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Immune 'add ons' in assisted reproduction

17 January 2022
By Professor Ashley Moffett
Ashley Moffett is emeritus professor of reproductive immunology at the University of Cambridge
Appeared in BioNews 1128

One of the most difficult challenges for doctors treating women with infertility or recurrent miscarriage is that no cause is found in around 50 percent of cases. A pervasive claim to explain failure to achieve a successful pregnancy is that the immune system is reacting to the embryo and rejecting it. This idea arose after scientists in the 1950s were studying why transplanted organs between unrelated individuals (who are genetically different) were rejected. The immune system can distinguish between the 'self' of the recipient's tissues and the 'non-self' of the donor's organ. The recipient's immune cells reject the transplanted organ, a response that is blocked by powerful immune-suppressive drugs that carry a risk of infection.

One scientist, Sir Peter Medawar, pointed out that although the mother and her fetus are related, they are also genetically different because half of the genetic component in the fetus is derived from the father. Medawar speculated about how the maternal immune system might adapt to allow this 'non-self' baby to coexist with the mother for nine months. However, he never proposed that the mother might ever reject the fetus causing pregnancy failure. Indeed, 70 years later, there is still no good evidence to suggest that fetal rejection ever happens.

Nonetheless, this idea was picked up by doctors working in reproductive medicine and women began to be offered treatments alleged to suppress this supposed damaging fetal rejection response. But, we now know much more about events occurring when the embryo embeds itself into the wall of the uterus (or womb) early in pregnancy. This reveals a quite different scenario to a rejecting immune response.

The fetus is always separated from the mother's blood and tissues by the placenta which is the first and largest organ that the embryo makes. The fetus depends entirely on the placenta for its growth and development. Critical to its function is the need to access the nutrients and oxygen supply from the mother. The placenta embeds itself into the wall of the uterus and taps into the crucial maternal arteries that are the supply line to the fetus via the placenta. The uterine wall is the site where the maternal and fetal tissues intermingle in close proximity and where a rejection response would be expected to occur. However, there are few of the typical components of transplant rejection (antibodies and T cells) present where the placenta implants.

Instead, unique immune cells amass at the placental/uterine interface that are related to, but different to lymphocytes circulating in the blood stream known as Natural Killer (NK) cells. NK cells in the blood are crucial in the early days of a viral infection and kill cells in the body that have become infected. Because of some similarities with blood NK cells, we named these cells 'uterine NK cells'. In retrospect, this was a mistake because there are also many differences between uterine and blood NK cells.

Crucially, uterine ones are not killers, they are not in contact with the fetus and cannot kill it or the placenta. Exactly what they do is still under investigation but they probably have a key role in drawing a boundary in the correct place in the uterus between the two individuals, mother and baby. The placental cells need to penetrate the uterine wall far enough to access the maternal arteries supplying oxygen and nutrients. In contrast, if placental cells penetrate too far, they can cause life-threatening haemorrhage and even rupture the uterus. Therefore, uterine NK cells probably mediate a compromise, balancing the needs of the baby and the mother so they both survive the pregnancy.

Why then are clinics still testing blood samples for NK cells when the ones in the uterus are quite different? These tests are pointless and give no information about what is happening during implantation. Why are drugs given supposedly to suppress uterine NK cells when their exact functions are still unknown? There is no scientific rationale for these test and treatments. They are expensive and have no proven benefit as shown by many trials. The risks of these treatments should also not be underestimated – overwhelming infections and other complications. The COVID-19 pandemic has revealed how we all depend on a fully functioning immune system, pregnant women no exception, and interfere with it at our peril.

One of the most widely used treatments has a bizarre story. Intralipid, an emulsion of soya and egg yolks, is used as an intravenous infusion for patients unable to eat normally. A trial for one immune treatment alleged to suppress the mother's rejection response used an infusion of ground-up placentas. It was never really explained how it might work. Because this liquid placental preparation was white, Intralipid, another white fluid was used as a control in the trial. Somehow later, for reasons that are hard now to understand, the control became the treatment because it seemed easier to buy a white liquid off the shelf than go to the trouble of making placental infusions. There is no benefit to this treatment as we outlined in the journal Human Reproduction in 2015.

Couples need reliable clear information and the Human Fertilisation and Embryology Authority (HFEA) has introduced a traffic light system to help them negotiate all the optional additional treatments now on offer in clinics. All immune treatments are red – lacking good evidence for their use. In the case of immune add-ons there is not even any scientific rationale to divert resources to test them. During the pandemic the HFEA advised clinics not to use any immunosuppressive treatments. Some clinics questioned why Intralipid was included as 'it was not immunosuppressive', begging the question why it was being offered in the first place?

The issues discussed in this article will be explored further in the following two free-to-attend online events.

28 March 2022 - by Joseph Hamilton 
Bed rest following embryo transfer during IVF has been linked with reduced pregnancy success...
31 January 2022 - by Sarah Norcross 
There has been much professional and public debate about the use of so-called fertility treatment 'add-ons' over the years...
20 December 2021 - by Manon Everard 
Endometrial scratching is currently being offered by 34 percent of IVF clinics in the UK, Australia, and New Zealand, according to a latest survey...
6 December 2021 - by Daniel Jacobson 
The Human Fertilisation and Embryology Authority has detailed potential updates to current laws regarding fertility treatment practices in the UK, including improved patient protection...
6 December 2021 - by Dr Eric J Forman 
A recent large randomised trial published in the New England Journal of Medicine is receiving significant attention with clinicians who are critical of preimplantation genetic testing for aneuploidy (PGT-A) claiming it provides evidence that PGT-A does not improve IVF outcomes and should not be used outside of research settings...
29 November 2021 - by Ruth Retassie 
A recent study found that preimplantation genetic testing for aneuploidy may not improve live birth rate...
9 August 2021 - by Sarah Lensen 
IVF add-ons are procedures, techniques or medicines which can be used in addition to standard IVF protocols. They are usually offered by IVF clinics, and used by patients, with the hope that they will improve the chance of IVF success...
Comment ( - 17/01/2022)
Unfortunately, much I sympathise with this perspective, the unfortunate truth is that 80% of autoimmune disorders are diagnosed in women and it takes, on average, 4.5 years to get a diagnosis.

As a result, logic suggests there will be a significant numbers of women who enter fertility treatment with undiagnosed and untreated autoimmune and other immune-related disorders.  In my case, I had been struggling to work for four years when I was prescribed Humira by a fertility clinic, which dramatically reduced my disease symptoms literally overnight.  I subsequently took Intralipids as an immunomodulator and fell pregnant naturally four months later after three years of unexplained infertility. I was also able to return to full-time work for the first time in four years during my pregnancy as a result of being treated with Humira and, later, IVIG. 

I went back again for further immune treatment after trying for a year for a second child because, by that point, I had been running 38 degree C + fevers every morning for two months. Again, my fevers, joint pain, profuse rashes and other symptoms were treated successfully by throwing Humira, IVIG and Intralipids at them and, within a few months, I had a successful natural FET on my first IVF.

Having now seen two rheumatologists (one a specialist in seronegative autoimmune disorders) and a specialist in autoinflammatory diseases, I still have no diagnosis due to the rarity of my condition, but it seems to be an innate immune system dysfunction of some type.  As I have no diagnosis, I can’t get treatment on the NHS and, unfortunately, the only way I’m currently getting any treatment for what is a deeply unpleasant and life-limiting recurrent fever syndrome is because I’m also trying for a third child.

This is totally shocking and it is not appropriate that IVF clinics should be treating these diseases due to the failure to treat them in the normal course of healthcare, but it is MUCH more complex than healthy women being immunosuppressed inappropriately with add-ons.

Regardless of mechanisms (and we actually know VERY little about the immune system), common sense would suggest that untreated immune disorders will affect fertility for the same reason many other untreated diseases affect fertility and, I suspect, the anecdotal *successes* of immune treatments come down simply to that.
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