Discussion

Among completed pregnancies with laboratory evidence of recent possible maternal Zika virus infection in the U.S. territories, about one in 20 fetuses or infants had a possible Zika-associated birth defect. When analysis was restricted to NAT-confirmed Zika virus infection in the first trimester, about one in 12 fetuses or infants had a possible Zika-associated birth defect. Zika-associated birth defects were reported after identification of maternal symptoms or positive test results in each trimester.

The overall estimate of 5% of fetuses or infants with possible Zika-associated birth defects among completed pregnancies with NAT-confirmed infections might be affected by the smaller proportion of total completed pregnancies with symptom onset or a positive test result during the first trimester (18%) than during the second or third trimesters (81%). Because available data suggest that the risk for birth defects is higher when infection occurs early in pregnancy (5,7) and there are ongoing pregnancies with infection in the first trimester, it will be important to continue to monitor pregnancy outcomes to determine the impact of infection early in pregnancy on the percentage of infants with possible Zika-associated birth defects. Possible Zika-associated birth defects were identified in pregnancies with symptoms or laboratory evidence of recent possible maternal Zika virus infection in each trimester of pregnancy. Challenges with determining the exact timing of infection limit interpretation; however, adverse outcomes following infection throughout pregnancy are consistent with adverse outcomes associated with some other congenital infections (8). For example, severe central nervous system sequelae (hearing loss, seizures, or chorioretinitis) have been reported following congenital cytomegalovirus infection later in pregnancy, with the highest risk following first trimester infection (8). The continued follow-up of infants is critical to elucidating the impact of Zika virus infection during pregnancy beyond abnormalities detected at birth. Monitoring of ongoing pregnancies with laboratory evidence of possible recent Zika virus infection and the continued follow-up of infant status beyond birth hospitalization can inform public health recommendations for testing, evaluation, and care. Additional information about the full spectrum of outcomes can improve access to early intervention (https://www2.ed.gov/programs/osepeip/index.htmlExternal ) and services for children with special health care needs (https://mchb.hrsa.gov/maternal-child-health-topics/children-and-youth-special-health-needsExternal ).

Consistent with previously reported data from the 50 U.S. states regarding primarily travel-associated Zika virus infections in pregnancy, about one in 20 fetuses or infants had possible Zika-associated birth defects (5). However, the report from U.S. states included a larger percentage of pregnancies with imprecise timing of infection, thereby limiting any direct comparison of the percentage of affected pregnancies by trimester of infection. This report from the territories, with more robust late pregnancy data, suggests a risk for birth defects throughout pregnancy; further study is needed to confirm this finding. The percentage of infants with possible Zika-associated birth defects after infection identified in the first trimester was 8% (95% CI = 5%–12%) in the U.S. territories compared with 15% (95% CI = 8%–26%) in the U.S. states (5); the confidence intervals for these estimates overlap and both are based on relatively small numbers. In addition, for the analysis of the U.S. territories data, a more restrictive definition of confirmed infection, limited to NAT-confirmed infection, was used.

The findings in this report are subject to at least seven limitations. First, the actual number of infants who had Zika virus testing and postnatal screenings might be underestimated because of delays in reporting results to medical records and changes to clinical guidance for infants in August 2016 (6). Second, misclassification of microcephaly might have occurred because of imprecise measurements of head circumference at birth and difficulties with consistent surveillance for microcephaly, which could result in overascertainment or underascertainment of microcephaly (9). Third, other potential etiologies for these birth defects (e.g., genetic or other infectious causes) were not assessed in this analysis. Fourth, lack of postnatal neuroimaging might have led to underascertaining brain abnormalities; just over half of infants had postnatal neuroimaging reported at birth, despite recommendations that all infants born to mothers with laboratory evidence of possible Zika infection receive such imaging (6). Some infants might have additional imaging in the outpatient setting; planned efforts to follow these infants at 2 months and beyond might provide additional data. Fifth, the actual number of Zika virus infections among pregnant women in the U.S. territories might be underestimated. Investigation of a 2007 Zika virus disease outbreak in Yap, Federated States of Micronesia, suggested that up to 80% of Zika virus infections might be asymptomatic or mildly symptomatic (10). The percentage of asymptomatic infections in the U.S. territories (38%) was much lower than that reported from Yap and lower than that suggested by data from the Zika pregnancy and infant registries from the U.S. states (62%) (5,10). However, in the U.S. territories, Zika virus testing of women during pregnancy was recommended regardless of symptom status, whereas a household survey of the general population was conducted in Yap. Sixth, because of limitations in the specificity of current serologic testing, some pregnant women who were reported to the Zika pregnancy and infant registries might have had other flavivirus infections. However, rates of dengue virus transmission were low in Puerto Rico and the U.S. Virgin Islands during 2016 (https://diseasemaps.usgs.gov/mapviewer/External ), and dengue virus infection is not known to cause birth defects. Finally, some women who were infected with Zika virus before pregnancy might have a persistent immunologic response resulting in a positive immunoglobulin M test detectable during pregnancy. Analyses restricted to pregnancies with NAT-confirmed Zika virus infection indicated a similar proportion of infants with birth defects. However, even with NAT testing, timing of maternal infection might be inexact, especially given that Zika virus RNA might persist during pregnancy (https://www.cdc.gov/zika/laboratories/lab-guidance.html), and because most Zika virus infections are asymptomatic or have mild, nonspecific symptoms.

This report adds information about the number of possible Zika-associated birth defects with laboratory evidence of recent possible or NAT-confirmed Zika virus infection during pregnancy among women living in the U.S. territories and supplements findings from the U.S. states. It also provides new estimates for the proportion of infants with a birth defect after identification of maternal Zika virus infection in the first, second, and third trimesters of pregnancy, and provides evidence that birth defects might occur following documentation of symptom onset or positive laboratory testing during any trimester. Moreover, based on data reported to the pregnancy and infant registries, this report highlights potential gaps in testing and screening of infants with possible congenital Zika virus infection in U.S. territories at birth. Identification and follow-up of infants born to mothers with laboratory evidence of recent possible Zika virus infection during pregnancy can facilitate timely and appropriate clinical intervention services and assessment of future needs (2,6). Information about adherence to the recommended newborn testing and screening can improve monitoring and care of infants affected by Zika.