目的:系统评价中药在辅助生育技术IVF-ET中干预卵巢过度刺激综合症发生及妊娠结局。方法:电子检索PubMed、Cochrane Library、Web of Science、中国知网数据库和万方数据库,检索自建库至2022年5月发表有关中药在辅助生育技术(IVF-ET)中干预卵巢过度刺激综合症发生及其妊娠结局的随机对照试验。按照既定的纳入及排除标准筛选文献,并对所纳入文献研究进行质量评价及提取数据,再以Review Manager 5.4.1软件进行Meta分析。结果:纳入14篇文献研究,共1854例。Meta分析显示:中药组在辅助生育技术IVF-ET中减低卵巢过度刺激综合症的发生优于对照组(OR = 0.32, 95% CI [0.24, 0.42], P < 0.00001);中药干预亦有效控制IVF-ET中的获卵数目(MD = −2.21, 95% CI [−4.03, −0.39], P = 0.02),而中药组的临床妊娠率较对照组高(OR = 1.68, 95% CI [1.31, 2.16], P < 0.0001)。结论:中药在辅助生育技术IVF-ET中有效减低卵巢过度刺激综合症发生,控制(降低)IVF-ET中的获卵数目,并提高临床妊娠率。但纳入研究质量偏低、疗效评价标准不一,尚需更多高质量、多中心的随机双盲试验,以进一步支持上述结论。 Objective: To systematically evaluate the effect of Chinese medicines on the incidence of ovarian hyperstimulation syndrome (OHSS) and pregnancy outcomes of patients undergoing in vitro fertilization and embryo transplantation (IVF-ET). Methods: Databases such as PubMed, Cochrane Library, Web of Science, CNKI and Wanfang database were searched to collect the randomized clinical trials about the effect of Chinese medicines on the incidence of OHSS and pregnancy outcomes of patients undergoing IVF-ET from the establishment of the database to May 2022. The literatures were screened according to the inclusion and exclusion criteria. The selected literatures underwent quality evaluation prior to data extraction. Then carry out meta-analysis which was performed by using Review Manager 5.4.1. Results: 14 literatures were included in this study, there were 1854 cases in total. The result of meta analysis showed that the effect of lowering the incidence of OHSS was more significant in Chinese medicines group than that of the control group (OR = 0.32, 95% CI [0.24, 0.42], P < 0.00001); Intervention of Chinese medicine could effectively control the number of oocytes retrieved in IVF-ET (MD = −2.21, 95% CI [−4.03, −0.39], P = 0.02). The clinical pregnancy rate in Chinese medicine group was higher than that of control group (OR = 1.68, 95% CI [1.31, 2.16], P < 0.0001). Conclusion: Using Chinese medicine in IVF-ET, it can effectively reduce the incidence of ovarian hyperstimulation syndrome, control (lower) the number of oocytes retrieved; and enhance the clinical pregnancy rate. However, for the poor quality of included RCTs and unstandardized evaluation standards, more randomized-double-blind trials with high quality and multicenter are needed to support the above mentioned conclusion.
目的:系统评价中药在辅助生育技术IVF-ET中干预卵巢过度刺激综合症发生及妊娠结局。方法:电子检索PubMed、Cochrane Library、Web of Science、中国知网数据库和万方数据库,检索自建库至2022年5月发表有关中药在辅助生育技术(IVF-ET)中干预卵巢过度刺激综合症发生及其妊娠结局的随机对照试验。按照既定的纳入及排除标准筛选文献,并对所纳入文献研究进行质量评价及提取数据,再以Review Manager 5.4.1软件进行Meta分析。结果:纳入14篇文献研究,共1854例。Meta分析显示:中药组在辅助生育技术IVF-ET中减低卵巢过度刺激综合症的发生优于对照组(OR = 0.32, 95% CI [0.24, 0.42], P < 0.00001);中药干预亦有效控制IVF-ET中的获卵数目(MD = −2.21, 95% CI [−4.03, −0.39], P = 0.02),而中药组的临床妊娠率较对照组高(OR = 1.68, 95% CI [1.31, 2.16], P < 0.0001)。结论:中药在辅助生育技术IVF-ET中有效减低卵巢过度刺激综合症发生,控制(降低)IVF-ET中的获卵数目,并提高临床妊娠率。但纳入研究质量偏低、疗效评价标准不一,尚需更多高质量、多中心的随机双盲试验,以进一步支持上述结论。
中药,辅助生育技术,体外受精–胚胎移植,卵巢过度刺激综合症,临床妊娠率,Meta分析
Chun Wang Yip1,2,3, Xiang Lin1,2,3, Jin Yu2,4,5, Nansun Zhu3,6, Haiyong Chen1,2,3*, Wei Meng1,2,3 *
1School of Chinese Medicine, The University of Hong Kong, Hong Kong
2Hong Kong Branch of Workstation of Distinguished Professor Yu Jin for Training and Research in Integrative Gynaecology, Hong Kong
3Hong Kong Branch of Workstation of National Master Zhu Nansun for Chinese Medicine Gynaecology, Hong Kong
4Obstetrics and Gynecology Hospital, Fudan University, Shanghai
5Shanghai Taikuntang Hospital of Traditional Chinese Medicine, Shanghai
6Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai
Received: Aug. 23rd, 2022; accepted: Sep. 16th, 2022; published: Sep. 26th, 2022
Objective: To systematically evaluate the effect of Chinese medicines on the incidence of ovarian hyperstimulation syndrome (OHSS) and pregnancy outcomes of patients undergoing in vitro fertilization and embryo transplantation (IVF-ET). Methods: Databases such as PubMed, Cochrane Library, Web of Science, CNKI and Wanfang database were searched to collect the randomized clinical trials about the effect of Chinese medicines on the incidence of OHSS and pregnancy outcomes of patients undergoing IVF-ET from the establishment of the database to May 2022. The literatures were screened according to the inclusion and exclusion criteria. The selected literatures underwent quality evaluation prior to data extraction. Then carry out meta-analysis which was performed by using Review Manager 5.4.1. Results: 14 literatures were included in this study, there were 1854 cases in total. The result of meta analysis showed that the effect of lowering the incidence of OHSS was more significant in Chinese medicines group than that of the control group (OR = 0.32, 95% CI [0.24, 0.42], P < 0.00001); Intervention of Chinese medicine could effectively control the number of oocytes retrieved in IVF-ET (MD = −2.21, 95% CI [−4.03, −0.39], P = 0.02). The clinical pregnancy rate in Chinese medicine group was higher than that of control group (OR = 1.68, 95% CI [1.31, 2.16], P < 0.0001). Conclusion: Using Chinese medicine in IVF-ET, it can effectively reduce the incidence of ovarian hyperstimulation syndrome, control (lower) the number of oocytes retrieved; and enhance the clinical pregnancy rate. However, for the poor quality of included RCTs and unstandardized evaluation standards, more randomized-double-blind trials with high quality and multicenter are needed to support the above mentioned conclusion.
Keywords:Chinese Medicines, Assisted Reproductive Technology, In Vitro Fertilization and Embryo Transplantation (IVF-ET), Ovarian Hyperstimulation Syndrome (OHSS), Clinical Pregnancy Rate, Meta-Analysis
Copyright © 2022 by author(s) and Hans Publishers Inc.
This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).
http://creativecommons.org/licenses/by/4.0/
始于八十年代的辅助生殖技术不断发展,不但为人类解决不孕问题,现代医学更视为人类优生辅助生育的重要手段。卵巢过度刺激综合症(ovarian hyperstimulation syndrome, OHSS)是体外受精–胚胎移植(in vitro fertilization + Embryo Transfer, IVF ET)以及促排卵药物使用,而引起的医源性并发症 [
中医将OHSS按其发病的症状及特征,归于「症瘕」、「子肿」及「腹痛」范畴 [
电子检索中文数据库:中国知网CKNI、万方医学网;英文数据库:PubMed、Cochrane Library、Web of Science数据库中有关中药在体外受精–胚胎移植(in vitro fertilization and embryo Transfer, IVF-ET)中预防卵巢过度刺激综合(ovarian hyperstimulation syndrome, OHSS)的临床随机对照研究。检索时间由数据库建库至2022年5月20日。中文检索词包括「体外受精–胚胎移植」、「卵巢过度刺激综合」、「中医」、「中药」、「随机对照」等,英文检索词为「in vitro fertilization」、「Embryo Transfer」、「ovarian hyperstimulation syndrome」、「Traditional Chinese Medicine」、「TCM」、「randomized controlled trial」等。检索采用主题词与自由词相结合的方式进行。
1) 研究类型:国内外期刊公开发表使用口服中药预防OHSS发生的随机对照试验,是否采用盲法、分配隐藏、中英文文献不限;
2) 研究对象:采用体外受精–胚胎移植助孕的对象,并具有OHSS的高危因素,研究对象的不孕病程、年龄不限;
3) 干预及对照措施:干预措施为IVF促排卵过程期间,采用常规促排卵或西药辅助,配合使用口服中药;对照措施为常规促排卵或西药辅助。干预措施的中药或中成药成份、份量、使用天数不限;
4) 结局指标:OHSS发生率(包括轻、中、重度),以Golan或Navot标准分度、促排卵后的获卵情况(平均获卵数)、临床妊娠率(临床妊娠数/植入总周期数)。
1) 非临床研究类文献;2) 非随机对照试验的文献;3) 重复发表、内容不全或无法获取全文的文献;4) 治疗组的干预措施中采用针灸、中药灌肠、穴位敷贴等中医针灸或外治法文献;5) 中医治疗OHSS相关文献研究
采用EndNote 20软件作文献管理,初步筛选各数据库重复的文献。阅读所得研究的题目与摘要,排除明显不符合纳入标准的研究文献,并筛选有可能符合相关标准的文献。下载并阅读全文以确定符合纳入标准。纳入文献后,按照设计提取研究资料。
采用Cochrane评估偏倚风险工具进行文献质量评价。包括随机分组、分组隐匿、分配盲法、测量盲法、结果完整性、选择性报告及其他偏倚;针对以上7项内容做出3种风险评估结果:低风险、不清楚、高风险。
采用RevMan5.4.1版本软件,以P = 0.1为检验界限,纳入试验,统一进行异质性检验。若异质性检验结果为P ≥ 0.1,I2 ≤ 50%,提示各试验之间一致性较好,采用固定效应模型;若异质性检验结果为P < 0.1,I2 > 50%,提示各试验之间异质性显著,采用随机效应模型。组间差异比较,当P < 0.05时,认为有统计学差异,分析结果用森林图表示。采用漏斗图来分析潜在的发表性偏倚。
按文献检索策略检索,共得CNKI:81篇、WF:68篇,PubMed 62篇,Cochrane Library 54篇,Web of Science 56篇共321篇。经初步筛选,剔除五个数据库重复发表及非相关的文献后为81篇。通过阅读标题与摘要,筛选后为25篇。全面仔细阅读全文后,最终纳入进行Meta分析数目为14篇(见图1)。
按文献检索策略检索,以PubMed作例子进行检索,共得文獻62篇。(见表1)。
经筛选后纳入进行Meta分析之14项研究 [
图1. PRISMA流程图
Search number | Query | Results |
---|---|---|
1 | “in vitro fertilisation” [All Fields] OR “fertilization in vitro” [MeSH Terms] OR (“fertilization” [All Fields] AND “vitro” [All Fields]) OR “fertilization in vitro” [All Fields] OR (“vitro” [All Fields] AND “fertilization” [All Fields]) OR “in vitro fertilization” [All Fields] OR (“embryo transfer” [MeSH Terms] OR (“embryo” [All Fields] AND “transfer” [All Fields]) OR “embryo transfer” [All Fields]) OR (“ovarian hyperstimulation syndrome” [MeSH Terms] OR (“ovarian” [All Fields] AND “hyperstimulation” [All Fields] AND “syndrome” [All Fields]) OR “ovarian hyperstimulation syndrome” [All Fields]) | 69,849 |
2 | “medicine, Chinese traditional” [MeSH Terms] OR (“medicine” [All Fields] AND “Chinese” [All Fields] AND “traditional” [All Fields]) OR “Chinese traditional medicine” [All Fields] OR (“traditional” [All Fields] AND “Chinese” [All Fields] AND “medicine” [All Fields]) OR “traditional Chinese medicine” [All Fields] OR (“trends cardiovasc med” [Journal] OR “case manager” [Journal] OR “tcm” [All Fields]) | 128,827 |
3 | #1 AND #2 | 619 |
4 | Filter: Randomized Controlled Trial | 62 |
表1. PubMed檢索式
纳入研究 | 组别 | 干预措施 | 促排卵方案 | 服药天数 | 结局指标 | |
---|---|---|---|---|---|---|
T/C | 中药组 | 对照组 | ||||
范月梅2021 [ | 41/41 | 参苓白术散 | 空白对照 | 长方案 | 14 | ①②③④ |
刘红丹2020 [ | 32/32 | 麒麟丸 | 阿司匹林及 强的松 | 长方案 | 10 | ①②③④ |
郭银华2020 [ | 25/25 | 补肾促排卵汤 | 空白对照 | 长方案 | 3个周期 | ①②③④⑤ |
姚俐2020 [ | 42/42 | 温阳利水活血方 | 空白对照 | 长方案 | 14 | ①②③④ |
李晓琴2019 [ | 110/108 | 姜黄四物汤 | 阿司匹林 | 长方案 | Gn开始至 取卵后3天 | ①②③④ |
陈小莉2018 [ | 150/48 | 陈皮杜仲水 | 空白对照 | 长方案 | 14 | ①②③④ |
陈小燕2017 [ | 148/150 | 益气血补肝肾中药 | 空白对照 | 长方案 | GnRH-a始至 取卵后10天 | ①②④ |
张连娣2016 [ | 43/43 | 坤灵丸 | 空白对照 | 长方案 | 月经后至卵泡排出 | ①③ |
赵芳2015 [ | 128/177 | 五皮饮加减 | 阿司匹林等 | 未提及 | 未提及 | ①②③ |
牛煜2013 [ | 56/56 | 补肾活血中药 | 空白对照 | 长方案 | 连用2~4天至排卵 | ①③ |
卢亦彬2013 [ | 43/32/32 | 五苓散合五皮饮加味 | 强的松组及 联合组 | 长方案 | Gn5-7天至 取卵后3天 | ①②③④ |
葛明晓2012 [ | 37/31 | 温阳健脾利湿中药 (经后增殖方 + 促黄体方) | 空白对照 | 长方案 | Gn开始至 取卵后10天 | ①②③ |
张宁2011 [ | 50/48 | 补肾化痰中药 | 空白对照 | 长方案 | 3个月 | ①②③④ |
邓伟民2011 [ | 115/134 | 益气血补肝肾中药 (经后增殖颗粒 + 促黄体 颗粒) | 空白对照 | 长方案 | GnRH-a始至 取卵后1周 | ①②③④ |
表2. 纳入研究的基本特征
T:治疗组,C:对照组。① OHSS发生率;② 获卵数;③ 临床妊娠率;④ 实验室数据(VEGF,E2等);⑤ 中医证候积分。① 为必要的结局指标。
按照Cochrane Handbook 5.1.0质量评价标准分析经筛选后纳入的14篇文献 [
图2. 随机对照试验的偏倚风险总结
图3. 偏倚风险评估汇总
14篇文献分析了中药组与对照组OHSS发生率 [
图4. 中药IVF ET中干预后OHSS发生率影响的森林圖
所选12篇文献 [
13篇文献 [
图5. 中药IVF ET中干预后获卵情况影响的森林圖
图6. 中药在IVF ET中干预后临床妊娠率影响的森林圖
图7. 中药IVF ET中干预后OHSS发生率相关文献的漏斗图
分析OHSS发生率的漏斗图以探讨相关文献的发表偏倚。漏斗图的右侧图点较少,出现右下侧缺角。但基本对称程度较大,图点皆处于置信区间,未见明显的发表偏倚情况。有可能因为部分研究样本量不足,或文献随机对照的质量偏低等原因造成。(见图7)。
从纳入的14篇文献中 [
排序 | 药物名称 | 药物类别 | 出现频次 |
---|---|---|---|
1 | 白术 | 补气药 | 9 |
2 | 地黄(包括生地及熟地黄) | 补血药 | 8 |
3 | 菟丝子 | 补阳药 | 7 |
4 | 茯苓 | 利水渗湿药 | 6 |
甘草(包括生甘草及炙甘草) | 补气药 | 6 | |
杜仲 | 补阳药 | 6 | |
5 | 陈皮 | 理气药 | 5 |
表3. 常用中药出现频次列表
所选的14篇文献中 [
本研究选取OHSS发生率、平均取卵数、临床妊娠率作分析,以上三种指标代表IVF-ET并发症(不良反应)的发生情况,卵巢刺激的情况及最终妊娠结局,从以探讨中药在IVF ET中的干预地位及优势。按上述文献的Meta分析,显示中药在IVF-ET中的干预有效降低OHSS发生率、控制过多取卵数目,并提高IVF-ET中临床妊娠率。首先,服用中药后的患者,卵巢处于相对稳定状态,卵泡发育数量下降,有助优质卵泡发育,最终有助提高成胚率 [
《金匮要略》曰:「夫治未病者,见肝之病,知肝传脾,当先实脾」。IVF ET发生OHSS与年龄、多囊卵巢综合症(Polycystic Ovarian Syndrome, PCOS)、基础性激素指标、促排卵方法等 [
中医药现时有针对IVF ET促排卵方案、体质、名老中医经验等方向进行研究。有指IVF ET的促排卵方案使大批的卵泡在短时间内同时发育成熟,属肾精耗损之举 [
从纳入的14篇文献中 [
本研究存在一定的局限性:
1) 纳入的文献质量总体不高,包括纳入之样本量不足,随机方法、分组隐匿、分配盲法、测量盲法、结果完整性、选择性报告、其他偏倚等描述过于简单或未有提及。有些随机方法存在错误,如按时序安排随机方法。
2) 中药干预IVF-ET中未有客观化标准,包括中药干预的时间,加减用药,相关方药、剂量等缺少可以遵循的规范。另外各研究接受IVF-ET患者的促排卵的流程及用药不一。所以都有机会影响随机试验异质性及文献质量。
3) 缺乏明确的循证依据,比较单用中药、中药联合西药干预IVF-ET的最佳方案。
4) 纳入研究之临床指标结果评价缺乏统一标准。
5) 因部分文献缺少其他关键性结局评价指标进行验证。未有探讨中药在IVF-ET中促排卵有效性及各项因子如管内皮生长因子、白介素-6等,诱使OHSS发生的因素。
中药在辅助生育技术IVF-ET中可有效减低卵巢过度刺激综合症(包括轻度、中度、重度)的发生,中药在IVF-ET中能效控制IVF-ET中的获卵数目,并有效提高临床妊娠率。
但因局限纳入研究数量不足、现有研究质量偏低、客观标准不一,故需要纳入更多研究质量高、设计严谨、样本量多、多中心的随机双盲临床研究,以进一步支持本研究。
叶俊宏,林 响,俞 瑾,朱南孫,陈海勇,孟 炜. 中药在辅助生育技术IVF-ET中干预卵巢过度刺激综合症发生及妊娠结局的Meta分析Meta-Analysis of Traditional Chinese Medicine in the Intervention of Ovarian Hyperstimulation Syndrome and Pregnancy Outcome in Assisted Reproductive Technology IVF-ET[J]. 中医学, 2022, 11(05): 980-992. https://doi.org/10.12677/TCM.2022.115141