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We offer the hypothesis that some forms of cerebral white matter damage (WMD) in preterm neonates might be caused by transplacental viral infection of the fetus during the first or second trimester of pregnancy. Potts and colleagues1 speculated on the possible role of a human pestivirus (PV) in the aetiology of congenital microcephaly. We suggest PV might be a candidate virus for some form of WMD. We further offer our view that a virus induced cytokine cascade might place the fetus at double jeopardy—that is, disturb white matter development and lead to preterm birth.
Virus related WMD
White matter damage is the most important predictor of childhood neuromotor disability among those born preterm. About 50% of infants who have echolucent zones in the periventricular white matter or ventriculomegaly on neonatal cranial ultrasound scans subsequently develop cerebral palsy.2 The multiple expressions of WMD, both on histological examination and neonatal cranial ultrasound scan, as focal, multifocal, or diffuse WMD,3 make multiple aetiologies likely. Some forms of WMD might be related to a hypoxic–ischaemic insult, but others might be associated with infection.
Four types of WMD can be distinguished on the basis of their location, histological patterns, and ultrasonographic appearance.3The first two forms comprise unifocal haemorrhagic infarctions, leading to periventricular echodensities on neonatal cranial ultrasound images, and multifocal necroses, leading to hypoechoic ultrasound images often described as “periventricular leucomalacia” (PVL). Current textbooks focus on fetal or newborn hypoxia–ischaemia as the pathogenesis of focal and multifocal forms of WMD.4 This is supported by studies showing that periventricular white matter damage can be induced by ligating the carotid arteries of mongrel pups.5 However, comparable white matter lesions have been induced in various animal models using bacterial and viral challenges. Newborn kittens exposed to intraperitoneal bacterial endotoxin6 and the offspring of rabbits who were exposed to inoculation of Escherichia coli via hysteroscopy developed WMD.7 Maternal infection with pestiviruses led to dysmyelination in lambs8 9 and cystic changes in the developing periventricular white matter of lamb fetuses.10
The two remaining diffuse WMD subtypes are histologically defined by either astrocytosis or pyknotic nuclei. These diffuse forms of WMD are not readily identified on early neonatal cranial ultrasound images. Their tendency to impair myelination probably results in ventriculomegaly on late neonatal ultrasound scans. Such a diffuse process raises the possibility that either or both is induced by a generalised infection of the developing brain.
White matter involvement is common in viral infections of the central nervous system. White matter damage, disturbances of myelination, and subsequent microcephaly follow herpes simplex encephalitis,11 exposure to rubella virus in utero,12 13 14 and canine distemper virus infection.15 Microcephaly, dysmyelination, glial proliferation,16 ventricular enlargement, and extensive necroses in the white matter10 are associated with pestivirus infection. Because these types of damage so closely resemble those of WMD in preterm neonates, we suggest that human pestivirus is a likely mediator of virus induced WMD.
If an unidentified virus infection during pregnancy indeed leads to transplacental infection of the fetus and subsequent WMD, the subclinical nature of some virus infections during pregnancy17 might explain why a viral cause of WMD has not yet been identified.
The two major PVs in animals are border disease virus (BDV) and bovine virus diarrhoea virus (BVDV). Pestivirus infections were thought to occur exclusively in animals until Giangaspero and coworkers recently reported the presence of specific anti-BVDV antibodies in up to 87% of animal handlers and veterinarians.18 Since then, lower prevalences of 15–16% have been reported in adults.19 20 Among children under 2 years, pestivirus antigens were present in 24% of specimens from diarrhoea episodes that could not be explained by more common enteric pathogens.21Thus pestivirus infections occur in humans, although infection during pregnancy and a possible association with preterm birth or WMD have not yet been investigated.
Exposure to the pestivirus BDV of lambs leads to hypomyelination of their brains.9 Hypomyelination is a symptom of some diffuse forms of WMD.3 Infection with the pestivirus BVDV leads to necroses and cysts in the periventricular white matter and enlarged ventricles in lamb fetuses.10 All of these are expressions of WMD in preterm human babies.3 4
Infection with BDV is accompanied by a decrease in thyroid hormone activity in lambs.8 Low thyroid hormone values are also an important predictor of maldevelopment among preterm infants.22-24 After adjustment for gestational age, Reuss and colleagues23 found an 11-fold increased risk of disabling cerebral palsy among preterm infants with severe hypothyroxinaemia. What is still unclear is whether low thyroid hormone values are the cause of the brain damage or merely an indicator of illness severity and/or immaturity related vulnerability, which conveys risk information above and beyond that given by gestational age information.
Does a virus induced cytokine cascade cause both preterm birth and WMD?
A common antecedent of both preterm birth and WMD could serve as a likely explanation for why WMD is more common among preterm than term infants.25 A transplacental virus infection early in pregnancy potentially fulfills the criteria of such a common antecedent (fig 1).
One in four women with asymptomatic shedding of herpes simplex virus at the onset of labour gave birth before the completion of 37 weeks of gestation; this percentage was only 12% among unaffected controls.17 In two other studies not involving uninfected newborns for comparison, 41%26 and 48%27 of infants with neonatal herpes simplex infection were born before term. Herpesviridae stimulate the production of cytokines such as IL-1β and TNFα by peripheral blood mononuclear cells.28 29 In maternal intrauterine infection these cytokines are presumably involved in a pro-inflammatory cascade eventually leading to prostaglandin induced preterm uterine contractions.30 Thus cytokines might offer the molecular link between virus infection and preterm birth (fig 1; pathway 1).
We recently reviewed the evidence that the pro-inflammatory cytokines IL-1, IL-6, and TNFα are produced at various levels of the materno-fetal unit (placenta, fetal blood cells, fetal microglia and astrocytes), can enter the fetal brain after crossing the placenta and blood–brain barrier, and might damage the white matter via various mechanisms including direct tissue damage and endothelial and/or ependymal disruption.31 Cytokines might be involved in the cytopathic effect of pestivirus infection in animals.32 In parallel, we argue here that cytokines are likely to be involved in the proposed virus related aetiology of WMD in preterm human babies (fig 1, pathway 2). For example, astrocytes produce α and β interferons, as well as TNF and IL-6, after stimulation with a neurotrophic (Newcastle disease) paramyxovirus.33 These cytokines have also been associated with WMD in preterm babies.34-36
Recently, IFNα has been detected in 29% of cases of unexplained fetal ventriculomegaly but in only 1% of controls.37Although IFNα might merely be a marker of virus induced WMD (fig 1, pathway 3), white matter abnormalities38 and cerebral palsy39 are among the adverse effects of treatment with interferon. Therefore, a directly damaging effect of IFNα (fig 1, pathway 4) on the developing white matter is possible.
Testing the hypothesis
Our hypothesis that a transplacental human pestivirus infection might be involved in the aetiology of WMD in preterm neonates is difficult to test. We consider the epidemiological approach, and in particular a case–control study design to be most rewarding. If a human pestivirus-like infection is indeed related to WMD, then characteristics of such an infection should be found significantly more often among preterm newborns with WMD than among non-affected controls, while adjusting for potential confounders such as gestational age. Despite the necessity to conduct a large scale, multicentre study to obtain a sufficient number of WMD cases, we believe that the opportunity to identify a possibly preventable antecedent of WMD in the preterm neonate would be worth the effort.
This work was supported by National Institute for Neurologic Disorders and Stroke Grant NS 27306 and United Cerebral Palsy Research and Educational Foundation Grant R-712-96.