JBRA Assist. Reprod. 2016;20 (3):159-164
SBRA PAGES
doi: 10.5935/1518-0557.20160034
SBRA - Brazilian Society of Assisted Reproduction Committee.
1GENESIS - Center for Assistance in Human Reproduction, Brasília, DF, Brazil
2Pontifical Catholic University of Minas Gerais, Belo Horizonte, MG, Brazil,
3CENAFERT, Salvador, BA, Brazil
4School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil
5President of SBRA - Brazilian Society of Assisted Reproduction
CONFLICT OF INTERESTS
No conflict of interest have been declared.
ABSTRACT
Although the causality between Zika virus, microcephaly, and other
central nervous system disorders has been taken for granted by the
scientific community, many uncertainties remain. The gap of knowledge
at the moment is large enough to remove part of the confidence
physicians have on the advice given to patients – and infertile women
in particular – on their reproductive plans. Pretreatment serologic
screening is a possible strategy to offer more confidence for
individuals choosing to bear children regardless of the Zika virus, but
the tests currently available do not seem to be sufficiently adequate.
Until now, there is no formal recommendation to avoid pregnancy solely
because of the Zika virus outbreak, and the choice of becoming pregnant
has been regarded as a personal decision to be made by each woman and
her family.
Keywords: Zika, microcephaly, human reproduction, bioethics, central nervous system disorders.
Zika virus
In the middle of the last century, child bearing was considered a
natural phenomenon, the outcome of the reproductive union of a couple.
Conception was seen as something final, and did not arouse greater
speculations or questions from society or science. The desire to have
children is an innate sense, inherent to the protection and survival of
all species, but with the advent of the Zika virus (ZIKV), women have
been advised to postpone pregnancy. The advocates of such advice find
support in the association between ZIKV, microcephaly, and other
disorders of the central nervous system (CNS), and in the observation
of other adverse events with the offspring.
ZIKV is a flavivirus closely related to the dengue, West Nile, Japanese
encephalitis and yellow fever viruses. In humans, it causes a disease
known as the Zika fever. The virus was first isolated in 1947 from the
serum of a Rhesus monkey in the Zika forest in Uganda; the virus was
isolated in humans in 1954 in Nigeria. Evidences of human infection
have been reported in other African countries such as Uganda, Tanzania,
Egypt, Central African Republic, Sierra Leone, and Gabon, and in parts
of Asia including India, Malaysia, the Philippines, Thailand, Vietnam
and Indonesia from 1951 to 1981 (World Health Organization, 2015).
The disease is transmitted by the Aedes aegypti and other Aedes
mosquito species, such as Aedes africanus, Aedes apicoargenteus, Aedes
furcifer, Aedes luteocephalus and Aedes vitattus. In 2009, it was
suggested that ZIKV could also be sexually transmitted between humans.
Professor Brian Foy, a biologist of the Arthropod-borne and Infectious
Disease Laboratory at Colorado State University, visited Senegal and
was bitten on several occasions during his research. A few days after
returning to the United States, Foy showed symptoms of ZIKV fever, but
not before having sex with his wife, who later developed symptoms of
the disease. Foy was the first person known to have transmitted the
virus to another human being by sexual contact (Taitson, 2016; Campos et al., 2015).
ZIKV infection was first detected in Northeastern Brazil in early 2015,
in several patients presenting mild fever, rash, conjunctivitis and
arthralgia. On April 29, 2015, researchers at the Federal University of
Bahia (UFBA) reported the identification of ZIKV by reverse
transcription polymerase chain reaction (RT-PCR) in eight of 25 samples
collected in the region of the city of Camaçari (MICROCEFALIA - Ministério da Saúde divulga boletim epidemiológico –Brazil, 2015).
On May 9, 2015, the Oswaldo Cruz foundation (Fiocruz) identified ZIKV
by the same technique in eight of 21 samples collected in the city of
Natal, in the state of Rio Grande do Norte (Zanluca et al, 2015).
Since then, almost all Brazilian states have identified the circulation
of suspected cases of ZIKV fever; the autochthonous transmission of
ZIKV has been confirmed in 38 countries and/or territories in the
Americas. According to official Epidemiologic Report number 25 (ER25)
from the Public Health Emergency Operations Center on Microcephaly,
there had been ten confirmed cases of sexually transmitted ZIKV
infection until May 5 in five countries: Argentina (1), Canada (1),
Chile (1), Peru (1) and United States (6) (Centro de Operações de Emergências em Saúde Pública sobre Microcefalias – Brazil, 2016).
Brazilian outbreak
Brazil has faced a ZIKV outbreak since mid 2015. Given that 80% of the
infected individuals do not show signs or symptoms of disease and most
of the patients do not seek treatment at a health care center, it is
impossible to know the actual number of cases of infection by ZIKV. The
use of RT-PCR, the best ZIKV detection method, is limited to the early
acute stages of infection (≤ 7 days) and serological tests have been
only recently available. Considering these diagnostic limitations, the
number of ZIKV cases was estimated from the number of patients ruled
out for dengue and projections based on the international literature.
Thus, the estimated number of ZIKV infections in Brazil since the
beginning of the outbreak varies between 872,347 to 2,734,911 cases,
considering only the States with ZIKV autochthonous circulation
confirmed by a reference laboratory. According to the Ministry of
Health, Brazilian research institutes are in the process of producing
more accurate projections (MICROCEFALIA - Ministério da Saúde divulga boletim epidemiológico, Brazil, 2015).
The number of cases of microcephaly reported in Northeastern Brazil increased dramatically since October of 2015 (Kleber de Oliveira et al., 2016).
According to the ER25, 7,438 cases of microcephaly and/or other
disorders of the CNS in newborns, stillbirths, miscarriages or fetuses
were notified in Brazil between November 8, 2015 and May 7, 2016. This
number includes the previous definition of operational case – normal
head circumference ≥ 33 cm – and the criteria for microcephaly adopted
by the surveillance protocol from December 09, 2015, which defined a
minimum accepted head circumference of 32 cm for full term newborns.
The reported cases were distributed among 1,394 cities, but 5,706 cases
(76.7%) were concentrated in the Northeast region. Most suspected cases
(n = 1,930), accounting for 25.9% of the total number of cases
registered across the country, are in the state of Pernambuco, the
first to identify an increase in the number of cases of microcephaly (Centro de Operações de Emergências em Saúde Pública sobre Microcefalias- Brazil, 2016).
The ER25 accounted for 4,004 completely investigated cases, and the
existence of microcephaly and/or other CNS disorders suggestive of
congenital infection was confirmed in 1,326 cases (33.1%). However,
only 205 (15.5%) of the cases with a confirmed association had ZIKV
identified by means of laboratory tests (PCR and/or serology); the rest
was diagnosed based on clinical and/or radiological criteria: typical
changes indicative of congenital infection, such as intracranial
calcifications, dilation of cerebral ventricles or changes in the
posterior fossa, and other clinical signs observed by imaging (Centro de Operações de Emergências em Saúde Pública sobre Microcefalias - Brazil, 2016).
ZIKV, microcephaly, and other central nervous system disorders
Although the Brazilian Ministry of Health took the association between
ZIKV and microcephaly for granted in early 2016, the scientific
community seemed to be divided on the subject until a few weeks ago.
Despite the identification of ZIKV in blood and tissues of fetuses and
infants with microcephaly or other CNS disorders, the vast majority of
the clinical data were obtained retrospectively, and many of the
clinical and radiological findings were nonspecific, requiring careful
differential diagnosis against other infectious diseases.
ZIKV was found in the amniotic fluid (Calvet et al., 2016) and in the tissues of miscarried fetuses and newborns dead shortly after birth (Martines et al., 2016).
In all cases described by Martines et al, the mothers had presented
clinical signs of ZIKV infection during the first trimester of
pregnancy. Researchers found significant changes in histopathology
parameters in the brains of newborns, such as calcified parenchyma,
microglial nodules, gliosis, cell degeneration, and necrosis. One of
the miscarried babies had heterogeneous chorionic villi calcifications,
fibrosis, fibrin deposition between villi and focal villitis (Martines et al., 2016).
A connection between ZIKV and other disorders of the central nervous
system (CNS), fetal hydrops or fetal death has been described in the
literature (Sarno et al., 2016; Microcephaly Epidemic Research Group, 2016).
In spite of the virus’ proven ability to cross the placenta and affect
a developing fetus, until recently there was no consensus over the
quality of the scientific evidence to establish a causal link between
CNS anomalies and ZIKV (Faria et al., 2016; Tetro, 2016).
On April 13, Rasmussen et al suggested that the literature now provides
sufficient evidence to establish a causal relationship between prenatal
ZIKV infection and microcephaly or other serious CNS anomalies, based
on specific criteria for the evaluation of potential teratogens
(Shepard’s criteria) and criteria for causation (Bradford Hill’s
criteria) (Rasmussen et al., 2016). Since then studies with pregnant mice (Miner et al., 2016; Lazear et al., 2016)
have looked into the effects of infection by ZIKV and provided
significant information on vertical transmission and ZIKV-related
pathogenesis, reinforcing the causal role of the virus in neurological
anomalies observed in humans.
The outbreaks in Brazil, Colombia and French Polynesia
A recent Brazilian study assessed 88 women at five to 38 weeks of
gestation from September 2015 to February 2016; seventy-two of them
(82%) were positive for ZIKV in blood and/or urine tests. Forty-two
ZIKV-positive women (58%) underwent ultrasound examination, and 12
cases of fetal abnormalities were detected. The adverse outcomes
reported in the study included two intrauterine deaths at 36 and 38
weeks of gestation; five cases of intrauterine growth restriction
with/without microcephaly; seven cases of CNS injury, especially
ventricular calcifications; seven fetuses with abnormal changes in
amniotic fluid volume or flow changes in the brain or umbilical
arteries (Sikka et al., 2016).
Many consider the data on ZIKV and CNS anomalies obtained to date
sufficient, but more evidence is required for the causal relationship
to gain strength. At least two situations call for further elucidation.
The first occurred in Sergipe, the Brazilian State with the largest
number of cases of microcephaly per population, where only recently
cases of infection by ZIKV have been identified. Among the cases of
microcephaly in Sergipe, samples of pregnant women and children from
the city of Itabaiana were analyzed with the aid of researchers from
the University of São Paulo; ZIKV antibodies were found in 7/8 women
and 4/8 children. Although these preliminary results confirm the
circulation of ZIKV in the State, another 172 blood samples were found
to be negative for ZIKV, and 976 samples were still awaiting assessment
until March 19 (Secretaria de Estado da Saúde – SES - Sergipe, 2016).
The other situation concerns the numbers from Colombia. Since the
confirmation of ZIKV circulation in the country and the beginning of
the epidemic phase in mid-2015 to mid-March 2016, there have been 2,355
laboratory-confirmed cases, 46,556 cases confirmed by clinical
criteria, and 6,813 suspected cases (Instituto Nacional de Salud – Colombia, 1016).
According to the last issue of the World Health Organization Situation
Report, the Colombian outbreak seems to be in decline, as no additional
cases of microcephaly have been reported in the country (World Health Organization, 2016a).
In the specific case of Brazil, one of the critical issues to be
addressed refers to the actual incidence of microcephaly in the
country. The increase observed in cases of microcephaly might be
largely attributed to the intense search for malformations encouraged
by media reports and the strong suspicion of their association with
ZIKV, in addition to misdiagnoses of pre-Zika phase disease, since
there is no consensus over diagnostic criteria (Butler, 2016).
In 2010, the Live Births Registry (SINASC) of the Brazilian Ministry of
Health described an incidence of microcephaly of 5.7/100,000 live
births, a very similar ratio to what had been described ten years
before, which would correspond to 176 neonates born with the
malformation (Simmins Jr, 2016).
However, a recent study held in the State of Paraíba and published by
the World Health Organization discussed the underreporting of
microcephaly cases in the country before the ZIKV outbreak. In the
Paraíba study, the data from 16,208 children born in public hospitals
between January 2012 and December 2015 revealed a prevalence of
congenital microcephaly between 4% and 8%, depending on the criteria
used. If these numbers were compared to the total number of live births
in Paraíba in 2014 (n = 58,147), 4,652 cases of microcephaly would have
occurred in the State according to the criteria adopted by the
Brazilian Ministry of Health; Fenton growth charts would yield a total
of 2,442 cases; 2,907 cases would have occurred according to
proportionality criteria; or yet 1,105 cases would have been found if
all diagnostic criteria were considered together (Soares de Araújo et al., 2016).
And if they were applied to the country as a whole, those percentages
would yield an incidence of 1,900/100,000 live births per year. In
other words, the estimated number of cases of microcephaly each year in
Brazil would be greater than 56,000 (Simmins Jr, 2016).
A retrospective study by Cauchemez and colleagues looked into the ZIKV
outbreak occurred in French Polynesia between October 2013 and April
2014, and found a prevalence of microcephaly of two cases per 10,000
newborns, and a risk of microcephaly associated with ZIKV of 95 cases
per 10,000 women infected in the first trimester, or 1% (Cauchemez et al., 2016).
Researchers analyzed viruses circulating in Brazil and other countries
in the Americas (Martinique, Colombia, Haiti, Guatemala, Suriname,
Puerto Rico) and Asia (French Polynesia, New Caledonia, Cook Islands,
Easter Island, Vanuatu, and Solomon Islands), and concluded that the
strain closest to the one emerged in Brazil comes from French Polynesia
(Musso, 2015). This confirmation may allow
Brazilian authorities to assume the same level of risk until more
reliable local data is available.
New statistical data have been
published in a recent study, but the authors admitted that the level of
uncertainty is still significant and that such a limitation might be
associated with unknown infection rates, especially in recently exposed
populations. According to Johansson et al. (2016),
microcephaly rates could vary from 1% to 13% depending on the
percentage of the population infected with the virus. Assuming that 10%
of the population of Bahia had been infected, the authors estimated the
prevalence of microcephaly at around 13% secondary to infection in the
first trimester; however, if 80% of the population in Bahia contracted
ZIKV, the risk would be close to the levels indicated by the study
carried out in French Polynesia.
In the face of uncertainty and
based on the recent recommendations of the World Health Organization on
microcephaly and its relation to ZIKV (March 9, 2016), the Brazilian
Ministry of Health adopted new parameters to measure the head
circumference of newborns and identify suspected cases of microcephaly.
Full term male and female infants are expected to have head
circumferences greater than 31.9 cm and 31.5 cm to be categorized as
normal, respectively. For preterm infants, the new recommendation
replaced the diagnostic parameters of the Fenton growth curves with the
guidelines established by the International Fetal and Newborn Growth
Consortium for the 21st Century, known as Intergrowth (Ministério da
Saúde – Brazil, 2016).
The decision to conceive
Some
questions remain unanswered. Is it right to counsel women to postpone
pregnancy plans? If so, when would it be safe to get pregnant? How can
the risk of having ZIKV-related microcephaly within the first months of
gestation be predicted? What advice should be given to them if the
numbers become more disappointing in the future?
Specialists in infectious diseases agree that the recent increase in
the number of cases may be due to the absence of immunity in much of
the population in countries where outbreaks have been reported, but
they differ when it comes to forecasting the future behavior of ZIKV.
In one scenario, it has been assumed that ZIKV may repeat the behavior
of other arboviruses such as dengue, with regular recurrences and small
peaks of cases during the rainy season. On the other hand, ZIKV may
disappear in a few years and spend decades in silence (Branswell, 2016).
This uncertainty prevents health care workers from recommending the
postponement of pregnancy for a specific period of time. No one can
tell with certainty how long a woman should wait before getting
pregnant.
The gap of knowledge at the moment is large enough to
remove part of the confidence physicians have on the advice given to
patients – and infertile or women of advanced reproductive age in
particular – on their reproductive plans. It may be prudent to postpone
pregnancy in ZIKV-affected regions. Some health authorities consider
the circumstantial evidence available too strong for anyone to take
their chances. However, many believe that as long as they are provided
with good information, women should decide whether they want to get
pregnant or not.
The Pernambuco Health Department stated that every woman should be
advised individually about ZIKV and microcephaly. And a health care
provider they trust should lead the counseling process. According to
the institution’s clinical and epidemiologic research protocol for
microcephaly, there is no formal recommendation to avoid pregnancy, and
the decision of getting pregnant is a matter of personal decision for
each woman and her family (Secretaria Estadual de Saúde de Pernambuco, 2015). The representation of the Pan American Health Organization/World Health Organization (2016) in Brazil adopts the same position.
It may be precocious and excessively invasive to advise women to
postpone their plans of pregnancy, for the simple fact that no one can
affirm that an outbreak of microcephaly is in effect. Formal records
are under suspicion and misdiagnosed cases of microcephaly in Brazil
might be subject to an independent investigation. In fact, the
scientific information to date only points to the emergence of a new
microcephaly causative agent, as a result of vertical transmission. And
this may be the sole conclusion in the end of the story. Assuming the
causation mechanism has been correctly identified, ZIKV should be added
to the TORCH complex as a new “other” agent. It has been suggested that
researchers may look at diseases like rubella as potential models for
how ZIKV damages the fetal CNS and how outbreaks can be stopped (Lafrance, 2016).
Caution is required and panic must be avoided. The population must be
advised to eliminate the mosquito and prevent mosquito bites, since
these are the two most important protective actions available at the
moment. Special attention is required from people at risk and pregnant
women in particular (World Health Organization, 2016b).
Patients and partners must be encouraged to use repellants, window
nets, and protective screens, put on long-sleeved shirts and long
pants, and wear condoms while having sex without reproductive purposes.
There is no consensus on how to counsel women – infertile women and
individuals of advanced reproductive age in particular – on whether
they should postpone their plans of getting pregnant. Women opting to
wait until the matter has been resolved may choose to have their
oocytes cryopreserved, thus providing them with a chance of enjoying
biological motherhood at a later time in their lives.
ZIKV screening
The use of
pre-pregnancy serologic screening is a possible strategy to offer more
confidence for those who prefer to carry on with their plans of
conceiving despite the ZIKV outbreak. However, the high cost of
screening has hampered the introduction of these tests in public and
supplementary health care services (Sociedade Brasileira de Patologia Clínica/Medicina Laboratorial, 2016).
Laboratory diagnosis of ZIKV may be achieved directly by RT-PCR
analysis, which allows the detection of the virus itself. The molecular
test can detect the presence of ZIKV in blood within the first seven
days of exposure; in urine samples, PCR can identify ZIKV for a period
of 15 days since the time of infection. Negative blood or urine RT-PCR
tests cannot rule out infection if the contact with the virus occurred
seven to 15 days before the samples were collected. Suspected cases
require antibody testing (Sociedade Brasileira de Patologia Clínica/Medicina Laboratorial, 2016).
RT-PCR is effective only during the very early acute phase of
infection. Therefore, serological tests appear to be an option in ZIKV
screening. Indirect immunofluorescence, immunochromatography,
enzyme-linked immunosorbent assay (ELISA), and plaque-reduction
neutralization test (PRNT) are currently available for ZIKV
identification. In indirect testing methods, the presence of IgM
antibodies characterizes acute infection; IgM is detectable four days
after exposure and remains constant for up to 12 weeks. In theory, a
negative serological test after 12 weeks from the supposed exposure
rules out infection (Sociedade Brasileira de Patologia Clínica/Medicina Laboratorial, 2016).
According to the Brazilian Society of Clinical Pathology and
Laboratorial Medicine, the sensitivity and specificity of the ZIKV
serology kits registered with the Brazilian National Health
Surveillance Agency (Anvisa) range from 96.8% to 100%, and 96.6% to
100%, respectively. However, the accuracy and applicability of the
tests have been questioned because of the number of false positive
results caused by cross-reactions with other viruses (Sociedade Brasileira de Patologia Clínica/Medicina Laboratorial, 2016).
Comparative neutralization tests may provide higher specificity. PRNT
may produce four-fold increases in neutralizing antibody titers in the
absence of increases in antibody titers by other flaviviruses, which is
considered sufficient evidence of recent ZIKV infection (World Health Organization, 2016c).
Regulations for assisted reproduction
Facing a ZIKV outbreak and the possibility of a microcephaly outbreak,
the regulatory board at Anvisa revised the regulations for the
operation of cell and germ tissue banks (CGTB). Since March 30, women
undergoing ovulation induction for in vitro fertilization or oocyte
cryopreservation procedures and biological material donors in Brazil
must be tested for ZIKV before any material is collected. The aim of
the new rule is to avoid contamination by ZIKV of children conceived
through assisted reproduction technologies, given the possibility of
the disease being transmitted sexually (ANVISA, 2016).
According to the document published by Anvisa, CGTBs can only collect
gametes or germ tissue for use in assisted reproduction procedures
after obtaining non-reactive or negative test results for ZIKV
infection no more than five days prior to gamete collection;
individuals whose laboratory tests yield positive or inconclusive
results will be temporarily suspended from treatment and tested again
30 days later (ANVISA, 2016).
A major challenge for many reproductive medicine centers is the
five-day period for gamete collection, which in practice only enables
ZIKV testing by PCR, once IgM testing may take up to eight days and the
rapid test is not broadly available. The official document clearly
establishes IgM as the standard test; formally, PCR, which is faster,
is not included in the standard, but it should be seen as an option
when the patient does not wish to postpone treatment.
Remaining questions
Assuming
there is a causal relationship between ZIKV and adverse birth outcomes,
researchers are expected to devote their efforts to shed light on the
many still unclear points and minimize the virus burden. Understanding
serologic curves in bodily fluids and the full spectrum of phenotypes
in congenital ZIKV infection syndrome is definitely a target, as is the
quantification of relative and absolute risks among exposed fetuses in
different times during pregnancy and the factors impacting risk levels
(Rasmussen et al., 2016).
Summary
Acknowledgements
The authors wish to acknowledge David Barreira Gomes Sobrinho, MD, MSc,
Eduardo Martins Netto, MD, PhD, and Henrique Beltrão, BSc, MSc, for
their technical contributions and thoughtful insights on the matters
presented in this paper.
REFERENCES
ANVISA
- Agência Nacional de Vigilância Sanitária, Brazil. Resolução de
Diretoria Colegiada - RDC/ANVISA no. 72, de 30 de março de 2016. Altera
a Resolução da Diretoria Colegiada - RDC nº 23, de 27 de maio de 2011,
que dispõe sobre o regulamento técnico para o funcionamento dos Bancos
de Células e Tecidos Germinativos e dá outras providências. Diário
Oficial da União; Poder Executivo, de 1 de abril de 2016. Available: http://portal.anvisa.gov.br/documents/33880/2568070/RDC_72_2016.pdf/14b66550-3af2-4761-a439-2140c33043cd.
Branswell H. Is Zika a permanent threat or a fleeting scare? STAT. 2016.https://www.statnews.com/2016/04/05/zika-here-to-stay-or-not/
Butler D. Zika virus: Brazil’s surge in small-headed babies questioned by report. Nature 2016:530:13-4.
Medline Crossref
Calvet
G, Aguiar RS, Melo AS, Sampaio SA, de Filippis I, Fabri A, Araujo ES,
de Sequeira PC, de Mendonça MC, de Oliveira L, Tschoeke DA, Schrago CG,
Thompson FL, Brasil P, Dos Santos FB, Nogueira RM, Tanuri A, de
Filippis AM. Detection and sequencing of Zika virus from amniotic fluid
of fetuses with microcephaly in Brazil: a case study. Lancet Infect
Dis. 2016;16:653-60
Medline Crossref
Campos GS, Bandeira AC, Sardi SI. Zika virus outbreak, Bahia, Brazil. Emerg Infect Dis. 2015;21:1885-6.
Medline Crossref
Cauchemez
S, Besnard M, Bompard P, Dub T, Guillemette-Artur P, Eyrolle-Guignot D,
Salje H, Van Kerkhove MD, Abadie V, Garel C, Fontanet A, Mallet HP.
Association between Zika virus and microcephaly in French Polynesia,
2013–15: a retrospective study. Lancet. 2016; 387:2125-32.
Medline Crossref
Centro de Operações de Emergências em Saúde Pública sobre Microcefalias – Brazil. Informe Epidemiológico no 25 - Semana Epidemiológica (SE) 18/2016 (01/05 a 07/05/2016), Monitoramento dos Casos de Microcefalia no Brasil. 2016.Available at: http://portalsaude.saude.gov.br/images/pdf/2016/maio/11/COES-Microcefalias---Informe-Epidemiol--gico-25--SE-18-2016--09mai2016-12h13.pdf. Accessed: 13/05/2016.
Faria
NR, Azevedo RD, Kraemer MU, Souza R, Cunha MS, Hill SC, Thézé J,
Bonsall MB, Bowden TA, Rissanen I, Rocco IM, Nogueira JS, Maeda AY,
Vasami FG, Macedo FL, Suzuki A, Rodrigues SG, Cruz AC, Nunes BT,
Medeiros DB, et al. Zika virus in the Americas: Early epidemiological
and genetic findings. Science. 2016;352:345-9.
Medline Crossref
Instituto Nacional de Salud - Colombia, Dirección de Vigilancia y Análisis del Riesgo en Salud Pública. Boletin Epidemiológico Semanal. Semana epidemiológica número 10 de 2016 (06 mar. al 12 mar). 2016. Available at: http://www.ins.gov.co/boletin-epidemiologico/Boletn%20Epidemiolgico/2016%20Bolet%C3%ADn%20epidemiológico%20semana%2010.pdf. Accessed: 25/03/2016.
Johansson
MA, Mier-Y-Teran-Romero L, Reefhuis J, Gilboa SM, Hills SL. Zika and
the Risk of Microcephaly. N Engl J Med. 2016 (In press)
Medline Crossref
Kleber
de Oliveira W, Cortez-Escalante J, De Oliveira WT, do Carmo GM,
Henriques CM, Coelho GE, Araújo de França GV. Increase in Reported
Prevalence of Microcephaly in Infants Born to Women Living in Areas
with Confirmed Zika Virus Transmission During the First Trimester of
Pregnancy - Brazil, 2015. MMWR Morb Mortal Wkly Rep. 2016;65:242-7.
Medline Crossref
Lafrance A. What Zika Researchers Can Learn From the Rubella Outbreak of 1964. The Atlantic. 2016. Available at:http://www.theatlantic.com/health/archive/2016/04/zika-rubella/477165/.
Lazear
HM, Govero J, Smith AM, Platt DJ, Fernandez E, Miner JJ, Diamond MS. A
Mouse Model of Zika Virus Pathogenesis. Cell Host Microbe.
2016;19:720-30.
Medline Crossref
Martines
RB, Bhatnagar J, Keating MK, Silva-Flannery L, Muehlenbachs A, Gary J,
Goldsmith C, Hale G, Ritter J, Rollin D, Shieh WJ, Luz KG, Ramos AM,
Davi HP, Kleber de Oliveria W, Lanciotti R, Lambert A, Zaki S. Notes
from the Field: Evidence of Zika Virus Infection in Brain and Placental
Tissues from Two Congenitally Infected Newborns and Two Fetal Losses -
Brazil, 2015. MMWR Morb Mortal Wkly Rep. 2016;65:159-60.
Medline Crossref
Microcephaly Epidemic Research Group. Microcephaly in infants, Pernambuco State, Brazil, 2015. Emerg Infect Dis. 2016;22:1090-3.
Medline Crossref
MICROCEFALIA - Ministério da Saúde divulga boletim epidemiológico - Brazil. Available at: http://portalsaude.saude.gov.br/index.php/cidadao/principal/agencia-saude/20805-ministerio-da-saude-divulga-boletim-epidemiologico. 2015. Accessed 27/03/2016.
Miner
JJ, Cao B, Govero J, Smith AM, Fernandez E, Cabrera OH, Garber C, Noll
M, Klein RS, Noguchi KK, Mysorekar IU, Diamond MS. Zika Virus Infection
during Pregnancy in Mice Causes Placental Damage and Fetal Demise.
Cell. 2016;165:1081-91.
Medline Crossref
Ministério da Saúde - Brazil. Secretaria de Vigilância em Saúde. Departamento de Vigilância das Doenças Transmissíveis. Protocolo de vigilância e resposta à ocorrência de microcefalia e/ou alterações do sistema nervoso central (SNC). Brasília: Ministério da Saúde, 2016. Available at: http://combateaedes.saude.gov.br/images/sala-de-situacao/Microcefalia-Protocolo-de-vigilancia-e-resposta-10mar2016-18h.pdf. Accessed: 20/03/2016.
Ministério da Saúde - Brazil. Uso de repelentes de inseto durante a gravidez. 2015 Available at http://portalsaude.saude.gov.br/images/pdf/2015/novembro/26/Nota-T--cnica-2015-Uso-de-repelentes-cosm--ticos-durante-a-gravidez.pdf. Accessed: 13/5/2016.
Musso D. Zika Virus Transmission from French Polynesia to Brazil. Emerg Infect Dis. 2015; 21:1887.
Medline Crossref
Pan American Health Organization/World Health Organization. Organização Mundial de Saúde no Brasil (OPAS/OMS). Representação da OPAS/OMS no Brasil divulga informações específicas sobre saúde da mulher e o vírus zika. 2016. Available at: http://www.paho.org/bra/index.php?option=com_content&view=article&id=5016:representacao-da-opasoms-no-brasil-divulga-informacoes-especificas-sobre-saude-da-mulher-e-o-virus-zika&Itemid=816 . Accessed: 27/3/2016.
Secretaria Estadual de Saúde de Pernambuco. Secretaria Executiva de Vigilância em Saúde. Protocolo Clínico e Epidemiológico para investigação de casos de microcefalia no estado de Pernambuco. Versão N° 02. Pernambuco: Secretaria Estadual de Saúde, 2015. Available at: http://media.wix.com/ugd/3293a8_cd11af48d2df47aeaf98b9dc1d757485.pdf.
Sarno
M, Sacramento GA, Khouri R, do Rosário MS, Costa F, Archanjo G, Santos
LA, Nery N Jr, Vasilakis N, Ko AI, de Almeida AR. Zika Virus Infection
and Stillbirths: A Case of Hydrops Fetalis, Hydranencephaly and Fetal
Demise. PLoS Negl Trop Dis. 2016;10:e0004517.
Medline Crossref
Secretaria de Estado da Saúde – SES - Sergipe. Núcleo Estratégico da SES – NEST.SES. Informe Epidemiológico no. 16 - Semana Epidemiológica 11/2016 (13/03 a 19/03/2016). 2016. Available at: http://observatorio.se.gov.br/saude/images/Informe_Semanal_16_micro_chik_e_dengue_21.03.2016.pdf.
Sikka
V, Chattu VK, Popli RK, Galwankar SC, Kelkar D, Sawicki SG, Stawicki
SP, Papadimos TJ. The Emergence of Zika Virus as a Global Health
Security Threat: A Review and a Consensus Statement of the INDUSEM
Joint working Group (JWG). J Glob Infect Dis. 2016;8:3-15.
Medline Crossref
Simmins
Jr CH. Establishing base levels of microcephaly in Brazil prior to the
arrival of Zika viral illnesses. Bull World Health Organ. E-pub:2016.
Crossref
Soares
de Araújo JS, Regis CT, Gomes RGS, Tavares TR, Rocha dos Santos C,
Assunção PM, Nóbrega RV, Pinto DFA, Bezerra BVD, Mattos SS .
Microcephaly in northeast Brazil: a review of 16 208 births between
2012 and 2015. Bull World Health. E-pub: 2016.
Crossref
Sociedade Brasileira de Patologia Clínica/Medicina Laboratorial. Posicionamento oficial da Sociedade Brasileira de Patologia Clínica/Medicina Laboratorial referente ao diagnóstico laboratorial do Zika vírus. Available at: http://www.sbpc.org.br/upload/conteudo/sbpcml_posicionamento_zika_virus.pdf
Taitson PF. Zika: Impactos epidêmicos e novas descobertas. Enfermagem Revista 2016;19. Available at: http://periodicos.pucminas.br/index.php/enfermagemrevista/article/view/11630/9317.
Tetro JA. Zika and microcephaly: causation, correlation, or coincidence? Microbes Infect. 2016;18:167-8.
Medline Crossref
World Health Organization. Zika Virus Microcephaly and Guillain-Barré Syndrome Situation Report. 2016a. Available at: http://www.who.int/emergencies/zika-virus/situation-report/24-march-2016/en/ Accessed 25/03/2016.
World Health Organization. WHO Director-General summarizes the outcome of the Emergency Committee regarding clusters of microcephaly and Guillain-Barré syndrome. 2016b. Available at: http://www.who.int/mediacentre/news/statements/2016/emergency-committee-zika-microcephaly/en/
World Health Organization. Laboratory testing for Zika virus infection. Interim guidance .2016c. Available at: http://apps.who.int/iris/bitstream/10665/204671/1/WHO_ZIKV_LAB_16.1_eng.pdf.
World Health Organization. Zika virus outbreaks in the Americas. Wkly Epidemiol Rec. 2015; 90: 609-10.
Medline
Zanluca
C, Melo VC, Mosimann AL, Santos GI, Santos CN, Luz K. First report of
autochthonous transmission of Zika virus in Brazil. Mem Inst Oswaldo
Cruz. 2015;110:569-72.
Medline Crossref