Recurrent miscarriages & Immunology - Q&A with Dr Shehata

An individual miscarriage is unfortunately quite common and is most often due to the embryo having abnormal chromosomes - something you can't do anything about. But when several miscarriages occur in a row, you may need treatment and identifying the underlying cause is therefore crucial.

Dr Hassan Shehata runs two clinics in UK that specialise in helping women who suffer from recurrent miscarriages or repeated (IVF) implantation failures - Center for reproductive immunology and pregnancy. He is a Consultant Obstetrician and Gynaecologist and a subspecialist in Maternal Medicine, and has managed and treated over 5,000 patients at the CRP Clinic with 80% success rate.

What is recurrent miscarriages?

Most individual miscarriages are due to the fact that the embryo was not healthy; it didn’t have normal chromosomes. No one has only healthy eggs and sperm, so when the doctor says your miscarriage was "bad luck", he/she basically means that you were unlucky enough to get pregnant with an egg and/or a sperm that was not chromosomally normal.

If you have several miscarriages in a row, the probability that it's "bad luck" decreases, and in the event of more than three miscarriages in a row, you are diagnosed with what is called "recurrent miscarriages". I that case a miscarriage investigation should be done to try to identify the reason, and if tests show anything, treatment is available. But the fact is that classic miscarriage investigations quite seldom identify an issue. In other words, the cause of most cases of recurrent miscarriages remain undiagnosed.

Through his research, Dr. Shehata has established that the factors tested in a classic investigation only cause a minority of cases. So there are basically gaps in our knowledge and research; we just don't know that much about recurrent miscarriages yet.

Why is the immune system relevant to consider?

That the immune system plays a role during pregnancy is well established. If you receive a donated kidney or heart, you must take immunosuppressant drugs for the body not to repel these genetically foreign body parts. But even though an embryo always consists of 50% genetically foreign material from the man (and sometimes 100% when donated eggs are used), the generally body doesn’t reject it. The immune system thus adapts in one way or another to support a pregnancy.

So a logical theory is that if a woman's immune system somehow doesn't work as it should, her body could repel embryos causing miscarriages. The immune system could be overactive, there could be an abnormal presence of different antibodies and/or the woman could have an autoimmune disease.

The view on to what extent the immune system and miscarriages are related and what we can do about it, varies from country to country. In som countries (e.g. Sweden) doctors don't think we know enough to do immunological testing or treatment while it's common in many other countries. Dr Shehata is an example of a doctor who does research on the topic and also treats women with immunological issues at his clinic.

Q&A with Dr Shehata

1. What immunological investigations and treatments do you do in case of repeated miscarriages?

In the event of repeated miscarriages, I do six different investigations that can lead to different treatment strategies.

Natural Killer cells (NK cells)

Some types of NK cells are found naturally in the uterus, but another group of NK cells (CD16 +, CD56 +, CD69) can cause miscarriage when they attack the uterus. NK cells can also prevent embryos from attaching during an IVF treatment. This can be treated by calming these cells with immunosuppressant, reducing their effect.

TH1/TH2 Cytokines

Elevated levels of TH1 / TH2 cytokines can lead to a miscarriage. Cytokines are small proteins that are crucial in controlling the growth and activity of other immune system cells and blood cells, and affect the growth of all blood cells and other cells that help the body's immune and inflammation responses. The activity of cytokine cells can be TH1 (pro-inflammatory) or TH2 (anti-inflammatory). The pro-inflammatory cells are needed when the blastocyst is to attach in the uterus and blood vessels are formed between the embryo and the woman, but if they become too many or remain for too long, they can instead become harmful. The treatment to inhibit this is different types of immunosuppressive drugs.

Antinuclear antibodies (ANA)

People who have the autoimmune disease SLE have ANA, and may have an increased risk of miscarriage. However, people who do not have SLE can also have an immune system that behaves in a similar way. Therefore, we investigate whether women have these antibodies, and if it's the case, treat them with Prednisolone (cortisone).

Thyroid antibodies

In case of thyroid disfunction, you're often considered treated if you have antibodies against the thyroid gland (TPO-ak, Tg-ak or TRAK) and the right dose of a medicine (e.g. Levaxin). In my opinion, the risk of miscarriage is greater if antibodies remain, so I give further treatment with Prednisolone (cortisone).

Gliadin antibodies (IgA)

These antibodies are found in those who have celiac disease (gluten allergy). Even if you don't show symptoms of gluten intolerance, these antibodies can occur and be the cause of repeated miscarriages. It's treated with a lifestyle change that involves a gluten-free diet.

Anticardiolipid antibodies (APS) - "Sticky blood"

Anticardiolipid antibodies make the blood thicker and thus increase the risk of blood clots, especially in pregnant women, which can cause miscarriage both late and early. However, it is not a common cause of miscarriage (only 0.83% according to one of my studies). The treatment entails blood thinners - a low dose of acetylsalicylic acid, which you start taking before pregnancy, and then injections of heparin.

2. Why are immunological causes of miscarriage still so debated?

Immunology is very complex if we talk clinical evidence. Even for general autoimmune diseases, tests very often don't deliver clear answers. For example, for a well-known autoimmune disease like rheumatism, tests only show positive in less than 20% of patients who carry the disease. Therefore, doctors have to look at symptoms like e.g. a swollen joint rather than just blood tests. And this makes it complicated when it comes to miscarriages and failed IVF attempts.

The lack of clear clinical evidence, is what complicates the debate. There is undeniably a strong correlation between pregnancy and the immune system, and although it has historically been seen as controversial to believe that the immune system can cause miscarriage, nowadays most people are convinced that there is a connection. The main debate regards how we test and treat, rather than why we test and treat. It's a discussion that will continue and the most important thing is that continued research is done within the area.

3. Is there an increased risk of miscarriages if you have rheumatism or another autoimmune illness?

In general, yes, if you have an autoimmune issue then there is an increased risk of miscarriages and it’s important to be tested for the cells related to your particular illness. There are certain immune disorders that are particularly associated with a much higher risk of miscarriage such as Lupus Disease.

4. What is an autoimmune disease?

Briefly explained, an autoimmune disease means that the body attacks itself. Antibodies are present in the body to protect us from viruses and bacteria. They are formed by different types of immune cells. For people who have an autoimmune disease, the body's immune system instead begins to break down cells that we need. The immune system mistakenly believes that these cells are invaders in the body.

About 5-7% of the population in the western world is affected by some type of autoimmune disease, and women are affected much more often than men. Examples of autoimmune diseases are type 1 diabetes, Hashimoto's (hypothyroidism / underactive thyroid), SLE (Lupus), rheumatoid arthritis (rheumatoid arthritis), celiac disease (gluten intolerance), Crohn's disease, Sjögren's disease and Addison's disease.

5. Can immunological disorders cause repeated implantation failure?

Yes, implantation failure could be considered a very early miscarriage and if the issue is not the embryo or anatomical abnormalities it is worth looking into.