I'm going to talk to you about the epidemic of microcephaly that started in Brazil in 2015, and now we recognise was caused by Zika virus infection during pregnancy. It was declared Public Health Emergency of International Concern by WHO. It's interesting how it started, just a few cases noticed by the doctors who eventually notified the Department of Health who investigated and recognised that something was going on. I think the best comparison to what's happening now is what would happen if rubella was introduced in a totally susceptible population. There would be big outbreaks and adults and pregnant women and children would have the disease and because it would be such a big outbreak a very large number of pregnant women would have it and there would be a big epidemic of congenital rubella. So I think that is probably what's happening now, Zika virus has started in a population with no immunity, and that's causing a big epidemic. Microcephaly is a very severe congenital malformation, it just means the head is small, it's small because the brain doesn't develop properly. The congenital rubella syndrome has been detected through microcephaly, it's very severe, the place of the brain that's been affected is the cortex, the cortex is where we have consciousness, presence and symbolic thinking and language, so that's the part that has been affected in the babies, and a large proportion of affected babies will have a very bad prognosis. There is a lot we don't know yet, we don't know exactly the risk of having a congenital malformation if you have Zika infection during pregnancy, we don't know the all spectrum of the syndrome, we don't know if there are mild cases as well as the severe cases that we're detecting. But also we don't know the prognosis of these neonates, we don't know how many would ever be able to talk or to walk or to think or interact. So there is a number of things we don't know yet that are important research questions, and this will have big implications for the needs of these children and for prevision to address those needs. So governments will have to think about social services, financial support for the families, maybe psychological support for the families affected, they have to think what these children will need in terms of clinical management, in terms of wheelchairs or facilities for them to learn to be able to eat, the luckier ones will be able to attend some kind of school there'll may be institutional care, so it's important to determine the prognosis so governments can prepare for the future. The epidemic has now expanded to Latin America, there are 33 countries with Zika, several of them already have birth with microcephaly and there's the potential to expand for many countries in the world, so it's important to continue to monitor, but I think we have to accept that all the countries where there are big outbreaks of Zika there will be big outbreaks of microcephaly and countries have to prepare for that. So now I would like to discuss the process of establishing the causal link. When the epidemic started, it took less than a month for the Brazilian government to suspect that the epidemic of Zika that happened a few months earlier was the cause of the epidemic of microcephaly. The first indication was the fact that the microcephalic babies had calcifications at radiological brain image, that's an indication of an infectious cause for the microcephaly. But there are other indications, a quick investigation with the mothers of the first 50 babies, suggested that about two thirds of the mothers had a rash during pregnancy, so they had an infectious disease of rash during pregnancy. There was also the time and space correlation, there were little epidemic of Zika about six seven months before the epidemic of microcephaly and they happened in the same places. One of the challenges was that the neonates were not excreting virus. Neonates of congenital rubella excrete a virus, it's very easy to detect the virus on those neonates, that was not the case for Zika. People were puzzled at the difficulty of isolating Zika virus from the neonates. It is still an interesting research question. But there were early isolates in the amniotic fluid of women who were pregnant and whose foetus was detected to have microcephaly in ultrasound. There's also isolates of viruses in women who have termination of pregnancy or had stillbirths. So earlier on, in the first month there was accumulating evidence, I think the most interesting evidence is quite preparian is quite proper, a philosophial science type of question, when the Brazilian suspected that the microcephaly might be caused by Zika, we postulated for that hypothesis to be true it was a requirement for confirmational hypothesis that there had been an epidemic of microcephaly, or at least a spike of microcephaly, when there was an epidemic of Zika in the French Polynesia. There was epidemic in the French Polynesia microcephaly had not been detected, our hypothesis required it that there was a spike there. So they went back to investigate and they did find increasing cases of microcephaly in pregnancies that happened during the outbreak in the French Polynesia, and those cases had not been detected because termination is legal there and a large majority of women show to have terminations and we don't monitor the reasons for termination. So that was quite clear evidence for causation and at the time WHO considered causation and they declared it to be very likely but not scientific proven. And then evidence started to accumulate and it was a very interesting process to examine. The additional evidence came from experiments growing neural cells and showing that Zika virus not only was attracted to these cells but was also very destructive of these cells. So we established the virus attacked brain cells. And then we have the evidence of women who were in Brazil while they were pregnant and then they went back to the US or Slovenia and their foetuses were diagnosed with microcephaly, and in both cases they chose to have terminations, and in the terminations they found the Zika virus. And I think the last piece of evidence came from cohorts of pregnant women with Zika. And basically these are studies that identify pregnant women, while they have a rash they test them and they find Zika virus infection in them and then they follow them and they establish that the proportion of babies with congenital malformations of which microcephalies are part is much higher than in women who didn't have Zika infection. And I think that was probably the final piece of evidence and WHO finally accepted there was a consensus in the scientific community. Finally, CDC produced a paper where they went through the frameworks to establish causation, and there are a number of frameworks that's been going on for a long time, and they went through the aspect of the framework, so there is one to establish teratogenicity, so it's not just use for congenital infections but for other causes of malformations, and then they went through the Bradford Hill criteria, which is just a criteria for causation, and then they went through the Koch's postulates which are criteria for infectious diseases and relate the present evidence to the criteria, and in their opinion the criteria were met and the causation was proved.
