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From our Archives – May 2016 |
Author:
Roger Bernier, PhD, MPH Despite an unprecedented surge in cases of microcepaly during the Brazilian outbreak of Zika virus, scientists have been hesitant to draw a direct causal link between the virus and neurological birth defects. Uncertainties about classification and verification of microcephaly cases, a lack of neurological effects from related flaviviruses and the fact that at least some previous Zika outbreaks in the Pacific Islands did not result in any reported cases of microcephaly were all major factors contributing to the cautious approach of the global health community.
However, mounting
evidence has recently spurred global public health officials to
conclude that Zika infection during pregnancy can in fact cause
microcephaly and other neurological defects in the developing fetus.
Following a statement by the World Health Organization in late March
that there is now “strong scientific consensus that Zika virus is a
cause of Guillain-Barre syndrome, microcephaly and other neurological
disorders”, the Centers for Disease Control published results of a
formal review in the New England Journal of Medicine (1)
concluding definitively that “a causal relationship exists between
prenatal Zika infection and microcephaly and other serious brain
abnormalities.” As CDC director Thomas Frieden told the New
York Times, “There is no longer any doubt that Zika causes
microcephaly.” 1. Maternal Zika infection must take place at a critical time in prenatal development. Substantial evidence from case studies and reports, as well as analysis of the timing of confirmed Zika transmission in different regions of Brazil has shown that severe microcephaly and other brain abnormalities are associated with maternal infection during the first or early second trimester of pregnancy, a critical period for neurological development. Since the current outbreak of Zika virus, Brazil has experienced a dramatic increase in cases of infants born with microcephaly and other brain abnormalities. After reporting an average of 163 cases of per year prior to the outbreak, officials have now confirmed over 1100 cases of microcephaly in Brazil since October alone. 2. Careful delineation of clinical findings with a specific defect or syndrome rather than a broad range of defects. Neurological defects in fetuses and infants with presumed prenatal Zika infection have a typical pattern that has come to be referred to as “congenital Zika syndrome”. This syndrome is characterized by severe microcephaly, brain calcifications and other abnormalities, including some that are not commonly seen in cases of microcephaly such as redundant scalp skin. 3. There must be an association between a rare exposure and a rare event. Microcephaly is historically considered a rare event (6 infants per 10,000 in the US). While infection with Zika virus in Brazil during the outbreak would not be considered rare, CDC’s experts argue that infection of pregnant women traveling to Brazil for a short time during the epidemic should be considered a rare exposure. They cite a number of documented cases of pregnant women briefly traveling to areas experiencing the Zika outbreak, testing positive for Zika antibodies and the subsequent development of fetal brain abnormalities or as evidence of an association between a rare exposure and a rare event. The logic behind this criterion being that the combination of a rare event such as microcephaly with a rare exposure implies causality as there should be an extremely low probability of the two happening together. 4. The association should make biologic sense There is now a wealth of evidence that the Zika virus is neurotropic. Zika virus can cross the placenta and has been detected in amniotic fluid. Live Zika virus has also been isolated from the brain of a fetus with severe abnormalities following a confirmed maternal infection at 11 weeks of gestation, while Zika RNA has been found in brains and placenta of infants and fetuses with microcephaly. In addition, a recent study has found that Zika readily infects neural progenitor cells in culture, leading to cell death and decreased growth of the cell population, suggesting a putative mechanism underlying microcephaly. Further Questions One important criterion that CDC’s panel of experts did not feel has yet been satisfied is the requirement for two epidemiologic studies of high quality to support the association. While the authors do cite two epidemiologic studies that offer support, one from Brazil and another retrospective analysis on a smaller outbreak in French Polynesia, they felt that limitations, including small sample sizes, in these studies prevented them from satisfying this criterion. Interestingly, the Brazilian study found that fetal abnormalities were detected by ultrasound in 29% (12 out of 42) of pregnant women who tested positive for Zika virus, while authors of the French Polynesia study estimated that only 1% of mothers infected during the first trimester gave birth to infants with microcephaly.
The wide discrepancy
in these findings combined with the fact that multiple previous
outbreaks in the Pacific Islands resulted in no reported cases of
microcephaly demonstrates the critical need for a better understanding
of both the true risk to infants born to mothers infected with Zika
virus, as well as the additional risk factors that may be involved in
adverse birth outcomes. With the outbreak continuing to spread across
South and Central America, ongoing larger epidemiological studies will
hopefully be able to shed light on these pressing questions. For now,
the achievement of a global consensus that Zika is inked to
neurological birth defects will allow the public health community to
shift focus and resources to important topics related to control and
prevention, including mosquito control efforts, improvement of
diagnostic methods and the ongoing effort to develop an effective Zika
vaccine. ■ |
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