Microcephaly is a serious birth defect characterized by an abnormally small head. In Brazil, this congenital malformation is typically rare—only about 150 babies among the nearly 3 million born in the country each year are diagnosed with microcephaly. However, since October 2015, close to 4,000 cases of microcephaly were reported in Brazil, and many of the cases come from the northeast corner of the country.
In response to the dramatic rise in the malformed small heads, the World Health Organization (WHO) declared a public health emergency (something the agency has done three times since 2007) to get scientists and global resources focused on the problem.
The cause of the rise in microcephaly remains unknown. While a handful of possible culprits have been proposed, from the beginning officials have turned all their attention to a single suspect: the Zika virus.
Until recently, Zika was an obscure mosquito-borne illness considered to have relatively mild symptoms compared to other mosquito-transmitted diseases such as malaria, West Nile, and dengue fever. It was first identified in a rhesus monkey in the Zika forest near Entebbe, Uganda, in 1947, and up until a decade ago there were fewer than 15 documented cases of people who had contracted the virus.
Zika began to make a name for itself in 2007, when Yap Island (located in the South Pacific just east of the Philippines) reported a few dozen inhabitants had caught the virus. In 2013 and 2014, more Pacific islands (French Polynesia and New Caledonia) saw a surge of what health workers initially thought was dengue fever, until tests revealed Zika. An estimated 20,000 people were infected, and then the virus seemed to vanish without a trace.
Next Zika was spotted in a new locale, South America, where it came on even stronger. By December 2015, the Ministry of Health estimated that as many as 1.5 million Brazilians were infected with Zika. The Brazilian government suggests the disease was brought over from Africa or the Pacific islands in 2014 during the World Cup.
Brazil’s rapid rise in Zika, the increase in microcephaly, and the few cases that have tested positive for both doesn’t exactly equal a smoking gun, but it has prompted the U.S. Centers for Disease Control (CDC) to issue a warning for pregnant women to avoid Zika-prone areas. It has also pushed officials in El Salvador, Colombia, and Brazil to urge women to refrain from getting pregnant until scientists can get to the bottom of what’s going on.
Evidence for Zika
Due to panic, over-reporting, and sensational headlines, it can be hard to tell what’s true when it comes to interpreting the microcephaly mystery.
One researcher who has been following the science and spread of Zika is Vincent Racaniello, Ph.D., a research virologist at the medical center at Columbia University in New York. In a Feb. 10 post on his virology blog, Racaniello notes three published reports that together suggest that Zika may cause microcephaly.
The “blockbuster” evidence according to Racaniello is a report recently published in the New England Journal of Medicine (NEJM) that documents a European woman living in northeastern Brazil who was infected with Zika, probably at the end of her first trimester of pregnancy. Her fetus, which was aborted at 32 weeks, had severe brain damage and Zika in its brain tissue.
Another report from the CDC found Zika in the amniotic fluid of two fetuses with microcephaly.
In earlier findings, Zika was merely suspected. In a report from late January, 35 Brazilian infants with microcephaly were born to mothers who either lived in or traveled to the regions where the Zika virus has been found. Most mothers had a rash during their first or second trimester indicative of the virus, but they were not formally tested for the virus.
“If we can get a few more cases studied like the one [published in NEJM] then I think we’ll be there,” Racaniello said. “If we have 10, 20, 30 babies born with defects that have Zika virus, that’s a really strong case. On the other hand, we should also look at normal babies and see if they have the virus or not. Is the virus affecting a lot of babies with no problem? We just don’t know that.”
Mutation Unlikely
When Brazilian health officials began to see a pattern of more microcephaly in the presence of Zika, scientists looked at Polynesia’s 2014 Zika outbreak to see if microcephaly rates had been higher there too. They found an increase in malformations of the central nervous system of fetuses and babies, confirming at least 17 cases reported from 2014 to 2015.
While scientists work out whether Zika causes microcephaly, there are several established causes, such as chromosomal abnormalities (Down syndrome), decreased oxygen to the fetal brain, exposure to drugs, alcohol, or certain toxic chemicals in the womb, and severe malnutrition.
There are also viruses that are known to cause microcephaly if they infect the fetus during pregnancy, such as Cytomegalovirus, rubella, and chickenpox. Other mosquito-borne infections also have the potential to cause premature birth, congenital defects, and microcephaly.
Since Zika wasn’t known to cause microcephaly in the past, some suggest that it must have mutated in such a way that it now causes birth defects. But Racaniello believes this is unlikely.
“In my experience, I don’t see viruses changing what they do,” he said. “My suspicion is that there has been a low rate of microcephaly with Zika before but we just haven’t seen it. I don’t think the virus has changed to be able to do this, but again, that’s something we’ll have to see.”
Contributing Factors
The microcephaly mystery comes at a particularly bad time for Brazil. The country is getting ready to host the Olympics this summer during the worst economic recession seen since the 1930s, while the Workers’ Party-led government provides an endless saga of corruption scandals.
Critics have called the WHO’s health emergency announcement premature as the majority of the microcephaly cases have yet to be verified. One major obstacle in verifying cases is the challenges associated with testing for Zika, especially in newborns.
According to the CDC, one common technique for testing (reverse transcription polymerase chain reaction, or RT-PCR) may not detect Zika in a newborn who had developed the infection in utero. Blood serum tests for Zika can often show a false positive because of cross-reacting antibodies against related viruses such as dengue and yellow fever. Plaque-reduction neutralization testing (PRNT) can be performed to measure virus-specific neutralizing antibodies to Zika virus, but neutralizing antibodies may still yield cross-reactive results in newborns due to maternal antibodies that were transferred to the infant.
A case in point: On Feb. 2, a major São Paulo newspaper reported that 404 cases of microcephaly had been confirmed (several hundred reports have been dismissed). Of these confirmed cases, only 17 have shown a connection to Zika. However, due to issues with testing, many researchers said that number is irrelevant, because the tests would find the virus in only a tiny percentage of cases.
“Some of the births we’ve seen, the children die very quickly afterward,” said Racaniello. “We could get samples from them and look for the virus. Unfortunately, the mothers had their infections months ago, so it’s hard to confirm Zika infection in them. That’s why another kind of study we would need would be to look for infection in a group of mothers, follow them as they go through pregnancy, and see what fraction of them have babies with developmental problems.”
Brazil’s health minister, Marcelo Castro, has claimed “100 percent certainty of the connection of the Zika virus with increasing cases of microcephaly,” but others aren’t so sure, as some data throws a wrench into the pattern. For example, Colombia—a country that has also seen a sharp rise in Zika this past year—has not demonstrated a similar rise in microcephaly. On Feb. 6, Colombian President Juan Manuel Santos announced that out of the 3,177 pregnant women in his country diagnosed with the Zika virus, not one case of microcephaly has been reported.
One theory that helps account for the discrepancy is that the microcephaly outbreak may not be caused by Zika alone, but by a confluence of factors.
A recent report, issued from the Argentine doctors’ organization Physicians in Crop-Sprayed Towns, notes that in the Brazilian state of Pernambuco—where a third of the microcephaly cases have been reported—a chemical larvicide used for the past year and a half was found to be producing malformations in mosquitoes. The group suggests it may be contributing to the malformation of children as well.
“This poison (pyroproxyfen) is applied by the State on drinking water used by the affected population,” states the report.
Another environmental hazard found in this region is paraquat. The herbicide has been deemed “highly poisonous” by U.S. regulators, but is still used extensively in Brazil.
However, unlike the rigorous scientific investigation aimed at Zika, little consideration has been given to a chemical cause for the microcephaly outbreak, and the theory thus far is based on speculation rather than evidence. But according to a statement from César Chelala, M.D., Ph.D., a global public health consultant for several U.N. and other international agencies, it’s not outside the realm of possibility. Chelala contributes as a freelancer to the opinion pages of this paper.
“Given the toxic effects of paraquat and other toxic pesticides used in the region it is not unreasonable to think that, at least in some cases, microcephaly may be due to excessive use of toxic pesticides and that these effects have been unmasked by the Zika virus infection. It is also possible to think that microcephaly in children may have a multi-causal origin,” Chelala wrote.
