Pregnancy presents a unique biological challenge. The mother carries a fetus for nine months, during which time, her body is working to interact with the baby in a way that does not result in the rejection of the semiallogenic fetus. This requires innate knowledge of the maternal immune system to support and nourish the growing child while avoiding complications of interaction between the two bodies which can be serious, even fatal.
Pregnancy. Image Credit: Subbotina Anna/Shutterstock.com
Pioneer of transplantation biology, Sir Peter Medawar, summarized this challenge in 1953, he concluded: “the immunological problem of pregnancy may be formulated thus: how does the pregnant mother contrive to nourish within itself, for many weeks or months, a fetus that is an antigenically foreign body?”.
Today, scientists are still working to fully answer this question and research efforts have formed the foundations of the field of reproductive immunology, which focuses on developing a deeper understanding of how the maternal immune system behaves during pregnancy. Discoveries made in this field are vital to furthering our knowledge of how to diagnose and treat a wide range of pregnancy complications including miscarriage and fertility problems. Currently, the field has made significant steps forward in treating cases previously described as “unexplained infertility” as well as recurrent miscarriage.
Reproductive immunology and recurrent miscarriage
Recurrent miscarriage describes cases where miscarriage, unfortunately, occurs three or more times consecutively. It happens to around 1% of couples (1 out of 100) who are trying to have a baby.
Multiple potential factors contribute to recurrent miscarriage, such as age, antiphospholipid syndrome (APS), diabetes, developmental problems of the baby, genetic factors, infection, the shape of the uterus, and immune factors. Reproductive immunology researches the theory that suggests immune factors underly some cases of recurrent miscarriage. It is hypothesized that for some women, miscarriage is triggered by an immune system response to the fetus.
Therefore, research is underway investigating the potential therapeutic success of immunizing women against ‘foreign’ cells of the fetus. Such immunotherapies that have already been developed include those that use the white blood cells of the baby’s father, those that use cells derived from early embryos, or those that use antibodies derived from blood.
Unfortunately, several recent studies have found no significant effect of these therapies on improving the live birth rate. For example, one 2014 study reviewing paternal cell immunization, third‐party donor leukocytes, trophoblast membranes, and intravenous immunoglobulin failed to find evidence of a significant effect of any therapy over placebo. Additionally, a 2018 study found that "immunomodulatory" treatments that use recombinant human granulocyte-colony stimulating factor (rhG-CSF) found no evidence that administering this treatment during the first trimester can improve outcomes in women who have a history of recurrent miscarriages.
While there have been disappointing research findings, it is still valuable to continue exploring this area of reproductive immunology to establish effective preventative therapies for those at risk of miscarriage.
Reproductive immunology and unexplained infertility
Roughly 30% of couples who are unable to conceive are diagnosed with unexplained infertility. In recent years, research into the possible causes of unexpected infertility has focused on exploring the role of immunology in reproductive failure.
While the exact role of the immune system in unexplained infertility has not completely been solved, current research has focused on the possible dis-regulation of immune cells including T helper (Th) 1, Th2, Th17, T follicular helper, CD8+ CD28− T, and regulatory T cells, as well as autoantibodies such as an antiphospholipid antibody, antithyroid antibody, antiovarian antibody, cytokines, and chemokines in unexplained infertility.
Further research is required to continue this body of work to eventually help develop effective therapeutic approaches for couples diagnosed with unexplained infertility.
The challenges faced by reproductive immunology
Due to the incredibly complex nature of the immune system in combination with competing conceptual models among immunologists, the field of reproductive immunology has developed to become confusing and difficult to follow (even for clinicians and scientists in the field). With at times conflicting results and disagreements on potential lines of investigation to follow within the field, reproductive immunology has faced a degree of skepticism. This skepticism has been fueled by the premature application of findings from animal models and disappointing observational trials, which has led to much scrutiny of the discipline.
However, the field is still relatively new, and as more research and data is collected, the truths of reproductive immunology will likely be revealed, opening the door to new potential therapies for reproductive problems.
The future of reproductive immunology
While the field of reproductive immunology faces the significant challenge of failing to produce consistent evidence and having to overcome past failures of applying reproductive immunological findings in real-world settings, scientists believe the field may prove to be fruitful.
The fact is that the immune system plays an irrefutable role in human fertility, and, therefore, continued research will likely play a key role in the development of future preventative, diagnostic, and therapeutic approaches to a wide range of reproductive problems, including recurrent miscarriage and unexplained infertility.
- Commonly used preventive therapy for recurrent miscarriage proved ineffective in large trial. EurekAlert. Available at: https://www.eurekalert.org/pub_releases/2018-07/esoh-cup062818.php
- Fertility and Sterility, 2006. Effectiveness and treatment for unexplained infertility. 86(5), pp.S111-S114. https://www.fertstert.org/article/S0015-0282(06)03249-3/abstract
- Shahbazi, M., Ehsani, M., Mohammadnia-Afrouzi, M., Mirzakhani, M. and Esmaeilzadeh, S., 2019. Female unexplained infertility: A disease with imbalanced adaptive immunity. Journal of Human Reproductive Sciences, 12(4), p.274. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937763/
- Young, S., 2016. Reproductive Immunology: Checkered Past and Bright Future. Fertility and Sterility, 106(3), pp.497-498. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010996/
- Wong, L., Porter, T., and Scott, J., 2014. Immunotherapy for recurrent miscarriage. Cochrane Database of Systematic Reviews, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7051032/