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

Abstract

Zika virus is a mosquito-transmitted flavivirus and was first linked to congenital microcephaly caused by a large outbreak in northeastern Brazil. Although the Zika virus epidemic is now in decline, pregnancies in large parts of the Americas remain at risk because of 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 how Zika virus and related viruses evade the immune response to injure the fetus. Recent reports indicate that the spectrum of fetal brain and other anomalies associated with Zika virus 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 Zika virus infection remains limited. New studies indicate that Zika virus 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 Zika virus-associated birth defects and long-term neurocognitive deficits are needed to better guide women with a possible infectious exposure. It is also imperative that we investigate why the Zika virus 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 the Zika virus 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 the Zika virus and related viruses to protect pregnancies and child health.

Keywords: Congenital Zika Syndrome; Zika virus; birth defect; microcephaly; pregnancy.

Figure 1.

Multiple brain abnormalities in a non-microcephalic neonate exposed to ZIKV. This figure depicts multiple brain anomalies in a neonate exposed to ZIKV in the first trimester with a normal head size at birth. A postnatal MRI demonstrated: (A) global decrease in cerebral volume, more pronounced on the right, (B) a smooth appearance of the right frontal and anterior temporal lobes suggested a neuronal migration anomaly, and, (C) right cerebellar peduncle atrophy. Diffuse, coarse calcifications throughout the white matter were also observed on postnatal cranial ultrasound (D, E, F, G). At birth, the infant was found to have a left eye hypopigmented retinal lesion (not shown).

Figure 2.

Other brain abnormalities associated with ZIKV infection. This figure demonstrates the spectrum of ZIKV-associated birth defects beyond the diagnosis of congenital microcephaly. For the first neonate, a postnatal MRI revealed abnormalities of the gyri (A-C; polymicrogyria and loss of gyri) and intracranial serpiginous calcifications (D, E). A second infant exposed to ZIKV in utero with a relatively large head at birth (HC, 96^th centile) was noted to have prominent axial fluid collections concerning for impending hydrocephalus (F, G).

Figure 3.

ZIKV-associated femur-sparing profile of fetal growth restriction. This figure illustrates how a femur-sparing profile of growth restriction, thought to be associated with ZIKV infection, compares to normal fetal growth and other aberrant patterns of growth restriction. A few studies indicate that growth of the femur is often spared in ZIKV infections, which may represent an internal standard to compare growth of the head or abdomen for possible ZIKV-associated viral injury of the fetus.

Figure 4.

Zika virus proteins associated with evasion of the early immune response. This schematic illustrates the protein-coding regions of the ZIKV genome and specific nonstructural (NS) proteins that have been implicated in inhibition of the innate immune response. Abbreviations: C, capsid; pr, precursor; M, membrane; E, envelope; IKKε, Inhibitor of kappa-B kinase subunit epsilon; TBK1, TANK-binding kinase 1; IRF3, Interferon regulatory factor 3; RIG-I, retinoic acid inducible gene I; JAK, Janus kinase; STAT, signal transducer and activator of transcription.