Infectious disease

Lessons about early neurodevelopment in children exposed to ZIKV in utero

Infants with congenital Zika virus infection are at risk for multiple abnormalities related to impairment in neurodevelopment. Although some findings apparent at birth may resolve with time, infants with no abnormalities apparent at birth may develop problems in early childhood.

Just over 3 years ago, Zika virus (ZIKV) emerged as a newly recognized congenital infection that could damage the developing brain1. With increasing understanding of the spectrum of neonatal abnormalities following in utero ZIKV infection, guidelines have been developed for the diagnosis, evaluation and care of infants with congenital Zika syndrome (CZS)2 or with possible prenatal ZIKV exposure3. The clinically evident pattern of findings associated with CZS includes microcephaly, seizures, eye abnormalities and hearing loss2, with more subtle effects also described shortly after birth in some infants with ZIKV exposure during pregnancy4. In this issue, Nielsen-Saines et al. report effects of congenital ZIKV exposure extending into early childhood5. They followed a cohort of ZIKV-exposed children born to mothers with symptomatic PCR-positive ZIKV infection during pregnancy since the 2015–2016 outbreak in Rio de Janeiro, Brazil6, with neurodevelopmental follow-up now available at 7–32 months of age for 216 of 233 (97%) live-born infants5. They found that although many children had normal assessments, 29% scored below average in at least one domain of neurologic development5.

Prior studies of ZIKV-exposed infants have demonstrated a higher risk of congenital anomalies when infection occurs early in gestation4,7,8. In addition to an increased risk of known ZIKV-related birth defects, the current study identified a progressively higher risk for developmental, eye and hearing abnormalities in early childhood that was associated with the trimester in which exposure to ZIKV occurred, with exposure in the first 3 months of pregnancy conferring the highest risk5. The authors evaluated child neurodevelopment by standard tests (Bayley-III) and/or by interviewing the parents in combination with a neurological assessment5. ZIKV has a tropism for immature neurons9, potentially explaining the ongoing susceptibility of young children to nervous system impairment after in utero exposure. Thus, even in the absence of microcephaly, earlier gestational age at exposure remains a consistent risk factor for neurodevelopmental, eye and hearing abnormalities (Fig. 1).

Fig. 1: Children with in utero Zika exposure may experience neurodevelopmental, eye, and hearing abnormalities that can revert.
figure1

Nielsen-Saines et al. followed a cohort of 216 infants exposed to ZIKV in the 2015–2016 outbreak in Rio de Janeiro, Brazil. They found that some children present with neurodevelopmental symptoms at birth, as indicated in red. The symptoms in these infants can resolve over time, and conversely, initially healthy infants (shown in blue) can develop neurodevelopmental symptoms years later. Ongoing, comprehensive neurodevelopmental surveillance is thus needed for all children with exposure to Zika virus in utero.

A novel observation in the current study is that the neurologic phenotype in some ZIKV-exposed children may change from abnormal to normal from birth into early childhood, and vice versa. In this cohort, 49 infants had abnormalities detected in the first month of life6. Intriguingly, 24 of these children (49%) had normal testing in the second or third years of life, suggesting that some abnormalities at birth potentially attributable to ZIKV may resolve over time5. This positive finding can provide hope of a good outcome for some babies with early milder concerns, though it is not known whether these children with abnormal findings at birth had any specific interventions to account for subsequent normal neurodevelopmental scores. Conversely, of the 68 infants that had normal birth assessments, 17 (25%) were either below average in developmental testing or had abnormalities in hearing or vision by 7 months of age or older5. This finding stresses the importance of ongoing follow-up of exposed infants and children, even when their initial evaluations may not suggest neurologic abnormalities.

How should the current study influence ongoing clinical management of infants born after pregnancies affected by ZIKV? Because a normal assessment at birth after congenital ZIKV exposure does not guarantee ongoing normal neurodevelopment or absence of sensory dysfunction, exposed infants should have regular developmental, ophthalmologic and auditory evaluations, even if initial evaluations are normal. Early detection of problems can accelerate referral of children to early intervention services for developmental delays, or promote earlier vision correction or hearing aids, as indicated. Unfortunately, many infants with prenatal ZIKV exposure do not receive all of the recommended early assessments and are not followed longitudinally10. Normal-appearing ZIKV-exposed children may unfortunately go unnoticed, yet may have lower neurodevelopmental scores. Likewise, during the ZIKV epidemic many more children may have been exposed than were recognized, particularly in cases of asymptomatic maternal infection5. With these children now approaching school age, understanding the full spectrum of neurodevelopmental abnormalities has important public health and educational system implications. Unfortunately, mothers may perceive stigmatization regarding ZIKV infection in their child, and this may affect compliance with recommended assessments. As it remains unknown whether infants initially assessed as normal might develop abnormalities into the fourth year of life or beyond, continued close follow-up is needed.

Because all children in the present cohort were born to mothers with symptomatic ZIKV infection, it is important to consider how these results might apply to children born to mothers with asymptomatic ZIKV infection during pregnancy. About 80% of ZIKV infections are thought to be asymptomatic in the general population11, though it is not well known how commonly asymptomatic infection occurs in pregnancy. However, maternal disease severity in symptomatic ZIKV infection during pregnancy was previously found in this cohort to not predict the likelihood of abnormal infant findings at birth12, and other studies have identified similar percentages of anomalies in infants exposed to symptomatic or asymptomatic maternal ZIKV infection4. One limitation of the current study is that the cohort was identified through the acute febrile illness clinic, where eligibility for the study included the presence of a rash at any time within the prior 5 days in a pregnant woman. As a result, observations in this cohort may not apply in infants exposed to ZIKV in utero when mothers have asymptomatic infection. Nevertheless, recommendations for longitudinal infant and child follow-up would be appropriate in the setting of asymptomatic maternal infection until a better understanding of congenital disease is reached.

We continue to learn about the longer-term implications of congenital ZIKV infection on the developing brain. Although many children exposed to ZIKV in utero have normal neurodevelopment in early childhood, including some with abnormal findings at birth, it is clear in the present study that a sizeable number do not. Somewhat unexpectedly, those with normal findings at birth may still develop abnormalities. Medical providers and public health and educational systems need to enhance ongoing surveillance and recognition of ZIKV-exposed children who may have gone undiagnosed. Efforts to prevent adverse outcomes from what is generally an otherwise apparently self-limited infection can inform public health prevention strategies for future ZIKV outbreaks and potentially shed light on ways to intervene for other neurotropic infections, particularly those that affect the developing brain. These studies in the Rio de Janiero cohort have greatly informed our understanding of the effects of in utero ZIKV exposure both in the immediate newborn period6 and in early childhood5 and provide a basis for recommending continued close clinical follow-up for these children.

References

  1. 1.

    Franca, G. V. et al. Lancet 388, 891–897 (2016).

    Article  Google Scholar 

  2. 2.

    Moore, C. A. et al. JAMA Pediatr 171, 288–295 (2017).

    Article  Google Scholar 

  3. 3.

    Adebanjo, T. et al. MMWR Morb. Mortal. Wkly Rep. 66, 1089–1099 (2017).

    Article  Google Scholar 

  4. 4.

    Honein, M. A. et al. JAMA 317, 59–68 (2017).

    Article  Google Scholar 

  5. 5.

    Nielsen-Saines, K. et al. Nat. Med. https://doi.org/10.1038/s41591-019-0496-1 (2019).

    CAS  Article  Google Scholar 

  6. 6.

    Brasil, P. et al. N. Engl. J. Med. 375, 2321–2334 (2016).

    Article  Google Scholar 

  7. 7.

    Shapiro-Mendoza, C. K. et al. MMWR Morb. Mortal. Wkly Rep. 66, 615–621 (2017).

    Article  Google Scholar 

  8. 8.

    Hoen, B. et al. N. Engl. J. Med. 378, 985–994 (2018).

    Article  Google Scholar 

  9. 9.

    Ho, C. Y. et al. Ann. Neurol. 82, 121–127 (2017).

    CAS  Article  Google Scholar 

  10. 10.

    Rice, M. E. et al. MMWR Morb. Mortal. Wkly Rep. 67, 858–867 (2018).

    Article  Google Scholar 

  11. 11.

    Duffy, M. R. et al. N. Engl. J. Med. 360, 2536–2543 (2009).

    CAS  Article  Google Scholar 

  12. 12.

    Halai, U. A. et al. Clin. Infect. Dis. 65, 877–883 (2017).

    Article  Google Scholar 

Download references

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Correspondence to William J. Muller.

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Muller, W.J., Mulkey, S.B. Lessons about early neurodevelopment in children exposed to ZIKV in utero. Nat Med 25, 1192–1193 (2019). https://doi.org/10.1038/s41591-019-0540-1

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  • Neurological Findings in Children without Congenital Microcephaly Exposed to Zika Virus in Utero: A Case Series Study

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