Zika-Associated Birth Defects Reported in Pregnancies with Laboratory Evidence of Confirmed or Possible Zika Virus Infection — U.S. Zika Pregnancy and Infant Registry, December 1, 2015–March 31, 2018

Zika virus infection during pregnancy can cause serious birth defects of the brain and eyes, including intracranial calcifications, cerebral or cortical atrophy, chorioretinal abnormalities, and optic nerve abnormalities (1,2). The frequency of these Zika-associated brain and eye defects, based on data from the U.S. Zika Pregnancy and Infant Registry (USZPIR), has been previously reported in aggregate (3,4). This report describes the frequency of individual Zika-associated brain and eye defects among infants from pregnancies with laboratory evidence of confirmed or possible Zika virus infection. Among 6,799 live-born infants in USZPIR born during December 1, 2015-March 31, 2018, 4.6% had any Zika-associated birth defect; in a subgroup of pregnancies with a positive nucleic acid amplification test (NAAT) for Zika virus infection, the percentage was 6.1% of live-born infants. The brain and eye defects most frequently reported included microcephaly, corpus callosum abnormalities, intracranial calcification, abnormal cortical gyral patterns, ventriculomegaly, cerebral or cortical atrophy, chorioretinal abnormalities, and optic nerve abnormalities. Among infants with any Zika-associated birth defect, one third had more than one defect reported. Certain brain and eye defects in an infant might prompt suspicion of prenatal Zika virus infection. These findings can help target surveillance efforts to the most common brain and eye defects associated with Zika virus infection during pregnancy should a Zika virus outbreak reemerge, and might provide a signal to the reemergence of Zika virus, particularly in geographic regions without ongoing comprehensive Zika virus surveillance.

Zika virus infection during pregnancy can cause serious birth defects of the brain and eyes, including intracranial calcifications, cerebral or cortical atrophy, chorioretinal abnormalities, and optic nerve abnormalities (1,2). The frequency of these Zika-associated brain and eye defects, based on data from the U.S. Zika Pregnancy and Infant Registry (USZPIR), has been previously reported in aggregate (3,4). This report describes the frequency of individual Zika-associated brain and eye defects among infants from pregnancies with laboratory evidence of confirmed or possible Zika virus infection. Among 6,799 live-born infants in USZPIR born during December 1, 2015-March 31, 2018, 4.6% had any Zika-associated birth defect; in a subgroup of pregnancies with a positive nucleic acid amplification test (NAAT) for Zika virus infection, the percentage was 6.1% of live-born infants. The brain and eye defects most frequently reported included microcephaly, corpus callosum abnormalities, intracranial calcification, abnormal cortical gyral patterns, ventriculomegaly, cerebral or cortical atrophy, chorioretinal abnormalities, and optic nerve abnormalities. Among infants with any Zika-associated birth defect, one third had more than one defect reported. Certain brain and eye defects in an infant might prompt suspicion of prenatal Zika virus infection. These findings can help target surveillance efforts to the most common brain and eye defects associated with Zika virus infection during pregnancy should a Zika virus outbreak reemerge, and might provide a signal to the reemergence of Zika virus, particularly in geographic regions without ongoing comprehensive Zika virus surveillance.
To monitor the impact of the 2015-2017 Zika virus outbreak, CDC, in collaboration with state, local, and territorial health departments, established USZPIR to conduct motherinfant linked longitudinal surveillance of outcomes in pregnant women and infants with laboratory evidence of confirmed or possible Zika virus infection during pregnancy* in the 50 U.S. states, the District of Columbia (DC), U.S. territories, and freely associated states. † Data from this cohort have been published previously (3)(4)(5) included in USZPIR with data reported as of December 2020 included in this report. Jurisdictions collected prenatal, pregnancy outcome, and follow-up information for infants and children (from birth through age 5 years) § from medical records in a standardized format.
All mother-infant data with an indication of a possible abnormality were reviewed by subject matter experts (which included CDC clinicians and researchers and external consultants); data reviewed included results from neuroimaging, ophthalmologic examinations, and clinical examinations for any criteria based on USZPIR surveillance case definition (6). Cases that met criteria for Zika-associated abnormalities were subsequently reviewed in detail by two or more clinicians (including pediatricians, obstetrician-gynecologists, and clinical geneticists), for confirmation and classification of the individual defect or defects. All discrepancies in classification were discussed and resolved among a panel of experts. Infants who had microcephaly and were not small for gestational age at birth underwent further review; those who met criteria for a potential birth head circumference measurement inaccuracy were not included as having microcephaly in USZPIR. ¶ Infants with other abnormal radiographic findings (e.g., mineralizing vasculopathy, and isolated subependymal cysts), which were § Infants and children in Puerto Rico and the U.S. Virgin Islands are followed through age 5 years; infants and children in U.S. states and DC, and U.S. territories and freely associated states are followed through age 3 years. ¶ https://www.researchsquare.com/article/rs-1189991/v1 deemed as having "unknown clinical significance" by experts, were not reported.
In this report, the number of infants with any Zika-associated birth defect and enumerated individual brain and eye defects identified in the entire cohort with laboratory evidence of confirmed or possible Zika virus infection from a maternal, placental, fetal, or infant specimen are presented. A subgroup of infants from pregnancies with confirmed Zika virus infection (i.e., positive Zika virus NAAT) are reported to examine whether findings are consistent with the entire cohort.** Zikaassociated birth defects among pregnancy losses are reported separately. † † In addition, the frequency of Zika-associated birth defects by location of birth, trimester with first evidence of Zika virus exposure (based on symptom onset, travel history to a region with endemic Zika virus transmission, or positive laboratory results), maternal symptom status, and reported neuroimaging and ophthalmology examinations are presented. Analyses were conducted using SAS (version 9.4; SAS Institute). CIs were calculated using exact Poisson regression. This activity was reviewed by CDC and was conducted consistent with applicable federal law and CDC policy. § § During December 1, 2015-March 31, 2018, among 6,799 live-born infants reported in USZPIR, 2,288 (33.7%) were born in U.S. states and DC and 4,511 (66.3%) in U.S. territories and freely associated states (Table 1). Zika virus exposure was reported for 2,121 (31.2%) pregnant women in the first trimester; 2,495 (36.7%) in the second trimester; and 2,039 (30.0%) in the third trimester. Symptoms compatible with Zika virus disease ¶ ¶ were reported in 35% of these women.
Among live-born infants reported in USZPIR, 4.6% (315 of 6,799) had any Zika-associated birth defect. In the subgroup with positive Zika virus NAAT during pregnancy, 6.1% (138 of 2,257) infants had any Zika-associated birth defect. Among pregnancies with positive Zika virus NAAT results, and thus less likelihood of exposure misclassification, the frequency of any Zika-associated birth defect was higher among those with first*** (8.0%) and second (6.0%) trimester infections compared with ** Includes maternal, placental, fetal, or infant laboratory evidence of Zika virus infection based on the presence of Zika virus RNA by a positive NAAT (e.g., RT-PCR). † † Pregnancy losses include spontaneous abortions, terminations, stillbirths, and pregnancy losses not specified. Information from prenatal or postnatal imaging and autopsy were used to determine presence of Zika-associated birth defects, although pregnancy losses often had less information reported and frequently lacked postnatal imaging that could verify prenatal findings and might identify additional abnormalities.  Table 2). A similar distribution of birth defects was observed in the total cohort and in the Zika virus NAAT-positive subgroup. Among infants with any Zikaassociated birth defect, one third (110 of 315) had more than one birth defect identified.

Discussion
During 2015-2017, large Zika virus outbreaks occurred throughout the United States (including U.S. territories and freely associated states). In the United States, infections during pregnancy were initially reported among U.S. travelers returning from affected countries. † † † During 2016, widespread local transmission was documented in the territories of Puerto Rico and the U.S. Virgin Islands, and limited transmission was documented in some counties in Florida and Texas. § § § Among completed pregnancies with laboratory evidence of Zika virus infection reported to USZPIR, 4.6% of live-born infants had any Zika-associated birth defect. Among the subgroup with NAAT-positive results, Zika-associated birth defects were reported with exposures throughout pregnancy but were more prevalent among infants born to mothers with exposure early in pregnancy. Approximately two thirds of pregnant women in this cohort reported asymptomatic infections. ¶  asymptomatic and symptomatic pregnant women is consistent with previous findings (3,5). Certain individual brain and eye defects associated with Zika virus infection were frequently reported in USZPIR cohort. A similar subset of Zika-associated birth defects was found to have significantly higher prevalence ratios in areas of widespread local transmission compared with areas without local transmission in the Zika Birth Defects Surveillance System.**** Given the short window for testing and that symptoms of Zika are often mild or absent, combining these two systems has identified the most prevalent Zika-associated birth defects. Using a surveillance system that monitored outcomes regardless of testing and a system that monitored outcomes among those possibly exposed to Zika virus has been critical to understanding the effects of Zika virus infection during pregnancy on infants and children. **** https://www.researchsquare.com/article/rs-1189990/v1 The findings in this report are subject to at least five limitations. First, these data are based on information abstracted from medical records. Although CDC provided specific guidance for evaluation of all infants born from pregnancies with possible Zika virus exposure during pregnancy (7), these evaluations might not have been feasible, were not always conducted, or were not found in records (4). Zika-associated birth defects, especially individual brain and eye defects might not have been detected without occurrence and reporting of neuroimaging and ophthalmologic examinations. Second, these findings are only applicable to live births. Pregnancy losses are likely underreported to USZPIR, and among those reported, postnatal studies to verify prenatal findings or identify additional defects are often lacking. Third, although routine testing during pregnancy occurred in areas with local Zika virus transmission, a potential bias could have been introduced in areas without local transmission, as differential testing might have occurred in  S. territories and freely associated states, symptom onset date or date of earliest laboratory evidence of Zika virus infection were used to calculate trimester of exposure. † † Unknown trimester of exposure is not shown because of small cell sizes; 144 pregnancies were missing trimester of exposure. § § Zika virus infections that occurred during the periconceptual period, which is defined as 4 weeks before last menstrual period, are included in the first trimester of exposure. ¶ ¶ Maternal symptom status is not shown because of small cell sizes; 38 pregnancies were missing maternal symptom status. *** Signs and symptoms included fever, arthralgia, conjunctivitis, rash, and other clinical signs or symptoms that are consistent with Zika virus disease.

TABLE 1. Frequency of Zika-associated birth defects,* by selected characteristics among live-born infants from pregnancies with laboratory evidence of confirmed or possible Zika virus infection -U.S. Zika Pregnancy and Infant
women reporting possible Zika virus exposure related to travel or sex or when birth defects were detected in the fetus or infant. Fourth, USZPIR surveillance case definition includes infants with microcephaly based on head circumference measurement at birth alone, and only one third of these had sufficient information to be evaluated for possible measurement error. Thus, misclassification of infants with microcephaly based on birth head circumference alone might still exist. Finally, pregnancies in persons with possible Zika virus exposure, including those with evidence of unspecified flavivirus infection were included; therefore, some might not have had Zika virus infection during pregnancy. Analysis of the subgroup with NAAT-positive results indicated higher frequency of any Zika-associated birth defects, but the distribution of individual defects was generally consistent between the total cohort and this subgroup.  § Zika-associated birth defects include selected congenital brain anomalies (intracranial calcifications, cerebral or cortical atrophy, abnormal cortical gyral patterns, corpus callosum abnormalities, cerebellar abnormalities, porencephaly, hydranencephaly, or ventriculomegaly/hydrocephaly); selected congenital eye anomalies (microphthalmia or anophthalmia; coloboma; cataract; intraocular calcifications; chorioretinal anomalies involving the macula, excluding retinopathy of prematurity; and optic nerve atrophy, pallor, and other optic nerve abnormalities); and/or microcephaly at birth (birth head circumference below the third percentile for infant sex and gestational age based on INTERGROWTH-21st online percentile calculator unless infants meet criteria of possible measurement inaccuracy. http:// intergrowth21.ndog.ox.ac.uk/ ¶ Among infants with brain abnormalities, microcephaly, or both, 24 (0.4%) and 11 (0.5%) infants also had arthrogryposis among pregnancies with laboratory evidence of confirmed or possible Zika virus infection during pregnancy and NAAT-confirmed Zika virus infection, respectively. ** Infants with birth head circumference below the third percentile based on INTERGROWTH-21st. http://intergrowth21.ndog.ox.ac.uk/ † † Among infants with microcephaly, 141 and 64 also had a birthweight below the 10th percentile (SGA) among pregnancies with laboratory evidence of confirmed or possible Zika virus infection during pregnancy and NAAT-confirmed Zika virus infection, respectively. § § Neuroimaging was available for 66.0% and 29.2% of infants with microcephaly only from pregnancies with laboratory evidence of confirmed or possible Zika virus infection during pregnancy and NAAT-confirmed Zika virus infection, respectively.

Summary
What is already known about this topic?
Zika virus infection during pregnancy can cause serious brain and eye birth defects.
What is added by this report?
This study describes the frequency of individual Zikaassociated birth defects from the U.S. Zika Pregnancy and Infant Registry (USZPIR). Approximately 5% of infants in USZPIR had any Zika-associated brain or eye defect. Several individual brain and eye defects were more commonly reported. One third of infants with any Zika-associated birth defect had more than one defect reported.
What are the implications for public health practice? Certain brain and eye defects in infants might prompt suspicion of prenatal Zika virus infection and might provide a signal to the reemergence of Zika virus, particularly in geographic regions without ongoing comprehensive Zika virus surveillance.
Much has been learned since the first infant with Zikaassociated birth defects was identified in the United States. This report is the first to describe Zika-associated birth defects from USZPIR with data combined from the U.S. states, DC, and U.S. territories and freely associated states. The study provides a description of the frequency of individual Zika-associated birth defects reported among infants from pregnancies with laboratory evidence of confirmed or possible Zika virus infection. Additional study is needed to define the full spectrum of Zika-associated outcomes, including any specific defects or combination of defects that might predict the presence of Zika virus infection and Zika virus circulation. Further monitoring of these infants for neurodevelopmental abnormalities is ongoing. Infants exposed to Zika virus infection in utero, but without structural birth defects, might also have neurologic sequelae and developmental delay (4,8). Zika virus outbreaks are tracked globally; Zika virus infection remains a nationally reportable disease in the United States. † † † † These findings can help to target surveillance efforts to the most common brain and eye defects associated with Zika virus infection during pregnancy should a Zika virus outbreak reemerge, and might provide a signal to the reemergence of Zika virus, particularly in geographic regions without ongoing comprehensive Zika virus surveillance