Kleijkers Sander H M, Mantikou Eleni, Slappendel Els, Consten Dimitri, van Echten-Arends Jannie, Wetzels Alex M, van Wely Madelon, Smits Luc J M, van Montfoort Aafke P A, Repping Sjoerd, Dumoulin John C M, Mastenbroek Sebastiaan
Department of Obstetrics & Gynaecology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands.
Center for Reproductive Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Hum Reprod. 2016 Oct;31(10):2219-30. doi: 10.1093/humrep/dew156. Epub 2016 Aug 23.
Does embryo culture medium influence pregnancy and perinatal outcome in IVF?
Embryo culture media used in IVF affect treatment efficacy and the birthweight of newborns.
A wide variety of culture media for human preimplantation embryos in IVF/ICSI treatments currently exists. It is unknown which medium is best in terms of clinical outcomes. Furthermore, it has been suggested that the culture medium used for the in vitro culture of embryos affects birthweight, but this has never been demonstrated by large randomized trials.
STUDY DESIGN, SIZE, DURATION: We conducted a multicenter, double-blind RCT comparing the use of HTF and G5 embryo culture media in IVF. Between July 2010 and May 2012, 836 couples (419 in the HTF group and 417 in the G5 group) were included. The allocated medium (1:1 allocation) was used in all treatment cycles a couple received within 1 year after randomization, including possible transfers with frozen-thawed embryos. The primary outcome was live birth rate.
PARTICIPANTS/MATERIALS, SETTING, METHODS: Couples that were scheduled for an IVF or an ICSI treatment at one of the six participating centers in the Netherlands or their affiliated clinics.
The live birth rate was higher, albeit nonsignificantly, in couples assigned to G5 than in couples assigned to HTF (44.1% (184/417) versus 37.9% (159/419); RR: 1.2; 95% confidence interval (CI): 0.99-1.37; P = 0.08). Number of utilizable embryos per cycle (2.8 ± 2.3 versus 2.3 ± 1.8; P < 0.001), implantation rate after fresh embryo transfer (20.2 versus 15.3%; P < 0.001) and clinical pregnancy rate (47.7 versus 40.1%; RR: 1.2; 95% CI: 1.02-1.39; P = 0.03) were significantly higher for couples assigned to G5 compared with those assigned to HTF. Of the 383 live born children in this trial, birthweight data from 380 children (300 singletons (G5: 163, HTF: 137) and 80 twin children (G5: 38, HTF: 42)) were retrieved. Birthweight was significantly lower in the G5 group compared with the HTF group, with a mean difference of 158 g (95% CI: 42-275 g; P = 0.008). More singletons were born preterm in the G5 group (8.6% (14/163) versus 2.2% (3/137), but singleton birthweight adjusted for gestational age and gender (z-score) was also lower in the G5 than in the HTF group (-0.13 ± 0.08 versus 0.17 ± 0.08; P = 0.008).
LIMITATIONS, REASONS FOR CAUTION: This study was powered to detect a 10% difference in live births while a smaller difference could still be clinically relevant. The effect of other culture media on perinatal outcome remains to be determined.
Embryo culture media used in IVF affect not only treatment efficacy but also perinatal outcome. This suggests that the millions of human embryos that are cultured in vitro each year are sensitive to their environment. These findings should lead to increased awareness, mechanistic studies and legislative adaptations to protect IVF offspring during the first few days of their existence.
STUDY FUNDING/COMPETING INTERESTS: This project was partly funded by The NutsOhra foundation (Grant 1203-061) and March of Dimes (Grant 6-FY13-153). The authors declare no conflict of interest.
NTR1979 (Netherlands Trial Registry).
1 September 2009.
DATE OF FIRST PATIENT'S ENROLMENT: 18 July 2010.
体外受精中胚胎培养基会影响妊娠及围产期结局吗？
体外受精中使用的胚胎培养基会影响治疗效果及新生儿出生体重。
目前在体外受精/卵胞浆内单精子注射治疗中存在多种用于人类植入前胚胎的培养基。就临床结局而言，哪种培养基最佳尚不清楚。此外，有观点认为用于胚胎体外培养的培养基会影响出生体重，但大型随机试验从未证实这一点。
研究设计、规模、持续时间：我们开展了一项多中心、双盲随机对照试验，比较体外受精中HTF和G5胚胎培养基的使用情况。2010年7月至2012年5月，纳入了836对夫妇（HTF组419对，G5组417对）。随机分组后1年内，一对夫妇接受的所有治疗周期均使用分配的培养基（1:1分配），包括可能进行的冻融胚胎移植。主要结局为活产率。
参与者/材料、环境、方法：计划在荷兰六个参与中心之一或其附属诊所接受体外受精或卵胞浆内单精子注射治疗的夫妇。
分配到G5组的夫妇活产率虽略高于分配到HTF组，但差异无统计学意义（44.1%（184/417）对37.9%（159/419）；相对风险：1.2；95%置信区间：0.99 - 1.37；P = 0.08）。与分配到HTF组的夫妇相比，分配到G5组的夫妇每个周期可利用胚胎数显著更多（2.8±2.3对2.3±1.8；P < 0.001），新鲜胚胎移植后的着床率更高（20.2%对15.3%；P < 0.001），临床妊娠率也更高（47.7%对40.1%；相对风险：1.2；95%置信区间：1.02 - 1.39；P = 0.03）。本试验中383例活产儿童中，获取了380例儿童（300例单胎（G5组：163例，HTF组：137例）和80例双胎儿童（G5组：38例，HTF组：42例））的出生体重数据。G5组出生体重显著低于HTF组，平均差异为158克（95%置信区间：42 - 275克；P = 0.008）。G5组单胎早产的比例更高（8.6%（14/163）对2.2%（3/137）），且经孕周和性别校正后的单胎出生体重（z评分）G5组也低于HTF组（-0.13±0.08对0.17±0.08；P = 0.008）。
局限性、注意事项：本研究的检验效能旨在检测活产率有10%的差异，而较小的差异仍可能具有临床相关性。其他培养基对围产期结局的影响仍有待确定。
体外受精中使用的胚胎培养基不仅会影响治疗效果，还会影响围产期结局。这表明每年在体外培养的数百万人类胚胎对其环境敏感。这些发现应提高人们的认识，引发机制研究，并促使立法做出调整，以在体外受精后代生命的最初几天保护他们。
研究资金/利益冲突：本项目部分由荷兰NutsOhra基金会（资助编号1203 - 061）和美国疾病控制与预防中心（资助编号6 - FY13 - 153）资助。作者声明无利益冲突。
NTR1979（荷兰试验注册库）。
2009年9月1日。
2010年7月18日。
