Summary

In this case-control investigation to assess the association of microcephaly and Zika virus, cases reported to the national database for microcephaly (on the basis of their birth head circumference and total body length), born between Aug 1, 2015, and Feb 1, 2016, were enrolled. Controls were identified from the national birth registry and matched them to cases by location, aiming to enrol a minimum of two controls per case. Blood samples from mothers and infants were tested for Zika virus IgM and neutralizing antibodies as evidence of recent infection. Prevalence of microcephaly and its association with Zika virus infection was determined using a conditional logistic regression model.

Of the total 164 infants enrolled at birth, 91 (55%) had microcephaly on the basis of their birth measurements, 36 (22%) were classified as small head, 21 (13%) as disproportionate head, and 16 (10%) were classified as not having microcephaly. Forty-three (26%) of the 164 infants had microcephaly at follow-up for an estimated prevalence of 5·9 per 1000 live births. Investigators enrolled 114 control infants matched to the 43 infants classified as having microcephaly at follow-up. Infants with microcephaly at follow-up were more likely than control infants to be younger (OR 0·5, 95% CI 0·4, 0·7), have recent Zika virus infection (OR 21·9, 95% CI 7·0, 109·3), or a mother with Zika-like symptoms in the first trimester (OR 6·2, 95% CI 2·8, 15·4). Based on the presence of Zika virus antibodies in infants, authors concluded that 35-87% of microcephaly occurring during the time of the investigation in Northeast Brazil, was attributable to Zika virus, and an estimated 2-5 infants per 1000 live births had microcephaly attributable to Zika virus.

Relevance: Zika virus (ZV) is a flavivirus that recently created a public health crisis in South America (and globally) [1]. Its transmission was detected during mid-2015 with a spurt in birth of infants with microcephaly in the North-East region of Brazil. The hallmark finding of microcephaly occurs in an estimated 2.3% (95% CI 1.0, 5.3%) infants of ZV-infected mothers [2]; although, this varies by timing (i.e., trimester) of infection. Affected infants have severe development disabilities and serious consequences, including seizures, motor disability, vision deficits and hearing defects [3,4]. There is a high mortality rate ranging from 7% to 10% [5]. Adult infections were associated with significantly increased risk of Guillain-Barré syndrome [6]. The recent Brazilian epidemic is the third such outbreak following those reported from Micronesia in 2007 and French Polynesia in 2013 [7], suggesting spread of the infection across the Pacific Ocean into South America.

This case control study in Paraiba (Brazil) reported that infants with microcephaly at the age of 1-7 months were more likely to have laboratory-confirmed recent ZV infection (OR 21·9, 95% CI 7·0, 109·3), and maternal history of ZV infection symptoms in the first trimester (OR 6·2, CI 2·8, 15·4) [8]. Microcephaly was not associated with the presence of ZV infection symptoms prior to pregnancy or during the other two trimesters. The overall population prevalence of microcephaly was calculated as 5.9 per 1000 live births, of which 35% to 87% could be attributed to ZV infection. There was no association between infant microcephaly and maternal age, education, household income, and a wide range of environmental factors, including mosquito exposure prior to pregnancy, type of water supply, consumption of fish, toxin exposure, and smoking or alcohol consumption during pregnancy

Critical appraisal: The investigators pursued three separate lines of inquiry in this case-control study [8] viz: (i) exploration of association between infant microcephaly and ZV infection, (ii) prevalence of microcephaly following ZV infection outbreak, and (iii) factors other than ZV infection that could be responsible for the spurt in microcephaly. It can be argued that the case-control design is not the best suited design for these outcomes, especially for calculating prevalence. However, in the limited time span during (and after) the epidemic, it is perhaps the most feasible approach. Table I summarizes a critical appraisal of the study methodology. Several methodological refinements were applied during the design and conduct of this study. Highly specific definitions were used for almost all parameters. Although the focus was on microcephaly, the investigators categorized this further into true microcephaly, small head and disproportionate head. Microcephaly identified from the database was re-examined and re-categorized during a follow-up visit at 1 to 7 months of age. Extensive efforts were made to match controls to cases by area of residence. Efforts were made to ensure that the cases and controls had spent at least 80% of intrauterine life in the area of interest.

TABLE I  Critical Appraisal Of The Study Methodology 

The national microcephaly database identified 836 microcephalic infants, whereas only 352 (42%) had microcephaly by definition. This discrepancy has two implications. First, the reporting system was probably highly sensitive (but poorly specific) as may be expected in an outbreak situation. Second, it confirms that the database could not be blindly believed. Further, even among 127 infants confirmed to be microcephalic at birth, only 50 (39%) were microcephalic at the follow-up visit, and a substantial 44% of the infants did not have microcephaly. This suggests that birth head circumference may have poor correlation with subsequent classifications of microcephaly.

Therefore, the present study [8] has to be viewed against the backdrop in which it was conducted. In early 2016, there was reasonable uncertainty whether ZV was actually associated with microcephaly [12], especially as other potentially responsible factors were also hypothesized, including maternal vaccination, pesticides, toxins etc. Putting all the available data together, Table II summarizes the Bradford-Hill criteria [13] for causality [8-10,14-27]. In order to establish a causal link between ZV infection and microcephaly, confirmation of baseline prevalence of microcephaly in the community (just prior to the epidemic) is important. This is somewhat hampered by multiple factors, including paucity of local data, variable reliability of data sources, different methods used to define microcephaly, variations in types of infants studied and inadequate investigations performed to identify cause.

Table II Bradford Hill Criteria for Assessment of Causal Role of Zikavirus Infection on Microcephaly

During the period from 2005 to 2014, data from over 100 hospitals located in 10 South American countries reported a microcephaly prevalence of 0.44 per 1000 live births for hospital deliveries and 0.30 per 1000 live births in the community. However, there were significant inter-country, inter-region and even inter-hospital differences [28]. The traditional intrauterine infections were together responsible for less than 4% cases. Similarly, over a five-year timeframe prior to the ZV epidemic, the Texas Birth Defects Registry recorded the prevalence of microcephaly as 1.47 per 1000 live births. Severe microcephaly was recorded in 0.48 per 1000 live births. Another US-based birth defect surveillance system identified an overall microcephaly prevalence of 0.87 per 1000 live births [29]. The Quebec province in Canada reported an overall microcephaly prevalence ranging from 0.30 to 0.53 per 1000 live births during an observation period comprising nearly 2 million births over 23 years [30].

In Brazil itself, a report of microcephaly prevalence during 2011-15 among >8200 infants in neonatal intensive care units located in areas not associated with the ZV epidemic, reported an overall prevalence of 5.6% (95% CI 5.1%, 6.1%) with severe microcephaly in 1.5% (95% CI 1.2% to 1.7%) [31]. Data from two urban Brazilian birth cohorts comprising >7300 and 4200 live births reported a pre-Zika microcephaly prevalence of 3.5% and 2.5% [32]. The corresponding prevalence of severe microcephaly were 0.7% and 0.5%. These represent unusually high prevalence rates. These variations highlight the importance of recognizing the pre-epidemic microcephaly prevalence in the area of interest.

Since neonatal microcephaly is associated with several non-infectious maternal risk factors (age >35-40 y as well as <20 y, ethnicity, low education levels, smoking, diabetes, exposure to teratogens, etc) [28-30,33] that vary with country/society, data from other settings cannot be extrapolated to the local setting. Therefore, besides the baseline prevalence of microcephaly from birth records, analysis of the possible causes is also important to determine the role of infections such as ZV. This is also missing in this study [8].

In general, ZV infections are associated with severe microcephaly [15]. A study of 87 infants with confirmed congenital ZV infection had mean (SD) head circumference of only 28.1 (1.8) cm, despite mean (SD) birth weight being 2577 (260) g and >80% being term deliveries [15]. A comparative analysis of infants without ZV infection versus those with probable or confirmed infection reported a difference of 1·45-1·72 (mean 1.58) Z-scores in head circumference [23]. Unfortunately, this study [8] did not provide such data.

The global Zika virus crisis also highlights the variability in microcephaly definitions used around the world. The commonly used ‘International Fetal and Newborn Growth Consortium’ definition is head circumference <–2 standard deviations of the mean for age and gender. This has been used in most studies [10,17,32]. In contrast, the European Surveillance of Congenital Anomalies (EUROCAT) program defines microcephaly as head circumference <–3 Z-scores below the mean for sex, gender, and ethnicity, with reduced brain size [34]. This definition corresponds to ‘severe’ microcephaly in the other system. However, a study of 16 European registries comprising >5.7 lakh births across 15 countries, showed that only approximately half these registries applied the EUROCAT definition of microcephaly, whereas some used a cut-off of <–2 Z-score, and over a third of the registries defined microcephaly on the basis of criteria used by individual clinicians [34]. One registry changed the definition during the review period. Not surprisingly, there was a ten-fold variability in the prevalence across the registries. Interestingly, those using the more stringent EUROCAT definition reported a higher prevalence of 0.17 compared to 0.12 per 1000 live births with the –2 Z-score cut-off.

Extendibility: Data from this study [8] confirming a causal role of recent ZV infection with infant microcephaly, can be extended (in principle) across the world, as the bulk of evidence points in this direction. However, a meaningful epidemiological interpretation necessitates estimates of local baseline microcephaly prevalence, a robust surveillance system, and an action-oriented public health response system. These are currently not well developed in our setting. Further, the other causes of microcephaly and their relative distribution in various infant cohorts are unknown. For these reasons, the data from the study [8] cannot be meaningfully extended to our setting.

Conclusion: This case-control study provided strong evidence of an association between infant ZV infection and microcephaly in early life. However, there are limitations in the validity of the data ruling out other possible causes for the spurt in microcephaly in the local setting of the study.

Funding: None; Competing interests: None stated.

Joseph L Mathew

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3. Pessoa A, van der Linden V, Yeargin-Allsopp M, Carvalho MDCG, Ribeiro EM, Van Naarden Braun K, et al. Motor abnormalities and epilepsy in infants and children with evidence of congenital zika virus infection. Pediatrics. 2018;141:S167-79.

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8. Krow-Lucal ER, de Andrade MR, Cananéa JNA, Moore CA, Leite PL, Biggerstaff BJ, et al. Association and birth prevalence of microcephaly attributable to Zika virus infection among infants in Paraíba, Brazil, in 2015-16: A case-control study. Lancet Child Adolesc Health. 2018. http://dx.doi.org/10.1016/S2352-4642(18)30020-8.

9. de Araújo TVB, Rodrigues LC, de Alencar Ximenes RA, de Barros Miranda-Filho D, Montarroyos UR, de Melo APL, et al. Association between Zika virus infection and microcephaly in Brazil, January to May, 2016: Preliminary report of a case-control study. Lancet Infect Dis. 2016;16:1356-63.

10. de Araújo TVB, Ximenes RAA, Miranda-Filho DB, Souza WV, Montarroyos UR, de Melo APL, et al. Association between microcephaly, Zika virus infection, and other risk factors in Brazil: final report of a case-control study. Lancet Infect Dis. 2018;18: 328-36.

11. Delaney A, Mai C, Smoots A, Cragan J, Ellington S, Langlois P, et al. Population-based surveillance of birth defects potentially related to Zika virus infection - 15 states and US territories, 2016. MMWR. 2018;67:91-6.

12. Liuzzi G, Puro V, Lanini S, Vairo F, Nicastri E, Capobianchi MR, et al. Zika virus and microcephaly: is the correlation causal or coincidental? New Microbiol. 2016;39: 83-5.

13. No authors listed. The Bradford Hill Criteria. Available from: http://www.southalabama.edu/coe/bset/johnson/bonus/Ch11/Causality%20criteria.pdf. Accessed March 10, 2018.

14. de Oliveira WK, de França GVA, Carmo EH, Duncan BB, de Souza Kuchenbecker R, Schmidt MI. Infection-related microcephaly after the 2015 and 2016 Zika virus outbreaks in Brazil: A surveillance-based analysis. Lancet. 2017; 390:861-70.

15. Meneses JDA, Ishigami AC, de Mello LM, de Albuquerque LL, de Brito CAA, Cordeiro MT, et al. Lessons learned at the epicenter of brazil’s congenital zika epidemic: evidence from 87 confirmed cases. Clin Infect Dis. 2017;64:1302-8.

16. Ribeiro IG, Andrade MR, Silva JM, Silva ZM, Costa MAO, Vieira MADCES, et al. Microcephaly in Piauí, Brazil: descriptive study during the Zika virus epidemic, 2015-2016. Epidemiol Serv Saude. 2018;27:e20163692.

17. Souza WV, Albuquerque MFPM, Vazquez E, Bezerra LCA, Mendes ADCG, Lyra TM, et al. Microcephaly epidemic related to the Zika virus and living conditions in Recife, Northeast Brazil. BMC Public Health. 2018;18:130.

18. Satterfield-Nash A, Kotzky K, Allen J, Bertolli J, Moore CA, Pereira IO, et al. Health and development at age 19-24 months of 19 children who were born with microcephaly and laboratory evidence of congenital Zika virus infection during the 2015 Zika virus outbreak - Brazil, 2017. MMWR. 2017;66: 1347-51.

19. Possas C. Zika: What we do and do not know based on the experiences of Brazil. Epidemiol Health. 2016;38:e2016023.

20. Bautista LE. Maternal Zika virus infection and newborn microcephaly-an analysis of the epidemiological evidence. Ann Epidemiol. 2018;28:111-18.

21. Ronchetti R, Bianco PM. Many doubts about the relationship between cases of microcephaly and Zika virus in Brazil. Epidemiol Prev. 2016;40:466-71.

22. Albuquerque MF, Souza WV, Mendes AD, Lyra TM, Ximenes RA, Araújo TV, et al. Pyriproxyfen and the microcephaly epidemic in Brazil - an ecological approach to explore the hypothesis of their association. Mem Inst Oswaldo Cruz. 2016;111:774-76.

23. França GV, Schuler-Faccini L, Oliveira WK, Henriques CM, Carmo EH, Pedi VD, et al. Congenital Zika virus syndrome in Brazil: A case series of the first 1501 live births with complete investigation. Lancet. 2016;388: 891-97.

24. Li S, Armstrong N, Zhao H, Hou W, Liu J, Chen C, et al. Zika virus fatally infects wild type neonatal mice and replicates in central nervous system. Viruses. 2018; 10: E49.

25. Shi Y, Li S, Wu Q, Sun L, Zhang J, Pan N, et al. Vertical transmission of the Zika virus causes neurological disorders in mouse offspring. Sci Rep. 2018;8:3541.

26. Cui L, Zou P, Chen E, Yao H, Zheng H, Wang Q, et al. Visual and motor deficits in grown-up mice with congenital Zika virus infection. EBio Medicine. 2017;20:193-201.

27. Kozak RA, Majer A, Biondi MJ, Medina SJ, Goneau LW, Sajesh BV, et al. Micro RNA and mRNA dysregulation in astrocytes infected with Zika virus. Viruses. 2017; 9:E297.

28. Orioli IM, Dolk H, Lopez-Camelo JS, Mattos D, Poletta FA, Dutra MG, et al. Prevalence and clinical profile of microcephaly in South America pre-Zika, 2005-14: prevalence and case-control study. BMJ. 2017;359:j5018.

29. Cragan JD, Isenburg JL, Parker SE, Alverson CJ, Meyer RE, Stallings EB, et al. Population-based microcephaly surveillance in the United States, 2009 to 2013: An analysis of potential sources of variation. Birth Defects Res A Clin Mol Teratol. 2016; 106:972-82.

30. Auger N, Quach C, Healy-Profitós J, Lowe AM, Arbour L. Congenital microcephaly in Quebec: baseline prevalence, risk factors and outcomes in a large cohort of neonates. Arch Dis Child Fetal Neonatal Ed. 2018;103:F167-72.

31. de Magalhães-Barbosa MC, Prata-Barbosa A, Robaina JR, Raymundo CE, Lima-Setta F, Antonio José LAC. Prevalence of microcephaly in eight south-eastern and midwestern Brazilian neonatal intensive care units: 2011-2015. Arch Dis Child. 2017; 102:728-34.

32. Silva AA, Barbieri MA, Alves MT, Carvalho CA, Batista RF, Ribeiro MR, et al. Prevalence and risk factors for microcephaly at birth in Brazil in 2010. Pediatrics. 2018;141:e20170589.

33. Hoyt AT, Canfield MA, Langlois PH, Waller DK, Agopian AJ, Shumate CJ, et al. Pre-Zika descriptive epidemiology of microcephaly in Texas, 2008-2012. Birth Defects Res. 2017;110:395-405.

34. Morris JK, Rankin J, Garne E, Loane M, Greenlees R, Addor MC, et al. Prevalence of microcephaly in Europe: population based study. BMJ. 2016; 354: i4721.

35. Souza WV, Araújo TV, Albuquerque Mde F, Braga MC, Ximenes RA, Miranda-FilhoDde B, et al. Microcephaly in Pernambuco State, Brazil: epidemiological characteristics and evaluation of the diagnostic accuracy of cutoff points for reporting suspected cases. Cad Saude Publica. 2016;32:e00017216.

In this case control study, Krow-Lucal et al. [1], provide confirmative evidence of association of maternal antenatal Zika virus infection with microcephaly in infants. Based on the presence of Zika virus antibodies in infants, the authors concluded that 35–87% of microcephaly occurring during the time of their investigation in northeast Brazil was attributable to Zika virus. They estimated that 2–5 infants per 1000 live births in Paraíba, Brazil had microcephaly attributable to Zika virus.

Even though, so far Zika virus is not an etiological consideration in the evaluation of microcephaly in infants in India (unless there is a history of maternal travel to Zika affected regions during pregnancy), there are a number of interesting learning points from this study for pediatricians and pediatric neurologists.

Microcephaly has been traditionally defined as significant reduction in the occipito-frontal head circumference (HC) compared with age- and gender-matched controls. Controversies persist whether a cut-off of less than –2SD or less than –3SD should be considered to define microcephaly. Some authors have advocated for defining severe microcephaly as an HC more than 3 SDs below the mean [1]. However, in the current study, and in most other studies, microcephaly was defined as HC more than 2 SDs (i.e., <3rd centile) below the mean for age and gender.

The importance of follow-up measurements is excellently demonstrated in this study. Out of 91 infants detected to have microcephaly at birth, only 34 (37%) had microcephaly at follow-up. Interestingly, out of the 21 infants who were classified as disproportionate at birth (normal head circumference but disproportionately small head as compared to the length), 3 infants (14%) were detected to have microcephaly at follow-up. This fact underscores the importance of interpreting the head circumference in relation to the length of the infant. Also, as the authors suggest, birth measurements have insufficient precision and several measurements might be needed to classify an infant as having microcephaly.

Funding: None; Competing interests: None stated.

Suvasini Sharma

1. Ashwal S, Michelson D, Plawner L, Dobyns WB. Practice Parameter: Evaluation of the child with microcephaly (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology. 2009;73:887-97.

2. Villar J, Giuliani F, Butta AZ, Ohuma EO, Ismail LC, Barros FC, et al. Postnatal growth standards for preterm infants: the Preterm Postnatal Follow-up Study of the INTERGROWTH-21st Project. Lancet Glob Health. 2015;3:e681-91.

This was a retrospective case control study to assess the association of microcephaly and Zika Virus (ZV) conducted in North-East Brazil and included cases – infants reported to national database for microcephaly – and age-matched controls from the same geographic area in the same period [1]. The national case definition for microcephaly was an infant with head circumference (HC) of 33 cm or less, which was later changed to HC of 32 cm or less for term infants and HC lower than 3rd centile for gestational age for preterm infants. To control the effect of sex and intrauterine growth retardation (IUGR), the researchers classified the children in 4 categories depending upon HC and ratio of HC to body length – microcephaly, small, disproportionate and no microcephaly. Mothers and infants were tested for Zika virus and dengue virus IgM antibodies and neutralizing antibodies. All infants had repeat measurements of HC and length at follow-up.

The study strengthens the evidence of causal association of ZV infection in pregnancy with microcephaly. Since no other factor was significantly associated with microcephaly, the article lays to rest the speculation of role of alternative risk factors such as environmental toxins. The role of effect modifier such as past or concurrent dengue infection remains uncertain as the study did not have sufficient power. A case-control study from same region similarly attributed the microcephaly epidemic in the area to ZV infection in pregnancy [2]. A recent meta -analysis of sample size of 2941 pregnancies of which 2648 were live births, provided a pooled prevalence of ZV-associated microcephaly of 2.3% of pregnancies and 2.7% of the live births, which is rather lower than expected [3]. A more reliable estimate of risk of Zika-associated birth defects depending upon the time of infection in pregnancy was provided by a prospective study from US territories that studied completed pregnancies with confirmed ZV infection. The percentages of fetuses or infants with possible Zika-associated birth defects with maternal infection with Zika virus infection in 1st , 2nd, and 3rd trimester was 8%, 5%, and 4%, respectively [4]. It is recognized that the risk of sequelae with ZV is not limited to first trimester alone, and infants born to mothers with ZV infection need close follow-up and monitoring.

The study documents importance of repeat measurements after birth as at follow-up only about one-fourth of the reported cases actually had microcephaly. The use of a single cut-off value of 33 cm at birth, which was used in the study, lacks specificity. The head circumference grows at rapid pace in the last trimester; therefore, using sex- and gestational age- specific head circumference charts such as Intergrowth-21 is recommended for preterm infants and term infants in whom exact gestational age is known [5]. In LMIC countries in which Low birth weight rates are high, use of a single cut-off, as used in Brazil will overestimate the burden of microcephaly.

A major challenge with ZV is difficulty in diagnosis since the PCR assay detects viral RNA and is therefore positive only during the brief period of viremia. The serological tests show significant cross-reactivity with other flaviviruses such as dengue which are often circulating in the same areas . The fetal abnormalities are detected late in pregnancy when it is often too late for termination of pregnancy. Besides it is not yet known whether asymptomatic infection poses a risk to the fetus.

Currently in absence of a vaccine against ZV infection, prevention remains the only method to reduce the burden of complications of ZV infection. In populations with established ZV transmission, congenital Zika Virus syndrome can be prevented by good vector control measures, preventing sexual transmission, and reducing the number of unplanned pregnancies. In countries with low or no transmission of ZV, checking importation of ZV and surveillance of congenital Zika virus syndrome and Guillian-Barre Syndrome should be in place. Clustering of microcephaly or suspected Congenital Zika virus syndrome can give a clue to the outbreak.

The public health implications of outbreak of Zika virus in India can be enormous. The weak surveillance system coupled with difficulty in clinically differentiating Zika virus infection from dengue and chikungunya can hamper the control measures. WHO has classified countries according to Zika virus circulation and transmission. As per this classification India falls in category 2 since there is historical evidence of virus circulation before 2015. The report of two patients with febrile illness testing positive for Zika Virus at Ahmedabad in 2017 raised alarm bells in our country. Till date 4 cases with acute febrile illness have tested positive for Zika Virus (3 from Gujarat and one from Tamil Nadu) suggesting foci of local transmission. However, no virus has been detected from mosquito population tested [6]. Needless to say that given the conducive environment in India, over a variable period, the mutations in the virus might render mosquitoes more susceptible, which in turn may increase transmission and result in outbreaks [7]. A similar situation has been seen with Chikungunya virus in recent past.

To estimate the extent of Zika virus infection in India, a long-term robust surveillance network is needed. Vector surveillance needs to be scaled up. Existing acute febrile illness and birth defect surveillance at sentinel sites needs to be strengthened. It may be added that phenotype of congenital Zika virus infection is expanding and besides microcephaly other congenital abnormalities such as club foot, arthrgryoposis and ocular abnormalities should be added for surveillance. Surveillance for Guillian Barre Syndrome (GBS) is another strategy that can be used in addition. Cases of Acute Flaccid Paralysis are reported routinely to the National Polio Surveillance Program. Detection of an increase in the number of cases of GBS in the AFP surveillance system may provide early warning of a Zika virus outbreak.

1. Krow-Lucal ER, de Andrade MR , Cananéa JNA, Moore CA, Leite PL, Biggerstaff BJ, et al. Association and birth prevalence of microcephaly attributable to Zika virus infection among infants in Paraíba, Brazil, in 2015–16: a case-control study. Lancet Child Adolesc Health. 2018;2:205-13.

2. de Araújo TVB, Rodrigues LC, de Alencar Ximenes RA, de Barros Miranda-Filho D, Montarroyos UR, de Melo APL, et al. Association between Zika virus infection and microcephaly in Brazil, January to May, 2016: Preliminary report of a case-control study. Lancet Infect Dis. 2016;16:1356-63.

3. Coelho AVC, Crovella S. Microcephaly prevalence in infants born to zika virus-infected women: A systematic review and meta-analysis. Int J Mol Sci. 2017;18:1714.

4. Shapiro-Mendoza CK, Rice ME, Galang RR, Fulton AC, VanMaldeghem K, Prado MV, et al. Pregnancy Outcomes After Maternal Zika Virus Infection During Pregnancy — U.S. Territories, January 1, 2016–April 25, 2017. MMWR. 2017;66:615-21.

5. World Health Organization . Screening, Assessment and Management of Neonates and Infants with Complications Associated with Zika Virus Exposure in utero. Available from: http://www.who.int/csr/resources/publications/zika/assessment-infants/en/ Accessed March 19, 2018.

6. Indian Council of Medical Research. Division of Epidemiology & Communicable Diseases. Zika Virus preparedness and response. Available from : http://www. icmr.nic.in/zika/Zika%20update%20-%20January% 202018.pdf. Accessed March 19, 2018.

7. Bhardwaj S, Gokhale MD, Mourya DT. Zika virus: Current concerns in India. Indian J Med Res. 2017;146:572-5.