{"paper_id":"249adc62-568f-4174-b6a2-3eddcc2bbb8d","body_text":"Endometriosis and Adverse Pregnancy Outcomes: A Dual-Cohort Study of Over 4 Million California Births | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Endometriosis and Adverse Pregnancy Outcomes: A Dual-Cohort Study of Over 4 Million California Births Bahar D. Yilmaz, Rebecca J. Baer, Umair Khan, Ophelia Yin, Linda C. Giudice, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7377239/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Although endometriosis is increasingly recognized as a risk factor for adverse pregnancy outcomes, large-scale analyses in U.S. populations remain limited. In this retrospective dual-cohort study, we analyzed over 4 million singleton births in California (2011–2020) and a complementary academic electronic medical record (EMR) dataset to evaluate adverse pregnancy outcomes in individuals with endometriosis. Adjusting for use of assisted reproductive technology, prenatal care, and comorbidities, we found consistent significant associations between endometriosis and placenta previa (aRR 4.9, 95% CI 4.4 to 5.4), placental abruption (aRR 1.9, 95% CI 1.6 to 2.3), preterm birth (aRR 1.5, 95% CI 1.4 to 1.6), hypertensive disorders of pregnancy (aRRs 1.3–1.4, 95% CI 1.1 to 1.5), gestational diabetes (aRR 1.2, 95% CI 1.1 to 1.3), cesarean delivery (aRR 1.6, 95% CI 1.6 to 1.7), and severe maternal morbidity (aRR 2.3, 95% CI 2.1–2.6). Findings were directionally consistent across both population-level and institutional cohorts, supporting the robustness of observed associations. This underscores the systemic impact of endometriosis beyond conception and calls for its integration into pregnancy risk assessment models. We also demonstrate the ability to leverage two complementary data sources (birth records and EMR) to better understand relationships and outcomes in reproductive health. Recognizing endometriosis as a chronic condition with obstetric consequences may offer new avenues for prevention and early intervention to improve maternal, fetal, and neonatal outcomes. Health sciences/Diseases Health sciences/Health care Health sciences/Medical research Health sciences/Risk factors Figures Figure 1 Introduction Endometriosis is a chronic, estrogen-dependent condition affecting up to 10% of reproductive-age women and nearly 50% of those with infertility 1 – 4 . The disease is defined by the presence endometrial-like tissue outside the uterine cavity, most commonly on the ovaries, pelvic peritoneum, and uterosacral ligaments 5 . While its adverse effects on fertility have long been recognized, women with endometriosis were historically presumed to have comparable obstetric outcomes once pregnancy was achieved 6 . Growing evidence suggests that endometriosis also impacts pregnancy outcomes 7 – 9 . Several observational studies and meta-analyses, including a 2017 synthesis by Zullo et al., have reported associations between endometriosis and adverse obstetric outcomes such as preterm birth, placenta previa, and cesarean delivery 7 . However, some of these studies lacked adjustment for key confounders, and others were limited to a single center or to surgically diagnosed populations, making it difficult to generalize findings. More recent large-scale studies have expanded the range of outcomes and addressed some confounding factors. For example, Lalani et al. used Canadian population data to show that women with endometriosis were at increased risk of hypertensive disorders of pregnancy, preterm birth, and NICU admission – even among those who conceived spontaneously – suggesting an independent effect of the disease 8 . More recently, Abdessamie et al. used national inpatient data to demonstrate elevated risks of severe maternal morbidity (SMM), including disseminated intravascular coagulation, sepsis, and transfusion in women with endometriosis 10 . While this work expanded the range of recognized complications, it could not account for mode of conception. Given the established link between endometriosis and infertility, assisted reproductive technology (ART) may complicate efforts to disentangle direct obstetric risks from treatment-related effects. A comprehensive 2024 meta-analysis by Busnelli et al. applied a causal inference framework to over 80 studies, concluding that endometriosis likely plays a causal role in adverse pregnancy outcomes such as preterm birth and placenta previa. Importantly, the authors found that risks persisted in both spontaneous and ART-conceived pregnancies, and that specific ART protocols – such as artificially prepared frozen embryo transfers – may further modify risk in affected individuals 9 . Despite these advances, important gaps remain. Most studies rely on a single dataset and vary in methodology, limiting replication and generalizability. Importantly, emerging evidence suggests that the impact of endometriosis may extend into the neonatal period with increased risks of NICU admission and possible downstream effects on child health 8 , 11 – areas that remain underexplored in large cohorts. If endometriosis contributes to obstetric complications, its relevance extends far beyond fertility, positioning it as a condition with important implications for maternal and newborn health at a population level. Recognizing and quantifying this broader impact is critical for informing preconception counseling, antenatal management, and long-term health planning. To address these gaps, we conducted a dual-cohort study evaluating the association between endometriosis and adverse pregnancy outcomes using two complementary datasets: a large, population-based cohort of singleton live births in California (SOMI) and a de-identified electronic medical record (EMR) cohort from a tertiary academic medical center (UCSF). This design enabled us to examine a comprehensive range of maternal and neonatal outcomes using harmonized definitions across cohorts, while adjusting for demographic and clinical confounders. By replicating findings across complementary data sources, our study provides a generalizable and robust understanding of the obstetric and early fetal/neonatal risks associated with endometriosis, informing risk stratification, counseling, and care. Methods Study of Outcomes in Mothers and Infants (SOMI) Cohort The sample included liveborn infants in California between 2011 and 2020. Birth certificates, maintained by California Vital Statistics 12 were linked to a hospital discharge, emergency department, and ambulatory surgery records maintained by the California Department of Health Care Access and Information (HCAI) 13 . The linkage algorithm included birth hospital, date of birth, sex, zip code, race/ethnicity, and diagnoses and procedures recorded in hospital discharge records that were also present on the birth certificate (e.g. cesarean birth, gestational age, birthweight) 14 . Hospital discharge, emergency department, and ambulatory surgery files provided diagnoses and procedure codes based on the International Classification of Diseases (ICD), as reported to the HCAI by the health care facilities. ICD 9th edition (ICD-9) 15 codes were reported for births from January 2011 through September 2015 and ICD 10th edition (ICD-10) 16 codes were reported for births from October 2015 through December 2020. The sample was restricted to singletons with linked birth certificates to maternal and infant discharge records (Fig. 1 ). Endometriosis diagnosis was obtained from pregnancy and birth HCAI ICD diagnostic fields (Appendix 1). Potential maternal covariates included age at birth, race/ethnicity, years of education, pre-pregnancy body mass index (BMI, calculated from height and pre-pregnancy weight), parity, adequacy of prenatal care (per Kotelchuck et al 17 , calculated from month of care initiation, number of visits, and gestation at delivery), previous cesarean delivery, conception via artificial reproductive technology, history of infertility, preexisting hypertension, and preexisting diabetes (Appendix 1) 17 . Adverse birth outcomes included preterm birth (< 37 weeks gestation), low birth weight (< 2500 grams), small for gestational age (SGA, < 10th percentile for sex and gestational age 18 ), large for gestational age (LGA, > 90th percentile for sex and gestational age, gestational hypertension, preeclampsia/eclampsia, gestational diabetes, cesarean delivery, placenta previa, placental abruption, SMM, and major birth defect (Appendix 1). The association between a diagnosis of endometriosis and each maternal covariate was assessed using Poisson log-linear regression with no endometriosis diagnosis as the referent population. Risk of each adverse outcome was calculated in a sequential fashion. First, crude (unadjusted) risk (RR1) of each adverse outcome was calculated. Next, risks were adjusted for demographic factors (age, race/ethnicity, and education) (RR2). The fully adjusted model (RR3) included demographic factors and BMI, parity, adequacy of prenatal care, assisted reproductive technology (ART), history of infertility, previous cesarean delivery, preexisting hypertension, and preexisting diabetes. We considered ART use as a potential mediator between endometriosis and adverse pregnancy outcomes. To assess its role, we conducted a mediation analysis estimating the direct and indirect effects of endometriosis through ART for each outcome. Results indicated that ART accounted for less than 2% of the total effect across all outcomes (Supplementary Table 2), suggesting minimal mediation. On this basis, we included ART as a covariate in adjusted models to improve model precision and account for potential differences in clinical care associated with ART use. All analyses were performed using Statistical Analysis Software version 9.4 (Cary, NC). Methods and protocols for the study were approved by the Committee for the Protection of Human Subjects within the Health and Human Services Agency of the State of California, and by the institutional review board at the University of California San Diego. UCSF EMR Data We analyzed the association between endometriosis and adverse birth outcomes using two complementary approaches in UCSF’s Observational Medical Outcomes Partnership (OMOP) de-identified electronic health records, which span from 1988 to the present day. In the first (birth-anchored approach), we identified all patients with a recorded live birth and compared outcomes by endometriosis status. In the second (endometriosis-anchored approach), we began with patients diagnosed with endometriosis and matched controls, then identified pregnancies via diagnosis codes. The birth-anchored approach enables clean capture of delivery outcomes (like cesarean delivery), while the endometriosis-anchored approach allows inclusion of patients who may have received prenatal or postpartum care at UCSF but delivered elsewhere. This strategy increases analytic power, reduces selection bias from conditioning on delivery at a tertiary center, and allows cross-validation of findings under different sampling assumptions. In both approaches, we define endometriosis cases as patients who at any point in their medical history were assigned at least one of the 49 standard Systematized Nomenclature of Medicine (SNOMED) condition IDs descended from “endometriosis” in OMOP’s concept hierarchy. In the birth-anchored approach, we identified all patients with a recorded “single live birth” in the OMOP condition table and then stratified them based on whether they had received an endometriosis diagnosis at any point in their medical history. In the endometriosis-anchored approach, we began with endometriosis patients and selected controls via 1:30 propensity score matching against cases on age, gender, race, and ethnicity using the MatchIt package in R (version 4.5.5, nearest neighbor method). These patients were then stratified based on whether they had received a diagnosis of any condition with the root string “pregnan”, with manual filtering of condition names to avoid false positives like “pregnancy test negative” (Fig. 1 ). For the analysis of birth outcomes, we translated the ICD-9 and ICD-10 codes used in the SOMI analysis (Supplementary Table 1) to OMOP concepts using the concept relationship table. Maternal covariates included age at first recorded birth (for the birth-anchored approach) or age at first recorded pregnancy condition (for the endometriosis-anchored approach), gender, race, and ethnicity. Outcomes analyzed for both approaches include presence of uterine fibroids, gestational hypertension, preeclampsia, gestational diabetes, cesarean delivery, placenta previa, and placental abruption. The association between endometriosis and each outcome was calculated using Poisson log-linear regression for both approaches and is reported as relative risk (RR) and associated 95% confidence interval (CI). Both unadjusted risk (RR1) and demographic-adjusted risk (RR4, adjusted for age, gender, race, and ethnicity) were calculated for each outcome. All statistical analyses were performed using the NumPy, pandas, and statsmodels packages in Python. Results Population-based cohort of singleton live births in California (SOMI) Outcomes Baseline maternal characteristics associated with endometriosis The analytic sample included 4,145,166 live births of whom 6,056 had a diagnosis of endometriosis. There was a significant association between endometriosis and each maternal baseline characteristics considered. People with a diagnosis of endometriosis were more likely to be 35 years or older, of Asian race/ethnicity, have >12 years education, have conceived using ART, have a history of infertility, have had a previous cesarean delivery, and have preexisting hypertension or diabetes compared to those without a diagnosis of endometriosis (RRs ranged from 1.6 (nulliparous) to 10.0 (history of infertility)) (Table 1). Maternal, fetal, and neonatal outcomes associated with endometriosis In the fully adjusted model, those with endometriosis were more likely to have a preterm birth, an LGA infant, gestational hypertension, preeclampsia/eclampsia, gestational diabetes, a cesarean delivery, placenta previa, placental abruption, and SMM. We did not find an increased risk of low birth weight, delivering an SGA infant, or an infant with a major birth defect. Notably, 11.1% of the population with endometriosis had a preterm birth was compared to 6.8% in the population without an endometriosis diagnosis (aRR 1.5, 95% CI 1.4 to 1.6), 73.9% of the population had a cesarean delivery versus 29.9% of those without (aRR 1.6, 95% CI 1.6 to 1.7), 6.3% had placenta previa versus 0.9% of those without (aRR 4.9, 95% CI 1.6 to 2.3), 2.0% had placental abruption versus 1.0% of those without (aRR 1.9, 95% CI 1.6 to 2.3), and 5.1% had SMM versus 1.9% of those without an endometriosis diagnosis (aRR 2.3, 95% CI 2.1 to 2.6) (Table 2). De-identified EMR Outcomes Baseline maternal characteristics associated with endometriosis The analytic sample included 35,331 patients in the birth-anchored approach, and 93,118 patients in the endometriosis-anchored approach. Like the SOMI dataset, there was an association between endometriosis and many of the maternal baseline characteristics considered. These associations were directionally consistent with the SOMI results, although some relative risks did not meet the threshold for statistical significance (likely due to the smaller patient sample). People with a diagnosis of endometriosis were more likely to be 35 years or older, of Asian race, and have preexisting hypertension compared to those without a diagnosis of endometriosis (Table 1). Maternal, fetal, and neonatal outcomes associated with endometriosis In the birth-anchored approach, which restricted the sample to individuals with a recorded live birth (n = 35,331) and stratified by endometriosis diagnosis, we identified 820 endometriosis cases and 34,511 controls (Table 2). In adjusted models, gestational hypertension (aRR 1.2, 95% CI 1.0 to 1.4), preeclampsia (aRR 1.2, 95% CI 1.0 to 1.4), gestational diabetes (aRR 1.3, 95% CI 1.1 to 1.5). Endometriosis was also associated with increased likelihood of cesarean delivery (aRR 1.6, 95% CI 1.4 to 1.8) and placenta previa (aRR 1.8, 95% CI 1.5 to 2.1), though not with placental abruption (aRR 1.3, 95% CI 1.0 to 1.8). In the endometriosis-anchored approach, which began with endometriosis cases compared to matched controls, and stratified based on evidence of a pregnancy-related condition, 2,533 endometriosis cases and 90,585 controls were analyzed (Table 2). Findings from this approach were directionally consistent and of larger magnitude in several cases. Adjusted risk of gestational hypertension (aRR 1.4, 95% CI 1.2 to 1.6) and preeclampsia (aRR 1.4, 95% CI 1.2 to 1.7) remained elevated. Gestational diabetes was again more common among individuals with endometriosis (aRR 1.2, 95% CI 1.1 to 1.4). Risks of cesarean delivery (aRR 2.1, 95% CI 1.9 to 2.4), placenta previa (aRR 2.2, 95% CI 1.8 to 2.6), and placental abruption (aRR 1.9, 95% CI 1.4 to 2.7) were also significantly elevated. Discussion In this study of over 4 million live births and a complementary EMR dataset, we found that individuals with endometriosis were at significantly increased risk for a range of obstetric and perinatal complications, including placenta previa, placental abruption, preterm birth, hypertensive disorders, cesarean delivery, and SMM. These associations were robust to multivariable adjustment. Beyond the breadth of associations identified, the novelty of this study lies in its methodological design. For the population dataset, we applied a robust set of covariate adjustments, extending beyond typical demographic factors to include ART use, adequacy of prenatal care, and chronic medical comorbidities. Although ART use may be hypothesized as a mediator between endometriosis and obstetric risk, our mediation analysis (Supplementary Table 2) suggests that ART accounts for only a negligible portion of the observed associations. For our EMR dataset, we anchored analyses on both births and endometriosis diagnoses, to enhance internal consistency and minimize bias. We yielded similar conclusions despite differences in cohort size and compositions. This approach, rarely used in obstetric epidemiology, allowed us to examine endometriosis-related risks from complementary clinical perspectives. The scale of the California birth cohort enabled precise estimation of even rare but clinically significant outcomes, and replication in the EMR dataset further strengthens the validity and generalizability of our findings. Together, these elements position our study as one of the most comprehensive U.S.-based investigations of endometriosis and pregnancy to date. Placenta previa emerged as one of the most strongly associated complications associated with endometriosis, with an adjusted ratio of 4.9 in the population-based cohort. This finding aligns with the results of a recent meta-analysis by Busnelli et. al, which reported an odds ratio of 2.84 for previa overall and up to sixfold risk with stage III/IV endometriosis 9 . This risk remained high after adjustment for ART use which aligns with previous analysis showing that increased risks including previa is independent of infertility diagnosis, or fertility treatment 19 . Complementary analyses in our EMR cohort confirmed this association, albeit with lower absolute risk estimates, reinforcing the robustness of the finding. It is likely that there is a dose-response relationship between disease severity and placental complications 9 , 20 . Biologically, endometriosis may predispose to abnormal implantation in the lower uterine segment through disrupted uterine peristalsis, altered endometrial receptivity, and progesterone resistance 6 , 21 , 22 . We also observed a consistent increased risk of placental abruption, reaching statistical significance in the population and endometriosis-anchored EMR analyses. The co-occurrence of these two distinct yet related placental pathologies points to a shared pathophysiologic mechanism, likely rooted in impaired decidualization, abnormal spiral artery remodeling, and abnormal trophoblast invasion – features increasingly recognized in endometriosis-affected endometrium 23 . This pathophysiologic continuum may also underlie the increased risk of hypertensive disorders observed in our study. Individuals with endometriosis had significantly higher rates of both gestational hypertension and preeclampsia, with adjusted risk ratios ranging from 1.3 to 1.4 across cohorts. These findings are consistent with prior population-based studies and meta-analyses and suggest that the vascular dysfunction associated with endometriosis extends beyond conception into placental development and systemic maternal adaptation 24 , 25 . Notably, we also observed an increased prevalence of preexisting hypertension in individuals with endometriosis, aligning with earlier prospective data linking endometriosis to chronic cardiovascular conditions 26 . This supports the growing recognition of endometriosis as a systemic inflammatory condition with long-term vascular implications 27 . Clinically, this reinforces the importance of early screening and risk mitigation strategies such as low-dose aspirin in this population. The risk of preterm birth was also significantly elevated in individuals with endometriosis, including a nearly twofold increase in deliveries before 32 weeks and a 1.5-fold increase before 37 weeks across both datasets. These findings are consistent with previous large-scale studies 11 , 28 , 29 and suggest that premature parturition may be a consequence of the same disrupted uterine environment that underlies abnormal placentation and vascular adaptation. Mechanistically, several pathways may contribute to early labor in endometriosis, including elevated intrauterine cytokines (e.g., IL-6, TNF-α), increased local prostaglandin synthesis, and impaired myometrial contractility – particularly in cases involving deep infiltrating endometriosis 20 . Notably, these risks were observed regardless of mode of conception, reinforcing the notion that the disease itself, rather than ART exposure, drives the association. From a clinical standpoint, these findings support closer surveillance of cervical length and consideration of prophylactic strategies in pregnancies at high risk for early delivery. We also observed a substantially increased risk of cesarean delivery among individuals with endometriosis, with adjusted risk ratios ranging from 1.6 in the population-based cohort to 2.1 in the EMR analysis. These findings are consistent with prior registry-based and meta-analytic data 8 , 9 , 11 , 24 , 28 . While higher rates of placenta previa, fetal malpresentation, and preterm birth likely contribute, the persistence of this association suggests additional underlying factors. From an obstetric perspective, altered uterine contractility, pelvic adhesions, and chronic inflammation may predispose to labor dysfunction or fetal intolerance, increasing intrapartum cesarean rates. Anticipated surgical complexity may also lead providers – and sometimes patients – to favor planned cesarean delivery. These findings reflect both the biological and clinical complexity of endometriosis and underscore the importance of individualized delivery planning by teams familiar with its obstetric implications. Our study also identified an increased risk of gestational diabetes and preexisting diabetes in individuals with endometriosis, with adjusted risk ratios up to 1.9. These findings extend prior observations and suggest a broader metabolic vulnerability in this population 23 , 24 . Proposed mechanisms include chronic low-grade inflammation, progesterone resistance, and cytokine-driven insulin resistance, which may hinder pancreatic β-cell adaptation during pregnancy 23 . However, evidence on this association remains mixed. Some studies have not found a significant link between endometriosis and gestational diabetes, particularly after accounting for ART use or BMI 11 , 30 . These discrepancies may reflect differences in study populations, diagnostic definitions, or residual confounding. Still, given our findings and emerging biological plausibility, early screening and individualized monitoring may be warranted in patients with endometriosis, especially those with additional metabolic risk factors. We found that individuals with endometriosis were at significantly increased risk for SMM, with an adjusted risk ratio of 2.3 in the population cohort. These findings are consistent with prior work from Canada and Europe 11 , 31 and reflect a broader pattern of obstetric complexity in this population. Common drivers of SMM in endometriosis include severe preeclampsia, hemorrhage, placental disorders, and ICU admission, all of which may result from a combination of abnormal placentation, vascular fragility, and underlying inflammation. The increased frequency of surgical delivery and operative challenges may further elevate risk. These findings reinforce the need for delivery in well-resourced settings, with multidisciplinary planning and anticipatory management for high-risk patients. Despite increased rates of preterm birth and placental complications, we did not observe a strong association between endometriosis and SGA infants or congenital anomalies. SGA risk was only marginally elevated (RR ~ 1.1), which is consistent with several prior U.S. and European studies 29 , 32 that also reported limited or no increase in SGA risk after adjusting for gestational age and ART use. This is somewhat surprising given the elevated rates of placenta-mediated complications and hypertensive disorders, both of which are typically associated with fetal growth restriction. However, other studies have similarly noted that while endometriosis may impair placentation, it does not consistently translate into fetal growth restriction, possibly due to early detection and clinical intervention 11 , 30 . Likewise, we observed no significant increase in major congenital anomalies, which is reassuring and aligns with most large registry studies that have found no teratogenic signal associated with endometriosis 33 . Notably, we did identify a modest increase in LGA infants (RR 1.4), a finding less commonly reported in the literature. While the biological basis remains unclear, possible explanations include metabolic dysregulation, subclinical glucose intolerance, or overcompensation in placental nutrient transport in the context of chronic inflammation. This finding warrants further investigation, as prior studies have largely focused on SGA and preterm birth, with less emphasis on fetal overgrowth. This study has several important limitations inherent to its retrospective and administrative data-based design. First, the identification of endometriosis was reliant on ICD-coded diagnoses, which are prone to underreporting and misclassification. Given the known prevalence of endometriosis in reproductive-age individuals (estimated at 5–10% 34 ) and estimated prevalence of endometriosis in pregnancy (4.5% 24 ), the low proportion (~ 0.1%) captured in our population-based cohort may identify a subset of patients with more severe, clinically apparent disease – potentially limiting generalizability to milder or undiagnosed cases. Second, we lacked detailed information on disease phenotype (e.g., superficial peritoneal, ovarian endometrioma, deep infiltrating endometriosis) and surgical or hormonal treatment history. These factors are increasingly recognized as modifiers of pregnancy risk and would have provided insight into potential effect heterogeneity. Third, although we adjusted for key covariates including maternal age, parity, and use of ART, residual confounding is possible – particularly in relation to socioeconomic status and comorbidities. Fourth, our EMR analysis, while complementary, was limited by smaller sample sizes and potentially differential coding practices, which may have affected power and precision for some associations (e.g., placental abruption). We also acknowledge that some of the births analyzed in the EMR analysis likely overlap with those recorded in the population data, though the subset of population data containing patients with endometriosis and births explicitly assigned to UCSF (n = 105) is much smaller than the same subset captured through UCSF EMR (n = 820). Nonetheless, the consistency of associations across two complementary cohorts, combined with alignment to mechanistic and prior epidemiologic data, supports the plausibility and relevance of our findings. Prospective studies incorporating phenotypic data, inflammatory biomarkers, and treatment history are needed to explore whether suppression of active disease mitigates pregnancy risks. The development of EMR-based tools to stratify risk and tailor obstetric care could transform management. Endometriosis should be integrated into pregnancy risk assessment models and early antenatal care plans. Conclusion Endometriosis is not merely a preconceptual condition – it imposes persistent risks throughout gestation. Our data highlight elevated risks for placental abnormalities, hypertensive and metabolic disorders, preterm birth, cesarean delivery, and SMM. Recognizing endometriosis as a chronic systemic condition with obstetric relevance can improve outcomes through targeted surveillance and early intervention. Declarations Author Contribution CDC, GB and MS came up with the question and designed the study. UK and RJB carried out the analysis. BDY, UK and RJB wrote the manuscript. LCG, TTO, BDY and OY provided clinical insight. Everyone reviewed and edited the manuscript. Acknowledgement ChatGPT 4o (released, April 2024 by OpenAI) was used in the preparation of this manuscript, specifically for refining language and improving readability. The authors take responsibility for the veracity and integrity of all final content. We would like to thank the members of the Sirota Lab for useful discussions. References Giudice, L. C. & Kao, L. C. Endometriosis. The Lancet 364, 1789–1799 (2004). Bulun, S. E. et al. Endometriosis. Endocrine Reviews 40, 1048–1079 (2019). Taylor, H. S., Kotlyar, A. M. & Flores, V. A. Endometriosis is a chronic systemic disease: clinical challenges and novel innovations. The Lancet 397, 839–852 (2021). Vercellini, P. et al. Association of endometriosis and adenomyosis with pregnancy and infertility. Fertil Steril 119, 727–740 (2023). Bulun, S. E. Endometriosis. N Engl J Med 360, 268–279 (2009). Leone Roberti Maggiore, U. et al. A systematic review on endometriosis during pregnancy: diagnosis, misdiagnosis, complications and outcomes. 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Endometriosis Is Associated with Adverse Pregnancy Outcomes: a National Population-Based Study. Reprod. Sci. 27, 1175–1180 (2020). Lafleur, N., Wei, S. Q., Bilodeau-Bertrand, M. & Auger, N. Association of Endometriosis and Severe Maternal Morbidity. Obstetrics & Gynecology 140, 1008–1016 (2022). Gebremedhin, A. T., Mitter, V. R., Duko, B., Tessema, G. A. & Pereira, G. F. Associations between endometriosis and adverse pregnancy and perinatal outcomes: a population-based cohort study. Arch Gynecol Obstet 309, 1323–1331 (2023). Tanovska, P. et al. Association Between Endometriosis and Congenital Uterine Malformations: A Single-Center Retrospective Study. Journal of Minimally Invasive Gynecology 32, 520–526 (2025). Tables Table 1 and 2 are available in the Supplementary Files section. Additional Declarations No competing interests reported. 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Baer\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"University of California San Francisco\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Rebecca\",\"middleName\":\"J.\",\"lastName\":\"Baer\",\"suffix\":\"\"},{\"id\":515520968,\"identity\":\"bd1962f1-6fb5-4db7-be85-3cd5c5ea592a\",\"order_by\":2,\"name\":\"Umair Khan\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"University of California San Francisco\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Umair\",\"middleName\":\"\",\"lastName\":\"Khan\",\"suffix\":\"\"},{\"id\":515520969,\"identity\":\"53419276-e737-4f77-9b18-b5d7d05cf6b7\",\"order_by\":3,\"name\":\"Ophelia Yin\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"University of California San Francisco\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Ophelia\",\"middleName\":\"\",\"lastName\":\"Yin\",\"suffix\":\"\"},{\"id\":515520970,\"identity\":\"b215633a-b1cd-4c65-b665-2905d03fb9a5\",\"order_by\":4,\"name\":\"Linda C. Giudice\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"University of California San Francisco\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Linda\",\"middleName\":\"C.\",\"lastName\":\"Giudice\",\"suffix\":\"\"},{\"id\":515520971,\"identity\":\"bc90bad6-2506-4be8-a193-10c7c0e94de3\",\"order_by\":5,\"name\":\"Tomiko T. Oskotsky\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"University of California San Francisco\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Tomiko\",\"middleName\":\"T.\",\"lastName\":\"Oskotsky\",\"suffix\":\"\"},{\"id\":515520973,\"identity\":\"482493c3-1d35-45b8-a787-aeea8155ec5a\",\"order_by\":6,\"name\":\"Gretchen Bandoli\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"University of California San Diego\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Gretchen\",\"middleName\":\"\",\"lastName\":\"Bandoli\",\"suffix\":\"\"},{\"id\":515520974,\"identity\":\"2a2ec5cb-7b1b-42ea-8261-02b4103489e4\",\"order_by\":7,\"name\":\"Christina D. 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The disease is defined by the presence endometrial-like tissue outside the uterine cavity, most commonly on the ovaries, pelvic peritoneum, and uterosacral ligaments\\u003csup\\u003e\\u003cspan citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e\\u003c/sup\\u003e. While its adverse effects on fertility have long been recognized, women with endometriosis were historically presumed to have comparable obstetric outcomes once pregnancy was achieved\\u003csup\\u003e\\u003cspan citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e\\u003c/sup\\u003e.\\u003c/p\\u003e\\u003cp\\u003eGrowing evidence suggests that endometriosis also impacts pregnancy outcomes\\u003csup\\u003e\\u003cspan additionalcitationids=\\\"CR8\\\" citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e\\u003c/sup\\u003e. Several observational studies and meta-analyses, including a 2017 synthesis by Zullo et al., have reported associations between endometriosis and adverse obstetric outcomes such as preterm birth, placenta previa, and cesarean delivery\\u003csup\\u003e\\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e\\u003c/sup\\u003e. However, some of these studies lacked adjustment for key confounders, and others were limited to a single center or to surgically diagnosed populations, making it difficult to generalize findings.\\u003c/p\\u003e\\u003cp\\u003eMore recent large-scale studies have expanded the range of outcomes and addressed some confounding factors. For example, Lalani et al. used Canadian population data to show that women with endometriosis were at increased risk of hypertensive disorders of pregnancy, preterm birth, and NICU admission \\u0026ndash; even among those who conceived spontaneously \\u0026ndash; suggesting an independent effect of the disease\\u003csup\\u003e\\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e\\u003c/sup\\u003e. More recently, Abdessamie et al. used national inpatient data to demonstrate elevated risks of severe maternal morbidity (SMM), including disseminated intravascular coagulation, sepsis, and transfusion in women with endometriosis\\u003csup\\u003e\\u003cspan citationid=\\\"CR10\\\" class=\\\"CitationRef\\\"\\u003e10\\u003c/span\\u003e\\u003c/sup\\u003e. While this work expanded the range of recognized complications, it could not account for mode of conception. Given the established link between endometriosis and infertility, assisted reproductive technology (ART) may complicate efforts to disentangle direct obstetric risks from treatment-related effects. A comprehensive 2024 meta-analysis by Busnelli et al. applied a causal inference framework to over 80 studies, concluding that endometriosis likely plays a causal role in adverse pregnancy outcomes such as preterm birth and placenta previa. Importantly, the authors found that risks persisted in both spontaneous and ART-conceived pregnancies, and that specific ART protocols \\u0026ndash; such as artificially prepared frozen embryo transfers \\u0026ndash; may further modify risk in affected individuals\\u003csup\\u003e\\u003cspan citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e\\u003c/sup\\u003e.\\u003c/p\\u003e\\u003cp\\u003eDespite these advances, important gaps remain. Most studies rely on a single dataset and vary in methodology, limiting replication and generalizability. Importantly, emerging evidence suggests that the impact of endometriosis may extend into the neonatal period with increased risks of NICU admission and possible downstream effects on child health\\u003csup\\u003e\\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e,\\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e\\u003c/sup\\u003e \\u0026ndash; areas that remain underexplored in large cohorts. If endometriosis contributes to obstetric complications, its relevance extends far beyond fertility, positioning it as a condition with important implications for maternal and newborn health at a population level. Recognizing and quantifying this broader impact is critical for informing preconception counseling, antenatal management, and long-term health planning.\\u003c/p\\u003e\\u003cp\\u003eTo address these gaps, we conducted a dual-cohort study evaluating the association between endometriosis and adverse pregnancy outcomes using two complementary datasets: a large, population-based cohort of singleton live births in California (SOMI) and a de-identified electronic medical record (EMR) cohort from a tertiary academic medical center (UCSF). This design enabled us to examine a comprehensive range of maternal and neonatal outcomes using harmonized definitions across cohorts, while adjusting for demographic and clinical confounders. By replicating findings across complementary data sources, our study provides a generalizable and robust understanding of the obstetric and early fetal/neonatal risks associated with endometriosis, informing risk stratification, counseling, and care.\\u003c/p\\u003e\"},{\"header\":\"Methods\",\"content\":\"\\u003cdiv id=\\\"Sec3\\\" class=\\\"Section2\\\"\\u003e\\u003ch2\\u003eStudy of Outcomes in Mothers and Infants (SOMI) Cohort\\u003c/h2\\u003e\\u003cp\\u003eThe sample included liveborn infants in California between 2011 and 2020. Birth certificates, maintained by California Vital Statistics\\u003csup\\u003e\\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e\\u003c/sup\\u003e were linked to a hospital discharge, emergency department, and ambulatory surgery records maintained by the California Department of Health Care Access and Information (HCAI)\\u003csup\\u003e\\u003cspan citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e\\u003c/sup\\u003e. The linkage algorithm included birth hospital, date of birth, sex, zip code, race/ethnicity, and diagnoses and procedures recorded in hospital discharge records that were also present on the birth certificate (e.g. cesarean birth, gestational age, birthweight)\\u003csup\\u003e\\u003cspan citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e\\u003c/sup\\u003e. Hospital discharge, emergency department, and ambulatory surgery files provided diagnoses and procedure codes based on the International Classification of Diseases (ICD), as reported to the HCAI by the health care facilities. ICD 9th edition (ICD-9)\\u003csup\\u003e\\u003cspan citationid=\\\"CR15\\\" class=\\\"CitationRef\\\"\\u003e15\\u003c/span\\u003e\\u003c/sup\\u003e codes were reported for births from January 2011 through September 2015 and ICD 10th edition (ICD-10)\\u003csup\\u003e\\u003cspan citationid=\\\"CR16\\\" class=\\\"CitationRef\\\"\\u003e16\\u003c/span\\u003e\\u003c/sup\\u003e codes were reported for births from October 2015 through December 2020. The sample was restricted to singletons with linked birth certificates to maternal and infant discharge records (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e).\\u003c/p\\u003e\\u003cp\\u003e\\u003c/p\\u003e\\u003cp\\u003eEndometriosis diagnosis was obtained from pregnancy and birth HCAI ICD diagnostic fields (Appendix 1). Potential maternal covariates included age at birth, race/ethnicity, years of education, pre-pregnancy body mass index (BMI, calculated from height and pre-pregnancy weight), parity, adequacy of prenatal care (per Kotelchuck et al \\u003csup\\u003e\\u003cspan citationid=\\\"CR17\\\" class=\\\"CitationRef\\\"\\u003e17\\u003c/span\\u003e\\u003c/sup\\u003e, calculated from month of care initiation, number of visits, and gestation at delivery), previous cesarean delivery, conception via artificial reproductive technology, history of infertility, preexisting hypertension, and preexisting diabetes (Appendix 1)\\u003csup\\u003e\\u003cspan citationid=\\\"CR17\\\" class=\\\"CitationRef\\\"\\u003e17\\u003c/span\\u003e\\u003c/sup\\u003e.\\u003c/p\\u003e\\u003cp\\u003eAdverse birth outcomes included preterm birth (\\u0026lt;\\u0026thinsp;37 weeks gestation), low birth weight (\\u0026lt;\\u0026thinsp;2500 grams), small for gestational age (SGA, \\u0026lt;\\u0026thinsp;10th percentile for sex and gestational age\\u003csup\\u003e\\u003cspan citationid=\\\"CR18\\\" class=\\\"CitationRef\\\"\\u003e18\\u003c/span\\u003e\\u003c/sup\\u003e), large for gestational age (LGA, \\u0026gt;\\u0026thinsp;90th percentile for sex and gestational age, gestational hypertension, preeclampsia/eclampsia, gestational diabetes, cesarean delivery, placenta previa, placental abruption, SMM, and major birth defect (Appendix 1).\\u003c/p\\u003e\\u003cp\\u003eThe association between a diagnosis of endometriosis and each maternal covariate was assessed using Poisson log-linear regression with no endometriosis diagnosis as the referent population. Risk of each adverse outcome was calculated in a sequential fashion. First, crude (unadjusted) risk (RR1) of each adverse outcome was calculated. Next, risks were adjusted for demographic factors (age, race/ethnicity, and education) (RR2). The fully adjusted model (RR3) included demographic factors and BMI, parity, adequacy of prenatal care, assisted reproductive technology (ART), history of infertility, previous cesarean delivery, preexisting hypertension, and preexisting diabetes.\\u003c/p\\u003e\\u003cp\\u003eWe considered ART use as a potential mediator between endometriosis and adverse pregnancy outcomes. To assess its role, we conducted a mediation analysis estimating the direct and indirect effects of endometriosis through ART for each outcome. Results indicated that ART accounted for less than 2% of the total effect across all outcomes (Supplementary Table\\u0026nbsp;2), suggesting minimal mediation. On this basis, we included ART as a covariate in adjusted models to improve model precision and account for potential differences in clinical care associated with ART use.\\u003c/p\\u003e\\u003cp\\u003eAll analyses were performed using Statistical Analysis Software version 9.4 (Cary, NC). Methods and protocols for the study were approved by the Committee for the Protection of Human Subjects within the Health and Human Services Agency of the State of California, and by the institutional review board at the University of California San Diego.\\u003c/p\\u003e\\u003c/div\\u003e\\n\\u003ch3\\u003eUCSF EMR Data\\u003c/h3\\u003e\\n\\u003cp\\u003eWe analyzed the association between endometriosis and adverse birth outcomes using two complementary approaches in UCSF\\u0026rsquo;s Observational Medical Outcomes Partnership (OMOP) de-identified electronic health records, which span from 1988 to the present day. In the first (birth-anchored approach), we identified all patients with a recorded live birth and compared outcomes by endometriosis status. In the second (endometriosis-anchored approach), we began with patients diagnosed with endometriosis and matched controls, then identified pregnancies via diagnosis codes. The birth-anchored approach enables clean capture of delivery outcomes (like cesarean delivery), while the endometriosis-anchored approach allows inclusion of patients who may have received prenatal or postpartum care at UCSF but delivered elsewhere. This strategy increases analytic power, reduces selection bias from conditioning on delivery at a tertiary center, and allows cross-validation of findings under different sampling assumptions.\\u003c/p\\u003e\\u003cp\\u003eIn both approaches, we define endometriosis cases as patients who at any point in their medical history were assigned at least one of the 49 standard Systematized Nomenclature of Medicine (SNOMED) condition IDs descended from \\u0026ldquo;endometriosis\\u0026rdquo; in OMOP\\u0026rsquo;s concept hierarchy. In the birth-anchored approach, we identified all patients with a recorded \\u0026ldquo;single live birth\\u0026rdquo; in the OMOP condition table and then stratified them based on whether they had received an endometriosis diagnosis at any point in their medical history. In the endometriosis-anchored approach, we began with endometriosis patients and selected controls via 1:30 propensity score matching against cases on age, gender, race, and ethnicity using the MatchIt package in R (version 4.5.5, nearest neighbor method). These patients were then stratified based on whether they had received a diagnosis of any condition with the root string \\u0026ldquo;pregnan\\u0026rdquo;, with manual filtering of condition names to avoid false positives like \\u0026ldquo;pregnancy test negative\\u0026rdquo; (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e).\\u003c/p\\u003e\\u003cp\\u003eFor the analysis of birth outcomes, we translated the ICD-9 and ICD-10 codes used in the SOMI analysis (Supplementary Table\\u0026nbsp;1) to OMOP concepts using the concept relationship table. Maternal covariates included age at first recorded birth (for the birth-anchored approach) or age at first recorded pregnancy condition (for the endometriosis-anchored approach), gender, race, and ethnicity. Outcomes analyzed for both approaches include presence of uterine fibroids, gestational hypertension, preeclampsia, gestational diabetes, cesarean delivery, placenta previa, and placental abruption.\\u003c/p\\u003e\\u003cp\\u003eThe association between endometriosis and each outcome was calculated using Poisson log-linear regression for both approaches and is reported as relative risk (RR) and associated 95% confidence interval (CI). Both unadjusted risk (RR1) and demographic-adjusted risk (RR4, adjusted for age, gender, race, and ethnicity) were calculated for each outcome. All statistical analyses were performed using the NumPy, pandas, and statsmodels packages in Python.\\u003c/p\\u003e\"},{\"header\":\"Results\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003ePopulation-based cohort of singleton live births in California (SOMI) Outcomes\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cem\\u003eBaseline maternal characteristics associated with endometriosis\\u003c/em\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003e\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;\\u0026nbsp;The analytic sample included 4,145,166 live births of whom 6,056 had a diagnosis of endometriosis. There was a significant association between endometriosis and each maternal baseline characteristics considered. People with a diagnosis of endometriosis were more likely to be 35 years or older, of Asian race/ethnicity, have \\u0026gt;12 years education, have conceived using ART, have a history of infertility, have had a previous cesarean delivery, and have preexisting hypertension or diabetes compared to those without a diagnosis of endometriosis (RRs ranged from 1.6 (nulliparous) to 10.0 (history of infertility)) (Table 1).\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cem\\u003eMaternal, fetal, and neonatal outcomes associated with endometriosis\\u003c/em\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003e\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;\\u0026nbsp;In the fully adjusted model, those with endometriosis were more likely to have a preterm birth, an LGA infant, gestational hypertension, preeclampsia/eclampsia, gestational diabetes, a cesarean delivery, placenta previa, placental abruption, and SMM. We did not find an increased risk of low birth weight, delivering an SGA infant, or an infant with a major birth defect. Notably, 11.1% of the population with endometriosis had a preterm birth was compared to 6.8% in the population without an endometriosis diagnosis (aRR 1.5, 95% CI 1.4 to 1.6), 73.9% of the population had a cesarean delivery versus 29.9% of those without (aRR 1.6, 95% CI 1.6 to 1.7), 6.3% had placenta previa versus 0.9% of those without (aRR 4.9, 95% CI 1.6 to 2.3), 2.0% had placental abruption versus 1.0% of those without (aRR 1.9, 95% CI 1.6 to 2.3), and 5.1% had SMM versus 1.9% of those without an endometriosis diagnosis (aRR 2.3, 95% CI 2.1 to 2.6) (Table 2).\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eDe-identified EMR Outcomes\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cem\\u003eBaseline maternal characteristics associated with endometriosis\\u003c/em\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003e\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;\\u0026nbsp;The analytic sample included 35,331 patients in the birth-anchored approach, and 93,118 patients in the endometriosis-anchored approach. Like the SOMI dataset, there was an association between endometriosis and many of the maternal baseline characteristics considered. These associations were directionally consistent with the SOMI results, although some relative risks did not meet the threshold for statistical significance (likely due to the smaller patient sample). People with a diagnosis of endometriosis were more likely to be 35 years or older, of Asian race, and have preexisting hypertension compared to those without a diagnosis of endometriosis (Table 1).\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cem\\u003eMaternal, fetal, and neonatal outcomes associated with endometriosis\\u003c/em\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eIn the birth-anchored approach, which restricted the sample to individuals with a recorded live birth (n = 35,331) and stratified by endometriosis diagnosis, we identified 820 endometriosis cases and 34,511 controls (Table 2). In adjusted models, gestational hypertension (aRR 1.2, 95% CI 1.0 to 1.4), preeclampsia (aRR 1.2, 95% CI 1.0 to 1.4), gestational diabetes (aRR 1.3, 95% CI 1.1 to 1.5). Endometriosis was also associated with increased likelihood of cesarean delivery (aRR 1.6, 95% CI 1.4 to 1.8) and placenta previa (aRR 1.8, 95% CI 1.5 to 2.1), though not with placental abruption (aRR 1.3, 95% CI 1.0 to 1.8).\\u003c/p\\u003e\\n\\u003cp\\u003eIn the endometriosis-anchored approach, which began with endometriosis cases compared to matched controls, and stratified based on evidence of a pregnancy-related condition, 2,533 endometriosis cases and 90,585 controls were analyzed (Table 2). Findings from this approach were directionally consistent and of larger magnitude in several cases. Adjusted risk of gestational hypertension (aRR 1.4, 95% CI 1.2 to 1.6) and preeclampsia (aRR 1.4, 95% CI 1.2 to 1.7) remained elevated. Gestational diabetes was again more common among individuals with endometriosis (aRR 1.2, 95% CI 1.1 to 1.4). Risks of cesarean delivery (aRR 2.1, 95% CI 1.9 to 2.4), placenta previa (aRR 2.2, 95% CI 1.8 to 2.6), and placental abruption (aRR 1.9, 95% CI 1.4 to 2.7) were also significantly elevated.\\u003c/p\\u003e\"},{\"header\":\"Discussion\",\"content\":\"\\u003cp\\u003eIn this study of over 4\\u0026nbsp;million live births and a complementary EMR dataset, we found that individuals with endometriosis were at significantly increased risk for a range of obstetric and perinatal complications, including placenta previa, placental abruption, preterm birth, hypertensive disorders, cesarean delivery, and SMM. These associations were robust to multivariable adjustment.\\u003c/p\\u003e\\u003cp\\u003eBeyond the breadth of associations identified, the novelty of this study lies in its methodological design. For the population dataset, we applied a robust set of covariate adjustments, extending beyond typical demographic factors to include ART use, adequacy of prenatal care, and chronic medical comorbidities. Although ART use may be hypothesized as a mediator between endometriosis and obstetric risk, our mediation analysis (Supplementary Table\\u0026nbsp;2) suggests that ART accounts for only a negligible portion of the observed associations. For our EMR dataset, we anchored analyses on both births and endometriosis diagnoses, to enhance internal consistency and minimize bias. We yielded similar conclusions despite differences in cohort size and compositions. This approach, rarely used in obstetric epidemiology, allowed us to examine endometriosis-related risks from complementary clinical perspectives. The scale of the California birth cohort enabled precise estimation of even rare but clinically significant outcomes, and replication in the EMR dataset further strengthens the validity and generalizability of our findings. Together, these elements position our study as one of the most comprehensive U.S.-based investigations of endometriosis and pregnancy to date.\\u003c/p\\u003e\\u003cp\\u003ePlacenta previa emerged as one of the most strongly associated complications associated with endometriosis, with an adjusted ratio of 4.9 in the population-based cohort. This finding aligns with the results of a recent meta-analysis by Busnelli et. al, which reported an odds ratio of 2.84 for previa overall and up to sixfold risk with stage III/IV endometriosis\\u003csup\\u003e\\u003cspan citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e\\u003c/sup\\u003e. This risk remained high after adjustment for ART use which aligns with previous analysis showing that increased risks including previa is independent of infertility diagnosis, or fertility treatment\\u003csup\\u003e\\u003cspan citationid=\\\"CR19\\\" class=\\\"CitationRef\\\"\\u003e19\\u003c/span\\u003e\\u003c/sup\\u003e. Complementary analyses in our EMR cohort confirmed this association, albeit with lower absolute risk estimates, reinforcing the robustness of the finding. It is likely that there is a dose-response relationship between disease severity and placental complications\\u003csup\\u003e\\u003cspan citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e,\\u003cspan citationid=\\\"CR20\\\" class=\\\"CitationRef\\\"\\u003e20\\u003c/span\\u003e\\u003c/sup\\u003e. Biologically, endometriosis may predispose to abnormal implantation in the lower uterine segment through disrupted uterine peristalsis, altered endometrial receptivity, and progesterone resistance\\u003csup\\u003e\\u003cspan citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e,\\u003cspan citationid=\\\"CR21\\\" class=\\\"CitationRef\\\"\\u003e21\\u003c/span\\u003e,\\u003cspan citationid=\\\"CR22\\\" class=\\\"CitationRef\\\"\\u003e22\\u003c/span\\u003e\\u003c/sup\\u003e.\\u003c/p\\u003e\\u003cp\\u003eWe also observed a consistent increased risk of placental abruption, reaching statistical significance in the population and endometriosis-anchored EMR analyses. The co-occurrence of these two distinct yet related placental pathologies points to a shared pathophysiologic mechanism, likely rooted in impaired decidualization, abnormal spiral artery remodeling, and abnormal trophoblast invasion \\u0026ndash; features increasingly recognized in endometriosis-affected endometrium\\u003csup\\u003e\\u003cspan citationid=\\\"CR23\\\" class=\\\"CitationRef\\\"\\u003e23\\u003c/span\\u003e\\u003c/sup\\u003e.\\u003c/p\\u003e\\u003cp\\u003eThis pathophysiologic continuum may also underlie the increased risk of hypertensive disorders observed in our study. Individuals with endometriosis had significantly higher rates of both gestational hypertension and preeclampsia, with adjusted risk ratios ranging from 1.3 to 1.4 across cohorts. These findings are consistent with prior population-based studies and meta-analyses and suggest that the vascular dysfunction associated with endometriosis extends beyond conception into placental development and systemic maternal adaptation \\u003csup\\u003e\\u003cspan citationid=\\\"CR24\\\" class=\\\"CitationRef\\\"\\u003e24\\u003c/span\\u003e,\\u003cspan citationid=\\\"CR25\\\" class=\\\"CitationRef\\\"\\u003e25\\u003c/span\\u003e\\u003c/sup\\u003e. Notably, we also observed an increased prevalence of preexisting hypertension in individuals with endometriosis, aligning with earlier prospective data linking endometriosis to chronic cardiovascular conditions\\u003csup\\u003e\\u003cspan citationid=\\\"CR26\\\" class=\\\"CitationRef\\\"\\u003e26\\u003c/span\\u003e\\u003c/sup\\u003e. This supports the growing recognition of endometriosis as a systemic inflammatory condition with long-term vascular implications\\u003csup\\u003e\\u003cspan citationid=\\\"CR27\\\" class=\\\"CitationRef\\\"\\u003e27\\u003c/span\\u003e\\u003c/sup\\u003e. Clinically, this reinforces the importance of early screening and risk mitigation strategies such as low-dose aspirin in this population.\\u003c/p\\u003e\\u003cp\\u003eThe risk of preterm birth was also significantly elevated in individuals with endometriosis, including a nearly twofold increase in deliveries before 32 weeks and a 1.5-fold increase before 37 weeks across both datasets. These findings are consistent with previous large-scale studies\\u003csup\\u003e\\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e,\\u003cspan citationid=\\\"CR28\\\" class=\\\"CitationRef\\\"\\u003e28\\u003c/span\\u003e,\\u003cspan citationid=\\\"CR29\\\" class=\\\"CitationRef\\\"\\u003e29\\u003c/span\\u003e\\u003c/sup\\u003e and suggest that premature parturition may be a consequence of the same disrupted uterine environment that underlies abnormal placentation and vascular adaptation. Mechanistically, several pathways may contribute to early labor in endometriosis, including elevated intrauterine cytokines (e.g., IL-6, TNF-α), increased local prostaglandin synthesis, and impaired myometrial contractility \\u0026ndash; particularly in cases involving deep infiltrating endometriosis\\u003csup\\u003e\\u003cspan citationid=\\\"CR20\\\" class=\\\"CitationRef\\\"\\u003e20\\u003c/span\\u003e\\u003c/sup\\u003e. Notably, these risks were observed regardless of mode of conception, reinforcing the notion that the disease itself, rather than ART exposure, drives the association. From a clinical standpoint, these findings support closer surveillance of cervical length and consideration of prophylactic strategies in pregnancies at high risk for early delivery.\\u003c/p\\u003e\\u003cp\\u003eWe also observed a substantially increased risk of cesarean delivery among individuals with endometriosis, with adjusted risk ratios ranging from 1.6 in the population-based cohort to 2.1 in the EMR analysis. These findings are consistent with prior registry-based and meta-analytic data\\u003csup\\u003e\\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e,\\u003cspan citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e,\\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e,\\u003cspan citationid=\\\"CR24\\\" class=\\\"CitationRef\\\"\\u003e24\\u003c/span\\u003e,\\u003cspan citationid=\\\"CR28\\\" class=\\\"CitationRef\\\"\\u003e28\\u003c/span\\u003e\\u003c/sup\\u003e. While higher rates of placenta previa, fetal malpresentation, and preterm birth likely contribute, the persistence of this association suggests additional underlying factors. From an obstetric perspective, altered uterine contractility, pelvic adhesions, and chronic inflammation may predispose to labor dysfunction or fetal intolerance, increasing intrapartum cesarean rates. Anticipated surgical complexity may also lead providers \\u0026ndash; and sometimes patients \\u0026ndash; to favor planned cesarean delivery. These findings reflect both the biological and clinical complexity of endometriosis and underscore the importance of individualized delivery planning by teams familiar with its obstetric implications.\\u003c/p\\u003e\\u003cp\\u003eOur study also identified an increased risk of gestational diabetes and preexisting diabetes in individuals with endometriosis, with adjusted risk ratios up to 1.9. These findings extend prior observations and suggest a broader metabolic vulnerability in this population\\u003csup\\u003e\\u003cspan citationid=\\\"CR23\\\" class=\\\"CitationRef\\\"\\u003e23\\u003c/span\\u003e,\\u003cspan citationid=\\\"CR24\\\" class=\\\"CitationRef\\\"\\u003e24\\u003c/span\\u003e\\u003c/sup\\u003e. Proposed mechanisms include chronic low-grade inflammation, progesterone resistance, and cytokine-driven insulin resistance, which may hinder pancreatic β-cell adaptation during pregnancy\\u003csup\\u003e\\u003cspan citationid=\\\"CR23\\\" class=\\\"CitationRef\\\"\\u003e23\\u003c/span\\u003e\\u003c/sup\\u003e. However, evidence on this association remains mixed. Some studies have not found a significant link between endometriosis and gestational diabetes, particularly after accounting for ART use or BMI\\u003csup\\u003e\\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e,\\u003cspan citationid=\\\"CR30\\\" class=\\\"CitationRef\\\"\\u003e30\\u003c/span\\u003e\\u003c/sup\\u003e. These discrepancies may reflect differences in study populations, diagnostic definitions, or residual confounding. Still, given our findings and emerging biological plausibility, early screening and individualized monitoring may be warranted in patients with endometriosis, especially those with additional metabolic risk factors.\\u003c/p\\u003e\\u003cp\\u003eWe found that individuals with endometriosis were at significantly increased risk for SMM, with an adjusted risk ratio of 2.3 in the population cohort. These findings are consistent with prior work from Canada and Europe\\u003csup\\u003e\\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e,\\u003cspan citationid=\\\"CR31\\\" class=\\\"CitationRef\\\"\\u003e31\\u003c/span\\u003e\\u003c/sup\\u003e and reflect a broader pattern of obstetric complexity in this population. Common drivers of SMM in endometriosis include severe preeclampsia, hemorrhage, placental disorders, and ICU admission, all of which may result from a combination of abnormal placentation, vascular fragility, and underlying inflammation. The increased frequency of surgical delivery and operative challenges may further elevate risk. These findings reinforce the need for delivery in well-resourced settings, with multidisciplinary planning and anticipatory management for high-risk patients.\\u003c/p\\u003e\\u003cp\\u003eDespite increased rates of preterm birth and placental complications, we did not observe a strong association between endometriosis and SGA infants or congenital anomalies. SGA risk was only marginally elevated (RR\\u0026thinsp;~\\u0026thinsp;1.1), which is consistent with several prior U.S. and European studies\\u003csup\\u003e\\u003cspan citationid=\\\"CR29\\\" class=\\\"CitationRef\\\"\\u003e29\\u003c/span\\u003e,\\u003cspan citationid=\\\"CR32\\\" class=\\\"CitationRef\\\"\\u003e32\\u003c/span\\u003e\\u003c/sup\\u003e that also reported limited or no increase in SGA risk after adjusting for gestational age and ART use. This is somewhat surprising given the elevated rates of placenta-mediated complications and hypertensive disorders, both of which are typically associated with fetal growth restriction. However, other studies have similarly noted that while endometriosis may impair placentation, it does not consistently translate into fetal growth restriction, possibly due to early detection and clinical intervention\\u003csup\\u003e\\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e,\\u003cspan citationid=\\\"CR30\\\" class=\\\"CitationRef\\\"\\u003e30\\u003c/span\\u003e\\u003c/sup\\u003e.\\u003c/p\\u003e\\u003cp\\u003eLikewise, we observed no significant increase in major congenital anomalies, which is reassuring and aligns with most large registry studies that have found no teratogenic signal associated with endometriosis\\u003csup\\u003e\\u003cspan citationid=\\\"CR33\\\" class=\\\"CitationRef\\\"\\u003e33\\u003c/span\\u003e\\u003c/sup\\u003e. Notably, we did identify a modest increase in LGA infants (RR 1.4), a finding less commonly reported in the literature. While the biological basis remains unclear, possible explanations include metabolic dysregulation, subclinical glucose intolerance, or overcompensation in placental nutrient transport in the context of chronic inflammation. This finding warrants further investigation, as prior studies have largely focused on SGA and preterm birth, with less emphasis on fetal overgrowth.\\u003c/p\\u003e\\u003cp\\u003eThis study has several important limitations inherent to its retrospective and administrative data-based design. First, the identification of endometriosis was reliant on ICD-coded diagnoses, which are prone to underreporting and misclassification. Given the known prevalence of endometriosis in reproductive-age individuals (estimated at 5\\u0026ndash;10%\\u003csup\\u003e34\\u003c/sup\\u003e) and estimated prevalence of endometriosis in pregnancy (4.5%\\u003csup\\u003e24\\u003c/sup\\u003e), the low proportion (~\\u0026thinsp;0.1%) captured in our population-based cohort may identify a subset of patients with more severe, clinically apparent disease \\u0026ndash; potentially limiting generalizability to milder or undiagnosed cases. Second, we lacked detailed information on disease phenotype (e.g., superficial peritoneal, ovarian endometrioma, deep infiltrating endometriosis) and surgical or hormonal treatment history. These factors are increasingly recognized as modifiers of pregnancy risk and would have provided insight into potential effect heterogeneity. Third, although we adjusted for key covariates including maternal age, parity, and use of ART, residual confounding is possible \\u0026ndash; particularly in relation to socioeconomic status and comorbidities. Fourth, our EMR analysis, while complementary, was limited by smaller sample sizes and potentially differential coding practices, which may have affected power and precision for some associations (e.g., placental abruption). We also acknowledge that some of the births analyzed in the EMR analysis likely overlap with those recorded in the population data, though the subset of population data containing patients with endometriosis and births explicitly assigned to UCSF (n\\u0026thinsp;=\\u0026thinsp;105) is much smaller than the same subset captured through UCSF EMR (n\\u0026thinsp;=\\u0026thinsp;820). Nonetheless, the consistency of associations across two complementary cohorts, combined with alignment to mechanistic and prior epidemiologic data, supports the plausibility and relevance of our findings.\\u003c/p\\u003e\\u003cp\\u003eProspective studies incorporating phenotypic data, inflammatory biomarkers, and treatment history are needed to explore whether suppression of active disease mitigates pregnancy risks. The development of EMR-based tools to stratify risk and tailor obstetric care could transform management. Endometriosis should be integrated into pregnancy risk assessment models and early antenatal care plans.\\u003c/p\\u003e\"},{\"header\":\"Conclusion\",\"content\":\"\\u003cp\\u003eEndometriosis is not merely a preconceptual condition \\u0026ndash; it imposes persistent risks throughout gestation. Our data highlight elevated risks for placental abnormalities, hypertensive and metabolic disorders, preterm birth, cesarean delivery, and SMM. Recognizing endometriosis as a chronic systemic condition with obstetric relevance can improve outcomes through targeted surveillance and early intervention.\\u003c/p\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\u003ch2\\u003eAuthor Contribution\\u003c/h2\\u003e\\u003cp\\u003eCDC, GB and MS came up with the question and designed the study. UK and RJB carried out the analysis. BDY, UK and RJB wrote the manuscript. LCG, TTO, BDY and OY provided clinical insight. Everyone reviewed and edited the manuscript.\\u003c/p\\u003e\\u003ch2\\u003eAcknowledgement\\u003c/h2\\u003e\\u003cp\\u003eChatGPT 4o (released, April 2024 by OpenAI) was used in the preparation of this manuscript, specifically for refining language and improving readability. The authors take responsibility for the veracity and integrity of all final content. We would like to thank the members of the Sirota Lab for useful discussions.\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\u003cli\\u003e\\u003cspan\\u003eGiudice, L. C. \\u0026amp; Kao, L. C. Endometriosis. \\u003cem\\u003eThe Lancet\\u003c/em\\u003e 364, 1789\\u0026ndash;1799 (2004).\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eBulun, S. E. \\u003cem\\u003eet al.\\u003c/em\\u003e Endometriosis. \\u003cem\\u003eEndocrine Reviews\\u003c/em\\u003e 40, 1048\\u0026ndash;1079 (2019).\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eTaylor, H. S., Kotlyar, A. M. \\u0026amp; Flores, V. A. 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Pregnancy outcomes in women with different endometriosis lesion types: A review of current evidence. \\u003cem\\u003eJ of Obstet and Gynaecol\\u003c/em\\u003e 51, e16321 (2025).\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eBulletti, C. \\u003cem\\u003eet al.\\u003c/em\\u003e Characteristics of uterine contractility during menses in women with mild to moderate endometriosis. \\u003cem\\u003eFertility and Sterility\\u003c/em\\u003e 77, 1156\\u0026ndash;1161 (2002).\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eVercellini, P. \\u003cem\\u003eet al.\\u003c/em\\u003e Pregnancy outcome in women with peritoneal, ovarian and rectovaginal endometriosis: a retrospective cohort study. \\u003cem\\u003eBJOG\\u003c/em\\u003e 119, 1538\\u0026ndash;1543 (2012).\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eSalmeri, N. \\u003cem\\u003eet al.\\u003c/em\\u003e Endometriosis increases the risk of gestational diabetes: a meta-analysis stratified by mode of conception, disease localization and severity. \\u003cem\\u003eSci Rep\\u003c/em\\u003e 13, 8099 (2023).\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eFarland, L. V. \\u003cem\\u003eet al.\\u003c/em\\u003e Endometriosis and Risk of Adverse Pregnancy Outcomes. \\u003cem\\u003eObstetrics \\u0026amp; Gynecology\\u003c/em\\u003e 134, 527\\u0026ndash;536 (2019).\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eDrummond, K. \\u003cem\\u003eet al.\\u003c/em\\u003e Association between Endometriosis and Risk of Preeclampsia in Women Who Conceived Spontaneously: A Systematic Review and Meta-analysis. \\u003cem\\u003eJournal of Minimally Invasive Gynecology\\u003c/em\\u003e 30, 91\\u0026ndash;99 (2023).\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eMu, F. \\u003cem\\u003eet al.\\u003c/em\\u003e Association Between Endometriosis and Hypercholesterolemia or Hypertension. \\u003cem\\u003eHypertension\\u003c/em\\u003e 70, 59\\u0026ndash;65 (2017).\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eWu, M.-H., Hsiao, K.-Y. \\u0026amp; Tsai, S.-J. 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W. \\u003cem\\u003eet al.\\u003c/em\\u003e Endometriosis Is Associated with Adverse Pregnancy Outcomes: a National Population-Based Study. \\u003cem\\u003eReprod. Sci.\\u003c/em\\u003e 27, 1175\\u0026ndash;1180 (2020).\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eLafleur, N., Wei, S. Q., Bilodeau-Bertrand, M. \\u0026amp; Auger, N. Association of Endometriosis and Severe Maternal Morbidity. \\u003cem\\u003eObstetrics \\u0026amp; Gynecology\\u003c/em\\u003e 140, 1008\\u0026ndash;1016 (2022).\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eGebremedhin, A. T., Mitter, V. R., Duko, B., Tessema, G. A. \\u0026amp; Pereira, G. F. Associations between endometriosis and adverse pregnancy and perinatal outcomes: a population-based cohort study. \\u003cem\\u003eArch Gynecol Obstet\\u003c/em\\u003e 309, 1323\\u0026ndash;1331 (2023).\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eTanovska, P. \\u003cem\\u003eet al.\\u003c/em\\u003e Association Between Endometriosis and Congenital Uterine Malformations: A Single-Center Retrospective Study. \\u003cem\\u003eJournal of Minimally Invasive Gynecology\\u003c/em\\u003e 32, 520\\u0026ndash;526 (2025).\\u003c/span\\u003e\\u003c/li\\u003e\\u003c/ol\\u003e\"},{\"header\":\"Tables\",\"content\":\"\\u003cp\\u003eTable 1 and 2 are available in the Supplementary Files section.\\u003c/p\\u003e\"}],\"fulltextSource\":\"\",\"fullText\":\"\",\"funders\":[],\"hasAdminPriorityOnWorkflow\":true,\"hasManuscriptDocX\":true,\"hasOptedInToPreprint\":true,\"hasPassedJournalQc\":\"\",\"hasAnyPriority\":false,\"hideJournal\":true,\"highlight\":\"\",\"institution\":\"\",\"isAcceptedByJournal\":false,\"isAuthorSuppliedPdf\":false,\"isDeskRejected\":\"\",\"isHiddenFromSearch\":false,\"isInQc\":false,\"isInWorkflow\":false,\"isPdf\":false,\"isPdfUpToDate\":true,\"isWithdrawnOrRetracted\":false,\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"researchsquare\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":true,\"externalIdentity\":\"\",\"sideBox\":\"\",\"snPcode\":\"\",\"submissionUrl\":\"/submission\",\"title\":\"Research Square\",\"twitterHandle\":\"researchsquare\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"\",\"reportingPortfolio\":\"\",\"inReviewEnabled\":false,\"inReviewRevisionsEnabled\":true},\"keywords\":\"\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-7377239/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-7377239/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003cp\\u003eAlthough endometriosis is increasingly recognized as a risk factor for adverse pregnancy outcomes, large-scale analyses in U.S. populations remain limited. In this retrospective dual-cohort study, we analyzed over 4\\u0026nbsp;million singleton births in California (2011\\u0026ndash;2020) and a complementary academic electronic medical record (EMR) dataset to evaluate adverse pregnancy outcomes in individuals with endometriosis. Adjusting for use of assisted reproductive technology, prenatal care, and comorbidities, we found consistent significant associations between endometriosis and placenta previa (aRR 4.9, 95% CI 4.4 to 5.4), placental abruption (aRR 1.9, 95% CI 1.6 to 2.3), preterm birth (aRR 1.5, 95% CI 1.4 to 1.6), hypertensive disorders of pregnancy (aRRs 1.3\\u0026ndash;1.4, 95% CI 1.1 to 1.5), gestational diabetes (aRR 1.2, 95% CI 1.1 to 1.3), cesarean delivery (aRR 1.6, 95% CI 1.6 to 1.7), and severe maternal morbidity (aRR 2.3, 95% CI 2.1\\u0026ndash;2.6). Findings were directionally consistent across both population-level and institutional cohorts, supporting the robustness of observed associations. This underscores the systemic impact of endometriosis beyond conception and calls for its integration into pregnancy risk assessment models. We also demonstrate the ability to leverage two complementary data sources (birth records and EMR) to better understand relationships and outcomes in reproductive health. Recognizing endometriosis as a chronic condition with obstetric consequences may offer new avenues for prevention and early intervention to improve maternal, fetal, and neonatal outcomes.\\u003c/p\\u003e\",\"manuscriptTitle\":\"Endometriosis and Adverse Pregnancy Outcomes: A Dual-Cohort Study of Over 4 Million California Births\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2025-09-17 04:51:00\",\"doi\":\"10.21203/rs.3.rs-7377239/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"researchsquare\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":true,\"externalIdentity\":\"\",\"sideBox\":\"\",\"snPcode\":\"\",\"submissionUrl\":\"/submission\",\"title\":\"Research Square\",\"twitterHandle\":\"researchsquare\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"\",\"reportingPortfolio\":\"\",\"inReviewEnabled\":false,\"inReviewRevisionsEnabled\":true}}],\"origin\":\"\",\"ownerIdentity\":\"a42f0bbf-f995-44bc-8ff9-6f3c02ba7376\",\"owner\":[],\"postedDate\":\"September 17th, 2025\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"posted\",\"subjectAreas\":[{\"id\":54762356,\"name\":\"Health sciences/Diseases\"},{\"id\":54762357,\"name\":\"Health sciences/Health care\"},{\"id\":54762358,\"name\":\"Health sciences/Medical research\"},{\"id\":54762359,\"name\":\"Health sciences/Risk factors\"}],\"tags\":[],\"updatedAt\":\"2026-02-20T18:09:23+00:00\",\"versionOfRecord\":[],\"versionCreatedAt\":\"2025-09-17 04:51:00\",\"video\":\"\",\"vorDoi\":\"\",\"vorDoiUrl\":\"\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-7377239\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-7377239\",\"identity\":\"rs-7377239\",\"version\":[\"v1\"]},\"buildId\":\"WvIrzKhiLBfengagbw6Ux\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC0","license_restricted":false}