Centre for Reproductive MedicineUZ Brussel, Brussels, Belgium.
Centre for Medical Genetics, UZ Brussel, Brussels, Belgium.
Hum Reprod. 2019 Aug 1;34(8):1595-1607. doi: 10.1093/humrep/dez086.
Does IVM of immature oocytes retrieved from small antral follicles in women with polycystic ovary syndrome (PCOS) have an impact on obstetric and neonatal outcomes compared to controlled ovarian stimulation (COS)?
Obstetric and neonatal outcomes after IVM appear to be similar to those after COS.
Women with PCOS have an increased risk of adverse pregnancy outcomes and congenital malformations in their offspring. For patients with PCOS who require IVF, IVM of germinal vesicle (GV)-stage oocytes retrieved from antral follicles has been adopted as a mild approach ART, with improved pregnancy rates over the last two decades. Although reports of obstetrical and neonatal outcomes after IVM have been reassuring, the limited sample sizes in previous studies preclude firm conclusions, and further study is warranted.
STUDY DESIGN, SIZE, DURATION: This is a retrospective observational study analysing obstetric and neonatal data from 1036 clinical pregnancies in unique patients with PCOS who conceived following a cycle of IVM or COS between January 2010 and December 2016 in a tertiary reproductive centre. In total, 393 singleton pregnancies with a gestational age beyond 20 weeks were included. A phenotypic approach was used for the diagnosis of PCOS. Pregnancies following oocyte donation, standard IVF (as opposed to ICSI) or preimplantation genetic testing and pregnancies requiring testicular biopsy in the male partners were excluded.
PARTICIPANTS/MATERIALS,SETTING, METHODS: Pregnancy outcomes were analysed in women with PCOS phenotype A, C or D, as defined by different combinations of the Rotterdam criteria. Data from 164 pregnancies beyond 20 weeks after IVM were compared with those from 229 pregnancies after COS. Pregnancies in the IVM group were obtained after minimal ovarian stimulation and IVF with ICSI of transvaginally collected GV oocytes that had reached the metaphase II stage in vitro after 28 to 40 h of culture. No hCG trigger was administered before oocyte retrieval. Outcome measures were analysed or reported in singleton pregnancies only and included adverse obstetric events and neonatal health parameters, in particular birthweight, prematurity, small-for-gestational age, large-for-gestational age, perinatal death and major/minor malformation rates. The incidence of hypertensive disorders of pregnancy (HDP) and birthweight was analysed by multiple linear and logistic regression, adjusted for relevant treatment variables and maternal characteristics.
The IVM and the COS groups differed significantly (P < 0.001) for maternal circulating AMH levels and PCOS phenotype distribution, with more of the PCOS phenotype A in the IVM group. Pregnant women in the IVM group were younger than pregnant women in the COS group (P = 0.05). With regard to obstetric complications in singleton pregnancies, in the unadjusted analysis, mothers of infants in the IVM group more often had HDP (29/164 (17.9%) vs 22/229 (9.6%), P = 0.02) compared with mothers in the COS group. Singletons born after IVM and COS had a similar birthweight standard deviation score (SDS) (0.51 ± 0.94 after IVM vs 0.33 ± 1.05 after COS, P = 0.19). Preterm birth rate (32-36.9 weeks) and early preterm birth rate (<32 weeks) were also similar in both groups. The total malformation rate was 4.1% in singletons after IVM and 2.4% in singletons after COS. Multivariate linear regression analysis accounting for relevant confounders demonstrated that parity was the only independent predictive factor (P = 0.04) for birthweight SDS. Multivariate logistic regression analysis showed that BMI, parity and type of ART (IVM as opposed to COS) were significantly correlated with the incidence of HDP. Only patients with the PCOS phenotype A showed a tendency towards a higher risk of HDP in those who underwent IVM compared to those who had COS.
LIMITATIONS, REASONS FOR CAUTION: The study is limited by its retrospective nature and loss to follow-up of a subset of children with no information regarding congenital malformations. Furthermore, the paediatricians who assessed the children after birth were not blinded for the type of ART procedure.
This study provides further evidence that, compared to COS, IVM of oocytes derived from small antral follicles does not adversely affect the neonatal health of the offspring of patients with PCOS. The observed increased risk of HDP in patients with PCOS phenotype A following IVM treatment warrants further scrutiny.
STUDY FUNDING/COMPETING INTEREST(S): Translational IVM research at Universitair Ziekenhuis Brussel (UZ Brussel) and Vrije Universiteit Brussel (VUB) has been supported by grants from the Institute for the Promotion of Innovation by Science and Technology in Flanders (Agentschap voor Innovatie door Wetenschap en Technologie-IWT, project 110680), the Fund for Research Flanders (Fonds Wetenschappelijk Onderzoek-Vlaanderen-FWO, project G.0343.13) and the Belgian Foundation Against Cancer (HOPE project, Dossier C69). Clinical IVM research was supported by research grants from Cook Medical and Besins Healthcare. M.D.V. reports honoraria for lectures from Cook Medical and Besins Healthcare outside the submitted work. S.S.R. reports honoraria for lectures by MSD and Besins and research grants by MSD, Ferring and Merck Serono outside of the submitted work. C.B. reports personal fees from Merck-Serono, Ferring, IBSA, Finox, MSD and Abbott outside the submitted work. H.T. reports grants from Merck, MSD, Goodlife, Cook, Roche, Besins, Ferring, Mithra (now Allergan) and the Research Fund of Flanders (FWO) and consultancy fees from Finox, Abbott, Obseva and Ovascience outside the submitted work. The other authors have nothing to disclose.
与控制性卵巢刺激（COS）相比，多囊卵巢综合征（PCOS）患者从小窦卵泡中取出的未成熟卵母细胞的 IVM 是否会对产科和新生儿结局产生影响？
IVM 后的产科和新生儿结局似乎与 COS 后相似。
患有 PCOS 的女性发生不良妊娠结局和后代先天畸形的风险增加。对于需要 IVF 的 PCOS 患者，已采用从窦卵泡中取出的生发泡期（GV）卵母细胞的 IVM 作为一种温和的 ART 方法，在过去二十年中提高了妊娠率。尽管有关 IVM 后产科和新生儿结局的报告令人放心，但先前研究中的样本量有限限制了结论的确定，需要进一步研究。
研究设计、规模、持续时间：这是一项回顾性观察性研究，分析了 2010 年 1 月至 2016 年 12 月在一家三级生殖中心接受 IVM 或 COS 周期后怀孕的 1036 例独特 PCOS 患者的产科和新生儿数据。总共纳入了 393 例超过 20 周妊娠的单胎妊娠。采用表型方法诊断 PCOS。排除了卵母细胞捐赠、标准 IVF（而非 ICSI）或植入前遗传检测以及男性伴侣需要睾丸活检的妊娠。
参与者/材料、设置、方法：分析了符合不同 Rotterdam 标准组合的 PCOS 表型 A、C 或 D 的女性的妊娠结局。将 164 例超过 20 周的 IVM 后妊娠与 229 例 COS 后妊娠进行比较。IVM 组的妊娠是在经过最小化卵巢刺激和体外受精后获得的，通过 ICSI 对经阴道收集的达到中期 II 期的 GV 卵母细胞进行培养，培养时间为 28 至 40 小时。在取卵前不给予 hCG 触发。仅对单胎妊娠进行了分析或报告了结果，包括不良产科事件和新生儿健康参数，特别是出生体重、早产、小于胎龄儿、大于胎龄儿、围产期死亡和主要/次要畸形率。通过多元线性和逻辑回归分析了高血压疾病（HDP）和出生体重的发生率，调整了相关治疗变量和母体特征。
IVM 组和 COS 组的母体循环 AMH 水平和 PCOS 表型分布差异显著（P<0.001），IVM 组中 PCOS 表型 A 更多。IVM 组孕妇的年龄小于 COS 组（P=0.05）。在单胎妊娠的产科并发症方面，在未调整分析中，IVM 组母亲发生 HDP 的比例（164 例中的 29 例[17.9%]）高于 COS 组（229 例中的 22 例[9.6%]）（P=0.02）。IVM 和 COS 后出生的单胎婴儿的出生体重标准差评分（SDS）相似（IVM 后为 0.51±0.94，COS 后为 0.33±1.05，P=0.19）。早产率（32-36.9 周）和早期早产率（<32 周）在两组中也相似。IVM 后单胎的总畸形率为 4.1%，COS 后单胎的畸形率为 2.4%。考虑到相关混杂因素的多元线性回归分析表明，产次是出生体重 SDS 的唯一独立预测因素（P=0.04）。多元逻辑回归分析表明，BMI、产次和 ART 类型（与 COS 相比，IVM）与 HDP 的发生率显著相关。只有 PCOS 表型 A 的患者在接受 IVM 治疗时与接受 COS 相比，发生 HDP 的风险有升高的趋势。
局限性、谨慎的原因：该研究受到回顾性研究性质的限制，并且在亚组中丢失了一些没有先天性畸形信息的儿童的随访数据。此外，评估出生后儿童的儿科医生对 ART 程序类型没有盲法。
这项研究进一步证明，与 COS 相比，从小窦卵泡中取出的卵母细胞进行 IVM 不会对 PCOS 患者后代的新生儿健康产生不利影响。在接受 IVM 治疗的 PCOS 表型 A 患者中观察到的 HDP 风险增加需要进一步研究。
研究资金/利益冲突：布鲁塞尔大学医院（UZ Brussel）和布鲁塞尔自由大学（VUB）的转化 IVM 研究得到了弗拉芒创新促进署（Agentschap voor Innovatie door Wetenschap en Technologie-IWT）、佛兰德斯研究基金会（Fonds Wetenschappelijk Onderzoek-Vlaanderen-FWO）和比利时抗癌基金会（HOPE 项目，Dossier C69）的资助。临床 IVM 研究得到了 Cook Medical 和 Besins Healthcare 的研究资助。M.D.V. 报告因在讲座中提及 Cook Medical 和 Besins Healthcare 而获得的讲课费，这些讲座均在提交的工作之外进行。S.S.R. 报告因在 Merck、Besins 和 Ferring 进行讲座以及在 Merck-Serono、Ferring、IBSA、Finox、MSD 和 Abbott 进行研究而获得的酬金，这些讲座和研究均在提交的工作之外进行。C.B. 报告因与 Merck、MSD、Goodlife、Cook、Roche、Besins、Ferring、Research Fund of Flanders（FWO）和 Finox、Abbott、Obseva 和 Ovascience 有合作关系而获得的咨询费，这些合作关系均在提交的工作之外进行。其他作者没有什么可透露的。
