Published online March 1, 2006
PEDIATRICS Vol. 117 No. 3 March 2006, pp. 936-939 (doi:10.1542/peds.2005-2729)
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COMMENTARY

Congenital Arboviral Infections: Something New, Something Old

Theodore F. Tsai, MD, MPH

Asia-Pacific Medical Affairs, Wyeth Research, Collegeville, Pennsylvania

Abbreviations: JE, Japanese encephalitis • JEV, Japanese encephalitis virus • CNS, central nervous system • WNV, West Nile virus • SLE, St Louis encephalitis • SLEV, St Louis encephalitis virus • WEE, Western equine encephalitis

Many of the arboviruses (arthropod-borne viruses) of public health importance in the United States and globally were discovered in the 1930s; yet, with few exceptions, little is known of their potential for vertical transmission to the fetus or as teratogens.

The recognition of congenitally acquired infections may have been obscured in developing countries by high infant mortality rates, but, perhaps as importantly, where these infections are transmitted in an endemic pattern, acquired immunity may limit infections in females by the time they reach childbearing age. In these circumstances, the potential for a virus to cause intrauterine infections might not be detected until it is introduced into an immunologically naive population (or conversely, when an immunologically naive traveler to an area with endemic transmission is infected). The former situation occurred when Japanese encephalitis (JE), an endemic mosquito-borne flaviviral infection that has been recognized as a major cause of epidemic encephalitis in East Asia, possibly as early as the 19th century,1 was introduced into Northern India. JE viral infections occur ubiquitously in rural areas of the continent where viral transmission from a pig and rice paddy–breeding mosquito amplification cycle results in high immunity rates by adolescence in the rural population. Despite the high level of endemic infection and the documented occurrence of widespread outbreaks in Japan, China, and Southeast Asia since 1935 (when the virus was discovered), no cases of congenitally acquired JE infection were reported until 1980, when a series of epidemics in Uttar Pradesh, India, signaled the introduction of the virus into an area in which it had not been recognized previously. Among 9 reported cases that occurred during pregnancy, 4 led to miscarriage, and JE virus (JEV) was isolated from products of conception, including fetal brain, in 3 cases.2,3 Infection of the central nervous system (CNS) in these cases was consistent not only with the virus' neurotropism in postnatal infection but also with the well-established teratogenicity of JEV in piglets that die of in utero infection, often with fatal CNS malformations including hydranencephaly (Fig 1). The scale of economic losses to Asian farmers resulting from swine fetal wastage prompted the early development of live-attenuated and inactivated pig vaccines in Japan, China, and Taiwan, interventions that continue to be used in public veterinary prevention programs throughout the region.4


Figure 1
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  		FIGURE 1 Hydranencephaly of brain in a fetal pig (~113 days gestation) with intrauterine Japanese encephalitis virus infection. Courtesy of T. W. Hso, DVM.

 
In 1999, West Nile virus (WNV), a member of the JEV antigenic complex of flaviviruses (family Flaviviridae) discovered in 1937, was introduced into the Western hemisphere, paralleling in some respects the emergence of JEV in northern India. The novel introduction of WNV into the immunologically naive US population has led to an ongoing epidemic, numbering now in >16000 cases in the United States. St Louis encephalitis virus (SLEV), discovered in 1933 and is the only other member of the JEV complex transmitted in the United States, has been reported to occur only in sporadic, geographically discrete outbreaks since a national outbreak in 1976, and flaviviral immunity from other natural infections or vaccination remains uncommon in the United States except among immigrants from dengue-endemic countries (dengue viruses are flaviviruses also).

In this setting, the report in 2003 of a congenitally acquired WNV infection in an infant with chorioretinal scarring and CNS malformations was, perhaps, not unexpected.5 After additional WNV infections in pregnant women were reported in that transmission season, albeit without evidence of fetal infection or harm, the Centers for Disease Control and Prevention established a national registry to describe the frequency and outcomes of WNV infections in pregnancy.6 Results of surveillance from 2003–2004, reported in this month’s Pediatrics Electronic Edition by O'Leary et al,7 disclosed no conclusive evidence for fetal infection among 77 women whose infections occurred, approximately, one third each in the 3 trimesters of pregnancy. In an accompanying report by Paisley et al,8 549 cord blood samples from infants delivered at a Northern Colorado community hospital after an acute WNV outbreak in 2003 disclosed no serologically confirmed case of congenital infection. Although the number of exposed cases in the Centers for Disease Control and Prevention registry was limited, the proportion of spontaneous abortions and preterm and low birth weight infants within the cohort were within expectations. Also, in none of 3 cases with major malformations that plausibly could be associated with the timing of maternal infection was there laboratory evidence of a WNV etiology. None of the laboratory investigations of cord blood samples for viral-specific IgM and cord blood or cord tissue specimens for viral gene products by polymerase chain reaction provided conclusive evidence of an intrauterine infection. In 1 case, in which the mother had onset of WNV illness 4 days before delivery, the placenta was polymerase chain reaction–positive on the fetal side, and both infant and mother had a transient rash at delivery. However, serologic test results for the infant were ambiguous. In 3 other cases—one with onset of meningitis 10 days after delivery, another born with a transient rash, and the last with clinical encephalitis appearing at 7 days of age—signs of WNV infection in the perinatal or neonatal period plausibly could be associated with intrauterine infection occurring 6 days before, the day of, and 3 weeks before delivery, respectively. Postnatal transmission from breastfeeding or an independent mosquito-borne infection could not be ruled out in 2 of the cases. However, collectively, these cases begin to describe a possible pattern of congenital WNV infection presenting in the neonate, at or shortly after birth, after infection acquired in the third trimester of pregnancy.

These cases are reminiscent of similar cases of congenital Western equine encephalitis (WEE) virus infection reported >50 years ago. WEE is a mosquito-borne alphaviral infection that, like WNV now, was a major cause of epidemic encephalitis in the western United States. Combined outbreaks of WEE and SLE occurred perenially in the California Central Valley at that time; in the 1952 outbreak, Shinefield and Townsend9 described twin infants who developed encephalitis at 5 days of age, confirmed to be cases of WEE by significant rises in complement-fixing antibodies in appropriately timed serum specimens. Their mother, who had developed clinical signs of CNS infection 2 days before delivery, also had an elevated complement-fixing antibody titer, indicating a recent WEE virus infection. Additional details on the outcomes of WEE occurring earlier in pregnancy and any attendant impact on morphogenesis have not been reported. Nevertheless, evidence for a teratogenic potential exists for another alphavirus, Venezuelan equine encephalitis virus (VEEV), which has been associated with fatal CNS malformations in spontaneously aborted fetuses during epidemics and fetal loss after receipt of live attenuated vaccine.10–12 Similar malformations had been modeled in experimental VEEV infections of monkeys, strengthening the association.13 Reports of congenital infections with other alphaviruses, including Ross River virus (an alphaviral polyarthropathy), remain unsettled.14,15

For clinicians, the recognition of congenital infection associated with 2 of the principal arboviral infections transmitted in the United States begs the question of whether other arboviruses of public health importance such as SLEV, Eastern equine encephalitis (EEE) virus (also an alphavirus), or California encephalitis viruses (family Bunyaviridae) also exhibit such a potential. In individual cases, EEE, and SLE, infections complicated by coma during pregnancy were followed by the delivery of apparently normal infants who had cord blood IgM antibody evidence of congenital infection (unpublished observations). No systematic studies to expand on these observations have been reported. Strong evidence exists, however, for congenital infection with other flaviviruses, especially dengue virus, that in numerous cases has produced severe perinatal disease in both the parturient women and their infants and for Wesselsbron virus, an important veterinary pathogen that causes CNS malformations and abortions in sheep. Taken together, these observations suggest that SLEV could have a similar capacity for intrauterine infection, as do its antigenic cousins JEV and WNV.16,17 No cases of human congenital infection with La Crosse virus or other California serogroup viruses have been reported; however, results of an exploratory serologic study suggested an association between abnormal infant head size and Bunyamwera serogroup virus infections in their mothers.18 It may be noteworthy that viruses in the taxonomic group are established agents of an arthrogryposis-hydranencephaly malformation complex in sheep.19,20 Mindful of the circumstantial nature of these observations, clinicians should remain vigilant for the possibility of bunyaviral infection in neonates with a similar unexplained pattern of malformation.

Finally, the capacity of JEV, WNV, and dengue viruses to infect the fetus may have implications for the design of preclinical, clinical, and postlicensure studies of live flaviviral vaccines that are under development for the respective diseases. Surprisingly little is known about the possibility of congenital infection and adverse outcomes in pregnancy after administration of live yellow fever vaccine, the best characterized of the flaviviral vaccines. Observations on a limited number of exposures have disclosed frequencies of adverse clinical outcomes such as spontaneous miscarriages, premature births, and major malformations, within expected ranges.21–24 Less is known about the capacity of yellow fever 17D-derived vaccine viruses to infect the fetus. After mass yellow fever vaccination campaigns in which women who were unaware they were pregnant received vaccine inadvertently, 1 study found 1 of 41 with an apparently silent congenital infection documented by viral-specific IgM in a cord blood sample.25 In another study, none of 341 exposed infants had specific IgM at 3 months of age.24 Although specific IgG persisted in 7% of the infants at 12 months, the authors viewed the result as inconclusive evidence of congenital infection, because residual, passively acquired antibody could not be ruled out. Additional opportunistic studies during mass campaigns and registries, similar to the rubella vaccination in pregnancy scheme, will help to expand our understanding of the vaccine's safety when administered during pregnancy.


   FOOTNOTES
 
Accepted Nov 8, 2005.

Address correspondence to Theodore F. Tsai, MD, MPH, Asia-Pacific Medical Affairs, Wyeth Research, Collegeville, PA 19426. E-mail: tsait{at}wyeth.com

Financial Disclosure: Dr Tsai is a full-time employee of Wyeth Research.


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PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics




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