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Immunological tests and treatments for fertility
For most patients, having a routine cycle of proven fertility treatment is effective without using any treatment add-ons.
Our ratings indicate whether the evidence from studies shows that a treatment add-on is effective at improving treatment outcomes for someone undergoing fertility treatment. Our ratings do not tell you how much that treatment add-on improves your chances of having a baby – please discuss this with your clinic.
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.
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.
Transplanted organs from a different individual are rejected by the recipient’s immune system unless powerful drugs are taken to suppress this immune rejection. The baby is a different individual from the patient as half its genes are inherited from the biological father. In some patients it was thought that the patient’s immune system could ‘reject’ their foetus unless their immune system was also altered and suppressed during pregnancy. However, it is now clear that immune rejection of the foetus 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?
If rejection of the foetus occurs a particular type of immune cell, the uterine Natural Killer (NK) cell, has been proposed as the root cause. 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 foetus 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 cause 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 having a baby.
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.
| Ratings for using Steroids (glucocorticoids) for fertility | |
|---|---|
| The use of steroids (glucocorticoids) is rated red for most fertility patients
Red traffic light
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The use of steroids (glucocorticoids) as part of fertility treatment in healthy patients is rated red for improving the chances of having a baby for most fertility patients. This is because there are potential safety concerns. |
| The use of steroids (glucocorticoids) is rated red for reducing the chances of miscarriage for most fertility patients
Red traffic light
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The use of steroids (glucocorticoids) as part of fertility treatment in heathy patients is rated red for reducing the chances of miscarriage for most fertility patients. This is because there are potential safety concerns. |
| The use of steroids (glucocorticoids) is rated red for improving the chances of having a baby for patient undergoing immunological testing
Red traffic light
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The use of steroids (glucocorticoids) as part of fertility treatment is rated red for improving the chances of having a baby for patients undergoing immunological testing, such as natural killer cell blood tests. This is because there are potential safety concerns. |
| The use of steroids (glucocorticoids) is rated red for reducing the chances of miscarriage for patients undergoing immunological testing
Red traffic light
|
The use of steroids (glucocorticoids) as part of fertility treatment is rated red for reducing the chances of miscarriage for patients undergoing immunological testing, such as natural killer cell blood tests. This is because there are potential safety concerns. |
| Ratings for using intralipids for fertility | |
|---|---|
| The use of intralipids is rated grey for most fertility patients
Grey traffic light
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The use of intralipids as part of fertility treatment in healthy patients is rated grey for improving the chances of having a baby for most fertility patients. This is because there is insufficient moderate/high quality evidence. |
| The use of intralipids is rated grey for reducing the chances of miscarriage for most fertility patients
Grey traffic light
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The use of intralipids as part of fertility treatment in healthy patients is rated grey for reducing the chances of miscarriage for most fertility patients. This is because there is insufficient moderate/high quality evidence. |
| The use of intralipids is rated grey for improving the chances of having a baby for patients undergoing immunological testing
Grey traffic light
|
The use of intralipids as part of fertility treatment is rated grey for improving the chances of having a baby for patients undergoing immunological testing, such as natural killer cell blood tests. This is because there is insufficient moderate/high quality evidence. |
| The use of intralipids is rated grey for reducing the chances of miscarriage for patients undergoing immunological testing
Grey traffic light
|
The use of intralipids as part of fertility treatment is rated grey for reducing the chances of miscarriage for patients undergoing immunological testing, such as natural killer cell blood tests. This is because there is insufficient moderate/high quality evidence. |
| Ratings for using intravenous immunoglobulins for fertility | |
|---|---|
| The use of intravenous immunoglobulins is rated red for most fertility patients
Red traffic light
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The use of intravenous immunoglobulins as part of fertility treatment in healthy patients is rated red for improving the chances of having a baby for most fertility patients. This is because there are potential safety concerns. |
| The use of intravenous immunoglobulins is rated red for reducing the chances of miscarriage for most fertility patients
Red traffic light
|
The use of intravenous immunoglobulins as part of fertility treatment in healthy patients is rated red for reducing the chances of miscarriage for most fertility patients. This is because there are potential safety concerns. |
| The use of intravenous immunoglobulins is rated red for improving the chances of having a baby for patients undergoing immunological testing
Red traffic light
|
The use of intravenous immunoglobulins as part of fertility treatment is rated red for improving the chances of having a baby for patients undergoing immunological testing, such as natural killer cell blood tests. This is because there are potential safety concerns. |
| The use of intravenous immunoglobulins is rated red for reducing the chances of miscarriage for patients undergoing immunological testing
Red traffic light
|
The use of intravenous immunoglobulins as part of fertility treatment is rated red for reducing the chances of miscarriage for patients undergoing immunological testing, such as natural killer cell blood tests. This is because there are potential safety concerns. |
What do the ratings mean?
There are five ratings that indicate whether a treatment add-on is effective at improving treatment outcomes for someone undergoing fertility treatment, according to the evidence from studies. To make it easier to understand the scientific evidence for each treatment add-on we have a range of symbols and colours for each rated add-on below.
Green traffic light
On balance, findings from high quality evidence shows this add-on is effective at improving the treatment outcome.
Yellow traffic light
On balance, it is not clear whether this add-on is effective at improving the treatment outcome. This is because there is conflicting moderate/high quality evidence – in some studies the add-on has been found to be effective, but in other studies it has not.
Grey traffic light
We cannot rate the effectiveness of this add-on at improving the treatment outcome as there is insufficient moderate/high quality evidence.
Black traffic light
On balance, the findings from moderate/high quality evidence shows that this add-on has no effect on the treatment outcome.
Red traffic light
There are potential safety concerns and/or, on balance, findings from moderate/high quality evidence shows that this add-on may reduce treatment effectiveness.
All treatment add-ons on our list will have a rating to indicate whether the evidence shows that the treatment add-on is effective at improving the chances of having a baby for most fertility patients. Some treatment add-ons on our list may also have additional ratings for specific treatment outcomes. For example, whether the evidence shows that the treatment add-on reduces miscarriage. There may also be further ratings for specific patient groups, for example whether the evidence shows that the treatment add-on is effective for those who are aged over 40. Please see the individual webpages for each treatment add-on for their ratings.
An agreement between the HFEA and other professional and patient bodies (the 19th October 2023 consensus statement) states that treatments that have no strong evidence of their safety and/or effectiveness should only be offered in a research setting. Patients should not be charged extra to take part in research, including clinical trials.
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 not enough good quality evidence to support their use as an add-on in fertility treatments.
At the October 2021 and July 2023 Scientific and Clinical Advances Advisory Committee (SCAAC) meetings the Committee evaluated the evidence base for immunological tests and treatments. Minutes of these discussions and the evidence used to inform them 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 the 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.
Studies reviewed for this treatment add-on
The HFEA have reviewed the following studies for steroids:
| Fawzy 2008 | 10.1007/s00404-007-0527-x |
| Fawzy 2013 | 10.1007/s00404-013-3020-8 |
| Gomaa 2014 | 10.1007/s00404-014-3262-0 |
| Taiyeb 2017 | 10.1007/s12020-017-1446-7 |
| Yeganeh 2017 | 10.1080/01443615.2017.1346593 |
| Kaye 2017 | 10.1016/j.fertnstert.2017.04.003 |
| Milardi 2017 | 10.1111/andr.12300 |
| Siristatidis 2018 | 10.1080/09513590.2017.1380182 |
| Liu 2018 | 10.1111/cen.13824 |
| Thalluri 2022 | 10.1093/humrep/deac142 |
| Turi 2010 | 10.1016/j.clinthera.2011.01.010 |
| Tang 2013 | 10.1093/humrep/det117 |
| Fan 2016 | 10.1111/aji.12559 |
| Huang 2021 | 10.1016/j.jri.2020.103245 |
| Gao 2021 | 10.1177/09612033211055816 |
| Zhou 2022 | 10.1186/s12884-022-04532-2 |
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 are no moderate/high quality studies to suggest that intralipids improve the chances of having a baby.
At the October 2021 and July 2023 Scientific and Clinical Advances Advisory Committee (SCAAC) meetings the Committee evaluated the evidence base for the use of intralipids for fertility. Minutes of these discussions and the evidence used to inform them 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.
Studies reviewed for this treatment add-on
The HFEA have reviewed the following studies for intralipids:
| El-Khayat 2015 | 10.1016/j.fertnstert.2015.07.080 |
| Gamaleldin 2018 | 10.1002/central/CN-01911196/full |
| Singh 2019 | 10.1016/j.ejogrb.2019.06.007 |
| Al-Zebeidi 2019 | 10.1080/09513590.2019.1631280 |
Intravenous immunoglobulin
What are intravenous immunoglobulins?
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 immunoglobulins?
There is no evidence to support the use of intravenous immunoglobulins as an add-on in fertility treatments. There are three randomised controlled trials providing moderate quality evidence, but the results are too inconclusive to determine effectiveness and no clinical benefit could be established in terms of improving the chances of having a baby or reducing the chances of miscarriage, including for those who have experienced recurrent miscarriages.
At the October 2021 and July 2023 Scientific and Clinical Advances Advisory Committee (SCAAC) meetings the Committee evaluated the evidence base for the use of IVIG in fertility. Minutes of these discussions and the evidence used to inform them are available on the SCAAC webpage.
Is this treatment add-on safe?
This is potentially a very harmful treatment as it is a blood product 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.
Studies reviewed for this treatment add-on
The HFEA have reviewed the following studies for intravenous immunoglobulins:
| Stephensen 2010 | 10.1093/humrep/deq179 |
| Christiansen 2014 | 10.1111/1471-0528.13192 |
| Jørgensen 2020 | 10.1016/j.jri.2020.103128 |
| Dendrinos 2009 | 10.1016/j.ijgo.2008.11.010 |
| Yamada 2015 | 10.1016/j.jri.2015.01.008 |
| Lee 2016 | 10.1111/aji.12442 |
| Meng 2016 | 10.1007/s00404-015-3922-8 |
| Ahmadi 2017 | 10.1016/j.imlet.2017.10.003 |
TNF-alpha blocking agents (TNF-α inhibitors) e.g. infliximab, adalimumab, etanercept
What are TNF-alpha inhibitors?
TNF-alpha 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 for other reasons like autoimmune conditions. By inhibiting the action Th1 cytokines, TNF-alpha blockers are used to dampen a patient's immune system and effectively treat autoimmune conditions.
What is the evidence for TNF-alpha inhibitors?
There is no evidence to support the use of TNF-alpha inhibitors as an add-on in fertility treatments.
At the October 2020 Scientific and Clinical Advances Advisory Committee (SCAAC) meeting the Committee discussed the use of TNF-alpha inhibitors in fertility, however no publications investigating TNF-alpha blocking agents were identified for inclusion in this review and therefore a rating has not been recommended. Minutes of these discussions are available on the SCAAC webpage.
Is this treatment add-on safe?
The most common side effects of TNF-alpha 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 TNF-alpha inhibitors are an increased susceptibility to infections such as septicaemia or tuberculosis.
What are treatment add-ons?
In vitro fertilisation (IVF) and intrauterine insemination (IUI) are established treatments that have been proven effective for most patients. Treatment add-ons are optional non-essential treatments that may be offered in addition to such proven fertility treatment. The HFEA provides information on add-ons that meet the following criteria:
- Additional treatments (to the core treatment e.g. IVF or IUI), that are being offered to the general patient population in licensed fertility clinics in the UK,
- Where there are published scientific studies which claim to demonstrate that the treatment add-on improves the chances of having a baby or other treatment outcomes rated by the HFEA; but
- where evidence of effectiveness for the use of the treatment in a clinical setting is lacking or absent; and
- where patients need unbiased information about the effectiveness and risks of this treatment.
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 to show that they are effective at improving your chances of having a baby and other relevant treatment outcomes. This provides useful information to patients and allows them to question the use of add-ons
Review date: 19 October 2025
