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Fever in early pregnancy causes birth defects
Researchers have known for decades that fevers in the first trimester of pregnancy increase the infant's risk for heart defects such as Patent ductus arteriosus (PDA), and facial deformities such as cleft lip or palate. Exactly how this happens was unclear, the debate considering whether a virus or other infection might causes the defects, or if fever acted alone.
Duke researchers now have evidence indicating that the fever itself, not the source of the fever, is what interferes with development of the heart and jaw in the first three to eight weeks of pregnancy.
Their findings, demonstrated in chick and zebra fish embryos, is published in the journal Science Signaling.
Strikingly, results suggest a portion of congenital birth defects could be prevented by lowering a mother's fever with judicious use of acetaminophen during her first trimester, according to Eric Benner MD PhD, neonatologist and assistant professor of pediatrics at Duke University, Durham, North Carolina and senior author.
"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." Benner explains: "While doctors advise most women to avoid any drug during pregnancy, there may be benefits to taking acetaminophen [also known as paracetamol] to reduce fever. Women should always discuss all risks and benefits with their doctors."
Nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and aspirin also reduce fevers, but are not safe to use during late stages of pregnancy. Benner advises there is also an ongoing debate over whether sustained use of acetaminophen is safe for managing ongoing conditions, such as arthritis, during pregnancy.
To observe how fever impacts a developing fetus, researchers tested zebrafish and chicken embryos. They discovered neural crest cells, critical building blocks for the heart, face and jaw, are particularly temperature-sensitive due to protein based ion channels that tunnel through cell walls allowing electric current flow in and out.
"They're the channels that, when you stick your hand in a hot cup of water, tell your body the temperature has changed," Benner explains.
Researchers engineered a magnet-based technology to increase current and create fever-like conditions in two temperature-sensitive ion channels called TRPV1 and TRPV4 found in neural crest cells. Subjecting these neural crest cells to conditions mimicking transient fever, embryos developed craniofacial disfigurement and heart defects, including double outlet right ventricle, Tetralogy of Fallot and outflow obstructions.
The type of defect depended on when fever occurred. During early fetal development at approximately 31 to 35 days post ovulation, the heart is forming, thus more damage was seen in valve formation between chambers of the heart. About 4 weekw later, during head and face development, disfigurement of neck and facial structures occurred. It is challenging for doctors to gather accurate data from mothers on the severity and duration of a fever experienced many months before, so researchers are still not clear about how severe in temperature and/or duration a fever must be to impact human 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.
Fevers, TRPV channels, and birth defects
Cardiac and craniofacial birth defects are common, but many cannot be attributed to specific mutations. An environmental trigger associated with these birth defects is fever during the first trimester. Using chick or zebrafish embryos, Hutson et al. found that hyperthermia activated temperature-sensitive TRPV1 and TRPV4 ion channels in neural crest cells, which give rise to the tissues affected by the birth defects. The authors developed a noninvasive method of transiently activating TRPV1 or TRPV4 in neural crest cells in chick embryos to mimic fever-induced stimulation of these channels. TRPV1 or TRPV4 activation resulted in cardiac and craniofacial birth defects similar to those induced by fever. These results suggest that preventing TRPV1 and TRPV4 activation during first trimester febrile episodes may reduce the incidence of common forms of birth defects.
Birth defects of the heart and face are common, and most have no known genetic cause, suggesting a role for environmental factors. Maternal fever during the first trimester is an environmental risk factor linked to these defects. Neural crest cells are precursor populations essential to the development of both at-risk tissues. We report that two heat-activated transient receptor potential (TRP) ion channels, TRPV1 and TRPV4, were present in neural crest cells during critical windows of heart and face development. TRPV1 antagonists protected against the development of hyperthermia-induced defects in chick embryos. Treatment with chemical agonists of TRPV1 or TRPV4 replicated hyperthermia-induced birth defects in chick and zebrafish embryos. To test whether transient TRPV channel permeability in neural crest cells was sufficient to induce these defects, we engineered iron-binding modifications to TRPV1 and TRPV4 that enabled remote and noninvasive activation of these channels in specific cellular locations and at specific developmental times in chick embryos with radio-frequency electromagnetic fields. Transient stimulation of radio frequency–controlled TRP channels in neural crest cells replicated fever-associated defects in developing chick embryos. Our data provide a previously undescribed mechanism for congenital defects, whereby hyperthermia activates ion channels that negatively affect fetal development.
Authors: Mary R. Hutson1, Anna L. Keyte, Miriam Hernández-Morales, Eric Gibbs, Zachary A. Kupchinsky, Ioannis Argyridis, Kyle N. Erwin1, Kelly Pegram1, Margaret Kneifel, Paul B. Rosenberg, Pavle Matak, Luke Xie, Jörg Grandl, Erica E. Davis, Nicholas Katsanis, Chunlei Liu, and Eric J. Benner
Disclosures: Co-senior authors Benner and Liu have filed a patent application relating to the use of FeRIC technology for cell modulation and treatments.
Search Terms: glutamate transmission, neuronal excitation, O-GlcNAc, post-translational modification, synaptic circuits. MULTIMEDIA: Author sound bytes, B-roll from the laboratory, an animation of a congenital heart defect and more are available for download. In addition to Benner, study authors include Mary R. Hutson, Anna L. Keyte, Eric Gibbs, Zachary A. Kupchinsky, Ioannis Argyridis, Kyle N. Erwin, Kelly Pegram, Margaret Kneifel, Paul B. Rosenberg, Pavle Matak, Luke Xie, Jörg Grandl, Erica E. Davis, Nicholas Katsanis of Duke, and Miriam Hernández-Morales and Chunlei Liu of the University of California, Berkeley. The research was supported by 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 (16GRNT30980012), and the National Institutes of Health (NIMH R01MH096979, NHLBI R21HL122759, and NIBIB P41EB015897), including grants specifically from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (K12HD043494, T32HD043728), and the National Institute of Biomedical Imaging and Bioengineering (T32EB001040). Return to top of page
Chick embryos were stained blue and red to identify craniofacial features. High temperatures cause severe craniofacial defects in chicks, dramatically shortening the upper beak. Image credit Chunlei Liu UC Berkeley, et al.