The massive microcephaly outbreak that rocked Brazil last year has confounded researchers who are trying to understand the cause. Although most scientists think there is a connection between the Zika virus and the huge spike in microcephaly cases in Brazil, a new study of Zika-infected mothers in Colombia casts doubt on this theory, because out of 12,000 confirmed cases of Zika-infected pregnant women, none had babies born with microcephaly.

Zika Mosquito

Many take for granted that the Zika virus is the cause of the spate of microcephaly in Brazil, especially since in April the Centers for Disease Control and Prevention (CDC) confirmed a causal relationship between them. But in June, the New England Complex Systems Institute (NESCI) released a report examining the rate of microcephaly cases in Brazil per Zika-infected mothers, against microcephaly in Colombia in Zika-infected mothers and found the rates to be vastly different, according to available data. If Zika infection in the first trimester of prenatal development was the sole cause of microcephaly in infants, scientists would expect the rates of microcephaly to be much higher in other areas where the Zika virus has hit hard, such as Colombia. This new study indicates such is not the case. There is also a huge difference between rates of microcephaly in certain areas of Brazil versus others, with the microcephaly “epicenter” being the city of Recife, Pernambuco in the Northeast. Other areas of Brazil have seen a lot of Zika infections and not nearly the same rates of microcephaly, which indicates that there might be some other cause of microcephaly, or perhaps even multiple causes in addition to Zika virus.

Earlier this year, a group of Argentine doctors suggested the pesticide pyriproxyfen might actually be causing the microcephaly epidemic. Inhabitat spoke with three experts about the possible links between pyriproxyfen and microcephaly or the Zika virus and microcephaly, in an effort to better understand emerging theories.

microcephaly baby

In February, an Argentinian organization called Red Universitaria de Ambiente y Salud published a report from Medicos de Pueblos Fumigados, or Physicians in the Crop-Sprayed Town, that raised concern over pyriproxyfen put in drinking water by the State. Pyriproxyfen affects developmental processes in mosquitoes, and some wonder if the chemical is somehow triggering a similar reaction in humans.

Related: Experimental Zika vaccine to be tested on humans for the first time

Pesticide Spraying, pyriproxyfen

So what do we know about pyriproxyfen? First off, it’s manufactured by Japanese company Sumitomo Chemical, a company that is not owned by Monsanto but has collaborated with them in the past. Second, the World Health Organization (WHO) approved its use, and the government began to add pyriproxyfen to drinking water in Brazilian favelas at the end of 2014. So the timing checks out, according to Dr. Yaneer Bar-Yam, founder of the New England Complex Systems Institute (NECSI), which has written their own reports on the Zika virus, microcephaly, and pyriproxyfen. The villages where pyriproxyfen was added weren’t monitored, Bar-Yam said, nor were pregnancies in those villages. He said, “All they did was test its effect on mosquitoes.”

The doctors said in their report that pyriproxyfen has been used in areas where people infected with the Zika virus live, and that other Zika virus epidemics in the past weren’t linked to birth defects.

Pyriproxyfen has not been linked decisively to microcephaly, but there may be reason for further research. The bulk of testing on pyriproxyfen has been carried out by Sumitomo, according to Bar-Yam. He said while there was evidence the pesticide affected the brain mass of rat fetuses, the testers could say those results weren’t important because they didn’t meet certain criteria. Specifically, as doses increase, the effects must worsen. In Sumitomo tests, a dose of pyriproxyfen in the middle of the study showed more problems in rats than at later points in the study where the rats were given more of the pesticide.

Microcephaly Symptoms, babies with microcephaly

“There are a lot of reasons why that might have been true, such as dosage variability or DNA variability. It’s hard to tell whether those tests are actually good tests,” Bar-Yam told Inhabitat. “Imagine if you have something that might have an effect in 1 percent of babies, or in 1 in 100 babies, if you test it only on 100 rats, you might not see the effect. In the studies they tested pyriproxyfen only on several dozen rats. It’s very hard to tell if the studies transfer from rats to people; the study is a very limited probe of what’s going on.”

A study done by four Oregon State University researchers published in September in the journal Environmental Pollution found pyriproxyfen led to “adverse morphological effects” in zebrafish. The researchers concluded “developmental toxicity of pyriproxyfen may not be limited to insects.”

Bar-Yam pointed out WHO’s approval doesn’t necessarily mean the pesticide is safe. “One could argue that WHO followed the standard protocol for approval of an insecticide, but that doesn’t mean the protocol is safe. There are other instances where it failed,” he said. “For example, methoprene was approved as insecticide, but now has been shown to cause development disorders in mammals. Pyriproxyfen and methoprene are in the same family of chemical. The fact that we have a member of the same family of chemicals known to cause the same problems in development doesn’t prove pyriproxyfen does but again surely raises the question of do we know enough.”

There are claims that pyriproxyfen has not been used in Recife, described in a NECSI report as a microcephaly epicenter. According to their report, however, those making the claims don’t distinguish between “the metropolitan area of Recife, where it is widely used, and the municipality, where it is not.”

According to Dr. Margaret “Peggy” Honein of the CDC, pyriproxyfen has been “used for decades” without being linked to microcephaly.

“Studies have found evidence of Zika virus in the brains of newborns with microcephaly. This strongly supports a causal link between Zika and microcephaly,” Honein told Inhabitat. She is the lead for the Pregnancy and Birth Defects Task Force for the Zika Response, and is a co-author on the preliminary report on the Zika virus in Colombia published by The New England Journal of Medicine. “Exposure to pyriproxyfen would not explain these study results showing the presence of Zika virus in the brains of infants born with microcephaly.”

Why wouldn’t the Zika virus be the clear cause of microcephaly, if it has been found in babies’ brains? According to Bar-Yam, “The rate at which microcephaly cases are linked to Zika is quite low. The problem is the additional pieces of information that would let us conclude Zika is causing microcephaly are not adding up.”

Microcephaly Cases in Brazil, microcephaly Brazil, map of microcephaly in Brazil

In Brazil, there are over 1,500 confirmed cases of microcephaly potentially related to the Zika virus. Researchers eagerly awaited data from Colombia, where Zika virus infections have been better reported than in Brazil, according to Bar-Yam. The CDC and Instituto Nacional de Salud in Colombia supported a study based on the data.

The Colombia study didn’t yield easy answers, however. Up to April 2, 2016, 65,726 cases of Zika Virus Disease were reported, and 2,485, or 4 percent, were confirmed. 11,944 pregnant women in Colombia were reported with the Zika virus, with 1,484, or 12 percent, confirmed. The researchers looked at a group of 1,850 pregnant women, and over 90 percent of the women who were reported infected with the Zika virus in their third trimester had delivered their babies. Microcephaly had not been identified in any of those babies.

Between January 1, 2016, and April 28, 2016, 50 infants with possible microcephaly cases were reported to the “national surveillance system.” Over half of those cases – 26 – were still under investigation when the report was written. 20 cases were linked to other causes, not the Zika virus. Four of the cases were linked potentially to the Zika virus through “laboratory evidence,” but none of the mothers had symptoms of Zika Virus Disease during pregnancy.

In this abstract of the article in the conclusion, the researchers wrote, “Preliminary surveillance data in Colombia suggest that maternal infection with the Zika virus during the third trimester of pregnancy is not linked to structural abnormalities in the fetus.”

Bar-Yam said the fact that we can’t make the Colombia data work with the Brazil data, where there are so many more cases of microcephaly potentially linked to the Zika virus but where the data may not be as reliable or complete, makes it “hard to draw a definitive conclusion.”

Microcephaly head size

Dr. Leslie Lobel, a leading virologist who has studied the Zika virus where it originally emerged in Uganda, gave the numbers some perspective by comparing the microcephaly outbreak with that of the German measles epidemic.

“From all evidence, it appears the Zika virus is related to the side effects. It happens a small percentage of the time, maybe 20 to 25 percent. In perspective, with the German measles epidemic, there were malformations 100 percent of time,” Lobel told Inhabitat.

He pointed out that while there appears to be a “preponderance of evidence that seems to indicate a relationship between Zika infections and microcephaly,” there are other factors involved. Dengue fever is also circulating in Brazil, and Lobel said those with Zika have often been infected with dengue either before or at the same time as with Zika, which could “dampen the immune response [to Zika] or accelerate it.”

Microcephaly can be caused by other elements as well. “CDC is investigating other factors such as another infection occurring at the same time as Zika virus infection, nutrition, or the presence of symptoms that might affect the risk for birth defects,” said Honein. “Other known causes of microcephaly can include rubella, cytomegalovirus, or toxoplasmosis infections during pregnancy; severe malnutrition; interruption of blood supply to the developing brain; or exposure to harmful substances such as alcohol and certain drugs and toxic chemicals.”

Pregnancy

All three experts Inhabitat spoke with said the Zika virus is likely connected to microcephaly. But the Zika virus may not be the only factor.

“It’s a little bit surprising that we would be in situation where at the same time two new things are both causing microcephaly. It’s not what you’d expect, but is it possible? Yes,” said Bar-Yam. “The point we’re making is not that we know pyriproxyfen is causing microcephaly, but that there’s a reason to look for another cause based on the available data, and there’s a reason to suspect pyriproxyfen might have a role because of its biological mechanism.”

Lobel said we need more testing on chemicals. “In small quantities you often don’t see problems but in big quantities the problems come out,” he said. He also called for more research on viruses.

“Nixon shifted funds away from virus research to cancer research. Now with global warming and globalization, we see the emergence of diseases once confined to one part of world,” said Lobel. “We’ve slept on this for many, many years. Viruses never sleep but we sleep.”

Another step would be the development of a vaccine, but that’s easier said than done.

“The problem with developing a vaccine is that the government wants it yesterday but we know so little about what reaction of the immune system to the virus causes the side effects,” said Lobel. “We need more research into the immune response to the virus.”

Furthermore, he said we should consider ecosystems more in our research of viruses and ways to combat them.

“There are potential side effects of chemicals or technology, such as what happens when you remove insects from the environment? I tend to believe you shouldn’t be doing that; there is a delicate balance in an ecosystem,” he said. “Right now the developing world is out of balance with the ecosystem with the sudden entry of something new in semi-sterile environment where viruses go wild. Right now there is no balance between the viruses and the environment. We need a deeper understanding of ecosystems.”

“I think eventually the truth will come out,” said Bar-Yam. “One might argue there’s a reason for some people to be concerned. If microcephaly is caused by a disease transmitted by mosquitoes, no one’s at fault. If it turns out pyriproxyfen is involved in microcephaly, people will be held accountable for it.”

Images via Wikimedia Commons, Free Stock Photos, Wikimedia (1, 2, 3), garycycles8 on Flickr, Latin American Science, Pexels, and dany13 on Flickr.