CDC Report Signals Achievement Of Scientific Consensus
On Causal Link Between Zika And Birth
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.”
The CDC’s review, conducted by a panel of experts led
by Sonja Rasmussen, examined the latest data from recent
outbreaks in Brazil and French Polynesia, including case studies,
epidemiologic data, and studies of fetuses from pregnant women
infected with Zika virus as well as infants suffering from
microcephaly. The panel assessed whether the data satisfied an
established set of criteria, known as Shepard’s criteria, that were
specifically created for determining whether maternal exposure to
infectious agents or poisons can be considered a direct cause of birth
defects. The authors argued that Zika satisfied the following four of
Shepard’s criteria, enough to conclusively establish causality:
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 linked 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.
(1)
https://tinyurl.com/zo88kqr
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