重组人促卵泡激素预充注射笔应用于有多囊卵巢综合征症状/体征患者的前瞻性、观察性研究

Application of recombinant Human Follitropin Alfa solution for injection in patients with symptoms/signs of polycystic ovary syndrome: a prospective, observational study

目的评估在至少有一项多囊卵巢综合征(polycystic ovary syndrome,PCOS)症状/体征的不孕症患者中,PCOS相关体征/症状组合与卵巢刺激过度反应之间的关系,同时评估使用重组人促卵泡激素(recombinant Human Follitropin Alfa,r-hFSHα)预充注射笔在卵巢过度刺激综合征(ovarian hyperstimulation syndrome,OHSS)高危患者人群中应用的疗效及安全性结局。方法采用前瞻性、观察性、IV期研究,于2015年12月至2017年9月期间在河北医科大学第二医院、山东大学附属生殖医院、空军军医大学唐都医院、大连市妇女儿童医疗中心、南京市妇幼保健院、江西省妇幼保健院、新疆医科大学第一附属医院、安徽医科大学第一附属医院及内蒙古医科大学附属医院,招募了1055例至少具有一种PCOS症状/体征的不孕症患者,使用r-hFSHα预充注射笔,进行了4个月以上的随访观察。评估的主要终点包括受试者出现多囊卵巢,血清睾酮水平升高,月经周期紊乱,出现多毛症,完成取卵。研究的有效性终点包括获卵数、MII卵数、生化妊娠率、临床妊娠率、着床率。结果在全分析集中(n=997),多囊卵巢率为54.5%(543/997);血清睾酮水平为(0.4±0.2)μg/L;月经周期紊乱率为45.0%(449/997);多毛症率为10.5%(105/997);在有PCOS症状或体征患者中,242例(24.3%)患者获卵超过15个,100例患者(10.0%)获卵超过20个,体质量指数每降低1 kg/m2,过度反应(获卵数>15)风险增加约9%,过度反应(获卵数>20)风险增加约9%。窦卵泡计数每增加1,过度反应(获卵数>15)风险增加约6%,过度反应(获卵数>20)风险增加约4%。促排卵后的平均获卵数为14.4个。每移植周期的临床妊娠率为53.6%(251/468),活产率为45.3%(212/468),生化妊娠率为60.9%(285/468),着床率为39.1%(349/893),鲜胚移植取消率为24.0%(239/997)。有1.8%(19/1054)的患者(安全集,n=1054)诊断为OHSS,其中有8例(0.8%)轻度,10例(0.9%)中度,1例(0.1%)重度。结论至少有一种PCOS症状/体征的患者中,卵巢过度刺激与低体质量指数和高窦卵泡计数相关,使用r-hFSHα预充注射笔后,患者获得了较好的临床收益。

Objective To evaluate the association between polycystic ovary syndrome(PCOS)-related symptom combinations and ovarian stimulation high response in infertile patients with PCOS symptoms and controlled ovarian stimulation treatment by recombinant Human Follitropin Alfa(r-hFSHα)solution for injection,and to evaluate the efficacy and safety outcomes of using the r-hFSHαprefilled injection pen in high-risk patients with ovarian hyperstimulation syndrome(OHSS).Methods This prospective,observational,phaseⅣstudy enrolled 1055 patients with at least one symptom/sign of PCOS using the r-hFSHαprefilled pen for over 4 months follow-up observation from December 2015 to September 2017 in the Second Hospital of Hebei Medical University,Center for Reproductive Medicine,Shandong University,Tangdu Hospital of the Air Force Military Medical University,Dalian Maternity and Child Health Care Hospital,Nanjing Maternity and Child Health Care Hospital,Jiangxi Maternity and Child Health Care Hospital,the First Affiliated Hospital of Xinjiang Medical University,the First Affiliated Hospital of Anhui Medical University,the Affiliated Hospital of Inner Mongolia Medical University.The primary endpoints assessed included the development of polycystic ovaries,elevated serum testosterone levels,menstrual cycle disturbances,development of hirsutism,and completion of egg retrieval.The efficacy endpoints of the study included the number of ocoytes retrieved,the number of MⅡoocyte,the biochemical pregnancy rate,the clinical pregnancy rate,and the implantation rate.Results In the full analysis set(n=997),polycystic ovary rate was 54.5%(543/997),serum testosterone level was(0.4±0.2)μg/L,menstrual cycle disorder rate was 45.0%(449/997),hirsutism rate was 10.5%(105/997).The average number of oocytes retrieved after ovarian stimulation was 14.4.The clinical pregnancy rate per transfer cycle was 53.6%(251/468),the live birth rate was 45.3%(212/468),the biochemical pregnancy rate was 60.9%(285/468),the implantation rate was 39.1%(349/893),and the fresh embryo transfer cancellation rate was 24.0%(239/997).OHSS incidence was diagnosed in 1.8%(19/1054)of patients(safety set,n=1054),including 8(0.8%)mild cases,10(0.9%)moderate cases and 1(0.1%)severe case.According to the results of exploratory analysis,a decrease in body mass index(BMI)was associated with an increased risk of high response.For every 1 kg/m2 decrease in BMI,the risk of high response(number of retrieved oocytes>15)increased by approximately 9%,the risk of high response(number of retrieved oocytes>20)increased by approximately 9%.For every 1 increase in antral follicle count(AFC),the risk of high response(number of retrieved oocytes>15)increased by approximately 6%and the risk of high response(number of retrieved oocytes>20)by approximately 4%.Conclusion Patients with at least one symptom/sign of ovarian hyperstimulation achieved good clinical outcomes with the use of the r-hFSHαprefilled pen,and high response was associated with lower BMI and AFC.