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University of Cambridge study reveals source of fetal growth problems in the womb

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A Cambridge-led study explains why some babies grow poorly in the womb - and could potentially lead to medication to promote normal development.

The researchers identified a key signal used by the fetus to control its supply of nutrients from the placenta in what has been described as a tug-of-war between genes inherited from the father and the mother.

Section of mouse fetus and placenta. Picture: Ionel Sandovici
Section of mouse fetus and placenta. Picture: Ionel Sandovici

About 10 to 15 per cent of babies grow poorly in the womb and in many of these cases there is reduced growth of the blood vessels in the placenta - a specialised organ that has cells from both baby and mother.

The fetus communicates its increasing needs for food to the mother and the study, led by University of Cambridge scientists, shows a signal is produced to encourage the growth of blood vessels in the placenta. These expand markedly in the middle and latter stages of a pregnancy, reaching an astonishing 320 kilometre at full term.

The research, carried out in genetically-engineered mice, shows the signal also causes modifications to other cells in the placenta, which allow more nutrients from the mother to reach the fetus.

Dr Ionel Sandovici, first author of a paper published in Developmental Cell, said: “As it grows in the womb, the fetus needs food from its mum, and healthy blood vessels in the placenta are essential to help it get the correct amount of nutrients it needs.

“We’ve identified one way that the fetus uses to communicate with the placenta to prompt the correct expansion of these blood vessels. When this communication breaks down, the blood vessels don’t develop properly and the baby will struggle to get all the food it needs.”

The signal - known as IGF2 - reaches the placenta through the umbilical cord.

Levels of IGF2 in the cord rise from 29 weeks of gestation to the end of pregnancy, with too much growth associated with higher levels and too little leading to low growth levels.

Babies that are too large or small are more likely to face problems or even die at birth, and they have a higher risk of develop diabetes and heart problems later in life.

Dr Sandovici added: “We’ve known for some time that IGF2 promotes the growth of the organs where it is produced. In this study, we’ve shown that IGF2 also acts like a classical hormone – it’s produced by the fetus, goes into the fetal blood, through the umbilical cord and to the placenta, where it acts.”

The researchers found that in mice the response to IGF2 in the blood vessels of the placenta is mediated by a protein called IGF2R.

The genes that produce IGF2 and IGF2R are ‘imprinted’, meaning molecular switches on the genes identify whether they come from the father or mother, and can turn the genes on or off.

Only the copy of the igf2 gene inherited from the father is active in this case, while only the copy of igf2r inherited from the mother is active.

Lead author Dr Miguel Constância said: “One theory about imprinted genes is that paternally-expressed genes are greedy and selfish. They want to extract the most resources as possible from the mother. But maternally-expressed genes act as countermeasures to balance these demands.

“In our study, the father’s gene drives the fetus’s demands for larger blood vessels and more nutrients, while the mother’s gene in the placenta tries to control how much nourishment she provides. There’s a tug-of-war taking place, a battle of the sexes at the level of the genome.”

The findings offer insight into the communication between the fetus, placenta and mother, which could lead to ways of measuring levels of IGF2 in the fetus.

It is hoped this could lead to ways of normalising these levels through medication, or promoting normal development of placental vasculature.

The work was carried out using mice because their genes can be manipulated to mimic developmental conditions and their physiology and biology share similarities with humans.

The lead researchers are based at the Department of Obstetrics and Gynaecology, the Medical Research Council Metabolic Diseases Unit, part of the Wellcome-MRC Institute of Metabolic Science, and the Centre for Trophoblast Research, all at the University of Cambridge. The research was largely funded by the Biotechnology and Biological Sciences Research Council, Medical Research Council, Wellcome Trust and Centre for Trophoblast Research.

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