Zika virus infection and congenital anomalies in the Americas: opportunities for regional action

The Zika virus (ZIKV) was identified in 1947 in the Zika forest in Uganda, but recently it has emerged as a public health threat. The first evidence of human infection occurred in 1952, but only in April 2007 was the first outbreak in humans recognized. In the Americas, a ZIKV outbreak began in Brazil in 2015, and from the second half of 2015 onward, a substantial number of newborns with severe microcephaly began to be reported to health authorities. In February 2016, the World Health Organization (WHO) declared that the clusters of microcephaly cases in areas affected by ZIKV constituted a Public Health Emergency of International Concern. Seldom has there been such a resultingly vast production of scientific literature in record time. In this report we discuss the impact of ZIKV infection during pregnancy, the diagnosis and surveillance of microcephaly, the recognition of a clinical phenotype of ZIKV congenital infection, and opportunities for public health action. We consider this to be a unique opportunity for countries in the Region of the Americas to develop, strengthen, and improve surveillance systems for congenital anomalies and teratogen information services. Creating health needs assessment tools for low- and middle-income countries may help them to develop effective policies to ensure primary, secondary, and tertiary prevention measures for congenital anomalies. Such initiatives will be useful for ZIKV congenital syndrome control and also for having a much wider impact on a significant proportion of preventable and manageable congenital conditions.

On 1 February 2016, the World Health Organization (WHO) declared that the clusters of microcephaly cases and other neurological disorders such as Guillain-Barré syndrome in some areas affected by Zika virus (ZIKV) constituted a Public Health Emergency of International Concern (PHEIC) (1). "The increased prevalence of microcephaly at birth is particularly alarming, because it is a painful burden on the families and communities," pointed out WHO Director-General Margaret Chan (2).
The Zika virus was identified in the 1940s in the Zika forest in Uganda in monkeys. The first evidence of infection in humans occurred in 1952. Some five decades later, the international community recognized that the first ZIKV outbreak in humans had occurred in April 2007 in Yap, one of the states of the Federal States of Micronesia, in the Pacific Ocean. At that time, the transmission was reported in 10 other Pacific island countries and areas (3). In the Americas, the virus entered through Brazil, probably in 2013 (3). By November 2016, 48 countries in the Americas had reported autochthonous cases (4), with the Aedes aegypti mosquito being the most significant vector (5).
In this report we discuss the impact of ZIKV infection in pregnancy, the diagnosis and surveillance of microcephaly, the recognition of a clinical phenotype of ZIKV congenital infection, and opportunities for public health action in countries in the Americas.

HOW THE MICROCEPHALY OUTBREAK WAS DETECTED
In early 2015, Brazil's Ministry of Health began to receive reports of cases of an eruptive condition of unknown cause, especially in states in the Northeast region (6), and by April 2015, ZIKV was detected in those patients (7). The clinical manifestations were mild, with many regressing spontaneously without any clinical intervention. From the second half of 2015 onward, cases of newborns with microcephaly (8) and eye abnormalities began to be reported (9).
Microcephaly is defined as a smaller than expected occipital-frontal head circumference (OFHC) for gender and gestational age. Since the growth of the cranium depends on the forces of the expanding brain, microcephaly is a measure of brain development. Measurement of newborn OFHC is a screening tool for detecting microcephaly independently from its cause. This condition is a clinical finding that can manifest in isolation or as part of different syndromes caused by genetics (genetic or chromosomal) or environmental factors.
In Brazil, between October 2015 and November 2016, 10 276 cases of microcephaly were reported in accordance with the definition of the Health Ministry's surveillance protocol, which includes newborns and fetal losses. Of these, 3 113 (30.3%) of the cases remain under investigation at the time of this manuscript submission, 2 189 cases (21.3%) have been confirmed for microcephaly and/or central nervous system abnormalities suggestive of congenital infection, and 4 974 cases were ruled out (10). In 2010, the Brazilian Live Birth Information System (SINASC) reported a prevalence of microcephaly in Brazilian newborns of 5.7 cases per 100 000 live births (11). However, according to the Latin American Network of Congenital Malformations (ECLAMC), in Brazil there had been no reliable data on microcephaly before the Brazilian epidemic, even for those cases considered to be severe. Thus, at this time, the focus on this anomaly could lead to overreporting and misdiagnosis (12).

CLINICAL PHENOTYPE AND THE RECOGNITION OF A NEW TERATOGENIC SYNDROME
In Brazil, by one year after the ZIKV outbreak, more the 1 500 cases of congenital microcephaly associated with maternal ZIKV infection had been described. The phenotype can be defined as an "embryo-fetal brain disruption sequence by the Zika virus" (EFDS-ZIKV). The phenotype involves severe cerebral lesions and a dysmorphic spectrum ranging from babies with mild/ moderate to severe microcephaly secondary to the brain disruption sequence, and often neurological signs of cortical damage such as hypertonia and arthrogryposis (13). Table 1 summarizes the clinical findings (from neuroimaging and pathology) from the reported cases, most of which were autochthonous infections in Brazil. Two reports are directed towards the neuroimaging findings, and two others have relevant information about the fetal postmortem findings. It is now acknowledged that microcephaly is perhaps only part of the spectrum of congenital ZIKV infection, where some babies born without microcephaly have manifested neurological abnormalities only after the neonatal period (14). Other modes of transmission, such as sex, blood transfusions, and organ transplants, may contribute (albeit on a much smaller scale) to the spread of the disease (15). Table 2 summarizes the main characteristics of congenital anomaly surveillance systems, along with the baseline for microcephaly prevalence at birth in Latin America before the ZIKV epidemic in 2015. Brazil, for example, has had the nationwide Live Birth Information System (SINASC). The certificate of live birth is compulsory, and the presence of congenital anomalies must be registered on it. It was precisely this system that, despite its many weaknesses (mainly underreporting), enabled the confirmation of the microcephaly outbreak in Brazil, which had been initially notified by pediatric neurologists. Costa Rica and Uruguay have had population-based systems for the surveillance of congenital anomalies, while other countries have had hospital-based systems, one of which includes data from various South American countries.

EPIDEMIOLOGICAL SITUATION OF ZIKA VIRUS AND SURVEILLANCE SYSTEMS FOR CONGENITAL ANOMALIES IN THE AMERICAS
It is important to note that in 2010 the 63rd World Health Assembly adopted a resolution urging countries to develop systems and to train staff in relation to the prevention of congenital anomalies, as well as to strengthen surveillance systems (16). The resolution also called on countries to provide appropriate health care for people with congenital anomalies and for their families. This step has been neglected in public agendas, despite the efforts of nongovernmental organizations, health professionals, and health authorities.
Beginning with the microcephaly outbreak in Brazil (6), and in accordance with WHO recommendations, several countries in the Americas began to implement actions focused on detecting ZIKV infections and microcephaly and other congenital anomalies. These actions by the ministries of health have mainly included training health professionals and developing and strengthening guidelines and registers. Another challenge has been to integrate different health functions that are generally conducted by separate departments in the health system, such as surveillance, prevention, and assistance related to Zika virus infections and the occurrence of microcephaly. The example of Brazil is illustrative: meetings and discussions led to production of a publication on integrated protocols for facing Zika virus infections, including surveillance and management of care for pregnancies and for affected infants (the latest version of this document is available at: http://portalarquivos.saude.gov.br/images/pdf/ 2016 /dezembro/12/orientacoes-integradasvigilancia-atencao.pdf).

PUBLIC HEALTH IMPORTANCE AND ACTION
The ZIKV outbreak in the Americas began in Brazil and has spread throughout the Region of the Americas. In contrast to other infections caused by arboviruses transmitted by the same vector (A. aegypti), such as dengue, chikungunya, and yellow fever (which can be fatal), Hypoplasia of the brain stem and spinal cord ND   ZIKV has mild symptoms in the affected person but has a devastating teratogenic potential (17,18). This situation is quite critical for families, as well as a challenge for health systems. The technology available has already enabled recognition of the genomic sequence of ZIKV, which may help explain the epidemiological findings and the neurotropism. The surveillance systems for communicable diseases are on maximum alert, and various government actions at the regional level have been taken in an attempt to reverse the current lack of data, improve information, and develop a common strategic plan to control the epidemic.
With ZIKV, there is no safe period in pregnancy, and babies can be adversely affected in all pregnancy trimesters (13). Therefore, the WHO has issued recommendations about monitoring infection by ZIKV and its consequences, including actions for surveillance and notification of cases of microcephaly and GBS. These recommendations differ according to a country's situation: a) with epidemic transmission of ZIKV; b) with possible endemic transmission of the virus; c) at risk of transmission of the virus; and d) with no risk or low risk of transmission of ZIKV by vector mosquitoes.
In general, in line with recommendation that the WHO has made to member states, some of the indicators that should be reported are: 1) number of ZIKV cases; 2) number of ZIKV deaths; 3) number of GBS cases and deaths; 4) number of microcephaly cases; 5) number of other anomalies; 6) number of countries with autochthonous transmission; and 7) number of newly affected countries.
In addition, cases of microcephaly should continue to be monitored, accuracy of OFHC measurement in newborns should be improved, and appropriate internationally established growth curves (such as those of the INTERGROWTH-21st Consortium (19)) should be used. Finally, in countries where the epidemic is already present, it is important to have a more sensitive but less specific tool to detect brain abnormalities, such as defining microcephaly to include head circumference less than 2 z-scores below the mean.
Nevertheless, this more inclusive definition of microcephaly cannot be generalized. In Brazil, for example, with 3 000 000 births per year, a less strict definition of microcephaly (head circumference of 33 cm or less) led to a significant number of healthy babies being included in routine exam protocols. The health system almost collapsed due to thousands of babies being referred for clinical and laboratory protocols. Therefore, both the risks and the benefits of different criteria for inclusion of suspected cases of brain anomalies should be assessed separately for each country and each scenario. A good discussion of different diagnostic criteria for suspected microcephaly is given by Victora et al. (19).
In the countries where Zika virus infection is spreading, other congenital infections, such as syphilis, cytomegalovirus, and toxoplasmosis, are also prevalent, but rarely diagnosed early. Microcephaly can also be secondary to prenatal alcohol consumption, which is also not diagnosed in the neonatal period. Therefore, surveillance systems that are sensitive to microcephaly will have the benefit of also diagnosing other preventable cases of this congenital defect. The focus should be on prevention, early detection, and management of cases and evaluation of health needs to help prioritize actions. Currently, there are cohorts of infants and pregnant women who are being followed very closely by the health systems of different countries in the Americas. This active search for congenital anomalies will uncover many more cases of microcephaly and other abnormalities that would otherwise be missed. Upon being detected by the health system, the babies and their families should be able to count on specific early diagnosis, in line with the Convention on the Rights of Persons with Disabilities (20).
The Latin American Network of Congenital Malformations (ECLAMC) is taking the first steps to form a regional surveillance network that aims to: a) disseminate, via a Web page, the base frequencies of congenital anomalies at birth and b) provide statistical programs that any person or ministry of health can use to analyze temporal (epidemic) or geographical (endemic) frequencies (12). In response to the WHO resolution on birth defects (16), another initiative involves specific courses directed to Latin American countries on surveillance of birth defects and prematurity (see, for example: http://www.paho.org/clap/index. php?option=com_content&view=article&id=421: comprometidos-en-la-prevencion-y-vigilancia-deanomalias-congenitas-y-partos-prematuros&Itemid= 354&lang=en).
It is important to ensure that all these activities help develop local efforts that work toward recognizing congenital anomalies and their causes, as well as training experts in disabilities and rehabilitation. One instrument that might help low-and middle-income countries in these endeavors is the Health Needs Assessment Toolkit for Congenital Disorders, which was developed by the PHG Foundation and is freely available (http://www.bornhealthy.org/toolkit.html).

CONCLUSIONS
Seldom has there been in the scientific literature such vast production in record time as has occurred with the congenital ZIKV infections and the microcephaly outbreak in Brazil. From the detection of cases of embryopathy by ZIKV, it is possible to delve into the etiology of microcephaly and other congenital anomalies. The neurological findings described initially may be the tip of the iceberg. We consider this to be a unique opportunity to develop, strengthen, and improve the surveillance systems for congenital anomalies, as well as teratogen information services, in the Region of the Americas. This will help develop knowledge on potential new and emerging teratogenic agents, and help establish networks to monitor indicators of progress in each country.
WHO has started coordinating ef forts to define the congenital Zika virus syndrome and has issued an open invitation to all partners to join in this effort (21). Creating health needs assessment tools for low-and middle-income countries may help to develop effective policies to ensure primary, secondary, and tertiary prevention measures for congenital anomalies. In addition, until a ZIKV vaccine is available, an informed society is the best ally in effectively acting on vector control and protecting individuals. Also critical is an intersectoral policy related to housing, sanitation systems (especially for quality water supply and garbage collection), and health care. These kinds of initiatives will be useful for ZIKV congenital syndrome control, and they can also have a much wider impact on a significant proportion of preventable and manageable congenital conditions.
La infección por el virus del Zika y las anomalías congénitas en la Región de las Américas: oportunidades para la acción regional