TABLE 1.

Summary of evidence for Zika virus evolving to produce increased teratogenicity versus Zika virus as a teratogen that had been previously missed

ZIKV evolution led to increased teratogenicity	ZIKV as a teratogen that had been previously missed
prM mutation (S139N) in ZIKV that arose in 2013 led to severe microcephaly in mice model (Yuan et al., 2017)	Case reports of two children born in Cambodia in 2009 and 2011, respectively, with clinical features of CZS (Chu et al., 2018) Case report of a child born in 2011 in Brazil with clinical features of CZS (Coelho et al., 2018)
A spontaneous NS1 (A982V) mutation led to increased antigenemia in mouse model and increased infectivity from mouse to mosquito, leading to increased prevalence and recognition of teratogenicity (Liu et al., 2017)	Increase in microcephaly cases in Hawaii during Pacific ZIKV outbreak (2007–2013) (Kumar et al., 2016)
E-V473M substitution that emerged between 2010 and 2013 likely increased neurovirulence in neonatal mice and maternal–fetal transmission (Shan et al., 2020)	Seasonal pattern in CZS-type birth defects that coincided with heightened mosquito season in West Africa (Majumder et al., 2018)
	Numerous factors, including challenges to detection, diagnosis, and surveillance of ZIKV infections and birth defects contributing to a delay in recognizing the teratogenicity of ZIKV