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Z
From Aix Marseille Université, Institut de ika virus (ZIKV) was discovered in Africa in 1947 and was first de-
Recherche pour le Développement (IRD), tected in Asia in 1966, yet its potential effect on public health was not rec-
Assistance Publique–Hôpitaux de Marseille,
Service de Santé des Armées, Vecteurs– ognized until the virus caused outbreaks in the Pacific from 2007 to 2015
Infections Tropicales et Méditerranéennes and began spreading throughout the Americas in 2015.1,2 The ability of ZIKV to
(VITROME), and Institut Hospitalo-Uni- cause congenital defects in fetuses and infants, as exemplified by the microcephaly
versitaire Méditerranée Infection, Marseille,
France (D.M.); private practice, Punaauia, epidemic in Brazil, is an unprecedented feature in a mosquito-borne viral infec-
Tahiti, French Polynesia (D.M.); Labora- tion.2-4 Although transmission of ZIKV has declined in the Americas, outbreaks
toire Eurofins Labazur Guyane, Eurofins, and infection clusters continue to occur in some regions, such as India and South-
French Guiana (D.M.); the Department
of Epidemiology of Infectious Diseases, east Asia, where there are large populations of women of childbearing age who
Yale School of Public Health, New Haven, are susceptible to the virus.5 We review the body of information that was acquired
CT (A.I.K.); Instituto Gonçalo Moniz, Funda- during the pandemic and discuss the epidemiologic trends, current knowledge
ção Oswaldo Cruz, Salvador, Brazil (A.I.K.);
and the Materno-foetal and Obstetrics Re- about the transmission and natural history of ZIKV infection and its sequelae, and
search Unit, Department Femme-Mère- the principles of diagnosis and clinical management.
Enfant, Centre Hospitalier Universitaire
Vaudois, and Faculty of Biology and Med-
icine, University of Lausanne, Lausanne, Epidemiol o gic Fe at ur e s
Switzerland (D.B.). Address reprint re-
quests to Dr. Musso at P.O. Box 380,222 ZIKV is a positive-sense RNA flavivirus in the family Flaviviridae, which also in-
Tamanu Punaauia, Tahiti, 98,713 French
Polynesia, or at didiermusso@mail.pf or cludes dengue (DENV), West Nile, yellow fever, and Japanese encephalitis viruses.6
dmusso12345@gmail.com. ZIKV was first isolated in 1947 in the Zika Forest in Uganda (Fig. 1),7 where trans-
N Engl J Med 2019;381:1444-57. mission of the ancestral African lineage of ZIKV was limited to enzootic circula-
DOI: 10.1056/NEJMra1808246 tion between nonhuman primates and sylvatic aedes mosquitoes, with sporadic
Copyright © 2019 Massachusetts Medical Society. spillover infection to humans.2 As ZIKV migrated to Asia, the Asian lineage of the
virus emerged (Fig. 2), which was capable of being transmitted by human-adapted
aedes mosquitoes (e.g., Aedes aegypti).1,2 Results of serologic and entomologic inves-
tigations suggest that ZIKV had an extensive geographic distribution in Africa and
Asia before 2007.1,9 However, fewer than 20 cases in humans were reported before
2007, and all had mild, self-limiting clinical manifestations.1,2,10
The first indications of a change in the epidemiology of ZIKV were the outbreaks
reported in the Pacific in the Yap Islands, Micronesia, in 2007 and French Polyne-
sia in 2013 and 2014, which were followed by pandemic spread of the virus to the
Figure 1 (facing page). Emergence and Spread of ZIKV and Timeline of the Zika Virus Pandemic.
Panel A shows the major epidemiologic events in the emergence and spread of Zika virus (ZIKV)
from its discovery in 1947 through 2018, including outbreaks during which cases of ZIKV-asso
ciated birth defects were identified in newborns (*). Panel B is a map of regions where con-
firmed cases of ZIKV infections have occurred from 2007 through 2018 (red) and areas where
Aedes aegypti is endemic but where ZIKV had not yet been identified (pink) as of 2018. Also
shown is the migration of African (blue arrow) and Asian (purple arrows) lineages of ZIKV during
its global emergence. The epidemiologic events associated with the spread of ZIKV are described
in detail in Figure S1 and Table S1 in the Supplementary Appendix.
A 1945 1955 1965 1975 2005 2010 2013 2014 2015 2016 2017 2018
Return to
Africa, 2015 Detection in
the Pacific, 2007
Discovery in Detection in
Africa, 1947 Asia, 1966
Detection in
the Americas, 2015
100,000 100
Reported Cases
No. of Reported Cases of ZIKV Infection
0 0
2006 2008 2010 2012 2014 2016 2018
Thailand Panama
Vietnam Nicaragua
Singapore Honduras
French Polynesia El Salvador
American Samoa Guatemala
Fiji Mexico
Tonga Martinique
China Guadeloupe
Japan Saint Barthelemy
Brazil U.S. Virgin Islands
Peru Puerto Rico
Ecuador Jamaica
Colombia Dominican Republic
French Guiana Haiti
Suriname Cuba
Venezuela United States
Figure 2. Reported Cases and Spread of the Virus during the Zika Pandemic.
Panel A shows the number of reported cases of ZIKV infection in the Americas, Pacific Islands, Africa, and Asia, as well as the cumulative
number of countries or territories worldwide that reported mosquito-borne transmission from January 2007 through December 2018.
Panel B shows a ZIKV time-resolved phylogenetic tree that was reconstructed by Nextstrain (https://nextstrain.org/zika, with permission
from Trevor Bedford and Richard Neher) with the use of 506 genomes from 32 countries sampled from February 2013 to September 2017.
The American subclade emerged from the Asian lineage and caused outbreaks throughout the Pacific Islands and the epidemic in the
Americas.6 The dashed line shows the estimated period (May through November 2013) when ZIKV was introduced into the Americas.8
The cluster of sequences that were obtained from outbreaks in Singapore in August 2016 and Thailand and Vietnam in 2016 and 2017,
which are indicated by an asterisk, are distinct from the sequences of pandemic strains from the Pacific Islands and the Americas.
Americas, the Caribbean, and Africa in 2015 duced into Brazil as early as late 2013 — more
(Fig. 1; and Table S1 in the Supplementary Ap- than 1 year before detection of the initial out-
pendix, available with the full text of this article break in the Americas (Fig. 2A and 2B).8 The
at NEJM.org).1,2,11-13 ZIKV may have been intro- ZIKV pandemic was an example of a “perfect
storm,” in which a new American subclade emergence and the risk of severe complications,
(strains isolated in the Americas) emerged from however, varied over time and with location. For
the Asian lineage of the virus (Figs. 1B and 2B) example, an increase in the Guillain–Barré syn-
and was introduced into a uniformly susceptible drome was observed during the 2015 and 2016
population that had not been previously exposed waves of ZIKV circulation in Brazil, whereas the
to ZIKV.8,14,15 The pandemic underscores the abil- increase in congenital malformations was de-
ity of the virus to be efficiently transmitted in tected mostly during the 2015 wave.3,24
aedes-infested settings and to spread across re- Although the pandemic yielded a large body
gions through human mobility and travel.1 of information about ZIKV, important knowl-
Another striking feature of the pandemic was edge gaps remain (Table S2 in the Supplemen-
the emergence of severe complications of ZIKV tary Appendix). Still unknown is whether the
infection. Clusters of the Guillain–Barré syn- ZIKV-associated complications that were iden-
drome were first identified during the outbreak tified during the pandemic were new emerging
in French Polynesia and later in the Americas phenomena — perhaps caused by the virus
(Fig. 1A).16,17 In Brazil, a dramatic increase in acquiring enhanced fitness, transmissibility, or
microcephaly cases was detected among new- disease severity phenotype — or had occurred
borns, which led to a declaration by the World previously but went undetected because of lim-
Health Organization (WHO) in February 2016 of ited surveillance or infrequent transmission.9,13
a public health emergency of international con- Data from in vitro studies and experimental
cern (Figs. 1A and 2A) and to the identification studies in animals suggest that ZIKV mutations
of a causal link between ZIKV and birth de- may increase the infectiousness of the virus in
fects.18-20 As of January 2018, more than 3700 the A. aegypti vector and the risk of fetal micro-
cases of congenital birth defects associated with cephaly.6,14,25,26 However, birth defects have been
ZIKV infection had been reported in the Ameri- associated with infections by strains that do
cas.21 However, accurate estimates of the burden not contain these mutations, and pathogen-
of the Guillain–Barré syndrome and birth de- specific markers that predict the risk of birth
fects attributable to ZIKV infection have been defects have not been identified.5 Therefore,
hampered by a lack of systematic surveillance of ZIKV strains not harboring these mutations can-
these syndromes before and during the pandem- not be considered low-risk, as was suggested by
ic.22 Initial reports overestimated microcephaly health authorities during the 2018 outbreak in
case numbers in Brazil because a sensitive yet India.
nonspecific case definition was used before the ZIKV and DENV share antigenic similarities
INTERGROWTH-21st reference-based standards and have overlapping geographic distributions.1
(https://intergrowth21.tghn.org/standards-tools/) The effect of preexisting immunity against flavi-
were implemented.22 Furthermore, accurate ascer- viruses on ZIKV infection outcomes — whether
tainment of microcephaly requires multiple mea- the immunity is elicited by infection or by im-
surements after birth, as shown by an investigation munization with flavivirus vaccines — is a matter
in Paraíba, Brazil, that confirmed microcephaly of debate. Laboratory investigations have yielded
in only 55% of infants who were initially re- contradictory findings with respect to whether
ported to have the condition.4 At present, con- DENV infection elicits an immune response that
genital birth defects have been reported only in protects against ZIKV infection or exacerbates
cases of infection by ZIKV strains belonging to infection by way of antibody-dependent enhance-
the Asian lineage, including those identified dur- ment.27,28 Prospective studies in humans showed
ing a 2016 outbreak in Angola.23 that prior dengue infection and preexisting anti-
The high infection rate in affected popula- DENV antibodies reduced rather than enhanced
tions was a major contributing factor to the de- the risk of ZIKV infection and disease.15,29 Fur-
tection of ZIKV-associated complications and to ther investigation is needed to determine wheth-
the disease burden of those complications dur- er these findings are generalizable across re-
ing the pandemic. In communities at the epicen- gions in which ZIKV has emerged, whether they
ter of the microcephaly epidemic in northeast apply to severe ZIKV-associated outcomes such
Brazil, more than 60% of the exposed popula- as the Guillain–Barré syndrome and birth de-
tion was infected.15,19 The magnitude of the ZIKV fects, and whether differing amounts or types of
Congenital 5–14%
20–30% Zika (microcephaly
Fetuses and Neonates Syndrome 4–6%)
with Infection
Asymptomatic
Medium- and long-
term sequelae
79–91%
70–80%
Fetuses and Neonates Uninfected
without Infection
to ZIKV by vertical transmission had no signs or Figure 4 (facing page). Clinical and Imaging Findings
symptoms of congenital Zika syndrome in the of Congenital Zika Syndrome.
first week of life.46 The majority of reports of Images illustrate selected features18 ,46,54-59 of the mani-
ZIKV-associated fetal and infant outcomes did festation of congenital Zika syndrome in fetuses and
not ascertain fetal infection due to vertical trans- newborns. Prenatal neurosonograms of fetuses with
mission. Figure 3 therefore summarizes the evi- ZIKV infection (Panels A, B, and C, at 22, 22, and 26
weeks of gestation, respectively) show linear calcifica-
dence on the proportions of fetal loss and con- tions (Cal, arrows, Panels A and B), increased pericere-
genital Zika syndrome that occurred among bral spaces (S, Panels A and B), ventriculomegaly (V,
fetuses of women who were infected with ZIKV Panel A), cortical thinning (C, Panel A), and dysgenesis
during pregnancy (see also Table S3 in the Sup- of the corpus callosum (arrow, Panel C). MRIs of a fetus
plementary Appendix). with ZIKV infection at 32 weeks of gestation (Panels D,
E, and F) show microcephaly (Panel D), hypoplasia of
Although infective ZIKV particles have been the cerebellum and vermis (arrow, Panel D), premature
detected in breast milk, milkborne transmission closure of the fontanels and partial collapse of the skull
has not been confirmed as a mode of transmis- (Panel D), increased pericerebral spaces (S, Panel E),
sion.47 At present, the WHO recommends that ventriculomegaly (V, Panel E), cortical thinning (C,
mothers with possible or confirmed ZIKV infec- Panel F), and dysgenesis of the corpus callosum and
gyral anomalies (Panel E). Photographs of three infants
tion continue to breast-feed their infants. — one at 1 week of age (Panels G and H) and 10 months
of age (Panel I); the second at 14 days of age (Panels J
and K); and the third at 51 days of age (Panel L) — show
Cl inic a l M a nife s tat ions findings of severe disproportionate microcephaly and
The majority (50 to 80%) of ZIKV infections are cranial dysmorphism (Panels G through L), arthrogry-
posis (arrow, Panel H), strabismus (Panel I), neck rigid
asymptomatic.1,2,9,11-13 Symptomatic ZIKV infec- ity caused by axial hypertonicity (Panel K), and talipes
tion has an incubation period of 3 to 14 days and equinovarus (arrow, Panel L).
is a mild illness, with a duration of up to 1 week,
that manifests as a rash, low-grade fever, arthral-
gia and myalgia, and conjunctivitis.1,11,12 Compli- the prognosis of ZIKV-associated Guillain–Barré
cations are infrequent, but when they occur, they syndrome was similar to that of Guillain–Barré
are severe and may be fatal (Fig. 3).1 The mani- syndrome associated with other infectious or non-
festations of acute ZIKV infection are similar infectious processes; however, findings from a
across age groups, in both sexes, and in preg- case–control study suggest that ZIKV-associated
nant women. Although ZIKV shows broad cellu- Guillain–Barré syndrome results in higher mor-
lar tropism, the striking feature of the clinical bidity and more frequent cranial neuropathy.51,52
manifestation is the neurologic complications Other autoimmune disorders, such as thrombo-
that result from postinfectious immune response cytopenic purpura, have also been associated
or direct viral neurotropism.48 with ZIKV infection.
A B C
S
C S
Cal
V
Cal
D E F
G H I
J K L
caused by a neurogenic process.55 Although these ciated microcephaly (Fig. 3, and Table S3 in the
anomalies are seen in other congenital infec- Supplementary Appendix).18,43-46,56,57 A study in-
tions, they appear to be more frequently associ- volving pregnant women from Rio de Janeiro
ated with congenital Zika syndrome.55 used a broader definition for ZIKV-associated
Newborns of women infected with ZIKV dur- outcomes and identified adverse outcomes in 42%
ing pregnancy have a 5 to 14% risk of congenital of fetuses and infants exposed to the virus.18
Zika syndrome and a 4 to 6% risk of ZIKV-asso- Although ZIKV infection in any trimester of
pregnancy may cause congenital Zika syndrome, mission and outcomes. Differences may also
the risk is greatest with infections occurring in reflect regional variation in transmission and in
the first trimester.18,43,44,56 Exposures to pesticides, the severity of complications. The full spectrum
toxins, medications, and maternal immuniza- and risk of congenital Zika syndrome therefore
tions have not been found to be risk cofactors.4,46 remain incompletely delineated.
Neonatal mortality in the first week of life
among infants with congenital Zika syndrome Di agnosis
may be as high as 4 to 7%; better estimates of
neonatal mortality past the first week of life are Since the clinical manifestation of acute ZIKV
needed.18,46 The absence of clinical and radio- infection is nonspecific, a definitive diagnosis
logic abnormalities indicative of congenital Zika relies on nucleic acid testing or serologic testing
syndrome at birth (Fig. 4) does not exclude the (Table 2, and Table S4 in the Supplementary Ap-
risk of abnormalities such as seizures, hearing pendix). Nucleic acid testing should be performed
loss, visual impairment, dysphagia, and develop- on whole blood or serum samples obtained dur-
mental delay later in life (Fig. 3). Among U.S. ing the first days of illness. However, testing paired
children who were born to mothers infected blood and urine samples obtained within 2 weeks
with ZIKV during pregnancy and who had no after the onset of illness is recommended given
identified birth defects, 9% had at least one the potentially prolonged duration of ZIKV RNA
neurodevelopmental abnormality before they in these fluids.60,63 Although ZIKV RNA detec-
reached 2 years of age, a finding that under- tion provides conclusive evidence of an infec-
scores the need for long-term surveillance of chil- tion, a negative result does not rule out the di-
dren born to mothers with ZIKV infection.46,57-59 agnosis.60,64 A positive nucleic acid test shows the
The use of varying definitions of cases and presence of ZIKV RNA but does not necessarily
complications, in particular microcephaly, as well indicate the presence of infectious virus.
as inclusion of suspected but unconfirmed cases Serodiagnosis is complicated by false positive
and bias in case reporting may have contributed results owing to cross-reactivity in persons who
to observed differences among studies in trans- have been exposed to other flaviviruses.60 Screen-
Patient Population and ZIKV Exposure ZIKV Laboratory Investigations (Schedule) Other Evaluations (Schedule)
Possible associated Guillain–Barré Paired serum and urine; testing of cere- Serum; testing of cerebrospinal fluid Nerve conduction studies
syndrome brospinal fluid should be considered should be considered Cerebrospinal fluid chemical analysis
Presenting for preconception screening Not recommended Not recommended Not recommended
Pregnant women
Possible ZIKV exposure; symptomatic Paired serum and urine (ASAP, up to Serum (ASAP, up to 12 weeks after Ultrasonography (at 18–22 weeks of gestation)
12 weeks after onset of illness) onset of illness) Serial ultrasonography (every 3–4 weeks)†‡
No universal recommendation for amniocentesis§
Possible ongoing ZIKV exposure; Paired serum and urine (at initial visit Not recommended Ultrasonography (at 18–22 weeks of gestation)
asymptomatic and during each trimester) Serial ultrasonography (every 3–4 weeks)†‡
No universal recommendation for amniocentesis§
Possible recent ZIKV exposure; no ongoing Paired serum and urine (ASAP, up to Serum (ASAP, up to 12 weeks after Ultrasonography (at 18–22 weeks of gestation)
n e w e ng l a n d j o u r na l
exposure; asymptomatic 12 weeks after onset of illness)† onset of illness)† Serial ultrasonography (every 3–4 weeks)†‡
Newborns
No findings of congenital Zika syndrome; Not recommended Not recommended Physical and neurologic examination at birth and at each
mother had possible ZIKV exposure (not follow-up visit
laboratory-confirmed) or was not tested
Downloaded from nejm.org on October 9, 2019. For personal use only. No other uses without permission.
No findings of congenital Zika syndrome; Paired serum and urine (within 2 days Serum (within 2 days after birth) Physical and neurologic examination at birth
mother had laboratory-confirmed ZIKV after birth) Head circumference retested 24 hours after birth
exposure during pregnancy Ultrasonography of the head by 1 month of age; consider
MRI if available
Ophthalmologic examination by 1 month of age
AABR testing by 1 month of age
Zik a Virus Infection
* Adapted from Centers for Disease Control and Prevention60,61 and World Health Organization62 recommendations. AABR denotes automated auditory brainstem response, and ASAP as
Screening for other causes of fetal abnormalities (genetic,
findings who is born to a mother with laboratory-con-
Same as for an infant without congenital Zika syndrome ing pregnancy. However, the response to the Zika
§ Amniocentesis has not been universally recommended because of the risk of false negative results and potential for iatrogenic pregnancy loss. The decision to pursue amniocentesis
Repeat serologic test in mother if previous results were
crisis, including the declaration by the WHO of
a public health emergency of international con-
cern, was enormous, as exemplified by the iden-
Other Evaluations (Schedule)
‖ Additional consultations may include infectious disease specialist, clinical geneticist, neurologist, or other clinical specialists, depending on clinical findings in the infant.
vice, and additional consultations‖ tification of the causal link between ZIKV and
firmed exposure during pregnancy
The ZIKV pandemic has waned, but the virus We thank the patients and their families who agreed to pro-
vide their photographs and radiologic images; Bruno Schaub,
still poses a public health threat, as shown by M.D., Michèle Bru-Gueneret, M.D., and Eugénie Jolivet, M.D.
continued reports of outbreaks in Asia, India, and (Pluridisciplinary Center for Prenatal Diagnosis, University Hos-
Africa. Although at present we do not have the pital of Martinique, France), for providing ultrasound images;
Clara Adenet, M.D., Tiphaine Cassan, M.D., and Catherine Lom-
tools to predict where and when the next large bard, M.D. (Unit of Radiology for Mother and Child, University
epidemic will happen, the large numbers of sus- Hospital of Martinique, France), for providing magnetic reso-
ceptible persons residing in aedes-infested re- nance images; Federico Costa, Ph.D., Adriana Mattos, M.D., An-
tonio Raimundo de Almeida, M.D., Ph.D., and Nivison Nery Jr.,
gions make a reemergence of ZIKV likely. Thus, M.Sc. (Federal University of Bahia and Oswaldo Cruz Founda-
there is a critical need to mobilize support and tion, Brazil), for their assistance in obtaining patient photo-
improve capacity in low- and middle-income graphs; Marie Solignac (Tahiti, French Polynesia) for assistance
in the design of the maps; Marcos Espinal, M.D., Ph.D., and
countries to respond to future ZIKV epidemics Thais dos Santos, M.Sc. (Pan-American Health Organization),
and the next emerging pathogens. for providing data on reported cases of ZIKV infection; Manon
Dr. Ko reports holding pending patent PCT/US2018/031540 Vouga, M.D., Milos Stojanov, Ph.D., and Leo Pomar, M.Sc. (Ob-
on methods and compositions for the detection of flavivirus in- stetric Research Unit, University Hospital of Lausanne, Switzer-
fections, licensed to the University of Pittsburgh. No other po- land), for critical review of the manuscript; and Nathan
tential conflict of interest relevant to this article was reported. Grubaugh, Ph.D. (Yale School of Public Health, United States),
Disclosure forms provided by the authors are available with for his contribution to phylogenetic analyses and critical review
the full text of this article at NEJM.org. of the manuscript.
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