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RAPID RESPONSE TO Morris JK et al, BMJ, 2016 Sep 13
“Prevalence of microcephaly in Europe: population-based study”
CONGENITAL
ZIKA
SYNDROME:
TIME
TO
HARNESS
SHARED
DATA
CENTRALIZED IN AN INTERNATIONAL REGISTRY
David Baud1, Patrick Gerardin2, Audrey Merriam3, Marco P. Alves4, Didier Musso5, Blaise
Genton6, Alice Panchaud7
1
Materno-fetal and Obstetrics Research Unit, Department "Femme-Mère-Enfant", University Hospital,
1011 Lausanne, Switzerland; Institute of Microbiology, Faculty of Biology and Medicine, University of
Lausanne and University Hospital, Lausanne, Switzerland
Pôle Femme Mère Enfant, Centre d'Investigation Clinique (INSERM CIC1410), UM 134 PIMIT
2
"Processus Infectieux en Milieu Insulaire Tropical" (Université de La Réunion, CNRS 9192, INSERM U
1187, IRD 249), CHU Réunion, Saint Pierre, Reunion,
3
Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Columbia University
Medical Center, New York, New York USA
4
Institute of Virology and Immunology, Department of Infectious Diseases and Pathobiology, University
of Bern, Switzerland
Unit of Emerging Infectious Diseases, Institut Louis Malardé, Tahiti, French Polynesia
5
6
Swiss Tropical and Public Health Institute, Basel, Switzerland; Infectious Disease Service and
Department of Ambulatory Care, University Hospital Lausanne, Lausanne, Switzerland
7
Swiss Teratogen Information Service, University Hospital, 1011 Lausanne, Switzerland; Division of
Clinical Pharmacology, University Hospital, 1011 Lausanne, Switzerland; School of Pharmaceutical
Sciences, University of Geneva and Lausanne, Geneva, Switzerland; Department of Epidemiology,
Harvard School of Public Health, Boston, MA, USA.
We welcome the paper by JK Morris et al. that emphasized the importance of congenital
anomaly surveillance systems providing accurate baseline estimates essential to detect new
teratogens in a timely manner [1]. The presented descriptive study highlights the critical task of
measuring variation in prevalence of rare events, such as microcephaly, even when harnessing
pooled data from registries covering births from a large population. In the study, substantial
variability was observed between the participating registries’ estimates. This fact coupled with
the rarity of the congenital anomaly studied leads to a lack of power to detect smaller variation in
prevalence. Pitfalls such as heterogeneity among registries in the definition of the event of
interest or ascertainment procedures were pinpointed as causes. The authors stated that increases
in prevalence of microcephaly such as expected in Zika virus (ZIKV) in a non-endemic region
would be unlikely to be detected in Europe through routine surveillance.
Beyond the potential lack of detection power by the existing surveillance systems raised by
EUROCAT contributors, to tackle the ZIKV situation, it’s time to move to the next step. Thus, as
a newly identified teratogen, ZIKV requires global and dedicated tools to allow a comprehensive
characterization of the risks associated to its materno-fetal transmission. Nearly a year after the
first reported increase in incidence of microcephaly in Brazil [2], the magnitude of the risks of
materno–fetal transmission and its associated potential cofactors remain unclear.
Several possible risk factors, such as symptomatic maternal infection, gestational age at onset
of infection, cross-reactive dengue antibodies or previous Herpes simplex 2 virus infection have
been brought forward by the scientific community and need to be evaluated [3- 6]. Beyond these
easily measurable exposures, the topic deserves even higher attention towards the exploration of
the whole "fetal exposome", including maternal exposures to environmental pollutants known to
be associated with low-magnitude risks, which requires larger populations to be studied.
Moreover, the range of fetal and neonatal anomalies that may compose the spectrum of the
congenital Zika syndrome remains to be defined. Even though microcephaly has become a
central component of this syndrome [7], additional malformations have been reported [8], which
enlarges considerably the range of the presumed spectrum and requires further investigation.
Case reports and congenital anomaly surveillance systems are indispensable tools to detect
new teratogens and have proven to be effective during the ZIKV outbreak in Brazil. However,
since these tools will not likely provide global information and allow an in-depth comprehension
of the association between a teratogen and its risks, epidemiological studies, such as case-control
studies and cohort studies with appropriate follow-up are required.
In order to facilitate these studies, we have launched an international web registry [9],
enrolling prospectively and anonymously pregnant women at any gestational age as soon as a
ZIKV exposure is suspected (i.e., mosquito bite, unprotected sexual intercourse, or other) and
ideally before any additional screening (i.e., a prospective registry). Follow-up information on
other risk factors and pregnancy, fetal, and neonatal outcomes is gathered after birth. Any healthcare provider supporting the registry by providing well documented exposures will be regarded
as a collaborator of the registry in any future peer-reviewed scientific publication (information
and login request for the registry at https://epgl.unige.ch/zika-in-pregnancy-registry/). The
collected data will be available to any research group provided that they have a clear, nonredundant research question and approval from a biomedical research ethics committee.
We hope that this centralized dataset of shared information will allow research to move to the
next step in acquiring a comprehensive characterization of the risks associated to ZIKV maternofetal transmission.
REFERENCES
1. Morris JK, Rankin J, Garne E, et al. Prevalence of microcephaly in Europe: population-based
study." BMJ 2016; 354: i4721.
2. Kleber de Oliveira W, Cortez-Escalante K, Gonçalves Holanda de Oliveira, et al. Increase in
reported prevalence of microcephaly in infants born to women living in areas with confirmed
Zika virus transmission during the first trimester of pregnancy - Brazil, 2015. MMWR Morb
Mortal Wkly Rep 2016; 65: 242-7.
3. Freitas AR, Napimoga MH, Donalisio MR. Could clinical symptoms be a predictor of
complications in Zika virus infection? Lancet 2016; 388: 338.
4. Panchaud A, Stojanov M, Ammerdorfffer A, Vouga M, Baud D. 2016. Emerging role of Zika
virus in adverse fetal and neonatal outcomes. Clin Microbiol Rev 2016; 29: 659-94.
5. Priyamvada L, Quicke KM, Hudson WH, et al. Human antibody responses after dengue virus
infection are highly cross-reactive to Zika virus. Proc Natl Acas Sci U S A 2016; 113: 7852-7.
6. Aldo P, You Y, Szigeti K, Horvath TL, Lindenbach B, Mor G. HSV-2 enchances ZIKV
infection of the placenta and induces apoptosis in first-trimester trophoblast cells. Am J
Reprod Immunol 2016 Sep 10. doi: 10.1111/aji.12578 [Epub ahead of print].
7. Araújo TVB, Rodrigues LC, Ximenes RAA, et al. Association between Zika virus infection
and microcephaly in Brazil, January to May, 2016: preliminary report of a case-control study.
Lancet Infect Dis 2016 Sep 15. http://dx.doi.org/10.1016/S1473-3099(16)30318-8.
8. Vouga M, Baud D. Imaging of congenital Zika virus infection: the route to identification of
prognostic factors. Prenatal Diagn 2016; 36: 799-811.
9. Panchaud A, Vouga M, Musso D. Baud D. An international registry for women exposed to
Zika virus during pregnancy: time for answers. Lancet ID 2016;9: 995–996.