Elsevier

The Lancet

Volume 387, Issue 10033, 21–27 May 2016, Pages 2125-2132
The Lancet

Articles
Association between Zika virus and microcephaly in French Polynesia, 2013–15: a retrospective study

https://doi.org/10.1016/S0140-6736(16)00651-6Get rights and content

Summary

Background

The emergence of Zika virus in the Americas has coincided with increased reports of babies born with microcephaly. On Feb 1, 2016, WHO declared the suspected link between Zika virus and microcephaly to be a Public Health Emergency of International Concern. This association, however, has not been precisely quantified.

Methods

We retrospectively analysed data from a Zika virus outbreak in French Polynesia, which was the largest documented outbreak before that in the Americas. We used serological and surveillance data to estimate the probability of infection with Zika virus for each week of the epidemic and searched medical records to identify all cases of microcephaly from September, 2013, to July, 2015. Simple models were used to assess periods of risk in pregnancy when Zika virus might increase the risk of microcephaly and estimate the associated risk.

Findings

The Zika virus outbreak began in October, 2013, and ended in April, 2014, and 66% (95% CI 62–70) of the general population were infected. Of the eight microcephaly cases identified during the 23-month study period, seven (88%) occurred in the 4-month period March 1 to July 10, 2014. The timing of these cases was best explained by a period of risk in the first trimester of pregnancy. In this model, the baseline prevalence of microcephaly was two cases (95% CI 0–8) per 10 000 neonates, and the risk of microcephaly associated with Zika virus infection was 95 cases (34–191) per 10 000 women infected in the first trimester. We could not rule out an increased risk of microcephaly from infection in other trimesters, but models that excluded the first trimester were not supported by the data.

Interpretation

Our findings provide a quantitative estimate of the risk of microcephaly in fetuses and neonates whose mothers are infected with Zika virus.

Funding

Labex-IBEID, NIH-MIDAS, AXA Research fund, EU-PREDEMICS.

Introduction

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

Section snippets

Study design

We analysed four datasets that documented all cases of microcephaly in French Polynesia from Sept 1, 2013, to July 31, 2015, the weekly number of consultations for suspected infection with Zika virus, seroprevalence for Zika virus antibodies at the start and end of the epidemic, and the number of births in French Polynesia. We used serological data to establish the overall proportion of the population infected during the epidemic and used epidemic curves to establish the weeks when infections

Results

The outbreak began in October, 2013 (week 41), peaked in December, 2013, and ended in April, 2014 (figure 1). By the end of the outbreak, public health officials had recorded 8750 suspected infections with Zika virus, of which 383 (4·4%) were confirmed in the laboratory. More than 31 000 patients were estimated to have sought consultations for suspected Zika virus infection during this outbreak (figure 1).32

Before this outbreak, the seroprevalence of Zika virus had been 0·8%.27 By the second

Discussion

The large outbreak of Zika virus infections in French Polynesia in 2013–14 enabled us to quantify and characterise the association between Zika virus infection in pregnancy and microcephaly. Of eight cases of microcephaly reported, seven occurred in a 4-month period around the end of the Zika virus outbreak. Such temporal clustering strongly supports the proposed association. Our mathematical model designed to predict temporal trends yielded three important conclusions. First, assumed periods

References (44)

  • Rapid risk assessment. Zika virus epidemic in the Americas: potential association with microcephaly and Guillain-Barré syndrome

  • J Soares de Araújo et al.

    Microcephaly in northeast Brazil: a review of 16 208 births between 2012 and 2015

  • S Ashwal et al.

    Practice parameter: evaluation of the child with microcephaly (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society

    Neurology

    (2009)
  • AJ Whitehouse et al.

    Fetal head circumference growth in children with specific language impairment

    Arch Dis Child

    (2012)
  • H Dolk

    The predictive value of microcephaly during the first year of life for mental retardation at seven years

    Dev Med Child Neurol

    (1991)
  • S Stoler-Poria et al.

    Developmental outcome of isolated fetal microcephaly

    Ultrasound Obstet Gynecol

    (2010)
  • A Tarrant et al.

    Microcephaly: a radiological review

    Pediatr Radiol

    (2009)
  • M von der Hagen et al.

    Diagnostic approach to microcephaly in childhood: a two-center study and review of the literature

    Dev Med Child Neurol

    (2014)
  • MJ Krauss et al.

    Microcephaly: an epidemiologic analysis

    Am J Obstet Gynecol

    (2003)
  • DR O'Leary et al.

    Birth outcomes following West Nile Virus infection of pregnant women in the United States: 2003–2004

    Pediatrics

    (2006)
  • P Gerardin et al.

    Neurocognitive outcome of children exposed to perinatal mother-to-child Chikungunya virus infection: the CHIMERE cohort study on Reunion Island

    PLoS Negl Trop Dis

    (2014)
  • WHO Director-General summarizes the outcome of the Emergency Committee regarding clusters of microcephaly and Guillain-Barré syndrome

  • Cited by (719)

    View all citing articles on Scopus

    Senior authors

    View full text