Chinè Alessandra, Reschini Marco, Fornelli Gianfranco, Basili Ludovica, Busnelli Andrea, Viganò Paola, Muzii Ludovico, Somigliana Edgardo
Department of Gynecology, Obstetrics and Urology, "Sapienza" University of Rome, Rome, Italy.
Infertility Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
Hum Reprod Open. 2023 May 19;2023(3):hoad026. doi: 10.1093/hropen/hoad026. eCollection 2023.
Do low levels of anti-Müllerian hormone (AMH) or antral follicle count (AFC) properly predict miscarriage in young women conceiving with ART?
Low ovarian reserve, as indicated by AMH or AFC, is not associated with miscarriage in young women conceiving with ART.
Presently, the impact of low ovarian reserve on the risk of miscarriage remains controversial. Some studies have reported an association between serum AMH levels and AFC and miscarriage, but others have failed to confirm these findings. The main limitation that undermines the reliability and consistency of the results is the confounding effect of female age. Indeed, after 35 years of age, on the one hand, the risk of miscarriage starts increasing because of impaired oocyte quality while, on the other, the physiological decline in AMH and AFC levels continues, thus hampering the possibility to properly explore the real effects of reduced ovarian reserve. Indeed, the two processes, i.e. the gradual loss of resting primordial follicles and the loss of oocyte quality, progress in parallel. In other words, the older the woman becomes, the higher is the risk of miscarriage, but one cannot distinguish between the effects of biological aging on oocyte quality and those mediated by a lower ovarian reserve.
The present retrospective monocentric cohort study was carried out at Fondazione IRCSS Ca Granda Ospedale Maggiore Policlinico, Milan. All women referred to the ART Unit between 2014 and 2021 and who underwent either conventional IVF (c-IVF), ICSI, or IUI were reviewed. Only women younger than 35 were eligible because, up to this age, the risk of miscarriage is steady and not strictly related to age.
PARTICIPANTS/MATERIALS SETTING METHODS: Women younger than 35 who achieved a singleton clinical pregnancy with c-IVF, ICSI, or IUI were selected. Women with patent causes of recurrent miscarriage were excluded, as well as those undergoing pregnancy termination for fetal or medical causes. Women who did and did not have a pregnancy loss before 20 weeks' gestation were compared. Detailed information was obtained from charts of the consulting patients. ART procedures were performed according to the standardized policy of our Unit. All women underwent serum AMH measurement and a transvaginal assessment of AFC prior to initiation of treatment. AMH levels were measured by a commercially available ELISA assay. To assess AFC, all identifiable antral follicles 2-10 mm in diameter at ultrasound were recorded. The primary outcome was the risk of miscarriage for women with serum AMH levels below 5 pmol/l.
There were 538 women were included, of whom 92 (17%) had a miscarriage. The areas under the ROC curves for prediction of miscarriage based on AMH levels and AFC were 0.51 (95% CI: 0.45-0.58) and 0.52 (95% CI: 0.45-0.59), respectively. The odds ratio (OR) of miscarriage for women with serum AMH levels below 5.0 pmol/l was 1.10 (95% CI: 0.51-2.36); the adjusted OR was 1.12 (95% CI: 0.51-2.45). Analyses were repeated considering other thresholds for AMH (2.9, 3.6 and 7.9 pmol/l) and for AFC (thresholds of 7 and 10). No associations emerged.
The retrospective design of the study hampered the collection of more precise but potentially relevant clinical information of the couples. We did not exclude women suffering from PCOS, a condition possibly associated with miscarriage. Moreover, the baseline characteristics of women who did and did not have a miscarriage differed in some characteristics. Thus, we adjusted the OR using a multivariate analysis, but we cannot fully exclude residual confounding effects. Finally, our results cannot be inferred to women older than 35. The mechanisms causing premature exhaustion of ovarian reserve may be different in younger and older women and this may lead to a different impact on the risk of miscarriage.
Women embarking on ART with low ovarian reserve should be informed of their likely poor response to ovarian stimulation but can be reassured that, if conception occurs, their risk of miscarriage is not increased.
STUDY FUNDING/COMPETING INTERESTS: This study was partially funded by Italian Ministry of Health-Current research IRCCS. E.S. reports grants from Ferring and honoraria for lectures from Merck-Serono and Gedeon-Richter. All the other authors do not have any competing interest to declare.
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抗苗勒管激素（AMH）水平低或窦卵泡计数（AFC）低能否准确预测接受辅助生殖技术（ART）受孕的年轻女性发生流产的情况？
以AMH或AFC表示的低卵巢储备与接受ART受孕的年轻女性流产无关。
目前，低卵巢储备对流产风险的影响仍存在争议。一些研究报告了血清AMH水平和AFC与流产之间的关联，但其他研究未能证实这些发现。影响结果可靠性和一致性的主要限制因素是女性年龄的混杂效应。事实上，35岁之后，一方面，由于卵母细胞质量受损，流产风险开始增加；另一方面，AMH和AFC水平的生理性下降仍在继续，从而妨碍了正确探究卵巢储备减少的实际影响的可能性。实际上，这两个过程，即静止原始卵泡的逐渐丢失和卵母细胞质量的丧失，是并行发生的。换句话说，女性年龄越大，流产风险越高，但无法区分生物衰老对卵母细胞质量的影响和较低卵巢储备介导的影响。
研究设计、规模、持续时间：本回顾性单中心队列研究在米兰的Fondazione IRCSS Ca Granda Ospedale Maggiore Policlinico进行。对2014年至2021年间转诊至ART科室并接受常规体外受精（c-IVF）、卵胞浆内单精子注射（ICSI）或宫腔内人工授精（IUI）的所有女性进行了回顾。仅纳入年龄小于35岁的女性，因为在此年龄之前，流产风险稳定且与年龄无严格关联。
参与者/材料、设置、方法：选择年龄小于35岁且通过c-IVF、ICSI或IUI实现单胎临床妊娠的女性。排除有复发性流产明确原因的女性，以及因胎儿或医学原因终止妊娠的女性。比较妊娠20周前发生流产和未发生流产的女性。从咨询患者的病历中获取详细信息。ART程序按照我们科室的标准化政策进行。所有女性在开始治疗前均接受血清AMH测定和经阴道AFC评估。AMH水平通过市售酶联免疫吸附测定（ELISA）法测量。为评估AFC，记录超声检查时所有可识别的直径为2-10毫米的窦卵泡。主要结局是血清AMH水平低于5 pmol/L的女性发生流产的风险。
共纳入538名女性，其中92名（17%）发生流产。基于AMH水平和AFC预测流产的ROC曲线下面积分别为0.51（95%CI：0.45-0.58）和0.52（95%CI：0.45-0.59）。血清AMH水平低于5.0 pmol/L的女性流产的优势比（OR）为1.10（95%CI：0.51-2.36）；调整后的OR为1.12（95%CI：0.51-2.45）。考虑AMH的其他阈值（2.9、3.6和7.9 pmol/L）和AFC的阈值（7和10）重复进行分析。未发现关联。
局限性、谨慎理由：本研究的回顾性设计妨碍了收集更多精确但可能相关的夫妇临床信息。我们未排除患有多囊卵巢综合征（PCOS）的女性，该疾病可能与流产有关。此外，发生流产和未发生流产的女性的基线特征在某些方面存在差异。因此，我们使用多变量分析调整了OR，但不能完全排除残留的混杂效应。最后，我们的结果不能外推至年龄大于35岁的女性。导致卵巢储备过早耗竭的机制在年轻女性和年长女性中可能不同，这可能对流产风险产生不同影响。
卵巢储备低且开始接受ART治疗的女性应被告知其对卵巢刺激可能反应不佳，但可以放心的是，如果受孕，其流产风险不会增加。
研究资金/利益冲突：本研究部分由意大利卫生部-当前研究IRCCS资助。E.S.报告从辉凌制药获得资助，并从默克雪兰诺和吉德昂-里奇特获得讲课酬金。所有其他作者均无利益冲突声明。
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