Zika virus and the nonmicrocephalic fetus: why we should still worry

Abstract

Zika virus (ZIKV) is a mosquito-transmitted flavivirus and was first linked to congenital microcephaly due to a large outbreak in Northeastern Brazil. Although the ZIKV epidemic is now in decline, pregnancies in large parts of the Americas remain at risk due to ongoing transmission and the potential for new outbreaks. This review presents why Zika virus is still a complex and worrisome public health problem with an expanding spectrum of birth defects and why ZIKV and related viruses may evade the immune response to injure the fetus. Recent reports indicate that the spectrum of fetal brain and other anomalies associated with ZIKV exposure is broader and more complex than microcephaly alone and includes subtle fetal brain and ocular injuries; thus, the ability to prenatally diagnose fetal injury associated with ZIKV infection remains limited. New studies indicate that ZIKV imparts disproportionate effects on fetal growth with an unusual femur-sparing profile, potentially providing a new approach to identify viral injury to the fetus. Studies to determine the limitations of prenatal and postnatal testing for detection of ZIKV-associated birth defects and long-term neurocognitive deficits are needed to better guide counseling for women with a possible infectious exposure. It is also imperative that we investigate why ZIKV is so adept at infecting the placenta and the fetal brain to better predict other viruses with similar capabilities that may give rise to new epidemics. The efficiency with which ZIKV evades the early immune response to enable infection of the mother, placenta and fetus is likely critical for understanding why the infection may either be fulminant or limited. Furthermore, studies suggest that several emerging and related viruses may also cause birth defects, including West Nile virus, which is endemic in many parts of the United States. With mosquito-borne diseases increasing worldwide, there remains an urgent need to better understand the pathogenesis of ZIKV and related viruses to protect pregnancies and child health.

Perceptions and Emotional State of Mothers of Children with and without Microcephaly after the Zika Virus Epidemic in Rural Caribbean Colombia

“…These results were expected because uncertainties and feelings of worrisome were detected during pregnancy, but when mothers delivered a healthy baby, their emotional state improved as feelings of worrisome decreased. In the long term, this low perception of risk could be a problem leading to lower attendance to medical visits and under-detection of neurodevelopmental disabilities, because healthy-at-birth infants born to mothers with confirmed ZIKV infection still need long-term follow up to detect neurodevelopmental delays [ 7 , 12 ].…”

“…ZIKV infection during pregnancy is a cause of poor pregnancy outcomes such as spontaneous abortions, microcephaly, and other severe congenital anomalies [ 3 , 4 , 5 ]. Neonates born with congenital Zika syndrome (CZS) present severe microcephaly, eye loss, brain damage (including ventriculomegaly, intracranial calcifications, and skull collapse), congenital contractures, and hypertonia [ 6 , 7 ]. Healthy at birth not-infected children with in-uterus exposure to ZIKV may also develop psychomotor delays, poor reactions to external stimulation, generalized spastic dystonia, and other neurodevelopmental delays during childhood [ 8 , 9 , 10 ].…”

Pathophysiology and Mechanisms of Zika Virus Infection in the Nervous System

“…We know from twin studies that there may be differences in fetal exposure as well as susceptibility to ZIKV. Furthermore, we need to look beyond gross developmental aberrations and begin to evaluate more subtle differences that may emerge in brain connectivity and function, which could lead to earlier behavioral interventions (Adams Waldorf et al 2018, Walker et al 2019).…”

CImP: Cellular Imprinting Proteomics applied to ocular disorders elicited by Congenital Zika virus Syndrome

“…The range of non-microcephalic anomalies associated to ZIKV infection pose an important clinical and social challenge. The identification of early molecular alterations can improve our understanding of these effects and help in predicting clinical outcome (161).Taken together, these results call for an active surveillance of ophthalmological complications in children exposed to ZIKV during the first trimester of gestation but without CZS.…”