Autopsy and Postmortem Studies Are Concordant: Pathology of Zika Virus Infection Is Neurotropic in Fetuses and Infants With Microcephaly Following Transplacental Transmission

Abstract

Context.-Pathology studies have been important in concluding that Zika virus infection occurring in pregnant women can result in vertical transmission of the agent from mother to fetus. Fetal and infant autopsies have provided crucial direct evidence that Zika virus can infect an unborn child, resulting in microcephaly, other malformations, and, in some cases, death.Objective.-To better understand the etiologic role and mechanism(s) of Zika virus in causing birth defects such as microcephaly, this communication analyzes the spectrum of clinical and autopsy studies reported from fetuses and infants who developed intrauterine Zika virus infection, and compares these findings with experimental data related to Zika virus infection.Design.-Retrospective analysis of reported clinical, autopsy, pathology, and related postmortem studies from 9 fetuses and infants with intrauterine Zika virus infection and microcephaly.Results.-All fetuses and infants examined demonstrated an overlapping spectrum of gross and microscopic neuropathologic abnormalities. Direct cytopathic effects of infection by the Zika virus were confined to the brain; in cases where other organs were evaluated, no direct viral effects were identified.Conclusions.-There is concordance of the spectrum of brain damage, reinforcing previous data indicating that the Zika virus has a strong predilection for cells of the fetal central nervous system following vertical transmission. The occurrence of additional congenital abnormalities suggests that intrauterine brain damage from Zika virus interferes with normal fetal development, resulting in fetal akinesia. Experimental in vitro and in vivo studies of Zika virus infection corroborate the human autopsy findings of neural specificity.

Placental Pathology of Zika Virus: Viral Infection of the Placenta Induces Villous Stromal Macrophage (Hofbauer Cell) Proliferation and Hyperplasia

“…15,[17][18][19][20][21][22][23] There now remains no doubt that Zika virus can reach the placenta during maternal viremia, be transmitted to the developing fetus, and cause brain damage, microcephaly, other malformations (congenital Zika syndrome) and, in some, cases, perinatal death. In all published autopsies of fetuses and neonates with microcephaly from mothers clinically suspected or confirmed as having Zika virus infection during pregnancy, the virus has been identified in the fetal brain tissue; it has also been identified from other fetal organs and the amniotic fluid.…”

“…In all published autopsies of fetuses and neonates with microcephaly from mothers clinically suspected or confirmed as having Zika virus infection during pregnancy, the virus has been identified in the fetal brain tissue; it has also been identified from other fetal organs and the amniotic fluid. [23][24][25] In vitro studies have provided evidence that Zika virus has an affinity for infecting cells of neural origin. [26][27][28] A murine model of congenital Zika virus transmission has been developed, which has demonstrated fetal demise, brain damage, and Zika virus present in trophoblast, consistent with transplacental infection.…”

Zika Virus Infection in Pregnancy, Microcephaly, and Maternal and Fetal Health: What We Think, What We Know, and What We Think We Know

“…All 4 cases were positive for the virus, with RT-PCR detection of viral RNA from either brain or placental tissues. In an analysis of 9 reported autopsies of fetuses and infants with laboratory-confirmed congenital ZIKV infection and microcephaly Schwartz 9 found an overlapping spectrum of viral-induced, gross and microscopic abnormalities in the brains. The microscopic neuropathologic changes among these autopsies consisted of a combination of necrosis that preferentially targeted neurons, degenerative changes of the glial and neuronal cells, white matter loss and axonal rarefaction, microcalcifications, microglial aggregates, gliosis, macrophage and mononuclear inflammatory cell infiltrates, neuronophagy, and perivascular lymphocytic cuffing.…”

“…This direct, viral-induced brain damage can account for many of the malformations observed in cases of CZS, including those of fetal akinesia deformation sequence (FADS), such as decreased fetal activity, craniofacial abnormalities, joint contractures, limb malformations and arthrogryposis, pulmonary hypoplasia, and cryptorchidism. 9,17,18 Similar to other congenital malformation syndromes, including those produced by some TORCH agents, variability exists in both the spectrum and the severity of the embryopathy in infants with CZS. In fact, there is recent evidence that the use of standard criteria for microcephaly may be insufficient to detect all cases of CZS.…”

“…5 On January 12, 2016, the US Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia, working in collaboration with health officials in Brazil, released information regarding the occurrence of 2 deaths of neonates with congenital microcephaly and 2 miscarriages from Brazil; tissue from all of these cases tested positive for ZIKV using reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemical techniques. 6 The WHO declared that the occurrence of maternal ZIKV infections, together with clusters of microcephaly and other neurologic disorders, constituted a Public Health Emergency of International Concern on February 1, 2016. 7 During the following weeks, additional cases of maternal ZIKV infection and infants with congenital microcephaly were identified, including detailed reports of autopsies of fetuses and neonates with microcephaly and intrauterine infections, 8,9 which strengthened the connection between ZIKV infection and fetal malformations. Any remaining doubts about the relationship between the virus and the consequences of intrauterine infection were eliminated on April 13, 2016, when investigators from the CDC reported that sufficient evidence had accumulated to infer a causal association between prenatal ZIKV infection, microcephaly, and other fetal malformations.…”