Unfortunately miscarriage is a fact of life, however, it can be a devastating fact of life for those that it impacts. Particularly if it happens repeatedly. We sit down with Dr Hassan Shehata a recurrent miscarriage specialist. Dr Shehata is also Medical Director and Founder of  the Centre for Reproductive Immunology and Pregnancy Miscarriage Clinic. His research and pioneering approach, increasingly goes against the established notions behind why this happens to some people. His rates of success are astounding. So, we wanted to discover what exactly is so different about his approach and why it works for so many people….

Q: Firstly, more broadly, are you seeing more miscarriage? 

A: Yes definitely, but I think one of the main reasons is because people have become more confident. More open in reporting it vs even ten to twenty years ago. Also, with the new development in pregnancy tests and the increase in their sensitivity we are now picking up even chemical pregnancy earlier. In the past, people wouldn’t have picked it up. Many wouldn’t have known they had miscarried. We are also doing earlier scans. 15-20 years ago people wouldn’t typically have a scan at 12 weeks so could miscarry before they even realised they have been pregnant. 

What about getting older when we have kids? The fact is that as you get older you have less chromosomally normal eggs. Is this another reason?

It is a possibility. However, I’m not sure it is responsible for recurrent miscarriage. That being said of course it can increase miscarriage risk. We do know that as women get older (+40yrs) there is an increased risk of chromosomal abnormality and therefore miscarriage. For men, it is slightly different, it takes a little longer with greater risk from +60 years old. It may well be worth profiling it a bit further in our own data. What I do see however is that women are postponing getting pregnant. That means lower chance of getting pregnant and more miscarriage. For example, when I look at my list today,  I can see mainly women in their mid 30s and early 40s. No one in their twenties. 

Your approach is different and you have amazing results: can you tell us a bit more about what you do that is so different? 

It is perhaps more holistic for one thing. It is also different in the sense that I look at both the female and the male partners. Traditionally no one looks at the male side. The old way of thinking is that if a sperm is good enough to achieve a pregnancy then it is good enough for the pregnancy to carry on. However there is really no scientific basis for that at all. Also, when we look at infertility ⅓ of the cause is male, ⅓ female and ⅓ is unexplained. Despite this, when it comes to recurrent miscarriage, we seem to ignore the male side completely. This just doesnt make sense. We now know that male side definitely contributes to miscarriage. Particularly when it comes to something known as sperm DNA fragmentation. This is how much DNA damage occurs within the sperm. Standard procedure for fertility patients is semen analysis: how many sperm, what they look like and how they swim. From a miscarriage point of view, my approach is to look at how much damage there is within the sperm. I believe this is a fundamental consideration. 

Is this damage caused primarily by oxidative stress (click here for more on what this is and how it matters) and how much would you say this is a function of lifestyle? 

Yes, I would say oxidative stress it is a big factor. I’m not sure about ‘modern’ because theoretically that should be good. However, for sure things that affect this are smoking, possibly vaping. We don’t know this for sure, but interesting I am seeing more patients that vape, particularly men in my clinic. Alcohol, excessive exercise, excessive cycling – anything that really heats the scrotum (including hot baths/hot tub and sauna). Plus of course people’s occupation. Age can also contribute to this. So this is one area I do differently. Tommy’s campaign has pledged £2m for research into sperm DNA fragmentation and we are going to be one of the centres to work on this but we investigate and treat this. 

Then when it comes to women, how is your approach different? 

So there are two things here. Miscarriage and Recurrent Miscarriage (often described as three consecutive pregnancy losses). The main cause of miscarriage is chromosomal abnormality. However, when it comes to recurrent miscarriage the conventional/established view is that it is caused by what is known as Thrombophilia – also known as ‘sticky blood’. There has been a lot of investigation into this. I do not believe this is the majority of the cause.

What is sticky blood/Thrombophilia? Why do you believe this doesn’t really explain recurrent miscarriage for the most part? 

Starting with what it is: in order for our blood to run properly we need factors that make our blood thin and factors that make our blood sticky. That balance between thin and sticky keeps it going round the body and nourishing the cells. It is also enough to ensure that if we cut our hand, we don’t bleed to death. Interestingly, when a woman falls pregnant the blood stickiness goes up about 2-3x. That is even before a woman discovers she is pregnant. This is a survival mechanism, essentially to make sure that during birth no one bleeds to death. There was a nice computer model simulation done a few years ago to look at the blood to assess what would happen if the blood didn’t do this. It projected that around 30-50% of women would have died at the time of delivery without it!

So, this stickiness essentially allows the woman not to have a severe hemorrhage at the time of birth. Theoretically therefore, if someone has pre existing ‘stickiness’ and then gets pregnant that extra stickiness on top could be enough to cut the blood supply and potentially cause a miscarriage. 

However, let’s take a look at the facts: 

A Thrombophilia screen consists of 80% genetic link (ie genetically inherited) and 20% acquired. There is now clear evidence that the inherited/genetic Thrombophilia has no relationship to miscarriages. There have been several small studies previously, but we presented our data in June in the Royal College World Congress and have shown on 2000 samples of women, that the prevelance of these genetic Thrombophilia is the same in the miscarriage population vs the general population. Which means we can categorically confirm that there is no increased prevelance in this miscarriage population. There have been a lot of studies looking at the treatment for these patients (blood thinners ie. Heparin), similarly there is evidence that it does not work. 

Then you have the acquired (ie. non genetic/inherited) form also known as Antiphospholipid syndrome. I also think this is an over exaggerated cause of miscarriage. I can tell you yesterday I saw a patient who was diagnosed with it pretty confidently, was given blood thinners, but still miscarried.

When you said acquired: you mean it just happens? 

Antiphospholipid syndrome is the number one cause of young adult stroke, young adult deep vein thrombosis and pulmonary embolism. In the general population however, it affects 0.4%. In some other studies it has been classified as low as 0.04%. So it is actually really quite rare. In terms of miscarriage studies it hovers between 1-5-2% of patients. Therefore we have 98% of the population with no diagnosis so this ‘sticky blood’ thesis as a ‘major cause’ is not right. Only around 2% should in reality be receiving blood thinners and are likely to be affected by this condition. 

So what about the other 98%? 

This is where my approach comes in. Will chromosomal abnormalities happen recurrently in people experiencing several miscarriages? Statistically unlikely. What about hormonal imbalances ie. abnormal thyroid/prolactin/PCOS? It is unlikely to cause such a high number. It is also unlikely because in order for you to have such a severe imbalance you are unlikely to conceive in the first place. Therefore one has to refocus on what else can cause an imbalance. This is where the immune system comes in but where there is a lot of controversy. 

My argument is assume that the immune system has no role – what else is causing miscarriage? We know sticky blood is only around 2%, hormonal imbalances are probably around 20% so what about the remaining 80%? There has to be a reason for this….

We presume that if there is a suspected serious hormonal imbalance there would be testing and treatment of that anyway?

Correct, so what about the other 80-90% of women experiencing recurrent miscarrage? This is where people need to come off their high horses and accept that the immune system has an important role. We know the immune system has a very important role in pregnancy. Think of it this way: how on earth does a woman not reject that embryo given foreign genetic material coming from the father? Even more, nowadays with egg donation becoming more commonplace, you have a completely ‘foreign’ entity within the body. How does it not get rejected?

We now know that natural killer cells and Toll-like receptors have an important role managing and protecting the pregnancy. The theory we have when it comes to multiple miscarriage is that that these cells are either more aggressive or higher in number. We think it is principally more aggressive in function. Essentially wrongly identifying the pregnancy as foreign, attacking it and causing a miscarriage. Similar to rheumatoid arthritis, Celiac etc. So the immune system attacks the pregnancy thinking it is foreign. 

How do you diagnose and treat this?

The diagnosis: people have moved on from when we were attacked 10-15yrs ago saying we were making things up or ‘quack doctors’. Now people accept that the immune system plays a role. However, the next controversy is how you actually test this? Do you do endometrial testing or blood testing? Again we have published several papers on this and we have moved away from natural killer cell counting (numerical assessment) and now look more at the function. It looks as though counting cells is not that reliable. For example, we have found it differs a lot even within a person (depending on cycle/other factors) so instead we actually we look more at how aggressive these cells are. We have managed to consistently show the levels around this. In fact, we have published a paper on it. We are were the first people in the world to establish what the ‘normal’ level is.

The next issue is treatment:

Where I have maybe created a revolution in treatment is that I start pre conception. I have certainly been the first person in the world to do this. Historically everyone else (even with Thrombophilia) were treating at the first sign of a positive pregnancy test. The trouble here is that the immune system is active all the time. It doesn’t play fair. It is not a referee waiting for a match to start. It will attack before a woman may even realise she is pregnant. So, when a woman discovers she is pregnant and has a high level of immune aggression it may already be too late. So, I have created a programme of starting treatment ahead ie. pre conception. 

This whole notion of our immune system being ‘too aggressive’ or misfiring. Is this linked to other autoimmune conditions? Does having one make you more vulnerable to this problem? Ie. If you have Celiac disease for example? 

Good question. We haven’t seen that necessarily. Not all people with these aggressive cells have a history of autoimmune conditions themselves or within their family and vice versa. So, I am not sure that is the case. However, we do know that chronic immune conditions can also lead to miscarriages just with their own antibodies. For example there is a higher risk of miscarriage with higher thyroid antibodies and with Celiac disease etc. 

So how do you actually treat someone? 

The principal is really important. Number one is preconception treatment. So, if someone asks me what has made a big difference in our success rate? It’s this. Plus, continuation of treatment to a stage where we feel it is safe to do so. The most common type of miscarriage is the first trimester loss. We normally start to wean off the treatment around 12 weeks because by this stage the baby and the placenta have started to produce their own immune calming substances. 

On this preconception treatment, you started by saying ⅓ of the issue is male and DNA fragmentation. So we presume you do a different treatment for men? What does this look like? 

So for the woman there is preconception medication. This is mostly steroids ie.  Prednisolone, which is very safe. Most of it does not cross the placenta and there is enough evidence to suggest that it is safe for pregnancy. We do not have evidence that it increases the risk of cleft lip/palate. Personally I have never seen any incidence and I have been treating people for a very long time. Another drug we use is something called Hydroxychloriquine. This is something I discovered as well. It is an immune modulator mainly used for things like Lupus (also a malaria drug) as well as a couple of others.

On the male side: it depends on how severe the abnormality is. The first thing we do is to test. We look at three parameters something called the low Comet score which is where we like the sperm to come from – the low score is the ‘good’ type. High comet score is the mostly damaged and the one in the middle is the average. You can’t choose the sperm. So, we try to increase the number of the ‘good’ type, by changing lifestyle and doing further investigation ie. urine test to check for hidden infection or varicose veins in the scrotum which can increase heat. There are a few tricks. For example gibing ready made antioxidant. We however have decided to go with medications that make your body produce its own antioxidants rather than giving antioxidants direct. 

So that would be something like N-Acetyl Cysteine for example?

Correct yes. We have seen evidence that if you take antioxidants that you don’t need it can actually cause further damage. This is why we prefer the body to produce its own as a first line. It is still a grey area. We are trying to develop in the lab more testing to choose the right and best medication for the individual. 

Do you test level of antioxidant in the blood?

No we don’t do the level of antioxidant, we test the sperm. There is something called Oxidative stress test and we are developing this test further. You look at the sugar content and that will tell us what the stress is of the sperm. 

What do your rates of success look like given this approach? 

Our success rate is around 80%. Of those who miscarry in our treatment programme if we manage to do a procedure and subsequent genetic testing 80-90% of the results come back with a chromosomal abnormality which means the treatment has not failed that is just bad luck/age etc. 

Some people have a genetic trait that they cannot absorb Folic Acid (MTHFR), if you did have that abnormality and you didn’t have aggressive killer cells could that be a reason for miscarriage? 

I dont think so, first of all 40% of the population are carriers and we dont have 40% miscarriage rate, then for those who miss both sides of the gene I haven’t seen evidence that this can cause recurrent miscarriage. However, I do treat my patients with extra Folic Acid if they have that trait – you can use either high dose Folic Acid or Methylfolate. 

You talk a lot about the immune system and the explosion of research around the microbiome and its impact on immune health. What is your view? 

The science isn’t there yet, but it is certainly an area I am very interested in. Actually it is one of my to-do things for this year because I have a great relationship with Professor Catharine Williamson at St Thomas’ who has done a lot of work on this. It is something I am going to try and explore alongside her to see what we can do related to recurrent miscarriage. No one has looked at it yet, but certainly it is an area of great interest to me. So yes, there will be something because it looks like it is affecting a lot of other autoimmune conditions. I am just not sure we are there quite yet – lots of unanswered questions but I am definitely interested in exploring it. 

For further information on Dr Shehata click here.

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