Immunomodulation of the Endometrium Using Oral Prednisolone in Pregnant Women with Unexplained Recurrent Miscarriage and Normal or High Level of Uterine Natural Killer (uNK) Cell Density in the Endometrium: A Randomized Controlled Trial

Abstract

Miscarriage is defined as the spontaneous loss of pregnancy before the fetus reaches viability. The term therefore includes all pregnancy losses from the time of conception until 24 weeks of pregnancy. Recurrent miscarriage is different from sporadic spontaneous miscarriage and is defined as the loss of three or more consecutive pregnancies and affects 1% of couples trying to conceive (RCOG: Green-top Guideline No. 17, 2011). Despite a wide range of investigations, no apparent cause is found in more than 50% of women with recurrent miscarriage and they are categorized as idiopathic or unexplained recurrent miscarriage (Li et al., 2002, Quenby et al., 1993). An abberant immune response- either auto- or alloimmune- has been postulated to underlie some cases of unexplained recurrent miscarriage and a variety of immune tests for reproductive failure have been introduced into clinical practice (RCOG: Scientific Impact Paper No. 5, 2008). Uterine NK cells are the most predominant leucocytes in the endometrium and their density varies throughout the menstrual cycle. Uterine NK cell density increases in number towards the mid-luteal phase and peaks in early pregnancy if implantation occurs (Bulmer et al., 1991). Uterine NK cells accumulate as a dense infiltrate at the implantation site near stromal cells, glands, blood vessels and trophoblast cells in early pregnancy (King et al., 1991). It is the intensity of CD56 antigen expression and the lack of two typical NK cell markers- CD16 and CD57 antigens, that differentiate uterine from peripheral NK cells. Around 80% of uNk cells are CD56bright and CD16- whereas 90% of PBNK cells show opposite characteristics; they are CD56dim and CD16+ (Nagler et al., 1989, King et al., 1991). Increased density of uNK cells in pre-implantation endometrium has been found in women with recurrent miscarriage compared to fertile controls (Clifford et al., 1999, Quenby et al., 1999&2005, Tuckerman et al., 2007). In a prospective study carried out in Liverpool investigated 85 women with unexplained recurrent miscarriage and 18 women with two or more normal pregnancies for uNk cell density via mid-luteal phase endometrial biopsy. The normal range of uNk cells was defined using the upper end of the inter-quartile range for the 18 control women. Thus, women with more than 5% uNk cells per stromal cell were considered to have high levels (Quenby et al., 2005). High numbers of uNk cells in pre-implantation endometrium of women with unexplained recurrent miscarriage can be reduced with administration of prednisolone 20 mg per day for 3 weeks (Quenby et al., 2005).