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    Original Investigation
    Infectious Diseases
    July 7, 2020

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

    Author Affiliations
    • 1Division of Infectious Diseases, Department of Pediatrics, David Geffen School of Medicine at University of California, Los Angeles
    • 2Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
    JAMA Netw Open. 2020;3(7):e209303. doi:10.1001/jamanetworkopen.2020.9303
    Key Points español 中文 (chinese)

    Question  What is the spectrum of clinical findings associated with antenatal Zika virus exposure, and does an association exist between head circumference at birth and neurodevelopmental outcomes among Zika virus–exposed children with normocephaly?

    Findings  This cohort study of 219 children found that antenatal Zika virus exposure was associated with a wide spectrum of clinical manifestations in normocephalic children beyond those previously described. The head circumference of normocephalic children was associated with neurodevelopmental outcomes.

    Meaning  Recognition of the variety of clinical phenotypes following antenatal Zika virus exposure, including evaluation of head circumference as a continuous variable, may help ensure early intervention, appropriate cross-disciplinary evaluation, and comprehensive therapeutic care.


    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.