http://www.who.int/bulletin/volumes/94/6/16-176990.pdf?ua=1
3.6. 2016
Rarely
have scientists engaged with a new research agenda with such a sense of
urgency and from such a small knowledge base as in the current epidemic
of microcephaly (6000 notified suspected cases in Brazil1 and the first case detected in Colombia in March, 20162)
associated with the Zika virus outbreak across the Americas. Indeed, in
2015, in a review of infections that have neurological consequences,
Zika virus was not even mentioned.3 In only 5 months since the detection of the first excess cases of microcephaly in Brazil,4
WHO has declared the clusters of microcephaly and other neurological
disorders to be a Public Health Emergency of International Concern.5
WHO had also stated that the causal relation of these disorders with
Zika virus infection had not yet been scientifically proven.5
The reluctance to accept the causal link stems from the rarity of
isolation of Zika virus or detection of RNA in neonates with
microcephaly.1
Before
the outbreak of Zika virus in the Americas, the largest documented
outbreak was in French Polynesia in 2013–14. An elegant piece of
evidence supporting the theory that Zika is the cause of microcephaly
comes from that outbreak. In the first investigation, no peak in the
number of fetuses or neonates with microcephaly was detected.6
The theory that mother-to-child Zika virus infection was a cause of the
microcephaly epidemic in Brazil, however, required that there had been
an increase in microcephaly associated with the Zika outbreak in French
Polynesia. Further investigation identified 17 cases of severe
neurological malformations, including microcephaly, and showed that a
peak had been missed because most women had terminations.7
In The Lancet, Simon Cauchemez and colleagues8
present a reanalysis of the data on Zika and microcephaly from the
French Polynesian outbreak to estimate the magnitude of risk in women
infected with Zika virus during pregnancy. They used serological data to
estimate the total number of infections during the outbreak and data
from surveillance on consultations for suspected Zika virus disease to
attribute these infections to the weeks of the outbreak. They did an
exhaustive search of medical records to identify all cases of
microcephaly during the period Sept 1, 2013, to July 31, 2015. Eight
cases of microcephaly were identified, seven of which occurred in a
4-month period around the end of the Zika virus outbreak. The baseline
prevalence of microcephaly was two (95% CI 0–8) per 10 000 neonates. The
researchers developed a mathematical model with six periods of assumed
increased risk of microcephaly given Zika infection to investigate when
the risk of infection and the magnitude of the risk were greatest. The
period of risk with the best fit was infection in the first trimester of
pregnancy. The risk of microcephaly associated with Zika virus
infection was 95 (34–191) per 10 000 women infected in the first
trimester: essentially a risk of microcephaly for infection in the first
trimester of around 1% (0·3–1·9)
The finding that the
highest risk of microcephaly was associated with infection in the first
trimester of pregnancy is biologically plausible, given the timing of
brain development and the type and severity of the neurological
abnormalities.9
However, the absolute risk of 1% estimated by Cauchemez and colleagues
is perhaps lower than expected. In the state of Pernambuco, Brazil,
where the risk was highest, during the 4 months of the epidemic 2% of
all neonates were notified as suspected cases of microcephaly, not only
those born to women known to have been infected.4 Half of the suspected cases were confirmed by the presence of calcifications, other brain abnormalities, or both.4 How to interpret the data has been the subject of some debate.10
After the paper by Cauchemez and colleagues8 was written, Brasil and colleagues11
reported preliminary results for 72 pregnant women with symptomatic,
laboratory-confirmed Zika virus infections, recruited in Rio de Janeiro
before fetal outcomes were known. Ultrasound images were available for
42 women, of which 12 (29%) showed abnormalities over the range of
gestational ages at infection.11
Nine women had rash and viraemia in the first trimester, and
microcephaly was detected by ultrasonography in two of these, which
corresponds to 22% risk of microcephaly after symptomatic Zika infection
in the first trimester.11
These three different approaches addressed different questions: the risk in all neonates during the epidemic in Pernambuco4
and the risk in neonates from women infected with Zika virus in the
first trimester of pregnancy in the other two studies (with clinical
symptoms in Rio de Janeiro11 and independently of clinical symptoms in French Polynesia8).
As expected the estimates are different, but are they consistent with a
single underlying risk or, alternatively, will risk be dependent on
other factors, such as the presence of clinical symptoms or previous
dengue infection? Further data will soon be available from Pernambuco,
Colombia, Rio de Janeiro, and maybe other sites that will gradually
answer these questions. The fast production of knowledge during this
epidemic is an opportunity to observe science in the making: from
formulation of new hypotheses and production of new results that will
provide confirmations and contradictions to the refinement of methods
and the gradual building of consensus. I expect we will teach our
students about the production of science using examples from this Public
Health Emergency of International Concern for many years to come.
I declare no competing interests.
References
- Teixeira, MG, Costa, MCN, de Oliveira, WK, Nunes, ML, and Rodrigues, LC. The epidemic of Zika virus-related microcephaly in Brazil: detection, control, etiology, and future scenarios. Am J Public Health. 2016; 106: 601–605
- Butler, D. First Zika-linked birth defects detected in Colombia. Nature. 2016; 531: 153
- John, CC, Carabin, H, Montano, SM et al. Global research priorities for infections that affect the nervous system. Nature. 2015; 527: S178–S186
- Centro de Operações de Emergências em Saúde Pública Sobre Microcefalias. Informe epidemiológico no 15–semana epidemiológica(SE)08/2016(21A 27/02/2016). http://combateaedes.saude.gov.br/images/pdf/informe_microcefalia_epidemiologico15.pdf; Aug 8, 2016. ((accessed March 3, 2016).)
- WHO. WHO Director-General summarizes the outcome of the Emergency Committee regarding clusters of microcephaly and Guillain-Barré syndrome. http://www.who.int/mediacentre/news/statements/2016/emergency-committee-zika-microcephaly/en/#; Feb 1, 2016. ((accessed March 3, 2016).)
- Mallet, HP, Vial, AL, and Nusso, D. Bilan de l'epidemie a virus Zika en Polynesie Francaise, 2013–2014. Bull Inf Sanit Epidemiol Stat. 2015; 13: 1–5
- Centre D'Hygiene et de Salubrite Publique. Note sur les investigations autour des malformations cérébrales congénitales ayant suivi l'épidémie de zika de 2013–2014. http://www.hygiene-publique.gov.pf/IMG/pdf/note_malformations_congenitales_cerebrales; December, 2015. ((accessed Dec 1, 2015).)
- Cauchemez, S, Besnard, M, Bompard, P et al. Association between Zika virus and microcephaly in French Polynesia, 2013–15: a retrospective study. Lancet. 2016; (published online March 15.)http://dx.doi.org/10.1016/S0140-6736(16)00651-6.
- Schuler-Faccini, L, Ribeiro, EM, Feitosa, IM et al. Possible association between Zika vírus infection and microcephaly—Brazil, 2015. MMWR Morb Mortal Wkly Rep. 2016; 65: 59–62
- Victora, CG, Schuler-Faccini, L, Matijasevich, A, Ribeiro, E, Pessoa, A, and Barros, FC. Microcephaly in Brazil: how to interpret reported numbers?. Lancet. 2016; 387: 621–624
- Brasil, P, Pereira, JP Jr, Gabaglia, CR et al. Zika virus infection in pregnant women in Rio de Janeiro—preliminary report. N Engl J Med. 2016; DOI: http://dx.doi.org/10.1056/NEJMoa1602412 (published online March 4.)