添加不同LH活性药物对卵巢慢反应患者妊娠结局的影响:一项回顾性队列研究

Effects of different exogenous LH activity drugs on pregnancy outcomes in patients with suboptimal ovarian response:a retrospective cohort study

目标比较早卵泡期长方案促排卵发生慢反应时,补充重组黄体生成素(recombinant luteinizing hormone,rLH)和人绝经期促性腺激素(human menopausal gonadotropins,hMG)对妊娠结局的影响。方法回顾性队列研究分析2017年1月至2020年1月期间南京医科大学第一附属医院生殖医学科首次接受体外受精/卵胞质内单精子注射-胚胎移植(in vitro fertilization/intracytoplasmic sperm injection and embryo transfer,IVF/ICSI-ET)助孕并采用卵泡期长方案促排卵患者的临床资料。纳入卵巢功能正常、促排卵发生慢反应的患者2336例,根据添加不同的LH活性药物,分为hMG组(1558例)和rLH组(778例)。比较两组患者的基本特征、促排卵的临床和实验室指标、新鲜胚胎移植及冻融胚胎移植周期的妊娠结局。通过logistic回归分析添加两种LH活性药物对卵巢慢反应患者累积活产率的影响。结果两组患者的年龄、不孕类型和病因、体质量指数和卵巢功能指标差异均无统计学意义(均P>0.05)。hMG组卵泡刺激素(follicle-stimulating hormone,FSH)的使用时间[(12.22±2.29)d]和总剂量[(2088.98±628.24)U]较rLH组[(11.89±2.37)d,P=0.001;(1866.90±602.65)U,P<0.001]显著升高。hMG组LH的使用时间[(7.40±3.52)d]和总剂量[(537.30±484.49)U]较rLH组[(5.67±3.78)d、(498.10±472.04)U,均P<0.001]显著升高。hMG组的LH水平在促性腺激素(gonadotropin,Gn)启动日[(0.78±0.77)U/L]和刺激第6天[(0.81±0.49)U/L]均高于rLH组[(0.67±0.32)U/L,P<0.001;(0.71±0.33)U/L,P=0.002],但人绒毛膜促性腺激素(human chorionic gonadotropin,hCG)注射日两组之间的LH水平差异无统计学意义(P=0.303)。hCG注射日hMG组的雌二醇水平[(8377.14±7000.63)pmol/L]和孕酮水平[(3.84±2.18)nmol/L]显著高于rLH组[(7644.91±5145.64)pmol/L,P=0.009;(3.14±1.80)ng/L,P<0.001]。两组新鲜胚胎移植和冻融胚胎移植的临床妊娠率、流产率和活产率差异均无统计学意义(均P>0.05)。rLH组的累积妊娠率[89.46%(696/778)]和累积活产率[78.02%(607/778)]高于hMG组[84.60%(1318/1558),P=0.001;72.98%(1137/1558),P=0.008]。多因素logistic回归分析显示,影响慢反应患者累积活产率的因素包括年龄(OR=0.930,95%CI:0.906~0.955,P<0.001)、窦卵泡计数(OR=1.029,95%CI:1.005~1.054,P=0.018)、获卵总数(OR=1.064,95%CI:1.029~1.100,P<0.001)、移植胚胎数(OR=1.714,95%CI:1.293~2.272,P<0.001)、移植胚胎的发育时期(OR=1.567,95%CI:1.243~1.975,P<0.001)、移植日子宫内膜厚度(OR=1.122,95%CI:1.077~1.170,P<0.001)以及添加不同的LH活性药物(OR=1.348,95%CI:1.101~1.651,P=0.004)。结论卵巢功能正常的患者行早卵泡期长方案促排卵,发生慢反应时添加rLH较添加hMG可以获得更高的累积活产率。

Objective To evaluate the effects of recombinant luteinizing hormone(rLH)and human menopausal gonadotropins(hMG)supplementation on pregnancy outcomes for suboptimal ovarian responders undergoing follicular phase long protocol.Methods The data of infertile patients who underwent in vitro fertilization/intracytoplasmic sperm injection and embryo transfer(IVF/ICSI-ET)for the first time with follicular phase long protocol from January 2017 to January 2020 in Reproductive Medicine Center of the First Affiliated Hospital of Nanjing Medical University Hospital were retrospectively cohort analyzed.Totally 2336 patients with normal ovarian reserve were included in the study with suboptimal ovarian response to ovarian stimulation.According to the different exogenous LH supplementation,they were divided into hMG group(n=1558)and rLH group(n=778).The clinical features and effects of ovulation induction were compared between the two groups and reproductive outcomes were compared in both fresh embryo transfer cycles and subsequent frozen-thawed embryo transfer(FET)cycles.Logistic regression analysis were performed to explore the relationship between different LH activity drugs supplementation and the cumulative live birth rate of suboptimal ovarian responders.Results The basic characteristics such as age,infertility type and diagnosis,body mass index and biomarkers of ovarian reserve were comparable between the two groups(all P>0.05).Total dosage[(2088.98±628.24)U]and duration[(12.22±2.29)d]of FSH used in the hMG group were significantly higher than those in the rLH group[(1866.90±602.65)U,P<0.001;(11.89±2.37)d,P=0.001].Total dosage[(537.30±484.49)U]and duration[(7.40±3.52)d]of LH used in the hMG group were significantly higher than those in the rLH group[(498.10±472.04)U,(5.67±3.78)d,P<0.001].The serum LH levels on the first day[(0.78±0.77)U/L]and the sixth day[(0.81±0.49)U/L]of gonadotropin stimulation in the hMG group were higher than those in the rLH group[(0.67±0.32)U/L,P<0.001;(0.71±0.33)U/L,P=0.002].However,the serum LH level was comparable on the trigger day between the two groups without significant difference(P=0.303).The levels of serum estrodiol[(8377.14±7000.63)pmol/L]and progesterone[(3.84±2.18)nmol/L]on the trigger day were significantly higher in the hMG group than in the rLH group[(7644.91±5145.64)pmol/L,P=0.009;(3.14±1.80)ng/L,P<0.001].The pregnancy outcomes including clinical pregnancy rates,abortion rates and live birth rates were comparable between the two groups in fresh embryo transfer cycles and the subsequent FET cycles(all P>0.05).The cumulative pregnancy rate(CPR)[89.46%(696/778)]and the cumulative live birth rate(CLBR)[78.02%(607/778)]in the rLH group were significantly higher than those in the hMG group[84.60%(1318/1558),P=0.001;72.98%(1137/1558),P=0.008].Multivariate logistic regression analysis showed that age was a risk factor for CLBR(OR=0.930,95%CI:0.906-0.955,P<0.001)and antral follicle count(OR=1.029,95%CI:1.005-1.054,P=0.018),total number of oocytes retrieved(OR=1.064,95%CI:1.029-1.100,P<0.001),the number of embryos transferred(OR=1.714,95%CI:1.293-2.272,P<0.001),the stage of embryos transferred(OR=1.567,95%CI:1.243-1.975,P<0.001),endometrial thickness on transfer day(OR=1.122,95%CI:1.077-1.170,P<0.001)and rLH supplementation(OR=1.348,95%CI:1.101-1.651,P=0.004)were protective factors for CLBR of suboptimal responders.Conclusion For suboptimal ovarian responders with normal ovarian reserve,rLH supplementation may achieve a higher CLBR than hMG supplementation in follicular phase long protocol.