Reproductive Immunology and Its Role in Fertility
The immune system plays a crucial role in human reproduction. In a healthy woman, it must be finely balanced so that it does not reject the embryo, which is genetically half paternal, but instead supports its implantation and further development.
However, this immune balance can sometimes be disrupted. The result may be infertility, recurrent pregnancy loss, or IVF treatment failure. In such cases, immunological testing and targeted treatment can help.
Why immunity is linked to fertility
The immune system plays a surprisingly important role in human reproduction. In a healthy woman, it must be finely balanced so that it does not reject the embryo, which is partly paternal and therefore “foreign,” but instead supports its implantation and further development. However, this immune balance can be disrupted. The result may be infertility, recurrent pregnancy loss, or IVF treatment failure. In such cases, immunological testing and targeted treatment can help.
Fertility and related disorders
- Infertility
- Primary and secondary infertility
- Recurrent pregnancy loss
- Recurrent implantation failure (RIF)
- Adverse pregnancy outcomes (APO)
Infertility
Infertility is the inability to achieve a clinical pregnancy after 12 months of regular unprotected sexual intercourse.
Primary and secondary infertility
We distinguish between primary infertility, when a woman has never been pregnant, and secondary infertility, when a pregnancy has occurred in the past (even if unsuccessful), but further conception is not possible.
In some couples, assessment is needed earlier than after one year, especially if the woman is over 35 or if other risk factors are present (irregular menstruation, severe abnormalities in the spermiogram, previous oncological treatment, etc.).
Recurrent pregnancy loss
Recurrent pregnancy loss is defined as the loss of two or more pregnancies, regardless of whether conception was spontaneous or assisted.
Only clinically confirmed pregnancies are counted — those verified by ultrasound or histology. So-called biochemical pregnancies (a positive pregnancy test without ultrasound confirmation) are not counted unless otherwise documented.
Recurrent implantation failure (RIF)
Recurrent Implantation Failure (RIF) does not yet have a fully unified definition. It refers to a situation where pregnancy does not occur after multiple embryo transfers, taking into account the number of transfers (fresh and frozen), embryo quality and the woman's age. With genetically confirmed good-quality embryos, RIF is defined as 2 unsuccessful transfers regardless of age. When the embryo has not been genetically tested, RIF is generally considered to be 2 implantation failures in women up to 35 years of age, 4 in women aged 36–40, and 6 in women over 40.
Adverse pregnancy outcomes (APO)
Complications of advanced pregnancy — one of the following serious complications:
- fetal loss after the 20th week of pregnancy (e.g. late miscarriage or stillbirth),
- severe preeclampsia (a serious condition associated with high blood pressure and organ dysfunction, if it occurs before the 36th week of pregnancy),
- severe intrauterine growth restriction, where the baby's birth weight is below the 10th percentile for the given week of pregnancy.
These complications can have various causes, including possible immunological intolerance between mother and fetus.
When to look for the cause in an immune disorder?
Immunological testing is not the first step for every infertile couple — quite the opposite. It is meaningful only once other causes (e.g. hormonal, anatomical or genetic) have been ruled out, or when fertility treatment repeatedly fails.
Immunological testing is recommended particularly in the following cases:
- recurrent implantation failure,
- recurrent pregnancy loss,
- complications of advanced pregnancy,
- suspected immunological burden — autoimmune disease in the personal or family history (e.g. autoimmune thyroiditis, lupus, celiac disease, rheumatoid arthritis, inflammatory bowel disease, and others),
- marked inflammatory conditions of unknown cause,
- oncological history.
Antibodies and their significance
- Antibodies against the zona pellucida (the outer layer of the egg) may prevent sperm from fertilising the egg.
- Anti-ovarian antibodies may impair ovarian function and reduce both the quantity and quality of eggs.
- Antiphospholipid antibodies may cause miscarriages, pregnancy complications or lead to vascular thrombosis.
- Antibodies against tissue transglutaminase and other celiac-associated antibodies may be linked to miscarriages, infertility or fetal growth disorders.
- Antinuclear antibodies (against cell nuclei) may be associated with certain autoimmune diseases and pregnancy complications.
- Anti-thyroid antibodies may affect fertility and the course of pregnancy.
- Anti-sperm antibodies may make natural conception more difficult.
Disorders of the complement system
The complement system is part of the immune system that helps the body fight infections. In some women, its activity may be insufficient, which can lead to miscarriages or placental problems. The most common is so-called MBL deficiency (mannose-binding lectin deficiency), which occurs more frequently in women at risk of miscarriage and other pregnancy complications.
Cells of the immune system
- NK cells in peripheral blood: their excessive activity directed against features of sperm and/or the fetus can reduce the chance of a successful pregnancy.
- KIR receptors of NK cells: certain sensors (receptors) of NK cells may fail to correctly recognize features of the fetus of paternal origin, which can lower the chances of conception and increase the risk of pregnancy complications.
- T lymphocytes (helper and regulatory): if they do not function properly, the body may reject the embryo.
- Uterine NK cells: white blood cells in the uterus that normally help nourish the embryo, but if they "switch to attack mode" the pregnancy may be at risk.
Why and when to test
Immunological testing is meaningful especially in women with recurrent miscarriages, repeated failure of multiple IVF cycles or in women with suspected autoimmune disease. Test results may open up new treatment options, but they must always be assessed in the context of the woman's overall health and the course of her IVF treatment.
Immunomodulatory treatment
Some immune disorders can prevent natural conception, complicate the course of assisted reproduction or lead to recurrent pregnancy loss. The immune system, whose task is to protect the body against harmful agents, may in these cases unintentionally interfere with the complex process of conception, embryo implantation and pregnancy development. If an immune disorder is confirmed by specialist testing and matches the patient's difficulties, so-called immunointervention treatment — targeted and controlled modulation of the immune system — can be considered.
Immunointervention can take several forms. We speak either of immunosuppressive treatment, which suppresses excessive or harmful immune activity; of immunosubstitution treatment, which replaces missing components of immunity; or of immunomodulation — a fine-tuning of the balance between the body's defences and tolerance toward the embryo. It is the immunomodulatory approaches that are most commonly used in reproductive medicine.
The principle is that every treatment must be precisely targeted and individually justified. It is not appropriate to prescribe medication "on trial" or based on what worked for another woman. It is equally inappropriate to start immunomodulation on the basis of a single outlying laboratory finding if the patient otherwise has no symptoms and the pregnancy is progressing normally. Our goal is not to "treat the immune system" but to support the establishment and development of a healthy pregnancy in a particular woman and a particular situation.
Medications and preparations
- Corticosteroids
- Intralipids
- Human immunoglobulins
- Hydroxychloroquine
- Filgrastim
- Other supportive medications (e.g. heparin, vitamin D, metformin)
Corticosteroids
The cornerstone of immunomodulatory therapy is corticosteroids, which are among the most effective and best-studied medications of this kind. They act directly inside cells, influencing the production of inflammatory substances, the activity of white blood cells and the production of unwanted antibodies. In reproductive medicine, corticosteroids are used, for example, when immunological testing reveals increased NK cell activity, an abnormal lymphocyte composition in the uterine lining or signs of chronic inflammation.
Both the dose and the duration of treatment are always chosen individually. Treatment often starts with a higher dose, which is gradually reduced to a maintenance level. The effect of corticosteroids develops gradually over several days to weeks, and their administration requires regular check-ups. Although they are well tolerated, they can have side effects, especially in women with diabetes, high blood pressure, excess weight or elevated intraocular pressure. The most frequently used preparation is prednisone; in some cases we choose methylprednisolone or dexamethasone, which have a different efficacy profile.
Intralipids
Another option is so-called intralipids. These are sterile fat emulsions based on soybean oil that dampen excessive activity of immune cells, particularly NK cells and T lymphocytes. They act very quickly and correct timing is essential. They are usually administered a few days before embryo transfer and may be repeated in early pregnancy.
Given that this is a medication prepared “tailor-made” for an individual patient, the infusion must always be scheduled in advance. Intralipids are safe and well tolerated; however, they must not be used in patients with allergies to soy, eggs, or peanuts, and are not suitable for women with severe disorders of lipid metabolism or liver function.
Human immunoglobulins
In some patients, particularly those with disorders of cellular immunity or autoimmune features, human immunoglobulins can be used. These are medicines containing antibodies obtained from the plasma of thousands of blood donors. These so-called polyspecific immunoglobulins help establish balance in the immune system and increase the number of so-called regulatory T lymphocytes, which play a crucial role in fetal tolerance.
Their use is considered only in selected situations (e.g. recurrent miscarriage, implantation failure with a confirmed immunological abnormality) and is always decided on an individual basis. Immunoglobulins are costly, their availability is limited, and they are not routinely covered by public health insurance outside defined indications. They are administered intravenously, subcutaneously, or intramuscularly in specialized centres with appropriate equipment and expertise.
Hydroxychloroquine
Hydroxychloroquine is another medication with an immunomodulatory effect that is sometimes used in reproductive immunology. It is a preparation long used to treat certain autoimmune diseases. Its effect lies in suppressing pro-inflammatory immune activity, stabilising cell membranes and supporting tolerance.
In reproductive immunology, it is considered mainly in women with autoimmune diseases who also have a fertility disorder. In the Czech Republic, hydroxychloroquine is not routinely prescribed directly for the treatment of infertility, but if a woman is taking it for other reasons, treatment is usually continued during pregnancy, as it is safe.
Filgrastim (G-CSF)
In recent years, filgrastim (G-CSF) has also begun to be used in reproductive medicine in certain indications. It is a growth factor that increases the number of regulatory immune cells and improves the environment of the uterine lining. It is administered as a subcutaneous injection. Its use is still off-label and always requires careful assessment.
Other supportive immunomodulatory medicines
In patients for whom corticosteroids are not suitable, or whose effect is insufficient, certain supportive immunomodulatory medicines can also be used, such as pentoxifylline, which suppresses the production of inflammatory cytokines and improves blood circulation.
As supplementary therapy, low-molecular-weight heparins or acetylsalicylic acid are also administered in certain situations; these influence not only blood clotting but also subtle regulatory processes in the immune network. In women with antiphospholipid syndrome, these medications can reduce the risk of pregnancy loss and preeclampsia.
Among other options that support the proper functioning of immunity, vitamin D should be mentioned; it is essential for the balance of immune cells in the uterus and for the development of the vessels supplying the embryo. Its supplementation is common in women with fertility disorders, and vitamin D levels are checked as part of the immunological examination.
Metformin, known primarily as a diabetes medication, can have an indirect anti-inflammatory effect in women with PCOS (polycystic ovary syndrome) and obesity, in whom the body's inflammatory state is one of the factors affecting fertility.
Safe and modern treatment
What we do not use
At our clinic, we do not use certain outdated treatment methods, such as immunisation with the partner's white blood cells. For fertility disorders we also do not use biological therapy, which carries a high risk of adverse effects. Medications such as tacrolimus or azathioprine, commonly used in severe autoimmune conditions or after transplantation, are continued in therapy if they have been prescribed for other reasons and are managed under specialist supervision; we ourselves do not prescribe them as primary treatment for infertility.
Individualized approach
Every woman is unique, and her treatment should be equally individualized. An experienced physician must carefully assess when immunomodulatory treatment truly makes sense, what benefits can be expected, and what risks need to be considered. The aim of our care is to support the body in accepting the embryo and to create the best possible conditions for a healthy pregnancy, in line with modern scientific knowledge and the needs of each individual patient.
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