Clinical Research, IVI Foundation, Health Research Institute la Fe, Valencia, Spain.
IVF Laboratory, IVI-RMA Valencia, Valencia, Spain.
Hum Reprod. 2022 Aug 25;37(9):1980-1993. doi: 10.1093/humrep/deac165.
Does culture in a high relative humidity atmosphere improve clinical outcomes when using a time-lapse integrated incubator and single-step culture medium?
Using an integrated time-lapse system and single-step culture medium, culture in a high relative humidity atmosphere increases the likelihood of embryos, especially those subjected to preimplantation genetic testing for aneuploidies, to achieve a pregnancy compared to those cultured in dry conditions.
The use of a humid atmosphere inside incubators can reduce changes in culture media osmolality, which has been reported to have a significant effect on embryo quality and morphokinetics. Studies assessing the effect of humid culture (HC) in clinical outcomes are, however, scarce and inconclusive, mostly due to a high variability in culture conditions and reduced sample size.
STUDY DESIGN, SIZE, DURATION: Retrospective cohort study performed over 1627 ICSI cycles performed during 3 consecutive years in which embryo cohorts were cultured in a time-lapse incubator with three dry and three humidified chambers, and using single-step culture medium. Clinical outcomes were compared between treatments in which embryo cohorts were cultured in either humid (n = 833) or dry (n = 794) conditions.
PARTICIPANTS/MATERIALS, SETTING, METHODS: The study includes autologous treatments, with (N = 492) and without (N = 372) preimplantation genetic testing for aneuploidies (PGT-A) and ovum donation treatments (N = 763), performed in three university-affiliated private IVF centres. Stimulation, oocyte pickup and fertilization were performed according to the standard procedures of the clinic. All embryo cohorts were cultured in the same model of time-lapse incubator, distributed to either a dry or humidified chamber, while the rest of the culture variables remained equal. The population was weighted by the inverse probability of treatment to control for all measured confounders. The association between HC and the main outcome was assessed by logistic regression over the weighted population. The E-value was reported as a way of considering for unmeasured confounders. Differences in embryo development and other secondary outcomes between the study groups were assessed by Pearson Chi-squared test, ANOVA test and Kaplan-Meier survival analysis.
An univariable logistic regression analysis, weighted by the inverse probability of treatment, determined that embryos cultured in humid conditions are more likely to achieve a clinical pregnancy than those cultured in dry conditions (odds ratio (OR) = 1.236 (95% CI 1.009-1.515), P = 0.041, E = 1.460). Through stratification, it was determined that said effect is dependent on the type of treatment: no improvement in clinical pregnancy was present in ovum donation or autologous treatments, but a statistically significant positive effect was present in treatments with preimplantation genetic testing (OR = 1.699 (95% CI 1.084-2.663), P = 0.021, E = 1.930). Said increase does not relate with an improvement in later outcomes. Differences were also found in variables related to embryo developmental morphokinetics.
LIMITATIONS, REASONS FOR CAUTION: The retrospective nature of the study makes it susceptible to some bias linked to the characteristics of the treatments. To lessen the effect of possible biases, cases were weighted by the inverse probability of treatment prior to the evaluation of the outcome, as means to assess for measured confounders. In addition, the E-value of the weighted OR was calculated as a sensitivity analysis for unmeasured confounders. A randomized prospective study could be performed for further assessing the effect of humid conditions in clinical outcome.
These results support that embryo culture under conditions of high relative humidity contributes to optimize clinical results in undisturbed culture in a time-lapse incubator with single-step medium. To our knowledge, this is the largest study on the matter and the first performing a propensity score-based analysis.
STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the ''Centro para el Desarrollo Tecnologico Industrial'' from the Spanish Ministry of Science, Innovation, and Universities (CDTI-20170310) and Generalitat Valenciana and European Social Fund (ACIF/2019/264). None of the authors have any competing interest to declare.
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在使用延时培养箱和单步培养液的情况下，高相对湿度的环境是否会改善临床结局？
与在干燥条件下培养相比，使用延时培养系统和单步培养液时，高相对湿度环境会增加胚胎（特别是经过胚胎植入前遗传学检测的胚胎）妊娠的可能性。
培养箱内使用高湿度环境可以降低培养液渗透压的变化，这已被报道对胚胎质量和形态动力学有重大影响。然而，评估湿培养（HC）对临床结局影响的研究很少且不一致，主要是因为培养条件的高度变异性和样本量减少。
研究设计、大小和持续时间：这是一项回顾性队列研究，在连续 3 年期间进行了 1627 个 ICSI 周期，其中胚胎队列在具有三个干燥腔室和三个加湿腔室的延时培养箱中使用单步培养液进行培养。在分别在加湿（n=833）或干燥（n=794）条件下培养胚胎的治疗中比较了临床结局。
参与者/材料、设置和方法：该研究包括自体治疗（N=492）和无胚胎植入前遗传学检测（PGT-A）（N=372）以及供卵治疗（N=763），在三个附属私立 IVF 中心进行。刺激、卵母细胞采集和受精均按照诊所的标准程序进行。所有胚胎队列均在同一型号的延时培养箱中培养，分配到干燥腔室或加湿腔室，同时保持其他培养变量相同。通过治疗的逆概率进行加权，以控制所有测量的混杂因素。通过对加权人群进行逻辑回归评估 HC 与主要结局之间的关联。E 值用于考虑未测量的混杂因素。通过 Pearson Chi-squared 检验、方差分析和 Kaplan-Meier 生存分析评估研究组之间胚胎发育和其他次要结局的差异。
单变量逻辑回归分析，通过治疗的逆概率加权，确定在潮湿条件下培养的胚胎比在干燥条件下培养的胚胎更有可能实现临床妊娠（优势比（OR）=1.236（95% CI 1.009-1.515），P=0.041，E=1.460）。通过分层确定，这种效果取决于治疗类型：供卵或自体治疗中没有改善临床妊娠，但在进行胚胎植入前遗传学检测的治疗中存在统计学上显著的积极效果（OR=1.699（95% CI 1.084-2.663），P=0.021，E=1.930）。这种增加与后期结局的改善无关。在与胚胎发育形态动力学相关的变量中也发现了差异。
局限性、谨慎的原因：研究的回顾性性质使其容易受到与治疗特征相关的一些偏差的影响。为了减轻可能存在的偏差的影响，在评估结局之前，通过治疗的逆概率对病例进行加权，以评估测量的混杂因素。此外，还计算了加权 OR 的 E 值作为未测量混杂因素的敏感性分析。可以进行随机前瞻性研究，以进一步评估高湿度条件对临床结局的影响。
这些结果支持在延时培养箱中使用单步培养液的情况下，高相对湿度的环境有助于优化临床结果。据我们所知，这是对此问题进行的最大规模研究，也是首次进行基于倾向评分的分析。
研究资金/利益冲突：这项工作得到了西班牙科学、创新和大学部（CDTI-20170310）和瓦伦西亚大区和欧洲社会基金（ACIF/2019/264）的“工业技术发展中心”的支持。作者均无任何竞争利益需要申报。
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