女性IVF/ICSI個體化FSH給藥方案，以卵巢儲備測試為基礎(chǔ)的：多中心試驗和成本-效果分析

Individualized FSH dosing based on ovarian reserve testing in women starting IVF/ICSI: a multicentre trial and cost-effectiveness analysis.

van Tilborg TC1, Oudshoorn SC1, Eijkemans MJC2, Mochtar MH3, van Golde RJT4,5, Hoek A6, Kuchenbecker WKH7, Fleischer K8, de Bruin JP9, Groen H10, van Wely M3, Lambalk CB11, Laven JSE12, Mol BWJ13,14, Broekmans FJM1, Torrance HL1; OPTIMIST study group.

Hum Reprod. 2017 Dec 1;32(12):2485-2495. doi: 10.1093/humrep/dex321. PMID: 29121350

研究問題：

女性IVF或者ICSI周期中，基于竇性卵泡計數(shù)（AFC）的個體FSH劑量與標準FSH卵泡注射劑量的活產(chǎn)率和或成本-效果分析有差異嗎？

總結(jié)：

女性開始IVF/ICSI周期時，基于AFC的FSH劑量不能顯著提高活產(chǎn)率或者降低成本（對比標準FSH計量使用）。

目前已知：

在IVF或ICSI周期中，卵巢儲備測試經(jīng)常被用來指導(dǎo)FSH用量，其目的是促使卵巢功能正常并最大化提高活產(chǎn)率。但是對于成本分析，目前沒有強有力證據(jù)。

實驗設(shè)計，范圍，持續(xù)時間：

在2011年3月至2014年3月，我們對IVF/ICSI進行多中心前瞻性隊列研究，里面含有2個隨機對照實驗研究?；贏FC，女性患者進入RCTs一組(RCT1: AFC < 11; RCT2: AFC > 15)，或者對照組(AFC 11-15).。首要考慮結(jié)果是隨機實驗后，在18個月內(nèi)持續(xù)妊娠，活產(chǎn)（24周后至少有一例活胎）。對照組中將體重0.5與隨機對照實驗組合并，進行數(shù)據(jù)分析。分析這兩組治療方式的效果和成本。

參與者，材料，方法：

在2組RCTs中，女性患者進行隨機分配(RCT1:450/225 IU, RCT2:100 IU)或者根據(jù)FSH劑量(150 IU)。在對照組中的女性患者接受的是標準劑量(150 IU)。對于RCT1組，激素劑量是按照預(yù)先指定的標準進行。對于RCT2組激素劑量2組均可。2組的成本-效果進行評估。

主要結(jié)果：

我們評估了1515位女性患者，其中483（31.9%）在對照組，511（33.7%）在RCT1，521（34.4%）在RCT2。活產(chǎn)率為420/747 (56.3)女性在個體化策略中，447/769 (58.2%)女性在標準策略中。個體化策略會更貴(delta costs/woman =€275 (95 CI, 40 to 499))。個體化策略會減少OHSS的發(fā)生率，并降低治療OHSS的費用(costs saved/woman were€35)。

實驗限制：

盡管本實驗有嚴格限制，但是AFC可能會有不同觀察者之間差異。此外，雖然有嚴格取消標準要求，但是對于個體劑量組（特別是不良反應(yīng)）不能被直接排出，在接下來的周期中，允許劑量有小范圍調(diào)整。但是，開放式實驗設(shè)計并未掩蓋個體化差異的優(yōu)勢；在不同策略中，第一個周期的活產(chǎn)率和累積活產(chǎn)率并未顯示有明顯差異。越來越多的人同意使用GnRH拮抗劑聯(lián)合治療，特別是有高反應(yīng)的患者，在這項研究中幾乎有80%的婦女使用促性腺激素釋放激素激動劑。因此，在這些女性中，在AFC和AMH的分析研究對垂體的抑制。由于促性腺激素釋放激素激動劑使用過程中，AFC和卵巢反應(yīng)之間的相關(guān)性不會受到影響，這可能不會影響分析。

本實驗的應(yīng)用：

不應(yīng)該過度追求在IVF/ICSI周期中進行個體化FSH劑量調(diào)控，因為它不能提高活產(chǎn)率并且它會增加花費。女性患者有正常的月經(jīng)周期，在進行IVF/ICSI周期中，應(yīng)推薦進行標準FSH劑量，150IU/天。但是在高反應(yīng)患者中個體化給藥安全管理有待進一步研究。

關(guān)鍵詞：FSH；ICSI;IVF；anti-Müllerian hormone；竇卵泡計數(shù)；成本-效果分析；個體化；活產(chǎn)率；卵巢反應(yīng)；卵巢激素測試；

Abstract

STUDY QUESTION:

Is there a difference in live birth rate and/or cost-effectiveness between antral follicle coun t (AFC)-based individualized FSH dosing or standard FSH dosing in women starting IVF or ICSI treatment?

SUMMARY ANSWER:

In women initiating IVF/ICSI, AFC-based individualized FSH dosing does not improve live birth rates or reduce costs as compared to a standard FSH dose.

WHAT IS KNOWN ALREADY:

In IVF or ICSI, ovarian reserve testing is often used to adjust the FSH dose in order to normalize ovarian response and optimize live birth rates. However, no robust evidence for the (cost-)effectiveness of this practice exists.

STUDY DESIGN, SIZE, DURATION:

Between May 2011 and May 2014 we performed a multicentre prospective cohort study with two embedded RCTs in women scheduled for IVF/ICSI. Based on the AFC, women entered into one of the two RCTs (RCT1: AFC < 11; RCT2: AFC > 15) or the cohort (AFC 11-15). The primary outcome was ongoing pregnancy achieved within 18 months after randomization resulting in a live birth (delivery of at least one live foetus after 24 weeks of gestation). Data from the cohort with weight 0.5 were combined with both RCTs in order to conduct a strategy analysis. Potential half-integer numbers were rounded up. Differences in costs and effects between the two treatment strategies were compared by bootstrapping.

PARTICIPANTS/MATERIALS, SETTING, METHODS:

In both RCTs women were randomized to an individualized (RCT1:450/225 IU, RCT2:100 IU) or standard FSH dose (150 IU). Women in the cohort all received the standard dose (150 IU). Anti-Müllerian hormone (AMH) was measured to assess AMH post-hoc as a biomarker to individualize treatment. For RCT1 dose adjustment was allowed in subsequent cycles based on pre-specified criteria in the standard group only. For RCT2 dose adjustment was allowed in subsequent cycles in both groups. Both effectiveness and cost-effectiveness of the strategies were evaluated from an intention-to-treat perspective.

MAIN RESULTS AND THE ROLE OF CHANCE:

We included 1515 women, of whom 483 (31.9%) entered the cohort, 511 (33.7%) RCT1 and 521 (34.4%) RCT2. Live births occurred in 420/747 (56.3%) women in the individualized strategy and 447/769 (58.2%) women in the standard strategy (risk difference -0.019 (95 CI, -0.06 to 0.02), P = 0.39; a total of 1516 women due to rounding up the half integer numbers). The individualized strategy was more expensive (delta costs/woman = €275 (95 CI, 40 to 499)). Individualized dosing reduced the occurrence of mild and moderate ovarian hyperstimulation syndrome (OHSS) and subsequently the costs for management of these OHSS categories (costs saved/woman were€35). The analysis based on AMH as a tool for dose individualization suggested comparable results.

LIMITATIONS, REASONS FOR CAUTION:

Despite a training programme, the AFC might have suffered from inter-observer variation. In addition, although strict cancel criteria were provided, s elective cancelling in the individualized dose group (for poor response in particular) cannot be excluded as observers were not blinded for the FSH dose and small dose adjustments were allowed in subsequent cycles. However, as both first cycle live birth rates and cumulative live birth rates show no difference between strategies, the open design probably did not mask a potential benefit for the individualized group. Despite increasing consensus on using GnRH antagonist co-treatment in women predicted for a hyper response in particular, GnRH agonists were used in almost 80% of the women in this study. Hence, in those women, the AFC and bloodsampling for the post-hoc AMH analysis were performed during pituitary suppression. As the correlation between AFC and ovarian response is not compromised during GnRH agonist use, this will probably not have influenced classification of response.

WIDER IMPLICATIONS OF THE FINDINGS:

Individualized FSH dosing for the IVF/ICSI population as a whole should not be pursued as it does not improve live birth rates and it increases costs. Women scheduled for IVF/ICSI with a regular menstrual cycle are therefore recommended a standard FSH starting dose of 150 IU per day. Still, safety management by individualized dosing in predicted hyper responders is open for further research.

KEYWORDS:

FSH; ICSI; IVF; anti-Müllerian hormone; antral follicle coun t; cost-effectiveness; individualized; live birth; ovarian reserve; ovarian reserve test.

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文檔下載：女性IVF/ICSIFSH給藥方案，個體化給藥效果也許并沒有那么好！