Conclusion and Comments

A total of 1,450 children aged ≥1 year were born to mothers with laboratory evidence of confirmed or possible Zika virus infection during pregnancy in the U.S. territories and freely associated states and were reported to the USZPIR. Among these children, approximately one in seven (14%) were identified during infancy or early childhood as having either a Zika-associated birth defect, a neurodevelopmental abnormality possibly associated with congenital Zika virus infection, or both.

The 6% with Zika-associated birth defects in this report can be viewed in the context of the previously published baseline frequency of brain and eye abnormalities potentially related to Zika virus infection. Before the introduction of Zika in the Region of the Americas the baseline frequency of brain and eye abnormalities potentially related to Zika virus infection among live-born infants was approximately 0.16% (21), suggesting a more than 30-fold increase over baseline.

Among all children aged ≥1 year by February 1, 2018, 68% had some follow-up care reported to the USZPIR. Of these children, 95% had at least a physical examination, 76% had developmental screening or evaluation, and 60% had neuroimaging. Approximately one half of the children (48%) had an ABR-based hearing screen or evaluation, and approximately one third of the children (36%) had an ophthalmologic evaluation reported to the USZPIR. Because the full spectrum of adverse outcomes related to congenital Zika virus infection is not yet known, careful monitoring and evaluation of children born to mothers with laboratory evidence of confirmed or possible Zika virus infection during pregnancy is essential for ensuring early detection of possible disabilities and early referral to intervention services that might improve outcomes. For example, with early identification of vision problems, a prescription for corrective eyeglasses might be beneficial to a child’s development (12). Among children without microcephaly detected at birth, brain or eye anomalies might have gone undetected without neuroimaging or ophthalmologic evaluation.

Many infants did not have Zika virus testing results reported. This could be because of changing recommendations for laboratory testing of infants born to mothers with laboratory evidence of confirmed or possible Zika virus infection during pregnancy (19). Among infants with testing reported, only 4% tested positive for Zika virus infection by IgM or NAT. In addition, limitations of laboratory testing for Zika virus have been previously described (19); Zika virus RNA is only transiently present in body fluids; thus, a negative NAT result does not rule out infection. Zika virus-associated birth defects and neurodevelopmental abnormalities possibly associated with congenital Zika virus infection also were identified in children with negative Zika virus NAT or IgM test results. These finding are consistent with other reports of infants with clinical findings suggestive of possible congenital Zika syndrome but with negative laboratory results (2,20,22).

Microcephaly is challenging to monitor accurately as an outcome because it is difficult to reliably measure head circumference in a newborn, it can be affected by inaccuracies in estimated gestational age, and it does not distinguish between a small head size related to underlying pathology and one that will subsequently exhibit typical brain development (3). The sensitivity analysis suggests that the number of infants with Zika-associated birth defects could be a modest overestimate.

This is the first analysis assessing neurodevelopmental abnormalities possibly associated with congenital Zika virus infection in addition to Zika-associated birth defects among children born to mothers in the U.S. territories and freely associated states with laboratory evidence of confirmed or possible Zika virus infection during pregnancy. Although there are large cohort studies monitoring pregnancies with and without Zika virus infection in several countries, the data in this report come from the largest cohort of children born to mothers with laboratory evidence of confirmed or possible Zika virus infection during pregnancy in the world who are currently being monitored as part of an enhanced surveillance system.

Whereas the cohort size is a strength of this analysis, the findings in this report are subject to at least five limitations. First, the data are limited to evaluations and clinical care received and reported to the USZPIR. The recommended services might not have been available to all children, and among those with reported follow-up care, information was limited for some children. In addition, data are limited to clinical records reported to the USZPIR; collecting these data are challenging because children might be seen in various outpatient settings and by multiple providers. To alleviate this barrier, territorial and state jurisdictions made extensive efforts to actively follow up, abstract, and report available data; CDC also provided substantial technical assistance. Second, it is possible that children with recognized health problems might have received follow-up care more frequently than did those without identified health problems, which might lead to an overestimate of the percentage of children with Zika-related health problems. Third, estimates of the baseline frequencies of neurodevelopmental abnormalities among very young children are available only for a few of the specific abnormalities; the lack of an appropriate comparison group limits assessment of whether the prevalence of reported neurodevelopmental abnormalities in the U.S. territories and freely associated states among children born to mothers with laboratory evidence of confirmed or possible Zika virus infection during pregnancy is an increase over baseline levels. Fourth, given the potential persistence, cross-reactivity, or nonspecific reactivity of IgM, some mothers included in the USZPIR might not have been infected with Zika virus during their pregnancy. For this reason, an analysis of child outcomes restricted to pregnancies with NAT-confirmed Zika virus infection was included, and similar percentages of children with a Zika-associated birth defect, a neurodevelopmental abnormality possibly associated with congenital Zika virus infection, or both were found. Finally, it might be difficult to distinguish between birth defects and neurodevelopmental abnormalities that might be causally linked to congenital Zika virus infection and those that might be attributable to unrelated causes; thus, this report describes occurrences without attributing causation.

Despite the limitations, this report extends understanding about the impact of congenital Zika virus infection. Whereas approximately 6% of children with congenital Zika virus exposure have Zika-associated birth defects, more children have neurodevelopmental abnormalities possibly associated with congenital Zika virus infection, identified during follow-up care, albeit without an appropriate comparison group on the baseline prevalence of these neurodevelopmental abnormalities among very young children. Given that most children did not have evidence of all recommended evaluations according to data reported to the USZPIR, additional unidentified anomalies might exist in this population. Furthermore, it is recognized that there were substantial disruptions to the provision of clinical care in Puerto Rico and the U.S. Virgin Islands related to hurricanes in 2017 (23); many families also were internally displaced or left the affected territories, potentially resulting in fewer follow-up care data reported to the USZPIR. Children who were most affected by Zika virus infection during pregnancy might have been either more or less likely to be displaced after hurricanes; there is no specific information on the impact of this displacement in these estimates. However, jurisdictional staff members attempted to find families and link them to the USZPIR in their new jurisdiction.

It is essential that health care providers who care for children have access to information regarding maternal exposure to Zika virus infection during pregnancy. This will improve the identification of children born to mothers with laboratory evidence of confirmed or possible Zika virus infection during pregnancy so that they can receive recommended postnatal evaluations. Zika virus transmission is far less prevalent in the Americas in 2018 than during 2015–2017 (https://www.cdc.gov/zika/reporting/case-counts.html); however, information about this cohort of children can inform and guide future responses to outbreaks of Zika virus that will inevitably occur among susceptible populations and disproportionately affect pregnant women and their children.