n engl j med 371;15 nejm.

org october 9, 2014

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Deep-Brain Stimulation
Tourettes syndrome (see inter-
active graphic, available with the
full text of this article at NEJM
.org). DBS therapy is
usually considered
only after all other
treatments have been exhausted,
but becoming bionic has pro-
vided many patients with a new
lease on life. Thanks in large
part to the contributions of two
extraordinary scientists, we have
entered the era of human neural-
network modulation.
Disclosure forms provided by the author
are available with the full text of this article
at NEJM.org.
From the Departments of Neurology and
Neurosurgery, University of Florida Health
Center for Movement Disorders and Neuro-
restoration, McKnight Brain Institute, and
University of Florida College of Medicine
all in Gainesville.
This article was published on September 8,
2014, at NEJM.org.
1. Alexander GE, DeLong MR, Strick PL. Par-
allel organization of functionally segregated
circuits linking basal ganglia and cortex.
Annu Rev Neurosci 1986;9:357-81.
2. Bergman H, Wichmann T, DeLong MR.
Reversal of experimental parkinsonism by le-
sions of the subthalamic nucleus. Science
1990;249:1436-8.
3. Benabid AL, Pollak P, Louveau A, Henry
S, de Rougemont J. Combined (thalamot-
omy and stimulation) stereotactic surgery
of the VIM thalamic nucleus for bilateral
Parkinson disease. Appl Neurophysiol 1987;
50:344-6.
4. Krack P, Batir A, Van Blercom N, et al.
Five-year follow-up of bilateral stimulation of
the subthalamic nucleus in advanced Parkin-
sons disease. N Engl J Med 2003;349:1925-
34.
5. Okun MS. Deep-brain stimulation for
Parkinsons disease. N Engl J Med 2012;367:
1529-38.
DOI: 10.1056/NEJMp1408779
Copyright 2014 Massachusetts Medical Society.
2009 H1N1 Influenza and Pregnancy 5 Years Later
Sonja A. Rasmussen, M.D., and Denise J. Jamieson, M.D., M.P.H.
I
n April 2009, a novel influen-
za A virus, now referred to as
influenza A(H1N1)pdm09 virus
(2009 H1N1), was identified in
two children in California, and
shortly thereafter, the second
U.S. death associated with 2009
H1N1 occurred in a previously
healthy pregnant woman. The
virus spread rapidly throughout
the United States and the world,
and on June 11, 2009, the World
Health Organization raised the
global pandemic alert to 6, its
highest level. Five years have now
passed since that pandemic, and
in that time, much has been
learned about influenzas effects
on pregnant women and infants.
Nevertheless, cases of severe in-
fluenza illness, hospitalizations,
and deaths among young and
middle-aged adults, including
pregnant women, were reported
during the 20132014 influenza
season, when 2009 H1N1 was
again the predominant circulat-
ing influenza virus in the United
States.
1
These severe outcomes
among pregnant women prompt-
ed us to review lessons learned
from the pandemic and ways of
reducing influenzas effects dur-
ing pregnancy in future influen-
za seasons.
Although data were available
before the 2009 pandemic sug-
gesting that pregnant women
were at increased risk for influ-
enza-associated complications, the
pandemic provided solid data
on this vulnerability.
2
Pregnant
women with 2009 H1N1 influ-
enza were at substantially higher
risk for hospitalization than the
general population, and they ac-
counted for approximately 5% of
deaths from 2009 H1N1 influenza
that were reported to the Centers
for Disease Control and Preven-
tion (CDC), even though preg-
nant women make up only about
1% of the population. Moreover,
the 2009 pandemic virus was
also bad for babies: infants born
to women who had been severely
ill with influenza complications
had increased risk for adverse
outcomes such as preterm birth
or small size for gestational age.
2
The 2009 H1N1 pandemic
brought a change in our approach
to treating influenza in pregnan-
cy. Previously, pregnant women
with influenza had been treated
primarily if they had other high-
risk medical conditions or severe
disease. During the 2009 pan-
demic, however, the CDC recom-
mended that empirical antiviral
therapy be initiated as soon as
possible during the clinical course
if the patient was pregnant or
had recently delivered. This rep-
resented a significant shift in
antiviral treatment guidance: it
was recommended that pregnant
women with suspected 2009
H1N1 influenza receive prompt
antiviral therapy, regardless of
risk factors, severity of illness,
history, or the results of diagnos-
tic testing.
2
Before the pandemic, we had
little information on the benefits
of treating pregnant women with
an antiviral medication, since
pregnant women had been ex-
cluded from clinical trials of
these medications. During the
pandemic, we learned that treat-
ing pregnant women with such
a medication makes a difference.
An interactive
graphic is avail-
able at NEJM.org
The New England Journal of Medicine
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PERSPECTI VE
n engl j med 371;15 nejm.org october 9, 2014
1374
A recent systematic review and
meta-analysis examining the ef-
fects of antiviral medications on
mortality due to 2009 H1N1 in-
fluenza among hospitalized preg-
nant women revealed that women
who received a neuraminidase
inhibitor within the first 2 days
after the onset of symptoms were
about one fifth as likely to die as
women who were treated later or
not at all.
3
In addition, although
treatment of influenza has been
shown to be most effective if ini-
tiated in the first 48 hours after
symptom onset, observational
studies have shown that starting
treatment even after 48 hours
has clinical benefit.
2
With in-
creased use of antiviral medica-
tions, it became possible to col-
lect data regarding their safety
during pregnancy, and the find-
ings have been reassuring.
4
Since the 2009 pandemic, much
more information has also become
available about the safety and
benefits of influenza vaccination
during pregnancy. Receiving an
influenza vaccine reduces the risk
of influenza not only for the
pregnant woman but also for her
infant during the first 6 months
of life. In addition, some studies
have shown reduced frequencies
of adverse outcomes such as
small size for gestational age
and preterm birth among infants
whose mothers received influen-
za vaccine during pregnancy.
2
We have also gained knowl-
edge about the barriers to and
motivators for influenza vacci-
nation during pregnancy. We
know that recommendations from
health care providers are a criti-
cal motivator for pregnant women
to be vaccinated. We also know
that pregnant women are con-
cerned about the safety of influ-
enza vaccine and are more likely
to be vaccinated if they under-
stand the benefits, especially to
their infants. The CDC used
knowledge about these barriers
and motivators and worked close-
ly with key partners such as the
American College of Obstetricians
and Gynecologists in order to in-
crease vaccine coverage.
Yet reports of pregnant women
becoming severely ill from or dy-
ing of 2009 H1N1 influenza dur-
ing the 20132014 influenza sea-
son were sadly reminiscent of the
pandemic 5 years ago, when we
received many calls from clini-
cians caring for critically ill or
dying pregnant women. Why are
pregnant women still getting so
sick and dying from influenza?
In part, the problem may arise
from misconceptions about influ-
enza or its prevention or treat-
ment that lead to missed oppor-
tunities for preventing influenza
illness or its complications dur-
ing pregnancy.
Despite our knowledge about
the benefits and safety of influ-
enza vaccine and recommenda-
tions from the Advisory Commit-
tee on Immunization Practices
and the American College of Ob-
stetricians and Gynecologists,
not all pregnant women get vac-
cinated. Substantial increases in
vaccination coverage occurred dur-
ing and after the pandemic, but
since the 20102011 season, cov-
erage has remained relatively
stagnant at less than 50%. Fewer
pregnant women follow the rec-
ommendation to receive influen-
za vaccine than follow other
health care recommendations; for
example, in keeping with CDC
guidelines, more than 85% of
pregnant women are screened for
group B streptococcus infection.
5

Some pregnant women, and even
a few clinicians, remain con-
cerned about vaccine safety, espe-
cially regarding vaccination dur-
ing the first trimester, even
though the evidence indicates
that influenza vaccination is safe
during pregnancy.
2
Similarly, not all pregnant
women with suspected influenza
receive treatment with oseltami-
vir, despite the current guide-
lines. We have four main recom-
mendations regarding treatment
during pregnancy. First, since
some women with signs and
symptoms of influenza may not
seek treatment promptly, health
care providers need to educate
pregnant women about these
signs and symptoms and the need
for early treatment.
Second, treatment should be
based on clinical evaluation rather
than on diagnostic testing, given
the limited sensitivity of rapid in-
fluenza antigen tests and the
time required for more definitive
testing. The sensitivity of the
rapid tests is generally 40 to 70%
of that of viral culture or reverse-
transcriptasepolymerase chain
reaction, and a sensitivity range
as wide as 10 to 80% has been
reported which means that
false negative results are common.
Treatment should not be delayed
until the results of more defini-
tive testing become available.
Third, pregnant women should
be treated regardless of whether
they have been vaccinated, be-
cause influenza vaccine is only
about 60% effective.
Finally, although it is ideal to
begin treatment with antiviral
medications less than 48 hours
after symptoms begin, there is
still clinical benefit when treat-
ment is begun later.
Five years ago, reports of se-
vere illness and deaths of preg-
nant women from H1N1 influenza
called attention to questions about
influenza during pregnancy and
led to a large number of publica-
tions and vastly improved knowl-
edge about influenza and its
treatment and prevention in this
2009 H1N1 Influenza and Pregnancy 5 Years Later
The New England Journal of Medicine
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Copyright 2014 Massachusetts Medical Society. All rights reserved.
n engl j med 371;15 nejm.org october 9, 2014
PERSPECTI VE
1375
2009 H1N1 Influenza and Pregnancy 5 Years Later
population. Unfortunately, preg-
nant women continue to become
seriously ill with influenza, and
some of them die. Research is
need ed to further elucidate the
reasons why some pregnant wom-
en are not vaccinated so that the
problems can be addressed. In ad-
dition, by implementing the cur-
rent antiviral treatment recom-
mendations, clinicians can prevent
complications in women with
influenza. We need to ensure
that the information about in-
fluenza and pregnancy that has
been gained in the 5 years since
the 2009 H1N1 pandemic is
translated into reductions in the
number of illnesses, hospitaliza-
tions, and deaths that occur in
future influenza seasons.
Disclosure forms provided by the authors
are available with the full text of this article
at NEJM.org.
From the Centers for Disease Control and
Prevention, Atlanta.
1. Uyeki TM. Preventing and controlling in-
fluenza with available interventions. N Engl J
Med 2014;370:789-91.
2. Rasmussen SA, Jamieson DJ. Influenza
and pregnancy in the United States: before,
during, and after 2009 H1N1. Clin Obstet
Gynecol 2012;55:487-97.
3. Muthuri SG, Venkatesan S, Myles PR, et al.
Effectiveness of neuraminidase inhibitors in
reducing mortality in patients admitted to
hospital with influenza A H1N1pdm09 virus
infection: a meta-analysis of individual par-
ticipant data. Lancet Respir Med 2014;2:395-
404.
4. Wollenhaupt M, Chandrasekaran A, Tomi-
anovic D. The safety of oseltamivir in preg-
nancy: an updated review of post-marketing
data. Pharmacoepidemiol Drug Saf 2014.
5. Prevention of perinatal group B strepto-
coccal disease revised guidelines from
CDC, 2010. MMWR Recomm Rep 2010;59:
1-36.
DOI: 10.1056/NEJMp1403496
Copyright 2014 Massachusetts Medical Society.
Ebola A Growing Threat?
Heinz Feldmann, M.D.
T
he recent emergence of Zaire
ebolavirus in West Africa
1
has
come as a surprise in a region
more commonly known for its
endemic Lassa fever, another vi-
ral hemorrhagic fever caused by
an Old World arenavirus. Yet the
region has seen previous ebolavi-
rus activity (see map). In the mid-
1990s, scientists discovered Cte
dIvoire ebolavirus (now known as
Ta Forest ebolavirus) as a cause of
a single reported nonfatal case in
a researcher who per-
formed a necropsy on
an infected chimpan-
zee. The episode initiated a major
research investigation in and
around the Ta Forest region
an effort that failed to identify the
reservoir of this new Ebola spe-
cies. Since that incident, West Af-
rican countries have not reported
any evidence of the presence of
ebolavirus.
Ebolaviruses belong to the
family Filoviridae, a taxonomic
group of enveloped, nonsegment-
ed, negative-strand RNA viruses
that includes the genera marburg-
virus and cuevavirus, with a sin-
gle species each, and ebolavirus,
with five distinct species (see
figure). All known African ebola-
viruses can infect humans and
cause similar symptoms, but they
vary in terms of disease progres-
sion and virulence, with case fa-
tality rates ranging from less than
40% for Bundibugyo ebolavirus to
approximately 50% for Sudan ebola-
virus to 70 to 90% for Zaire ebola-
virus.
2
The virulence of Ta Forest
ebolavirus is difficult to assess be-
cause there has been only a single
recorded case, and the only iden-
tified Asian species, Reston ebola-
virus, seems to cause asymptom-
atic infection in humans.
Humans infected with ebola-
viruses commonly present initial-
ly with nonspecific symptoms
such as fever, vomiting, and se-
vere diarrhea, with visible hemor-
rhage occurring in less than half
the cases,
2
as in the current out-
break.
1
Owing to poor infra-
structure, biosafety concerns as-
sociated with processes of patient
care and autopsy, and the essen-
tial focus on disease contain-
ment during outbreaks, there has
been little empirical study to
elucidate the pathogenesis or pa-
thology of human ebolavirus in-
fection. The closest surrogate dis-
ease models are cynomolgus and
rhesus macaques, which show
clinical signs of viral hemorrhag-
ic fever when infected with most
ebolaviruses. Zaire ebolavirus is uni-
formly lethal in these macaques,
and experts have assumed that its
pathology and pathophysiology
closely resemble those of ebola-
virus infections in humans; im-
munosuppression, increased vas-
cular permeability, and impaired
coagulation have been identified
as hallmarks of the disease.
2

Evidence of microscopic hemor-
rhage is usually found, but the
degree of bleeding ranges from
undetectable to acutely visible.
The recently introduced term Eb-
ola virus disease may not con-
vey the seriousness of a viral
hemorrhagic fever, a clinical syn-
drome that should trigger isola-
tion guidelines that ensure ap-
propriate case management and
implementation of infection-con-
trol measures.
Updates on the
Ebola outbreak are
available at NEJM.org
The New England Journal of Medicine
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Copyright 2014 Massachusetts Medical Society. All rights reserved.