辅助生殖促排卵过程中使用褪黑素与治疗结局关系的Meta分析

doi:10.12280/gjszjk.20200396

摘要/Abstract

摘要：

目的:系统评价在控制性超促排卵（COH）过程中使用褪黑素对辅助生殖助孕的有效性。方法:检索PubMed、Embase、The Cochrane Library、中国知网、维普、万方数据库及中国生物医学数据库公开发表的全部文献,检索时间是自建库至2020年1月。纳入关于COH过程中使用褪黑素治疗与辅助生殖治疗结局的随机对照试验（RCT）,由两位评价员根据纳入与排除标准独立进行文献筛选、资料提取和质量评价后,采用RevMan 5.3软件进行Meta分析。结果:共纳入6篇 RCT研究,共767个周期,褪黑素组419个周期,对照组348个周期。褪黑素组人绒毛膜促性腺激素（hCG）日雌二醇（E₂）水平、MⅡ期卵母细胞数、优质胚胎数比对照组高,差异有统计学意义（均P<0.05）。褪黑素组临床妊娠率高,但差异无统计学意义（WMD=1.34,P=0.08,95%CI：0.96~1.86）。而2组患者的获卵数、受精率、移植胚胎数、流产率比较差异均无统计学意义（P>0.05）。结论:在辅助生殖助孕COH过程中添加褪黑素可以增加成熟卵和优质胚胎数,且临床妊娠率可能有所改善,该结论仍需更多的大样本量、多中心的RCT研究加以证实。

关键词: 生殖技术, 辅助, 褪黑激素, 排卵诱导, 随机对照试验, Meta分析

Abstract:

Objective: To evaluate the effectiveness of melatonin supplementation during controlled ovarian hyperstimulation for women undergoing assisted reproductive technology.Methods: We searched PubMed, Embase, the Cochrane Library, the CNKI Database, VIP Database, Wanfang Database and the Chinese Biomedicine (CBM) Database for eligible studies published by the end of January 2020. Two independent evaluators screened the randomized controlled trials retrieved the effects of melatonin supplementation during controlled ovarian hyperstimulation in women undergoing assisted reproductive technology. The quality of the included studies was assessed, and the data were extracted for meta-analysis using RevMan 5.3.Results: A total of 6 RCTs involving 767 cycles were included. Among them, 419 cycles were in the melatonin group and 348 cycles in the control group. The meta-analysis showed that the numbers of MⅡ oocytes, high-quality embryos and the E₂ levels on hCG day in the melatonin group was significantly higher than those in the control group (P<0.05). The melatonin supplementation during controlled ovarian hyperstimulation moderately elevated the clinical pregnancy rate, but the difference was not significant (WMD=1.34, P=0.08, 95%CI: 0.96-1.86). However, there were no significant differences in the number of oocytes retrieved and embryos transplanted, fertilization rate and abortion rate between the two groups (P>0.05).Conclusions: The currently available evidence suggests that melatonin supplementation during controlled ovarian hyperstimulation for women undergoing assisted reproductive technology can improve the numbers of MⅡ oocytes and high-quality embryos, and clinical pregnancy rate. Larger sample size and multicenter RCTs are needed to verify the above conclusions.

Key words: Reproductive techniques, assisted, Melatonin, Ovulation induction, Randomized controlled trial, Meta-analysis

周丽媛, 文壹, 唐君, 康革华, 毛增辉. 辅助生殖促排卵过程中使用褪黑素与治疗结局关系的Meta分析[J]. 国际生殖健康/计划生育, 2021, 40(1): 11-17.

ZHOU Li-yuan, WEN Yi, TANG Jun, KANG Ge-hua, MAO Zeng-hui. Meta-Analysis of Melatonin Supplementation during Controlled Ovarian Hyperstimulation for Women Undergoing Assisted Reproductive Technology[J]. Journal of International Reproductive Health/Family Planning, 2021, 40(1): 11-17.

图/表 11

参考文献 28

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纳入研究	样本量（周期）	年龄（岁）	COH方案	药物使用情况	使用时间	观察指标	ART
Batıolu等^[13] （2012年）	褪黑素组：40个周期对照组：45个周期	褪黑素组：（30.4±5.6）岁对照组：（29.7±4.9）岁	激动剂长方案：月经黄体中期开始使用GnRHa降调节,当达到降调标准后使用FSH 150 U/d启动,当主导卵泡平均直径达18 mm时用hCG扳机,hCG扳机后36 h取卵。	褪黑素组：褪黑素3 mg/d（未说明服用时间及方法）; 对照组：空白对照	IVF助孕期间	①②③⑥⑦	IVF
Eryilmaz等^[14] （2011年）	褪黑素组：30个周期对照组：30个周期	褪黑素组：（30.1±4.0）岁对照组：（29.9±3.6）岁	激动剂长方案：月经第21天开始使用亮丙瑞林0.5 mg/d,使用10~14 d,当达到垂体脱敏后使用FSH 150 U/d启动,当3个及3个以上卵泡直径达18 mm以上时使用hCG扳机,hCG扳机后36 h取卵。	褪黑素组：褪黑素3 mg/d,每晚 22：00~23：00单次服用; 对照组：空白对照	取卵周期月经第3~5天开始至hCG扳机日	①②③⑤⑦	IVF
Fernando等^[15] （2018年）	褪黑素组：120个周期对照组：40个周期	褪黑素组：（35.5±4.1）岁对照组：（35.2±4.2）岁	拮抗剂方案：所有患者均接受固定GnRH_A方案,FSH 150~450 U/d启动,专家决定hCG扳机时机,hCG扳机后36 h取卵。	褪黑素组：褪黑素（2mg,2次/d; 4 mg,2次/d;8 mg,2次/d）; 对照组：安慰剂,2次/d	取卵周期月经第2天开始至取卵日	②④⑤⑥⑦	IVF/ICSI
Jahromi等^[16] （2017年）	褪黑素组：32个周期对照组：34个周期	褪黑素组：（35.0±5.1）岁对照组：（35.1±5.1）岁	激动剂长方案：月经第21天开始使用亮丙瑞林0.2 mg/d,月经第2天使用FSH启动,当2个及2个及以上卵泡直径达17~18 mm以上时使用hCG扳机,hCG扳机后34~36 h取卵。	褪黑素组：褪黑素3 mg/d,睡前服用; 对照组：安慰剂,睡前服用	促性腺激素促排卵周期上一个月经周期的第15天开始至取卵日	①③④⑤⑥⑦	IVF/ICSI
Pacchiarotti等^[17] （2016年）	褪黑素组：165个周期对照组：166个周期	褪黑素组：（31.2±2.1）岁对照组：（31.5±2.8）岁	激动剂长方案：月经第21天开始使用曲普瑞林0.1 mg/d,月经第2天使用FSH 225 U/d启动,50%的卵泡直径达到20mm时使用hCG扳机,hCG扳机后36 h取卵。	褪黑素组：褪黑素3 mg/d +肌醇 4 000 mg/d+叶酸400 mg/d,每晚20：00~21：00服用对照组：肌醇4 000 mg/d+叶酸400 mg/d,每晚20：00~21：00服用	取卵周期月经第1天至胚胎移植后14 d	①②⑤⑦	IVF/ICSI
Rizzo等^[18] （2010年）	褪黑素组：32个周期对照组：33个周期	褪黑素组：（37.81 ± 2.61）岁对照组：（38.09 ± 1.97）岁	激动剂长方案：月经黄体中期开始使用GnRHa降调节,当达到降调标准后使用FSH 150 U/d启动,当主导卵泡直径达18 mm时注射hCG,hCG扳机后36 h取卵。	褪黑素组：褪黑素（3 mg/d,1次/d）+肌醇（2 g,2次/d）+叶酸（200 mg,1次/d）（未规定具体服药间）; 对照组：肌醇（2 g,2次/d）+叶酸（200 mg,1次/d）（未规定具体服药间）	GnRHa降调日开始至hCG日	①②③④⑤⑥⑦	IVF

纳入研究	样本量（周期）	年龄（岁）	COH方案	药物使用情况	使用时间	观察指标	ART
Batıolu等^[13] （2012年）	褪黑素组：40个周期对照组：45个周期	褪黑素组：（30.4±5.6）岁对照组：（29.7±4.9）岁	激动剂长方案：月经黄体中期开始使用GnRHa降调节,当达到降调标准后使用FSH 150 U/d启动,当主导卵泡平均直径达18 mm时用hCG扳机,hCG扳机后36 h取卵。	褪黑素组：褪黑素3 mg/d（未说明服用时间及方法）; 对照组：空白对照	IVF助孕期间	①②③⑥⑦	IVF
Eryilmaz等^[14] （2011年）	褪黑素组：30个周期对照组：30个周期	褪黑素组：（30.1±4.0）岁对照组：（29.9±3.6）岁	激动剂长方案：月经第21天开始使用亮丙瑞林0.5 mg/d,使用10~14 d,当达到垂体脱敏后使用FSH 150 U/d启动,当3个及3个以上卵泡直径达18 mm以上时使用hCG扳机,hCG扳机后36 h取卵。	褪黑素组：褪黑素3 mg/d,每晚 22：00~23：00单次服用; 对照组：空白对照	取卵周期月经第3~5天开始至hCG扳机日	①②③⑤⑦	IVF
Fernando等^[15] （2018年）	褪黑素组：120个周期对照组：40个周期	褪黑素组：（35.5±4.1）岁对照组：（35.2±4.2）岁	拮抗剂方案：所有患者均接受固定GnRH_A方案,FSH 150~450 U/d启动,专家决定hCG扳机时机,hCG扳机后36 h取卵。	褪黑素组：褪黑素（2mg,2次/d; 4 mg,2次/d;8 mg,2次/d）; 对照组：安慰剂,2次/d	取卵周期月经第2天开始至取卵日	②④⑤⑥⑦	IVF/ICSI
Jahromi等^[16] （2017年）	褪黑素组：32个周期对照组：34个周期	褪黑素组：（35.0±5.1）岁对照组：（35.1±5.1）岁	激动剂长方案：月经第21天开始使用亮丙瑞林0.2 mg/d,月经第2天使用FSH启动,当2个及2个及以上卵泡直径达17~18 mm以上时使用hCG扳机,hCG扳机后34~36 h取卵。	褪黑素组：褪黑素3 mg/d,睡前服用; 对照组：安慰剂,睡前服用	促性腺激素促排卵周期上一个月经周期的第15天开始至取卵日	①③④⑤⑥⑦	IVF/ICSI
Pacchiarotti等^[17] （2016年）	褪黑素组：165个周期对照组：166个周期	褪黑素组：（31.2±2.1）岁对照组：（31.5±2.8）岁	激动剂长方案：月经第21天开始使用曲普瑞林0.1 mg/d,月经第2天使用FSH 225 U/d启动,50%的卵泡直径达到20mm时使用hCG扳机,hCG扳机后36 h取卵。	褪黑素组：褪黑素3 mg/d +肌醇 4 000 mg/d+叶酸400 mg/d,每晚20：00~21：00服用对照组：肌醇4 000 mg/d+叶酸400 mg/d,每晚20：00~21：00服用	取卵周期月经第1天至胚胎移植后14 d	①②⑤⑦	IVF/ICSI
Rizzo等^[18] （2010年）	褪黑素组：32个周期对照组：33个周期	褪黑素组：（37.81 ± 2.61）岁对照组：（38.09 ± 1.97）岁	激动剂长方案：月经黄体中期开始使用GnRHa降调节,当达到降调标准后使用FSH 150 U/d启动,当主导卵泡直径达18 mm时注射hCG,hCG扳机后36 h取卵。	褪黑素组：褪黑素（3 mg/d,1次/d）+肌醇（2 g,2次/d）+叶酸（200 mg,1次/d）（未规定具体服药间）; 对照组：肌醇（2 g,2次/d）+叶酸（200 mg,1次/d）（未规定具体服药间）	GnRHa降调日开始至hCG日	①②③④⑤⑥⑦	IVF