Miscarriage research and endometriosis, endometritis and adenomyosis

An explanation of research into links between miscarriage and endometriosis, endometritis and adenomyosis.

By Rebecca Sweetman, Senior Digital Health Project Manager with Professor Siobhan Quenby, Professor of Obstetrics, Tommy's National Centre for Miscarriage Research

 

There are several conditions of the uterus that can affect your chance of having a successful pregnancy. You may have been diagnosed with one of these conditions, or you might have symptoms of one or more.

 

  • Endometriosis

  • Adenomyosis

  • Endometritis
     

It is often difficult to obtain a successful diagnosis for endometriosis, endometritis or adenomyosis. These are all chronic inflammatory conditions that effect the endometrium (lining of the womb).

Symptoms of these conditions can vary. Some people have severe symptoms and others may not notice them. Sometimes there are no symptoms at all (known as asymptomatic). 

If you have been diagnosed with one of these conditions, or you are showing signs or symptoms, it may make you worry about your chance of having a successful pregnancy. Especially if you have had one or more miscarriages before. 

Research into these conditions is ongoing. Healthcare professionals are trying hard to understand what causes them and if they have a definite link with miscarriage and/or conception. We are not there yet. We need to do more research, on a big enough scale to be able to give definite answers. 

Two conditions that are often confused are endometriosis and endometritis. Although these conditions sound very similar, they are in fact, different.

 

Endometriosis

What is endometriosis?

In endometriosis, tissue similar to the endometrium (tissue that lines the womb) grows outside of the womb elsewhere in the body (for example, on the bowels or bladder) triggering a local inflammatory response and causing pain1.

Research has shown that having endometriosis can make it harder to get pregnant2. There is no cure for endometriosis but there are treatments to help manage the condition, which may increase your chance of getting pregnant naturally. 

 

Endometriosis and miscarriage

The link between endometriosis and miscarriage is still unclear. Although several researchers have suggested endometriosis may cause an increased risk of miscarriage due to complications with implantation (when the embryo implants into the uterus at the start of pregnancy) or the formation of the placenta3.

In 2017 a systematic review (the highest standard of assessing published research) set out to evaluate the link between endometriosis and miscarriage4. Only 4 research studies could be included in the review. These studies compared pregnancy outcomes for those with and without endometriosis. From these 4 studies, miscarriage rates were higher in the endometriosis group4. Until this study, research had only produced conflicting results, with no clearly established link.

In 2019, a large cohort study also showed a link between endometriosis and an increased risk of miscarriage5. As both these studies are quite recent, we still don’t exactly know why this may be the case, especially when previous studies have failed to find any connection 6,7.  More high-quality research is needed to find out if there is a clear link between endometriosis and miscarriage.  

 

Endometritis

What is endometritis?

Endometritis is the inflammation of the endometrium (the tissue that lines the womb). Endometritis can be acute, which means there is usually a likely known cause, such as bacterial infection. Symptoms may include pelvic pain, fever or abnormal vaginal bleeding8.  Endometritis can also be chronic, which means it can cause ongoing, prolonged inflammation with noticeable symptoms9. 

It can be hard to diagnose chronic endometritis (CE) because there are no symptoms. Clinicians also need to do an endometrial biopsy to confirm the condition. This as an invasive procedure that involves taking a sample of tissue from the lining of the uterus.  Clinicians may be reluctant to perform this procedure without any symptoms.

Endometritis is most often confirmed by the presence of plasma cells (an immune cell responsible for fighting disease) in the endometrial biopsy. But there is currently no universal standard as to what indicates a positive result. This means confirming a diagnosis can be difficult. This also means that it is often hard to compare endometritis research as many different methods are used. 

We still don’t know exactly what causes chronic endometritis. But there is lots of research currently happening in this area to discover the cause and create a universal standard for diagnosis. 

 

Endometritis and miscarriage

A large amount of research has focused on CE and recurrent miscarriage in recent years. Some researchers have found miscarriage rates increased in women who have tested positive for CE10. However, there are also studies that conclude there is no increase in recurrent miscarriage in women diagnosed with CE11.

These differences could be due to different methods being used in the research. One study, comparing different diagnostic methods to diagnose CE suggested that different methods can yield different results. This showed that the link between CE and recurrent miscarriage may be overestimated based on past diagnostic methods12.

Researchers are now trying to focus on the cause of chronic inflammation in the endometrium in order to create a universally adopted test and diagnostic criteria. To date, some of this research has found oral antibiotics may be an effective treatment13. Antibiotics are currently being tested in a clinical trial. CERM (Chronic Endometritis in Recurrent Miscarriage) is a randomised controlled trial to test the effects of antibiotics on CE. Using the latest recommended diagnostic methods, and looking at a graded approach to disease severity, this trial aims to see what criteria indicates a positive diagnosis and if antibiotics are effective in reducing the inflammation in the endometrium and can improve pregnancy outcomes.  
CERM: Can doxycycline prevent miscarriage in women with endometritis?

Most researchers believe women who experience recurrent miscarriage are more likely to have CE. But more high-quality research and supporting clinical trials are needed before we can say for sure that CE increases the risk of miscarriage. If this research finds the cause of CE it is also more likely that effective treatments will be developed.

 

Adenomyosis

What is adenomyosis?

Adenomyosis is where the lining of the uterus (endometrium) grows in the muscle layer of the uterus (myometrium). It is unknown why this happens. Like CE, sometimes there are no symptoms. But some women may have pelvic pain or heavier, irregular periods14. Without symptoms, diagnosis may take a long time. 

 

Adenomyosis and miscarriage

The link between adenomyosis and miscarriage has focused on the cellular and biochemical changes that can occur in the muscle layer of the uterus. These changes may cause the structure of the uterus to change and inhibit its ability to contract correctly15.

As with CE, research in this area is contradictory. Some research suggests a link between adenomyosis and miscarriage, whereas others dismiss a connection16-19. However, all these studies looked at conceiving via IVF, which may have different results to those who get pregnant naturally. 
Studies that show adenomyosis may increase the risk of recurrent miscarriage recommend hormone treatment to improve the health of the myometrium. But clinical trials have not yet looked at the effect of this treatment on future pregnancy outcomes20. 

Research into these conditions and the effect on reproductive health has increased vastly in recent years. However, even though some studies may show a significant link between these conditions and recurrent miscarriage, it's important for this to be researched accurately and comprehensively.

If there is a possible link, we need to find out why, and what is causing this effect. Only then will scientists and researchers be able prove the cause and develop treatments.

Unfortunately, it seems the importance and urgency for research into women’s health conditions and recurrent miscarriage has previously not been seen as a priority.

Many women are told they must experience repeated miscarriage before investigations begin, or worse, are told miscarriage is “just one of those things”.

This is beginning to change, and there are many campaigns to improve miscarriage care. But we still need more research to happen before we can tell you for certain how these conditions may affect your risk of miscarriage.

If you are worried about any of these conditions, or worried about any symptoms you have, please talk to your GP.

  1. Stephen Kennedy, Agneta Bergqvist, Charles Chapron, Thomas D’Hooghe, Gerard Dunselman, Robert Greb, Lone Hummelshoj, Andrew Prentice, Ertan Saridogan, on behalf of the ESHRE Special Interest Group for Endometriosis and Endometrium Guideline Development Group, ESHRE guideline for the diagnosis and treatment of endometriosis, Human Reproduction, Volume 20, Issue 10, October 2005, Pages 2698–2704, https://doi.org/10.1093/humrep/dei135.
  2. Macer, M. L., & Taylor, H. S. (2012). Endometriosis and infertility: a review of the pathogenesis and treatment of endometriosis-associated infertility. Obstetrics and gynecology clinics of North America, 39(4), 535–549. https://doi.org/10.1016/j.ogc.2012.10.002.
  3. A Brosens I, Pijnenborg R, Benagiano G. Defective myometrial spiral artery remodelling as a cause of major obstetrical syndromes in endometriosis and adenomyosis. Placenta 2013;34:100–5. http://dx.doi.org/10.1016/j.placenta.2012.11.017.  
  4. Minebois H, De Souza A, Mezan de Malartic C, Agopiantz M, Guillet May F, Morel O, Callec R. Endométriose et fausse couche spontanée. Méta-analyse et revue systématique de la littérature [Endometriosis and miscarriage: Systematic review]. Gynecol Obstet Fertil Senol. 2017 Jul-Aug;45(7-8):393-399. French. doi: 10.1016/j.gofs.2017.06.003. Epub 2017 Jul 13. PMID: 28712793.
  5. Farland LV, Prescott J, Sasamoto N, Tobias DK, Gaskins AJ, Stuart JJ, Carusi DA, Chavarro JE, Horne AW, Rich-Edwards JW, Missmer SA. Endometriosis and Risk of Adverse Pregnancy Outcomes. Obstet Gynecol. 2019 Sep;134(3):527-536. doi: 10.1097/AOG.0000000000003410. PMID: 31403584; PMCID: PMC6922084.
  6. Paul Pirtea, Dominique de Ziegler, Jean Marc Ayoubi, Effects of endometriosis on assisted reproductive technology: gone with the wind, Fertility and Sterility, Volume 115, Issue 2, 2021, Pages 321-322, ISSN 005-0282, https://doi.org/10.1016/j.fertnstert.2020.08.1431.  
  7. Umberto Leone Roberti Maggiore, Simone Ferrero, Giorgia Mangili, Alice Bergamini, Annalisa Inversetti, Veronica Giorgione, Paola Viganò, Massimo Candiani, A systematic review on endometriosis during pregnancy: diagnosis, misdiagnosis, complications and outcomes, Human Reproduction Update, Volume 22, Issue 1, January/February 2016, Pages 70–103
  8. Singh N, Sethi A. Endometritis - Diagnosis,Treatment and its impact on fertility - A Scoping Review. JBRA Assist Reprod. 2022 Aug 4;26(3):538-546. doi: 10.5935/1518-0557.20220015. PMID: 35621273; PMCID: PMC9355436.
  9. Kitaya K, Takeuchi T, Mizuta S, Matsubayashi H, Ishikawa T. Endometritis: new time, new concepts. Fertil Steril. 2018 Aug;110(3):344-350. doi: 10.1016/j.fertnstert.2018.04.012. Epub 2018 Jun 28. PMID: 29960704.
  10. Cicinelli, E., Matteo, M., Tinelli, R., Lepera, A., Alfonso, R., Indraccolo, U., Marrocchella, S., Greco, P., & Resta, L. (2015). Prevalence of chronic endometritis in repeated unexplained implantation failure and the IVF success rate after antibiotic therapy. Human reproduction (Oxford, England), 30(2), 323–330. https://doi.org/10.1093/humrep/deu292.
  11. Southcombe JH, Mounce G, McGee K, et al. An altered endometrial CD8 tissue resident memory T cell population in recurrent miscarriage. Scientific Reports. 2017;7(1):41335.
  12. Liu Y, Chen X, Huang J, et al. Comparison of the prevalence of chronic endometritis as determined by means of different diagnostic methods in women with and without reproductive failure. Fertil Steril. 2018;109(5):832-839.
  13. McQueen, D. B., Perfetto, C. O., Hazard, F. K., & Lathi, R. B. (2015). Pregnancy outcomes in women with chronic endometritis and recurrent pregnancy loss. Fertility and sterility, 104(4), 927–931. https://doi.org/10.1016/j.fertnstert.2015.06.044.
  14. Lacheta J. (2019). Uterine adenomyosis: pathogenesis, diagnostics, symptomatology and treatment. Děložní adenomyóza: patogeneze, diagnostika, symptomatologie a léčba. Ceska gynekologie, 84(3), 240–246.
  15. Paul Pirtea, Ettore Cicinelli, Rosalba De Nola, Dominique de Ziegler, Jean Marc Ayoubi, Endometrial causes of recurrent pregnancy losses: endometriosis, adenomyosis, and chronic endometritis, Fertility and Sterility, Volume 115, Issue 3, 2021, Pages 546-560, ISSN 0015-0282, https://doi.org/10.1016/j.fertnstert.2020.12.010.
  16. 96. Younes G, Tulandi T. Effects of adenomyosis on in vitro fertilization treatment outcomes: a meta-analysis. Fertil Steril 2017;108:483–90.e3.
  17. 97. Vercellini P, Consonni D, Dridi D, Bracco B, Frattaruolo MP, Somigliana E. Uterine adenomyosis and in vitro fertilization outcome: a systematic review and meta-analysis. Hum Reprod 2014;29:964–77. 
  18. 98. Benaglia L, Cardellicchio L, Leonardi M, Faulisi S, Vercellini P, Paffoni A, et al. Asymptomatic adenomyosis and embryoimplantation in IVF cycles. Reprod Biomed Online 2014;29:606–11. 
  19. 99. Sharma S, Bathwal S, Agarwal N, Chattopadhyay R, Saha I, Chakravarty B. Does presence of adenomyosis affect reproductive outcome in IVF cycles? A retrospective analysis of 973 patients. Reprod Biomed Online 2019;38: 13–21. 
  20. CW, Choi MH, Yang KM, Song IO. Pregnancy rate in women with adenomyosis undergoing fresh or frozen embryo transfer cycles following gonadotropin-releasing hormone agonist treatment. Clin Exp Reprod Med 2016;43:169–73.

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