Produção Nacional
Revisado por pares
Effectiveness and safety of time-lapse imaging for embryo culture and selection: it is still too early for any conclusions?
2017; Elsevier BV; Volume: 108; Issue: 3 Linguagem: Inglês
10.1016/j.fertnstert.2017.07.1156
ISSN1556-5653
AutoresCatherine Racowsky, Wellington P. Martins,
Tópico(s)Assisted Reproductive Technology and Twin Pregnancy
ResumoPerhaps the biggest challenge that persists in clinical in vitro fertilization (IVF) is identification of a validated and truly robust methodology for predicting embryonic implantation potential, which has both proven effectiveness and safety. In this context, effectiveness is associated with the improvement in the likelihood of having at least a viable pregnancy to 12 weeks' gestation, while safety refers to obstetrical and perinatal health and, ultimately, the health of mother and child. Much work has recently focused on the efficacy of time-lapse technology for embryo evaluation with algorithms being built from substantial amounts of kinetic and morphological data acquired. Indeed, the Meseguer group in Valencia published one of the first randomized-controlled trials (RCT) to evaluate the efficacy of time-lapse imaging (TLI) for embryo culture and selection (1Rubio I. Galan A. Larreategui Z. Ayerdi F. Bellver J. Herrero J. et al.Clinical validation of embryo culture and selection by morphokinetic analysis: a randomized, controlled trial of the EmbryoScope.Fertil Steril. 2014; 102: 1287-1294.e5Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar). And now in this issue of Fertility and Sterility, this same group tackles the question of safety of a TLI system by comparing obstetrical and perinatal risks for women included in their previously published RCT. Before appraising this present article (2Insua M.F. Cobo A.C. Larreategui Z. Ferrando M. Serra V. Meseguer M. Obstetric and perinatal outcomes of pregnancies conceived with embryos cultured in a time lapse monitoring system.Fertil Steril. 2017; 108: 498-504Scopus (20) Google Scholar), it is useful to evaluate available evidence regarding the effectiveness of this technology in improving reproductive outcomes. Seven RCTs have been published to date. In one, only clinical pregnancy was reported with similar results between groups (3/16: 19% vs. 3/15: 20%, TLI vs. control, respectively), while the remaining six reported ongoing pregnancy. In three of six, different incubators and different embryo selection methods were used, thereby resulting in comparison of the whole system, rather than any efficacy of the TLI selection method as such; in one study, the embryo selection was the same in both groups but the incubator was different, thereby resulting in comparison of the incubators; while in the other two studies, the same incubator was used in the two groups, but embryos were selected using TLI in the test group and conventional morphology in the control group, thereby allowing comparison of the embryo selection method itself. The combined pooled result of these six studies (Fig. 1) does not suggest any evidence of benefit of time-lapse (RR = 1.02; 95% CI = 0.85–1.22) and when combining only the results of the three studies judged to be at low risk of bias, the ongoing pregnancy rate was almost significantly worse in the time-lapse group (RR = 0.80; 95% CI = 0.64–1.02). In fact, the latest published systematic reviews on this issue (3Chen M. Wei S. Hu J. Yuan J. Liu F. Does time-lapse imaging have favorable results for embryo incubation and selection compared with conventional methods in clinical in vitro fertilization? A meta-analysis and systematic review of randomized controlled trials.PLoS One. 2017; 12: e0178720Google Scholar, 4Racowsky C. Kovacs P. Martins W.P. A critical appraisal of time-lapse imaging for embryo selection: where are we and where do we need to go?.J Assist Reprod Genet. 2015; 32: 1025-1030Crossref PubMed Scopus (66) Google Scholar) pointed out that the only study showing a significant benefit of TLI was considered to be at high risk of bias for several reasons. The main conclusion of these reviews is that, compared with conventional approaches, there is currently insufficient evidence to support time-lapse as superior for embryo culture and/or selection. Nevertheless, the present study (2Insua M.F. Cobo A.C. Larreategui Z. Ferrando M. Serra V. Meseguer M. Obstetric and perinatal outcomes of pregnancies conceived with embryos cultured in a time lapse monitoring system.Fertil Steril. 2017; 108: 498-504Scopus (20) Google Scholar) has appraised the safety of this technology in clinical IVF. In this observational study of 378 deliveries, 216 were from the TLI group and 162 from the control group. A sub-analysis was also performed of the 271 singleton deliveries, 149 of which were from the TLI group and 122 were from the control. The authors evaluated the usual range of outcome variables including gestational diabetes, premature rupture of membranes, pregnancy-induced hypertension, preterm and very preterm birth, low and very low birth weight and incidence of minor and major malformations. After adjustment for the majority of potential confounders, the obstetrical and perinatal outcomes were compared. No differences between the TLI and control groups were observed either with analysis of all deliveries, regardless of the number of babies born, or after analysis of only the singleton deliveries. The authors conclude that their study, “demonstrates that no detrimental effects on obstetric or perinatal outcomes are observed when a time-lapse incubator is employed rather than a conventional incubator.” While on the face of it, these findings might be considered reassuring for the ever-evolving field of time-lapse technology in clinical IVF, several aspects of the datasets and analyses performed warrant consideration.•As noted elsewhere (3Chen M. Wei S. Hu J. Yuan J. Liu F. Does time-lapse imaging have favorable results for embryo incubation and selection compared with conventional methods in clinical in vitro fertilization? A meta-analysis and systematic review of randomized controlled trials.PLoS One. 2017; 12: e0178720Google Scholar, 4Racowsky C. Kovacs P. Martins W.P. A critical appraisal of time-lapse imaging for embryo selection: where are we and where do we need to go?.J Assist Reprod Genet. 2015; 32: 1025-1030Crossref PubMed Scopus (66) Google Scholar), there are high risks of bias in the authors' original RCT, with respect to attrition, selection, selective reporting and, last but not least, performance. With regard to the latter, unfortunately the two groups differed regarding different incubators, culture dishes, media volumes and method of culture (embryos grouped vs. cultured one/drop). This RCT therefore did not test effectiveness of the TLI technology itself, but rather efficacy of the overall system (i.e. the EmbryoScope + TLI for embryo selection vs. a standard box incubator + selection using conventional morphology evaluation without TLI). As such, when comparing the results of standard box-type tissue culture incubators vs. new bench-top incubators, any observed difference might be attributable to the use of the modern incubators, which are more stable. Therefore, comparison of obstetrical and perinatal outcomes of the TLI and control groups in Insua et al. (2Insua M.F. Cobo A.C. Larreategui Z. Ferrando M. Serra V. Meseguer M. Obstetric and perinatal outcomes of pregnancies conceived with embryos cultured in a time lapse monitoring system.Fertil Steril. 2017; 108: 498-504Scopus (20) Google Scholar) does not allow any statement to be made regarding safety of the TLI technology as such, but rather of the overall “system” as noted by the authors.•The demographic and descriptive characteristics of women delivering only singletons are not provided, yet those for the whole population are, which included deliveries of one or more baby. The study objectives (as stated in the Abstract) were to compare outcomes of exclusively singleton pregnancies, so inclusion of the characteristics restricted only to this subpopulation would therefore have been more relevant.•Although use of autologous vs. egg donation was controlled for in the analyses, potential variations in uterine receptivity between the two groups cannot be discounted.•Although day of transfer (day 3 or day 5) was controlled for in the regression analysis, the small sample size and increased risk of adverse outcomes associated with blastocyst transfer versus cleavage stage transfer (5Martins W.P. Nastri C.O. Rienzi L. van der Poel S.Z. Gracia C.R. Racowsky C. Obstetrical and perinatal outcomes following blastocyst transfer compared to cleavage transfer: a systematic review and meta-analysis.Hum Reprod. 2016; 31: 2561-2569Crossref PubMed Scopus (38) Google Scholar) weaken the analyses.•The number of fetuses was not included as a confounder in the analysis of all pregnancies, despite the accepted association between increased obstetrical and perinatal risks associated with multiple pregnancies.•The presence of vanishing twins appears not to have been taken into account despite evidence supporting an adverse association between vanishing twins and perinatal outcome and the fact that more than one embryo was transferred in many of the participants. In addition to the considerations just mentioned, note should also be given to the low numbers of singleton pregnancies assessed by Insua et al. (2Insua M.F. Cobo A.C. Larreategui Z. Ferrando M. Serra V. Meseguer M. Obstetric and perinatal outcomes of pregnancies conceived with embryos cultured in a time lapse monitoring system.Fertil Steril. 2017; 108: 498-504Scopus (20) Google Scholar): 149 for the TLI group versus 122 for the control. Notably, the authors observed a prevalence of each of the adverse obstetrical and perinatal outcomes of less than 15%, except for that of Cesarean section which was oddly more prevalent in the control than the TLI group (60.5% vs. 36.9%, respectively). Thus, the sample sizes assessed would only enable identification of enormous effects (Table 1): a 10-fold increase in the risk of a condition with a prevalence of approximately 1% (e.g. an increase of major malformations from 1% to 10%); a 4-fold increase in the risk with a prevalence of approximately 3% (e.g. an increase in very preterm birth from 3% to 12%); a 2.4-fold increase in the risk with a prevalence of 10% (e.g. an increase in preterm birth from 10% to 24%); and a 2.0-fold increase in the risk with a prevalence of 15% (e.g. an increase in pregnancy-induced hypertension from 15% to 30%). Any smaller, but still clinically relevant, differences would pass unnoticed. Therefore, due to the low prevalence of these common adverse outcomes, very substantial numbers of individuals are required for appropriate assessment of whether the TLI system is really safe. As such, sufficiently precise estimates are only possible by assessing outcomes in registry databases, which unfortunately are currently lacking for TLI technology.Table 1Sample size estimation to have sufficient power to detect clinically relevant differences depending on the prevalence of the condition; and detectable difference with the sample sizes evaluated by the present study.Condition prevalence, %Required sample size to have 80% power to detect a differenceDetectable differenceaSample size = 149 vs. 122. Values in parentheses are examples. (sample size = 149 vs. 122)RR ≥ 1.2RR ≥ 1.3RR ≥ 1.5144,000 per group20,000 per group8,000 per groupRR ≥ 10 (1% vs. 10%)314,000 per group7,000 per group2,600 per groupRR ≥ 4.0 (3% vs. 12%)104,000 per group2,000 per group730 per groupRR ≥ 2.4 (10% vs. 24%)152,500 per group1,150 per group450 per groupRR ≥ 2.0 (15% vs. 30%)Note: RR = risk ratio.a Sample size = 149 vs. 122. Values in parentheses are examples. Open table in a new tab Note: RR = risk ratio. Although Insua et al. (2Insua M.F. Cobo A.C. Larreategui Z. Ferrando M. Serra V. Meseguer M. Obstetric and perinatal outcomes of pregnancies conceived with embryos cultured in a time lapse monitoring system.Fertil Steril. 2017; 108: 498-504Scopus (20) Google Scholar) should be commended for this first attempt to assess any adverse effects of a TLI system on obstetrical and perinatal outcomes, readers should take into consideration the limitations of their study, beyond those noted by the authors. In particular, the omissions of important confounders in their analyses, and the small size of their study population unfortunately limit the value of the study. Based on the data they report, we therefore respectfully disagree that their “study demonstrates that no detrimental effects on obstetric or perinatal outcomes are observed when a time-lapse incubator is employed rather than a conventional incubator”. On the other hand, TLI makes IVF even more expensive, increasing the total costs of the lab and staff time. We therefore take the position that it is still very premature to draw any meaningful conclusion about the effectiveness and safety of TLI; and since its utilization increases the total costs, such technology should be used only for research purposes and without charge to patients. Obstetric and perinatal outcomes of pregnancies conceived with embryos cultured in a time-lapse monitoring systemFertility and SterilityVol. 108Issue 3PreviewTo compare obstetric and perinatal outcomes of singleton pregnancies resulting from embryos incubated in a time-lapse system (TLS) with those of embryos grown in standard IVF incubators (SI). Full-Text PDF
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