Cases of the most severe form of herpes infection in newborns rose significantly following the COVID pandemic, often not presenting classic symptoms of the condition, according to a recent study in Pediatrics.

The findings also suggest herpes simplex virus 1 (HSV-1) has become the dominant subtype among infants with the infection. HSV-1 accounted for 61% of cases, HSV-2 accounted for 32%, and the remainder had an unknown subtype, according to the researchers.

That shift reflects a broader change in HSV epidemiology, said William Schaffner, MD, an infectious disease specialist at Vanderbilt University Medical Center in Nashville, Tennessee. Historically, HSV-1 infections were more often oral, whereas HSV-2 caused genital disease. But that distinction has blurred.

“We see now HSV-1 becoming genital strains causing infection,” which may contribute to neonatal transmission, said Schaffner, who was not involved in the new study.

Tara L. Greenhow, MD, a pediatric infectious disease specialist at Kaiser Permanente Northern California in Oakland, California, said the documented patterns likely reflect several overlapping factors, including that less women were exposed to HSV during the pandemic because of social distancing and therefore lacked antibodies when they later became pregnant.

“Coupled with an increasingly vulnerable HSV naive population, this allowed for many pregnant persons to have primary HSV at delivery,” Greenhow hypothesized.

Greenhow and her colleagues reviewed electronic health records from 632,979 babies born in Northern California between 2008 and 2024. They identified 62 cases of symptomatic HSV infection in infants aged 0-42 days an overall incidence of 9.8 cases per 100,000 births (95% CI, 7.6-12.5).

Overall, the most common form of infection involved the skin, eyes, or mouth, which along with central nervous system infections involving the brain remained stable during the study period, with 5.4 cases per 100,000 births and 1.6 per 100,000 births, respectively.

However, statistical modeling showed an increase in disseminated infections beginning in 2021. From 2021 through 2024, the incidence of disseminated HSV increased from about 1-2 per 100,000 births to about 6-7 per 100,000 at the end of the study period (P < .05).

The results showed most newborns did not present with classical symptoms, which usually include fever, hypothermia, ill-appearance, skin or oral lesions, and could also include neurologic symptoms.

A little over 85% of symptomatic infants had detailed clinical data available, and many of these did not present with classic presentations. Only 21% of these infants had fever and 11% had hypothermia, and just over one half had visible skin or oral lesions. About one third were described as “ill-appearing,” defined as lethargy, poor feeding, respiratory distress, or signs of sepsis.

Limiting evaluation to infants with abnormal temperature would have missed 68% of cases, according to the study. Greenhow said she is now trying to better define risk factors among infants with different temperatures, including those who appear well.

Most infections occurred within the first 2 weeks of life. Nearly half of the infants were girls and about one quarter were born prematurely. Premature infants had a higher incidence of HSV infection than term infants — 28.3 per 100,000 births and 8.1 per 100,000 births, respectively.

Betsy Herold, MD, chief of the Division of Pediatric Infectious Diseases and Vice Chair for Research at Children’s Hospital at Montefiore Einstein in Bronx, New York, said higher rates among premature infants are consistent with what researchers know about how protective antibodies are transferred during pregnancy. Antibody transfer increases late in pregnancy, meaning infants born earlier may receive less protection.

“If the birthing parent only recently acquired HSV, there is insufficient time to develop antibodies,” said Herold, who is also a member of the American Academy of Pediatrics Committee on Infectious Diseases and was not involved in the current study. “The amount of antibodies that crosses the placenta increases after 33 weeks and exceeds maternal levels after about 37 weeks.”

Testing

Testing for HSV declined over time, falling from about 895 tests per 100,000 births in 2011 to roughly 595 per 100,000 births in 2021 — an average decrease of about 30 tests per 100,000 births per year.

Once clinicians suspected HSV and ordered testing, treatment typically followed quickly. The average time between symptom onset and diagnosis was about 2 days, and antiviral therapy was usually started the same day testing was performed.

Six infants died, which corresponded to a mortality rate of 0.9 deaths per 100,000 births, the researchers noted. Mortality differed significantly by disease type. No infants with skin, eye, or mouth disease died; 28% of infants with disseminated disease and 10% of those with central nervous system disease died (P < .001).

Schaffner said he was struck by the patterns described in the study.

“I had not been aware personally that we’ve had an increase in neonatal HSV,” Schaffner said, adding that the California-based data will need to be confirmed in other parts of the country.

If sexual behavior and exposure patterns return to pre-pandemic norms, neonatal HSV trends could also stabilize or return to pre-pandemic levels, Greenhow said. However, more research and long-term surveillance are needed to confirm whether the current rise is temporary, she said.

“We need to continue to study trends,” Greenhow said. “Disseminated disease is typically associated with primary first episode of HSV disease.”

Increasing awareness among clinicians, particularly in birthing hospitals, could help ensure that infants with atypical symptoms are evaluated promptly, he added.

“Getting this kind of information out to increase awareness, which may well result in more testing, I think is very important,” he said.

Herold said the next critical step is investing in prevention. She and other researchers are investigating prophylactic vaccines and monoclonal antibodies that could help protect infants from infection.

Greenhow and Schaffner reported having no relevant financial conflicts of interest.

Lara Salahi is a health journalist based in Boston.