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      Prednisolone Trial: Study protocol for a randomised controlled trial of prednisolone for women with idiopathic recurrent miscarriage and raised levels of uterine natural killer (uNK) cells in the endometrium

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      Trials
      BioMed Central

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          Abstract

          Background

          Idiopathic recurrent miscarriage is defined as 3 consecutive pregnancy losses with no contributing features found on investigations. At present there are no treatments of proven efficacy for idiopathic recurrent miscarriage. Uterine natural killer (uNK) cells, the most predominant leucocyte in the endometrium are adjacent to foetal trophoblast cells and thought to be involved in implantation. The exact mechanisms of how uNK cells affect implantation are not clear but are probably through the regulation of angiogenesis. Multiple studies have shown an association between high density of uterine natural killer cells and recurrent miscarriage. We have shown that prednisolone reduces the number of uNK cells in the endometrium. The question remains as to whether reducing the number of uNK cells improves pregnancy outcome.

          Methods

          We propose a randomised, double-blind, placebo controlled trial of prednisolone with a pilot phase to assess feasibility of recruitment, integrity of trial procedures, and to generate data to base future power calculations. The primary aim is to investigate whether prednisolone therapy during the first trimester of pregnancy is able to improve live birth rates in patients with idiopathic recurrent miscarriage and raised uNK cells in the endometrium. Secondary outcomes include conception rate, karyotype of miscarriage, miscarriages (first and second trimester), stillbirths, pregnancy complications, gestational age at delivery, congenital abnormality and side effects of steroids. The trial has 2 stages: i) screening of non-pregnant women and ii) randomisation of the pregnant cohort. All patients who fit the inclusion criteria (<40 years old, ≥3 consecutive miscarriages with no cause found and no contraindications to prednisolone therapy) will be asked to consent to an endometrial biopsy in the mid-luteal phase to assess their levels of uNK cells. Women with high levels of uNK cells (≥5%), will be randomised to either prednisolone or placebo when a pregnancy is confirmed. Follow-up includes 2 weekly ultrasound scans in the first trimester, an anomaly scan at 20 weeks gestation, growth scans at 28 and 34 weeks gestation and a postnatal follow-up at 6 weeks.

          Trial Registration

          Current Controlled Trials ISRCTN28090716

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          Most cited references24

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          Recurrent miscarriage.

          Many human conceptions are genetically abnormal and end in miscarriage, which is the commonest complication of pregnancy. Recurrent miscarriage, the loss of three or more consecutive pregnancies, affects 1% of couples trying to conceive. It is associated with psychological morbidity, and has often proven to be frustrating for both patient and clinician. A third of women attending specialist clinics are clinically depressed, and one in five have levels of anxiety that are similar to those in psychiatric outpatient populations. Many conventional beliefs about the cause and treatment of women with recurrent miscarriage have not withstood scrutiny, but progress has been made. Research has emphasised the importance of recurrent miscarriage in the range of reproductive failure linking subfertility and late pregnancy complications and has allowed us to reject practice based on anecdotal evidence in favour of evidence-based management.
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            Natural killer cells and pregnancy.

            The fetus is considered to be an allograft that, paradoxically, survives pregnancy despite the laws of classical transplantation immunology. There is no direct contact of the mother with the embryo, only with the extraembryonic placenta as it implants in the uterus. No convincing evidence of uterine maternal T-cell recognition of placental trophoblast cells has been found, but instead, there might be maternal allorecognition mediated by uterine natural killer cells that recognize unusual fetal trophoblast MHC ligands.
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              Oxygen measurements in endometrial and trophoblastic tissues during early pregnancy.

              Placental and endometrial partial pressures of oxygen (PO2) were measured using a polarographic oxygen electrode during the first trimester of pregnancy. Between 8-10 weeks' gestation, placental PO2 levels were significantly lower (P less than .001) than endometrial levels. A significant (P less than .001) increase was observed for placental PO2 values measured at 12-13 weeks compared with those obtained at 8-10 weeks. We suggest that the increase of placental PO2 at the end of the first trimester is related to the establishment of continuous maternal blood flow in the intervillous space.
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                Author and article information

                Journal
                Trials
                Trials
                BioMed Central
                1745-6215
                2009
                10 November 2009
                : 10
                : 102
                Affiliations
                [1 ]School of Reproductive and Developmental Medicine, University of Liverpool, Liverpool Women's Hospital, Crown Street, Liverpool, L8 7SS, UK
                Article
                1745-6215-10-102
                10.1186/1745-6215-10-102
                2785777
                19903335
                6428c080-b233-47d5-bb32-27df2e786a25
                Copyright ©2009 Tang et al; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 2 July 2009
                : 10 November 2009
                Categories
                Study protocol

                Medicine
                Medicine

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