辅助生殖技术并发症诊断及处理共识

促排卵治疗是辅助生殖技术(ART)的重要内容之一,但其改善临床妊娠率的同时,亦使卵巢过度刺激综合征(OHSS)、多胎妊娠、多部位妊娠等并发症发生几率增高。本文从ART并发症的诊断、治疗及预防等方面进行阐述,结合近年来国内、外相关领域研究进展及临床应用,中华医学会生殖医学分会部分专家对ART并发症的诊断和处理达成共识,以指导规范的临床应用。     

卵巢高反应患者的促排卵策略

理想的个性化促排卵方案包括在获得最佳的卵子数、胚胎数及良好妊娠结局的同时,避免发生中、重度卵巢过度刺激综合征(OHSS).欧洲人类生殖与胚胎学会(ESHRE)将成功进行辅助生殖技术(ART)治疗定义为获得无OHSS的临床妊娠,获得单胎妊娠和足月健康婴儿.通过控制胚胎移植数可以有效控制多胎妊娠的发生,而OHSS仍然是ART临床中具有潜在生命风险的主要医源性并发症之一,早发型OHSS主要与卵巢高反应直接相关,迟发型(或称晚发型)OHSS主要与妊娠直接相关,亦与卵巢高反应有关,避免中、重度OHSS的发生在体外受精(IVF)临床仍然是值得重点关注和尚未解决的重大问题.     

辅助生殖技术相关血栓性疾病的防治

辅助生殖技术(ART)并发血栓性疾病的报道逐年增加,口服避孕药(OCs)、促排卵药物的应用、卵巢过度刺激综合征(OHSS)以及多胎妊娠是血栓性疾病发生的高危因素。在促排卵治疗过程中,应高度警惕高危人群血栓性疾病的发生,早期诊断并积极治疗。血栓性疾病的发生重在预防。对于既往有血栓病史或血栓家族史的高危患者必要时可行相关易栓症的遗传性筛查。     

超声检查在辅助生殖技术(ART)典型并发症中的研究应用

目的:探讨超声检查在辅助生殖技术(assisted reproductive technology,ART)治疗后发生典型并发症诊疗中的应用价值。方法:对经ART治疗后发生1例重度卵巢过度刺激综合征(ovarian hyperstimulation syndrome,OHSS)合并双侧卵巢破裂出血、1例单侧输卵管双胎妊娠和1例超促排卵妊娠五胞胎病例进行超声检查分析研究。结果:1例重度OHSS卵巢破裂急性出血在超声图像上无特征性表现,主要是呈多房性的卵巢出血处组织局部迅速膨大,内部回声杂乱无章,边界不清,卵巢周围出现游离无回声。1例单侧输卵管双胎妊娠超声显示增粗的输卵管内2个孕囊。1例超促排卵妊娠五胞胎超声显示子宫内5个孕囊及胚芽。结论:ART时严格掌握促排卵尤其超促排卵助孕的合理应用,控制胚胎移植的数量,加强超声检查,检测卵泡发育,预测OHSS程度,及早检出宫外孕和多胎妊娠,以期母婴安全。     

卵巢过度刺激综合征32例临床分析

卵巢过度刺激综合征(OHSS)是采用辅助生殖技术(ART)治疗不孕症患者的常见并发症，主要病理生理机制为血管通透性升高，体液外溢而导致的一系列问题，严重者危及患者生命。现将我院自2000年1月至2004年1月开展ART以来所收治的32例OHSS患者的资料分析如下。     

辅助生殖促排卵药物治疗专家共识

辅助生殖技术(ART)的重要内容之一是促排卵治疗,其应用改善了临床妊娠率,但多胎妊娠、卵巢过度刺激综合征(OHSS)等并发症发生几率较高。促排卵最常用药物为克罗米芬(CC),芳香化酶抑制剂、促性腺激素(Gn)类和促性腺激素释放激素类似物(Gn RHa),包括激动剂(Gn RH-a)和拮抗剂(Gn RH-A)近年来的应用也逐渐增加。各种药物有不同的适应证、禁忌证和用药方案,另外还可使用其他促排卵辅助药物,如口服避孕药(OC)、二甲双胍、多巴胺受体激动剂等,这些促排卵治疗效果可通过常用的疗效评估指标及计算方法来统计。中华医学会生殖医学分会部分专家结合近年来国内、外相关领域研究进展及临床应用,对促排卵药物在ART中的应用达成共识,以指导规范的临床应用。     

黄体期改良超长方案在子宫内膜异位症患者IVF中的应用

目的:探讨改良后的黄体期超长方案降调节在子宫内膜异位症(EMs)和卵巢储备功能稍低患者行IVF治疗中的临床效果。方法:选取行IVF并确诊为EMs的患者112例,其中58例患者给予传统黄体期长效长方案降调节作为对照组,54例患者第1次降调节不理想后再次给予降调节者作为研究组,对比分析研究组和对照组患者的周期取消率、促性腺激素(Gn)使用量、Gn使用天数、获卵数、受精率、临床妊娠率、早期流产率及重度卵巢过度刺激综合征(OHSS)发生率。结果:研究组患者的临床妊娠率和受精率提高,周期取消率、流产率和重度OHSS发生率都有所降低。结论:改良黄体期长方案能够提高EMs患者的临床妊娠率和受精率,同时减少了周期取消率,是一种经济有效的降调节方案。     

口服避孕药在辅助生殖技术中的应用

口服避孕药(OCP)在辅助生殖技术(ART)中有着广泛的应用,但是不同的学者的研究结果不一。多数研究认为,OCP可以改善体外受精的妊娠结局。在助孕周期前应用OCP预处理,可以计划性安排治疗时机、改善卵巢反应性、提高妊娠率、降低周期取消率、预防卵巢过度刺激综合征(OHSS)以及功能性卵巢囊肿等并发症的发生。     

基础窦卵泡数在评价卵巢的反应性及预测人类辅助生殖技术(ART)结局中的作用

目的:探讨基础总窦卵泡数(tAFC)在评价卵巢功能和预测ART结局中的作用。方法:回顾性分析1 353例接受常规体外受精(IVF)/卵母细胞质内单精子显微注射(ICSI)治疗的不孕患者早卵泡期窦卵泡计数的资料,按tAFC分组:A组<5个,B组5~10个,C组11~15个,D组>15个,分别统计各组促性腺激素(Gn)用量、hCG注射日直径≥14 mm卵泡数、获卵数、2原核(2PN)数、可利用胚胎数及妊娠结局。结果:tAFC对卵巢反应性和卵巢储备功能的预测价值优于年龄和基础卵泡刺激素(bFSH),tAFC<10个预示卵巢低反应性,>12个则预示卵巢高反应性;tAFC对ART结局的预测价值稍优于年龄和bFSH,tAFC>10个则预示临床妊娠可能性大,tAFC>15个或<5个则预示周期取消率增加。新鲜周期妊娠率随tAFC增多而上升(C组最高42.3%),周期取消率随tAFC增多而下降,但tAFC>15个时,周期取消率上升至24.2%,主要原因是卵巢过度刺激综合征(OHSS)。结论:基础tAFC与影响ART结局的各种因素密切相关,可作为预测ART结局的参考指标,并且直接有效地评价卵巢储备功能和卵巢反应性,是患者接受ART前的首选检查,临床应用中值得推广。     

体外受精联合未成熟卵母细胞体外培养技术在辅助生殖中的应用价值

近年来卵母细胞体外培养成熟(IVM)技术的应用得到迅速拓展。IVM技术可用于治疗难治 性多囊卵巢综合征(PCOS)的不孕;在常规COH中可以预防卵巢过度刺激综合征(OHSS),拯救在 控制促排卵周期中卵巢的反应不良;自然周期下联合IVM技术可以进一步提高IVF的妊娠率。人 卵母细胞IVM的培养体系的改善提高了IVM的妊娠率。IVM技术因本身价廉、避免药物副作用 以及防止发生OHSS的优点,将会在临床上得到日益广泛的应用。     

拮抗剂方案中hCG的临床应用

促性腺激素释放激素拮抗剂(GnRH-A)在控制性超促排卵(COH)中被用于防止早现的内源性促黄体激素(LH)峰,与GnRH激动剂(GnRH-a)相比较,GnRH-A具有以下优点:没有低雌激素副作用、没有点火效应、起效快且作用可逆。2011年最新的循证医学证据显示,GnRH-A方案联合GnRH-a促发卵子最终成熟在获得了与GnRH-a方案类似的临床妊娠率的同时,可以显著降低卵巢过度刺激综合征(OHSS)的发病率,该方案值得进一步推广和优化。但由于GnRH-A导致体内LH水平显著低于生理水平,可能影响部分患者的卵泡发育,以及GnRH-a应用后对LH活性的抑制可能对黄体功能产生不利影响,LH活性的补充成为近来研究的热点。hCG可以结合体内的LH受体,且半衰期更长、亲和力更高,其效能是LH的6倍左右,hCG在拮抗剂方案中的应用值得进一步研究。     

血管内皮生长因子及其他血管活性物质在卵巢过度刺激综合征发病中的作用

随着生殖辅助技术的不断开展及促超排卵技术的广泛应用 ,卵巢过度刺激综合征呈不断上升的趋势 ,其具体的发病机理不清。因此 ,尽快找到确切的发病机制并进行有效的预防和治疗就成为目前的关键所在。参考近年国外文献 ,着重阐述血管内皮生长因子及其他血管活性物质在卵巢过度刺激综合征发病中的作用     

Live births after management of severe OHSS by GnRH antagonist administration in the luteal phase

Ovarian hyperstimulation syndrome (OHSS) is a serious complication of ovarian stimulation protocols. Currently, no curative therapy exists and the main preventive option is cycle cancellation. Gonadotrophin-releasing hormone (GnRH) antagonist administration in the luteal phase was recently proposed as a new approach for the management of patients with established severe OHSS. Three polycystic ovarian syndrome patients undergoing IVF treatment developed severe OHSS, diagnosed 6 days after oocyte retrieval. On day 6, the patients underwent blastocyst transfer and received GnRH antagonist for 4 days, combined with luteal phase support using exogenous oestradiol and progesterone. Two patients had successful pregnancies that resulted in births of healthy infants, while one patient had a biochemical pregnancy. In all patients, established severe OHSS regressed to a moderate form of the syndrome, no pregnancy-induced life-threatening OHSS was observed, while a short monitoring period was required at an outpatient level, avoiding the need for patient hospitalization. This is the first report in the literature on GnRH antagonist administration in the luteal phase, combined with embryo transfer and exogenous oestradiol and progesterone supplementation. This novel treatment was effective in the regression of established severe OHSS, and resulted in the birth of healthy infants.     

Ovarian hyperstimulation syndrome prevention strategies: use of gonadotropin-releasing hormone antagonists

The most serious complication of ovarian stimulation for in vitro fertilization is severe ovarian hyperstimulation syndrome (OHSS), a rare but potentially life-threatening condition. The present review discusses the place of gonadotropin-releasing hormone antagonists (GnRH-ant) in primary, secondary, and tertiary prevention of OHSS. Sound evidence indicates that the routine use of GnRH-ant instead of GnRH agonists (GnRHa) during ovarian stimulation drastically reduces the relative risk of OHSS. GnRH-ant are therefore useful for primary OHSS prevention, and an increased use of antagonists should help reduce the overall incidence of severe OHSS with its associated risks and complications. In patients on antagonist protocols identified to be at risk of developing severe OHSS, replacing human chorionic gonadotropin with GnRHa as a trigger of final oocyte maturation has been proposed as an effective measure of secondary prevention. A concept of combining GnRHa triggering with cryopreservation of all oocytes or embryos has yielded promising results as far as total avoidance of OHSS is concerned while providing a good chance of pregnancy for the patient in later frozen-thawed embryo transfers. In patients with early onset of OHSS, reinitiation of GnRH-ant in the luteal phase as a measure of tertiary prevention might lead to rapid regression of the syndrome; however only limited data on this new concept are available in the literature.     

多囊卵巢综合征(PCOS)患者在IVF-ET中发生严重卵巢过度刺激综合征(OHSS)的特点分析

目的:通过总结IVF-ET中多囊卵巢综合征(PCOS)患者应用控制性超促排卵(COH)后发生卵巢过度刺激综合征(OHSS)的特点,提出防止中、重度OHSS发生的有效措施。方法:将IVF/ICSI治疗时出现中、重度OHSS的患者根据有无PCOS史分成PCOS组和对照组。比较分析PCOS组和非PCOS组在COH中的雌激素水平、卵泡数、取卵数及发生中、重度OHSS的时间等临床资料;分析妊娠对OHSS的影响。结果:PCOS组的Gn用药总量及hCG注射日的血清E2水平比对照组低,其总卵泡数、中小卵泡数明显高于对照组,发生中、重度OHSS的时间早,妊娠可能加重OHSS病情发展。结论:卵泡总数、中小卵泡数可作为PCOS患者预测中、重度OHSS独立的重要指标,建议即使取卵前E2水平不高、获卵数不多也考虑行全胚冷冻,以阻止严重的OHSS发生。     

Ovarian hyperstimulation syndrome prevention strategies: cryopreservation of all embryos

Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic potentially life-threatening condition resulting from excessive ovarian stimulation. The crucial event in the development of OHSS is the administration of human chorionic gonadotropin (hCG). The early onset of OHSS typically presents in the luteal phase as a consequence of ovulatory hCG. The late onset of OHSS presents in early gestation when endogenous hCG further stimulates the ovary. Many strategies have been proposed for OHSS prevention, but they may reduce but not eliminate the risk. This article reviews the evidence related to the elective cryopreservation of all embryos and their subsequent transfer in women at risk of OHSS. More research is needed to determine whether using elective cryopreservation of embryos can reduce the rate of severe OHSS in in vitro insemination (IVF)/intracytoplasmic sperm injection (ICSI). Results from many retrospective studies are encouraging, but prevention in terms of (1) identification of the high-risk population using new biochemical markers of ovarian response such as anti-Müllerian hormone, (2) tailoring ovarian stimulation and using less aggressive protocols (gonadotropin-releasing hormone antagonists or mild IVF), and (3) blastocyst culture to allow clinical monitoring of early-onset OHSS, with eventual blastocyst cryopreservation, might represent a multistep approach worth further investigation.     

Ovarian response and pregnancy rates in in vitro fertilization, gamete intrafallopian transfer, and in vivo fertilization therapies after combined gonadotropin-releasing hormone agonist/human menopausal gonadotropin stimulation

Ovarian stimulation cycles were initiated using human menopausal gonadotropin (HMG) in 318 women (643 cycles) without pretreatment and in 341 women (525 cycles) after pituitary desensitization by pretreating with the gonadotropin-releasing hormone agonists (GnRH-A) buserelin acetate or triptorelin acetate. Significantly higher pregnancy rates were observed in the GnRH-A/HMG group (15%) as compared to the HMG group (7%) following in vitro (p less than 0.05) but not in vivo fertilization therapy (14 vs. 9%, respectively). After in vitro fertilization, the rates increased with increasing length of the active phase of follicular maturation. Gamete intrafallopian transfer, performed only in the GnRH-A/HMG group, led to a pregnancy rate of 34%. Overall, there was a clear trend to higher pregnancy rates in the GnRH-A/HMG group (16%) as compared to the HMG group (8%). Abortion rates were comparable in both groups (24 vs. 19%). The higher pregnancy rates in the GnRH-A/HMG group were attributable to enhanced follicular maturation and optimized ovarian stimulation produced by the hypogonadotropic state. However, an increased risk of the ovarian hyperstimulation syndrome was observed in these patients.     

Vascular endothelial growth factor response to exogenous chorionic gonadotropic hormone in the luteal phase of women with a history of severe ovarian hyperstimulation syndrome

Ovarian hyperstimulation syndrome (OHSS) is a severe complication of ovarian stimulation. No reliable test exists to predict the syndrome. The objective of the present prospective observational study was to examine vascular endothelial growth factor (VEGF) secretion after human chorionic gonadotropin (hCG) administration in the luteal phase of a spontaneous cycle of women with a history of severe OHSS. Five women with a history of severe OHSS were administered 250 μg recombinant hCG intravenously on day 21 of a spontaneous menstrual cycle. Plasma samples were collected at regular intervals from 15 min before hCG to 6 h thereafter and the free VEGF plasma concentrations were determined. Plasma levels of free VEGF remained at the lower detection limit of the assay throughout the observational period. Women with previous severe OHSS do not show a significant short-time response of VEGF secretion upon hCG administration. No evidence was found to support the notion that women inclined to develop a severe form of the syndrome after ovarian stimulation could possibly be identified by the VEGF short-time secretory response to exogenous hCG in the luteal phase of a spontaneous cycle.     

Clinical aspects of ovarian hyperstimulation syndrome.

Ovarian hyperstimulation syndrome (OHSS) is characterized by massive transudation of protein-rich fluid (mainly albumin) from the vascular space into the peritoneal pleural and to a lesser extent to the pericardial cavities. The intensity of the syndrome is related to the degree of the follicular response in the ovaries to the ovulation inducing agents. OHSS is still a threat to every patient undergoing ovulation induction. The pathophysiology of OHSS is of extreme importance in the face of the increased use of ovulation induction agents as well as the development of sophisticated assisted reproductive techniques. The correlation found between plasma cytokine activities and the severity of OHSS suggests that plasma cytokines may be involved in the pathogenesis of OHSS and may serve as a means of monitoring the syndrome during the acute phase and throughout convalescence. The interactions between cytokine and non-cytokine mediators of the syndrome, such as the renin-angiotensin system and vascular endothelial growth factor were recently clarified. Awareness of possible mechanisms and factors in the pathophysiology of OHSS will hopefully provide opportunities to design specific treatment regimens effective for both prevention and treatment of this potentially fatal iatrogenic condition. Among IVF patients with severe and critical OHSS, pregnancy rates, multiple gestations, miscarriage, preterm premature rupture of the membranes, prematurity, and low birth weight rates are significantly higher than those reported previously for pregnancies after assisted conception. The incidence of other obstetrical complications, as well as congenital malformations and Cesarean section rates are not significantly different.     

Production of 6-keto-PG F1 alpha in hyperstimulated cycles: in vivo and in vitro studies.

Prostacyclin (PG12), a potent vasodilator, is believed to be involved in increasing permeability within the wall of the preovulatory follicle. In ovarian hyperstimulation syndrome (OHSS), increased vascular permeability has been shown to lead to massive fluid accumulation in ovarian cysts and the peritoneal cavity. The objective of the in vitro and in vivo studies reported herein was to examine the production of 6-keto PGF1 alpha (a breakdown metabolite of PG12) during the luteal phase of women who develop OHSS, as well as the capacity of human granulosa luteal cells (GLC) obtained from stimulated in vitro fertilization (IVF) cycles to synthesize PGF1 alpha in vitro in long-term cultures. The in vivo results showed that during the luteal phase of women with OHSS, there is no increase in 6-keto PGF1 alpha production compared with the levels obtained from the luteal phase of normal ovulatory women. The GLC (representing early corpus luteum function) secreted significant amounts of 6-keto PGF1 alpha, but only in the first 48 hours of culture. Human chorionic gonadotropin (hCG) had no additional augmentative effect upon the production of 6-keto PGF1 alpha throughout the culture period. It is concluded that 6-keto PGF1 alpha is not produced in significant amounts during the luteal phase, and therefore PG12 probably does not play a major role in the etiology of OHSS.