The definition of recurrent miscarriage is a loss of three consecutive pregnancies before the 20th week of gestation. Recurrent miscarriage affects approximately 1% of the population (Regan and Rai 2000) and causes immense sadness and distress. In about 50% of cases the reason for, and therefore the provision of treatment for recurrent miscarriage in unknown. Reasons for recurrent miscarriage may be roughly divided as due to abnormalities in the embryo or abnormalities in the mother.
Known causes of maternal abnormalities include blood clotting disorders, autoimmune defects, hormone disorders and defects in the lining of the womb (Li 1998, Regan and Rai 2000, Li et al 2002).
Figure 1. Tissue section of human endometrium in the secretory phase made visible with a blue stain called haematoxylin. The glands are tube like structures that open onto the surface of the womb.
The average woman has a monthly cycle from menstrual period to menstrual period of around 28 days. Directly after a menstrual period the lining of the womb or endometrium is thin and the glands that are contained within it are small and underdeveloped. During the first (or proliferative) half of the cycle the glands and the cells in which they are embedded grow in size and number. This growth is predominantly controlled by oestrogens. In the middle of the menstrual cycle, about 14 days after the last menstrual period, a change occus in the endometrium in preparation for acceptance of a fertilised egg. Growth stops and the glands start to produce various substances which are believed to be required for successful embryo implantation. In addition white blood cells that are unique to the endometrium increase in number. These cells are believed to be involved in regulating implantation of the embryo into the endometrium and the formation of the placenta. This second (or secretory) phase is under the control of progesterone.
I work on identifying whether there are differences in the secretory endometrium in women who suffer from unexplained recurrent miscarriage compared to women with an uncomplicated history of childbirth.
Figure 2. Immunostaining in tissue sections of human endometrium. The blue cells are negative, areas of brown staining show the presence of a) LIF and b) IL-6.
Initially my work focused on substances produced by the endometrial glands. We and others have shown that levels of placental protein 14 (PP14, glycodelin A) (Dalton et al 1998) , leukaemia inhibitory factor (LIF) (Laird et al 1997), interleukin 1 (IL-1), interleukin 6 (IL-6) (Cork et al 1999) are lower in some women who suffer from unexplained recurrent miscarriage compared to women with normal fertility.
Figure 3. Immunostaining in tissue sections of human endometrium. The blue cells are negative, the CD56+ cells stain brown a) CD56+ natural killer cells in a woman with recurrent miscarriage. b) CD56+ natural killer cells in a woman with repeated implantation failure after IVF.
We are currently investigating the role of white blood cells in implantation, especially the levels of CD56+ or uterine natural killer cells in the endometrium during the ‘window of implantation’ (the time when the embryo would be expected to implant). Previous research has suggested that high levels of these cells may predict recurrent miscarriage (Quenby et al 1999). Our most recent findings show that although levels of uterine natural killer cells appear to be higher in some women with recurrent miscarriage, a high number of cells does not predict miscarriage. In fact, some women with high numbers of natural killer cells have a normal pregnancy resulting in a live baby.
In addition, we have found that some women who repeatdly do not become pregnant after in vitro fertilisation also have high numbers of uterine natural killer cells, and we are investigating the reason and significance of this finding.
Tuckerman E., Laird S.M., Prakash A. and Li T.C. (2007) Prognostic value of the measurement of uterine natural killer (uNK) cells in the endometrium of women with recurrent miscarriage. Hum. Reprod (in press).
Cork B., Tuckerman E.M., Warren M.A., Li T.C. and Laird S.M. (1999) Expression of LIF in endometrial cells of normal fertile women and women who suffer from recurrent miscarriage. Hum. Reprod. 14, P174.
Dalton C.F., Laird S.M., Serle E., Saravelos H.G., and Li T.C. (1998) Endometrial protein PP14 and CA125 in recurrent miscarriage patients; correlation with pregnancy outcome. Hum. Reprod. 13, 3197-3202
Laird S.M., Tuckerman E.M., Dalton C.F., Dunphy B.C., Li T.C. and Zhang X. (1997) The production of leukaemia inhibitory factor (LIF) by human endometrium; presence in flushings and production by cells in culture. Hum. Reprod. 12, 569-574
Li T.C. (1998) Guides for practitioners Recurrent Miscarriage: principles of management. Hum. Reprod. , 13, 478-483
Li T.C., Mackris M., Tomsu M., Tuckerman E.M., and Laird S.M. (2002) Recurrent miscarriage, aetiology, management and prognosis. Hum. Reprod. Update , 8, 463-481
Quenby S., Bates M., Doig T., Kewis-Jones D.I., Johnson P.M., and Vince G. (1999) Pre-implantation endometrial leukocytes in women with recurrent miscarriage. Hum. Reprod., 14, 2386-2391.
Regan L. and Rai R. (2000) Epidemiology and medical cause of miscarriage. Bailliere’s Clin. Obstet. Gynaecol., 14, 839-854
