Causal Effects of Endometriosis Stages on Adverse Pregnancy and Perinatal Outcomes: A Mendelian Randomization Study

Wen Zhao,1 Zeting Li,2 Jianping Ou1 1Center for Reproductive Medicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People’s Republic of China; 2Department of Endocrinology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, People’s Republic of ChinaCorrespondence: Jianping Ou, Center for Reproductive Medicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510630, People’s Republic of China, Email [email protected] Zeting Li, Department of Endocrinology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, 518107, People’s Republic of China, Email [email protected]: This mendelian randomization (MR) study aimed to investigate whether endometriosis, overall and stratified by stage (I/II vs III/IV), confers causal effects on adverse pregnancy and perinatal outcomes.Methods: Exposure data came from FinnGen for ASRM-staged endometriosis (stage I/II and III/IV) and the largest cross-ancestry GWAS meta-analysis of endometriosis, while 12 adverse pregnancy outcomes from FinnGen or GWAS catalog were defined by ICD codes. The inverse variance weighted (IVW) method was used for primary estimates, and sensitivity analyses including heterogeneity tests, horizontal pleiotropy tests, and leave-one-out analyses were performed using R packages.Results: The IVW analysis revealed that endometriosis was causally associated with an increased risk of intrahepatic cholestasis of pregnancy (ICP) [odds ratio (OR) 1.29, 95% confidence interval (CI) 1.01– 1.64, p = 0.045] and premature rupture of membranes [OR 1.14, 95% CI 1.01– 1.29, p = 0.028]. The advanced stages of endometriosis (III–IV) (OR 1.24, 95% CI 1.06– 1.44, p = 0.006) play a more prominent role in increasing the risk of ICP compared to early stages (I–II) (OR 1.16, 95% CI 0.94– 1.43, p = 0.159). However, no significant causal relationships were found between endometriosis and other adverse pregnancy outcomes. Sensitivity analyses indicated most results were robust without pleiotropy (p> 0.05), except for significant heterogeneity in premature separation of placenta across stages and potential horizontal pleiotropy in gestational hypertension.Conclusion: Our findings suggest stage III/IV endometriosis as an independent causal factor for ICP, necessitating intensified hepatobiliary function monitoring in these patients. The lack of causal association between endometriosis and other obstetric complications highlights the multifactorial nature of adverse pregnancy outcomes. Future multicenter studies should explore biomarkers reflecting endometriosis-associated hepatobiliary dysfunction to guide targeted interventions.Keywords: endometriosis, endometriosis stages, pregnancy complications, perinatal outcomes, Mendelian randomization