Reproductive immunology is the study of how the immune system interacts with fertility, implantation, and pregnancy.

Your immune system doesn’t just fight infections, it plays a critical role in recognising an embryo (which is always partly “foreign” to your body), allowing it to implant, and then tolerating it for nine months.

This process is called immunotolerance. When that tolerance doesn’t function properly, it can contribute to failed implantation, miscarriage, or pregnancy complications.

Natural killer (NK) cells are a type of immune cell. There are two main types of immunity relevant here: cytotoxic immunity (TH1), which includes NK cells that detect and attack foreign cells, and humoral immunity (TH2), which involves immunoglobulins that mediate and decide whether to tolerate something foreign. In the luteal phase of your cycle (when implantation is meant to happen), you should have more TH2/humoral immunity — the “tolerant” type. If there’s too much TH1/cytotoxic activity at that point, it can interfere with implantation.

No, NK cells are essential. Uterine NK cells play a crucial role in blood vessel remodelling, which is how the placenta forms properly and delivers blood to the developing embryo. The concern is not that NK cells exist, but whether they are overactive (potentially attacking the embryo or preventing proper implantation) or underactive (not providing enough support for placental development). Both extremes can be problematic.

This is an important distinction. Peripheral (blood) NK cells circulate in your bloodstream and are the “killers” that fight viruses and cancer cells. Uterine NK cells are found in the lining of the womb and behave quite differently — they don’t attack embryos but instead help build the placenta and shape blood vessels. Blood NK cell levels do not always reflect what’s happening in the uterus. At Avenues, we test both: systemic NK cell response through a blood test, and localised uterine NK cell response through an endometrial biopsy.

Traditionally, recurrent miscarriage is defined as three or more first-trimester miscarriages. However, newer guidelines from the European Society of Human Reproduction and Embryology (ESHRE) say we shouldn’t wait for three miscarriages to start investigating. At Avenues, we encourage investigation after two miscarriages,  or even after one if you’re over 35, because there may be things within our control that could prevent another loss.

The five major areas we investigate are:

1. Thyroid function — Subclinical hypothyroidism or thyroid antibodies can cause first-trimester miscarriage. This is often easily treated with medication.

2. Genetic factors — 85% of single miscarriages are caused by chromosomal abnormalities in the embryo. In recurrent loss, we may check both partners’ karyotypes (about 1% of the population has a balanced translocation that doesn’t affect them but can affect embryo genetics).

3. Uterine factors — Fibroids, polyps, or a septum in the womb. A 3D ultrasound can detect these.

4. Blood clotting factors — Autoimmune conditions like antiphospholipid syndrome (APS), or genetic factors like Factor V Leiden and prothrombin gene mutations, can cause excessive clotting that affects pregnancy. These are treated with blood-thinning medications, not immunological treatments.

5. Immunological factors — Overactive or underactive NK cells, TH1/TH2 imbalance, and autoimmune antibodies.

While approximately 1 in 4 pregnancies ends in miscarriage, recurrent miscarriage (defined as three or more) affects only about 1–3% of women. It’s less common than people think, but still represents a significant proportion of patients who are actively trying to conceive.

Recurrent implantation failure is generally defined as the failure of three good-quality blastocyst embryos to implant, or, more specifically,  the failure of two genetically normal (euploid) embryos to implant. The “true” definition requires genetically tested embryos because without that, we can’t rule out that the embryo itself (not the uterine environment) was the reason for failure.

Depending on your history, testing may include:

What immunotherapy treatments are available?

Treatment is always personalised based on your test results. The main options include:

Your NK cell test results come back with specific data on how your cells responded to different treatments in the lab. The report tells us, for example, that intralipids reduced your NK cell activity by X%, IVIG by Y%, and prednisolone by Z%. Based on those results, we tailor your treatment — you might need one therapy, a combination, or sometimes none at all if everything comes back normal.

No. Many patients benefit from natural conception support. We can introduce progesterone, blood-thinning injections, or immunotherapies once you have a positive ovulation or pregnancy test.

It’s the specific time frame when your uterus is receptive to an embryo. ERA testing helps identify your unique window, which can vary from patient to patient.

Unfortunately, no. Age primarily affects the genetic quality of the egg. However, once a genetically normal (euploid) embryo is found, immunology investigations help ensure the uterine environment isn’t the reason for failure.