As a young postgraduate in 1942, Peter Medawar was asked to look into the reason skin grafts given to injured airmen were quickly rejected by the body. His work introduced the concept of a biological ‘self’. He found that the patient’s immune system not only recognised the ‘non-self’ tissue of the graft but saw it as a hostile intruder and tried to destroy it. This led to the development of drugs to suppress the immune system, allowing human organs to be successfully transplanted. In 1960 Medawar won a Nobel Prize.
Seven years earlier, he wrote an essay on pregnancy that has left an unintentional legacy. At conception genetic material from two different individuals merges to form the embryo so that, in relation to the mother, the embryo is both ‘self’ and ‘non-self’. Medawar asked why mammalian foetuses were not rejected by the mother’s immune system. He didn’t suggest that an immune response might account for the failure of some pregnancies, but it wasn’t long before doctors drew an analogy with transplant rejection, and began to prescribe immunosuppressants to women attending fertility clinics or who had experienced multiple miscarriages.
An early intervention, known as lymphocyte immunisation therapy (LIT), involved injecting women with infusions of white blood cells from the father or another male. The injections were supposed to prevent maternal rejection of the baby by generating ‘blocking antibodies’. The treatment was fashionable in the early 1980s, but as the Aids epidemic worsened so did fears that the injections might be contaminated by HIV and other viruses. In 2002, LIT treatments were banned in the US by the Food and Drug Administration.
Another treatment soon emerged that purported to avoid the risks of LIT. An infusion was prepared by grinding up the placentas of women who had had normal pregnancies. This produced a white liquid that, like LIT, was said to generate the magical blocking antibodies. The control arm of a clinical trial to test this method used a similar-looking white liquid, Intralipid, as a placebo. Intralipid is a simple emulsion of soya bean and egg yolk used to feed sick patients intravenously. The trial was a failure and placental infusions were abandoned. But, bizarrely, Intralipid itself is still in widespread use in fertility clinics – not as a placebo, but as a treatment to improve the chances of successful pregnancy. Quite how soya beans and egg yolk might achieve this has never been explained.
Human pregnancy is unlike that of any other species, even primates. This is in part because the development of our large brains before birth requires considerable investment of maternal resources. Nutrients and oxygen are delivered to the foetus via the placenta, which the foetus itself has made. The placental cells must infiltrate deeply into the wall of the uterus – far deeper than in any other species – to open up the mother’s arteries. If the mother’s arteries are not fully opened up by the invading placental cells, the foetus will run out of resources towards the end of pregnancy, with potentially disastrous consequences, including stillbirth.
Placental invasion, essential for successful human reproduction, is remarkably similar to the invasiveness of tumours. Excessive intrusion into the uterus would have damaging consequences for the mother, so a delicate balancing act begins, in which specialised immune cells in the mother’s uterus play a key role. These maternal cells co-operate with the placental cells to form a boundary between the mother and the foetus. They ensure the invasion of the placenta is kept to the right depth to meet the nutritional needs of the foetus but protect the mother from uterine haemorrhage or other dangerous complications. Far from mediating immunological rejection of the kind observed in transplants, the uterine immune cells work with the placental cells to establish an appropriate interface across which nutrients and oxygen can flow.
The immune cells that accumulate at the boundaries of the placental cell invasion into the uterus are unique. They are not found anywhere else in the mother, and are never found in men. The identification of these cells in 1990 was an important moment for human biology. Unfortunately, in the excitement of their discovery, we called these cells ‘uterine Natural Killer (NK) cells’ because of their similarity to NK cells in the blood, which react rapidly to kill cells infected by viruses. But although the NK cells found in the uterus share some features with blood NK cells, they are very poor at killing anything. Despite this, some fertility doctors, short of treatments and desperate for answers, wilfully or unconsciously promote the theory that uterine NK cells might be a cause of miscarriage. This misconception has led to such lurid Daily Mail headlines as ‘My body tried to kill my baby.’ Uterine NK cells do not kill the foetus. In fact, because they interact with placental cells to establish the boundary across which nutrients and oxygen are delivered, they are probably essential to its survival.
The naming of these cells gave further impetus to the idea that maternal immune cells must be suppressed to improve the chances of a successful pregnancy. A long list of fertility treatments, including powerful immunosuppressive drugs normally used to treat severe autoimmune or inflammatory conditions such as rheumatoid arthritis, are now in widespread use as add-ons to conventional treatment. One of these therapies, intravenous immunoglobulins (IVIG), is prepared from the blood of thousands of individuals. It is not only a risky treatment with many side effects, but hugely expensive and in very short supply. It is tightly regulated and available for use within the NHS only by special application. For a small number of rare and dangerous conditions, it can be life-saving. It is now used to treat the very rare but potentially fatal inflammatory complications of Covid-19 seen in children. Even so, the limited supplies of IVIG have often been used in fertility clinics where they are given to healthy women to interfere with their immune systems during early pregnancy, thus depleting a scarce and valuable resource.
Other treatments on offer include high doses of steroids and the notorious hydroxychloroquine, which Presidents Trump and Bolsonaro both falsely claimed could cure Covid. And LIT is still available from private fertility clinics in the UK despite being banned in the US. One website claims that ‘the associated risks from LIT are no greater than the risk presented by any other vaccine we give ourselves to prevent infection.’ LIT is not a vaccine and it does not prevent infection. On the contrary, injecting immune cells from another individual carries an obvious risk of infection.
In the UK, more than 60 per cent of IVF takes place in private clinics where evidence-based medicine and NICE guidelines are often ignored. For most couples, this is their first exposure to private medicine. Many clinics make overblown and oversimplified claims for their therapies. Couples should be told of the potential harms of the ‘immune’ treatments on offer, and that there is no evidence of any benefits. The temptation to try anything is strong. Mysterious white liquids may be expensive but, according to the Daily Mail, they lead to ‘Mayonnaise Miracle Babies!’ The costs of add-on tests and treatments are seldom explained upfront, and it’s not made clear that many are pointless. Blood tests to count the number of NK cells in the bloodstream, for instance, can cost more than £1000, although there is no good quality evidence to suggest any connection between NK cell counts and a successful pregnancy.
A statement from bodies including the Royal College of Obstetricians and Gynaecologists, the Royal College of Nursing and the Human Fertilisation and Embryology Authority (HFEA) in 2018 came out strongly against clinics profiting from ‘add-ons’. The HFEA has more recently provided a ‘traffic light’ system for people trying to navigate this murky area. All the treatments or tests based on the theory of targeting uterine NK cells have a red light, but they are still being advertised prominently on clinic websites. In June, the Advertising Standards Agency, the Competition and Markets Authority and HFEA sent an enforcement notice to IVF clinics. One of their key concerns is that patients are not being properly informed ‘of the limited evidence base for add-on treatments increasing the chances of a live birth, or the risk associated with certain add-on treatments’. Perhaps the era of magical thinking, and selling hocus-pocus treatments to couples experiencing pregnancy failure, is coming to an end.
NK cells are our first defence against viruses. Covid has shown how vulnerable our immune systems can be in the face of a new virus, but it shouldn’t require a pandemic to alert us to the dangers of giving immunosuppressive drugs to otherwise healthy women. The HFEA last year sent a strongly worded message discouraging the use of immunosuppressive treatments by fertility clinics. Strangely enough, there was pushback from some clinics, requesting that Intralipid, the supposed suppressor of uterine NK cells, be left out because it was not immunosuppressive. Even they know it’s just mayonnaise.
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