Today’s addition of 16 new cases of Zika infection – the smallest number added for the past week – brings the total number of confirmed Zika infections to 258. No links to prior clusters were found in 4 cases. It is too soon to know whether this drop in cases reported represents a blip or if the epidemic is starting to wane, thanks largely to vector control measures initiated since more than a week ago. What is welcome news is that the Ministry of Health Singapore (MOH) has announced that Zika-infected persons need no longer be isolated in the hospitals. Given the scale of local transmission, and that 80% of Zika infections result in no symptoms, hospital isolation as a policy must have seemed increasingly costly while adding less and less value as an outbreak control measure to the MOH officials.

There remains considerable concern about the pregnancy-related complications of Zika, which is natural.

Firstly, current evidence strongly suggests that the Zika virus is a cause of congenital abnormalities, particularly if infection occurs during the first trimester of pregnancy. Microcephaly is by far the most well known of these, but there are a host of others, including craniofacial disproportion, spasticity, seizures, ocular (eye) and cardiac (heart) abnormalities among others. Koch’s postulates tend to be difficult to fulfil for viruses, but Zika has ticked most of the possible boxes with regards to causing congenital abnormalities. The virus has been found in the placental tissue of mothers who had Zika infections during their pregnancies; it has also been found in the brain tissue and cerebrospinal fluid of spontaneous abortions and newborn babies with microcephaly born to prior Zika-infected pregnant women; the pathway by which it preferentially infects developing brain cells has also been identified. Therefore there is biological plausibility, temporality, and a certain degree of consistency, if one were to apply Hill’s criteria for causation.

Secondly, the ability of the virus to cause congenital abnormalities is probably not limited to the Brazilian offshoot of the Asian lineage of Zika. In an excellent paper that still remains in Biorxiv for now, researchers also used a strain of Zika isolated in Cambodia in 2010, and it performed no differently from the Brazilian strain in infecting placental or neural progenitor cell lines. Representative viruses from the African lineage of Zika have not been similarly tested. Note however the all important clause that effects seen in cell lines and laboratory animals, while important from a scientific perspective, are not proof that the same happens in humans. Microcephaly and other congenital abnormalities had not been associated with Zika in Africa or even on the Micronesian island of Yap in the past, but this can easily be explained by the fact that it would take a very large outbreak for such associations to be noticed. More than 70% of the inhabitants on the island of Yap were infected during the outbreak of 2007, but the population of Yap numbers just about 11,000, and hence it is very unlikely that pregnancy-associated complications would be picked up and attributed to Zika.

Thirdly and perhaps most importantly, what is the actual risk of congenital abnormalities should a pregnant woman be infected? Almost all the research to date has focused on microcephaly, which is perhaps the most obvious physical effect on the fetus (although measurements need to be standardized). The risk is quite clearly highest in the first trimester of pregnancy, and the oft-quoted risk of 0.88% to 13.2% is based almost entirely on events occurring in Bahia at the northeastern part of Brazil. But the 13.2% was quite clearly stated to be an extreme situation where Zika had only infected 10% of the population of Bahia and there was no over-reporting of microcephaly at all – a situation which was necessary to include for scientific rigour in modelling, but otherwise unrealistic. This seems to be borne out by the Brazilians themselves questioning whether there could be some other cause for the high numbers of microcephaly cases in Bahia, and seeking assistance from London and Seattle scientific teams. I include a screenshot of the table of Zika-associated congenital abnormalities from the Pan American Health Organization’s (PAHO’s) Regional Zika Epidemiological Update on 25th August 2016 (the updates are once a fortnight), which shows quite evidently how much of an outlier Brazil is in terms of Zika-associated congenital malformations.

PAHO report 2016

Screenshot of the 25th August 2016 PAHO epidemiological Zika update.

Note that the second country on the list – Colombia – had close to 100,000 reported cases of Zika (although only slightly more than 8.000 were laboratory-confirmed cases) and was monitoring more than 17,000 infected pregnant women, but had only reported 29 cases of Zika-associated congenital syndrome to date. Coupled with the estimate from French Polynesia (0.9% microcephaly in Zika-infected pregnant women), it seems highly likely that a more reliable overall estimate of Zika-associated microcephaly might be closer to 1% than to 13.2%. In many ways, the risks may not be higher than infections caused by other TORCH organisms during pregnancy.

But there remain many unknowns about Zika’s effect on the unborn fetus, which well-conducted longitudinal surveys may be able to provide. Zika has been linked to miscarriages, the scale of which is unknown. Other TORCH pathogens are capable of causing developmental delays, hearing loss, etc. even in children born without obvious congenital abnormalities, and further research will be necessary to understand if the same applies to Zika.

Finally, here is a link to MOH’s guideline and FAQ on Zika-related pregnancy complications, and practical advice on what to do and how to seek help during various stages of family planning and pregnancy.

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Outbreak, Public Health, Singapore, Viral Infection