Download PDF
CC BY-NC-ND 4.0 · Thromb Haemost
DOI: 10.1055/a-2407-9498
Stroke, Systemic or Venous Thromboembolism

Unravelling the Causal Relationship between Endometriosis and the Risk for Developing Venous Thromboembolism: A Pooled Analysis

Pauline De Corte 
1   Berlin Center for Epidemiology and Health Research, Berlin, Germany
,
Igor Milhoranca
1   Berlin Center for Epidemiology and Health Research, Berlin, Germany
,
Sylvia Mechsner
2   Department of Gynaecology, Charité – Universitätsmedizin Berlin, Endometriosis Centre Charité, Berlin, Germany
,
Anna Sara Oberg
3   Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
,
Tobias Kurth
4   Institute of Public Health, Charité – Universitätsmedizin Berlin, Berlin, Germany
,
Klaas Heinemann
1   Berlin Center for Epidemiology and Health Research, Berlin, Germany
› Author Affiliations
› Further Information
Also available at
   Permissions and Reprints


Abstract

Objective To investigate the effect of endometriosis on venous thromboembolism (VTE) in oral contraceptive (OC) users. Pooled analysis on a harmonized dataset compromising international patient-centric cohort studies: INAS-VIPOS, INAS-SCORE, and INAS-FOCUS. Eleven European countries, the United States, and Canada. Individuals being newly prescribed an OC with or without an endometriosis and no VTE history.

Methods Detailed information was captured using self-administered questionnaires at baseline and every 6 to 12 months thereafter. Self-reported VTEs were medically validated and reviewed by an independent adjudication committee. Incidence rates (IRs) were calculated per 10,000 woman-years. The association of endometriosis on VTE was determined in a time-to-event analysis, calculating crude and adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) using stabilized inverse probability of treatment weighting (IPTW).

Results A total of 22,072 women had an endometriosis diagnosis, and 91,056 women did not. Women with endometriosis contributed 78,751 woman-years during which 41 VTE events occurred (IR: 5.2/10,000, 95% CI: 3.7–7.1) compared to 127 VTEs during 310,501 woman-years in women without endometriosis (IR: 4.1/10,000, 95% CI: 3.4–4.9). The hazard ratio of VTE in women with endometriosis was 1.79 (95% CI: 1.24–2.57) using stabilized IPTW controlling for age, body mass index, smoking, education, age at menarche, and family history of VTE. Subgroup and sensitivity analyses showed similar results.

Conclusion These results highlight the importance of considering endometriosis as a potential factor contributing to VTE in women using OC; however, further research on the relationship between endometriosis and VTE is warranted.

Keywords

endometriosis - venous thromboembolism - oral contraceptive

Authors' Contribution

All authors contributed to the conceptualization and writing (review and editing) of this research; P.D.C., A.S.O., and T.K. contributed to the methodology of the study. P.D.C. contributed to data curation, writing (original draft), and visualization; P.D.C. and I.M. contributed to software, formal analysis, and validation. All authors take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.


Supplementary Material



Publication History

Received: 24 March 2024

Accepted: 20 August 2024

Accepted Manuscript online:
02 September 2024

Article published online:
18 September 2024

© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

Georg Thieme Verlag KG
Stuttgart · New York

 

  • References

  • 1 Giudice LC. Clinical practice. Endometriosis. N Engl J Med 2010; 362 (25) 2389-2398
    CrossrefPubMedSearch in Google Scholar
  • 2 Fan Y-H, Leong P-Y, Chiou J-Y, Wang Y-H, Ku M-H, Wei JC-C. Association between endometriosis and risk of systemic lupus erythematosus. Sci Rep 2021; 11 (01) 532
    CrossrefPubMedSearch in Google Scholar
  • 3 Surrey ES, Soliman AM, Johnson SJ, Davis M, Castelli-Haley J, Snabes MC. Risk of developing comorbidities among women with endometriosis: a retrospective matched cohort study. J Womens Health (Larchmt) 2018; 27 (09) 1114-1123
    CrossrefPubMedSearch in Google Scholar
  • 4 Teng S-W, Horng H-C, Ho C-H, Yen M-S, Chao H-T, Wang P-H. Taiwan Association of Gynecology Systematic Review Group. Women with endometriosis have higher comorbidities: Analysis of domestic data in Taiwan. J Chin Med Assoc 2016; 79 (11) 577-582
    CrossrefPubMedSearch in Google Scholar
  • 5 Mu F, Rich-Edwards J, Rimm EB, Spiegelman D, Missmer SA. Endometriosis and risk of coronary heart disease. Circ Cardiovasc Qual Outcomes 2016; 9 (03) 257-264
    CrossrefPubMedSearch in Google Scholar
  • 6 Farland LV, Degnan III WJ, Bell ML. et al. Laparoscopically confirmed endometriosis and risk of incident stroke: a prospective cohort study. Stroke 2022; 53 (10) 3116-3122
    CrossrefPubMedSearch in Google Scholar
  • 7 Mu F, Rich-Edwards J, Rimm EB, Spiegelman D, Forman JP, Missmer SA. Association between endometriosis and hypercholesterolemia or hypertension. Hypertension 2017; 70 (01) 59-65
    CrossrefPubMedSearch in Google Scholar
  • 8 Heinemann K, Imthurn B, Marions L. et al. Safety of Dienogest and other hormonal treatments for endometriosis in real-world clinical practice (VIPOS): a large noninterventional study. Adv Ther 2020; 37 (05) 2528-2537
    CrossrefPubMedSearch in Google Scholar
  • 9 Becker K, Heinemann K, Imthurn B. et al. Real world data on symptomology and diagnostic approaches of 27,840 women living with endometriosis. Sci Rep 2021; 11 (01) 20404
    CrossrefPubMedSearch in Google Scholar
  • 10 Dinger JC RS. INternational Active Surveillance Study - Folate and Oral Contraceptives Utilization Study (INAS-FOCUS); INAS-FOCUS Study: 12th update report. Available at: https://catalogues.ema.europa.eu/sites/default/files/document_files/IFOC_FinalStudyReport_Public%20Version%2020200819.pdf
    PubMed
  • 11 Jürgen D, Klaas H, Sabine M. Combined oral contraceptives containing dienogest and estradiol valerate may carry a lower risk of venous and arterial thromboembolism compared to conventional preparations: Results from the extended INAS-SCORE study. Front in Womens Health 2020; 05 (01) 1-8
    PubMedSearch in Google Scholar
  • 12 Heinemann K, Reed S, Moehner S, Minh TD. Comparative contraceptive effectiveness of levonorgestrel-releasing and copper intrauterine devices: the European Active Surveillance Study for Intrauterine Devices. Contraception 2015; 91 (04) 280-283
    CrossrefPubMedSearch in Google Scholar
  • 13 Heinemann K, Reed S, Moehner S, Minh TD. Risk of uterine perforation with levonorgestrel-releasing and copper intrauterine devices in the European Active Surveillance Study on Intrauterine Devices. Contraception 2015; 91 (04) 274-279
    CrossrefPubMedSearch in Google Scholar
  • 14 Austin PC. An introduction to propensity score methods for reducing the effects of confounding in observational studies. Multivariate Behav Res 2011; 46 (03) 399-424
    CrossrefPubMedSearch in Google Scholar
  • 15 Austin PC. The use of propensity score methods with survival or time-to-event outcomes: reporting measures of effect similar to those used in randomized experiments. Stat Med 2014; 33 (07) 1242-1258
    CrossrefPubMedSearch in Google Scholar
  • 16 Hernán MA, Robins JM. Casual Inference: What If. Boca Raton, FL: CRC Press; 2021
    Search in Google Scholar
  • 17 Rosenbaum PR, Rubin DB. The central role of the propensity score in observational studies for causal effects. Biometrika 1983; 70 (01) 41-55
    CrossrefPubMedSearch in Google Scholar
  • 18 Robins JM, Hernán MA, Brumback B. Marginal structural models and causal inference in epidemiology. Epidemiology 2000; 11 (05) 550-560
    CrossrefPubMedSearch in Google Scholar
  • 19 Rosenbaum PRRD. Reducing bias in observational studies using subclassification on the propensity score. Journal of the American Statistical Association. J Am Stat Assoc 1984; 79: 516-524
    CrossrefPubMedSearch in Google Scholar
  • 20 Greenland S, Pearl J, Robins JM. Causal diagrams for epidemiologic research. Epidemiology 1999; 10 (01) 37-48
    CrossrefPubMedSearch in Google Scholar
  • 21 van Buuren S. Multiple imputation of discrete and continuous data by fully conditional specification. Stat Methods Med Res 2007; 16 (03) 219-242
    CrossrefPubMedSearch in Google Scholar
  • 22 Moscovici R. Combining survival analysis results after multiple imputation of censored event times. PharmaSUG;2017(Paper SP05). Accessed September 10, 2024 at: https://www.pharmasug.org/proceedings/2017/SP/PharmaSUG-2017-SP05.pdf
    PubMed
  • 23 UCLA Statistical Methods and Data Analytics. Testing the proportional hazard assumption in Cox models. Accessed June 16, 2024 at: https://stats.oarc.ucla.edu/other/examples/asa2/testing-the-proportional-hazard-assumption-in-cox-models/
    PubMed
  • 24 Cole SR, Hernán MA. Adjusted survival curves with inverse probability weights. Comput Methods Programs Biomed 2004; 75 (01) 45-49
    CrossrefPubMedSearch in Google Scholar
  • 25 Trenor III CC, Chung RJ, Michelson AD. et al. Hormonal contraception and thrombotic risk: a multidisciplinary approach. Pediatrics 2011; 127 (02) 347-357
    CrossrefPubMedSearch in Google Scholar
  • 26 Nnoaham KE, Hummelshoj L, Webster P. et al; World Endometriosis Research Foundation Global Study of Women's Health consortium. Impact of endometriosis on quality of life and work productivity: a multicenter study across ten countries. Fertil Steril 2011; 96 (02) 366-373.e8
    Search in Google Scholar
  • 27 Hudelist G, Fritzer N, Thomas A. et al. Diagnostic delay for endometriosis in Austria and Germany: causes and possible consequences. Hum Reprod 2012; 27 (12) 3412-3416
    CrossrefPubMedSearch in Google Scholar
  • 28 Okoth K, Wang J, Zemedikun D, Thomas GN, Nirantharakumar K, Adderley NJ. Risk of cardiovascular outcomes among women with endometriosis in the United Kingdom: a retrospective matched cohort study. BJOG 2021; 128 (10) 1598-1609
    CrossrefPubMedSearch in Google Scholar
  • 29 Tan J, Taskin O, Iews M. et al. Atherosclerotic cardiovascular disease in women with endometriosis: a systematic review of risk factors and prospects for early surveillance. Reprod Biomed Online 2019; 39 (06) 1007-1016
    CrossrefPubMedSearch in Google Scholar
  • 30 Chiang H-J, Lan K-C, Yang Y-H. et al. Risk of major adverse cardiovascular and cerebrovascular events in Taiwanese women with endometriosis. J Formos Med Assoc 2021; 120 (1, Pt 2): 327-336
    CrossrefPubMedSearch in Google Scholar
  • 31 Mehedintu C, Plotogea MN, Ionescu S, Antonovici M. Endometriosis still a challenge. J Med Life 2014; 7 (03) 349-357
    PubMedSearch in Google Scholar
  • 32 Marchandot B, Curtiaud A, Matsushita K. et al. Endometriosis and cardiovascular disease. Eur Heart J Open 2022; 2 (01) oeac001
    CrossrefPubMedSearch in Google Scholar
  • 33 Scutiero G, Iannone P, Bernardi G. et al. Oxidative stress and endometriosis: a systematic review of the literature. Oxid Med Cell Longev 2017; 2017: 7265238
    CrossrefPubMedSearch in Google Scholar
  • 34 Bedaiwy MA, Falcone T, Sharma RK. et al. Prediction of endometriosis with serum and peritoneal fluid markers: a prospective controlled trial. Hum Reprod 2002; 17 (02) 426-431
    CrossrefPubMedSearch in Google Scholar
  • 35 Dinger JC, Bardenheuer K, Assmann A. International Active Surveillance Study of Women Taking Oral Contraceptives (INAS-OC Study). BMC Med Res Methodol 2009; 9: 77
    CrossrefPubMedSearch in Google Scholar
  • 36 Ananth CV, Schisterman EF. Confounding, causality, and confusion: the role of intermediate variables in interpreting observational studies in obstetrics. Am J Obstet Gynecol 2017; 217 (02) 167-175
    CrossrefPubMedSearch in Google Scholar
  • 37 Practice bulletin no. 114: management of endometriosis. Obstet Gynecol 2010; 116 (01) 223-236
    CrossrefPubMedSearch in Google Scholar
  • 38 Felix Wong WS, Danforn Lim CE. Hormonal treatment for endometriosis associated pelvic pain. Iran J Reprod Med 2011; 9 (03) 163-170
    PubMedSearch in Google Scholar
  • 39 Brown J, Crawford TJ, Datta S, Prentice A. Oral contraceptives for pain associated with endometriosis. Cochrane Database Syst Rev 2018; 5 (05) CD001019
    CrossrefPubMedSearch in Google Scholar
  • 40 Ray WA. Evaluating medication effects outside of clinical trials: new-user designs. Am J Epidemiol 2003; 158 (09) 915-920
    CrossrefPubMedSearch in Google Scholar
  • 41 Bosco JLF, Silliman RA, Thwin SS. et al. A most stubborn bias: no adjustment method fully resolves confounding by indication in observational studies. J Clin Epidemiol 2010; 63 (01) 64-74
    CrossrefPubMedSearch in Google Scholar
  • 42 Pearl J. Causal diagrams for empirical research. Biometrika 1995; 82 (04) 669-688
    CrossrefPubMedSearch in Google Scholar
  • 43 Neuberg LG. CAUSALITY: MODELS, REASONING, AND INFERENCE, by Judea Pearl, Cambridge University Press, 2000. Econ Theory 2003; 19 (04) 675-685
    CrossrefPubMedSearch in Google Scholar