Certain birth defects of the face and heart can occur when babies' mothers have a fever during the first trimester of pregnancy, a crucial time in an embryo's development. Now scientists have figured out the molecular players that make it so.
In an experiment with chicken embryos, a temporary rise in incubation temperature — meant to mimic feverlike conditions — was enough to produce defects to the face and heart. Such an elevation in temperature, called hyperthermia, affects the activity of heat-sensitive channels in cells necessary for an embryo's development, researchers report online in the journal Science Signaling.
Although a connection between fever and these birth defects has been known for decades, says report co-author Eric Benner, a neonatologist at the Duke University School of Medicine, there has been some debate as to whether the fever itself or an infectious agent behind the fever is the culprit.
The new work shows that "hyperthermia in and of itself can cause these birth defects, and, on a molecular level, here's how it happens," Benner says.
While birth defects of the heart and face can have a genetic cause, that doesn't explain all cases of these common health problems. In the United States, more than 35,000 babies are born with congenital heart defects each year. Nearly 4,500 infants are born with a malformation of the lip called cleft lip, which can occur with or without a cleft palate, and more than 2,500 babies are born with a cleft palate only.
Although the face and heart don't end up so close together, they arise from the same type of precursor cells, called neural crest cells. These cells orchestrate the development of the jaws and other facial bones as well as the heart and its major vessels, Benner says. The researchers discovered that two members of a class of ion channels that can sense a change in temperature were present in neural crest cells from chickens and mice. (Ion channels are passages through a cell's membrane that allow charged particles, or ions, into or out of the cell.) A temperature change can affect the activity of these two channels, called TRPV1 and TRPV4.
The scientists heated chicken embryos to about 105 degrees for an hour and compared them with embryos incubated at a standard laboratory temperature of 98.6 degrees. Those chicks exposed to a high "fever" developed craniofacial defects, such as a shorter upper beak, and cardiovascular defects. Chicks that developed continuously at the standard temperature did not. What's more, treating the embryos with a molecule that blocked TRPV1 before temporarily raising the temperature prevented craniofacial defects and reduced cardiovascular defects. And using a drug that activates TRPV4 in regular-temperature conditions induced birth defects.
The research is the first to detail the mechanism that connects a fever to birth defects, "and it will hopefully get people thinking about this," says medical geneticist Richard Finnell of the Baylor College of Medicine in Houston, who was not involved in the study. "I was awfully impressed."
Still, it's unclear how high a fever has to be, how long it needs to last and exactly when within the first trimester it needs to occur to cause such birth defects, Benner says. "Fevers are very common in pregnancy, and the vast majority of the time, women who have had fevers are going to deliver healthy babies," he says. He also points to two clinical studies that have shown that the fever-reducer acetaminophen — commonly sold as Tylenol — decreased fever-associated birth defects, and he suggests that doctors and patients consider the drug's use to treat fevers early in pregnancy.