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Analysis

Natural born killer

21 January, 2014

Natural born killer

Fertility scientists say they have made a ‘crucial breakthrough’ in understanding why some women have repeated miscarriages. Elizabeth Lynch investigates.
Midwives magazine: Issue 1 :: 2014

Fertility scientists say they have made a ‘crucial breakthrough’ in understanding why some women have repeated miscarriages. Elizabeth Lynch investigates.

I have made a very exciting find’, says Professor Siobhan Quenby. ‘I have had a lot of problems with my research, but despite their name, natural killer cells have little ability to kill other cells particularly in early pregnancy,’ she adds.

Director of the Biological Medical Research Unit in Reproductive Health at Warwick University, Professor Quenby is referring to the latest data published by her team of researchers, which shows that elevated uterine natural killer (NK) cells in the lining of the womb indicate the deficient production of steroids. This deficiency reduces the formation of fats and vitamins that are essential for pregnancy nutrition.

The issues covered in the study, published in the Journal of Clinical Endocrinology & Metabolism (Kuroda et al, 2013), have divided the scientific community for decades on just how significant NK cells are in pregnancy failure. But, says Professor Quenby, ‘after years of controversy and doubt… we have excellent scientific justification for steroid-based treatment to prevent miscarriage’.

RCM director for midwifery Louise Silverton thinks this research is interesting. ‘There is a group of women who have recurrent miscarriages where there has been no solution to their issue. Their hormones aren’t good, so we give them hormone injections, or maybe they are having abnormalities, so we will do some genetic screening. But there is still this group of women who are having up to 15 miscarriages and are very distressed about the whole thing.’

In 2006, Rachel Small, miscarriage midwife specialist at the Heart of England NHS Foundation Trust, attended a conference at which Professor Quenby gave a talk on elevated uterine NK cells. In 2010, she was invited to join Professor Quenby’s Warwick clinical trial team as the specialist midwife.

Rachel’s role on the team was to take the women’s history, scan the women every fortnight in the first few weeks to ensure the pregnancy was progressing well, and offer counselling throughout this difficult period. The women also had access to a telephone support line anytime during the day, from Monday to Friday.

Also on hand was The Miscarriage Association, which offers patient support by giving independent telephone advice and an internet chat room was set up to encourage the women to share their feelings, which proved to be popular with all the participants.

Initially, 160 women took part in the Warwick pilot. The criteria were that the woman had to be under 40, she had to have had three recurrent miscarriages, as well as negative test results to all known causes of miscarriage.

Around one woman in every 100 has recurrent miscarriages (RCOG, 2004). At present, NHS guidelines stipulate that the woman has to have three or more miscarriages before she is referred to a specialist (NICE, 2013). These checks include karyotyping and ultrasound scans, as well as blood and diabetes tests. In about 50% of all cases of recurrent miscarriages, the cause is unknown and referred to as ‘idiopathic’ (Duckitt and Qureshi, 2008).

All 160 eligible women in the pilot study were invited to be screened for an endometrial biopsy, ideally on day 21 of their cycle. A sample of the woman’s lining was taken and then sent off to the laboratory to test if the woman had high levels of NK cells.

‘It is normal for women to have NK cells because they kill infection and fight cancer – they are good things to have. However, in a small group of women they will have too many NK cells, which makes the cells a bit unhelpful,’ says Rachel.

If a woman had NK cells, but there were less than 5% in her lining, then that was considered normal; if the woman had over 5% of NK cells in her lining, this was viewed as a potential reason why she miscarried.

Professor Quenby’s 5% benchmark on NK cells resulted from research she carried out many years before, when women attended her sterilisation trial following two or more healthy pregnancies (Quenby et al, 2005).

Out of the 160 women who were screened, 72 proved to be positive for high uterine NK cells and from this figure, 40 women returned when pregnant for randomisation.

In the group of 20 women who took the steroid treatment prednisolone, there was a 60% success live birth rate against the 20 women who took the placebo, where there was only a 40% chance that the woman would go on to have a live baby.

The NK cells examination, which is similar to a smear test and can be carried out in any NHS pathology laboratory, can cost as little as £100, with another £100 fee for the consultation. In contrast, the NHS cost for the blood tests is £500 and the consultation cost is around £100.

‘Most of the time the blood test results come back as normal’, says Professor Quenby. ‘And, if they state abnormal, this doesn’t tell the GP exactly why the miscarriages occurred,’ she adds.

Consultant midwife and clinical trials manager at King’s College London Annette Briley says of Professor Quenby’s work: ‘Miscarriage is common and the causes are likely to be multifactorial. While this research looks exciting, we need to be cautious when interpreting the findings.’

Professor Andrew Shennan, consultant obstetrician for the baby charity Tommy’s, says: ‘We know that miscarriages are usually caused by a genetic mix-up in the fetus, but this is interesting research that may prove relevant for some recurrent miscarriages.

‘What we don’t know is whether the presence of high levels of NK cells are a proxy for another problem, such as the low level of steroids. More research needs to be done before we can fully determine the relationship between the cells and miscarriage,’ Professor Shennan adds.

It may be feasible to treat women with idiopathic recurrent miscarriage for high uterine NK cells using the steroid treatment prednisolone. However, Professor Quenby now needs to evidence her work by securing funding for a larger clinical trial to ensure it stands up to full and thorough scrutiny.


References

Duckitt K, Qureshi A. (2008) Recurrent miscarriage. American Family Physician 78(8): 977-78.

Kuroda K, Venkatakrishnan R, James S, Šućurović 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 & Metabolism 98(11): 4429-37. See: jcem.endojournals.org/content/early/2013/09/05/jc.2013-1977.abstract (accessed 3 January 2014).

NICE. (2013) Miscarriage. See: cks.nice.org.uk/miscarriage#!scenariorecommendation:4 (accessed 10 January 2014).

Quenby S, Kalumbi C, Bates M, Farquharson R, Vince G. (2005) Prednisolone reduces preconceptual endometrial natural killer cells in women with recurrent miscarriage. Fertility and Sterility 84(4): 980-4.

RCOG. (2004) Couples with recurrent miscarriage: what the RCOG guideline means for you. RCOG: London. See: www.rcog.org.uk/files/rcog-corp/uploaded-files/PICouplesWithRecurrentMiscarriages2004.pdf (accessed 15 January 2014).






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