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Modern medicine has made great strides in the way pregnancy is monitored, but in many cases serious problems or miscarriages still occur. According to a doctoral thesis defended at the University of Tartu, studying the placenta offers hope for a better understanding and prevention of complications.
The year 2024 brought a historic low point for Estonia. For the first time, fewer than 10,000 births were registered during the year. At a time when demographics are making the success of every pregnancy increasingly important, the number of pregnancy complications is on the rise.
In Estonia and elsewhere in the world, hypertensive disorders affect around 7–21% of pregnancies, and gestational diabetes and fetal growth defects occur in around 5–10% and 10% of pregnancies, respectively. 1–5% of couples experience recurrent miscarriages.
“Getting pregnant at a later age can further increase these risks, which is why prevention and early intervention are critical,” emphasised Mario Reiman, who holds a PhD in gene technology from the University of Tartu. This is also important in Estonia, where the age of first-time mothers has been rising steadily hand-in-hand with an ageing population. In 2003, women had their first child at the age of 24.7, but in 2023, they had their first child at the age of 28.7.
A unique research method
Several pregnancy complications are caused by disruptions in the functioning of placental genes. “Of all the organs in the human body, the placenta is one of the most mysterious,” says Reiman. “It is formed after fertilisation from the same cells that develop into the fetus and exists only during pregnancy.”
The placenta is essential for fetal development. The organ supplies the developing fetus with oxygen and nutrients, removes waste products from the fetus’s bloodstream, produces hormones to help the mother adapt to pregnancy, protects the fetus from potential harmful effects and regulates fetal growth and development.
Reiman’s PhD study was one of the first in the world to use whole-genome sequencing to study the placenta, covering the largest dataset of its kind to date. Reiman compared placental tissue samples from normal pregnancies (controls) and pregnancies with complications (cases). To better understand the role of the placenta, the team sequenced the RNA extracted from the samples into sequencing libraries prepared for this purpose.
The rate of gene expression played a key role. To find the differences between normal and complicated pregnancies, Reiman compared the number and type of RNA molecules the cells made from genes in the placenta.
Extensive impacts
Mario Reiman observed the most extensive changes in pre-eclampsia, which, in the worst case, puts both mother and baby at risk. Compared to pregnancies without problems, there were differences in the expression of 215 genes. The discovery confirmed the researchers’ earlier theory that pre-eclampsia originates in the placenta. In the case of repeated miscarriages, the team saw changes in the expression of 189 genes. This illustrates how drastically the placental genes are disrupted at this time.
For other pregnancy complications, the changes were smaller: Reiman and colleagues found four altered genes in gestational diabetes, two in low birth weight pregnancies and one in high birth weight pregnancies. “The low number of changes suggests that gestational diabetes, for example, does not seem to originate in the placenta, but rather is linked to maternal or fetal gene expression,” acknowledges Reiman.
However, by analysing the function of the affected genes, Reiman concluded that by the time the samples were taken, the placental cells had already started to die as they were programmed to. In other words, the body was trying to end the pregnancy, not maintain it. “We seem to have identified a gene expression-mediated mechanism that brings about the end of pregnancy. However, we are still unable to identify the specific signal that triggers the process of recurrent pregnancy loss and how it contrasts with sporadic miscarriage,” Reiman explains.
Surprisingly, Reiman observed that the gene expression patterns seen during all late pregnancy complications were similar. The number of gene mutations varied. Pre-eclampsia and pregnancies with fetal growth problems were particularly strongly linked. “This suggests that in all cases the placenta is trying to adapt to a situation where it cannot support the fetus well enough,” explains Reiman.
This may be because the placenta is unable to deliver enough oxygen and nutrients to the fetus earlier, which, in turn, lowers the fetus’s weight. It can also happen that the fetus starts to grow exceptionally fast, but the placenta is unable to respond. To compensate for this, pathways that rapidly increase the fetal blood flow and raise the mother’s blood pressure may be activated.
If it is indeed found that many of the complications share similar causes, this could pave the way for the development of more effective treatments.
Influence of one parent
Compared to previous studies, the University of Tartu researchers used a more sensitive whole-genome sequencing method. This made it possible to measure more accurately from which parent the genes were expressed in the placenta.
Usually, genes are expressed equally from copies of genes inherited from both parents. An exception is a phenomenon called imprinting, where a gene is expressed only through a copy of the gene inherited from one parent, while the copy of the gene from the other parent is completely silenced.
It turned out that only a small fraction of the genes studied, less than an eighth, followed the classical imprinting pattern. These genes were unique to the placenta, but according to the gene expression atlas, they can also be expressed in the adrenal glands. Many remaining genes showed a partial preference for one of the parental copies. In their case, 65–90% of the gene activity came from one parent, a new discovery in imprinting research.
More effective prevention
New scientific discoveries, such as Mario Reiman’s placenta study, can help doctors better understand and prevent potential pregnancy complications. This could make the cost of pregnancy safer. “Although this is only a research project at the moment, the results may help to develop more accurate screening and more personalised treatments in the future,” believes Reiman.
The results of the study are particularly significant for monitoring higher-risk pregnancies, such as those of older first-time mothers, couples with recurrent miscarriages, women with chronic illnesses and those with a history of pregnancy complications.
According to Reiman, pregnancy needs to be planned carefully. The presence of risk factors does not automatically mean problems, but every pregnancy is different. So, it is advisable to consult a doctor even before getting pregnant, to follow a healthy lifestyle but also not stress too much about potential risks that have not yet been realized.
Mario Reiman defended his doctoral thesis “Placental transcriptome in normal and complicated pregnancies” on January 21 at the University of Tartu. Professor of Human Genetics Maris Laan supervised the work, which was opposed by Dr Hannele Laivuori from Tampere University.
This article was first published as part of the “Science in 3 Minutes” competition organized by the Estonian Academy of Sciences.
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