Center for Reproductive Medicine, Universitair Ziekenhuis Brussel, Brussels, Belgium.
Hum Reprod. 2013 Feb;28(2):442-52. doi: 10.1093/humrep/des389. Epub 2012 Nov 7.
Is the ovarian response to controlled ovarian stimulation (COS) related to the ongoing pregnancy rate when taking into account the main covariates affecting the probabilities of pregnancy following fresh embryo transfer?
In patients treated with corifollitropin alfa or daily recombinant FSH (rFSH) in a GnRH-antagonist protocol, a high ovarian response did not compromise ongoing pregnancy rates and increased cumulative pregnancy rates following fresh and frozen-thawed embryo transfer.
A strong association between the number of oocytes and pregnancy rates has been described but this is the first comprehensive analysis assessing important confounders that might affect pregnancy rates.
In a large, prospective, double-blind, randomized trial (Engage; n = 1506), patients were treated with either a single dose of 150 μg corifollitropin alfa or daily 200 IU rFSH for the first 7 days of COS in a GnRH-antagonist (ganirelix) protocol. In this retrospective analysis, patients were categorized into five groups according to the number of oocytes retrieved (0-5, 6-9, 10-13, 14-18 and >18 oocytes). The number of good-quality embryos obtained and transferred, as well as the ongoing pregnancy rates, live birth rates and cumulative ongoing pregnancy rates per started cycle by group were evaluated. Univariate analysis was performed to identify factors that predict the chance of ongoing pregnancy. Logistic regression analysis on the dependent variables ongoing pregnancy and cumulative ongoing pregnancy, respectively, including oocyte category as an independent factor in the model, was performed by treatment group (corifollitropin alfa and rFSH) and overall. The likelihood of ongoing pregnancy and cumulative ongoing pregnancy was then evaluated taking into account ovarian response as well as other identified significant predictors of success.
In total, 1506 patients had been randomized in a ratio of 1:1 to either of the treatment groups. Patients were aged ≤ 36 years and had a body weight >60 kg.
The ongoing pregnancy rates per started cycle increased in the corifollitropin alfa and rFSH groups from 31.9 and 31.3%, respectively, in the lowest response group (0-5 oocytes) to 41.9 and 43.4% in the highest response group (>18 oocytes) with a significant linear trend (P = 0.04). The cumulative pregnancy rates taking frozen-thawed embryo transfers into account increased from 33.0 and 31.3% to 60.8 and 55.9% in the corifollitropin alfa and rFSH groups, respectively. Univariate logistic regression analyses of ongoing pregnancy showed significant effects for the following factors: embryo transfer (double or single, P < 0.01), region of treatment (North America or Europe, P < 0.01), progesterone level on the day of hCG (>1.5 or ≤ 1.5 ng/ml, P < 0.01), start day of the stimulation (cycle day 2 or 3, P = 0.02) and age (P = 0.04). Logistic regression analysis of ongoing pregnancy using 10-13 oocytes as the reference category, per treatment group and overall revealed estimated odds ratios (OR) close to 1.0 versus the reference, without statistically significant differences with and without adjustment for significant predictive factors affecting pregnancy rates. Unadjusted OR for cumulative pregnancy reflected significantly lower odds of pregnancy for the lowest response group and significantly higher odds of pregnancy for the highest response group in comparison with the reference. When adjusted for the predictive factors, the cumulative ongoing pregnancy OR (95% confidence interval) of the highest response group versus the reference group was 1.87 (1.34-2.59) when the data of both treatment groups were pooled.
BIAS, CONFOUNDING AND OTHER REASONS FOR CAUTION: The number of covariates included in the final model was limited to five major factors and not all other potentially significant predictive factors were available for evaluation.
This analysis is limited to IVF patients with a regular menstrual cycle up to 36 years of age and a body weight >60 and ≤ 90 kg treated with a GnRH-antagonist protocol and cannot be extrapolated to other patient populations or treatment regimens.
在考虑影响新鲜胚胎移植后妊娠概率的主要混杂因素的情况下，卵巢对控制性卵巢刺激（COS）的反应与持续妊娠率相关吗？
在 GnRH 拮抗剂方案中接受 corifollitropin alfa 或每日重组 FSH（rFSH）治疗的患者中，高卵巢反应并未降低持续妊娠率，并增加了新鲜和冷冻解冻胚胎移植后的累积妊娠率。
已经描述了卵母细胞数量与妊娠率之间存在很强的关联，但这是首次全面分析评估可能影响妊娠率的重要混杂因素。
在一项大型前瞻性、双盲、随机试验（Engage；n=1506）中，患者在 GnRH 拮抗剂（ganirelix）方案中接受单次 150μg corifollitropin alfa 或每日 200IU rFSH 治疗 7 天。在这项回顾性分析中，患者根据获得的卵母细胞数量（0-5、6-9、10-13、14-18 和 >18 个）分为五组。评估每组获得的优质胚胎数量和移植数量，以及持续妊娠率、活产率和每个启动周期的累积持续妊娠率。进行单变量分析以确定预测持续妊娠机会的因素。通过治疗组（corifollitropin alfa 和 rFSH）和总体，对依赖变量持续妊娠和累积持续妊娠分别进行 logistic 回归分析，将卵母细胞类别作为模型中的独立因素。然后考虑卵巢反应以及其他确定的成功预测因素来评估持续妊娠和累积持续妊娠的可能性。
共有 1506 名患者按 1:1 的比例随机分配至两个治疗组。患者年龄≤36 岁，体重>60kg。
corifollitropin alfa 和 rFSH 组的启动周期持续妊娠率从最低反应组（0-5 个卵母细胞）的 31.9%和 31.3%分别增加到最高反应组（>18 个卵母细胞）的 41.9%和 43.4%，呈显著线性趋势（P=0.04）。考虑冷冻解冻胚胎移植后，corifollitropin alfa 和 rFSH 组的累积妊娠率从 33.0%和 31.3%分别增加到 60.8%和 55.9%。持续妊娠的单变量 logistic 回归分析显示以下因素具有显著影响：胚胎移植（双胚胎或单胚胎，P<0.01）、治疗区域（北美或欧洲，P<0.01）、hCG 日的孕激素水平（>1.5 或≤1.5ng/ml，P<0.01）、刺激开始日（周期第 2 天或第 3 天，P=0.02）和年龄（P=0.04）。按每 10-13 个卵母细胞作为参考类别，对每个治疗组和总体进行持续妊娠的 logistic 回归分析显示，与参考相比，估计的优势比（OR）接近 1.0，且无统计学差异，无论是否调整对妊娠率有影响的显著预测因素。未调整的累积妊娠 OR 反映了最低反应组妊娠的可能性显著降低，而最高反应组妊娠的可能性显著增加，与参考相比。当调整预测因素时，两组数据合并时，最高反应组与参考组的累积持续妊娠 OR（95%置信区间）为 1.87（1.34-2.59）。
偏倚、混杂因素和其他注意事项：最终模型中包含的协变量数量限于五个主要因素，并非所有其他潜在的显著预测因素都可用于评估。
该分析仅限于年龄在 36 岁以下、体重在 60 至 90 公斤之间、有正常月经周期的 IVF 患者，且接受 GnRH 拮抗剂方案治疗，不能外推至其他患者人群或治疗方案。
