A possible molecular basis for recurrent miscarriage identified

January 16, 2013Carole No Comments »

When we think of infertility, we immediately think about the problem of not being able to get pregnant. But getting pregnant is not the same as having a child. The other end of the sharp stick in the eye that is infertility is the problem of getting pregnant- sometimes easily- but not being able to maintain the pregnancy. The problem of recurrent pregnancy loss is a no less distressing form of infertility. This article offers some support and additional links  for patients suffering from recurrent pregnancy loss.

A paper published in PLOSOne, “Disordered IL-33/ST2 Activation in Decidualizing Stromal Cells Prolongs Uterine Receptivity in Women with Recurrent Pregnancy Loss” describes the identification of a signalling molecule (IL33) which appears to be important for normal implantation to occur and when dysregulated, may result in early miscarriage.

To understand this study, it is important to understand how implantation works. The uterus is not one uniform organ, but is made up of layers of various cell types. Think of the uterus as a frosted layer cake. The icing is the topmost layer of the cake just as uterine epithelial cells are the topmost layer of cells lining the uterus on the inside. These uterine epithelial cells contain docking proteins for the early blastocyst to attach itself to. After attaching to the sticky uterine epithelial layer (the frosting) , the embryo begins to invade deeper into the next lower cell layers (the stromal cells) or cake layers below the frosting. Okay, maybe a tortured analogy–I must be hungry– but I want you to imagine the uterus in 3D.

These invading trophoblast cells cells continue their progress,  eroding the blood capillaries of the stromal layer as they move deeper into the stromal cells so that the embryo has access to nutrients in the blood since there is no placenta formed yet. This blood-letting by the invading embryo also explains why some women experience spotting around the time of implantation.  By the 13th day after implantation starts, the embryo is fully embedded and has established the most primitive beginnings of a circulatory system between the uterus and the earliest placenta-like structure. Here’s a link to a diagram of human implantation in the earliest stages with lots of technical detail and jargon. Here’s another- less technical- explanation here.

As the embryonic  invasion continues, a cascade of signalling events begin which cause some of the uterine stromal cells to respond by transforming into a cell type called a decidual cell. The process of transformation of a stromal cell to a decidual cell is called decidualization. Decidualization is necessary to convert the lowly stromal cell into a lush secretory cell that pumps out molecular signals that further support the pregnancy. Some of these secretory signals include interleukin 33 which, according to this new report,  seems to play a role in limiting the decidual response and thus limiting the  length of the implantation window.

This study by Madhuri Salker et al. supports the idea that activation of the IL-33 pathway controls the expression of other genes that are directly responsible for controlling the receptive period in a woman’s cycle. The implantation process can only happen during a specific period of time- the implantation window- approximately four to seven days long normally. This report suggests that women who have an abnormally high level of IL-33 secretion, a molecule whose level normally drops off during decidualization, have a much longer window of implantation, more like 10 days. This abnormally long implantation window may allow these early stages of decidualization to occur.  The embryo produces hCG as it implants (so the pregnancy test is positive) but the less-than-optimal receptive uterus is not compatible with a on-going pregnancy and birth- exactly the trajectory seen with recurrent pregnancy losses.

This discovery can not explain all cases of recurrent pregnancy loss, but it adds another possibility. Problems with the embryo, hormonal dysfunction and structural problems with the uterus are just some of the other causes of recurrent pregnancy loss. Hopefully,  a better understanding of the molecular causes of at least some cases of recurrent pregnancy loss may lead to medical treatments to normalize the length of the implantation window and prevent early pregnancy loss from this cause.


© 2013, Carole. All rights reserved.

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