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Comments on Congenital Zika virus syndrome in Brazil

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The Lancet has just released online an important study about the occurrence of microcephaly in Brazil and its relationship to maternal Zika viral illnesses. “Congenital Zika virus syndrome in Brazil: a case series of the first 1501 live births with complete investigation” [1] presents the first analysis of the medical records and associated data from the microcephaly reports investigated by the Brazilian Ministry of Health or state ministries. The data is a significant addition to what is known about the situation in Brazil. The study’s authors, however, raise some questions and their conclusions may not be well supported by their data.

The study divided the 1,551 cases into five categories. 899 cases were discarded by the investigators, 60 percent of the total. The remaining cases consisted of those considered by the study team as definite, highly probable, moderately probable and somewhat probable with respect to their causation by a maternal Zika viral illness.

The data shows some inconsistent reporting, with missing data points, for some cases. The most serious lack of data, however, is in the testing of the neonates for Zika and for other potential causes of microcephaly.

I sent the corresponding author five questions or concerns that I have with the paper. Here they are, with added commentary and references.

Q1.

In 80% of those cases considered definite, there was no serology eliminating congenital syphilis, congenital toxoplasmosis or congenital CMV. I cannot understand how any definitive conclusion can be reached without a full TORCHS assay.

Medline describes the TORCHS assay as “a group of blood tests that check for several different infections in a newborn.” It tests for congenital toxoplasmosis, rubella, congenital cytomegalovirus, herpes simplex, syphilis and HIV. All of these infections are known to cause serious birth defects and most of them can result in microcephaly in a fetus or newborn. The blood test is standard in the United States.

As described by the study, the sole criteria for a case to be considered definite was “laboratory evidence of Zika virus infection during pregnancy through serology or PCR, independently of other findings.” If other causes of microcephaly cannot be ruled out, how can Zika be definitely considered the cause?

Q2.

In the United States, the headlines are concluding that defects have been demonstrated in infants whose mothers had a Zika rash in the third trimester. The study cites just two sources for the conclusions in that respect, and both were in lab work using neural progenitors. If I understand correctly, that cell type disappears at around a gestational age of 17 weeks. I am not clear on how Petri dish work on early gestational cell types translates into “Malformations associated with late-pregnancy rashes” as the study states.

[2] [3]

Q3.

The discussion of neonatal mortality in Brazil, especially in NE Brazil, has confused me. If I read the study correctly, the normal neonatal mortalities for Brazil and for NE Brazil are compared to the neonatal mortality rates for the patients in the study, including the discarded cases. How can “normal” rates be compared to rates in a cohort that is born with birth defects?

A group of neonates with serious birth defects ought to have a much greater mortality rate than the average. However, comparing the two is the old “apples and oranges” issue, comparing two different subjects as if they were similar.

Q4.

From 2010 to 2014, Brazil reported an average of 156 cases of microcephaly a year. That appears to be the basis of the statement that “fewer than 15 newborns with microcephaly were reported monthly in Brazil”. There exists a number of studies that suggest that the actual pre-Zika numbers may be 100 times greater or more. The lack of data on the discarded cases, admittedly containing patients with microcephaly not due to an infection, is worrisome given the existing under-reporting issues.

As an example of the oddity of the reported Brazilian numbers, the U.S. state of Texas in the period 2006 to 2010 averaged 372 cases yearly in an average of 323,000 live births.

[4] [5]

First, a correction. The 100 times stated above ought to be 30 times. My mistake, while writing late at night.

As an accountant in senior level positions for 20 years, and as an adult Aspergers, numbers are a thing. The minute I first saw the number of microcephaly cases reported by Brazil, I had questions. The reported number of cases is far too low.

Mattos, et al, reviewed over 16,000 births in NE Brazil. [6] They used three criteria to establish the existence of microcephaly, with each stricter than the last. When they applied all three criteria, the strictest application, they found that 2.07% of the births involved microcephaly. That worked out to 1,105 estimated cases in the state of Paraíba for the year 2014.

Campos, et al, looked at a group of live births in NE Brazil in 2007. [7] They found that 2.8% of the births, 38 cases of 958 births, were microcephalic.

Based upon these studies, NE Brazil should see between 2.07% and 2.8% of all births resulting in microcephaly. The remainder of the country may, or may not, be different. However, the incidence of microcephaly in the region clearly exceeds the number of cases being reported by the Ministry of Health.

A possible upper limit calculation for the entire nation, using 2.07% and 2,954,000 births, for 2015 results in over 61,000 cases of microcephaly. I suspect that even the Ministry could not ignore that level of birth defects and that the actual number is much lower, but it is NOT 156.

My work on the pre-Zika incidence of microcephaly in the United States can be found at the link.

Q5.

There are studies which demonstrate the rates for Down’s syndrome, fetal alcohol syndrome, congenital toxoplasmosis and congenital CMV in Brazil. In a paper currently being considered by the WHO Bulletin, I have suggested that these four causes of microcephaly alone may be responsible for over 4,600 cases of microcephaly in Brazil in 2015. The incidence of these four combined is 15.816 per 10,000.

My paper is available in PDF here. At this time, the WHO has it in the review process. This is a resubmission, at their request, and I attempted to fold in the suggestions of the editors of the Bulletin and the reviewers.

References and Citations:

[1] França, G V A, et. al. Congenital Zika virus syndrome in Brazil: a case series of the first 1501 live births with complete investigation. Lancet. doi: http://dx.doi.org/10.1016/S0140-6736(16)30902-3
[2] Garcez, PP, Loiola, EC, Madeiro da Costa, R et al. Zika virus impairs growth in human neurospheres and brain organoids. Science. 2016; 352: 816–818
[3] Tang, H, Hammack, C, Ogden Sarah, C et al. Zika virus infects human cortical neural progenitors and attenuates their growth. Cell Stem Cell. 2016; 18: 587–590
[4] Brazilian Ministry of Health. Ministério da Saúde divulga novos dados de microcefalia. http://portalsaude.saude.gov.br/index.php/o-ministerio/principal/secretarias/svs/noticias-
svs/21020-ministerio-da-saude-divulga-novos-dados-de-microcefalia
[5] National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention. Major Birth Defects Data from Population-based Birth Defects Surveillance Programs in the United States, 2006-2010. http://www.nbdpn.org/docs/DataDirectory2013_NBDPN_AR.pdf
[6] de Araújo, J. S. S., Regis, C. T., Gomes, R. G. S., & Tavares, T. R. (2016). Microcephaly in northeastern Brazil: a review of 16 208 births between 2012 and 2015. Bull World Health Organ, 4.
[7] Campos, J. S., Cunha, A. J. L. A. D., Machado, M. M. T., Rocha, S. G. M. O., Silva, A. C., Rocha, H. A. L., … & Correia, L. L. (2016). Microcephaly: normality parameters and its determinants in northeastern Brazil: a multicentre prospective cohort study. doi: http://dx.doi.org/10.2471/BLT.16.171215


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