Foetal face and heart abnormalities caused by high fever

12 October 2017
Posted by Chris Smith.

Fever during pregnancy might cause developmental heart and facial abnormalities, a new study has shown.

Congenital, or in-born abnormalities of the heart are one of the most common problems afflicting newborns, with up to 1% of live births are affected. Craniofacial abnormalities, like cleft lips and palates also affect thousands of children. Genetic risk factors for these conditions have been identified, but they account for only 15% of cardiac problems and less than a third of craniofacial cases. This means that unknown influences are responsible for the rest.

Now researchers have evidence that succumbing to a fever at a critical point in pregnancy might be responsible for many of these cases. 

Previously, scientists had blamed infecting organisms themselves rather than the fever per-se for causing pregnancy-related problems. Indeed, some infections do have a strong track record of crossing the placenta from mother to baby and damaging foetal tissues: Zika virus, CMV and toxoplasmosis are three common examples.

But hyperthermia - becoming too hot - just through sitting in a hot tub has also been linked to foetal abnormalities, which prompted Duke University Medical Center researcher Mary Hutson and her colleagues to try to understand why, by using developing chickens. 

Chicks grow very quickly and develop in eggs so the conditions under which the developing chick embryos grow can be carefully controlled; chicks also follow very similar patterns of development to more complex animals like humans, making them an ideal study subject.

By transiently elevating the temperatures of clutches of eggs from their normal 37 degrees Celsius to a hotter 41 degrees Celsius, mimicking a mother with a fever, the Duke team produced chicks born with shorter beaks and abnormal hearts.

These anatomical structures form from a population of cells called the neural crest which, the Duke team found, strongly express genes that make them temperature sensitive. The same genes are used by nerve cells in adult birds and humans to detect changes in temperature. They code for proteins called TRPV1 and TRPV4, which cause nerve cells to fire off electrical impulses as the temperature rises and signalling a burning sensation.

The role that these genes are playing in the developing heart and face is not known, but it seems likely that the TRPV1 and TRVP4-encoding genes may well be involved in sending signals between the neural crest cells to help them to coordinate the delicate dance they perfom as they organise themselves into complex tissue structures.

When the researchers blocked the action of TRPV1 and TRPV4 using drugs, the damaging effects of temperature on heart and beak development went away. Increasing the action of the gene products, on the other hand, increased the rates of heart and beak abnormalities, even if the temperature was not raised. 

More convincing still, when the researchers genetically coupled one of the TRP proteins to a molecule that binds iron, meaning that they could use radio waves to activate the protein at will, this too led to heart and beak abnormalities. And manipulating the same genes in developing zebrafish also produced heart and facial changes.

The timing of these events is critical, because the heat, or gene manipulation effects, need to be present during the window when the neural crest cells are migrating into the developing heart and face regions. This suggests that there is a window of vulnerability while this process is occurring during which fever and high temperatures could drown out the normal cellular signals that are guiding cells to the correct tissue destinations.

Together, these results, published this week in the journal Science Signaling, suggest that mothers unfortunate enough to fall ill and develop a fever early in pregnancy, when the foetal heart, head and face are developing, might therefore be at higher risk of this happening. The temperatures sufficient to produce the effects in the chicks were well within the realms of what a nasty dose of flu can do to a human. That said, this was work done in chickens and needs to be corroborated in humans, or at least another mammalian species, to confirm the proposed mechanism.

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