Association Between Antenatal Exposure to Zika Virus and Anatomical and Neurodevelopmental Abnormalities in Children

Abstract

Importance: Zika virus (ZIKV) is a mosquito-borne flavivirus recognized as teratogenic since the 2015 to 2016 epidemic. Antenatal ZIKV exposure causes brain anomalies, yet the full spectrum has not been delineated.

Objective: To characterize the clinical features of ZIKV infection at a pediatric referral center in Rio de Janeiro, Brazil, among children with antenatal ZIKV exposure.

Design, setting, and participants: Retrospective cohort study conducted from May to July 2019 of a prospective cohort of 296 infants with antenatal ZIKV exposure followed up since December 2015 at a tertiary maternity-pediatric hospital.

Exposures: Zika virus infection during pregnancy.

Main outcomes and measures: Characterization of clinical features with anthropometric, neurologic, cardiologic, ophthalmologic, audiometric, and neuroimaging evaluations in infancy and neurodevelopmental assessments (Bayley Scales of Infant and Toddler Development, Third Edition) from 6 to 42 months of age, stratified by head circumference at birth (head circumference within the reference range, or normocephaly [NC] vs microcephaly [MC]).

Results: Antenatal exposure to ZIKV was confirmed for 219 of 296 children (74.0%) referred to Instituto Fernandes Figueira with suspected ZIKV infection through positive maternal or neonatal polymerase chain reaction analysis or IgM serology results. Of these children, 110 (50.2%) were boys, ages ranged from 0 to 4 years, and 53 (24.2%) had congenital microcephaly. The anomalies observed in ZIKV-exposed children with MC or NC were failure to thrive (MC: 38 of 53 [71.7%]; NC: 73 of 143 [51.0%]), cardiac malformations (MC: 19 of 46 [41.3%]; NC: 20 of 100 [20.0%]), excess nuchal skin (MC: 16 of 22 [72.7%]; NC: 35 of 93 [37.6%]), auditory abnormalities (MC: 13 of 50 [26.0%]; NC: 14 of 141 [9.9%]), and eye abnormalities (MC: 42 of 53 [79.2%]; NC: 28 of 158 [17.7%]). Although they experienced fewer neurologic abnormalities than children born with MC, those with NC also had frequent neurologic abnormalities (109 of 160 [68.1%]), including hyperreflexia (36 of 136 [26.5%]), abnormal tone (53 of 137 [38.7%]), congenital neuromotor signs (39 of 93 [41.9%]), feeding difficulties (15 of 143 [10.5%]), and abnormal brain imaging results (44 of 150 [29.3%]). Among 112 children with NC with Bayley-III evaluations, 72 (64.3%) had average or above-average scores; 30 (26.8%) scored 1 SD below average in at least 1 domain; and 10 (8.9%) scored 2 SD below average in at least 1 domain. Among 112 children with NC, a smaller head circumference at birth was significantly associated with subsequent below-average cognitive scores (U = 499.5; z = -2.833; P = .004) and language scores (U = 235.5; z = -2.491; P = .01).

Conclusions and relevance: Children without MC who were exposed to ZIKV in utero had a high frequency of anatomical and neurodevelopmental abnormalities. The head circumference at birth for children with NC was associated with neurocognitive development. Recognition of the wide spectrum of clinical phenotypes is critical to ensure early referral to rehabilitative interventions.

Figure 1.. Flowchart of Included Participants

PCR indicates polymerase chain reaction. ^aTwo infants died within 24 hours of birth, and 2 infants were lost to follow-up at birth; head circumference was not recorded for any of these 4 infants. Prebirth data of these infants were included in our study. Postbirth outcomes were not used owing to limited data.

Figure 2.. Frequency of Abnormal Findings in Zika Virus–Exposed Children Categorized by Head Circumference at Birth

Bars depict the total number of children evaluated in each category stratified by head circumference. CBC represents complete blood count.

Figure 3.. Individual Scores on the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III), According to Head Circumference z Score at Birth of Children With Normocephaly

Scores below 85 (blue dashed line) indicate risk of developmental delay; scores below 70 (orange dashed line) indicate risk of severe developmental delay. Each dot represents the most recent Bayley-III score of 1 of 112 children with normocephaly. Each solid line represents the line of best fit (correlation coefficient R²). Among children with normocephaly, a smaller head circumference (z score) at birth was significantly associated with “below-average” Bayley-III cognitive scores (U = 499.5; z = −2.833; P = .004) and language scores (U = 235.5; z = −2.491; P = .01).