What is the cause of Brazil's microcephaly outbreak?

Question

It has been claimed that Brazil is suffering from an outbreak of Microcephaly.

Several possible causes have been proposed.

Zika Virus

Perhaps the most popular one is the zika virus. For example, the NY Times wrote:

The possibility that the Zika virus causes microcephaly – unusually small heads and often damaged brains – emerged only in October, when doctors in northern Brazil noticed a surge in babies with the condition.

It may be that other factors, such as simultaneous infection with other viruses, are contributing to the rise; investigators may even find that Zika virus is not the main cause, although right now circumstantial evidence suggests that it is.

However, some people are pouring doubt on this claim. For example the (Australian) ABC's Health Report radio show says:

But now there are fresh questions about the suspected link between the Zika virus and microcephaly which causes small heads in babies.

A four-year survey of over 100,000 newborn babies in north eastern Brazil has uncovered previously unrecognised patterns of microcephaly.

It suggests that the rise in cases may not be a new phenomenon, and questions whether Zika virus is actually the cause.

Pesticide

Another claim is that it might be caused by pyriproxyfen, a pesticide.

For example, The Ecologist reports:

With the proposed connection between the Zika virus and Brazil's outbreak of microcephaly in new born babies looking increasingly tenuous, Latin American doctors are proposing another possible cause: Pyriproxyfen, a pesticide used in Brazil since 2014 to arrest the development of mosquito larvae in drinking water tanks.

The article is based on this report by PCST ("Physicians in the Crop-Sprayed Towns", but the name is variously translated).

Is there scientific consensus around the evidence? Has there been a recent outbreak of microcephaly in Brazil, and is the cause the Zika virus, pyriproxyfen, some combination or neither?

Answer 1

Summary

Based on current evidence, the Zika virus appears to be the likely cause of Brazil's microcephaly outbreak.

There is limited evidence to support pyriproxyfen as a cause, but further, more specific, studies are required to test this hypothesis.

Zika Virus

There are several strands of evidence which point to the Zika virus as the likely (but not definite) cause:

• The microcephaly outbreak has so far been reported only in Brazil and French Polynesia, which have suffered from the Zika virus.

  So far an increase in microcephaly and other neonatal malformations has only been reported in Brazil and French Polynesia, although two cases linked to a stay in Brazil were detected in the United States of America and Slovenia. Reported cases of microcephaly and/or congenital malformation in Colombia are under investigation.

  Source: WHO Zika Virus, Microcephaly and Guillain-Barré Syndrome Situation Report, 10 March 2016

• Initial research studies have shown a relationship between Zika virus infection during pregnancy and microcephaly.

  A recently published cohort study in Brazil shows an increased risk of microcephaly and other congenital abnormalities associated with a Zika virus infection during pregnancy and provides further information to support the possible causal relationship between Zika virus and microcephaly and other congenital abnormalities.

  [...]

  Zika virus is not yet proven to be a cause of the increased incidence of microcephaly in Brazil. However, given the temporal and geographical associations between Zika virus infections and microcephaly, the repeated discovery of virus in fetal brain tissue, and in the absence of a compelling alternative hypothesis, a causal role for Zika virus is a strong possibility that is under active investigation.

  Source: WHO Zika Virus, Microcephaly and Guillain-Barré Syndrome Situation Report, 10 March 2016

• Research on autopsy findings of a fetus suggest that Zika does target the brain:

  No presence of virus and no pathological changes were detected in any other fetal organs apart from the brain, which suggests a strong neurotropism of the virus.

  Source: Zika Virus Associated with Microcephaly.

• A Lancet paper tries to quantify the size of the risk:

  In this model, the baseline prevalence of microcephaly was two cases (95% CI 0–8) per 10 000 neonates, and the risk of microcephaly associated with Zika virus infection was 95 cases (34–191) per 10 000 women infected in the first trimester.

  The Verge published a more readable summary of this Lancet paper, in an article entitled Zika virus associated with 1 in 100 risk of microcephaly, says study:

  The researchers used this data and statistical modeling to create the estimated risks associated with Zika. However, the study does not take into account other abnormalities that may be associated with the virus, and its authors warn that the risk may differ from outbreak to outbreak. Speaking to The Wall Street Journal, the study's co-author Arnaud Fontanet said: "The one percent we describe here is not the end of the story."

• There is good evidence linking Zika virus infections during pregnancy and congenital central nervous system malformations.

  The evidence regarding a causal link between Zika virus infections during pregnancy and congenital CNS malformations is substantial. Although the available information is not yet sufficient to scientifically confirm it, there is sufficient evidence to warrant public health actions as supported by the declaration of a Public Health Emergency of International Concern on 1 February 2016. Source: ECDC

• A short term stem cell study also showed that Zika virus might influence microcephaly in fetuses.

“While this study doesn’t definitely prove that Zika virus causes microcephaly, it’s very telling that the cells that form the cortex are potentially susceptible to the virus, and their growth could be disrupted by the virus.” Ming led the research team along with Hongjun Song, Ph.D., a professor of neurology and neuroscience in the Institute for Cell Engineering, and Hengli Tang, Ph.D., a virologist at Florida State University. Source: Hopkinsmedicine.org

Conclusion

Latest research, as of March 2016, provides more evidence for the suspected link between infection with Zika virus during pregnancy and microcephaly.

Pyriproxyfen

Pyriproxyfen is an insect growth regulator used against insect pests, houseflies, mosquitoes and cockroaches. It is manufactured by Sumimoto Chemical, a Japanese subsidiary of Monsanto.

Pyriproxyfen has been studied prior to the current microcephaly outbreak, and research suggests it is safe.

• It has a WHO hazard classification of U, which means unlikely to present acute hazard in normal use.

• A toxicology evaluation study sponsored jointly by FAO and WHO with the support of the International Programme on Chemical Safety (IPCS) in 1999 based on Sumitomo's self submitted toxicological and ecotoxicological data found reduction in number of implantations and live fetuses in rats. As of 2006, the panels recommended no acute reference dose due to low acute toxicity of pyriproxyfen. [2]

  Pyriproxyfen was evaluated by the FAO/WHO JMPR in 1999 and 2001. The 1999 JMPR established an ADI of 0-0.1 mg/kg bw, on the basis of a 1-year study in dogs and a safety factor of 100 and concluded that it was not necessary to establish an acute reference dose because of low acute toxicity of pyriproxyfen. The 2001 JMPR assessed the safety of pyriproxyfen as a mosquito larvicide in potable water and concluded that intake at the target concentration for control would not present unacceptable risks. Source: WHO

• A peer review by European Food Safety Authority of the pesticide risk assessment of the active substance pyriproxyfen in 2009 found no teratogenic effects.

  Acceptable Daily Intake (ADI)

  The dog was the most sensitive species. As proposed in the DAR, the agreed ADI was 0.1 mg/kg bw/day based on the 1-year dog study, with the use of a safety factor of 100.

  Acute Reference Dose (ARfD)

  Based on the toxicity profile of pyriproxyfen, the experts agreed that the derivation of an acute reference dose was not necessary. Source: EFSA

• As of 2011, FAO adopted the same WHO hazard summary of pyriproxyfen as unchanged from 2005.

  The Meeting recommended that:

  (i) the specifications for pyriproxyfen TC and GR proposed by Sumitomo, as amended, should be adopted by WHO;

  (ii) the specifications for pyriproxyfen TC and EC proposed by Sumitomo, as amended, should be adopted by FAO. Source: FAO

• Research of Pyriproxyfen in Drinking-water by WHO in 2008 found that it did not cause developmental toxicity.

  The developmental toxicity of pyriproxyfen has been studied in rats and rabbits. In rats, a NOAEL for maternal toxicity was not identified, as decreased body weight gain was observed at 100 mg/kg of body weight per day, the lowest dose tested. Pyriproxyfen caused little developmental toxicity and was not teratogenic. In a study of developmental toxicity in rabbits, signs of maternal toxicity (abortion and premature delivery) were evident at doses of ≥300 mg/kg of body weight per day (NOAEL = 100 mg/kg of body weight per day). No developmental toxicity was observed, the NOAEL being 1000 mg/kg of body weight per day, the highest dose tested. Source: WHO

• A 1999 FAO document suggested consumption of pyriproxyfen residues resulting from its use was unlikely to be a public health concern and this view had not changed until 2011.

  International Estimated Daily Intakes for the 5 GEMS/Food regional diets, based on estimated STMRs, were effectively 0% of the ADI. The Meeting concluded that the intake of residues of pyriproxyfen resulting from its uses that have been considered by the JMPR is unlikely to present a public health concern. Source: FAO

• There was a 2% frequency of occurrence of pyriproxyfen pesticide residues in the 2011 Total Diet Study which was performed in domestic and import food samples. The residues levels of the pesticide found in food were generally considered acceptable by the FDA.

  A total of 5,977 samples of both domestically produced and imported food from 99 countries were analyzed for pesticide residues in FY 2011. No residues were found in 60.5 percent of domestic and 64.5 percent of import samples analyzed under FDA's regulatory monitoring approach in FY 2011. Only 1.6 percent of domestic and 7.1 percent of import samples had residue levels that were violative. The findings for FY 2011 demonstrate that pesticide residue levels in foods are generally well below EPA tolerances; the increased import sample violation rate reflects the expansion of the analytical scope of pesticide residues from the implementation of new technologies in 2010 and 2011. Source: FDA

• A case report confirmed no prenatal development toxicity

  Pyriproxyfen is a hormonal insecticide analogue to high estrogenic activity designed to interfere with the insects' developmental processes. When treated with pyriproxyfen, both female and male insects yield young with physical abnormalities. However, animal experiments do not show prenatal developmental toxicity in the presence of maternal toxicity. Source: Household exposure to pesticides and bladder exstrophy in a newborn baby boy: a case report and review of the literature

Conclusion:

Up until 2011, safety authorities around the world have not found any teratogenic effects of pyriproxyfen, such as microcephaly. There was minimal or nil researched or documented clinical evidence or methodology for pyriproxyfen causing microcephaly.

However, more focused teratogenic studies are needed to confirm or deny the recent 2016 claim of connection between pyriproxyfen and microcephaly by physicians in the crop-sprayed villages.

References

1.CDC

2.INCHEM.ORG

Answer 2

The CDC now say the Zika virus is the cause.

On April 13, 2016, a new report was published by doctors from the CDC in the New England Journal of Medicine.

• Zika Virus and Birth Defects — Reviewing the Evidence for Causality, DOI: 10.1056/NEJMsr1604338

This review examined the available evidence and concluded:

On the basis of this review, we conclude that a causal relationship exists between prenatal Zika virus infection and microcephaly and other serious brain anomalies. Evidence that was used to support this causal relationship included Zika virus infection at times during prenatal development that were consistent with the defects observed; a specific, rare phenotype involving microcephaly and associated brain anomalies in fetuses or infants with presumed or confirmed congenital Zika virus infection; and data that strongly support biologic plausibility, including the identification of Zika virus in the brain tissue of affected fetuses and infants.

An AP report published in the Daily News discusses this paper at more readable level:

Confirming the worst fears of many pregnant women in the United States and Latin America, U.S. health officials said Wednesday there is no longer any doubt the Zika virus causes babies to be born with abnormally small heads and other severe brain defects.

They explain about how this represents a change of stance for epidemiologists:

Most experts were cautious about drawing a firm connection. But now the U.S. Centers for Disease Control and Prevention says enough evidence is in.

[...]

“We’ve been very careful over the last few months to say, ‘It’s linked to, it’s associated with.’ We’ve been careful to say it’s not the cause of,” said the CDC’s Dr. Sonja A. Rasmussen.

“I think our messages will now be more direct.”

The article does include a tiny chink in the armour of their argument:

CDC officials relied on a checklist developed by a retired University of Washington professor, Dr. Thomas Shepard. He listed seven criteria for establishing if something can be called a cause of birth defects.

They still don’t have some of the evidence they hope for. So far, for example, there have been no published studies demonstrating Zika causes such birth defects in animals. There’s also a scarcity of high-quality studies that have systematically examined large numbers of women and babies in a Zika outbreak area.

“The purist will say that all the evidence isn’t in yet, and they’re right but this is public health and we need to act,” the WHO’s Aylward said.