Tuesday, January 14, 2020

Neurodevelopmental abnormalities in children with in utero Zika virus exposure without congenital Zika syndrome

Mulkey SB, Arroyave-Wessel M, Peyton C, Bulas DI, Fourzali Y, Jiang J, Russo S, McCarter R, Msall ME, du Plessis AJ, DeBiasi RL, Cure C. Neurodevelopmental Abnormalities in Children With In Utero Zika Virus Exposure Without Congenital Zika Syndrome. JAMA Pediatr. 2020 Jan 6. doi: 10.1001/jamapediatrics.2019.5204.[Epub ahead of print]


The number of children who were born to mothers with Zika virus (ZIKV) infection during pregnancy but who did not have apparent disability at birth is large, warranting the study of the risk for neurodevelopmental impairment in this population without congenital Zika syndrome (CZS).

To investigate whether infants without CZS but who were exposed to ZIKV in utero have normal neurodevelopmental outcomes until 18 months of age.

This cohort study prospectively enrolled a group of pregnant women with ZIKV in Atlántico Department, Colombia, and in Washington, DC. With this cohort, we performed a longitudinal study of infant neurodevelopment. Infants born between August 1, 2016, and November 30, 2017, were included if they were live born, had normal fetal brain findings on magnetic resonance imaging and ultrasonography, were normocephalic at birth, and had normal examination results without clinical evidence of CZS. Seventy-seven infants born in Colombia, but 0 infants born in the United States, met the inclusion criteria.

Prenatal ZIKV exposure.

Infant development was assessed by the Warner Initial Developmental Evaluation of Adaptive and Functional Skills (WIDEA) and the Alberta Infant Motor Scale (AIMS) at 1 or 2 time points between 4 and 18 months of age. The WIDEA and AIMS scores were converted to z scores compared with normative samples. Longitudinal mixed-effects regression models based on bootstrap resampling methods estimated scores over time, accounting for gestational age at maternal ZIKV infection and infant age at assessment. Results were presented as slope coefficients with 2-tailed P values based on z statistics that tested whether the coefficient differed from 0 (no change).

Of the 77 Colombian infants included in this cohort study, 70 (91%) had no CZS and underwent neurodevelopmental assessments. Forty infants (57%) were evaluated between 4 and 8 months of age at a median (interquartile range [IQR]) age of 5.9 (5.3-6.5) months, and 60 (86%) underwent assessment between 9 and 18 months of age at a median (IQR) age of 13.0 (11.2-16.4) months. The WIDEA total score (coefficients: age = -0.227 vs age2 = 0.006; P < .003) and self-care domain score (coefficients: age = -0.238 vs age2 = 0.01; P < .008) showed curvilinear associations with age. Other domain scores showed linear declines with increasing age based on coefficients for communication (-0.036; P = .001), social cognition (-0.10; P < .001), and mobility (-0.14; P < .001). The AIMS scores were similar to the normative sample over time (95% CI, -0.107 to 0.037; P = .34). Nineteen of 57 infants (33%) who underwent postnatal cranial ultrasonography had a nonspecific, mild finding. No difference was found in the decline of WIDEA z scores between infants with and those without cranial ultrasonography findings except for a complex interactive relationship involving the social cognition domain (P < .049). The AIMS z scores were lower in infants with nonspecific cranial ultrasonography findings (-0.49; P = .07).

This study found that infants with in utero ZIKV exposure without CZS appeared at risk for abnormal neurodevelopmental outcomes in the first 18 months of life. Long-term neurodevelopmental surveillance of all newborns with ZIKV exposure is recommended.

Honein MA, Woodworth KR, Gregory CJ. Neurodevelopmental Abnormalities Associated With In Utero Zika Virus Infection in Infants and Children-The Unfolding Story. JAMA Pediatr. 2020 Jan 6. doi: 10.1001/jamapediatrics.2019.5257. [Epub ahead of print]

Infants exposed to Zika virus before birth but without congenital Zika syndrome (CZS) are at risk for neurodevelopmental delays as they get older, a new study shows.

"This study supports the recommendations by the Centers for Disease Control and Prevention to perform long-term follow-up of all infants exposed to ZIKV in utero, not just those with manifestations of CZS at birth," Dr. Sarah Mulkey of Children's National Hospital, in Washington, D.C., and colleagues say.

"Neurodevelopmental delays may be mild and subclinical and can influence multiple areas of development. Without standardized assessment, developmental abnormalities may not be detected, and opportunities to optimize early developmental intervention may be missed," they note in JAMA Pediatrics.

The researchers report neurodevelopmental outcomes out to age 18 months in a cohort of 70 Columbian infants with laboratory-confirmed in utero exposure to ZIKV, normal fetal MRI and ultrasonography findings, and no evidence of CZS or microcephaly at birth.
"Thus, these infants were expected to have low risk for subsequent neurodevelopmental deficits, yet these deficits emerged in the first year of life and without a reduction in head circumference," Dr. Mulkey and colleagues report.

Although many of the infants had normal initial neurodevelopmental scores (beginning at age 4 months), overall scores declined in some children as they aged, with the most decreases seen in the domains of mobility and social cognition, which could indicate impaired neurocognitive development, they observed.

Nonspecific findings on postnatal neuroimaging comprising lenticulostriate vasculopathy, germinolytic or subependymal cysts, and choroid-plexus cysts, were associated with lower scores on the social cognition domain and "may be potential risk factors for worse early neurodevelopmental outcomes," they note, adding, "To our knowledge, this study is the first to show that these nonspecific imaging findings may indicate subtle brain injury potentially associated with impaired neuromotor development."

In email to Reuters Health, Dr. Mulkey said, "Healthcare providers should continue to ask patients about Zika exposure and discuss risk for neurodevelopmental abnormalities in all exposed infants and children. Every child with in utero Zika virus exposure should continue to have neurodevelopmental assessments to school age, even if the child looks normal and is doing well. We continue to learn about the long-term consequences of in utero Zika virus exposure in children."
The authors of a linked editorial say the findings in this cohort "add to the growing evidence of the need for long-term follow-up for all children with Zika virus exposure in utero to ensure they receive the recommended clinical evaluations even when no structural defects are identified at birth."

"Although the clinical significance of these nonspecific findings is not yet clear, the importance of postnatal neuroimaging for all children with Zika virus exposure in utero was made extremely clear," write Dr. Margaret Honein and co-authors from the Centers for Disease Control and Prevention in Atlanta.

"Evaluation of infants solely at the time of birth is clearly inadequate, as growing evidence exists of infants with clinically normal assessments who subsequently developed neurodevelopmental issues and infants with documented microcephaly at birth whose microcephaly was resolved and whose neurodevelopmental assessment results were normal on follow-up," they add.

The study had no commercial funding.


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