Zika Virus, Part 2: The Link to Birth Defects, Is It Real?

Zika virus was discovered in the Zika Forest of Uganda in 1947 and, despite its current prominence in the media, until this past year it was thought to be relatively benign. However, matters changed dramatically in 2015 when Zika virus emerged in Brazil, where it has since been associated with a striking surge in the incidence of infants born with microcephaly (abnormally small heads and brains). Astonishingly, the number of Brazilian children born with microcephaly allegedly jumped from 147 in 2014 to 4,783 cases as of February 2, 2016.

A December 2015 photo of a Brazilian infant with microcephaly.
A December 2015 photo of a Brazilian infant with microcephaly.

The link between Brazil’s cases of microcephaly and in-utero infection with Zika virus was first implied by the geographic and temporal correspondence between the emergence of the virus in Brazil and the remarkable rise in the number of Brazilian cases of microcephaly (1). Subsequently, Brazilian health officials investigated 1,113 of their microcephaly cases and confirmed that 404 of them could be linked to Zika infection. In addition, actual Zika virus was detected in the amniotic fluid of several microcephalic fetuses, and anti-Zika virus antibodies were detected in the amniotic fluid of others—evidence that the virus indeed might cross the placenta and possibly infect the fetus (2). With those sorts of findings at hand, why do public health authorities still refer to the Zika/microcephaly link as merely suggested?

Some health officials and researchers claim that the surge in the Brazilian incidence of microcephaly, which allegedly occurred after the Zika outbreak, was merely an artifact, accounted for by a significant under-reporting of cases before the Zika outbreak. To that point, 21 Brazilian medical centers recently collaborated to reassess the head circumferences of 16,208 Brazilian neonates from Northeast Brazil (which contained the epicenter of the 2015 Zika epidemic) from late 2012 until the entry of the Zika virus into Brazil in mid-2014. As reported earlier this month (3), they found an astonishing incidence of microcephaly during that pre-Zika period; ranging from 2% to 8%. Moreover, and importantly, the number of affected babies actually peaked in 2014, before Zika virus had even been seen in Brazil! See Aside 1.

[Aside 1: These researchers also found an increased incidence of the most extreme cases of microcephaly in the last quarter of 2015, after Zika virus emerged in Brazil; a finding consistent with the possibility that something new was occurring after the Zika outbreak. See Note below.]

What might explain the under-reporting of microcephaly cases in Brazil, before its Zika outbreak? The authors of the collaborative study claim that it was mainly because there are no standardized criteria for diagnosing microcephaly—loosely defined as a condition, not an illness, characterized by an occipital-frontal head circumference smaller than expected for gestational age and gender. The absence of standardized diagnostic criteria was said to account for the discrepancies between the incidence of microcephaly found by the authors of the collaborative study and that recorded earlier in official sites. [A lack of consensus over the defining limits of microcephaly also accounts for the wide range in incidence of cases, of from 2% to 8%, in the collaborative study’s report.] See Note 1, below.

Interestingly, when these investigators narrowed the criteria for microcephaly to include only the most extreme cases (i.e., those neonates who fell into the lower third of all three criteria enumerated in Note 1; see below) the rates (0.04 percent to 1.9 percent) were still high, although now within the ranges reported elsewhere in the world. Consequently, the authors conclude: “It is possible that a high incidence of milder forms microcephaly has been occurring well before the current outbreak, but that only those extreme cases, with classical phenotypes, were being notified. And as the number of extreme cases increased over these past three or four months so did the awareness of health professionals who started to notify milder forms (3).”

The authors call attention to the fact that the clinical significance of the milder forms of microcephaly, which comprise the vast majority of reported cases, remains to be determined. They then assert that, “These observations highlight the need to review the situation carefully. Many questions need to be answered prior to concluding what problem we are facing, how it came about and which consequences it is likely to bring to the Brazilian population in years to come… We can only conclude that we are facing a new and challenging public health problem and that limited epidemiological and clinical data hinders conclusions at this early stage.”

In February 2016 another team of Brazilian researchers claimed that the lack of standardized diagnostic criteria for microcephaly led to an overestimate of the incidence of microcephaly after the Zika outbreak, rather than to an underestimate before the outbreak (5). That is, an increased incidence of microcephaly was reported after the outbreak because normal children, whose heads were small, actually comprised the majority of alleged cases.

Here is another reason for questioning the link between Zinka infection and microcephaly. Whereas Zika virus was discovered in Uganda more than 60 years ago, and has since spread to more than a dozen countries, the recent surge of microcephaly in Brazil is the only case-in-point, anywhere in the world, in which microcephaly has been associated with Zika virus. Brazil’s neighbor, Colombia, is the world’s second-most Zika-affected country, with around 20,000 confirmed Zika infections. Yet while more than 2,000 of the Columbian Zika infections were of pregnant women, none of their fetuses were diagnosed with microcephaly.

Moreover, and in contrast to the lack of an association between Zika and microcephaly outside of Brazil, the Zika outbreak has been associated with a surge in Guillain-Barré syndrome (a temporary paralysis) in Colombia, El Salvador, Suriname, Venezuela, and French Polynesia, as well as in Brazil. The apparent universal association of Zika with Guillain-Barré syndrome, but not with microcephaly, might be taken as an argument against an etiologic role for Zika virus in microcephaly.

Yet, even in the case of Guillain-Barré syndrome, the World Health Organization considers the link to Zika to be tenuous; in part because other arthropod-borne viruses, including dengue, chikungunya and Zika viruses, have all been circulating simultaneously in the Americas (5). [Guillain-Barré syndrome occurs after infection by a variety of pathogens, including dengue and chikungunya viruses, which are related to Zika.] Likewise, the circulation of these other arthropod-borne viruses in areas hard hit by Zika raises the possibility that they might be involved in microcephaly.

So, where do we stand? Uncertainty regarding the connection between Zika and microcephaly underscores the need for clinicians to come to a consensus regarding the criteria that define that condition. Moreover, since most of the mothers who participated in earlier epidemiologic studies were not tested for Zika (even if they might have been infected), and since Zika causes a relatively mild illness that often goes undetected, and since other pathogenic arthropod-borne viruses also circulate in areas in which Zika is prevalent, there is a crucial need for a convenient and unambiguous molecular diagnostic test to identify these infections. See Aside 2.

[Aside 2: A convenient diagnostic test for Zika virus is also needed to protect the blood supply in countries were the virus is spreading by local transmission. Many of these countries are poverty stricken and already suffer from low donation rates and dwindling blood supplies. They can not long depend on outside sources of blood for their transfusions.]

But even with standardized diagnostic criteria for microcephaly, as well as accurate tests for infection, important gaps still remain in our knowledge of Zika virus—gaps that must be filled before the role of the virus in microcephaly can be known with certainty.

But isn’t the presence of Zika virus in the amniotic fluid of microcephalic fetuses proof enough? It isn’t because the handful of other viruses that are able to cross the human placenta (e.g. rubella, cytomegalovirus) are not known to cause microcephaly at the extraordinary rates currently being reported in Brazil. Thus, it is necessary to establish with certainty that Zika virus does, in fact, target and harm the fetal brain. [If it were ascertained that Zika virus does target the fetal brain, then it will be important to know how much time elapses after the mother is infected, before the virus can strike the fetus. Moreover, it will be important to determine whether the fetal brain is at risk to Zika during all, or during only some stages of its development.] See Aside 3.

[Aside 3: The MMR vaccine largely protects American children against congenital rubella. However, worldwide, more than 100,000 children continue to be born each year with this condition. Cytomegalovirus, for which there is no vaccine, causes at least 5,000 cases of birth defects each year in the United States alone.]

Importantly, despite the reservations noted above, many, if not most researchers believe that Zika virus indeed is the agent behind a very real surge in the incidence of microcephaly in Brazil. Moreover, the World Health Organization declared that the rise in microcephaly constitutes a global health emergency. Thus, while we await more rigorous proof of the Zika/microcephaly connection, it remains essential to act as though it were real.

Note 1:

“In this study (3), classification of microcephaly was based on three different criteria, as follows:

1. Brazilian Health Ministry proposed criteria, where microcephaly equals an occipital-frontal head circumference (OFC) smaller than 32 cm for term neonates.

2. Fenton curves, where microcephaly equals an OFC less than -3 standard deviation (SD) for age and gender.

3. Proportionality criteria, where microcephaly equals an OFC less than ((height/2) + 10) ± 2.

Microcephaly classification:

Neonates were classified with microcephaly according to each one of the three criteria.
A separate group was created for those who fulfilled all three criteria. Finally, those who fell into the lower third in each criterion were grouped as extreme cases of microcephaly.”

References:

1. Zika Virus: Background, Politics, and Prospects, Posted on the blog February 4, 2016.

2. Oliveira Melo AS, Malinger G, Ximenes R, Szejnfeld PO, Alves Sampaio S, Bispo de Filippis AM. Zika virus intrauterine infection causes fetal brain abnormality and microcephaly: tip of the iceberg? 2016 Ultrasound Obstet Gynecol. 47: 6–7.

3. Soares de Araújo JS, Regis CT, Gomes RGS, Tavares T R, 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.16.17063

4. Victora CG, Schuler-Faccini L, Matijasevich A, Erlane Ribeiro A, Pessoa A,
Fernando Celso Barros FC. Microcephaly in Brazil: how to interpret reported numbers? The Lancet, Published Online February 5, 2016 http://dx.doi.org/10.1016/
S0140-6736(16)00273-7.

5. WHO’s February 12 Zika Situation Report

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