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expert reaction to modelling study looking at Zika infection and microcephaly cases in the 2013-14 Zika outbreak in French Polynesia

A group of scientists have published their work in The Lancet journal in which they retrospectively analysed data from a previous Zika outbreak in French Polynesia. In their follow up modelling study they reported Zika virus infection during the first trimester of pregnancy led to higher than expected rates of microcephaly. The association between Zika virus infection and microcephaly, however, has not been precisely quantified.

All our previous output on the Zika outbreak can be seen here.

 

Dr Clare Taylor, Senior Lecturer in Medical Microbiology and General Secretary for the Society for Applied Microbiology, said:

“The study by Cauchemez et al. is based on a small number of cases of microcephaly which have been retrospectively identified from records relating to the outbreak of Zika which occurred in French Polynesia between 2013 and 2015. The study identified eight cases of microcephaly which occurred during the period examined but does not establish if the mothers were seropositive for Zika, hence no direct relationship between microcephaly and Zika is established.

“However, the authors have reported that the estimated seroprevalence of Zika in the population had risen to 66% by the end of the outbreak. Thus, based on the number of pregnancies, and the number of seropositive Zika cases, the authors have assumed a high likelihood that the mothers were infected.

“The estimated 1% chance of microcephaly occurring during the first trimester of pregnancy is based on the clustering of seven of the cases of microcephaly which were identified within a four month period, and modelling against six scenarios of which the first trimester model gives the best fit. Given the timing of neurological development in a normal foetus, this is also a plausible biological explanation.

“However, the study is subject to a number of limitations which the authors identify. Importantly, their findings are based on estimations which are calculated from historical data in which there could be inaccuracies for a number of reasons. It would be inadvisable to extrapolate to any outbreaks occurring elsewhere, but the study provides a reasoned foundation for further investigations.”

 

Dr Nathalie MacDermott, Clinical Research Fellow, Imperial College London, said:

“The authors have used mathematical modelling to calculate a risk for the possible association between Zika virus and microcephaly and when this risk may be greatest, based on data from the Zika outbreak in French Polynesia. Using their methods they identify the first trimester of pregnancy as being at greatest risk for the development of microcephaly if Zika virus infection were to occur during this time, and they calculate the risk as being approximately 1 case of microcephaly per 100 first trimester pregnancies infected with Zika virus.

“The study makes the assumption that Zika virus is linked to the development of microcephaly, for which there is still not proven causality, although there is increasing suggestion that this may be the case. While incidence of microcephaly was significantly increased in the French Polynesia outbreak, numbers of cases of microcephaly were proportionally lower in comparison to the numbers of suspected cases currently being reported in Brazil – this may well be related to possible over-reporting of suspect cases in Brazil.

“While these calculations may be applicable to the current outbreak situation in Brazil, this is difficult to determine without knowing the true increased incidence of microcephaly in Brazil and the proportion of these cases which may be linked to Zika virus – this is still being determined. Also, as the authors note, the populations in the currently affected South American countries are significantly genetically diverse from the population in French Polynesia and this may well play a role in the development of microcephaly which may alter whether these calculations apply to the current outbreak in South America.

“That the first trimester may be when the risk of microcephaly is greatest would make sense from our understanding of the brain development of the foetus, but this does not mean that abnormalities could not occur in the second and third trimesters also, the early to mid second trimester being of particular concern as this is when neuronal migration occurs.

“The results of studies from South America are now awaited to further understand the potential link and demonstrate possible causality between Zika virus and microcephaly. Such results will also assist in determining the accuracy of these calculations and further clarify the stages of pregnancy at which Zika virus infection may pose the greatest risk.”

 

Dr Melissa Gladstone, Senior Lecturer in Paediatric Neurodisability, University of Liverpool, said:

“This paper adds another piece to the puzzle surrounding the link between Zika virus and microcephaly and particularly highlights the likelihood of Zika infection being most risky in the first trimester of pregnancy when structural brain development is at its peak. The unique situation of French Polynesia of having routine antenatal ultrasound screening from early on in pregnancy, clear discharge notes with measures of microcephaly along with blood surveillance data is extremely helpful in providing good quality data for modelling. The authors have done an extensive search of all cases of microcephaly in the region and have utilised an expert panel to review all cases. The rates of microcephaly are lower than reported in Brazil but still concerning considering the high rate of infection that can occur in pregnant women.

“It needs to be made clear that this study has used epidemiological modelling methods and has not been able to directly link Zika virus with the microcephaly in these babies. Unless direct links are made and/or full investigations of babies are undertaken to exclude other causes and to identify Zika infection in infants, it will be difficult to entirely link Zika with microcephaly. Furthermore, we may have a long way to go in terms of knowing whether there are more subtle effects of Zika virus on infants and children in the long term which span beyond microcephaly to developmental and learning difficulties. The widespread effort by researchers to quickly address the questions and provide answers should be congratulated but some of the longer term concerns will only be able to be addressed with time.”

 

Dr Derek Gatherer, Lecturer in the Division of Biomedical and Life Sciences, Lancaster University, said:

“This is the first published study that moves us in the direction of being confident that Zika virus infection in pregnancy can cause microcephaly. It deals with the French Polynesia outbreak of late 2013 to early 2014, which is believed, on the basis of other phylogenetic studies, to be the source of the outbreak in South America. French Polynesia has the advantage that it has good medical records and that the outbreak is now over, so a complete dataset of a Zika virus outbreak can be analysed from beginning to end.

“The new study recalculates the total percentage of the French Polynesian population that were infected with Zika virus as high as 66% and identifies eight babies born with microcephaly during the period of the outbreak. Because the total number of microcephalic babies was small, and the prevalence of Zika infection so high, reaching a firm statistical conclusion is difficult. The authors achieved this by adopting a model-based approach in which they devised various scenarios of different total levels of infection, different risk to the pregnancy from Zika virus and different risk periods during the pregnancy. They ensured that all possibilities were covered using a computational technique called simulated annealing, which allows a large number of often subtly different versions of events to be compared. The statistical testing was done using a further computational technique called maximum likelihood.

“These advanced statistical techniques do not produce a single answer, but allow us to ask the question – what is most likely to have been the scenario that produced the situation we see? It turns out that Zika virus infection in the first trimester (first third) of pregnancy producing microcephaly at a rate of about one case per hundred Zika-infected pregnant mothers is more likely than any other scenario, including Zika not being a risk factor or Zika being a risk factor at other times of pregnancy.

“This is an important finding because, as well as advancing our confidence that Zika can be the cause of microcephaly, it also helps us for the first time to begin to think about defining a risk period during pregnancy which is sure to have major implications for travel to affected areas by pregnant women.”

 

Prof. Mark Woolhouse, Professor of Infectious Disease Epidemiology, University of Edinburgh, said:

“This is a valuable study showing that the occurrence of a small cluster of microcephaly cases in French Polynesia in 2014 could have been due to the mothers being exposed to Zika virus in the first 3 months of pregnancy. It adds to the growing evidence that Zika virus can cause microcephaly and heightens the public health concern around the much larger epidemic now under way in the Americas.

“The analysis was made possible by the availability of public health surveillance data, both on birth defects and, unusually, on rates of exposure to Zika virus. If this kind of work were done routinely we would have had much earlier warning of the potential risks of Zika and would have had a much better chance of preventing the current health emergency.”

 

Prof. Peter Openshaw, Professor of Experimental Medicine, Imperial College London, said:

“This new evidence is, on the surface, reassuring. The finding that the risk of microcephaly is only about 1% in those infected in the first trimester of pregnancy is surprising, given that a recently published preliminary report from Rio de Janeiro estimated the risk to be over 20%. As the authors point out, the risk of birth defects from other viruses that put unborn children at risk is much higher: 13% in primary cytomegalovirus infections, and between 38% and 100% in mothers infected with rubella in the first trimester of pregnancy. Both these infections are fortunately rare, whereas Zika is undergoing explosive spread.

“An important question that the authors do not discuss is the possibility that the virus has undergone mutations that make it better able to cross the placenta and/or infect neuronal tissue. We saw progressive changes in the genetic makeup of influenza during the 2009-10 pandemic, and with that the virus seemed to change its biological effects. Might the same be happening with Zika? The finding that of the eight cases of microcephaly reported in French Polynesia, seven were seen during the last four months of the outbreak again hints that the virus might have changed. If this is so, the findings in French Polynesia may not be so reassuring after all.

“We won’t know if this is the case until more clinical studies and epidemiological studies, mapping of viral evolution and well-controlled experimental infection of different tissue types are published. For now, concerns should remain that the devastating legacy of Zika could be seen for many decades to come.”

 

Prof Ira Longini, Professor of Biostatistics, Emerging Pathogens Institute, University of Florida, said:

“This is an important analysis, based on retrospective data.  Such estimates are subject to bias, but the estimate of a 1 in 100 risk for microcephaly for women who may have been infected in the first trimester of pregnancy is useful as an order of magnitude estimate, i.e., the risk is probably not as high as 1 in 10 or as low as 1 in 1000. Not much more can be said from this analysis.

“It is unclear if the risk is the same in the Americas with different ethnicity of the pregnant Zika-infected women, a possibly mutated virus, and possibly different potential cofactors. The prospective studies of Zika-infected pregnant women in countries such as Colombia and Nicaragua will yield more definitive results, at least for the Americas.”

 

‘Association between Zika virus and microcephaly in French Polynesia, 2013–15: a retrospective study’ by Simon Cauchemez et al. will be published in the Lancet at 23:30 UK time on Tuesday 15 March 2016, which is also when the embargo will lift. 

 

 

Declared interests

Dr Clare Taylor: “No conflicts of interest to declare.”

Dr Nathalie MacDermott: “I am a paediatrician. I am also undertaking a PhD in Ebola virus disease at Imperial College London funded by the Wellcome Trust.”

Dr Melissa Gladstone: “I have no competing interests.”

Dr Derek Gatherer: “No relevant conflicts of interest.”

Prof. Mark Woolhouse: “I have no conflicts of interest to declare.”

Prof. Peter Openshaw: “Prof Peter Openshaw’s research is funded by the Wellcome Trust, the MRC, BBSRC and the European Union. He has received honoraria or consultancy fees from GSK, Janssen, and Mucosis BV.”

Prof. Ira Longini: “I have no competing interests.”

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