Zika virus is an arthropod-borne virus in the genus of Flavivirus.1 Since identification of Zika virus infection in Brazil in May, 2015, the virus has spread throughout the Americas. Up to Feb 19, 2016, 28 countries of the region had reported cases.2 Although infection with Zika virus often leads to mild disease, its emergence in the Americas has coincided with a steep increase in patients developing Guillain-Barré syndrome (an autoimmune disorder that causes acute or subacute flaccid paralysis) and the birth of babies with neurological complications, such as congenital microcephaly.3, 4, 5
Congenital microcephaly is a neurological abnormality that is present at birth and defined as head circumference at least 2 SD smaller than the mean for sex, age, and ethnicity,6 with head circumference at least 3 SD smaller being deemed severe.7 Microcephaly might occur alone or in combination with other abnormalities. The condition is associated with a reduction in brain volume and frequently with intellectual disabilities, motor disabilities, or both, including speech impairment,8 poor neurocognitive outcome,9 and behavioural issues.10 Causes include genetic11 or environmental factors12 during pregnancy that affect fetal brain development.13 Prenatal viral infections (eg, rubella or cytomegalovirus),14 maternal alcohol use,15 and hypertensive disorders16 have been associated. Cases have also been reported after intrauterine infection with West Nile virus (another flavivirus)17 and chikungunya virus.18
On Feb 1, 2016, WHO declared the suspected link between Zika virus and microcephaly to be a Public Health Emergency of International Concern.19 To reduce the risk of microcephaly, women who were pregnant and of childbearing age were recommended to avoid travelling to affected countries, to use condoms with partners returning from affected countries, and to delay pregnancy.20, 21 The amount of monitoring that is required for pregnant women during Zika virus epidemics is being investigated. Ideally, clinical management, individuals' decisions regarding family planning, and the response of the broader public health community would be informed by precise calculations of the risk of microcephaly in fetuses and neonates whose mothers have been infected with Zika virus. However, although evidence of an association is growing,22, 23 this risk has not yet been clearly quantified.
Timely assessment of this association from data gathered in an ongoing epidemic, such as that in the Americas, poses potential difficulties. First, delays might occur between infection of mothers with Zika virus and the diagnosis of microcephaly in fetuses or neonates. Ascertainment of all potentially associated cases, therefore, could take some time. Second, surveillance systems detect only a small proportion of Zika virus infections24 and, therefore, the true number of pregnant women who have been infected is unknown. The total number of infections can be estimated by serological cross-sectional surveys only once an epidemic is over. Thus, the numerator and denominator needed to calculate the risk of microcephaly per infected pregnant woman remain uncertain while outbreaks continue.
Research in context
Evidence before this study
Microcephaly is defined by head circumference at least 2 SD smaller than normal head circumference. Its incidence is estimated to be between 5·8 per 100 000 livebirths in the USA and 18·7 per 100 000 livebirths, stillbirths, and medical abortions in Europe. Long-term outcomes of this condition are heterogeneous, but it has been associated with several neurological disorders, such as epilepsy or intellectual deficiencies. Following the Zika virus epidemic in South America, microcephaly in neonates has been reported in several countries, leading WHO to declare a Public Health Emergency of International Concern. The association between Zika virus and microcephaly, however, remains to be quantified.
Added value of this study
We did a retrospective analysis of a large Zika virus outbreak in French Polynesia in 2013–14, based on four datasets that provided information on all cases of microcephaly, the weekly number of consultations for suspected infection with Zika virus, seroprevalence for Zika virus antibodies, and the number of births during the outbreak. Use of mathematical models enabled us to provide strong statistical support for the association between Zika virus infection and microcephaly and to establish that the period of risk in pregnancy when infection of mothers increases the risk of microcephaly in fetuses and neonates was likely to contain the first trimester of pregnancy (possibly also the second and third trimesters). We estimated that the number of microcephaly cases associated with Zika virus was 95 (95% CI 34–191) per 10 000 women infected in the first trimester.
Implications of all the available evidence
Our findings strongly support the previously suspected link between infection with Zika virus during pregnancy and microcephaly. They emphasise the need for health authorities of affected countries to organise fetal monitoring, promote vector control, and provide evidence-driven information for pregnant women.
We did a retrospective analysis of a large Zika virus outbreak that took place in French Polynesia in October, 2013, to April, 2014,25 to assess and characterise the strength and nature of the association with microcephaly. In particular, we assessed the risk of microcephaly in fetuses or neonates whose mothers had been infected by Zika virus. The French Polynesian outbreak had various properties that support such an assessment. First, it was the largest documented Zika virus outbreak before that in the Americas. Second, French Polynesia has strong infrastructures for surveillance of infectious diseases and detection of complications during pregnancy. Third, sufficient time has elapsed since the end of the outbreak for all cases of microcephaly potentially associated with Zika virus infection to be detected. Finally, serological data, which are necessary to estimate the number of pregnant women who were infected during the epidemic, are available.26, 27