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.
'Adding Up What We Know: A Global Perspective on Fertility Treatment Add-Ons', taking place next week on Wednesday 26 January – register here.
'Prioritising Patient Safety: How to Minimise Risk in Fertility Treatment', taking place next month on Wednesday 9 February (with Professor Ashley Moffett on the speaker panel) – register here.