有关不孕不育研究及管理英国指南Investigatingandtreatingsubfertility

1、有关不孕不育研究及管理英国指南InvestigatingandtreatingsubfertilityOutline目录Philosophy of NICE guidance NICE（ 英国国家卫生医疗质量标准署）的指导理念Diagnosis 诊断When to treat 治疗时机 Treatment 处置NICE versus professional guidelinesNICE与专业指南左图为2013年2月发布的临床指南下图为更新至2015年3月的指南Levels of evidence依据的等级RCT实验的Meta分析和系统回顾至少一个随机对照实验至少一个设计良好的对照实验至少一个

2、设计良好的准实验设计良好的描述性实验，例如对比研究、相关性分析、病例研究等专家报告、观点；官方临床经验等A survey of clinical trials of antibiotic prophylaxis in colon surgery: evidence against further use of no-treatment controls.ML Baum, DS Anish, TC Chalmers, HS Sacks, H Smith and RM Fagerstrom, New Engl J Med 305 (1981), pp. 795799关于在结肠手术中预防性使用抗生素

3、的临床实验的调查研究：证据提示在进一步的临床试验中不得使用空白对照组5图表显示通过预防性使用抗生素减少的结肠手术术周死亡情况等级划分临床证据的质量和建议的可靠性临床指南和其依据的临床证据和评价具有同等效力，GRADE的目标是让临床医生更容易的评估建议的可靠性。Quality of evidence for each outcomeStudy design 实验设计Study quality 实验质量Consistency 实验一致性Directness 实验直接相关性GRADE working group, BMJ, 2004 临床结果证据的质量Quality of evidence实验证据的

4、质量 The extent to which one can be confident that an estimate of effect is correct.在多大程度上，人们可以相信预估结果是正确的呢.GRADE working group, BMJ, 2004 高 中 低 很低预估结果不受其他实验的影响预估结果可能受其他实验的影响预估结果很可能受其他实验的影响预估结果本身就非常的不确定Infertility不孕不育“Failure to conceive after 12 months during which there is sexual intercourse with no

5、use of contraception”“女性在1年不采取避孕措施的性交后未能成功妊娠”Prevalence: 1 in 7 couples患病率：七分之一（每七对夫妇有一对不孕不育）Aims of investigations调查目的To screen筛查To make a diagnosis诊断To predict outlook 预后Evers, 2002 Lancet: 360,151-159Investigations in the female女性调查Routine常规检查Test of ovulation 排卵检查Endocrine screen in anovulatory

6、women 不排卵女性的内分泌筛查Tests of tubal patency 输卵管通畅试验Others其他检查Chlamydia screen 衣原体筛查Uterine assessment 子宫的评估Potential screening tests潜在筛查Prediction of poor response 不良反应的预测Test of ovulation排卵检查Gold standard is pregnancy 妊娠是排卵的金标准History of regular cycles associated with 95% chance of ovulation Behre et a

7、l, HR 2000 在常规的月经周期下，有95%的排卵几率Other tests inferential 其他测试推论Menstrual cycle history 月经周期的历史Mid-luteal serum progesterone 黄体血清孕酮Ultrasound: labour intensive 超声:密集性Endometrial biopsy: invasive 子宫内膜活检:侵袭性Anovulation: endocrine tests排卵障碍：内分泌检查 FSHE2ProlactinSite of lesionLow低Low低Normal正常Hypothalamus下丘脑N

8、ormal正常Normal正常Normal正常Hypo-pit-ov axis下丘脑-垂体-卵巢轴High高Low低Normal正常Ovary卵巢Low低Low低High高Central中枢Also test for thyroid disease (TSH), LH, Testosterone 促卵泡激素 雌二醇 催乳素 病变部位 同时也要检查甲状腺疾病（促甲状腺激素），黄体生成素，睾酮PCOS: Rotterdam consensus criteria多囊卵巢综合征：鹿特丹会议专家推荐标准Oligo and / or anovulation 排卵少和/或不排卵Clinical and bi

9、ochemical signs of hyperandrogenism 临床和生化检查显示雄激素过高Polycystic ovaries 多囊性卵巢Exclusion of other etiologies (Cushings, adrenal hyperplasia) 排除其他病因（库欣综合征，肾上腺增生症）Human Reproduction, 2004Tubal evaluation: predictive value输卵管检查：预测价值 敏感性 特异性Land et al, 1998, Mol et al, 1999子宫输卵管造影 病史衣原体抗体检查Should laparoscopy

10、 be mandatory in the work up of the infertile couple? (Lavy et al EJOGRB 2004)腹腔镜检查是否应该强制性用于不孕夫妇的检查？HSG检查结果样本量腹腔镜检查结果一致腹腔镜检查结果不一致正常或单侧闭塞63603 (5%)双侧闭塞23167 (30%)Retrospective study of 86 patients有关86名患者的回顾性研究Laparoscopy can be omitted in normal HSG findings在HSG正常的患者中腹腔镜检查可以省略Laparoscopy should be pe

11、rformed if bilateral occlusion在双侧输卵管闭塞的患者中腹腔镜检查应该实施HSG vs Lap: pregnancy rate子宫输卵管造影vs腹腔镜：妊娠率LapHSG无闭塞单侧闭塞双侧闭塞总计无闭塞11%0%0%11%单侧闭塞8%12%0%20%双侧闭塞9%5%3%17%总计28%17%3%Mol et al, 1999Routine Hysteroscopy常规子宫镜检查Uterine abnormalities in 10-15% Wallach, 1972 10-15%子宫异常Causal relationship between fibroids and

12、 subfertility unconfirmed Donnez, 2002有关子宫肌瘤和生育能力低下的因果相关性尚未得到证实Fibroids reduce chance of conception 子宫肌瘤减小妊娠概率Hart, 2001No RCTs or controlled studies没有随机对照实验或者对照研究No evidence for routine hysteroscopy 没有关于常规子宫镜检查的临床证据 NICE 2004Laparoscopy v HSG v Ultrasound腹腔镜检查 V 子宫输卵管造影 V 超声检查Diagnosis of tubal blo

13、ckage (laparoscopy as gold standard)腹腔镜检查是诊断输卵管阻塞的金标准Ultrasound超声检查Sensitivity敏感性 95% (78-99%)Specificity特异性 93% (89-96%)HSG子宫输卵管造影Sensitivity敏感性 94% (74-99%)Specificity特异性92% (87-95%)Maheux-Lacroix et al 2014 HRSemen analysis精液分析Volume 精子计数Concentration 浓度Motility (%) 能动性Normal morphology 正常形态Non-r

14、outine: 非常规检查：DNA fragmentation DNA分裂指数Anti-sperm antibody 抗精子抗体Viability tests 发育能力测试AUC:Motility能动性Morphology 形态学Sripada et al, Fertil. Steril. 2009Age and FSH: area under ROC curve年龄和促卵泡激素：受试者特征曲线下面积Chuang et al, 2003. Fertil Steril. 79(1); 63680.63(0.60, 0.66)0.55(0.51, 0.58)0.62(0.58, 0.65)Preg

15、nancy妊娠Age & FSH年龄&促卵泡激素FSH促卵泡激素Age年龄Broekmans et al, 2006Basal serum FSH: 基础血清促卵泡激素：test accuracy测试准确度Summary ROC curve: 37 studiesPoor ovarian response 卵巢反应低下Non-pregnancy未妊娠Broer et al, 2008Antral Follicle Count vs Anti Mullerian Hormone窦卵泡计数vs抗穆氏管荷尔蒙Poor ovarian response 卵巢反应低下Non-pregnancy未妊娠Ba

16、sic tests基础检查Mid-luteal progesterone (D21 in 28 day cycle) 黄体中期孕酮检查（28天月经周期的第21天）Rubella screen 风疹病毒筛查Semen analysis 精液分析Tubal assessment 输卵管评估Bongaarts 1975 adapted by te Velde et al. 2000)怀孕的概率红线指刚停止采取避孕措施蓝色指1年内未妊娠绿色指3年内未妊娠Chances of getting pregnant within the next month次月怀孕的概率尝试妊娠的月份数369122436Ag

17、e 251815121063Age 30161311942Age 351297621Age 40754310.5 Treatments used in infertility治疗不孕不育的方法Tubal输卵管:IVF体外受精, tubal surgery输卵管手术Male 男性:IUI人工授精, IVF体外受精/ICSI卵胞浆内 单精子注射, DIAnovulation不排卵女性: ovulation induction诱导排卵Endometriosis子宫内膜异位症: surgery手术, IUI人工授精, IVF体外受精Unexplained无法解释的原因:expectant期待疗法, e

18、mpirical经验主义Male factor infertility男性不孕症人工授精vs按时规律性交手术或栓塞vs不予处置人工授精vs经宫颈受精（捐精）Anovulation不排卵症TreatmentOR (95% CI)Clomiphene vs no treatment3.41 (1.23 to 9.48)Hughes et al. 2003, Cochrane FSH vs HMG0.89 (0.53 to 1.49)Nugent et al. 2003, Cochrane GnRH agonist in PCOS 1.50 (0.72 to 3.12)Hughes et al. 2

19、003, Cochrane 克罗米芬vs不予处置促卵泡激素vs促性腺激素促性腺激素释放激素激动剂在多囊卵巢综合征中应用Clomiphene v Letrozole克罗米芬v来曲唑Clomiphene (n=376)Letrozole (n=374)SignificanceOvulation rates排卵率48.3%61.7%P=0.001Live birth rates活产率19.1%27.5%P=0.007Pregnancy loss流产率29.1%31.8%NSTwins双胞胎7.4%3.4%NSCongenital anomalies先天异常14P=0.65Legro et al NE

20、JM 2014rFSH v urinary gonadotrophinsfor ovarian stimulation in ART cycles重组人卵泡促激素vs促性腺激素在辅助生殖技术周期卵巢刺激作用Type of urinary gonadotrophin v rec FSHLB or OP with urinaryLB or OP with rFSHRelative effect (95% CI)Number of participants (studies)Quality of the evidence (GRADE)All urinary gonadotrophins245 /

21、1000239 / 1000OR 0.97 (0.87 1.08)7339 (28 studies)highHMG/HMG-HP255 / 1000223 / 1000OR 0.84 (0.72-0.99)3197 (11 studies)HighFSH-P170 / 1000205 / 1000OR 1.26 (0.96 1.64)1430 (5 studies)HighFSH-HP267 / 1000273 / 1000OR 1.03 (0.86 1.22)2712 (13 studies)HighOHSS19 / 100022 / 1000OR 1.18 (0.86 1.61)7740

22、(32 studies)HighCochrane Database Syst Rev. 2011 Feb 16; Recombinant versus urinary gonadotrophin for ovarian stimulation in assisted reproductive technology cycles.van Wely M, Kwan I, Burt AL, Thomas J, Vail A, Van der Veen F, Al-Inany HGEndometriosis and Infertility (RCOG)子宫内膜异位症与不孕不育（英国皇家妇产科学会）No

23、 role for medical treatment药物治疗没有作用 (A)Mild disease: Laparoscopic ablation may improve fertility (A)病情较轻时：腹腔镜下切除可能提高生育能力Mild disease: IUI + SO helpful (A) 病情较轻时：人工授精+超促排卵Moderate disease: surgery may improve fertility (B)病情中等时：手术可能提高生育能力Mild endometriosis and infertility: laparoscopic surgery轻度子宫内膜异

24、位症与不孕不育：腹腔镜手术Jacobson et al, 2003, CochraneMild endometriosis: IUI + superovulation轻度子宫内膜异位症：人工授精+超促排卵Peto OR (95% CI)0.5 1 2 5 10OR 2.7 (1.2 to 5.8)Tummon 1997Fedele 1992Favours controlFavours IUI/ SOUnexplained infertility (UI)原因不明的不孕不育Prevalence 20% - 30% 发病率20%-30%Documented ovulation 常规排卵Normal

25、 semen parameters 精液参数正常Patent fallopian tubes 输卵管正常Clomifene in Unexplained Infertility克罗米芬在原因不明的不孕不育中的应用Anti-oestrogen雌激素拮抗物Corrects subtle ovulatory problems纠正排卵问题Endometrial thinning子宫内膜薄化Multi-follicular ovulation多囊卵巢Oral tablet (days 2-6)口含片Inexpensive 便宜Multiple pregnancy 多胎妊娠Clomifene in une

26、xplained infertility克罗米芬在原因不明的不孕不育中的应用0.99 0.61, 1.600.75 0.43, 1.31Live birthPregnancyHughes et al, 2009, Cochrane LibraryIntra-uterine insemination (IUI) + SO人工授精+ 超促排卵Overcomes hostile cervical factors克服不良的子宫颈因素Ensures proximity of sperm & egg保证精子和卵子结合Less invasive than IVF比体外受精微创Cheaper than IVF

27、 比体外受精便宜SO: risk of multiple pregnancy超促排卵：多胎妊娠的风险Verhulst et al, Cochrane 2006Stimulated IUI vs stimulated TI: live birth宫腔内人工授精vs阴道内人工授精：活胎1.59 0.88, 2.88Veltman-Verhulst et al, Cochrane 2011Natural cycle IUI vs stimulated IUI: live birth自然周期的人工授精vs刺激下人工授精：活胎2.02 1.18, 3.45Favours IUIFavours IUI + SOExpectant期待疗法N = 127IUI + COH人工授精+控制性超排卵N = 126Mean (SD) years of infertility不孕不育的平均时间2.0 ( 0.5) 1.9 (0.5)Mean (SD) female age (years)女性平均年龄33 (3.4)33 (3.1)Ongoing pregnancy继续妊娠率40 (32%)34 (27%)(RR 0.85, 95% CI 0.63 1.1)IUI alone vs expectant management单一人工授