Evidence for a causal link between ZIKV and microcephaly is now very strong and widely accepted [
24] (Table
1). Despite the lack of data from adequately powered prospective longitudinal studies, the link between ZIKV and microcephaly is supported by applying Shepard’s Criteria for Proof of Teratogenicity in Humans [
24] and the Bradford–Hill criteria for causality [
25], especially for the aspects of temporality, biological plausibility, and analogy. For example, temporality of the association is supported by individual case reports as well as the ~6-month delay between ZIKV outbreaks and the increase in the incidence of microcephaly in French Polynesia [
21] and Brazil [
22], suggesting a causal link between microcephaly and ZIKV infection in the first/early second trimester. Moreover, modeling of French Polynesia cases demonstrated that “the best-fitting models of period-of-risk all included the first trimester of pregnancy, with that including only the first trimester having the best fit” [
21], even if central nervous system abnormalities have been reported for fetuses infected as late as 27 weeks of gestation [
26]. Plausibility is supported by the detailed study of an aborted microcephaly case from Ukraine for which other infectious causes of microcephaly were ruled out [
27]. This case had evidence of ZIKV infection in the fetal brain, suggesting ZIKV can cross the fetal blood–brain barrier. This is supported by reports of vertical transmission of ZIKV in a mouse model, leading to impaired fetal brain development [
28]. Furthermore, ZIKV can infect human neural progenitor cells and attenuate their growth [
29]. These findings have been replicated in a mouse model in which ZIKV targets primarily neural progenitor cells, causing their cell-cycle arrest, apoptosis, and inhibition of differentiation, resulting in cortical thinning and microcephaly [
30]. This and other animal models have recently provided evidence that ZIKV infection can lead to microcephaly (reviewed in [
31]), indicating that a causal link between early pregnancy ZIKV infection and microcephaly is plausible in humans (see below for possible mechanisms). Mouse models point to the importance of a type I IFN response in the susceptibility to ZIKV infection and in the development of clinical symptoms (including microcephaly) [
32,
33]. The relevance of these findings in humans is unclear. There is also an analogy between ZIKV and other viruses (including flaviviruses) for which a link with microcephaly has been demonstrated; for example, rubella can cause microcephaly with cerebral calcifications [
34], as described with ZIKV infection [
27] and cytomegalovirus [
35].
Table 1
Evidence for a causal link between ZIKV and microcephaly
| Increase in microcephaly cases coincides with increase in ZIKV transmission (with a 6-month delay) |
| Data modeling shows that the main period at risk is the first trimester of pregnancy |
| Of the microcephaly cases investigated in Brazil, 32 % were linked to ZIKV |
| Case study: Miscarriage of a baby with microcephaly was positive for ZIKV (including in its brain), but negative for other known infectious causes of microcephaly |
Laboratory studies
|
| ZIKV can infect human neural progenitor cells and attenuate their growth in vitro |
Primary human placental macrophages and trophoblasts are permissive to ZIKV infection in vitro |
Animal models
|
| Mouse model of ZIKV display signs of microcephaly |
Analogy to related viruses
|
| Rubella virus, another flavivirus, causes microcephaly when infection occurs during pregnancy |