【作者】 殷莉；

【导师】 马丁； 朱桂金；

【作者基本信息】 华中科技大学 ， 妇产科学， 2013， 博士

【摘要】 第一部分辅助生殖技术治疗后妊娠结局分析目的：回顾性分析辅助生殖技术(assissted reproductive technologies, ART)治疗的妊娠结局,探讨不同ART方式对妊娠结局的影响及ART治疗后不良妊娠结局的风险。方法：选取1997年1月至2011年12月在同济医院生殖中心接受体外受精-胚胎移植治疗(包括新鲜胚胎移植,冻融胚胎移植)并获得临床妊娠的全部周期。通过病例回顾及随访了解其妊娠结局,分析常规体外受精-新鲜胚胎移植组(in vitro fertilization fresh embryo transfer,简称IVF组)、卵细胞浆内单精子注射-新鲜胚胎移植组(intracytoplasmic sperm injection fresh embryo transfer,简称ICSI组)、冷冻复苏胚胎移植组(frozen-thawed embryo transfer,简称FET组)流产率、宫外孕发生率、活产率,妊娠期并发症发病率、多胎妊娠率、多胎分娩率、早产率、出生性别比、新生儿出生缺陷等指标。结果：1.1997年-2011年本中心共有9360个ART临床妊娠周期,随访到最终妊娠结局9303个周期。新鲜移植周期6307个(随访到最终妊娠结局周期6260个),其中IVF4527个(随访到最终妊娠结局周期4496个),ICSI1780个(随访到最终妊娠结局周期1764个),复苏移植周期(FET组)共3052个(随访到最终妊娠结局周期3043个)。2.ART总流产率13.19%(1227/9303),早期流产率12.49%(1162/9303)。IVF组流产率13.21%(594/4496),早期流产率12.41%(558/4496)；ICSI组流产率11.96%(211/1764),早期流产率11.39%(201/1764)；FET组流产率13.87%(422/3043),早期流产率13.24%(403/3043)。各组无差异(p>0.05)。3.ART总宫外孕发生率3.88%(361/9303),宫内外同时妊娠发生率0.32%(30/9303)。IVF组宫外孕率5.27%(237/4496),宫内外同时妊娠发生率0.40%(18/4496)；ICSI组宫外孕率2.49%(44/1764),宫内外同时妊娠发生率0.11%(2/1764)；FET组宫外孕率2.63%(80/3043),宫内外同时妊娠发生率0.33%(10/3043)。ICSI组宫外孕发生率低于IVF组(p<0.05),FET组宫外孕发生率低于新鲜移植周期组(IVF组+ICSI组,4.49%,281/6260)(p<0.05)。4.ART临床妊娠中活产周期比例81.23%(7557/9303)。ICSI组临床妊娠中活产周期比例84.07%(1483/1764)高于IVF组活产周期比例79.78%(3587/4496)(p<0.05)。FET组活产周期比例81.73%(2487/3043)与新鲜周期活产周期比例80.99%(5070/6260)比较,二组无差异(p>0.05)。5.ART妊娠期并发症发病率6.56%(610/9303),IVF组8.11%(365/4496),ICSI组7.99%(141/1764),二组无差异(p>0.05)。FET组妊娠期并发症发病率3.42%(104/3043)低于新鲜周期妊娠期并发症发病率8.08%(506/6260)(p<0.05)。6.ART多胎妊娠率33.29%(3116/9360),多胎分娩率28.41%(2147/7557)。ICSI组多胎妊娠率32.64%(581/1780)、多胎分娩率27.78%(412/1483)与IVF组多胎妊娠率34.72%(1572/4527)、多胎分娩率30.28%(1086/3587)均无差异(p>0.05)。复苏移植周期多胎妊娠率31.54%(863/3053)、多胎分娩率26.1%(649/2487)均低于新鲜移植周期多胎妊娠率34.14%(2153/6307)、多胎分娩率29.55%(1498/5070),(p<0.05)。7.活产分娩周期中,ART总早产率19.96%(1500/7515),ICSI组早产率17.91%(265/1480)低于IVF组早产率20.52%(732/3568)(p<0.05)。复苏移植周期早产率20.39%(503/2467)与新鲜移植周期早产率19.75%(997/5048)无差异(p>0.05)。8.ART活产儿平均出生体重3.00±0.72kg。IVF活产儿平均出生体重2.99±0.68kg与ICSI活产儿平均出生体重2.98±0.68kg无差异(p>0.05)。复苏移植周期活产儿平均出生体重3.03±0.72kg高于新鲜移植周期活产儿平均出生体重2.99±0.68kg(p<0.05)。9.ART活产儿中出生缺陷率1.41%(137/9715),ART男婴出生缺陷率1.64%(85/5196)高于女婴出生缺陷率1.13%(52/4509)(p<0.05)。IVF组活产儿出生缺陷率1.52%(71/4678)与ICSI组活产儿出生缺陷率1.58%(104/6573)无差异(p>0.05)。复苏移植周期活产儿出生缺陷率1.05%(33/3142)低于新鲜移植周期活产儿出生缺陷率1.58%(104/6573)(p<0.05)。10.ART活产儿男女性别比1.15(5196/4509),ICSI组男女性别比0.93(911/984)低于IVF组男女性别比1.22(2565/2110)(p<0.05)。复苏移植周期男女性别比1.22(1720/1415)与新鲜移植周期男女性别比1.12(3476/3094)无差异(p>0.05)。结论：1.与文献报道的普通人群妊娠结局相比,ART没有增加流产和妊娠并发症的风险,活产儿性别比也无差异,但是ART多胎妊娠率和宫外孕发生率明显升高。2.与常规IVF技术相比,ICSI或FET技术并没有增加不良妊娠结局及子代畸形的风险。但是ICSI出生的男婴性别比降低。第二部分辅助生殖技术治疗后活产儿出生缺陷分析目的：分析ART活产儿出生时及出生后婴幼儿期先天畸形发生情况,探讨不同ART方式可能对子代健康的影响。方法：选取1997年1月至2008年12月在同济医院生殖中心接受IVF或ICSI治疗(包括新鲜胚胎移植,冻融胚胎移植)获得活产分娩的全部周期。新生儿出生时及出生2年后随访,记录分娩时母婴情况,发现的畸形(由医院确诊)及治疗结局。比较不同ART方式出生缺陷发生率。结果：1.新生儿出生时随访到3278个活产周期4236个活产儿,发现出生缺陷儿94个,出生缺陷率2.22%(94/4236)。IVF组出生缺陷率2.28%(58/2543),ICSI组2.86%(26/908),FET组1.27%(10/785),各组出生缺陷率没有差异。2.新生儿出生2年后随访到2908个婴幼儿,新发现出生缺陷儿86个。二次随访总出生缺陷率5.16%(150/2908),IVF组5.08%(88/1731),ICSI组6.73%(40/594),FET组3.77%(22/583),各组无差异。ICSI组男孩出生缺陷率8.62%(25/290)高于IVF组男孩5.21%(50/959),p<0.05。结论：与常规IVF技术相比,FET没有增加出生缺陷的风险。但是远期随访发现ICSI出生的男孩先天缺陷的风险增加。部分畸形在子代生长发育过程中才会被发现,因此,评估ART子代安全性需要更长时间的随访。更多还原

【Abstract】 Part ⅠThe Pregnancy Outcome of Artificial Reproductive TechnologyObjective:Pregnancy outcome of patients conceived by assissted reproductive treatments were retrospectively analyzed to evaluate the effect of different assissted reproductive technologies on clinical pregnancy outcome.Methoeds:All clinical pregnancy cycles after assissted reproductive technologies (ART)-including in vitro fertilization fresh embryo transfer (IVF), intracytoplasmic sperm injection fresh embryo transfer (ICSI), frozen-thawed embryo transfer (FET), in the Center of Reproductive Medicine, Tongji Hospital from1st January1997to31th December2011were retrospectively analyzed. The rates of miscarriage, ectopic pregnancy, live birth delivery, disorders in pregnancy, multiple pregnancy, multiple delivery, preterm labor, sex ratio at birth and birth defect in group ICSI and group FET were compared with that in group IVF.Result:1. A total of9360clinical pregnancy cycles were analyzed, and the pregnancy outcome was followed up in9303cycles. There were6307cycles (6260cycles followed up) of fresh embryo transfer, including4527IVF cycles (4496cycles followed up), and1780ICSI cycles (1764cycles followed up). There were3052cycles of frozen-thawed embryo transfer (3043cycles followed up).2. The miscarriage rate in all ART cycles was13.19%(1227/9303), and early miscarriage rate was12.49%(1162/9303). There were no difference in the three groups:IVF13.21%(594/4496), ICSI11.96%(211/1764), FET13.87%(422/3043).3. The rate of ectopic pregnancy in all cycles was3.88%(361/9303), and the rate of heterotopic pregnancy was0.32%(30/9303). Compared with group IVF, the rates of ectopic pregnancy in group ICSI was decreased (ICSI2.49%-44/1764vs. IVF5.27%-237/4496,p<0.05). Compared with group fresh embryo transfer, the rates of ectopic pregnancy in group FET was decreased (FET2.63%-80/3043vs. fresh embryo transfer4.49%-281/6260,p<0.05).4. The rate of live birth delivery was81.23%(7557/9303), that in group ICSI was higher than in group IVF (ICSI84.07%-1483/1764vs. IVF79.78%-3587/4496,p<0.05). The rate of live birth delivery was81.73%(2487/3043) in group FET, and it was80.99%(5070/6260) in group fresh embryo transfer (p>0.05).5. The incidence of pregnancy complication in all clinical pregnancy cycles was6.56% (610/9303), and was no difference between group IVF8.11%(365/4496) and group ICSI7.99%(141/1764). The incidence of pregnancy complication in group FET (3.42%,104/3043) was lower than group fresh embryo transfer (8.08%,506/6260)(p<0.05).6. The multiple pregnancy rate was33.29%(3116/9360), and the multiple delivery rate was28.41%(2147/7557). The multiple delivery rates in group ICSI (27.78%-412/1483) was comparable with that in group IVF (30.28%,1086/3587), p>0.05. The multiple delivery rates in group FET (26.1%,649/2487) was lower than that in group fresh embryo transfer (29.55%,1498/5070), p<0.05.7. In live birth cycles, preterm labor rate was19.96%(1500/7515). This rate in group ICSI (17.91%,265/1480) was lower than in gruop IVF (20.52%,732/3568),P<0.05. The preterm labor rate in FET (20.39%,503/2467) was comparable with that in group fresh embryo transfer (19.75%,997/5048),p>0.05.8. The mean birth weight of live births was3.00±0.72kg. There was no difference between group IVF2.99±0.68kg and group ICSI2.98±0.68kg,p>0.05. The mean birth weight of live births in group FET (3.03±0.72kg) was higher than that in group fresh embryo transfer2.99±0.68kg (p<0.05).9. Birth defect rate in ART live births was1.41%(137/9715). There was no difference between group IVF (1.52%,71/4678) and group ICSI (1.58%,104/6573)(p<0.05). Birth defect rate in group FET (1.05%,33/3142) was lower than that in group fresh embryo transfer (1.58%,104/6573)(p<0.05).10. Sex ratio at birth of ART babies was1.15(male/female,5196/4509), and that was lower in ICSI babies (0.93,911/984), compared with IVF babies (1.22,2565/2110),p<0.05. There was no difference between group FET (1.22,1720/1415) and group fresh embryo transfer (1.12,3476/3094), p>0.05. Conclusion:1. ART may not increase the risk of miscarriage and disorders in pregnancy, and not change the sex ratio at birth, when compared with the pregnancy outcome in population cohort reported. However, the incidence of multiple pregnancy and ectopic pregnancy was increased significantly.2. Compared with conventional IVF, ICSI and FET may not increase the risk of adverse pregnancy outcome and the risk of birth defect. However, the proportion of boy babies born after ICSI was decreased. Part ⅡAnalysis of Birth Defects Among Children Conception Through Assisted Reproductive TechnologyObjective:To comparatively assess the rates of birth defects in children conceived by assisted reproduction technology (ART), especially to compare the congenital malformation at birth and over3-year longitudinal follow-up.Method(s):Live birth infants, conceived by in vitro fertilization fresh embryo transfer (IVF), intracytoplasmic sperm injection fresh embryo transfer (ICSI) or frozen-thawed embryo transfer (FET) in Reproductive Center of Tongji Hospital (Wuhan, China) between1997and2008, were followed up at birth and after2years-old. Congenital malformation were compared.Result(s):1. A total of4236children were born after3278ART cycles (IVF2543, ICSI908, FET785). There were94children with birth defect (birth defect rate2.22%,94/4236). Congenital defects were comparable in all groups at birth (IVF2.28%-58/2543, ICSI2.86%-26/908, FET1.27%-10/785).2. In total,2908children participated in the second follow-up, and the cases of birth defects had doubled (2-years:5.16%-150/2908, birth:2.22%-94/4236). The birth defect rate in boys conceived through ICSI was significantly higher than the IVF group after2-year follow-up (ICSI boys:8.62%-25/290, IVF boys:5.21%-50/959,p<0.05), even though there was no significant difference at birth. Conclusion(s):Compared with IVF, FET may not increase risk of birth defects. Children conceived through ICSI, especially males, had higher rates of congenital malformations that were inapparent at birth. So longitudinal monitoring may provide insights into the risks of ART.更多还原