The Immune Connection: Cytokines, Microbiome, and Miscarriage Risk

Key Points

• Proinflammatory Cytokines as Guardians: Explore the critical role played by proinflammatory cytokines in the immune response and their association with pregnancy loss, shedding light on the immune system's intricate mechanisms during gestation.
• Microbial Microcosm: Dive into the complex world of the vaginal microbiome, uncovering how changes in microbial composition can disrupt the immune balance and potentially contribute to miscarriage.
• Immune Dysregulation: Understand how an imbalance in the production of cytokines can lead to immune dysregulation, creating a hostile environment for a developing fetus and increasing the risk of miscarriage.
• Preventing Miscarriage: Discover strategies and interventions that leverage this newfound knowledge, such as probiotics and prebiotics, to maintain a healthy vaginal microbiome and reduce the chances of miscarriage.
• Future Perspectives: Delve into the ongoing research and future prospects in this field, highlighting the potential for microbiota-based therapies and a deeper understanding of the immune-microbiome connection in pregnancy.

Introduction

Pregnancy, a period of profound transformation, is a testament to the intricate balance between life's creation and potential loss.

Within this delicate dance lies the enigmatic world of the vaginal microbiome and its profound influence on pregnancy outcomes.

Emerging research has unveiled the vital role of proinflammatory cytokines, the body's immune warriors, in orchestrating this symphony.

In this exploration, we delve into the fascinating interplay between cytokines, the vaginal microbiome, and the heightened risk of miscarriage.

Join us as we navigate through this realm of immunity and microbiology to unravel the mysteries of miscarriage risk and discover potential pathways for prevention.

How Vaginal Health Impacts Pregnancy

The female reproductive system possesses a remarkable defense mechanism, comprising immune cells and receptors, designed to recognize and respond to microorganisms. A Trusted Source Wira, C. R., Fahey, J. V., Sentman, C. L., Pioli, P. A., Shen, L. (2005). Innate and adaptive immunity in female genital tract: cellular responses and interactions. Immunol. Rev. 206, 306–335. doi: 10.1111/j.0105-2896.2005.00287.x PubMed Abstract | CrossRef Full Text | Google Scholar

However, alterations in the vaginal microbiota and its interaction with the immune system can lead to pregnancy complications, including miscarriages.

Recent research by Villa et al. has unveiled that cells lining the vaginal and upper genital tracts can detect both friendly and harmful bacteria through receptors like NOD, TLRs, and dectin-1 . A Trusted Source Buchta, V. (2018). Vaginal microbiome. Ceska Gynekol 83 (5), 371–379. PubMed Abstract | Google Scholar

Notably, women experiencing recurrent spontaneous miscarriages (RSM) tend to produce more embryotoxic Th1 cytokines in response to trophoblast antigens.

In 2020, Al-Nasirya et al. proposed several pathways through which bacteria influence implantation.

One pathway involves non-commensal bacteria compromising the endometrial barrier, allowing pathogens to enter and trigger an immune response, activating T cells.

However, an imbalance in cytokine production can favor pro-inflammatory Th1 cells, potentially leading to complications.

Unlocking Miscarriage Mysteries: The Vaginal Microbiome Connection

The intricate relationship between changes in the vaginal microbiome and miscarriage remains a subject of ongoing research, with multiple proposed mechanisms. A Trusted Source Giakoumelou, S., Wheelhouse, N., Cuschieri, K., Entrican, G., Howie, S. E.M., Horne, A. W. (2016). The role of infection in miscarriage. Hum. Reprod. Update 22 (1), 116–133. doi: 10.1093/humupd/dmv041 PubMed Abstract | CrossRef Full Text | Google Scholar A Trusted Source El Hachem, H., Crepaux, V., May-Panloup, P., Descamps, P., Legendre, G., Bouet, P-E. (2017). Recurrent pregnancy loss: current perspectives. Int. J. Womens Health 9, 331–345. doi: 10.2147/IJWH.S100817 PubMed Abstract | CrossRef Full Text | Google Scholar

These mechanisms encompass factors like inflammation, infection, immune responses, microbial translocation, hormonal influences, and pathogen ascent.

Alterations in the vaginal microbiome can disrupt the balance of beneficial and pathogenic bacteria, leading to dysbiosis.

This dysbiosis triggers inflammation within the vaginal tissues, affecting the cervix and its surroundings. A Trusted Source Chee, W. J. Y., Chew, S. Y., Than, L. T. L. (2020). Vaginal microbiota and the potential of Lactobacillus derivatives in maintaining vaginal health. Microb. Cell Fact 19 (1), 203. doi: 10.1186/s12934-020-01464-4 PubMed Abstract | CrossRef Full Text | Google Scholar A Trusted Source Holdcroft, A. M., Ireland, D. J., Payne, M. S. (2023). The vaginal microbiome in health and disease-what role do common intimate hygiene practices play? Microorganisms 11 (2), 298. doi: 10.3390/microorganisms11020298 PubMed Abstract | CrossRef Full Text | Google Scholar

Furthermore, changes in the vaginal microbiota are associated with conditions like bacterial vaginosis (BV), which may be linked to miscarriage. A Trusted Source Lewis, F. M. T., Bernstein, K. T., Aral, S. O. (2017). Vaginal microbiome and its relationship to behavior, sexual health, and sexually transmitted diseases. Obstet Gynecol 129 (4), 643–654. doi: 10.1097/AOG.0000000000001932 PubMed Abstract | CrossRef Full Text | Google Scholar

The vaginal microbiome plays a crucial role in regulating the local immune response in the female reproductive system. A Trusted Source Adapen, C., Reot, L., Menu, E. (2022). Role of the human vaginal microbiota in the regulation of inflammation and sexually transmitted infection acquisition: Contribution of the non-human primate model to a better understanding? Front. Reprod. Health 4, 992176. doi: 10.3389/frph.2022.992176 PubMed Abstract | CrossRef Full Text | Google Scholar

Alterations in the vaginal microbiome can disrupt this immunological balance, potentially leading to miscarriage.

For example, infections like Chlamydia trachomatis in endometrial stromal cells can impair chemokine production, contributing to miscarriage risk. A Trusted Source Grewal, K., Lee, Y. S., Smith, A., Brosens, J. J., Bourne, T., Al-Memar, M., et al. (2022). Chromosomally normal miscarriage is associated with vaginal dysbiosis and local inflammation. BMC Med. 20 (1), 38. doi: 10.1186/s12916-021-02227-7 PubMed Abstract | CrossRef Full Text | Google Scholar

Dysbiosis may also compromise cervical tissue integrity, resulting in cervical insufficiency A Trusted Source Mitra, A., MacIntyre, D. A., Marchesi, J. R., Lee, Y. S., Bennett, P. R., Kyrgiou, M. (2016). The vaginal microbiota, human papillomavirus infection, and cervical intraepithelial neoplasia: what do we know and where are we going next? Microbiome 4 (1), 58. doi: 10.1186/s40168-016-0203-0 PubMed Abstract | CrossRef Full Text | Google Scholar , a condition linked to early cervix dilation and miscarriage.

Additionally, research suggests that harmful bacteria from the vaginal microbiome can migrate to the uterine cavity and placenta during pregnancy, potentially triggering an inflammatory response that affects fetal development and raises miscarriage risk. A Trusted Source Wang, J., Li, Z., Ma, X., Du, L., Jia, Z., Cui, X., et al. (2021). Translocation of vaginal microbiota is involved in impairment and protection of uterine health. Nat. Commun. 12 (1), 4191. doi: 10.1038/s41467-021-24516-8 PubMed Abstract | CrossRef Full Text | Google Scholar

Understanding these intricate connections between the vaginal microbiome and miscarriage holds promise for improving reproductive health outcomes.

Promoting Healthy Pregnancy and Understanding Miscarriage

It's crucial to recognize that while some early miscarriages result from genetic abnormalities or remain unexplained, there are proactive steps to enhance a healthy pregnancy and reduce the risk of miscarriage.

1. Early Prenatal Care: Schedule prenatal care as soon as pregnancy is confirmed. Early check-ups help detect potential health issues that could lead to miscarriage.
2. Vaginal Health: Treat any vaginal infections promptly, as they can disrupt the normal vaginal environment. Avoid vaginal washes that may disturb this balance.
3. Avoid Harmful Habits: Refrain from smoking, alcohol, and illicit drugs, as they increase miscarriage risk.
4. Healthy Diet: Consume a balanced diet rich in fruits, vegetables, whole grains, and lean proteins to lower miscarriage risk.
5. Stay Active: Engage in safe physical activity, discussed with your healthcare provider before pregnancy, to maintain overall health.
6. Manage Stress: High-stress levels during pregnancy can increase the risk of miscarriage. Explore relaxation techniques like yoga, meditation, or counseling if needed.
7. Avoid Harmful Substances: Minimize exposure to chemicals, pollutants, and radiation to lower miscarriage risk.

Regular prenatal care is vital for monitoring pregnancy progression and identifying issues promptly.

Maintaining a healthy lifestyle, including proper nutrition, hydration, and avoiding harmful substances, is essential.

Early prenatal screenings and tests can proactively detect complications, with prescribed prenatal vitamins playing a crucial role.

While understanding the link between the vaginal microbiome and miscarriage is evolving, further research is needed to establish causality and mechanisms.

Such studies can lead to preventive measures and targeted therapies like probiotics.

Emerging diagnostic methods, like fetal genetic testing from maternal plasma, are advancing prenatal care. A Trusted Source Chiu, R. W., Lo, Y. M. (2013). Clinical applications of maternal plasma fetal DNA analysis: translating the fruits of 15 years of research. Clin. Chem. Lab. Med. 51 (1), 197–204. doi: 10.1515/cclm-2012-0601 PubMed Abstract | CrossRef Full Text | Google Scholar

These methods can detect genetic abnormalities as early as week seven of pregnancy. A Trusted Source Kitzman, J. O., Synder, M. W., Ventura, M., Lewis, A. P., Qiu, R., Simmons, L. E., et al. (2012). Noninvasive whole-genome sequencing of a human fetus. Sci. Transl. Med. 4 (137), 137ra76. PubMed Abstract | Google Scholar

However, more research is required to comprehend the vaginal microbiota's role in miscarriage and develop effective interventions for pregnant individuals.

Probiotics, Prebiotics, and Antibiotics: A New Frontier in Preventing Miscarriages

The composition of the vaginal microbiota, a key player in women's reproductive health, can be influenced by various factors, including antibiotics, pre, and probiotics, among others. A Trusted Source Macklaim, J. M., Clemente, J. C., Knight, R., Gloor, G. B., Reid, G. (2015). Changes in vaginal microbiota following antimicrobial and probiotic therapy. Microbial Ecol. Health Dis. 26 (1), 27799. doi: 10.3402/mehd.v26.27799 CrossRef Full Text | Google Scholar

These factors can serve as intervention tools to modify the vaginal microbiome and promote desired health outcomes.

Probiotics are living microorganisms consumed orally or applied topically to enhance health. A Trusted Source Hill, C., Guarner, F., Reid, G., Ribson, G. R., Merenstein, D. J., Pot, B., et al. (2014). The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat. Rev. Gastroenterol. Hepatol. 11 (8), 506–514. doi: 10.1038/nrgastro.2014.66 PubMed Abstract | CrossRef Full Text | Google Scholar

Prebiotics, on the other hand, are foods that support healthy human microbiota, often high-fiber meals.

Research has shown that women who have experienced miscarriages often exhibit reduced levels of Lactobacillus spp. in their vaginal microbiota. A Trusted Source Shahid, M., Quinlivan, J. A., Peek, M., Castaño-Rodríguez, N., Mendz, G. L. (2022). Is there an association between the vaginal microbiome and first trimester miscarriage? A prospective observational study. J. Obstet Gynaecol Res. 48 (1), 119–128. doi: 10.1111/jog.15086 PubMed Abstract | CrossRef Full Text | Google Scholar

Although studies exploring the use of probiotics and prebiotics for miscarriage prevention are limited, the concept of using lactobacilli species as probiotics or employing prebiotics to nurture protective organisms emerged in the mid-1980s.

Lactobacillus strains like L. rhamnosus GR-1 and L. reuteri RC-14 were among the first probiotics utilized for vaginal health improvement. A Trusted Source Reid, G., Cook, R. L., Bruce, A. W. (1987). Examination of strains of lactobacilli for properties that may influence bacterial interference in the urinary tract. J. Urol 138 (2), 330–335. doi: 10.1016/S0022-5347(17)43137-5 PubMed Abstract | CrossRef Full Text | Google Scholar

Human studies showed that GR-1 effectively inhibited gram-negative pathogens, while RC-14 hindered gram-positive coccal adhesion. A Trusted Source Bruce, A. W., Reid, G., McGroarty, J. A., Taylor, M., Preston, C. (1992). Preliminary study on the prevention of recurrent urinary tract infection in adult women using intravaginal Lactobacilli. Int. Urogynecology J. 3 (1), 22–25. doi: 10.1007/BF00372644 CrossRef Full Text | Google Scholar

Oral probiotic consumption has been found to decrease irregular microbiota presence and increase Lactobacillus abundance. A Trusted Source López-Moreno, A., Aguilera, M. (2021). Vaginal probiotics for reproductive health and related dysbiosis: systematic review and meta-analysis. J. Clin. Med. 10 (7), 1461. doi: 10.3390/jcm10071461 PubMed Abstract | CrossRef Full Text | Google Scholar A Trusted Source Bhandari, P., Prabha, V. (2015). Evaluation of profertility effect of probiotic Lactobacillus plantarum 2621 in a murine model. Indian J. Med. Res. 142 (1), 79–84. doi: 10.4103/0971-5916.162127 PubMed Abstract | CrossRef Full Text | Google Scholar

Additionally, Lactobacilli have been consumed orally via yogurt, which may have a prebiotic effect, safeguarding organisms through the GI tract and reducing the risk of urogenital infections. A Trusted Source Beereport, M. A. J., Ter Riet, M., Nys, S., van der Wal, W. M., De Borgie, C. A. J. M., De Reijke, C. J., et al. (2009). Women with recurrent urinary tract infections: antibiotic resistance and nonantibiotic prophylaxis. Google Scholar

Furthermore, probiotics used alongside antibiotics or antifungals have improved the effectiveness of treatment for conditions like Bacterial Vaginosis (BV) and Vulvovaginal Candidiasis (VVC). A Trusted Source Anukam, K. C., Osazuwa, E., Osemene, G. I., Ehigiagbe, F., Bruce, A. W., Reid, G., et al. (2006). Clinical study comparing probiotic Lactobacillus GR-1 and RC-14 with metronidazole vaginal gel to treat symptomatic bacterial vaginosis. Microbes Infect. 8 (12-13), 2772–2776. doi: 10.1016/j.micinf.2006.08.008 PubMed Abstract | CrossRef Full Text | Google Scholar

Mixed Lactobacillus-based probiotics have shown benefits in reducing recurrence rates and symptoms.. A Trusted Source Reznichenko, H., Henyk, N., Maliuk, V., Khyzhnyak, T., Tynna, Y., Filipiuk, I., et al. (2020). Oral intake of lactobacilli can Be helpful in symptomatic bacterial vaginosis: A randomized clinical study. J. Lower Genital Tract Dis. 24 (3), 284–289. doi: 10.1097/LGT.0000000000000518 CrossRef Full Text | Google Scholar A Trusted Source Russo, R., Karadja, E., De Seta, F. (2019). Evidence-based mixture containing Lactobacillus strains and lactoferrin to prevent recurrent bacterial vaginosis: a double blind, placebo controlled, randomised clinical trial. Beneficial Microbes 10 (1), 19–26. doi: 10.3920/BM2018.0075 PubMed Abstract | CrossRef Full Text | Google Scholar

While antibiotics are not primarily used for miscarriage prevention, they are often administered during surgical procedures following pregnancy loss to prevent infections. A Trusted Source Verma, U., Crespo, F. A. (2020). Hysteroscopic removal of retained products of conception: historic approach or new iteration? Ann. Transl. Med. 8 (19), 1210. doi: 10.21037/atm-2020-119 PubMed Abstract | CrossRef Full Text | Google Scholar

Infections following miscarriage can have serious consequences, such as pelvic scarring and infertility. A Trusted Source Melese, T., Habte, D., Tsima, B. M., Mogobe, K. D., Chabaesele, K., Rankgoane, G., et al. (2017). High levels of post-abortion complication in a setting where abortion service is not legalized. PLoS One 12 (1), e0166287. doi: 10.1371/journal.pone.0166287 PubMed Abstract | CrossRef Full Text | Google Scholar

Prophylactic antibiotics are effective in preventing pelvic infections during surgical abortion. A Trusted Source Low, N., Mueller, M., Van Vliet, H. A. A. M., Kapp, N. (2012). Perioperative antibiotics to prevent infection after first-trimester abortion. Cochrane Database Syst. Rev. 2012 (3), Cd005217. doi: 10.1002/14651858.CD005217.pub2 PubMed Abstract | CrossRef Full Text | Google Scholar

Prophylactic antibiotics are prescribed for uterine evacuation procedures in nearly 50% of women in some countries, and they have shown potential to improve outcomes.

Additionally, drugs like low-dose aspirin and metformin have demonstrated promise in reducing the risk of miscarriage in women with specific medical conditions. A Trusted Source Naimi, A. I., Perkins, N. J., Sjaarda, L. A., Mumford, S. L., Platt, R. W., Silver, R. M., et al. (2021). The effect of preconception-initiated low-dose aspirin on human chorionic gonadotropin-detected pregnancy, pregnancy loss, and live birth : Per protocol analysis of a randomized trial. Ann. Intern. Med. 174 (5), 595–601. doi: 10.7326/M20-0469 PubMed Abstract | CrossRef Full Text | Google Scholar

In conclusion, as we increasingly recognize the importance of a "healthy" vaginal microbiota in preventing miscarriages, the future holds promise for the expanded use of probiotics, prebiotics, and other medications to promote vaginal health.

Discussion

• Complex Immune Dynamics: The discussion begins by delving into the complex immune dynamics involved in pregnancy. It emphasizes the role of proinflammatory cytokines in both protecting against infections and, paradoxically, posing a risk of miscarriage when overproduced.
• Microbiome's Crucial Role: The article explores the critical role of the vaginal microbiome in maintaining a healthy pregnancy. It discusses how shifts in microbial composition can disrupt the immune balance, increasing the risk of complications like miscarriage.
• Imbalance and Immune Dysregulation: The discussion focuses on the concept of immune dysregulation resulting from an imbalance in cytokine production. It explains how this imbalance can create an inflammatory environment, potentially harming the developing fetus.
• Intervention Strategies: The article highlights various intervention strategies, including probiotics and prebiotics, that hold promise in rebalancing the vaginal microbiome and mitigating miscarriage risk.
• Clinical Implications: This section explores the potential clinical implications of the immune-microbiome connection, including the development of targeted therapies and the importance of early prenatal care in monitoring immune factors.

Conclusion

• A Complex Interplay: The conclusion reiterates the complexity of the immune-microbiome interplay in pregnancy and its impact on miscarriage risk.
• Hope on the Horizon: It emphasizes that while challenges remain, there is hope on the horizon. Continued research in this field may lead to innovative approaches for preventing miscarriages.
• Call for Further Studies: The article concludes by calling for further research to fully understand the immune-microbiome connection, develop effective preventive measures, and improve the management of miscarriages.
• Empowering Pregnancy Health: Ultimately, the conclusion underscores the importance of this knowledge in empowering women and healthcare providers to enhance pregnancy health and reduce the devastating impact of miscarriages.

Frequently Asked Questions

Review date not set.