体外受精前进行生活方式干预并不能提高肥胖女性的胚胎利用率和累积活产率：一项巢式队列研究。

Lifestyle intervention prior to IVF does not improve embryo utilization rate and cumulative live birth rate in women with obesity: a nested cohort study.

作者信息

Wang Zheng, Groen Henk, Van Zomeren Koen C, Cantineau Astrid E P, Van Oers Anne, Van Montfoort Aafke P A, Kuchenbecker Walter K H, Pelinck Marie J, Broekmans Frank J M, Klijn Nicole F, Kaaijk Eugenie M, Mol Ben W J, Hoek Annemieke, Van Echten-Arends Jannie

机构信息

Department of Obstetrics and Gynecology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.

Department of Epidemiology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.

出版信息

Hum Reprod Open. 2021 Aug 7;2021(4):hoab032. doi: 10.1093/hropen/hoab032. eCollection 2021.

STUDY QUESTION

Does lifestyle intervention consisting of an energy-restricted diet, enhancement of physical activity and motivational counseling prior to IVF improve embryo utilization rate (EUR) and cumulative live birth rate (CLBR) in women with obesity?

SUMMARY ANSWER

A 6-month lifestyle intervention preceding IVF improved neither EUR nor CLBR in women with obesity in the first IVF treatment cycle where at least one oocyte was retrieved.

WHAT IS KNOWN ALREADY

A randomized controlled trial (RCT) evaluating the efficacy of a low caloric liquid formula diet (LCD) preceding IVF in women with obesity was unable to demonstrate an effect of LCD on embryo quality and live birth rate: in this study, only one fresh embryo transfer (ET) or, in case of freeze-all strategy, the first transfer with frozen-thawed embryos was reported. We hypothesized that any effect on embryo quality of a lifestyle intervention in women with obesity undergoing IVF treatment is better revealed by EUR and CLBR after transfer of all fresh and frozen-thawed embryos.

STUDY DESIGN SIZE DURATION

This is a nested cohort study within an RCT, the LIFEstyle study. The original study examined whether a 6-month lifestyle intervention prior to infertility treatment in women with obesity improved live birth rate, compared to prompt infertility treatment within 24 months after randomization. In the original study between 2009 and 2012, 577 (three women withdrew informed consent) women with obesity and infertility were assigned to a lifestyle intervention followed by infertility treatment (n = 289) or to prompt infertility treatment (n = 285).

PARTICIPANTS/MATERIALS SETTING METHODS: Only participants from the LIFEstyle study who received IVF treatment were eligible for the current analysis. In total, 137 participants (n = 58 in the intervention group and n = 79 in the control group) started the first cycle. In 25 participants, the first cycle was cancelled prior to oocyte retrieval mostly due to poor response. Sixteen participants started a second or third consecutive cycle. The first cycle with successful oocyte retrieval was used for this analysis, resulting in analysis of 51 participants in the intervention group and 72 participants in the control group. Considering differences in embryo scoring methods and ET day strategy between IVF centers, we used EUR as a proxy for embryo quality. EUR was defined as the proportion of inseminated/injected oocytes per cycle that was transferred or cryopreserved as an embryo. Analysis was performed per cycle and per oocyte/embryo. CLBR was defined as the percentage of participants with at least one live birth from the first fresh and subsequent frozen-thawed ET(s). In addition, we calculated the -score for singleton neonatal birthweight and compared these outcomes between the two groups.

MAIN RESULTS AND THE ROLE OF CHANCE

The overall mean age was 31.6 years and the mean BMI was 35.4 ± 3.2 kg/m in the intervention group, and 34.9 ± 2.9 kg/m in the control group. The weight change at 6 months was in favor of the intervention group (mean difference in kg vs the control group: -3.14, 95% CI: -5.73 to -0.56). The median (Q25; Q75) number of oocytes retrieved was 4.00 (2.00; 8.00) in the intervention group versus 6.00 (4.00; 9.75) in the control group, and was not significantly different, as was the number of oocytes inseminated/injected (4.00 [2.00; 8.00] vs 6.00 [3.00; 8.75]), normal fertilized embryos (2.00 [0.50; 5.00] vs 3.00 [1.00; 5.00]) and the number of cryopreserved embryos (2.00 [1.25; 4.75] vs 2.00 [1.00; 4.00]). The median (Q25; Q75) EUR was 33.3% (12.5%; 60.0%) in the intervention group and 33.3% (16.7%; 50.0%) in the control group in the per cycle analysis (adjusted B: 2.7%, 95% CI: -8.6% to 14.0%). In the per oocyte/embryo analysis, in total, 280 oocytes were injected or inseminated in the intervention group, 113 were utilized (transferred or cryopreserved, EUR = 40.4%); in the control group, EUR was 30.8% (142/461). The lifestyle intervention did not significantly improve EUR (adjusted odds ratio [OR]: 1.36, 95% CI: 0.94-1.98) in the per oocyte/embryo analysis, taking into account the interdependency of the oocytes per participant. CLBR was not significantly different between the intervention group and the control group after adjusting for type of infertility (male factor and unexplained) and smoking (27.5% vs 22.2%, adjusted OR: 1.03, 95% CI: 0.43-2.47). Singleton neonatal birthweight and -score were not significantly different between the two groups.

LIMITATIONS REASONS FOR CAUTION

This study is a nested cohort study within an RCT, and no power calculation was performed. The randomization was not stratified for indicated treatment, and although we corrected our analyses for baseline differences, there may be residual confounding. The limited absolute weight loss and the short duration of the lifestyle intervention might be insufficient to affect EUR and CLBR.

WIDER IMPLICATIONS OF THE FINDINGS

Our data do not support the hypothesis of a beneficial short-term effect of lifestyle intervention on EUR and CLBR after IVF in women with obesity, although more studies are needed as there may be a potential clinically relevant effect on EUR.

STUDY FUNDING/COMPETING INTERESTS: The study was supported by a grant from ZonMw, the Dutch Organization for Health Research and Development (50-50110-96-518). A.H. has received an unrestricted educational grant from Ferring pharmaceuticals BV, The Netherlands. B.W.J.M. is supported by an NHMRC Investigator grant (GNT1176437). B.W.J.M. reports consultancy for Guerbet, has been a member of the ObsEva advisory board and holds Stock options for ObsEva. B.W.J.M. has received research funding from Guerbet, Ferring and Merck. F.J.M.B. reports personal fees from membership of the external advisory board for Merck Serono and a research support grant from Merck Serono, outside the submitted work.

TRIAL REGISTRATION NUMBER

The LIFEstyle RCT was registered at the Dutch trial registry (NTR 1530). https://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1530.

研究问题

体外受精（IVF）前进行包括能量限制饮食、增加体育活动和动机咨询在内的生活方式干预，是否能提高肥胖女性的胚胎利用率（EUR）和累积活产率（CLBR）？

简要回答

在首次IVF治疗周期中，至少获取了一个卵母细胞的肥胖女性，在IVF前进行6个月的生活方式干预，既未提高EUR，也未提高CLBR。

已知信息

一项评估IVF前低热量液体配方饮食（LCD）对肥胖女性疗效的随机对照试验（RCT），未能证明LCD对胚胎质量和活产率有影响：在本研究中，仅报告了一次新鲜胚胎移植（ET），或者在全冻策略的情况下，首次解冻胚胎移植。我们假设，对于接受IVF治疗的肥胖女性，生活方式干预对胚胎质量的任何影响，在所有新鲜和冻融胚胎移植后的EUR和CLBR中能得到更好的体现。

研究设计、规模、持续时间：这是一项在RCT（LIFEstyle研究）中的巢式队列研究。原研究探讨了肥胖女性在不孕治疗前进行6个月的生活方式干预，与随机分组后24个月内立即进行不孕治疗相比，是否能提高活产率。在2009年至2012年的原研究中，577名（3名女性撤回知情同意）肥胖不孕女性被分配接受生活方式干预后再进行不孕治疗（n = 289）或立即进行不孕治疗（n = 285）。

参与者/材料、设置、方法：只有来自LIFEstyle研究且接受IVF治疗的参与者符合当前分析条件。共有137名参与者（干预组n = 58，对照组n = 79）开始了第一个周期。25名参与者的第一个周期在卵母细胞获取前取消，主要原因是反应不佳。16名参与者开始了第二个或第三个连续周期。将成功获取卵母细胞的第一个周期用于本分析，结果干预组有51名参与者，对照组有72名参与者。考虑到IVF中心之间胚胎评分方法和ET日策略的差异，我们使用EUR作为胚胎质量的替代指标。EUR定义为每个周期中作为胚胎移植或冷冻保存的受精/注射卵母细胞的比例。分析按每个周期和每个卵母细胞/胚胎进行。CLBR定义为首次新鲜及随后冻融ET后至少有一次活产的参与者百分比。此外，我们计算了单胎新生儿出生体重的z评分，并比较了两组之间的这些结果。

主要结果及机遇的作用

干预组的总体平均年龄为31.6岁，平均BMI为35.4±3.2kg/m²，对照组为34.9±2.9kg/m²。6个月时的体重变化有利于干预组（与对照组相比，kg的平均差异：-3.14，95%CI：-5.73至-0.56）。干预组获取的卵母细胞中位数（Q25；Q75）为4.00（2.00；8.00），对照组为6.00（4.00；9.75），差异无统计学意义，受精/注射的卵母细胞数量（4.00[2.00；8.00]对6.00[3.00；8.75]）、正常受精胚胎数量（2.00[0.50；5.00]对3.00[1.00；5.00]）以及冷冻保存的胚胎数量（2.00[1.25；4.75]对2.00[1.00；4.00]）也无显著差异。在每个周期分析中，干预组的EUR中位数（Q25；Q75）为33.3%（12.5%；60.0%），对照组为33.