DISCLAIMER This paper was submitted to the Bulletin of the World Health Organization and was posted to the Zika open site, according to the protocol for public health emergencies for international concern as described in Christopher Dye et al. (http://dx.doi.org/10.2471/blt.16.170860). The information herein is available for unrestricted use, distribution and reproduction in any medium, provided that the original work is properly cited as indicated by the Creative Commons Attribution 3.0 Intergovernmental Organizations licence (CC BY IGO 3.0). RECOMMENDED CITATION Simmins Jr CH. Establishing base levels of microcephaly in Brazil prior to the arrival of Zika viral illnesses [Submitted]. Bull World Health Organ E-pub: 8 Feb 2016. doi: http://dx.doi.org/10.2471/blt.16.171223 Establishing base levels of microcephaly in Brazil prior to the arrival of Zika viral illnesses Charles H Simmins Jr a a 200 Meadow Circle, Rochester, New York, NY 14609, United States of America.. Correspondence to Charles H Simmins, Jr (email: chuck@simmins.org). (Submitted: 7 February 2016 Published online: 8 February 2016) Page 1 of 8
Abstract: The only way to determine if there is an increase in any medical condition is to know what the norm was before the increase. Brazil is reporting 4,783 cases of microcephaly in the period from Oct. through the end of January. In order to determine what the normal incidence and number of cases of microcephaly are for Brazil, a search of the websites of national and multinational public health agencies was conducted. In addition, searches were conducted to identify studies that related specifically to Brazil. Additional searches were carried out to identify the prevalence in Brazil of two known microcephaly agents, congenital toxoplasmosis and congenital cytomegalovirus infections. It became clear that the incidence being reported by Brazilian authorities was under-reporting the situation. A variety of rates were found from a number of official sources as well as those from papers presented in the last two months which bear directly upon the current situation. A minimum norm was determined, of 2,725 microcephaly cases annually. The minimum incidence for the condition was determined to be 92/100,000. Page 2 of 8
Introduction: Brazilian public health authorities began to receive reports of increased numbers of microcephaly in Oct. 2015. The reports originated from throughout the country with the vast majority were being reported from states in the northeast. Small numbers of microcephaly have been reported in that time frame from other Latin American nations but Brazil seems to be the locus for the greatest numbers. The Brazilian Live Birth Information System has released incidence rates for microcephaly twice recently. In 2000, it reported that the incidence rate for microcephaly was 5.5/100,000 live births. A decade later, that incidence was reported as 5.7/100,000 [1]. In contrast, one study published by the U.S. Centers for Disease Control and Prevention suggested that the expected incidence for Brazil should be between 10/100,000 and 20/100,000 [2]. A situation report issued by the World Health Organization on Feb. 5 states that the Brazilian Ministry of Health had received 4,783 reports of microcephaly or central nervous system malformations through Jan. 30 [3]. Analysis of 1,113 of those reports has been conducted and some 63 percent have been discarded as incorrect diagnoses. It is clear that a significant portion of the total number of reports will be discarded. The normal incidence of microcephaly and the normal number of cases in Brazil is an important part of determining if there is an unusual number of cases, an outbreak, or if the current reports are a belated recognition of a medical problem that preexisted the arrival of Zika viral illnesses in the late spring of 2015. The World Health Authority has declared a Public Health Emergency of International Concern [4] based upon the reports of microcephaly, and those of increased instances of Guillain-Barré syndrome in other nations. There are a number of statements by national and international public health authorities which suggest expected incidence rates of microcephaly in a standard population. There are studies that explore those rates with respect to Brazil. In addition, there are studies that explore the incidence rates of microcephaly or case numbers for specific, known causes of microcephaly which are prevalent in Brazil. The published data can be used to establish a range of incidence rates and case numbers and can suggest, with some confidence, if the outbreak since Oct. 2015 is beyond expected norms. Methodology: All of the data is converted to a standard incidence of x per 100,000 births. Data is presented for four years, 2000 and 2010 as well as 2014 and 2015. The data for Brazilian live births is taken from the U.S. Census Bureau, which rounds their estimates to the nearest thousand [5]. The Study: In the year 2000, the Brazilian Live Birth Information System reported an incidence of 5.5 microcephaly cases per 100,000 births. This calculates to an estimated 202 newborns with that birth defect. In 2010, the incidence was reported to be 5.7/100,000, but the number of live births had declined by 16 percent so the calculated number of microcephaly cases was 176. Those two incidence rates can then be applied to the live births for 2014 and 2015. [Table 1] Page 3 of 8
There are a number of other estimates available from national and international public health authorities. The U.S. Centers for Disease Control and Prevention uses an incidence range of between 20 and 120 microcephaly cases per 100,000 on its Facts page [6]. EUROCAT, European Surveillance of Congenital Anomalies estimates an incidence of 28.5/100,000 for the combined nations within its network [7]. [Table 2] There are two recent studies from Brazil that maintain that the official Brazilian incidence rates are understating the extent of microcephaly in that country. The first was produced Dec. 30, 2015, by the Latin American Collaborative Study of Congenital Malformations (ECLAMC). The study estimates that the incidence rate for microcephaly in Brazil is 19.8/100,000 [1]. A report posted to the WHO site on Feb. 4, titled Microcephaly in northeastern Brazil: a review of 16,208 births between 2012 and 2015 [3] looks at one state in the northeastern part of the country. The rates of microcephaly that the authors found vary by the definition of the conditions that is applied, but they ranged from two to eight percent of live births in that state. For 2014, the number of predicted cases fulfilling the strictest diagnostic criteria in their study equaled 1,105. That calculates to an incidence rate of 1,900/100,000 and over 56,000 estimated microcephaly cases nationally. Among the medical conditions which are known to result in microcephaly in newborns are congenital toxoplasmosis and congenital cytomegalovirus infections. A number of studies have looked at the prevalence of these microcephaly-producing conditions in the Brazilian population. Congenital toxoplasmosis is found in a large number of Brazilian newborns. Carvalheiro, et al, in their 2005 paper estimated an incidence rate of 33/100,000 [8]. In a 2012 paper, Dubey and colleagues suggested an incidence of 100/100,000 [9]. They found that 35 percent of their sample presented with neurological disease including microcephaly. That calculated to just over 1,000 cases per year. Congenital cytomegalovirus infections were estimated to occur at a rate of 1.08 percent in a 2009 study by Dr. Mussi-Pinhata and colleagues [10]. Studies by Bopanna, et al [11] and Lombardi, et al [12] suggest that 10 to 15 percent of these children will have clinical abnormalities at birth. Bopanna suggests that 53 percent of that number will exhibit microcephaly. Discussion: There appears to be little consensus in the public health community on the incidence of microcephaly in general, and in Brazil, in particular. Brazil, as a society, suffers from the effects of alcohol and drug abuse, poor prenatal nutrition and the effect of a number of infectious diseases that all can result in microcephaly in newborns. The perceived surge in cases in northeastern Brazil has resulted in attention being given to a subject that has been under-reported. Is it possible to use existing data and studies to arrive at norm for the condition which can then be used to evaluate any increase in cases? The Mattos study was a retrospective study that looked at births occurring before the arrival of the Zika virus in Brazil in May, 2015. In 2014, it found an estimated 1,105 microcephaly cases in just one of Brazil's states. Gross application of their data to the nation as a whole suggests over 56,000 cases. The study's authors note that much of Brazil has not experienced any surge in cases and that their data may only be reflective of the situation in the northeast. The ECLAMC report offers similar observations. Page 4 of 8
The incidence of microcephaly in Brazil, at a normal level, includes those newborns affected by congenital toxoplasmosis and congenital cytomegalovirus infections. Based upon existing studies done in Brazil, the country saw between 2,725 and 3,570 microcephaly cases from just those two causes in 2015, and between 2,752 and 3,605 in 2014. The actual number of microcephaly cases in Brazil should be no lower than 2,725. That is an incidence of 92/100,000 live births. Offering some support for that conclusion is the Dec. 10 Rapid Risk Assessment from the European Centre for Disease Prevention and Control (ECDC) which shows an incidence for the Months of Oct. through Dec. 2015 of 99.7/100,000 [13]. Page 5 of 8
YEAR Publication: Bulletin of the World Health Organization; Type: Research in emergencies TABLE 1 - Brazilian Live Birth Information System LIVE BIRTHS INCIDENCE OF MICROCEPHALY CALCULATED CASES OF MICROCEPHALY 2015 2,954,000 5.7/100,000 168 2015 2,954,000 5.5/100,000 162 2014 2,983,000 5.7/100,000 170 2014 2,983,000 5.5/100,000 164 2010 3,079,000 5.7/100,000 176 2000 3,664,000 5.5/100,000 202 Table 2 Other Public Health Authorities SOURCE YEAR LIVE BIRTHS INCIDENCE OF MICRO- CEPHALY CALCULATED CASES OF MICROCEPHALY CDC fact sheet 2015 2,954,000 20 591 CDC fact sheet 2015 2,954,000 120 3,545 CDC fact sheet 2014 2,983,000 20 597 CDC fact sheet 2014 2,983,000 120 3,580 EUROCAT 2015 2,954,000 28.5 842 EUROCAT 2014 2,983,000 28.5 850 Year Toxoplasmosis produced microcephaly Table 3 Microcephaly Produced by Infections Congenital cytomegalovirus 10 % Congenital cytomegalovirus 15 % Minimum cases Maximum cases 2015 1,034 1,691 2,536 2,725 3,570 2014 1,044 1,707 2,561 2,752 3,605 2013 1,053 1,722 2,584 2,776 3,637 2012 1,062 1,737 2,605 2,799 3,667 2010 1,078 1,762 2,644 2,840 3,721 2000 1,282 2,097 3,146 3,380 4,428 Page 6 of 8
References and Citations: 1) Latin American Collaborative Study of Congenital Malformations (ECLAMC) Final Document http://www.nature.com/polopoly_fs/7.33594!/file/ns-724-2015_eclamc- ZIKA%20VIRUS_V-FINAL_012516.pdf 2) 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 3) Soares de Araújo JS, Regis CT, Gomes RGS, Tavares TR, Rocha dos Santos C, Assunção PM, et al. Microcephaly in northeast Brazil: a review of 16 208 births between 2012 and 2015. [Submitted] Bull World Health Organ, E-pub: 4 Feb 2016. doi: http://dx.doi.org/10.2471/blt.16.170639 4) WHO Director-General summarizes the outcome of the Emergency Committee regarding clusters of microcephaly and Guillain-Barré syndrome http://www.who.int/mediacentre/news/statements/2016/emergency-committee-zikamicrocephaly/en/ 5) U.S. Census Bureau International Data Base https://www.census.gov/population/international/data/idb/informationgateway.php 6) U.S. Centers for Disease Control and Prevention Facts about Microcephaly http://www.cdc.gov/ncbddd/birthdefects/microcephaly.html 7) EUROCAT Prevalence Tables http://www.eurocatnetwork.eu/accessprevalencedata/prevalencetables 8) C. G. CARVALHEIRO, M. M. MUSSI-PINHATA, A. Y. YAMAMOTO, C. B. S. DE SOUZA and L. M. Z. MACIEL (2005). Incidence of congenital toxoplasmosis estimated by neonatal screening: relevance of diagnostic confirmation in asymptomatic newborn infants. Epidemiology and Infection, 133, pp 485-491. doi:10.1017/s095026880400353x. 9) J. P. DUBEY, E. G. LAGO, S. M. GENNARI, C. SU and J. L. JONES (2012). Toxoplasmosis in humans and animals in Brazil: high prevalence, high burden of disease, and epidemiology. Parasitology, 139, pp 1375-1424. doi:10.1017/s0031182012000765. 10) Marisa M. Mussi-Pinhata, Aparecida Y. Yamamoto, Rosângela M. Moura Brito, Myriam de Lima Isaac, Patricia F. de Carvalhoe Oliveira, Suresh Boppana, and William J. Britt. Birth Prevalence and Natural History of Congenital Cytomegalovirus Infection in a Highly Seroimmune Population. Clin Infect Dis. (2009) 49 (4): 522-528. doi: 10.1086/600882 11) PRENATAL THERAPY OF CONGENITAL CYTOMEGALOVIRUS INFECTION: Suresh B. Boppana, Shannon A. Ross, and Karen B. Fowler. Congenital Cytomegalovirus Infection: Clinical Outcome. Clin Infect Dis. (2013) 57 (suppl 4): S178-S181 doi:10.1093/cid/cit629 Page 7 of 8
12) Congenital cytomegalovirus infection: treatment, sequelae and follow-up. Giuseppina Lombardi, Francesca Garofoli, Mauro Stronati. The Journal of Maternal-Fetal & Neonatal Medicine. Vol. 23, Iss. Sup3, 2010 13) European Centre for Disease Prevention and Control (ECDC) - Rapid risk assessment: Zika virus epidemic in the Americas: potential association with microcephaly and Guillain-Barré syndrome 10 Dec 2015 http://ecdc.europa.eu/en/publications/publications/zika-virus-americasassociation-with-microcephaly-rapid-risk-assessment.pdf Page 8 of 8