PMC

A. Cumulative reported cases of Zika in Brazil and Colombia. B. Total microcephaly cases reported in Brazil and Zika associated microcephaly cases reported in Colombia. The number of Zika cases in Colombia is lower by a factor of 2, while the number of microcephaly cases is lower by a factor of 50. (Brazil reports total microcephaly numbers and does not distinguish those linked to Zika. Colombia reports only Zika-linked microcephaly cases. The historical background rate of microcephaly in Colombia is 140 per year.)

Microcephaly cases ZIKV laboratory-confirmed by qRT-PCR and/or ZIKV-specific IgM (n = 31), microcephaly cases with negative results by qRT-PCR and/or ZIKV-specific IgM (n = 58) and controls without microcephaly (n = 89).

Imaging characteristics of microcephaly. (A–C) Microcephaly with normal gyration. In this 9-year-old male with head circumference (50 cm) below the third centile for age, gyrification is normal. Both corpus callosum and hindbrain are also well proportioned. (D–F) Microcephaly with simplified gyral pattern. The gyri are less numerous, and the sulci shallower and less deep than normal. Corpus callosum is also thin (arrow), and the vermis is mildly hypoplastic. (G–I) Microcephaly with lissencephaly. In this neonate, there is profound microcephaly with an almost complete absence of gyrification and thick cortex. There is concomitant ventriculomegaly, and pontine and corpus callosum hypoplasia (case courtesy of Zoltan Patay, USA). (J–L) Microcephaly with lissencephaly and agenesis of the corpus callosum. In this neonate, there is slightly less severe degree of microcephaly and simplified gyrification with thick cortex. There is associated pontine hypoplasia and corpus callosum agenesis (case courtesy of Zoltan Patay, USA). (M–O) Microcephaly with lissencephaly and midbrain-hindbrain involvement. In this patient with VLDLR1 mutation, microcephaly is associated with gyral simplification and a thickened cortex. The corpus callosum is normal, and appears paradoxically larger. There is concomitant profound pontocerebellar hypoplasia, with prevalent vermis involvement (arrow). (P and R) Microcephaly with polymicrogyria. In this patient with WDR62 mutation, microcephaly is associated with bilateral perisylvian polymicrogyria and with a simplified, aberrant gyral pattern in both parietal lobes. The corpus callosum and hindbrain are normal.

Newborns with microcephaly are more likely to be tested for congenital CMV than newborns without microcephaly, as are newborns with sensorineural hearing loss (SNHL) who fail the newborn hearing screen (or have other congenital CMV–related symptoms). Thus, there are more newborns tested, and more with a positive CMV test result, among those with microcephaly, resulting in upwardly biased estimates of the association of congenital CMV with microcephaly. To avoid this surveillance bias, we restricted to newborns with CMV testing, as represented by the box around CMV testing in the second directed acyclic graph. However, among tested newborns, both individuals with and without microcephaly may be more likely to have congenital CMV–related symptoms such as SNHL that triggered the test. Thus, among tested newborns, there would be an overrepresentation of CMV-positive infants in both the case and referent groups, resulting in biased estimates of the association of congenital CMV with microcephaly.