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Recurrent miscarriage

Miscarriage is the most common complication of pregnancy.

It has been estimated that one in three of all implanting embryos are lost before six weeks of pregnancy. In addition, more than 10% of more advanced pregnancies end in miscarriage. Most distressing, a significant number of couples find history repeats itself and they have three or more repeated miscarriages. In addition to the physical trauma, miscarriage, and especially recurrent miscarriage, is a major cause of psychological stress, with a third of women suffering from clinical depression or severe anxiety. Moreover, a history of recurrent miscarriages increases the risk of a variety of problems in a subsequent pregnancy, including preterm delivery, low birth weight, physical handicap and even death of a baby.

Miscarriage can be caused by chromosomal abnormalities in the embryo or because the mother has some problem. Although numerous anatomical, endocrine, immunological, clotting and genetic abnormalities have been associated with recurrent miscarriages, none of these are specific or particularly common. Moreover, for most of these conditions, the mechanisms that would account for this persistent loss of life are either entirely speculative or simply unknown.

In collaboration with the Recurrent Miscarriage Clinic at St Mary’s Hospital (Professor Regan and Mr Rai), the IVF unit at Hammersmith Hospital (Mr Trew and Mr Lavery), and researchers at the Universities of Utrecht (Professor Heijnen) Southampton (Professor Macklon) and Warwick (Professor Quenby), we have discovered an entirely novel mechanism that accounts for miscarriages, irrespective of whether the embryo is chromosomally normal or not.

Professor Brosen’s group has established that the lining of the womb is capable of recognising and responding to abnormal embryos but only when adequately prepared for pregnancy. This process is termed ‘decidualization’. Second, we found that the ability of the lining of the womb to decidualize (to prepare itself for pregnancy) is defective in women suffering from recurrent miscarriages. Combined these observations indicate that impaired decidualization and lack of embryo quality control at the time of implantation is the primary cause of miscarriage.

Our findings explain why many women suffering from recurrent miscarriages report that they become pregnant very easily yet are unable to carry the pregnancy. As decidualization is essential for the formation of a functional placenta in the first trimester of pregnancy, our model also explains why the likelihood of miscarriage drops markedly after the first 12 weeks. Finally, abnormal decidualization and lack of embryo quality control predict that many patients will experience a mixture of chromosomally normal and abnormal pregnancy losses, which turns out to be exactly the case.

As a result of ground-breaking research, we confirmed the ability of cells of the lining of the womb to initiate a pregnancy response. All that is needed is the examination of a small piece of the lining under a microscope. This raises a number of exciting clinical opportunities which include sophisticated large-scale analyses to discover ‘markers’ in the lining of the womb that predict subsequent adverse pregnancy outcome. By studying decidualization in the laboratory, we can now research new ways of enhancing the process of endometrial preparation before implantation. These studies will help predict and prevent pregnancy complications. Such a strategy may change the treatment of women at risk of late obstetrical complications, such as pre-eclampsia and preterm birth, as well as early pregnancy failure.