Recurrent Miscarriage and Implantation Failure

The information below information sets out how we investigate recurrent miscarriage or repeated treatment failure where a good quality embryo has failed to attach and implant into the uterus (known as implantation failure).  You will also find explanations for some of the treatments that we can offer you if your fertility is affected by any of these scenarios.

Who can be helped by investigations and treatments for recurrent implantation failure and miscarriage?

At the Zita West Clinic, we think you might benefit from specialist investigations if you have

• had two or more consecutive miscarriages or two or more failed IVF cycles (especially after transfer of an embryo known to have the usual number of chromosomes following PGT-A testing)
• miscarried a baby where tissue analysis showed there were no chromosomal abnormalities
• an existing autoimmune illness (rheumatoid arthritis, lupus, Crohn’s disease, thyroid illness or psoriasis for example)
• had previous pregnancies where you had a small for dates baby (known as fetal growth restriction) or significant pre-eclampsia (high blood pressure in pregnancy).

What are the causes of recurrent implantation failure and miscarriage?

Sadly, there are likely to be many reasons why an embryo doesn’t attach in the uterus or miscarries in early pregnancy. Medical science has yet to help us fully understand all the possible reasons but in general terms miscarriage or implantation failure can arise either because the embryo is not viable or because the environment of the uterus isn’t as it should be.

The embryo

We do know from scientific evidence that genetic abnormalities in embryos increase with the age of the egg provider. It is also possible for a perfectly healthy person to have rearrangements in their chromosomes that don’t cause any problems for them, but cause serious genetic imbalances in embryos created with their eggs or sperm. Genetic abnormalities can lead to failed implantation and miscarriage.

The endometrium

The conditions in the uterus have to be just right for an embryo to implant.

There is a carefully coordinated interaction between an embryo and the endometrium at the time of embryo attachment. There is very limited time when the embryo is able to attach called the “window of implantation”. The embryo transfer procedure is carefully timed to make sure the embryo is in the uterus at the right time to implant but there are studies that suggest the window of implantation can be slightly earlier or later in some women.  This asynchrony might be a factor in repeated implantation failure.

While it’s normal to have bacteria in the vagina and uterus, occasionally the levels and type of bacteria can change. Although this change doesn’t cause any outward signs of infection it can be associated with changes in the conditions inside the uterus (the uterine environment can become more acidic for example) and this can affect fertility. Sometimes even very low-grade infections in the uterus can affect the cells lining the uterus causing inflammation that may affect an embryos ability to implant.

Our bodies are usually protected from bacteria and viruses by our immune system which works by killing and removing cells that it recognises as invaders because of their different genetic code. When attacking invaders are detected by the immune system, chemical signals called cytokines are released that cause inflammation. It is believed that the immune response in the uterus is usually moderated to allow an embryo to implant and grow without being attacked by the immune system or triggering inflammation.  Some scientists believe that in some cases of miscarriage, the mother’s immune system may fail to accept an embryo because it has a different genetic code and that having an illness caused by a more vigorous immune system than usual (known as an autoimmune illness) could be a risk factor in implantation failure or miscarriage.

Finally, the preparation of the uterus for implantation and support of the growing embryo is dependent on a good blood supply. Some studies have suggested that there is an increased risk of miscarriage where the woman carrying the pregnancy has a higher than usual risk of their blood clotting as small blood clots can restrict vital blood flow.

 How are these possible causes of implantation failure or miscarriage investigated?

We do two stages of tests to investigate possible causes of implantation failure or miscarriage

Stage 1 tests rule out the more straightforward medical problems that can cause recurrent IVF failure or miscarriage.

The tests we recommend if you are planning to carry a pregnancy might include

• Thrombophilia screening to check whether you are at risk of your blood clotting more easily than it should. This screening looks at levels of anticardiolipin antibodies, antithrombin III, Factor V Leiden, activated protein C resistance, protein C, protein S, lupus anticoagulant, polymorphism of PAIP factor II and prothrombin.
• Screening for auto-immune antibodies that might be present if your body is making antibodies against itself including anti-nuclear, thyroid peroxidise and anti-mitochondrial antibodies,
• An Endometrial Receptivity Array test (ERA or ER Peak) to pinpoint the time when the lining of your uterus is most likely to be receptive to an implanting embryo (the window of implantation).
• EMMA (Endometrial Microbiome Metagenomic Analysis) to check the microbiome of the womb to ensure that there is the correct balance of probiotic, or protective bacteria present.
• ALICE (Analysis of Chronic Infective Endometritis) screening which is a more focused test than EMMA and looks specifically for bacteria that cause chronic, low grade infection of the womb lining (endometritis),

The tests we may recommend if you are providing eggs

• Karyotype screening for chromosome abnormalities or rearrangements (although such abnormalities are thought to cause fewer than 1% of cases of recurrent miscarriage)

The tests we may recommend if you are providing sperm

• Karyotype screening for chromosome abnormalities or rearrangements
• CARE SOS screening to determine is the sperm is under significant oxidative stress that can lead to DNA fragmentation

Stage 2 tests are more in-depth investigations we may recommend if you are planning to carry a pregnancy.  These tests include

• Natural Killer (NK) cell assay – NK cells are a type of white blood cell that protect us from bacteria and viruses and other invaders but some research has suggested that raised NK levels in the blood and raised numbers of NK cells in the endometrium may be associated with recurrent IVF failure and recurrent miscarriage
• TH1/TH2 intracellular cytokine ratios. Cytokines are chemical messengers produced by immune cells. Cytokines produced by TH2 immune cells are thought to support pregnancy whereas the cytokines produced by TH1 immune cells may inhibit pregnancy. For successful pregnancy it has been suggested that the TH2 cytokines should be dominant and that If the TH1 cytokines are dominant this may impact adversely on pregnancy outcomes.

What treatments are available if the tests show something that might be affecting fertility?

We offer a range of treatment options and we specifically tailor to the findings of your own investigations.

Thrombophilia – if you are planning on carrying the pregnancy and any of your test results show you might be at increased risk of blood clotting (thrombophilia) we may recommend treatment with low dose aspirin or an anticoagulant (blood thinner) called heparin if you are planning to carry the pregnancy.

Immune abnormalities -the presence of auto-immune antibodies, antiphospholipid antibodies and/or positive lupus anticoagulant screening may be associated with an increased risk of thrombophilia and inflammatory immune response. If your test results show the presence of these autoantibodies and you are planning to carry the pregnancy, we may recommend treatment with heparin (to moderate blood clotting and the immune response) and steroid treatment to dampen the inflammatory response.

If level 2 specialist blood tests show an increased TH1:TH2, cytokine ratio or increased natural killer cell numbers and/or activity, then we may recommend treatment with steroids, low dose aspirin, heparin and/or intravenous intralipid infusion.

 ERA or ER Peak testing – if your test results suggest that the window of implantation is earlier or later than expected then embryo transfer can be timed to be in synchrony with your own window of implantation.

EMMA and ALICE screening – if these test results show the presence of bacteria that may make the uterus or endometrium a less than ideal environment then the screening also identifies which antibiotics and/or probiotics can be prescribed by your doctor to improve the balance of bacteria in your uterus.

Chromosomal abnormalities – if tests identify a chromosome imbalance or abnormality then we can offer treatment using pre-implantation genetic testing (known as PGT-A) to help us select only those embryos with the usual number of chromosomes for treatment.

DNA damage or oxidate stress in the sperm – if tests suggest there may be high levels of DNA damage or oxidative stress in sperm then we may suggest antioxidant supplements or the use of ICSI.

What are the costs?

You can find information about the costs of these therapies in the Zita West Clinic fees schedule. You should be aware that the tests and investigations can be expensive.

What are the risks of the treatments?

Intralipid, steroid and anticoagulant treatments can have side effects, some of which are serious.   If you are considering using any of these therapies your doctor will make sure the medication or treatment is safe for you and explain the possible risks and/or side effects.