In some cases NK cells may stop an embryo implanting in the womb
Suffering a miscarriage can be a very distressing experience but for many women their next pregnancy is a normal one. For women, however, who suffer recurrent miscarriage, where they have three or more in a row, it can be utterly devastating.
More frustrating still is that in many cases – more than half – doctors are unable to find an underlying cause or offer more than just a handful of options for treatment.
Now researchers from Warwick University claim to have made a breakthrough. Not only by making a firmer case for the role of natural killer (NK) immune cells in some cases of recurrent miscarriage, but also in bridging the gap between scientists and the medical profession in what has become a controversial area of research.
Despite their name, NK cells actually play a beneficial role in the development of an embryo. But abnormally high levels of NK cells are found in the uterus of some women (around a sixth) who recurrently miscarry. NK cells are a key player in the innate immune system, which can be triggered to defend the body from infection. One theory is that in some cases they may stop an embryo implanting in the womb.
However, little is known about this mechanism. And the potential role that NK cells might play in recurrent miscarriage has caused significant controversy.
The authors of the new study, published in The Journal of Clinical Endocrinology & Metabolism, make a link between more NK cells in the lining of the womb and a deficient production of natural steroids. Having this deficiency in turn leads to a reduction in the formation of fats and vitamins that provide essential nutrition during pregnancy. They suggest that NK cells can be used as an indicator of steroid deficiency.
Steroids, which are thought to work by reducing the percentage of NK cells in the womb, are commonly used as a treatment for recurrent miscarriage and do appear to help some women to go on to have a normal pregnancy. But many experts agree this is based more on empirical evidence that a firm scientific understanding.
Siobhan Quenby, Professor of Obstetrics at Warwick Medical School and one of the authors of the study, said treatments for recurrent miscarriage often came “out of guesswork, not science” and said the research provided an “excellent scientific justification for steroid-based treatment to prevent miscarriage.”
“If you have NK cells in the blood they do things like fight infection. In the uterus they also have a good function – for example they help in the development of the blood supply to the foetus.
“But we now have some light at the end of the tunnel; in some ways everyone is right. NK cells are good but high end NK cells are also associated with local steroid deficiency.”
Quenby said that the research suggests the deficiency causes an increase in the higher percentage of NK cells, rather than the other way round.
Nick Macklon, Professor of Obstetrics and Gynaecology at Southampton University and an expert in IVF, said: “The problem is that we haven’t really understood the mechanisms behind recurrent miscarriage. We now know that an important determinant is the lining of the womb and how it helps embryos to implant. A lot of treatment has been empirical, adopting theoretical treatments not on the science.
“Quenby has done a lot of work to try and understand the role of NK cells, which hasn’t been very clear. The key thing is that the researchers aren’t saying they are bad but when there’s an increase it might be a useful marker. It could allow for treatment to be rationalised. Steroids have side effects and have been used very blindly. But they do seem to make a difference and also to the needs of doctors and patients looking for help.”
Macklon said recurrent miscarriage was probably caused by a number of different factors across different cases. “One possible cause is the ability of the lining of the womb to recognise and select good embryos and in some women it isn’t able to do this early enough.”
A previous small randomised trial carried out by Quenby showed a marked difference in the chances of going on to have a baby in a group of 20 women treated with steroids versus an identical sized group given placebos. But she admits that to draw solid conclusions, a trial size of around 700 women is needed.
Kuroda K, Venkatakrishnan R, James S, Sucurovic S, Mulac-Jericevic B, Lucas ES, Takeda S, Shmygol A, Brosens JJ, & Quenby S (2013). Elevated Periimplantation Uterine Natural Killer Cell Density in Human Endometrium Is Associated With Impaired Corticosteroid Signaling in Decidualizing Stromal Cells. The Journal of clinical endocrinology and metabolism PMID: 24025400