The relation between Zika virus and microcephaly is widely assumed to be causal because of strong evidence of an association. However, evidence so far comes from case reports, case series, modelling studies, and preliminary reports from cohort studies - none of which have included appropriate control groups.
Today, researchers from Brazil and the UK report the preliminary findings of the first case-control study examining the association between microcephaly and in utero Zika virus infection. The study, published in The Lancet Infectious Diseases journal, was requested by the Brazilian Ministry of Health to investigate the causes of the microcephaly epidemic that was declared a Public Health Emergency of International Concern in 2016.
The study included all infants born with microcephaly delivered in eight public hospitals in Pernambuco State in North Eastern Brazil between 15 January and 2 May 2016. For each case, two controls were selected. Controls were the first two infants born the following morning without microcephaly in one of the eight hospitals. Controls and cases were matched for region of residence and expected date of delivery.
Blood samples from cases and controls were collected and samples of cerebrospinal fluid were collected from cases with microcephaly. Samples were tested for Zika virus and Zika virus antibodies. Blood samples were collected from mothers and analysed for Zika and dengue virus. Infants with microcephaly had their head circumference measured and most underwent brain imaging.
24 of 30 (80%) mothers of infants with microcephaly had Zika virus infection, compared with 39 of 61 (64%) mothers of controls. 13 of 32 cases (41%) tested positive for Zika virus infection in blood or cerebrospinal fluid samples, and none of the 62 controls tested positive for Zika virus infection in blood samples. A high proportion of mothers also tested positive for dengue and other infections such as cytomegalovirus (a type of herpes), rubella, and toxoplasma but there was no significant difference between mothers of cases and controls. Additionally, only seven of the 27 cases with microcephaly who had a brain scan had brain abnormalities, suggesting that congenital Zika virus syndrome can be present in neonates with microcephaly and no brain abnormalities.
"A high proportion of mothers of newborns with and without microcephaly had been infected with Zika virus, reflecting the rapid spread of Zika infection in this region. However, when we compared laboratory confirmed Zika virus infection in newborns with and without microcephaly, we found that about half of the cases with microcephaly had laboratory confirmed Zika virus infection, compared to none of the healthy controls. The presence of Zika virus antibodies in the cerebrospinal fluid indicates infection in the neural system of the neonate, but interestingly not all cases of microcephaly had brain abnormalities," says article author Dr Thália Velho Barreto de Araújo, Federal University of Pernambuco, Recife, Brazil.
The authors warn that preliminary analyses can overestimate the strength of an association, so the true size of the effect needs to be treated with caution. The full study, which will include 200 cases and 400 controls will help quantify the risk more precisely and shed light on the role of co-factors.
The authors add that detecting the presence of Zika virus or antibodies in blood and cerebrospinal fluid is the only current method of testing for Zika virus in newborns but the reliability of this method, especially when infections occur early in pregnancy, is not fully understood. The authors say that these limitations might partly explain why 19 (59%) of microcephaly cases were not confirmed as positive for Zika virus.
"This is the first case-control study to examine the association between Zika virus and microcephaly using molecular and serological analysis to identify Zika virus in cases and controls at the time of birth. Our findings suggests that Zika virus should be officially added to the list of congenital infections alongside toxoplasmosis, syphilis, varicella-zoster, parvovirus B19, rubella, cytomegalovirus, and herpes. However, many questions still remain to be answered including the role of previous dengue infection" says Dr Thália Velho Barreto de Araújo.
The study was led by Fiocruz-Pernambuco, Federal University of Pernambuco, State University of Pernambuco, the Pan American Health Organization and the London School of Hygiene & Tropical Medicine (UK).
Writing in a linked Comment, Dr Patricia Brasil, Fiocruz RJ, Rio de Janeiro, Brazil and Professor Karin Nielsen-Saines, Department of Pediatrics, UCLA, Los Angeles, CA, USA, write: "as acknowledged by Araújo and colleagues, microcephaly remains a poorly defined disorder, and a uniform diagnostic approach is urgently needed. There is much debate in Brazil and worldwide about ascertainment of microcephaly, and the issue of disproportionate and proportionate microcephaly needs further clarification. Infants might be diagnosed with microcephaly when in fact they are globally small -- ie, small for gestational age, without true isolated microcephaly. This issue deserves attention, especially because in-utero growth restriction leading to the birth of small-for-gestational age infants is also a feature of congenital Zika virus syndrome. Although disproportionate microcephaly has been the most publicised feature of congenital Zika virus infection, proportionate microcephaly is also identified in the setting of in-utero growth restriction caused by maternal Zika virus infection during pregnancy, not unlike other congenital infections such as cytomegalovirus. The distinction, however, is important because there might be distinct prognostic implications. Although microcephaly has been associated with poor outcome in children with congenital cytomegalovirus disease, other researchers have not found such an association. A possible source of discrepancy is failure to adjust the head size to the weight of the infant when defining microcephaly." They add: "As our knowledge of the clinical repercussions of congenital Zika virus infection advances, it becomes apparent that microcephaly is only one possible adverse outcome among a range of disorders that might be part of congenital Zika virus syndrome."
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