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Immunological tests and treatments for fertility

Treatment add-on with limited evidence

For most patients, having a routine cycle of proven fertility treatment is effective without using any treatment add-ons.

 

The information on this page refers only to immunological tests and treatments when offered as an add-on to routine In vitro fertilisation (IVF)/Intracytoplasmic sperm injection (ICSI) in healthy patients. It does not apply to their use as treatment for an immunological disease. Some patients require immunological therapies as part of their medical treatment and for those cases, steroids and other drugs which affect the immune system should continue under the supervision of their immunologist.

Red traffic light

Red

The use of immunological tests and treatments as part of fertility treatment in healthy patients is rated red. This is because there is no evidence from randomised controlled trials (RCTs) to show that they are effective at improving the chances of having a baby for most fertility patients.

On this page

What does this traffic light rating mean?

Our traffic-light rated list of add-ons consists of three colours that indicate whether the evidence, in the form of high-quality RCTs, shows that a treatment add-on is effective at improving the chances of having a baby for most fertility patients.

We give a red symbol for an add-on where there is no evidence from RCTs to show that it is effective at improving your chances of having a baby.

The January 2019 consensus statement between the HFEA and ten other professional and patient bodies agreed that treatments that have no strong evidence of their safety and/or effectiveness should only be allowed in a research setting. Patients should not be charged extra to take part in research, including clinical trials.

For specific patient groups there may be reasons for the use of a treatment add-on other than improving your chances of having a baby. In these situations, it may be appropriate for you to be offered a treatment add-on as part of your treatment and not in a research setting.

Our traffic light ratings only indicate the effectiveness of a treatment add-on, at improving your chances of having a baby. Specific safety concerns about a treatment add-on are included under the dedicated section ‘Is this treatment add-on safe?’.

Why are immune therapies offered by clinics?

For many patients experiencing fertility problems, no underlying causes are found. Due to this inability to explain why a successful pregnancy does not occur, one theory widely shared is that the cause may be the patient’s immune system. 

The baby is a different individual from the patient as half its genes are inherited from the father. In the same way that transplanted organs from a different individual are rejected by the recipient’s immune system unless powerful drugs are taken to suppress this immune rejection, it was thought that the patient’s immune system could ‘reject’ their fetus unless their immune system was also altered and suppressed during pregnancy. It is now clear that immune rejection of the fetus rarely, if ever, happens.

Suppressing the immune system of a pregnant patient also exposes the patient and baby to considerable risks, including life-threatening infections. 

Does the patient’s immune system ever reject their baby?

A particular type of immune cell, the uterine Natural Killer (NK) cell, has been proposed as the root cause of rejection of the baby. The NK cells in the womb or uterus were given this name as they are related to NK cells circulating in our blood. Blood NK cells are essential in the early stage of viral infections when they kill infected cells. 

NK cells are naturally present in the uterus but the placenta is always a physical barrier between the patient’s immune cells and their baby. Thus, despite their name, these uterine NK cells are never in contact with the fetus and do not attack the embryo.

Indeed, it is now becoming clear that they are beneficial for pregnancy and work in cooperation with the placenta so it can successfully become established in the uterus.

​​​What do the blood tests measure?

Despite the lack of any evidence that immune therapies are beneficial during pregnancy, many patients are also offered blood tests first. A range of measurements can be requested by clinics. Frequently, the number and activity of NK cells are measured. However, because these tests are looking at NK cells in the blood and not the special NK cells in the uterus, they offer no useful information in relation to pregnancy outcomes.

Other tests measure ‘Th1/Th2 ratios’ in the blood. This is said to show whether the patient’s immune cells might attack the embryo. 

There is no convincing evidence that any maternal immune cells cause pregnancy failure.

Are there tests that can measure uterine NK cells?

Some clinics offer tests to look at the specialised uterine NK cells. The lining of the uterus, the endometrium, changes over the menstrual cycle. These changes prepare the endometrium for implantation. If implantation does not occur, then menstruation follows at the end of the cycle. An increase in the number of uterine NK cells after ovulation is a natural component of these changes. Tests to study the endometrium are invasive and frequent biopsies are needed. It is also difficult to accurately count NK cells and it is unknown whether numbers reflect how the NK cells function. Because of all these uncertainties, biopsies to assess the state of the endometrium should only be offered in a research setting.

What do the therapies do and why are they so risky?

A range of treatments may be offered that potentially have a profound and serious impact on the patient’s immune system. The main ones used are steroids, intravenous immunoglobulins (IVIG), Humira (TNF blockers) and Intralipid. Because there is no evidence that any immune cells, including uterine NK cells, ever do prevent a pregnancy, there is no reason for any patient without an immunological disease to take these therapies.

None of these treatments are harmless and some of their side-effects are serious. For example, they can give rise to severe allergic reactions or make patients susceptible to infections that could also affect the baby.

All the good evidence to date shows that there is a risk of considerable harm without any increase in the chances of a live birth.

At the time of a global pandemic due to SARS-Cov2 (COVID-19), therapies that suppress the immune system should not be used without expert medical advice.

If you have any questions about risks, your clinic will be able to discuss whether a treatment add-on would be safe for you to use considering your medical history and personal circumstances.

Steroids – Prednisolone, Methylprednisolone, Dexamethasone and other glucocorticoids

What are steroids?

Steroids, also called corticosteroids, are a class of drug used to reduce inflammation and suppress immune system activity.

What’s the evidence for the use of steroids?

There is no scientific rationale for the use of steroids and no good quality evidence to support their use as an add-on in fertility treatments.

At the October 2019 Scientific and Clinical Advances Advisory Committee (SCAAC) meeting the Committee evaluated the evidence base for immunological tests and treatments. Minutes of this discussion and the evidence used to inform this discussion are available on the SCAAC webpage.

Is this treatment add-on safe?

Short courses of low-dose steroids generally do not cause significant side effects, but the likelihood and severity of side effects increase with higher doses used in IVF clinics. Side effects also become increasingly likely with longer courses of more than two months or many repeated short courses.

Common side effects include weight gain, restlessness, sleep disturbance, sweating, muscle pain/weakness and abdominal discomfort.

Steroids inhibit the immune system so put patients at increased risk of infections, from the minor to the very serious. These infections can cause considerable harm not just to the patient but also to the baby.

Other serious side effects are rarer but include fluid retention (swelling in your hands or ankles), breathlessness, high blood sugar, high blood pressure, mood/behaviour changes, visual disturbance, abnormal bruising/bleeding and risk of peptic ulcer. There is also the risk of allergic reactions which range from minor rashes to serious anaphylaxis with facial swelling and difficulty breathing.

While taking steroids, patients should carry a card on them to alert medical professionals in the event of serious complications. Patients taking steroids should not stop suddenly as they can suffer serious and life-threatening withdrawal symptoms.

Intralipids

What are intralipids?

Intralipid is a fat emulsion, a white liquid mix of fat (mainly soybean oil) and water which is administered intravenously to provide very ill patients with additional nutrients. The body breaks down these fats into essential fatty acids which you normally ingest orally to maintain good health.

What’s the evidence for intralipids?

There is little evidence that intralipid improves live birth rate.

At the October 2019 Scientific and Clinical Advances Advisory Committee (SCAAC) meeting the Committee evaluated the evidence base for immunological tests and treatments. Minutes of this discussion and the evidence used to inform this discussion are available on the SCAAC webpage.

Is this treatment add-on safe?

Some common minor side effects include headache, nausea, vomiting, dizziness and flushing.

Intralipid is given by intravenous infusion (a drip) that always carries a risk of introducing infectious agents directly into the blood stream. More serious side effects are unlikely but may include signs of infection (e.g. fever, persistent sore throat), pain/swelling/redness at the injection site, pain/swelling/redness of arms/legs, bluish skin, sudden weight gain or back/chest pain.

Very rarely there may be emotional/mood changes, bone pain, muscle weakness, yellowing skin/eyes, dark urine, easy bruising/bleeding, severe stomach/abdominal pain and difficulty breathing.

Intralipids are not suitable for people with allergies to eggs, soya beans or peanut oil as they would be at risk of severe reaction. There is also a risk of reactions in patients without known allergies. Those range from minor rashes to serious anaphylaxis with facial swelling and difficulty breathing.

Intravenous immunoglobulin

What is intravenous immunoglobulin?

Immunoglobulins, also known as antibodies, are present throughout the body as a component of a healthy immune system. When immunoglobulins are used as a treatment, they have been purified from the blood of thousands of donors before they are given intravenously (IVIG). Treatment with IVIG is used for a wide range of severe autoimmune and inflammatory diseases. Although the way they work is not fully understood, they should only be used in these situations. They are in short supply so their use in fertility clinics may limit availability for these very sick patients.

What’s the evidence for intravenous immunoglobulin?

There is no evidence to support the use of intravenous immunoglobulin as an add-on in fertility treatments.

At the October 2019 Scientific and Clinical Advances Advisory Committee (SCAAC) meeting the Committee evaluated the evidence base for immunological tests and treatments. Minutes of this discussion and the evidence used to inform this discussion are available on the SCAAC webpage.

Is this treatment add-on safe?

This is potentially a very harmful treatment that is given by weekly infusions. It is also very expensive. Because of this risk, IVIG should not be taken as a fertility treatment.

Common side effects can include headache, muscle pain, fever, chills and low back pain.

Mild symptoms of allergies are common but serious reactions such as facial swelling or breathing difficulty are rare.

More serious side effects include thrombosis (blood clots) or kidney failure.

TNF-alpha blocking agents (THF-α inhibitors) e.g. infliximab, adalimumab, etanercept

What are THF-α inhibitors?

THF-α inhibitors are a class of drug which inhibit the action of molecules called cytokines. Th1 cytokines are released into the blood when the body is fighting an infection or is very sick for other reasons like autoimmune conditions. By inhibiting the action Th1 cytokines, THF-α blockers are used to dampen a patient's immune system and effectively treat autoimmune conditions.

What is the evidence for THF-α inhibitors?

There is no evidence to support the use of THF-α inhibitors as an add-on in fertility treatments.

At the October 2019 Scientific and Clinical Advances Advisory Committee (SCAAC) meeting the Committee evaluated the evidence base for immunological tests and treatments. Minutes of this discussion and the evidence used to inform this discussion are available on the SCAAC webpage.

Is this treatment add-on safe?

The most common side effects of THF-α inhibitors are abdominal pain, back pain, chest pain and nausea.

Other minor side effects include candidiasis (thrush), diarrhoea, pruritus (generalised itching), sinusitis, and vomiting.

There is always the risk of allergic reactions which can range from minor rashes to serious anaphylaxis with facial swelling and difficulty breathing.

Serious side effects of THF-α inhibitors are an increased susceptibility to infections such as septicaemia or tuberculosis.

What are treatment add-ons?

  • optional additional treatments, also referred to as ‘supplementary’, ‘adjuvants’ or ‘embryology treatments’.
  • often claim to be effective at improving the chances of having a baby (live birth rate) but the evidence to support this for most fertility patients is usually missing or not very reliable.
  • likely to involve an additional cost on top of the cost of a routine cycle of proven fertility treatment. Some treatment add-ons can cost hundreds or thousands of pounds each.

It is important to keep in mind that for most patients, having a routine cycle of proven fertility treatment is effective without using any treatment add-ons. If you are paying directly for your own treatment, you may want to think about whether it might be more effective and/or affordable to pay for multiple routine proven treatment cycles, rather than spending large sums of money on a single treatment cycle with treatment add-ons that haven’t been proven to be effective at increasing the likelihood of you having a baby.

We aim to publish clear and reliable information about some of the treatment add-ons that don’t have enough evidence, from high-quality randomised control trials (RCTs), to show that they are effective at improving your chances of having a baby.

To make it easier to understand the scientific evidence for each treatment add-on we have developed our traffic-light rated list of add-ons.

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Review date: 19 April 2023

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