Microcephaly in Brazil: how to interpret reported numbers? (2016)

Brazil is facing its first outbreak of Zika virus, particularly in the northeast region. Most cases of Zika virus infection are self-limited and without sequelae, but there have been clusters of cases of microcephaly in some areas of known Zika virus transmission. Although strongly suspected, the causal relation between in-utero exposure to Zika and microcephaly is yet to be established. The increased number of microcephaly cases in Brazil has led to a high level of concern among pregnant women throughout the country. On Feb 1, 2016, WHO's International Health Regulations Emergency Committee advised that the clusters of microcephaly and other neurological disorders and their possible association with Zika virus constitutes a Public Health Emergency of International Concern.1WHOWHO statement on the first meeting of the International Health Regulations (2005) (IHR 2005) Emergency Committee on Zika virus and observed increase in neurological disorders and neonatal malformations.http://www.who.int/mediacentre/news/statements/2016/1st-emergency-committee-zika/en/Date: Feb 1, 2016Google Scholar Measurement of newborn head circumference is useful as a screening tool for detecting microcephaly, independently of its cause. Before 2015, the annual numbers of reported cases of microcephaly in Brazil were consistently below 200.2Brasil Ministério da SaúdeDATASUS. Tabulação de anomalia ou defeito congênito em nascidos vivos (in Portuguese).http://www2.aids.gov.br/cgi/tabcgi.exe?caumul/anoma.defGoogle Scholar Between mid-2015 and Jan 30, 2016, 4783 suspected cases of microcephaly were reported, including newborn and fetal losses.3Brasil Ministério da SaúdeCentro de Operações de Emergências em Saúde Pública sobre Microcefalias. Monitoramento de Casos de Microcefalia no Brasil. Informe epidemiológico 11—semana epidemiológica 04/2016 (24 a 30/01/2016). Ministério da Saúde, Brasília2016Google Scholar Of these, 1103 cases have completed clinical, laboratory, and imaging examinations, and 404 (36·2%) were classified as confirmed cases of microcephaly. Among the confirmed cases, brain abnormalities were detected by imaging in 387 babies and Zika virus was detected in 17 babies, including in two fetal losses.3Brasil Ministério da SaúdeCentro de Operações de Emergências em Saúde Pública sobre Microcefalias. Monitoramento de Casos de Microcefalia no Brasil. Informe epidemiológico 11—semana epidemiológica 04/2016 (24 a 30/01/2016). Ministério da Saúde, Brasília2016Google Scholar The remaining 709 cases were discarded and 3670 suspected cases of microcephaly remain under investigation.3Brasil Ministério da SaúdeCentro de Operações de Emergências em Saúde Pública sobre Microcefalias. Monitoramento de Casos de Microcefalia no Brasil. Informe epidemiológico 11—semana epidemiológica 04/2016 (24 a 30/01/2016). Ministério da Saúde, Brasília2016Google Scholar Although 36·2% seems to be a high rate of true positives, it has to be interpreted with caution because in the present situation newborn babies with visible cranial deformities are likely to be fast-tracked for in-depth examination. This temporal increase in suspected cases of microcephaly could also be distorted given both raised awareness, with more children than usual being measured and reported, and changing definitions of microcephaly over time. The possibility of over-reporting and misdiagnosis was recently raised by the Latin American Network of Congenital Malformations,4Latin American Network of Congenital MalformationsMicrocefalias en el ECLAMC y en Brasil (in Portuguese).http://www.eclamc.org/microcefaliaarchivos.phpDate: Dec 5, 2015Google Scholar and their report led to speculation in the international scientific press on the magnitude of the increase in microcephaly cases.5Butler D Brazil's surge in small-headed babies questioned by report.Nature. 2016; 530: 13-14Crossref PubMed Scopus (47) Google Scholar To help interpret these numbers, it is instructive to assess how head circumference criteria for defining suspected cases of microcephaly have evolved (table). Before Dec 8, 2015, Brazil's Ministry of Health6Brasil Ministério da SaúdeSecretaria de Vigilância em Saúde. Departamento de Vigilância Note Informativa 01/2015. COES Microcefalias. Ministério da Saúde, Brasília2015Google Scholar recommended a cutoff for head circumference of less than or equal to 33 cm for term newborn babies (both sexes and all gestational ages); for preterm babies, the cutoff was the 3rd centile of the Fenton7Fenton TR Kim JH A systematic review and meta-analysis to revise the Fenton growth chart for preterm infants.BMC Pediatr. 2013; 13: 59Crossref PubMed Scopus (1399) Google Scholar curves of head circumference by gestational age and sex. On Dec 8, 2015, the Ministry of Health in Brazil revised the case definition for suspected microcephaly in newborn babies and reduced the head circumference criterion in term newborn babies to less than or equal to 32 cm.8Brasil Ministério da SaúdeSecretaria de Vigilância em Saúde. Departamento de Vigilância das Doenças Transmissíveis. Protocolo de vigilância e resposta àocorrência de microcefalia relacionada à infecção pelo vírus Zika. Ministério da Saúde, Brasília2015Google Scholar On Jan 21, 2016, the Pan American Health Organization (PAHO)9Pan American Health OrganizationLineamientos preliminares de vigilancia de microcefalia en recién nacidos en entornos con riesgo de circulación de virus Zika. Jan 22, 2016. Pan American Health Organization, Washington, DC2016Google Scholar proposed the use of fixed cutoffs of 32·0 cm and 31·6 cm for term boys and girls, on the basis of the 3rd percentile for term newborn babies of any gestational age according to the WHO Growth Standards.10WHOThe WHO child growth standards.www.who.int/childgrowth/en/Google Scholar For preterm babies, PAHO9Pan American Health OrganizationLineamientos preliminares de vigilancia de microcefalia en recién nacidos en entornos con riesgo de circulación de virus Zika. Jan 22, 2016. Pan American Health Organization, Washington, DC2016Google Scholar recommended use of the 3rd centile of either the Fenton7Fenton TR Kim JH A systematic review and meta-analysis to revise the Fenton growth chart for preterm infants.BMC Pediatr. 2013; 13: 59Crossref PubMed Scopus (1399) Google Scholar or InterGrowth11Villar J Cheikh Ismail L Victora CG et al.for the International Fetal and Newborn Growth Consortium for the 21st Century (INTERGROWTH-21st)International standards for newborn weight, length, and head circumference by gestational age and sex: the Newborn Cross-Sectional Study of the INTERGROWTH-21st Project.Lancet. 2014; 384: 857-868Summary Full Text Full Text PDF PubMed Google Scholar curves. Use of fixed cutoff head circumference measurements for all term infants is inappropriate since it does not account for the fact that 68·1% of term newborn babies in Brazil are below 40 weeks' gestational age, partly owing to the fact the country has the highest caesarean section rate in the world.12Gibbons L Belizan JM Lauer JA Betran AP Merialdi M Althabe F Inequities in the use of cesarean section deliveries in the world.Am J Obstet Gynecol. 2012; 206: e1-19Summary Full Text Full Text PDF PubMed Scopus (203) Google ScholarTablePreliminary estimates of the specificity, sensitivity, and number of suspected cases of microcephaly in Brazil according to different screening criteriaCutoffsSpecificity*Based on applying the InterGrowth standards to the distribution of livebirths by gestational age in Brazil.Sensitivity†Preliminary results based on a case series of 31 newborn babies with radiological evidence of brain abnormalities.Estimated annual number of suspected cases (thousands)‡Calculated on the basis of sensitivity and the gestational age distribution of Brazilian newborn babies.Northeast BrazilBrazilBrazil's Ministry of Health6Brasil Ministério da SaúdeSecretaria de Vigilância em Saúde. Departamento de Vigilância Note Informativa 01/2015. COES Microcefalias. Ministério da Saúde, Brasília2015Google Scholar (up to Dec 8, 2015)≤33 cm for term newborn babies of both sexes; <−2 SD of Fenton reference7Fenton TR Kim JH A systematic review and meta-analysis to revise the Fenton growth chart for preterm infants.BMC Pediatr. 2013; 13: 59Crossref PubMed Scopus (1399) Google Scholar by gestational age and sex for preterm babies79·3%92%158602Brazil's Ministry of Health8Brasil Ministério da SaúdeSecretaria de Vigilância em Saúde. Departamento de Vigilância das Doenças Transmissíveis. Protocolo de vigilância e resposta àocorrência de microcefalia relacionada à infecção pelo vírus Zika. Ministério da Saúde, Brasília2015Google Scholar (after Dec 8, 2015)≤32 cm for term newborn babies of both sexes; <−2 SD of Fenton reference by gestational age and sex for preterm babies93·8%86%46178Pan American Health Organization9Pan American Health OrganizationLineamientos preliminares de vigilancia de microcefalia en recién nacidos en entornos con riesgo de circulación de virus Zika. Jan 22, 2016. Pan American Health Organization, Washington, DC2016Google Scholar<3rd percentile (WHO child growth standards10WHOThe WHO child growth standards.www.who.int/childgrowth/en/Google Scholar) for term newborn babies (<31·6 cm for girls and 32·0 cm for boys) and of the Fenton or InterGrowth reference for preterm babies96·1%80%29114Below −2 SD, InterGrowth standards11Villar J Cheikh Ismail L Victora CG et al.for the International Fetal and Newborn Growth Consortium for the 21st Century (INTERGROWTH-21st)International standards for newborn weight, length, and head circumference by gestational age and sex: the Newborn Cross-Sectional Study of the INTERGROWTH-21st Project.Lancet. 2014; 384: 857-868Summary Full Text Full Text PDF PubMed Google Scholar<−2 SD (InterGrowth standards) for gestational age and sex, all newborns97·8%85%1863Below −3 SD, InterGrowth standards11Villar J Cheikh Ismail L Victora CG et al.for the International Fetal and Newborn Growth Consortium for the 21st Century (INTERGROWTH-21st)International standards for newborn weight, length, and head circumference by gestational age and sex: the Newborn Cross-Sectional Study of the INTERGROWTH-21st Project.Lancet. 2014; 384: 857-868Summary Full Text Full Text PDF PubMed Google Scholar<−3 SD (InterGrowth standards) for gestational age and sex, all newborns99·9%57%0·83* Based on applying the InterGrowth standards to the distribution of livebirths by gestational age in Brazil.† Preliminary results based on a case series of 31 newborn babies with radiological evidence of brain abnormalities.‡ Calculated on the basis of sensitivity and the gestational age distribution of Brazilian newborn babies. Open table in a new tab The reasons for choosing the Fenton7Fenton TR Kim JH A systematic review and meta-analysis to revise the Fenton growth chart for preterm infants.BMC Pediatr. 2013; 13: 59Crossref PubMed Scopus (1399) Google Scholar reference are unclear. The Fenton chart is based on a meta-analysis of six pre-existing studies from high-income countries with non-standardised methods, as is the case for most neonatal anthropometric charts.13Giuliani F Ohuma E Spada E et al.Systematic review of the methodological quality of studies designed to create neonatal anthropometric charts.Acta Paediatr. 2015; 104: 987-996Crossref PubMed Scopus (22) Google Scholar Instead, we applied the sex-specific and gestational-age specific InterGrowth standards11Villar J Cheikh Ismail L Victora CG et al.for the International Fetal and Newborn Growth Consortium for the 21st Century (INTERGROWTH-21st)International standards for newborn weight, length, and head circumference by gestational age and sex: the Newborn Cross-Sectional Study of the INTERGROWTH-21st Project.Lancet. 2014; 384: 857-868Summary Full Text Full Text PDF PubMed Google Scholar to the gestational age distribution of Brazilian infants in 201214Brasil Ministerio da SaudeDATASUS. Sistema Nacional de Nascidos Vivos (in Portuguese).http://tabnet.datasus.gov.br/cgi/deftohtm.exe?sinasc/cnv/nvuf.defDate: 2016Google Scholar to estimate the specificity of evolving definitions of suspected cases of microcephaly (table). InterGrowth11Villar J Cheikh Ismail L Victora CG et al.for the International Fetal and Newborn Growth Consortium for the 21st Century (INTERGROWTH-21st)International standards for newborn weight, length, and head circumference by gestational age and sex: the Newborn Cross-Sectional Study of the INTERGROWTH-21st Project.Lancet. 2014; 384: 857-868Summary Full Text Full Text PDF PubMed Google Scholar is a prescriptive standard for fetal and newborn growth based on healthy gestations from eight countries. In this prospective, multicentre study, women had a reliable ultrasound estimate of gestational age using crown–rump length before 14 weeks of gestation or biparietal diameter if antenatal care started between 14 weeks and 24 weeks or less of gestation.11Villar J Cheikh Ismail L Victora CG et al.for the International Fetal and Newborn Growth Consortium for the 21st Century (INTERGROWTH-21st)International standards for newborn weight, length, and head circumference by gestational age and sex: the Newborn Cross-Sectional Study of the INTERGROWTH-21st Project.Lancet. 2014; 384: 857-868Summary Full Text Full Text PDF PubMed Google Scholar Newborn anthropometric measures were obtained by identically trained anthropometric teams using the same equipment at all sites, which included Brazil. The InterGrowth study was designed to be fully consistent with the WHO Growth Standards,15Villar J Papageorghiou AT Pang R et al.Monitoring human growth and development: a continuum from the womb to the classroom.Am J Obstet Gynecol. 2015; 213: 494-499Summary Full Text Full Text PDF PubMed Scopus (36) Google Scholar which are used throughout the world, thus providing a comparable standard for fetal growth and newborn size. Both standards are perfectly matched for term newborn babies. Because microcephaly cases were excluded from the InterGrowth samples, the distribution of head circumferences in the standard is appropriate for estimating specificity of a given cutoff. The use of a cutoff of −3 SD below the mean value for newborn head circumference was proposed by a 2013 systematic review of microcephaly, on the basis of the finding that most newborn babies with head circumferences between −2 SD and −3 SD below the mean range do not have any evidence of malformation.16Woods CG Parker A Investigating microcephaly.Arch Dis Child. 2013; 98: 707-713Crossref PubMed Scopus (100) Google Scholar The −3 SD cutoff has been used traditionally by the Latin American Collaborative Study of Congenital Malformations.4Latin American Network of Congenital MalformationsMicrocefalias en el ECLAMC y en Brasil (in Portuguese).http://www.eclamc.org/microcefaliaarchivos.phpDate: Dec 5, 2015Google Scholar A WHO manual on surveillance of birth defects defines microcephaly as a head circumference below −2 SD of sex-specific and gestational-age specific curves, but only if accompanied by structural abnormalities of the brain.17WHOBirth defects surveillance: a manual for programme managers. World Health Organization, Geneva2014Google Scholar The WHO manual explicitly states that absence of such abnormalities rules out a diagnosis; it does not recommend diagnostic workouts for all children with small heads.17WHOBirth defects surveillance: a manual for programme managers. World Health Organization, Geneva2014Google Scholar We derived preliminary estimates of sensitivity from 31 cases of confirmed microcephaly from ten states in Brazil, including eight northeastern states.18Schuler-Faccini L Ribeiro EM Feitosa IM et al.Brazilian Medical Genetics Society–Zika Embryopathy Task ForcePossible association between Zika virus infection and microcephaly—Brazil, 2015.MMWR Morb Mortal Wkly Rep. 2016; 65: 59-62Crossref PubMed Scopus (787) Google Scholar The newborn babies had head circumferences below the Ministry of Health cutoff at the time of birth and had brain abnormalities confirmed by imaging that were compatible with congenital infection (mainly brain calcifications, lissencephaly, and ventriculomegaly). These are the first consecutive confirmed cases available to our coauthors who are involved in surveillance in the ten states. In these 31 babies with microcephaly there was no evidence of intrauterine exposure to other infectious diseases, such as syphilis, toxoplasmosis, rubella, cytomegalovirus, and herpesvirus. The average head circumference was 28·4 cm (SD 2·3), with a mean InterGrowth Z score of −3·5 (SD 1·4). Only three newborn babies had head circumferences greater than or equal to 32 cm, all with mild radiological signs of brain abnormalities. The table shows the sensitivity of the different diagnostic criteria for suspected microcephaly based on our case series. These preliminary results must be interpreted with caution given the small number of cases, the fact that most measurements were rounded to full cm instead of mm, and the possibility of notification bias. Although the specificity of the cutoffs used so far seem high, in a country with almost 2·9 million annual births there would still be many newborn babies classified as suspected cases who would require in-depth investigation. The table shows that the number of cases of suspected microcephaly range from more than 600 000 with the initial criterion from the Ministry of Health6Brasil Ministério da SaúdeSecretaria de Vigilância em Saúde. Departamento de Vigilância Note Informativa 01/2015. COES Microcefalias. Ministério da Saúde, Brasília2015Google Scholar to just over 3000 if −3 SD is used as the cutoff. The fact that 3670 of the 4783 suspected cases of microcephaly identified in the past months are still under investigation is not surprising given delays in obtaining access to advanced diagnostic facilities in Brazil's national health system.19Solla J Chioro A Atenção ambulatorial especializada.in: Giovanella L Escorel S Lobato LVC Noronha JC Carvalho AI Políticas e sistema de saúde no Brasil. Editora Fiocruz, Rio de Janeiro2008: 627-663Google Scholar This backlog of cases under investigation may become worse as increasing numbers of suspected cases are reported and babies' head circumferences are measured more often than in the past. Another consideration is the emotional stress for parents whose healthy babies with small heads are incorrectly screened as positive. There is a trade-off between specificity and sensitivity. Since there is no effective treatment for congenital microcephaly, there is a strong argument to prioritise specificity over sensitivity. Increasing specificity would reduce the iatrogenic potential of radiation during brain tomography, which is 100 times higher than that for a chest x-ray,20Davies HE Wathen CG Gleeson FV Risks of exposure to radiological imaging and how to minimize them.BMJ. 2011; 342: 589-593Crossref Scopus (90) Google Scholar and would help alleviate the emotional effects on parents of healthy children who are given a false-positive result in the screening assessment. This approach would also reduce the burden and costs to an already overstretched health system. Although true cases of microcephaly that are missed by a less sensitive cutoff could benefit from early intellectual stimulation, there would still be opportunities to detect their condition later during infancy. Arguments for prioritising sensitivity include the fact that we are in the early stages of a new epidemic about which little is known. It is also conceivable that babies with microcephaly who would profit most from early intellectual stimulation could be exactly those whose head circumference is closer to the normal range. On the basis of our results (table), we recommend use of a consistent set of diagnostic criteria for suspected microcephaly that take into account gestational age for term and preterm newborn babies; such criteria are provided by the InterGrowth standards.11Villar J Cheikh Ismail L Victora CG et al.for the International Fetal and Newborn Growth Consortium for the 21st Century (INTERGROWTH-21st)International standards for newborn weight, length, and head circumference by gestational age and sex: the Newborn Cross-Sectional Study of the INTERGROWTH-21st Project.Lancet. 2014; 384: 857-868Summary Full Text Full Text PDF PubMed Google Scholar These are preliminary recommendations that can be revised once a larger case series is accrued. The sensitivity of a cutoff for head circumference of −3 SD seems to be too low, particularly during what seems to be a new epidemic of microcephaly, when one does not want to miss many cases. We favour a cutoff of −2 SD, which has similar sensitivity to the current Ministry of Health8Brasil Ministério da SaúdeSecretaria de Vigilância em Saúde. Departamento de Vigilância das Doenças Transmissíveis. Protocolo de vigilância e resposta àocorrência de microcefalia relacionada à infecção pelo vírus Zika. Ministério da Saúde, Brasília2015Google Scholar and PAHO9Pan American Health OrganizationLineamientos preliminares de vigilancia de microcefalia en recién nacidos en entornos con riesgo de circulación de virus Zika. Jan 22, 2016. Pan American Health Organization, Washington, DC2016Google Scholar recommendations, with the advantage of greatly reducing the number of newborn babies who will need investigation. Although −2 SD and the 3rd percentile seem to be close, the latter cutoff would classify an additional 0·7% of the population as suspected cases, or about 20 000 Brazilian newborn babies per year. The recent availability of a computer and mobile-phone based application for the estimation of head circumference Z scores by gestational age and sex will contribute to the field implementation of the InterGrowth standards;21InterGrowth21st. Oxford University, Oxford2016http://intergrowth21.ndog.ox.ac.uk/en/ManualEntryGoogle Scholar Portuguese and Spanish versions have also been made available. Although there is evidence of an increased number of cases of microcephaly in Brazil, we show that the number of suspected cases relied on a screening test that had very low specificity and therefore overestimated the actual number of cases by including mostly normal children with small heads. We recommend that national and international agencies should refrain from reporting suspected cases and speed up investigation to report on confirmed cases with laboratory or radiological evidence. It is also important that health workers measure head circumference in all newborn babies using standardised anthropometric techniques, and report results in mm. The present situation in Brazil is certainly a severe public health challenge. Better measurement and use of the appropriate growth standards are essential for the continued surveillance of microcephaly cases that are potentially associated with the Zika virus infection. CGV and FCB were part of the team of researchers that created the InterGrowth standards; the standards are in public domain and the researchers involved in their creation do not receive any financial benefits from their use.