Solving the mystery of molar miscarriages

Therapy Breakthroughs 5. aug 2019 3 min Associate professor Karin Lykke-Hartmann Written by Morten Busch

Pregnancy is usually a happy time, but for some couples the joy is short lived if the pregnancy is abnormal and results in a miscarriage, which can occur at different times during pregnancy. Molar pregnancies always end up in miscarriages because all or part of the fetus is transformed into a tumour that forms clusters that resemble grapes. Researchers are now discovering the early-stage mechanisms that can result in these unfortunate pregnancies. This new knowledge will make the causes easier to understand and untangle and can eventually lead to the development of treatment.

The first 3–5 days are critical for a fetus. In that time, the egg develops from one cell into a small, highly organized mass of cells. Some of the cells develop into an embryo, and others form the cells that will make the embryo implant in the uterus. Sometimes, however, something goes completely wrong. In molar pregnancies, the organization of the cells is almost non-existent, which means that these pregnancies usually end with miscarriages. Why these pregnancies go wrong, however, has been a mystery, but now researchers are discovering the very early key mechanisms.

“A defect in the mother’s genes causes the early fetus to develop into a molar pregnancy. We are not certain whether there is one effect or more simultaneous effects, but at least we are now discovering the much earlier molecular effects we have struggled so long to find. This means that we cannot merely find the reasons why these pregnancies go wrong. We can also predict them, and perhaps improve treatment in the long term for the people who are affected,” explains Karin Lykke-Hartmann, Associate Professor, Department of Biomedicine, Aarhus University. 

The project is a longstanding collaboration between Karin Lykke-Hartmann and MD, professor, ph.d. Lone Sunde, Aarhus University Hospital and Department of Biomedicine, Aarhus University.

Mice do not have molar pregnancies

Molar pregnancies result from the abnormal development of the early fetus. In molar pregnancies, the placenta is filled with fluid that resembles grape-like clusters. A molar pregnancy thus only rarely leads to the birth of a child. So far, however, researchers have had great difficulty understanding what goes wrong in early pregnancy.

“Investigating this type of pregnancy has been very difficult since we cannot conduct experiments on fetuses and because mice do not develop molar pregnancies. To examine this more closely, we decided to study more generally how a specific group of genes influences molar pregnancies and miscarriages. Although mice do not develop molar pregnancies, we have managed to identify some of the same dysfunctional mechanisms in mouse fetuses.”

The researchers were surprised to discover that genetic defects in some of the cell receptors that are otherwise normally associated with the immune system may be associated with molar pregnancies. These nucleotide-binding oligomerization domain (NOD)–like receptors (NLRPs) are recognized for their important roles in innate immunity and apoptosis (programmed cell death), which ensures that old or malfunctioning (infected) cells die and are replaced.

“These receptors usually recognize bacteria and fungi, but they also seem to regulate embryonic development at the very early stages of pregnancy. This is probably only one of several important mechanisms, but the evidence suggests that, if something goes wrong at this stage, the fetus develops into a clump of cells that lacks the normal cohesion and interaction.”

The grape-like cells in a molar pregnancy are the cells that normally interact with the cells in the uterus to ensure proper implantation, a process that is similar to immune system processes, and the NOD-like receptors being present in embryos therefore makes some sense.

Some of these NOD-like receptors are present in the egg before fertilization. As the egg develops, some molecules from the mother’s cells are transferred to the egg, which will help both the egg and the embryo to develop. Following fertilization, the egg completely depends on the mother’s contribution of molecules for the first 3–5 days. The activity of these NOD-like receptors originating from the mother therefore depends on whether the moderating genes have defects. Curiously, a small group of these NOD-like receptors is already present in the egg before fertilization. A defect in the mother’s genes can make the receptors not work optimally, resulting in miscarriages and sometimes the development of molar pregnancies.

Can lead to cancer

Although the NOD-like receptors appear to play a very important role in the early fetal stages, the research by Karin Lykke-Hartmann and her colleagues indicates that other important factors appear to influence whether pregnancies go wrong. Epigenetic signals appear to be one of these very clear factors.

“The number of methyl groups on the DNA strands in the fetal cells is clearly correlated with the development of the fetus in the early stages. So this means that errors in specific NOD-like receptors can cause changes in the epigenetic imprinting, thus destroying the normal regulation of other genes. Epigenetics – how the DNA is chemically modified in the cells – is very important in determining which genes are expressed and thus how the fetus develops.”

Thus, genes are especially important for forming the early-stage fetus so that the correct cells are present to produce both the embryo and the surrounding cells that facilitate implantation in the uterus.

Epigenetic defects are common in cancer. This makes the association between NOD-like receptors, miscarriages and the development of cancer much more relevant to investigate.

Molar pregnancies can also lead to choriocarcinoma cancer. Molar pregnancies are fortunately relatively rare and only occur in about 1 in 1000 pregnancies, but their physical and mental effects are so great that the examinations and explanation are very important for parents experiencing a miscarriage.

“It is surprising how little we still know about the early human development , but learning to understand these molecular mechanisms may partly help us to unravel what exactly goes wrong when things go wrong – not only for molar pregnancies but also for miscarriages generally. In any case, our experiment showed that, when we eliminate specific NOD-like receptors in an early fertilized egg, the embryo stops developing prematurely. Although we cannot induce molar pregnancies in mice, we can still learn much about the process. If we are really fortunate and skilled, we may even be able to screen for these changes and eventually even find a treatment.”

The pivotal roles of the NOD-like receptors with a PYD domain, NLRPs, in oocytes and early embryo development” has been published in Biology of Reproduction. In 2017, the Novo Nordisk Foundation awarded a grant to Karin Lykke-Hartmann for the project How Growth and Related Factors Regulate Follicle Activation in Ovaries.

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