BACKGROUND Women with endometriosis may constitute a group at a particularly increased risk of pregnancy-related complications. Furthermore, women selected for assisted reproductive technology (ART) are exposed to additional endocrinological and embryological factors that have been associated with adverse pregnancy outcomes. OBJECTIVE AND RATIONALE This study aimed to investigate the independent effect of endometriosis, adenomyosis, and various ART-related factors on adverse maternal, placental, fetal, and neonatal outcomes. SEARCH METHODS Published randomized controlled trials, cohort studies, and case-control studies were considered eligible. PubMed, MEDLINE, ClinicalTrials.gov, Embase, and Scopus were systematically searched up to 1 March 2024. This systematic review and meta-analysis was performed in line with the PRISMA and the MOOSE reporting guidelines. To thoroughly investigate the association between endometriosis/adenomyosis and adverse pregnancy outcomes, sub-analyses were conducted, whenever possible, according to: the method of conception (i.e. ART and non-ART conception), the endometriosis stage/phenotype, the coexistence of endometriosis and adenomyosis, any pre-pregnancy surgical treatment of endometriosis, and the form of adenomyosis. The odds ratio (OR) with 95% CI was used as effect measure. The quality of evidence was assessed using the GRADE approach. OUTCOMES We showed a higher risk of placenta previa in women with endometriosis compared to controls (34 studies, OR 2.84; 95% CI: 2.47, 3.26; I2 = 83%, moderate quality). The association was observed regardless of the method of conception and was particularly strong in the most severe forms of endometriosis (i.e. rASRM stage III-IV endometriosis and deep endometriosis (DE)) (OR 6.61; 95% CI: 2.08, 20.98; I2 = 66% and OR 14.54; 95% CI: 3.67, 57.67; I2 = 54%, respectively). We also showed an association, regardless of the method of conception, between endometriosis and: (i) preterm birth (PTB) (43 studies, OR 1.43; 95% CI: 1.32, 1.56; I2 = 89%, low quality) and (ii) cesarean section (29 studies, OR 1.52; 95% CI: 1.41, 1.63; I2 = 93%, low quality). The most severe forms of endometriosis were strongly associated with PTB. Two outcomes were associated with adenomyosis both in the main analysis and in the sub-analysis that included only ART pregnancies: (i) miscarriage (14 studies, OR 1.83; 95% CI: 1.53, 2.18; I2 = 72%, low quality) and (ii) pre-eclampsia (7 studies, OR 1.70; 95% CI: 1.16, 2.48; I2 = 77%, low quality). Regarding ART-related factors, the following associations were observed in the main analysis and confirmed in all sub-analyses conducted by pooling only risk estimates adjusted for covariates: (i) blastocyst stage embryo transfer (ET) and monozygotic twinning (28 studies, OR 2.05; 95% CI, 1.72, 2.45; I2 = 72%, low quality), (ii) frozen embryo transfer (FET) and (reduced risk of) small for gestational age (21 studies, OR 0.59; 95% CI, 0.57, 0.61; P < 0.00001; I2 = 17%, very low quality) and (increased risk of) large for gestational age (16 studies, OR 1.70; 95% CI, 1.60, 1.80; P < 0.00001; I2 = 55%, very low quality), (iii) artificial cycle (AC)-FET and pre-eclampsia (12 studies, OR 2.14; 95% CI: 1.91-2.39; I2 = 9%, low quality), PTB (21 studies, OR 1.24; 95% CI 1.15, 1.34; P < 0.0001; I2 = 50%, low quality), cesarean section (15 studies, OR 1.59; 95% CI 1.49, 1.70; P < 0.00001; I2 = 67%, very low quality) and post-partum hemorrhage (6 studies, OR 2.43; 95% CI 2.11, 2.81; P < 0.00001; I2 = 15%, very low quality). WIDER IMPLICATIONS Severe endometriosis (i.e. rASRM stage III-IV endometriosis, DE) constitutes a considerable risk factor for placenta previa and PTB. Herein, we recommend against superimposing on this condition other exposure factors that have a strong association with the same obstetric adverse outcome or with different outcomes which, if coexisting, could determine the onset of an ominous obstetric syndrome. Specifically, we strongly discourage the use of AC regimens for FET in ovulatory women with rASRM stage III-IV endometriosis or DE. We also recommend single ET at the blastocyst stage in this high-risk population. REGISTRATION NUMBER CRD42023401428.

中文翻译：

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解开子宫内膜异位症、子宫腺肌病和 ART 相关因素对孕产妇、胎盘、胎儿和新生儿不良结局的独立影响：系统评价和荟萃分析的结果。


背景 患有子宫内膜异位症的女性可能构成一个妊娠相关并发症风险特别高的群体。此外，被选中接受辅助生殖技术 （ART） 的妇女会暴露于与不良妊娠结局相关的其他内分泌和胚胎学因素。目的和基本原理 本研究旨在调查子宫内膜异位症、子宫腺肌病和各种 ART 相关因素对孕产妇、胎盘、胎儿和新生儿不良结局的独立影响。检索方法 已发表的随机对照试验、队列研究和病例对照研究被认为符合条件。系统检索了截至 2024 年 3 月 1 日的 PubMed、MEDLINE、ClinicalTrials.gov、Embase 和 Scopus。本系统评价和荟萃分析是根据 PRISMA 和 MOOSE 报告指南进行的。为了彻底调查子宫内膜异位症/子宫腺肌病与不良妊娠结局之间的关联，尽可能根据以下因素进行子分析：受孕方法（即 ART 和非 ART 受孕）、子宫内膜异位症分期/表型、子宫内膜异位症和子宫腺肌病的共存、子宫内膜异位症的任何孕前手术治疗以及子宫腺肌病的形式。使用 95% CI 的比值比 （OR） 作为效应测量。使用 GRADE 方法评估证据质量。结果 我们显示，与对照组相比，子宫内膜异位症女性患前置胎盘的风险更高（34 项研究，OR 2.84;95% CI：2.47,3.26;I2 = 83%，中等质量）。无论采用何种受孕方法，都可以观察到这种关联，并且在最严重的子宫内膜异位症形式中尤其强烈（即 rASRM III-IV 期子宫内膜异位症和深部子宫内膜异位症 （DE））（OR 6.61;95% CI：2.08,20。98;I2 = 66% 和 OR 14.54;95% CI：3.67,57.67;I2 = 54%）。我们还显示，无论采用何种受孕方法，子宫内膜异位症与以下方面之间存在关联：（i） 早产 （PTB）（43 项研究，OR 1.43;95% CI：1.32,1.56;I2 = 89%，低质量）和 （ii） 剖宫产（29 项研究，OR 1.52;95% CI：1.41,1.63;I2 = 93%，低质量）。最严重的子宫内膜异位症与 PTB 密切相关。在主要分析和仅包括 ART 妊娠的子分析中，两个结局与子宫腺肌病相关：（i） 流产（14 项研究，OR 1.83;95% CI：1.53,2.18;I2 = 72%，低质量）和 （ii） 先兆子痫（7 项研究，OR 1.70;95% CI：1.16,2.48;I2 = 77%，低质量）。关于 ART 相关因素，在主要分析中观察到以下关联，并在进行的所有子分析中通过仅合并针对协变量调整的风险估计来证实：（i） 囊胚期胚胎移植 （ET） 和同卵双胞胎（28 项研究，OR 2.05;95% CI，1.72,2.45;I2 = 72%，低质量），（ii） 冷冻胚胎移植 （FET） 和小于胎龄儿（降低风险）（21 项研究，OR 0.59;95% CI，0.57,0.61;P < 0.00001;I2 = 17%，极低质量）和大于胎龄儿（风险增加）（16 项研究，OR 1.70;95% CI，1.60,1.80;P < 0.00001;I2 = 55%，极低质量），（iii） 人工周期 （AC）-FET 和先兆子痫（12 项研究，OR 2.14;95% CI：1.91-2.39;I2 = 9%，低质量）、PTB（21 项研究，OR 1.24;95% CI 1.15、1.34;P < 0.0001;I2 = 50%，低质量）、剖宫产（15 项研究，OR 1.59;95% CI 1.49,1.70;P < 0.00001;I2 = 67%，极低质量）和产后出血（6 项研究，OR 2.43;95% CI 2.11,2.81;P < 0.00001;I2 = 15%，质量非常低）。 更广泛的影响 严重的子宫内膜异位症（即 rASRM III-IV 期子宫内膜异位症，DE）构成前置胎盘和 PTB 的相当大的危险因素。在此，我们建议不要在这种情况下叠加与相同的产科不良结果或不同结果密切相关的其他暴露因素，如果共存，则可能决定不祥产科综合征的发作。具体来说，我们强烈不鼓励对患有 rASRM III-IV 期子宫内膜异位症或 DE 的排卵女性使用 AC 方案进行 FET。我们还建议在这个高危人群的囊胚期进行单次 ET。注册号 CRD42023401428。