Fever during the first trimester of pregnancy may boost the risk of heart defects and facial deformities such as cleft lip or palate.
Researchers have known about the risks for decades, but how it happens has been unclear. Is a virus or other infection source—or fever alone—the underlying problem?
Now, a new study in Science Signaling points to the fever itself, not its root source, that can interfere with the development of the heart and jaw during the first three to eight weeks of pregnancy.
“Our study identified a specific molecular pathway that links maternal fever directly to some of those defects.”
The findings, demonstrated in animal embryos, provide new leads as scientists continue investigating heart defects, which affect 1 percent of live births in the US, and cleft lip or palate, affecting about 4,000 infants per year.
“Congenital heart and cranial facial defects are very common in live births, but most of the time they have unknown causes,” says co-senior author Chunlei Liu, an associate professor of neuroscience and electrical engineering and computer sciences at the University of California, Berkeley. “Our study identified a specific molecular pathway that links maternal fever directly to some of those defects.”
The animal models suggest a portion of congenital birth defects in humans might be prevented if fevers are treated through means including the judicious use of acetaminophen during the first trimester, says co-senior author Eric Benner, a neonatologist and assistant professor of pediatrics at Duke University.
Take some Tylenol?
“My hope is that right now, as women are planning to become pregnant and their doctors advise them to start taking prenatal vitamins and folic acid, their doctor also informs them if they get a fever, they should not hesitate to call and consider taking a fever reducer, specifically acetaminophen (Tylenol), which has been studied extensively and determined to be safe during the first trimester.
“While doctors advise most women to avoid any drug during pregnancy, there may be benefits to taking acetaminophen to reduce fever. Women should discuss all risks and benefits with their doctors.”
Benner cautions that nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and aspirin also reduce fevers, but women shouldn’t use aspirin, naproxen, or ibuprofen during pregnancy. There is also ongoing debate over whether sustained use of acetaminophen is safe during pregnancy to manage ongoing conditions such as arthritis, he says.
“However, its judicious use for an acute problem such as fever is considered safe. These findings suggest we can reduce the risk of birth defects that otherwise could lead to serious health complications requiring surgery.”
Neural crest cells
To observe how fever impacts a developing fetus, researchers studied zebrafish and chicken embryos and found that neural crest cells—cells that are critical building blocks for the heart, face, and jaw—contain temperature-sensitive properties.
“We found that these neural crest cells contain temperature-sensitive ion channels that typically are found in your sensory neurons,” Benner says. “They’re the channels that, when you stick your hand in a hot cup of water, tell your body the temperature has changed.”
Researchers engineered a noninvasive magnet-based technology to create fever-like conditions in two specific temperature-sensitive ion channels called TRPV1 and TRPV4 in the neural crest cells involved in developing the heart and face.
When those neural crest cells were subjected to conditions mimicking a transient fever, the embryos developed craniofacial irregularities and heart defects, including double outlet right ventricle, Tetralogy of Fallot, and other outflow obstructions.
Women “shouldn’t just tough it out if they develop a fever.”
“With electrical magnetic waves coupled with engineered ion channel proteins, we are able to impact specific biological cells remotely without affecting other biochemical environments,” Liu says. “The technique can be applied to study many different cell types and their roles at various developmental stages.”
The type of defect depends on whether the fever occurs during heart development or head and face development in the embryo. What researchers still don’t know is whether or how the severity or duration of a fever impacts development.
“We have known since the early 1980s that fevers are associated with birth defects, but how that was happening has been a complete mystery,” Benner says. It is challenging to gather data from mothers on the circumstances, severity, or duration of a fever from many months before.
“I hope moving forward, we can educate more women about fever as a risk factor for birth defects and let them know they shouldn’t just tough it out if they develop a fever,” Benner says. “They should ask their doctor before getting pregnant whether they may benefit from taking a fever-reducer such as acetaminophen in the event they develop a fever.”
The Jean and George Brumley Jr. Neonatal Perinatal Research Institute, the Zeist Foundation, the Hartwell Foundation, the Mandel Foundation, the Duke Health Scholars Award, the American Heart Association, and the National Institutes of Health supported the work.
Benner and Liu have filed a patent application relating to the use of FeRIC technology for cell modulation and treatments.