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Infectious Cause of Microcephaly May Not be Zika

In any differential diagnosis of microcephaly, clinicians should consider other infections as well, depending on the setting and history of the patient.

By now, the healthcare community is aware that the Zika virus causes microcephaly—at least among some babies born to mothers infected with the mosquito-borne virus.

It was an aspect of the epidemic in South America and the Caribbean between 2014 and 2016—and its coverage in the media—that was both heartbreaking, and unavoidable.

However, there are other infectious causes of the birth defect, which carries with it significant neurologic complications, and that is just what the authors of a review, published in The Lancet in August 2017, want to emphasize. Their hope is that clinicians keep a watchful eye on pregnant women who present with symptoms of these infections, and appropriately manage their treatment with the goal of preventing microcephaly-related complications.

“We think that Zika is very important and [it] has raised the profile of microcephaly; [however], there are many other infectious and noninfectious causes,” Delanjathan Devakumar, MPH, PhD, Lecturer in Public Health, Institute for Global Health, University College-London, told Contagion®. “A lot of research is being focused on Zika, but globally there will be more cases of microcephaly due to other infectious causes and this is a great opportunity to allow all patients with infectious microcephaly to benefit from research findings.”

In their review, Dr. Devakumar and his colleagues focus on the infections “with the largest disease burden and the strongest evidence for causation” of microcephaly—namely, cytomegalovirus (CMV), herpes simplex virus (HSV), rubella virus, Toxoplasma gondii, and, of course, Zika virus. Each plays a distinct role in the potential development of the birth complication. Citing earlier research, for example, they note that CMV has been linked with alterations in the “progenitor and neuronal fates” via downregulation of multipotency markers such as Sox2 and Nestin. However, more recently, peroxisome proliferator-activated receptor γ (PPARγ) has been shown to increase following CMV infection of human neural stem cells and fetal brain sections, and that activation alone has proved sufficient to “impair neuronal differentiation.”

Notably, although the prevalence of congenital CMV infection in high-income countries is estimated to be 0.7% of all live births (versus 1% to 5% in low-income countries), the risk of mother-to-fetus transmission increases with advancing gestational age, from 35% in the first trimester to 65% in the third.

Conversely, the authors of The Lancet review write that HSV has been shown to “infect multiple brain cell types,” but how infection results in microcephaly remains unknown, though animal studies suggest the virus may induce “an immune response that stimulates neural stem cell proliferation” to cause the defect. Thankfully, they note, primary microcephaly is a relatively rare complication of perinatal HSV infection (with in-utero infection accounting for 5% of cases). Similarly, they add, rubella’s role in the pathogenesis of microcephaly remains unknown, even as research suggests that “brain vessels have been found to degenerate following… infection,” indicating that “a neurodegenerative mechanism could be a potential underlying cause.” Although most countries have vaccination programs in place for rubella, nearly 10% of pregnant women worldwide are seronegative, and incidence of congenital rubella syndrome in the developing world (where vaccine programs are typically not fully implemented) is as high as 300 per 100,000 live births.

Finally, the global incidence of congenital toxoplasmosis (T. gondii) is approximately 1.5 per 1,000 live births, with the highest incidence in South America. Dr. Devakumar and colleagues note that research suggests that mother-to-child transmission occurs during pregnancy following primary infection.

“In any differential diagnosis of microcephaly, these infections should be considered, [but] the degree to which a clinician would see one of these causes depends on the setting they are working in,” Dr. Devakumar explained. “When a clinician is faced with a case, the broad differential should be remembered, and that infection should be investigated and treated appropriately. Certainly, communication with parents is [also] important. In every situation, a decision has to be made about how much information to give, when to give it, and in what way. As we have highlighted a diagnosis of microcephaly itself and an infectious cause is often not straightforward, so this can be complicated.”

Brian P. Dunleavy is a medical writer and editor based in New York. His work has appeared in numerous healthcare-related publications. He is the former editor of Infectious Disease Special Edition.