Finding Fertility Answers Through Reproductive Immunology

If you or your patients are struggling to have a baby, then you’re probably familiar with how much precious time and money can be wasted searching for answers without any success. That’s because, even when you’ve exhausted the standard suite of genetic, anatomical and endocrinological evaluations, around half of recurrent pregnancy losses and other reproductive failures will remain unexplained. And without an explanation, there is no answer.

Although most of us are familiar with the ways that hormones like estrogen and progesterone help orchestrate a successful pregnancy, less people are aware of how the immune system helps establish and maintain pregnancy – or how it can hurt. Despite its importance, the sheer complexity of the immune system has prevented many fertility experts from looking to it for answers. That’s why we created Pregmune: To make reproductive immunology’s insights and treatments accessible to patients and their doctors.

This article covers the basics of reproductive immunology, the lessons our founding clinic has learned about diagnosing and treating immunological-based fertility issues, and how this can be applied to your own medical practice or personal fertility issues today as part of a more comprehensive approach to reproductive success.

What is reproductive immunology?

Reproductive immunology is a medical field and branch of science that studies the many different ways that the immune system interacts with the reproductive system, with an emphasis on how it helps the female body tolerate and support a genetically unique fetus for 9 months.

Although it’s easy to take pregnancy for granted as something our mammalian bodies just do, anyone familiar with organ transplantation will know just how difficult it can be to keep the human body from rejecting foreign tissue. Because babies are semi-allogeneic (only sharing some of their genes with their mothers), a developing embryo has the potential to set off the immune system’s intruder alert and be rejected. However, when properly functioning, the immune system works with the female reproductive system to not only tolerate, but actively protect the fetus and maintain a healthy pregnancy.

In order to do this, the immune system must first learn to recognize an embryo’s distinct genetic signature as something to protect, and then it needs to help divert nourishment to the fetus. When this system is a little off balance, a mother might experience complications like preeclampsia or a preterm birth. If it’s more dysfunctional, then the patient might struggle with recurrent miscarriages. And if their immune system prevents embryos from ever being able to establish a foothold, it could manifest as recurrent implantation failures and/or infertility.

What can we learn from reproductive immunology testing?

Assessing the immune system to find causes of reproductive failure might sound like a straightforward concept, but in practice, it can be anything but. The immune system contains over 1,500 different proteins (a whopping 7% of our genes) and an immense diversity of cell types… if you take into account all the many ways they interact with each other and the other systems of the body, even trained immunologists can struggle to keep up with it all. This makes it unsurprising that very few fertility-focused doctors look to the immune system for answers.

That said, if you have been closely following the field of reproductive immunology, you’ll have noticed that a few important issues stand out more than others. Here are the 3 main types of problems that should be evaluated as part of a comprehensive immune workup, and the best ways to identify them:

Autoimmune disease

It’s estimated that approximately 8-9% of people are affected by autoimmune diseases, with the majority of those cases being in women. Unfortunately, many autoimmune diseases can raise a patient’s chances for adverse pregnancy outcomes, which is why expectant mothers with antiphospholipid syndrome, lupus, rheumatoid arthritis, and other autoimmune disorders are considered high-risk pregnancies. People with these diseases are generally recommended to work with their doctors to treat and monitor their symptoms before conceiving and throughout the pregnancy.

However, many people silently suffer from undiagnosed autoimmune diseases – making it difficult to provide them with appropriate care. Furthermore, research shows that whether or not a woman is diagnosed with an autoimmune disease, if she has autoantibodies (signs that the immune system is attacking “self”), she is more likely to experience recurrent pregnancy loss.

The reasons why people develop autoimmune diseases are diverse and not completely understood. In some cases, genetics can predispose a person to be higher risk. But for the most part, it’s best to directly check for the presence of autoantibodies and other signs of active autoimmune disease. Once identified, appropriate therapies can be pursued.

For people who’ve been experiencing unexplained reproductive problems, we believe it’s important to assess the following autoimmune disease markers:

• Antiphospholipid antibodies
• Antinuclear antibodies
• Markers for rheumatoid arthritis
• Markers for thyroid disease
• Genetic predisposition to autoimmune disease

Inflammation

The word “inflammation” can have a bad reputation amongst medical professionals because it’s often used as a buzz term to peddle cure-alls, which sets the stage for misunderstandings between doctors and their patients. As a standalone term, it can mean almost everything and nothing at the same time. However, when connected with specific cell types, cytokines and other molecules of the immune system, different inflammatory measures can be incredibly useful indicators of overall health and potential challenges to people and their future babies’ health.

Certain inflammatory measures are more relevant to pregnancy than others. The balance between Type I helper T cells and Type II helper T cells (Th1:Th2) is often highlighted, since research shows that early in the first trimester of a healthy pregnancy, a woman’s Th2 cells quickly predominate. Some evidence links recurrent pregnancy loss with a bias towards Th1 cell production, but we now know that looking at this value on its own is an oversimplification of maternal immune status. Other T cells also have a strong influence on inflammation in the uterus, like regulatory T cells, which actively dampen the immune response and keep inflammation in check. Studies find that low circulating regulatory T cells are linked to pregnancy loss, lowered IVF success and preeclampsia.

Although bloodwork can be used to help infer the inflammatory status of the uterus, it should only be used within the context of its limitations. For instance, reproductive immunology workups often contain a measure of natural killer cell activity. However, both peripheral (bloodstream) and uterine natural killer cells are two very different cell populations with different inflammatory properties, and at least one study has found their levels to be uncorrelated. As such, bloodwork-based assays of natural killer cell activity should be interpreted with a grain of salt and only factor into the larger framework of the patient’s inflammatory status.

In order to get a balanced insight into a patient’s inflammatory status, we believe it’s useful to combine what we learn from autoimmune testing with the following tests:

• Immunoglobulin levels
• Complement activity
• Th1/Th2 T helper cell balance
• Natural killer cell activity
• Regulatory T cell levels

Parental histocompatibility

Although compatibility is a much larger issue for organ transplants than for pregnancies, there are some histocompatibility issues that are shared between the two. This similarity rests in a diverse array of proteins called human leukocyte antigens (HLAs), which are actively displayed on our cell surfaces like barcodes, unique to each of us. These barcodes are available for the immune system to scan, judge, and decide how to proceed.

With organ transplants, careful selection of matching HLAs (in addition to blood type) help prevent the body from rejecting the transplant. But in the uterus during pregnancy, the role of these HLA barcodes is more complex, and it’s not as simple as desiring the most similar HLAs between mother and child. In one of its roles, HLAs help the mother’s immune system decide how much nutrition and oxygen it should divert from the mother to the embryo through spiral artery remodeling. And unfortunately, a specific combination of an embryo’s HLAs (HLA-C2) and mother’s genes (KIR AA) can result in insufficient remodeling and significantly lower live birth rates.

Beyond spiral artery remodeling, HLAs are involved in many other aspects of pregnancy as well. Because half of a developing embryo’s HLAs come from their father, a full HLA workup should examine both maternal and paternal DNA. Sometimes, two parents’ HLAs might be too similar and result in higher chances of pregnancy loss, as we’ve learned from studies on a small, closed community of Hutterites. Or, a mother’s HLAs might be predisposed to raise the alarm when they encounter antigens encoded in the Y chromosome – seen as a reduced ability to have additional children after giving birth to a boy. And other times, the mother’s body will develop antibodies to the father’s HLAs, which have been found to be associated with a reduced chance for a live birth. For these reasons, we suggest examining the following aspects of parental histocompatibility:

• Maternal KIR and embryonic HLA-C interaction
• HLA mismatches
• HY immunity
• HLA antibodies

What else goes into a comprehensive immunological assessment?

We’ve only covered tests that are directly related to the immune system, but there are many other diseases, health concerns, and other factors that tie into overall immunological health. For instance, diabetes and PCOS, neither of which are classically considered immunological disorders, can deeply impact a person’s immune system – and might even have roots in it.

ACOG, the American College of Obstetricians and Gynecologists, lists antiphospholipid syndrome, diabetes and PCOS as their top examples of medical conditions that can increase a person’s risk for recurrent miscarriages. (FYI, they also acknowledge blood tests to detect problems with the immune system as one of the methods to determine the cause of recurrent pregnancy loss.) Testing for these conditions is essential when searching for answers to unexplained pregnancy failures.

Nutritional status also has a strong impact on the immune system and can sometimes point to easy interventions, like dietary supplements or meal planning tips. Omega 3 fatty acids and vitamin D are both undeniably important at controlling inflammation, and testing for them is easy but often neglected.

Overall, a comprehensive immunological assessment should incorporate many of the same tests that a thorough doctor would check in patients experiencing recurrent pregnancy loss, infertility or multiple failed IVF implantations. These include:

• Chromosome analysis
• Thrombophilia markers
• Insulin resistance
• PCOS markers
• Nutritional deficiencies

Who can benefit from reproductive immunology testing?

Although most people could benefit from learning if they suffer from an undiagnosed autoimmune disease or other immunological challenge, comprehensive reproductive immunology testing is an involved process. Some people choose to undergo this testing before they begin their pregnancy journey, but most others wait to perform immunological tests until they’ve already experienced some level of reproductive failure.

Doctors used to reserve immunological testing for patients who experienced three or more miscarriages or failed IVF cycles, but this is a heartbreaking, exhausting and expensive period of time to endure – time that many hopeful parents don’t have to waste. By finding answers earlier in their pregnancy journey, patients can gain a more comprehensive view of their potential challenges and treatment options moving forward. In some cases, proper testing and treatment can even eliminate the need for costly IVF procedures.

In our experience, people can benefit most from comprehensive reproductive immunology testing if they have experienced any of the following:

• Tried unsuccessfully to conceive for more than 1 year
• Experienced a miscarriage or stillbirth of a genetically normal fetus
• Experienced two or more early miscarriages in a row
• Failed IVF cycles of good quality embryos (including donor eggs)
• Prior history of pregnancy complications like preeclampsia
• Suffer from an autoimmune disease
• History of endometriosis
• Diagnosed with PCOS
• Have diminished ovarian reserve or poor egg quality

How are reproductive immunology issues treated?

Some of the issues that are revealed with immunological testing have very straightforward fixes. If someone has a vitamin D deficiency, then they should take a vitamin D supplement. Or if they have antiphospholipid antibodies or a predisposition to thrombophilia (blood clotting disorder), then they’ll probably want to be on a blood thinner while pregnant.

On the other hand, treatments for some conditions are based on smaller trials and don’t come with official guidance. For instance, the use of tacrolimus to treat inflammatory conditions or intravenous immunoglobulin (IVIg) to address HLA antibodies. In this case, when using our testing platform, we provide medical professionals with a simplified review of the best treatment options for their patients’ conditions and evidence for their use.

Some treatments have been supported by more trials than others, and some treatments are more affordable than others. All of this should factor into how different immunological conditions are treated. Ultimately, the appropriate treatment plan will be a decision that patients and their doctors make together.

A comprehensive path to reproductive success

Our founding clinic, Braverman IVF & Reproductive Immunology, has used this testing strategy to help thousands of women find reproductive success. We specialize in the most difficult cases, and for women who’ve experienced at least five miscarriages (and as many as 15), our tests and treatments have helped 70% of them give birth to a baby using their own eggs.

Instead of keeping our success strategy to ourselves, we’ve decided to share this knowledge with other medical practices. Everyone deserves access to answers, which is why we founded Pregmune.

We put together an Immunological Reproductive Multifactor Assessment (IRMA) that combines all the panels and information we’ve outlined in this article into a streamlined testing process and single easy-to-read report. In addition to the test results, we also provide an AI-generated prediction of a patient’s chances of having a successful pregnancy if they choose to use immunological treatments. This added feature helps doctors and their patients decide how aggressively to approach treatment, what to expect, and whether or not they should start considering alternative options such as egg donation or even surrogacy.

With this report, we’ll also provide the referring physician with treatment suggestions to help them navigate the best path forward for their patient. Sometimes a comprehensive report will lead to straightforward answers, and other times it will pick up on clues suggesting other health conditions that require follow-up testing to diagnose – like endometriosis. Every case is unique, which is why a trained in-house medical professional will review every report before it’s sent to both doctor and patient.

We’re committed to helping people grow their families and helping doctors provide answers and support to their patients. Don’t hesitate to reach out to us if you think that means we can help you.

Contact us at care@pregmune.com

About Pregmune: We’re an innovative reproductive health technology company, built on a solid foundation of data gained from decades of experience and thousands of successful pregnancies. Our team of fertility specialists and scientists are using artificial intelligence to decipher the complexity of the immune system and help patients grow the families of their dreams.

Our first product, IRMA, provides patients and their doctors with a personalized report and evidence-based treatment plan that addresses immunological sources of unexplained infertility, recurrent pregnancy loss, and recurrent implantation failure.