In early 2015, an outbreak of Zika virus, a flavivirus transmitted by
Aedes
mosquitoes, was identified in northeast Brazil, an area where dengue
virus was also circulating. By September, reports of an increase in the
number of infants born with microcephaly in Zika virus-affected areas
began to emerge, and Zika virus RNA was identified in the amniotic fluid
of two women whose fetuses had been found to have microcephaly by
prenatal ultrasound. The Brazil Ministry of Health (MoH) established a
task force to investigate the possible association of microcephaly with
Zika virus infection during pregnancy and a registry for incident
microcephaly cases (head circumference ≥2 standard deviations [SD] below
the mean for sex and gestational age at birth) and pregnancy outcomes
among women suspected to have had Zika virus infection during pregnancy.
Among a cohort of 35 infants with microcephaly born during
August–October 2015 in eight of Brazil’s 26 states and reported to the
registry, the mothers of all 35 had lived in or visited Zika
virus-affected areas during pregnancy, 25 (71%) infants had severe
microcephaly (head circumference >3 SD below the mean for sex and
gestational age), 17 (49%) had at least one neurologic abnormality, and
among 27 infants who had neuroimaging studies, all had abnormalities.
Tests for other congenital infections were negative. All infants had a
lumbar puncture as part of the evaluation and cerebrospinal fluid (CSF)
samples were sent to a reference laboratory in Brazil for Zika virus
testing; results are not yet available. Further studies are needed to
confirm the association of microcephaly with Zika virus infection during
pregnancy and to understand any other adverse pregnancy outcomes
associated with Zika virus infection. Pregnant women in Zika
virus-affected areas should protect themselves from mosquito bites by
using air conditioning, screens, or nets when indoors, wearing long
sleeves and pants, using permethrin-treated clothing and gear, and using
insect repellents when outdoors. Pregnant and lactating women can use
all U.S. Environmental Protection Agency (EPA)-registered insect
repellents according to the product label.
An outbreak of Zika virus infection was recognized in northeast Brazil in early 2015 (
1).
In September 2015, health authorities began to receive reports from
physicians in this region of an increase in the number of infants born
with microcephaly. In October, the MoH confirmed an increase in birth
prevalence of microcephaly in northeast Brazil, compared with previously
reported estimates (approximately 0.5/10,000 live births), which are
based on review of birth certificates and include descriptions of major
congenital anomalies. The MoH rapidly established a microcephaly
registry in Brazil. On November 17, 2015, the MoH reported the increase
in microcephaly cases, and possible association of microcephaly with
Zika virus infection during pregnancy on its website;* and the Pan
American Health Organization (PAHO) published an alert regarding the
increase in occurrence of microcephaly in Brazil (
2). In
December, PAHO reported the identification of Zika virus RNA by reverse
transcription-polymerase chain reaction (RT-PCR) in amniotic fluid
samples from two pregnant women whose fetuses were found to have
microcephaly by prenatal ultrasound, and the identification of Zika
virus RNA from multiple body tissues, including the brain, of an infant
with microcephaly who died in the immediate neonatal period (
3). These events prompted new alerts from the MoH, the European Centre for Disease Prevention and Control (
4), and CDC (
5) concerning the possible association of microcephaly with the recent outbreak of Zika virus infection.
A comprehensive protocol for notification and investigation of all
infants with microcephaly and all women with suspected Zika virus
infection during pregnancy was developed by the MoH and implemented
nationwide. In addition, the Brazilian Society of Medical Genetics
established the Zika Embryopathy Task Force (SBGM–ZETF), which includes
clinical geneticists, obstetricians, pediatricians, neurologists, and
radiologists, to review all incident cases of microcephaly as well as
all infants born to mothers with suspected Zika virus infection during
pregnancy. Task force members collect data concerning the pregnancy
(including exposure history, symptoms, and laboratory testing), physical
examination of the infant, and any additional studies using a
standardized spreadsheet. Microcephaly was defined as neonatal head
circumference ≥2 SD below the mean for gestational age and sex of the
infant at birth. Infection with Zika virus is difficult to confirm
retrospectively because serological immunological tests might
cross-react with other flaviviruses, especially dengue virus (
6).
Therefore a mother’s report of a rash illness during pregnancy was used
as a proxy indicator of potential Zika virus infection.
Although 37 infants with microcephaly were evaluated, only 35 cases
are included in this report. Two infants with microcephaly were excluded
from the original cohort of 37 babies: one had autosomal recessive
microcephaly with sibship recurrence, and one had cytomegalovirus
infection. Overall, 26 (74%) mothers of infants with microcephaly
reported a rash during the first (n = 21) or second (5) trimester (
Table).
Residence in or travel during pregnancy to areas where Zika virus is
circulating was confirmed for all mothers, including women without a
history of rash. Twenty-five (74%) infants had severe microcephaly (head
circumference >3 SD below the mean for gestational age). Computed
tomography scans and transfontanellar cranial ultrasounds showed a
consistent pattern of widespread brain calcifications, mainly in the
periventricular, parenchymal, and thalamic areas, and in the basal
ganglia, and was associated in approximately one third of cases with
evidence of cell migration abnormalities (e.g., lissencephaly,
pachygyria). Ventricular enlargement secondary to cortical/subcortical
atrophy was also frequently reported. Excessive and redundant scalp
skin, reported in 11 (31%) cases, also suggests acute intrauterine brain
injury, indicating and arrest in cerebral growth, but not in growth of
scalp skin. Four (11%) infants had arthrogryposis (congenital
contractures), indicative of central or peripheral nervous system
involvement (
7). All 35 infants in the cohort tested negative for
syphilis, toxoplasmosis, rubella, cytomegalovirus, and herpes simplex
virus infections. CSF samples from all infants enrolled in the cohort
were sent to a reference laboratory in Brazil for Zika virus testing;
the results are not yet available.
Discussion
Microcephaly usually results from abnormal brain development. The
long-term consequences of microcephaly depend on underlying brain
anomalies and can range from mild developmental delays to severe motor
and intellectual deficits, like cerebral palsy. In addition to
congenital infections, microcephaly can result from chromosomal
abnormalities; exposure to drugs, alcohol, or other environmental
toxins; premature fusion of the bones of the skull (craniosynostosis);
and certain metabolic disorders. The sudden increase in the number of
infants born with microcephaly associated with cerebral damage
characteristically seen in congenital infections in a region where an
outbreak of a newly circulating virus has recently occurred is
suggestive of a possible relationship. The association between maternal
infections and congenital anomalies has long been recognized, especially
when infection occurs during the first 12 weeks of pregnancy (8).
Brazil’s vaccination program has eliminated some infections that result
in congenital anomalies, such as rubella. Congenital infections can
affect multiple organ systems, and many are associated with specific
brain damage, including microcephaly, calcifications (predominantly
periventricular, but also in the basal ganglia and in cerebral
parenchyma), ventriculomegaly, neuronal migration disorders (pachygyria,
polymicrogyria, lissencephaly, and schizenchephaly), cerebellar
hypoplasia, and white matter anomalies (8). Ongoing surveillance
and evaluation of new cases are important to describe the phenotypic
spectrum of potential Zika virus-associated congenital infections. In
addition, special studies, including case-control studies, are needed to
confirm the association, determine the magnitude of the potential risk,
and identify other possible risk factors.
CDC recently tested samples from two pregnancies that ended in
miscarriage and from two infants with microcephaly who died shortly
after birth. All four cases were from Brazil and were positive for Zika
virus infection, indicating that the infants had become infected during
pregnancy. Zika virus was present in the brain of the full term infants,
and genetic sequence analyses show that the virus in all four cases was
the same as the Zika virus strain currently circulating in Brazil. All
four mothers reported having experienced a febrile rash illness during
their pregnancies.†
Prevention strategies established by the MoH include aggressive
efforts to eliminate mosquito breeding areas by removing standing water
containers, as well as recommendations for personal protective measures,
including preventing mosquito bites among pregnant women by applying
insect repellents, wearing long-sleeved shirts and long pants, and using
mosquito nets, as well as risk communication and community mobilization
(3). Pregnant and lactating women can use all EPA-registered insect repellents according to the product label.
This findings in this report are subject to at least four
limitations. First, historical birth prevalence of microcephaly in
Brazil, approximately 0.5 cases per 10,000 live births, calculated from
birth certificates, was lower than expected estimates of 1–2 cases per
10,000 live births (9), which might indicate general
underascertainment of microcephaly in Brazil. However, during the second
half of 2015 alone, >3,000 suspected cases of microcephaly
(approximately 20 cases per 10,000 live births) were reported to the MoH
through the special notification protocol, suggesting a sharp increase
in birth prevalence, although the special notification protocol might
have also increased case reporting. Second, before the November MoH
alert, although descriptions of congenital anomalies were reported,
infant head circumference was not routinely recorded. Hence, it is
possible that mild cases of microcephaly might not have been reported.
Since the MoH alert and the attendant media coverage of the outbreak,
surveillance for microcephaly and physician reporting of suspected cases
have increased. Third, because Zika virus infection was not
laboratory-confirmed in infants or their mothers, the history of a
nonspecific rash illness during pregnancy is subject to recall bias and
might have resulted in misclassification of potential Zika virus
exposure. Finally, this report does not comment on other features
characteristic of intrauterine infections such as hepatosplenomegaly,
rash, and chorioretinitis, or on some features that have been reported
in cases with presumed Zika including hearing loss, pale maculas, and
swallowing difficulties.
As of January 2016, there has been confirmed autochthonous
transmission of Zika virus in 19 countries in the Americas outside
Brazil (10). Although other countries in the Americas, including
Uruguay and Argentina, have not reported autochthonous Zika virus, the
presence of a competent vector, Ae. aegypti, in these countries poses a potential risk for further spread of the virus.
Acknowledgments
Patricia
S. Sousa, Luciana S.S. Melo, Elza C.C.S. Barros, Brazilian Medical
Genetics Society–Zika Embryopathy Task (SBGM–ZETF), Maranhão; Tirzah
Lajus, SBGM–ZETF, Rio Grande do Norte; Bethânia F.R. Ribeiro, SBGM–ZETF,
Acre; Luiz Carlos Santana da Silva, Gloria Colonelli, SBGM–ZETF, Pará;
Larissa S.M. Bueno, Angelina X. Acosta, Joanna G.C. Meira, Manoel Sarno,
SBGM–ZETF, Bahia; Liane Giuliani, SBGM–ZETF, Mato Grosso do Sul;
Cynthia A.M.S. Pacheco, Claudia N. Barbosa, Sheila M. Pone, Patricia S.
Correia, SBGM–ZETF, Rio de Janeiro; Antonio F. Moron, Amelia M.N.
Santos, Ana Beatriz Alvarez Perez, Rayana E. Maia, Victor E.F. Ferraz,
SBGM–ZETF, São Paulo; Tani M.S. Ranieri, Andre A. Silva, Fernanda S.L.
Vianna, Alberto Abeche, Julio Cesar L. Leite, SBGM–ZETF, Rio Grande do
Sul; Mariela Larrandaburu, SBGM–ZETF, Uruguay.
1Universidade Federal do Rio Grande do Sul, Brazil; 2Hospital Infantil Albert Sabin, Fortaleza, CE, Brazil; 3Universidade Federal de Pernambuco, Brazil; 4Fundação Oswaldo Cruz, Rio de Janeiro, Brazil; 5University of Campinas, Sao Paulo, Brazil; 6Hospital Infantil Juvencio Mattos, Maranhao, Brazil; 7Universidade Potiguar, Rio Grande do Norte, Brazil; 8University of Sao Paulo, Ribeirao Preto, Brazil; 9Secretaria de Estado da Saúde do Espírito Santo, Brazil; 10Universidade Federal de Sao Paulo, Brazil; 11Centro Universitário do Estado do Pará, Brazil; 12Universidade do Estado do Rio de Janeiro, Brazil; 13Hospital de Clinicas de Porto Alegre, Brazil; 14Brazilian Medical Genetics Society–Zika Embryopathy Task Force.
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TABLE. Main
phenotypical findings of the first 35 patients enrolled in the
Brazilian Society of Medical Genetics–Zika Embryopathy Task Force
Registry — Brazil, 2015
| Characteristic | n (%) |
|---|
| Reported maternal rash during pregnancy |
|---|
| First trimester | 21 (57) |
| Second trimester | 5 (14) |
| Not reported | 9 (26) |
| Sex |
| Female | 21 (60) |
| Male | 14 (40) |
| Gestational age at birth (34)* |
| Term | 31 (91) |
| Preterm | 3 (9) |
| Weight |
| ≥2,500g | 26 (74) |
| <2,500g | 9 (26) |
| Defect |
| Head circumference >3 SD | 25 (71) |
| Head circumference >2 SD to 3 SD | 10 (29) |
| Excessive and redundant scalp skin | 11 (31) |
| Talipes (clubfoot) | 5 (14) |
| Arthrogryposis (contractures) | 4 (11) |
| Other defects (microphthalmia) | 1 (3) |
| Abnormal funduscopic examination (11) | 2 (18) |
| Neurologic examination |
| Any abnormality | 17 (49) |
| Hypertonia/Spasticity | 13 (37) |
| Hyperreflexia | 7 (20) |
| Irritability | 7 (20) |
| Tremors | 4 (11) |
| Seizures | 3 (9) |
| Neuroimaging (27) |
| Any abnormality | 27 (100) |
| Calcifications | 20 (74) |
| Ventricular enlargement | 12 (44) |
| Neuronal migration disorders (lissencephaly, pachygyria) | 9 (33) |
| Abbreviation: SD = standard deviations. |
* Number of patients sampled was less than total (35).
Suggested citation for this article:
Schuler-Faccini L, Ribeiro EM, Feitosa IM, et al. Possible Association
Between Zika Virus Infection and Microcephaly — Brazil, 2015. MMWR Morb
Mortal Wkly Rep 2016;65:59–62. DOI:
http://dx.doi.org/10.15585/mmwr.mm6503e2.
(Biblioteca Nacional de Medicina)
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