Table 2.

Supporting and controversial evidence of the association between ZIKV infection during pregnancy and fetal abnormalities

Supporting evidence	Controversial evidence
Fetal involvement with maternal infection occurring during first trimester or early second trimester
Presence of ZIKV antibodies in maternal serum45,48,49	ZIKV infection inferred only by epidemiological/clinical criteria44,49,53,54,56
Isolation of ZIKV during pregnancy (maternal serum/urine, amniotic fluid)3,41,42,49,50,58	Risk of infection after first trimester could not be excluded
Isolation of ZIKV antibodies in samples from fetus/neonates (fetal necropsy, cerebrospinal fluid)45–48,51,52	Despite the fact that infection seems to cause more severe disease in fetus during the first trimester, data regarding exposure and disease cannot be totally explained
Common phenotype in cases with isolation of ZIKV in fetus/neonates
Microcephaly41,42,47,48,51,52,58	Mild phenotypes could also be associated with ZIKV infection, since only severe cases have been reported
Fetal death40,47,49,50
Intracranial calcifications47,51–53
Cerebral atrophy45,48,52
Destructive lesions47
Anomalies of cortical development/gyration51–53
Common phenotype in cases with presumed infection
Ocular lesions60,61
Reports of fetuses and infants with microcephaly who are born to women who travel to countries with active ZIKV transmission
In Slovenia, a pregnant woman who was living in the northeast of Brazil during ZIKV outbreak.45 A pregnant woman who had been to Mexico, Guatemala, and Belize on holiday48
Six pregnant women who had traveled to areas with active transmission of ZIKV49
Virus presence in fetal and neonatal samples, and similar findings are presented in other congenital infections  The findings of microcephaly, premature fetal death, intracranial calcifications, and CNS abnormalities are similar to the effects of other known congenital infectious agents and environmental toxins69	The evaluation of placental tissues, fetal death and neonatal death are necessary to determine the effect of gestational age during maternal illness on fetal outcomes. Experimental evidence of infection of neural stem cells in in vitro75,76 and animal models76,77
Strong temporal and geographical association of ZIKV and neurological involvement Brazil  Brazilian Ministry of Health36,55  Northeast51,52  Southeast54 French Polynesian  Retrospective studies56,58,59	Due to changes in microcephaly definition, obligatory notification, and absence of confirmation of etiology in several cases, an overestimation of ZIKV-affected infants should be considered in Brazil.39,65–67 Other etiologies of microcephaly should also be ruled out.69 Ideally, consistent findings should be performed by two or more high-quality epidemiologic studies, with the control of confounding factors, sufficient numbers, exclusion of positive and negative bias factors, prospective studies if possible, and relative risk higher than 6.0.(br)However, literature until now includes only surveys and retrospective or short-term cohort studies. Therefore, until a large epidemiological study is published, it is not possible to confirm the association between maternal exposure and fetal involvement

Abbreviations: CNS, central nervous system; ZIKV, Zika virus.