title: Uterine natural killer (uNK) cells and recurrent miscarriage: a pilot randomised controlled trial of prednisolone in women with high uNK cells and recurrent miscarriage
Creators: name: Tang, Ai-Wei
Publisher: name: University of Liverpool Repository
Year: 2014

description: Recurrent miscarriage (RM) is stressful. One reason for this is because no causes can be found for the pregnancy loss in the majority of cases. Focus has been on the endometrium which undergoes decidualisation in preparation for implantation. Any problems in the finely organised interactions between the endometrium and invading trophoblast cells may contribute towards a miscarriage. Immunological mechanisms are thought to be one of the pathways involved as there is the need of maternal adaptation of her immune response to the semi-allogenic developing embryo. Uterine natural killer (uNK) cells are the most abundant in the endometrium during the window of implantation. They interact with trophoblast cells, and are involved in vascular remodelling, an important step in implantation. Hence, they have a biological plausibility of playing a major role in RM. Both peripheral NK (pNK) and uNK cells tests have been developed as assessments of immunological causes of RM. A systematic review performed showed inadequate evidence for both pNK and uNK cells tests as markers for adverse pregnancy outcomes. There were only twelve studies, with 446 patients reporting pregnancy outcomes. There was no accepted consensus of normality and methodology for analysing NK cells. The conclusion was the need for well-designed studies to assess the role of NK cell tests as a clinically useful marker for screening. This led to the conduct of the pilot phase of a RCT of prednisolone in early pregnancy in women with idiopathic RM and raised uNK cells density. The main aim of this trial was to assess feasibility of recruitment and tolerability of prednisolone. Secondary clinical outcomes included live birth, types of miscarriage, miscarriage karyotype, gestational age at delivery, birthweight and pregnancy complications (eg: pre-eclampsia, gestational diabetes, fetal abnormality, stillbirth, IUGR). 160 women were screened for uNK cells density and 40 were randomised, despite the majority (85%) desiring prednisolone if given a choice. There was a trend towards improved live birth rate with prednisolone treatment but this was not significant. There were equal numbers of biochemical, sac and fetal pregnancy losses in both groups. All completed treatment with main reported side effects in the prednisolone group of insomnia. There were no pregnancy complications. The analysis of uNK cells was found to be very time consuming. To accommodate potentially large numbers who will be screened in the definitive trial, an alternative, quicker and equally accurate method of analysing uNK cells was developed using the colour deconvolution and area measurement plug-ins of a public domain image analysis package, Image J. Women supported this trial. Randomisation was acceptable. The prednisolone was safe. UNK cell density is a valid biomarker of severe outcomes. There was a trend towards improvement in live birth rates. This trial paves the way for the development of an endometrial based test to screen for the subgroup of women with RM that could potentially benefit from individualised treatment.