Abstract
Purpose
The improvement of clinical outcome provided by time-lapse technology (TLT) in IVF over conventional incubation (CI) still remains controversial. This study aimed at evaluating whether the exclusive use of time-lapse technology (TLT) during whole IVF care improves total cumulative live birth rate (TCLBR) and shortens time to live birth (TTLB) as compared to the use of CI in couples undergoing ICSI.
Methods
This retrospective cohort study was conducted in couples with male infertility undergoing their first ICSI cycle in 2014–2015 and for whom embryo culture system remained the same during their whole IVF care, i.e., TLT or CI. Couples were followed up up to 2020, including all following frozen-embryo transfers and ICSI cycles (if any). Survival analysis was used to compare clinical outcome and time-related endpoints between both groups.
Results
A total of 151 and 250 couples underwent their whole IVF care with the exclusive use of TLT and CI, respectively. Survival analysis showed that TCLBR after whole IVF care was significantly higher in TLT than in CI group (66.9 vs 56.4%, p=0.02, log-rank test). Median live birth time was significantly shorter in TLT than CI group (464 vs 596 days, p=0.01).
Conclusions
We found that TCLBR and TTLB were significantly improved with TLT over CI in couples undergoing ICSI for male factor. This study fuels the debate on the clinical benefit of using TLT. The use of time-related endpoints adds important information for both patients and practitioners.
Keywords: Time-lapse, IVF, Cumulative live birth rate, Time to live birth
Introduction
While offering the best clinical care to infertile patients undergoing in vitro fertilization (IVF) has always been the main concern for infertility specialists, emphasis has obviously been put on improving clinical outcome. Several clinical endpoints can be used, depending on study question and design, but it is generally considered that cumulative live birth rate (CLBR) per cycle is the most relevant outcome to compare or evaluate a clinical procedure in the field of IVF [1]. However, while CLBR gives information on one IVF cycle and allows proper patient’s information and counseling, it does not provide information on the overall chance of achieving live birth throughout the whole IVF journey, potentially including several cycles. In this respect, total cumulative live birth (TCLBR) could provide relevant and complementary information, as it allows evaluating the overall chance of achieving live birth. Meanwhile and quite surprisingly, the timeframe in which IVF clinical outcomes take place has hardly been considered in the literature. Yet, time taken to achieve a live birth (TTLB) is an important consideration when selecting fertility treatment and managing patient expectations, as thoroughly reviewed in a very recent opinion paper, where the importance of using standardized time-related treatment measures in fertility studies is presented and discussed [2].
Among the several technical innovations proposed over the last 2 decades to improve embryo culture and quality assessment, and subsequently optimize treatment outcome, time-lapse technology (TLT) has gained particular interest, as it offers both undisturbed culture environment and continuous monitoring of embryo development, with unprecedented access to all embryo development [3]. Several studies reported significant associations between embryo morphokinetic parameters (alone or combined into algorithms) and clinical outcomes such as blastocyst development, implantation, clinical pregnancy, or live birth (reviewed in [4]). Interestingly, some studies also reported the clinical usefulness of TLT as an exclusion tool for embryos with extremely low implantation potential despite fair morphology [5]. More specifically, embryos displaying abnormal cleavages at early stages, such as direct, uneven, or reverse cleavage, have been shown to have negligible, if not zero, chances of implantation [6, 7]. Altogether, improving the evaluation of both high- and low-quality embryos should make TLT a relevant method to improve clinical outcome and shorten time to live birth. However, this remains debated [8], as no randomized controlled trial (RCT) reported indisputable improvement in live birth rate using TLT rather than conventional incubation (CI) system [9–12]. This was further illustrated by various meta-analyses leading to conflicting conclusions, with some showing improved live birth rate using TLT over CI [13] while other did not find any significant benefit from using TLT [12, 14]. Besides this ongoing debate, only one study reported CLBR as main endpoint to our knowledge [15]. In this retrospective study, the authors found comparable CLBR after one cycle using TLT or CI. However, TTLB was not evaluated.
In order to include time-related treatment measures and to evaluate the overall chance of achieving live birth throughout the whole IVF care, we performed a retrospective study comparing TCLBR and TTLB in couples undergoing ICSI with the exclusive use of either TLT or CI system.
Materials and methods
Study design
This retrospective cohort study was conducted in all consecutive couples with male infertility (defined as abnormal semen analysis with less than 5 million motile sperm cell available after migration) undergoing their first ICSI cycle between January 2014 and December 2015 in a single university-based center. Data were anonymously collected from the local database, in accordance with the French National Commission for Information and Liberties (CNIL). Patients gave their consent for the anonymous use of their data for retrospective studies. The protocol was approved by local ethics committee (GNEDS). Couples were followed up up to August 2020, including all following frozen-embryo transfers and ICSI cycles (if any) performed in the same IVF center. Couples were grouped according to the embryo culture system used during their whole IVF care (follow-up period up to August 2020), i.e., TLT or CI. Couples with a mix of TLT and CI during IVF care were excluded from the analysis.
Ovarian stimulation
Before stimulation, all women had complete ovarian reserve exploration, including FSH, LH, E2, AMH, and antral follicle count (AFC). All patients underwent controlled ovarian stimulation with the antagonist protocol (Cetrorelix, Merck Serono). A gonadotropin-starting dose was chosen according to female age, ovarian reserve, and previous IVF cycles, if they had been undertaken. Cycle monitoring consisted of hormonal assays and ultrasonography, and ovulation was triggered with recombinant hCG when at least 3 follicles reached 18mm in diameter. Oocyte retrieval was performed 36 h later.
Patients’ allocation
Patients were assigned to either time-lapse technology (TLT) or conventional incubation (CI) system depending on the space available. No inclusion criteria (apart from male infertility) were used to recommend the use of TLT. Patients could not choose one of the 2 incubation systems, and were not charged for anything related to embryo culture.
Embryo culture and assessment
In both cases, all mature oocytes were injected and were then cultured under low oxygen atmosphere (6%CO2, 5%O2) in individual microdrops (25μl) in Vitrolife® sequential media (G1plus® from day 0 to day 3, followed by G2plus® from day 3 to day 6). Of note, culture media later shifted to single-step version (GTL®, Vitrolife) during study follow-up period (in 2017). Specifically designed culture dishes were used for TLT (EmbryoSlides®, Vitrolife) and for CI (microdroplets dishes, Vitrolife). The TLT system used in the TLT group was the Embryoscope® (ES-D version, Vitrolife). The incubators used in the CI group were Panasonic® MCO-5M and Thermo Heracell® 150. After checking fertilization on day 1, embryo development was monitored daily according to consensus morphological criteria [16].
In the TLT group, each embryo was investigated by detailed time-lapse analysis measuring the exact timing of the developmental events in hours after ICSI procedure, as described in [17]. Embryos with abnormal division (i.e., chaotic cleavage, reverse cleavage, or direct cleavage from zygote to >2 daughter cells) were discarded, as they have been shown to lead to extremely low implantation rates [6, 9]. Transfer was canceled when only embryos with abnormal cleavage were available. No prediction/ranking model based on morphokinetic markers was used throughout the study period, for fresh or frozen embryos.
On the morning of day 5 and/or day 6, each blastocyst was evaluated according to Gardner and Schoolcraft classification. On day 5, all blastocysts (early cavitating B1 to hatched B6) could be considered usable for transfer or freezing, except those with grade C trophectoderm. Top-grade embryos were evaluated as ≥B3AA on day 5. Top-grade blastocyst rate refers to the proportion of ≥B3AA embryos among all usable blastocyst available on D5. When no blastocyst was available on day 5, culture was prolonged up to day 6, where only blastocysts ≥ B3BB could be considered for transfer or freezing. Embryos with abnormal division (as described above) were discarded and not evaluated on day 5/6.
Vitrification was performed with VitBlast® kit (Vitrolife®, Goteborg, Sweden) according to the manufacturer’s instructions. Thawing was performed with WarmBlast® (Vitrolife®) kit according to the manufacturer’s instructions. One or two blastocysts were transferred according to couple’s history, characteristics and wish, as well as IVF cycle rank and embryo quality. In brief, single blastocyst transfer was systematically recommended in women aged <35 years and/or with a history of previous pregnancy and/or undergoing their first ICSI cycle and/or with at least one top quality blastocyst (≥B3AA).
Parameters investigated in the study
For data analysis, women were divided into 2 groups according to incubation system, i.e., TLT or CI. Main outcome measure was total cumulative live birth rate (TCLBR), defined as the proportion of couples achieving live birth throughout the whole IVF journey, potentially including several ICSI cycles. Secondary outcome measures were time to live birth (TTLB), live birth rate (LBR) after first fresh transfer, and cumulative live birth rate (CLBR) after first ICSI cycle. Embryology outcomes were also recorded, i.e., fertilization rate, proportion of cycles with no blastocyst available, proportion of cycles with at least 1 additional blastocyst available for freezing, and day 5 blastocyst usable rate (D5BUR), defined as the proportion of normally fertilized zygotes leading to a clinically usable blastocyst (see above), as reported in Hammond and Morbeck [18].
Statistical analysis
GraphPad Prism 5 software was used (GraphPad Software, USA). Baseline patients’ characteristics, cycle and embryology parameters, as well as clinical outcomes were compared between the two groups. More specifically, survival analysis was performed (Kaplan-Meier curves) in both groups, with live birth considered as “event.” Couples not achieving live birth during study period (January 2014 to August 2020) were censored. Log-rank test was performed in order to compare total cumulative live birth rate between TLT and CI groups. Results were expressed as hazard ratio (HR) with 95% CI. Time to live birth (TTLB) was measured in days (among women achieving live birth). In order to standardize its calculation, the onset of the first controlled ovarian hyperstimulation was used as start time point. Date of live birth was used as end time point. Median TTLB was calculated as the time when 50% of all the patients of the group have achieved live birth and was compared between both groups.
Results
A total of 620 consecutive couples performed their first ICSI cycle during the 2014–2015 period. Among them, 401 underwent their whole IVF care with the exclusive use of either TLT (n=151 couples) or CI (n=250 couples) and were included in the analysis (Fig. 1). The remaining 219 couples had a mix of TLT and CI throughout their IVF care and were thus excluded from the analysis. The demographic characteristics of the 401 included couples are presented in Table 1. TLT and CI groups were comparable in terms of basal characteristics, ovarian stimulation parameters, and ovarian response to stimulation, except for the number of mature oocytes retrieved which was significantly higher in the CI than in TLT group (Table 1).
Fig. 1.
Flow chart. TLT stands for time-lapse technology and CI for conventional incubation
Table 1.
Demographic and cycle characteristics in conventional incubator (CI) and time-lapse technology (TLT) groups
| Conventional incubator (n=250) | Time-lapse technology (n=151) | P value | |
|---|---|---|---|
| Female age (years) | 31.8±4.7 | 32.4±4.3 | 0.1 |
| Female BMI (kg/m2) | 23.9±5.1 | 23.8±4.7 | 0.2 |
| Active smoking % (n) | 29.7% (73/246) | 22.9% (33/144) | 0.2 |
| Basal FSH (IU/L) | 6.4±2.7 | 6.5±2.1 | 0.2 |
| AMH (μg/L) | 4.6±3.6 | 4.4±3.9 | 0.4 |
| Surgical sperm % (n) | 6.4 (16/250) | 7.3 (11/151) | 0.8 |
| Antagonist protocol % (n) | 97 (243/250) | 97 (146/151) | 0.9 |
| E2 hCG day (pg/ml) | 2026±954 | 2218±931 | 0.8 |
| Endometrial thickness (mm) | 9.1±1.9 | 8.9±1.5 | 0.2 |
| Total dose of gonadotropin (IU) | 2340±1019 | 2423±1071 | 0.4 |
| Oocytes injected | 11.5±6.2 | 9.2±4 | <0.001 |
Results are presented as mean ± standard deviation or proportion when relevant
BMI body mass index, E2 estradiol
p<0.05 was consiered statistically significant
Embryology outcomes were comparable between both groups in terms of fertilization rate, proportion of cycles with at least 1 frozen embryo, top-grade blastocyst rate, proportion of day 5 blastocyst transfer, and mean number of embryo transferred (Table 2). The proportion of cycles with no blastocyst available was significantly lower in TLT than in CI group. Day 5 blastocyst usable rate (D5BUR) tended to be higher in TLT than in CI group, but the difference did not reach statistical significance.
Table 2.
Embryology outcome in conventional incubator (CI) and time-lapse technology (TLT) groups
| Conventional incubator (n=250) | Time-lapse technology (n=151) | P value | |
|---|---|---|---|
| Fertilization rate (%) | 58.3±24.2 | 58.2±22 | 0.8 |
| Cycles with at least 1 frozen embryo (%, n) | 54 (135/250) | 52.3 (79/151) | 0.8 |
| Cycles with no blastocyst available (%, n) | 18 (45/250) | 10.6 (16/151) | 0.045 |
| D5BUR (%) | 31.3±29.8 | 37.2±31 | 0.06 |
| Top-grade blastocyst rate (%) | |||
| Number of embryos transferred | 1.22±0.32 | 1.25±0.43 | 0.5 |
| Proportion of day 5 transfer (%) | 92 (165/179) | 89 (109/123) | 0.3 |
| Freeze all (%, n) | 12.7 (26/205) | 9.7 (12/135) | 0.3 |
Results are presented as mean ± standard deviation or proportion when relevant
D5BUR day 5 blastocyst usable rate
p<0.05 was consiered statistically significant
Clinical outcomes in both groups are presented in Table 3. LBR per fresh embryo transfer and LBR per ovum pickup during the first ICSI cycle were not statistically different between both groups. Cumulative LBR (CLBR) after first ICSI cycle during the first ICSI cycle was not statistically different between both groups. When the whole IVF care up to August 2020 was considered, survival analysis followed by log-rank test showed that the total cumulative LBR (TCLBR) was significantly higher in the TLT group than in CI group (66.9 vs 56.4%, respectively, HR 1.35 95% CI [1.036–1.76]) (p=0.025) (Fig. 2). Among women who achieved live birth, mean time to live birth, number of ovum pickups, and embryo transfers were comparable in both groups. However, median live birth time was significantly shorter in TLT than in CI group (464 vs 596 days, respectively, p=0.01), reflecting that half of the women of the TLT group achieved live birth significantly faster than in CI group.
Table 3.
Clinical outcome in conventional incubator (CI) and Time-lapse technology (TLT) groups
| Conventional incubator (n=250) |
Time-lapse technology (n=151) |
P value | |
|---|---|---|---|
| LBR per fresh embryo transfer during 1st ICSI cycle (%, n) | 41.8 (72/179) | 46.3(57/123) | 0.3 |
| LBR per OPU during 1st ICSI cycle (%, n) | 28.8 (72/250) | 37.7 (57/151) | 0.06 |
| CLBR after 1st cycle (%, n) | 41.2 (103/250) | 47.7 (72/151) | 0.2 |
| TCLBR throughout whole IVF process (%, n) | 56.4 (141/250) | 66.9 (101/151) | 0.02* |
| TTLB mean±sd [range] (days) | 426±276 [181-1776] | 391±175 [249-1022] | 0.4 |
| MLBT (days) | 596 | 464 | 0.01 |
| Number of OPUs per live birth | 1.41±0.7 | 1.3±0.6 | 0.2 |
| Number of embryo transfers per live birth | 1.71±1.09 | 1.65±1.08 | 0.6 |
Results are presented as mean ± standard deviation, median or proportion when relevant. Time To Live Birth (TTLB) corresponds to the time necessary to achieve a live birth (amongst all women achieving live birth). (MLBT) Median live birth time corresponds to the time when 50% of all the patients of the group have achieved live birth. *log-rank (Mantel-Cox) test
Abbreviations: LBR live birth rate, CLBR Cumulative Live Birth Rate, TCLBR Total Cumulative Live Birth Rate, MLBT Median Live Birth Time, OPU Ovum Pick Up, TTLB Time To Live Birth
p<0.05 was consiered statistically significant
Fig. 2.
Total cumulative live birth rate (TCLBR) in the time-lapse technology (TLT) (blue) and conventional incubation (CI) (orange) groups. TCLBR showed a significance between the TLT and the CI groups (log-rank test, p=0.025)
Discussion
In this study, we report for the first time an improved total cumulative live birth rate and shorter time to live birth in couples undergoing ICSI when TLT is exclusively used throughout IVF care as compared to conventional incubation system.
Since its release on the market in 2010, TLT has raised a lot of hope as a way to improve IVF success rate. However, its clinical usefulness still remains debated [8], and an indisputable increase of IVF success rates with the use of TLT remains to be firmly proven. Among all studies comparing TLT and CI reported up to now, only one used CLBR as primary endpoint [15]. In this large retrospective study, the authors found similar CLBR using TLT or CI, although LBR after fresh embryo transfer was significantly higher for TLT cycles. Although CLBR is a relevant clinical outcome measure in IVF, it only gives information on one IVF cycle, and does not provide information on the overall chance of achieving live birth throughout the whole IVF care, and yet some infertile couples undergo several successive fresh and/or frozen-thawed embryo transfer cycles. This is why we decided to use total cumulative live birth (TCLBR), including all IVF cycles performed throughout a given time period, in order to gain a broader picture of the overall chance of achieving live birth in IVF according to the type of incubation system. Whether TCLBR is a more accurate outcome than CLBR on one IVF cycle remains to be addressed. However, it can be postulated that TCLBR can help improve patients’ information and counseling.
Although very rarely considered in fertility studies, time taken to achieve live birth is of utmost importance, not only for infertile couples but also for healthcare professionals, in order to provide appropriate counseling on the most time-efficient strategy. A very recent opinion paper synthesized all these time-related aspects in fertility studies [2]. Strikingly, the authors performed a literature review, and could not find any well-defined treatment time measure for clinical research in fertility studies. We took inspiration from the proposed definitions for start time points and end time points. As timeframe varies significantly in couples during the period before the onset of stimulation (infertility workup, consultations, personal constraints, etc.), we decided to use the onset of controlled ovarian stimulation as the most standard start time point, although not the most precise outcome. The end time point was obviously live birth, as this was the aim of the study. The time to event in each group was calculated in days and allowed calculating time to live birth and median live birth time in order to limit the potential bias associated with hazard ratio calculation. This methodological approach with time-related outcomes had not been evaluated yet in time-lapse studies to our knowledge.
In this study, we aimed at comparing these 2 aspects, i.e., extensive cumulative outcome and time efficiency, in TLT and CI. Therefore, we evaluated both TCLBR over a 6-year period and time to live birth (TTLB). First, we found comparable CLBR after one cycle when TLT is exclusively used as compared to CI. This is in agreement with the only available study reporting cumulative outcome, where CLBR after one cycle was comparable in TLT and CI groups [15]. Then, we went one step further with TCLBR, which was found to be superior with TLT than CI. This might be relevant, as patients not only want to know their short-term prognosis for one given IVF cycle but rather their long-term chance of having a child following IVF care, after multiple cycles if unfortunately necessary. Then, the evaluation of TTLB in both groups showed that the exclusive use of TLI was associated with significantly shorter median live birth time than CI. This has not been reported before, and we believe that this information (if confirmed in further studies) is highly relevant for both patients and practitioners and significantly adds to the ongoing debate on the clinical usefulness of TLT.
Whether for improved TCLBR or shorter TTLB, it is hazardous to speculate on the respective impact of undisturbed culture conditions and embryo evaluation on these apparently improved outcomes with TLT. However, it can be speculated that better embryo quality assessment with TLT has a critical role in shortening time to outcome, as morphokinetic criteria and models allow selecting embryos with high implantation potential first and putting aside embryos with low implantation potential [5]. On the other hand, improved culture conditions might lead to better embryo development and higher embryonic yield, ultimately resulting in better cumulative outcome. Our study was not designed to address this important question and might be used to fuel the ongoing debate [4, 8].
We acknowledge some limitations for this study. First, its retrospective design exposes inherent risk of bias and limited statistical power and thus advocates for further prospective large-scale randomized trials. Meanwhile, these results should be considered with care and should not be applied directly to new patients. Second, our results might not be generalizable to cleavage-stage embryo transfer strategy and to couples with non-male factor infertility. Third, we arbitrarily chose August 2020 as end date for analysis, as the precise date when the patients have decided not to pursue further IVF treatment was not systematically recorded. Fourth, embryos with abnormal cleavage could only be observed and excluded in the TLT group, not in CI group with punctual morphological assessment. Finally, the significantly lower number of oocytes available for ICSI in the TLT group than in the CI group can be explained by the design of the TLT embryo culture dishes where 12 individual culture wells are available. Although this was not a recommendation, this might have punctually lead embryologists to direct cycles with a number of oocytes just above 12 to CI rather than TLT.
Conclusion
In this study, we report for the first time that the exclusive use of TLT is associated with better total cumulative live birth rate and shorter time to live birth in patients undergoing ICSI. Although this needs further confirmation on large-scale prospective studies, we feel that this original approach significantly fuels the ongoing debate on the clinical usefulness of TLT. The use of cumulative and time-related endpoints as well as survival analysis adds important information for both patients and practitioners and paves the way for better counseling and improved research in the field of clinical embryology.
Declarations
Competing interests
T Fréour receives personal fees from Vitrolife. All other authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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