Background The emergence of Zika virus (ZIKV) in the Americas has coincided with an increase in the report of birth of infants with microcephaly. On 1 February 2016, the World Health Organization declared the suspected link between ZIKV and microcephaly a Public Health Emergency of International Concern. However, to date, precise quantification of this association is lacking. Methods We retrospectively analysed data from a ZIKV outbreak in French Polynesia in October 2013–April 2014, which was the largest ever documented prior to the outbreak in the Americas. Serological and surveillance data were used to estimate the probability of ZIKV infection for each week of the epidemic. We also conducted an exhaustive search of medical records to identify all microcephaly cases from September 2013–July 2015. Simple models were developed to determine the period during pregnancy when ZIKV infection may increase the risk of microcephaly and estimate the associated risk. Findings Sixty-six percent (95% CI: 62, 70) of Polynesians were infected by ZIKV. Of the eight microcephaly cases identified during the 23-month study period, seven (88%) occurred in the four-month period following the ZIKV outbreak. This pattern was best explained by a model that assumed ZIKV infection in the first trimester of pregnancy increased the risk of microcephaly. In this model, the risk of microcephaly associated with ZIKV infection was 95 (95 CI: 34, 191) per 10,000 women infected in the first trimester of pregnancy while the prevalence of microcephaly was 2 (95% CI: 0, 8) per 10,000 neonates. Models where the risk of microcephaly also increased if infection occurred in trimesters 2 and 3 were not significantly worse fitting than this model. Interpretation This study provides the first quantitative estimate of the risk of microcephaly in a foetus/neonate whose mother was infected by ZIKV. Funding Labex-IBEID, NIH-MIDAS, AXA Research fund and EU-PREDEMICS.

We detected an unusual increase in congenital cerebral malformations and dysfunction in fetuses and newborns in French Polynesia, following an epidemic of Zika virus (ZIKV), from October 2013 to March 2014. A retrospective review identified 19 cases, including eight with major brain lesions and severe microcephaly, six with severe cerebral lesions without microcephaly and five with brainstem dysfunction without visible malformations. Imaging revealed profound neurological lesions (septal and callosal disruption, ventriculomegaly, abnormal neuronal migration, cerebellar hypoplasia, occipital pseudocysts, brain calcifications). Amniotic fluid was drawn from seven cases at gestation weeks 20 to 29. ZIKV RNA was detected by RT-PCR and infectious ZIKV isolates were obtained in four of five microcephalic, but not in two non-microcephalic cases with severe brain lesions. Medical termination of pregnancy was performed in eleven cases; two cases with brainstem dysfunction died in the first months of life; six cases are alive, with severe neurological impairment. The results show that four of seven tested fetuses with major neurological injuries were infected with ZIKV in utero. For other non-microcephalic, congenital abnormalities we were not able to prove or exclude ZIKV infection retrospectively. The unusual occurrence of brain malformations or dysfunction without microcephaly following a ZIKV outbreak needs further studies.

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