Most individual brain and eye defects examined had significantly higher prevalence in areas with widespread ZIKV transmission compared to areas without local transmission. When these defects were pooled together (i.e., Group A), significantly higher prevalence was found in three of five quarters. A similar pattern was observed by Smoots et al., which examined all 16 brain and eye defects together and found an increase in prevalence in the same time periods (Smoots, 2020). For Group B birth defects, those defects without significant differences between areas with and without widespread local ZIKV transmission, the prevalence over the study period remained relatively stable. This suggests that the nine pooled brain and eye defects (i.e., intracranial calcifications, chorioretinal abnormalities, brainstem abnormalities, cerebral cortical atrophy, optic nerve abnormalities, abnormal cortical gyral patterns, ventriculomegaly/hydrocephaly, microcephaly, and corpus callosum abnormalities) are primarily responsible for the almost four-fold increase in prevalence of brain and eye defects that occurred six months after the outbreak peak. The brain and eye defects observed to have a significantly higher prevalence in areas of widespread local transmission have all consistently been described in infants with congenital Zika syndrome (Moore, 2017).
The prevalence of microcephaly was almost three times higher in areas with widespread local ZIKV transmission. Interestingly, the prevalence of intracranial calcifications, cortical/cerebral atrophy, brainstem abnormalities, and chorioretinal abnormalities were approximately seven to 12 times higher, a much larger increase in prevalence than observed for microcephaly. These defects could be more specific for in-utero ZIKV exposure than microcephaly, which is a very heterogeneous condition (Freitas, 2020). Only the prevalence of porencephaly, cerebellar abnormalities, microphthalmia, coloboma, and congenital cataracts were similar between areas with and without widespread local transmission. For some birth defects, this could indicate that these particular defects are not related to ZIKV infection or be due in part to the rarity of the outcome (i.e., intraocular calcifications and hydranencephaly). Further, while eye defects such as microphthalmia, coloboma, and congenital cataracts have been described in infants with congenital Zika syndrome, optic nerve abnormalities and chorioretinal abnormalities are more commonly observed (de Oliveira Dias, 2018).
This analysis is subject to several limitations. First, our analysis was underpowered to detect small changes in prevalence over time because many of the individual birth defects are rare events. Second, heightened awareness of birth defects in areas with known transmission of ZIKV could have contributed to a larger portion of infants receiving recommended evaluations and identification of birth defects. This might partially explain the significantly higher prevalence of birth defects in areas of limited and widespread local ZIKV transmission. For example, milder forms of birth defects such as corpus callosum abnormalities or microcephaly might be more likely to be identified. Additional limitations of the surveillance data overall, specific to population demographics, case finding methodology, and laboratory testing, have been previously described (Smoots, 2020).
It is unlikely that heightened awareness fully explains the differences in prevalence observed. Birth defects such as cortical/cerebral atrophy, abnormal cortical gyral patterns, brainstem abnormalities, and optic nerve abnormalities often have noticeable clinical neurodevelopmental manifestations that make them more likely to be identified in the first year of life. Further, the defects observed to have the largest difference in prevalence in areas of widespread transmission (i.e., intracranial calcifications, cerebral/cortical atrophy, brainstem abnormalities, and chorioretinal abnormalities) are uncommon defects that have consistently been described in infants with congenital Zika syndrome (Del Campo, 2017; de Oliveira Dias, 2018).
Based on our findings, birth defects surveillance programs, especially those with limited capacity, could consider monitoring a smaller subset of birth defects potentially related to ZIKV in pregnancy. Birth defects surveillance programs with limited capacity or resources could opt to monitor rarer defects that showed larger increases in prevalence such as intracranial calcifications and chorioretinal abnormalities to monitor for outbreaks and expand to monitor all 16 defects in the event of a known or suspected outbreak of ZIKV. This approach must be balanced because less severe presentations or more common defects may not be identified when ascertaining a more limited set of birth defects. For those jurisdictions that have the resources, continued surveillance of all sixteen brain and eye defects is important for continuing to understand these defects in the context of ZIKV.
This study highlights the importance of population-based birth defects surveillance for understanding the full impact of new and re-emerging teratogens. In the United States, timing of testing and the high percentage of asymptomatic cases made it difficult to identify all ZIKV exposed pregnancies. Birth defects surveillance programs were able to capture defects of interest, regardless of Zika laboratory testing status, and these data have helped strengthen our understanding of the specific birth defects that are potentially the most influenced by congenital ZIKV exposure.
Footnotes:
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TORCH testing is set of tests for infectious diseases in pregnant women including toxoplasmosis, rubella, cytomegalovirus, herpes simplex virus, HIV, syphilis, hepatitis B, varicella-zoster virus, and parvovirus B19
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Pregnancy losses included miscarriages, fetal deaths, and terminations. Not all birth defects surveillance programs were able to ascertain pregnancy losses.