Along with preterm labor, preeclampsia is the main complication of pregnancy. Characterized by a sudden rise in blood pressure, it can affect the health of mother and child, endangering the life of the first and affecting the development of the second in the most severe cases. Of unknown origin, it begins to be detected in the third trimester of pregnancy. Except for taking aspirin, there is no treatment and it only disappears with childbirth, often early because of her. Now, a group of researchers has been able to predict which pregnant women will suffer pre-eclampsia weeks before it is detectable. And they have done it with a fascinating combination of genetics, machine learning, and mathematical algorithms.
At the end of the last century, several studies managed to identify genetic material in the blood of pregnant women that came from the fetus. That advance allowed, already in this century, the development of non-invasive analytics to study the DNA of the unborn child, looking for anomalies such as Down syndrome. This allowed us to corner techniques as dangerous as amniocentesis. Looking further, scientists have begun using this approach to detect and anticipate potential pregnancy complications, such as pre-eclampsia.
Scientists from the Mirvie company (San Francisco, USA) have been able to predict most cases of pre-eclampsia with a simple blood test. The president and founder of the Californian company Maneesh Jain explains it: “We show that the RNA technology developed by Mirvie can detect 75% of women who will develop pre-eclampsia, including those with premature deliveries, months before symptoms appear” . This involves multiplying by up to four the effectiveness of traditional screening, based on biographical profiles made with pregnancy history, age, body mass index or race.
In addition to the high prediction capacity, this work also highlights anticipation in prediction. Although pre-eclampsia begins at the same time that the placenta (placentation) forms, the symptoms that allow it to be detected do not appear until after the 20th week of pregnancy. In this research, recently published in Nature, the detection was carried out on average a month and a half before.
“By analyzing circulating RNA [en la sangre de la madre] we saw differences between women who ended up developing pre-eclampsia and those who did not “
Joan Camuñas, computational biologist in Mirvie
Barcelona’s Joan Camuñas (from Arenys de Munt) is a computational biologist in Mirvie and is a co-author of this research. “By analyzing circulating RNA [en la sangre de la madre] We saw differences between women who ended up developing pre-eclampsia and those who did not, ”she says. Among this RNA, which is believed to be waste, there is it of non-human, viral or bacterial origin. But also from the fetus and the placenta. As Jain says, “RNA transcripts from the fetus can exit the fetal blood vessels in the villi of the placenta and into the maternal bloodstream.” And this genetic material promises to be a window into pregnancy and its progression.
“Our algorithms allow us to detect different patterns between the two populations, [embarazadas y no embarazadas]”, Camuñas comments. To feed these algorithms, the researchers trained them with a machine learning system that they used to analyze the genetic material present in 2,539 blood samples from the women in the study. They thus identified residues of a series of genes related to the development of the placenta and the fetus itself. Half of the samples were taken in the second trimester of pregnancy, weeks before the possible emergence of pre-eclampsia and the rest when it should have already arisen.
Before the work of Camuñas, Jain and others, the genetic material of the fetus present in the mother’s blood had already been used. In fact, diagnostic tests that analyze fetal DNA obtained from the maternal bloodstream have been marketed for a few years. The one with the greatest impact is the one that looks for chromosomal abnormalities, such as Down syndrome.
With RNA, in 2020 researchers from the Illumina company (also from California) also used circulating RNA to detect molecular signs of preeclampsia. In that work, blood samples were taken once the pathology developed, but it was key to validating this brand-new approach.
Fiona Kaper, head of research at Illumina and co-author of that study, explains the key to these works: how to relate a certain genetic material present in maternal blood with the fetus: “For any RNA molecule, you cannot say with complete certainty of where it comes from because we are seeing it in plasma and not in the tissues themselves [de los que procede]. So we can only assign these transcripts [ARN residual circulante] to possible tissues of origin ”, he explains. To do this, they turn to existing databases that accumulate each new connection that is discovered between an RNA present in the blood and its origin. “For example, if the ‘A’ transcript is expressed five times more in fetal tissue than in other tissues, we assign it to the fetal category. If the “B” transcript is expressed twice as high in placental tissue than in others, it is assigned to the category of placenta ”, he details. It is not an infallible system, but, as Kaper adds, “it gives us confidence that seeing alterations in many transcripts that are more expressed, for example, in placental tissue, indicates that there is an increase in circulating RNA from placental sources” .
“Any disease that involves deterioration or change in the functioning of an organism’s system has the potential to generate a circulating RNA signal”
Fiona Kaper, Head of Research at Illumina
This window to pregnancy that opens in the maternal blood promises to go far beyond pre-eclampsia. For the Illumina scientist, “forms of gestational hypertension that are not pre-eclampsia, HELLP syndrome [que provoca descomposición de los glóbulos rojos], fetal growth restriction, gestational diabetes, etc., are also possible complications that could generate signals in the circulating RNA ”. But Kapel goes further: “Any disease that involves deterioration or change in the functioning of an organism’s system has the potential to generate a circulating RNA signal. Of course, much larger studies will be needed to prove it. “
In addition to fetal DNA and RNA, other researchers look for other presences of the fetus or placenta in the blood. Miguel Pericacho’s team, from the Salamanca Biomedical Research Institute, has investigated biomarkers to detect pre-eclampsia. This is the case of the endoglin protein, whose degree of solubility appears to be both a cause and a consequence of this pregnancy complication. Her colleague from the Salamanca University Hospital Sandra Muntion and her team are studying another possible biomarker, in her case plasma vesicles from the mother’s blood. Everything leads to the same place: different fetal or placental genetic material in maternal blood.
For Pericacho, work with preeclampsia is just the first step. “They have used it as a test to validate this approach, but it could well be a step towards a method to detect other diseases or to follow the growth of the fetus.” Being the most common serious complication, it makes the algorithms work easier.
Dr. Juan Luis Delgado, coordinator of the pre-eclampsia practical assistance guide of the Spanish Society of Gynecology and Obstetrics (SEGO), highlights the connection between mother and child. “The impressive thing about these works is that they are based on the fetal or placental genetic material secreted in the blood, in the maternal circulation.” And he agrees with Pericacho: “Accessing the RNA is accessing the fetus’s instruction book. In a short time, not only pathologies will be detected; with a single blood test we will have his entire genome complete “.
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