What are Natural Killer (NK) cells?

Natural Killer (NK) cells are immune system cells that normally help the body fight infections. NK cells are one type of lymphocyte (an immune cell) normally circulating in blood. The lining of the womb (uterus) contains immune cells that resemble NK cells in blood, so they are called uterine NK cells.

What do uterine NK cells do?

Uterine NK cells (uNK cells) are present in large numbers in the wall of the womb at implantation and in the early months of pregnancy. They seem to help the placenta link up with your blood vessels and so set up a healthy supply line to the fetus. These cells have been found to regulate and promote the attachment of an embryo to the endometrium (implantation). Unfortunately they appear to be unbalanced in women that experience infertility and miscarriage. uNK cell numbers vary during the menstrual cycle and occasionally sustained high levels, especially in the latter half of the cycle, are detrimental to conceiving and maintaining a pregnancy both spontaneously and through IVF treatment.

Who can benefit from this test done?

The prevalence of raised uNK cells in women with implantation failure and recurrent miscarriage is 28%. Based on the best available current evidence, women who have had repeated miscarriages and women who have had recurrent implantation failure with assisted conception treatment (2 or more failed embryo transfers) may benefit from this test and treatment thereafter if the uNK level is high.

When and where is the test done?

This test in done during the “window of implantation” of your menstrual cycle. This is 7-10 days after the detection of ovulation using LH/ovulation sticks. It is important that you are not pregnant when the procedure is performed so you must use barrier methods, such as condoms, for the 4 weeks prior to having your sample taken. If the sample is taken whilst you are pregnant it could possibly cause a miscarriage, although the risk is small. The risk of any damage to your womb during the procedure is minimal and even if any damage does occur, it should heal without further treatment.

The procedure is carried out at GCRM and does not usually require any anaesthetic.

How is the test done?

The test aims to obtain a small sample of endometrium (the lining of the womb), which is shed with every menstrual bleed and regenerates during the next cycle. The test is exactly the same as an endometrial scratch – a procedure which causes a small intentional injury or ‘scratch’ to the endometrium prior to IVF and may itself improve the chances of implantation and pregnancy.

We will ask you to sign a consent form. You will then have an ultrasound scan and, in a procedure similar to having a smear test, a vaginal speculum will be inserted to visualise the cervix (neck of the womb). Then a small flexible tube (catheter) is passed through the cervix and a small amount of the endometrial tissue is taken to be analysed for the uNK cells.

What are the side effects of the test?

It only takes a few seconds and whilst it may cause some mild discomfort and cramping, it should not be too painful. Nevertheless we would suggest taking some paracetamol and/or ibuprofen an hour or so before the procedure. A small amount of spotting or very light bleeding is not uncommon for a day or so after the procedure. Having a comfortably full bladder will often help to make this procedure easier, so please refrain from emptying your bladder when arriving at the clinic. However, in a small number of cases, it may not be possible to pass the small tube easily in to position. The procedure may need to be rebooked. If this is required,some light sedation may be given to alleviate any discomfort this may cause.

What should I do next?

You will need to buy an ovulation kit from your local Chemist shop and you must use condoms to avoid conceiving.You should start monitoring your ovulation according to the instructions provided with your ovulation kit and when it is “positive” you should contact us immediately to make an appointment the biopsy.

How do get I the result?

Once the tissue is taken, we send it to the laboratory at the John Radcliffe Hospital in Oxford where it is analysed by a specialised team at Oxford Fertility. It can take up to 3 weeks to get the result but we will contact you when we receive the result. If the uNK concentration is above 5%, you will be offered treatment aimed at suppressing the uNK cells. If below 5%, there is no evidence to recommend treatment.

What treatments are offered and what are their possible side effects?

Several treatments have been proposed in terms of treating abnormal uNK cell levels. Different immune-modifying treatments have been studied including oral steroid tablets, anti-coagulant therapy, intravenous lipid infusions and intravenous immunoglobulins. We recommend the use of steroid tablets and anti-coagulant therapy based on the available evidence although there is now some evidence that intralipid infusions can also be helpful.

Steroids

Oral steroid tablets (prednisolone) are thought to supress high levels of uNK cells and therefore help promote pregnancy and prevent miscarriage. Steroids are chemicals (hormones) that occur naturally in the body. They decrease inflammation as well as blocking a chemical called histamine (released during an allergic reaction) through suppressing the cells of the immune system. This includes uNK cells. Steroids are routinely used in the treatment of arthritis, asthma and other autoimmune disorders. The treatment is commenced the day before the embryo transfer until 12 weeks of pregnancy. This is taken orally as a tablet in the morning.

Whilst the human observational data are reassuring, animal studies show a slight increase in cleft palate, similar to that seen in diabetic pregnancies. As such, prednisolone, should be used in conjunction with folic acid 5mg/day (as opposed to the usual 400 μg/day) as this higher dose of folic acid reduces the risk.

Clexane (anti-coagulant therapy)

Clexane is a low molecular weight heparin. It is a protein molecule that modifies the immune response by affecting receptors in the endometrium. It is safe in pregnancy but it is a daily injection, starting the day before the embryo transfer until 12 weeks of pregnancy.

Intralipid Infusion

The evidence to date suggests that intralipids suppress the NK cells and when given prior to embryo transfer may reduce the incidence of immunological rejection of implantation. “Intralipids” are soya-based products which modulate the immune response. The solution consists of a mix of soya bean oil, egg yolk, glycerin and water. This is given via an intravenous drip directly into the bloodstream. This means if you are allergic to soya oil, eggs, shellfish or peanut oil, or have certain medical conditions, you cannot have an intralipid infusion.

It is a non-human product and therefore does not carry the potential infection risk (virus or prions) of other treatment modalities such as intravenous immunoglobulins.