapse variables for prediction of embryo viability. However, these variables have not been evaluated in combination with conventional morphological grading and patient characteristics. The aim of this study was to assess the ability of patient characteristics and embryo morphology together with morphokinetic variables to predict live birth after day 2 transfer. This retrospective analysis included 207 transferred embryos from 199 couples cultured in a time-lapse system up to day 2 of development. Good prediction of live birth or ranking of embryos with respect to live birth potential was achieved with early cleavage combined with fragmentation grade at 43-45 h. These variables were selected as the strongest predictors of live birth, as assessed by stepwise logistic regression, and additional inclusion of morphokinetic variables did not improve the model significantly. Also, neither logistic regression models nor classification tree models with morphokinetic variables were able to achieve equally good prediction of live birth, as measured by AUC on an external data set not used for model development. In conclusion, for fresh day 2 transfers early cleavage in combination with fragmentation grade at 43-45 h should be considered when selecting between good quality embryos. (C) 2016 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.
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| 3. |
- Ahlström, Aisling, 1976, et al.
(författare)
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Cross-validation and predictive value of near-infrared spectroscopy algorithms for day-5 blastocyst transfer.
- 2011
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Ingår i: Reproductive biomedicine online. - : Elsevier BV. - 1472-6491 .- 1472-6483.
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Tidskriftsartikel (refereegranskat)abstract
- Near-infrared (NIR) spectroscopic metabolomic profiling of spent embryo-culture media has been used to calculate a viability score for individual embryos. These scores have been found to correlate to the reproductive potential of cleavage-stage embryos. In this study, 137 spent blastocyst media samples were collected after single-embryo transfer and analysed by NIR spectroscopy to generate an algorithm and calculate viability scores. To blindly validate the algorithm development process, another algorithm was trained on 47 preselected samples from clinic 1 and then used to predict the outcome of 42 samples from clinic 2. The overall pregnancy rate from the two clinical sites was 50.4%. A positive correlation (R(2)=0.82, P=0.03) was observed with the increasing viability score quintiles and their associated implantation rates. Cross-validation of an algorithm generated from NIR analysis of media samples at one clinical setting blindly was shown to predict implantation potential of blastocysts cultured at another clinic in a different culture media and culture volume. This study demonstrates that metabolomic profiling by NIR spectroscopic analysis of day-5 spent embryo-culture media can predict the implantation potential of blastocysts. Furthermore, this method may not be restricted to a specific set of culturing conditions. The successes of IVF treatment cycles are in part limited by the ability to select the best single embryo from a cohort of patient embryos for transfer back to the woman. Routine procedures of embryo selection are based on morphology, including cell number and size, and the timing of cell division. These methods are favoured because they are quick and easy to assess. Human embryos are grown in culture solutions, which are specific for their stage of development. Recent studies analysing the culture solution in which the embryo are grown, by near infrared (NIR) spectroscopic analysis, have been able to predict if an embryo will implant or not. As culture conditions often vary between IVF laboratories the questions remained if the NIR technique could be used to independently predict the implantation potential of an embryo cultured at one laboratory using an algorithm trained on embryos at a second clinic, a so-called cross-validation. The results of this study show that NIR spectroscopy can predict the ability of embryos to implant even when grown in different IVF laboratories and in two different culture solutions. This information supports the idea that NIR spectroscopy can be used globally not relying on specific culture conditions or media.
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| 4. |
- Ahlström, Aisling, 1976
(författare)
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Prediction of embryo viability by morphology and metabolomic profiling
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Abstract The ultimate challenge for all in vitro fertilisation (IVF) clinics is to develop the ability to select for transfer the best single embryo first, from the patient’s cohort of embryos, thereby maximising the chance of pregnancy while the incidence of multiple pregnancies is kept to a minimum and fewer transfer cycles are required. This ambition has driven extensive research and development into methods that can be used to predict embryo viability. The aims of this thesis were to investigate two non-invasive methods; one new method of metabolomic profiling using Near Infrared (NIR) spectroscopy to analyse spent embryo culture media and the most routine method of morphological grading at the blastocyst stage. In our initial study we investigated metabolimic profiling by NIR spectroscopy and demonstrated that there were distinct differences between NIR spectral profiles of spent embryo culture media of implanting embryos and non-implanting embryos on day 5 of development. These differences were successfully used in a predictive model to calculate viability scores that were positively correlated (R2 = 0.82, P = 0.03) to implantation rates. In addition, viability scores were not related to morphology indicating that this method could be used as an adjunct to current morphological selection criteria. We also showed, by a method of cross-validation, that a predictive algorithm was accurate even when used at different clinics using different blastocyst culture media. These findings, in addition to other published studies, suggest that selection of embryos with high NIR viability scores could potentially improve implantation rates. Unfortunately, when the application of this technology was tested in a prospective randomized controlled trial (RCT) for selection of embryos on day 2 and day 5 for transfer, its use in adjunct to morphology did not significantly improve the ongoing pregnancy rate when compared to morphology alone (34.8% versus 35.6%, P = 0.97). As such, NIR spectroscopy, in its current form, did not improve selection of the most viable embryo for transfer. These results demonstrate the importance of performing RCT’s before committing to the clinical application of any new technology or treatment. We also investigated the independent predictive strength of morphological parameters used to predict blastocyst viability in both fresh and frozen-thawed cycles. We found through our retrospective studies looking at blastocyst morphology and prediction of live birth found that trophectoderm (TE) morphology was the most important predictor after fresh single blastocyst transfer cycles and one of the most important predictors after frozen thawed transfer cycles. Expansion grade was found to be the other most important predictor of live birth after frozen-thawed transfer cycles. The inner cell mass (ICM) in both studies was not shown to be one of the most significant predictors of live birth. We have shown, for the first time, the predictive strength of TE grade over ICM for selecting the best blastocyst for embryo replacement. It may be that, even though ICM is important, a strong TE layer is essential at this stage of embryo development, allowing successful hatching and implantation. Furthermore, we found that for thawed blastocysts degree of re-expansion was the most important post thaw morphological predictor of live birth. In conclusion, we have been able to show that morphology is a strong predictor of embryo viability and by understanding the predictive strength of each parameter being used in a grading system, we can better use these parameters when making our decisions. Furthermore, there is still a need for alternative methods to predict embryo viability, but these new methods should be validated in properly conducted studies before clinical implementation, as shown by the conflicting results in our two studies when testing the NIR technology platform.
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| 5. |
- Ahlström, Aisling, 1976, et al.
(författare)
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Prediction of live birth in frozen-thawed single blastocyst transfer cycles by pre-freeze and post-thaw morphology.
- 2013
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Ingår i: Human reproduction (Oxford, England). - : Oxford University Press (OUP). - 1460-2350 .- 0268-1161. ; 28:5, s. 1199-209
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Tidskriftsartikel (refereegranskat)abstract
- What pre-freeze and post-thaw morphological parameters can be used to predict live birth outcomes after frozen-thawed blastocyst transfer cycles? SUMMARY ANSWER: Pre-freeze blastocoele expansion and trophectoderm (TE) grade and post-thaw degree of re-expansion are the most significant predictors of live birth in frozen-thawed blastocyst transfer cycles. WHAT IS KNOWN ALREADY: Currently, blastocoele re-expansion after thawing is used to indicate blastocyst cryosurvival and reproductive potential. The predictive roles of other pre-freeze and post-thaw morphological parameters are neglected. STUDY DESIGN, SIZE, DURATION: This was a retrospective study of all the patients who received a frozen-thawed single blastocyst transfer (n = 1089) at our clinic between March 2008 and October 2011. PARTICIPANTS/MATERIALS, SETTING, METHODS: Pre-freeze morphological parameters analyzed for all blastocysts included grade of blastocoele expansion, inner cell mass and TE. A group of blastocysts (n = 243) were also graded for post-thaw parameters: degree of blastocoele re-expansion, viability and cell contour. Univariate and multivariate generalized estimating equations (GEEs) models were used to identify the confounders that statistically significantly affected live birth outcomes and to investigate the independent effect of significant pre-freeze and post-thaw morphological parameters. Stepwise logistic regression analysis was used to select the best independent morphological predictors of live birth. Pearson correlations and linear regression analyses were performed to determine the relationship between morphological parameters and possible covariates. MAIN RESULTS AND THE ROLE OF CHANCE: Multivariate GEE models estimated that the odds of live birth increased by ∼36% for each grade of expansion (P = 0.0061) and decreased by 29% for blastocysts with grade B TE compared with grade A TE (P = 0.0099). Furthermore, the odds of live birth increased by ∼39% (P = 0.0042) for each 10% increase in degree of re-expansion. Blastocoele expansion and TE grade were selected as the most significant pre-freeze morphological predictors of live birth and degree of re-expansion was selected as the best post-thaw parameter for prediction of live birth. LIMITATIONS, REASONS FOR CAUTION: Blastocysts with poorer grades of morphology were not cryopreserved or transferred, limiting the ability to generalize our findings for grades of morphology not included in this study. WIDER IMPLICATIONS OF THE FINDINGS: Blastocysts with higher pre-freeze grades of expansion and TE, irrespective of day of cryopreservation, should be given priority when thawing. Subsequently, re-expanding blastocysts, assessed within 2-4 h, with >60% viability should be transferred. STUDY FUNDING/COMPETING INTEREST(S): No external funding was obtained for this study. There was no competing interest.
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| 6. |
- Seli, Emre, et al.
(författare)
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Receiver operating characteristic (ROC) analysis of day 5 morphology grading and metabolomic Viability Score on predicting implantation outcome.
- 2011
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Ingår i: Journal of assisted reproduction and genetics. - : Springer Science and Business Media LLC. - 1573-7330 .- 1058-0468. ; 28:2, s. 137-44
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Tidskriftsartikel (refereegranskat)abstract
- Assessment of embryo viability is a key component of in vitro fertilization (IVF) and currently relies largely on embryo morphology and cleavage rate. In this study, we used receiver operating characteristic (ROC) analysis to compare the Viability Score (generated by metabolomic profiling of spent embryo culture media using near infrared (NIR) spectroscopy) to morphologic grading for predicting pregnancy in women undergoing single embryo transfer (SET) on day 5.
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