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ObjectiveZika virus (ZIKV) targets neural stem cells in the developing brain. However, the majority of ZIKV-exposed children are born without apparent neurological manifestations. It remains unclear if these children were protected from ZIKV neurotropism or if they harbour subtle pathology that is disruptive to brain development. We assess this by comparing neurodevelopmental outcomes in normocephalic ZIKV-exposed children relative to a parallel control group of unexposed controls.DesignCohort study.SettingPublic health centres in Grenada, West Indies.Patients384 mother–child pairs were enrolled during a period of active ZIKV transmission (April 2016–March 2017) and prospectively followed up to 30 months. Child exposure status was based on laboratory assessment of prenatal and postnatal maternal serum.Main outcome measuresThe INTERGROWTH-21st Neurodevelopment Assessment (INTER-NDA) package and Cardiff Vision Tests, administered and scored by research staff masked to child’s exposure status.ResultsA total of 131 normocephalic ZIKV exposed (n=68) and unexposed (n=63) children were assessed between 22 and 30 months of age. Approximately half of these children completed vision testing. There were no group differences in sociodemographics. Deficits in visual acuity (31%) and contrast sensitivity (23%) were apparent in the ZIKV-exposed infants in the absence of cognitive, motor, language or behavioural delays.ConclusionsOverall neurodevelopment is likely to be unaffected in ZIKV-exposed children with normal head circumference at birth and normal head growth in the first 2 years of life. However, the visual system may be selectively vulnerable, which indicates the need for vision testing by 3 years of age.

Children with Congenital Zika Syndrome and microcephaly are at high risk for epilepsy; however, the risk is unclear in normocephalic children with prenatal Zika virus (ZIKV) exposure [Exposed Children (EC)]. In this prospective cohort study, we performed epilepsy screening in normocephalic EC alongside a parallel group of normocephalic unexposed children [Unexposed Children (UC)]. We compared the incidence rate of epilepsy among EC and UC at one year of life to global incidence rates. Pregnant women were recruited from public health centers during the ZIKV outbreak in Grenada, West Indies and assessed for prior ZIKV infection using a plasmonic-gold platform that measures IgG antibodies in serum. Normocephalic children born to mothers with positive ZIKV results during pregnancy were classified as EC and those born to mothers with negative ZIKV results during and after pregnancy were classified as UC. Epilepsy screening procedures included a pediatric epilepsy screening questionnaire and video electroencephalography (vEEG). vEEG was collected using a multi-channel microEEG® system for a minimum of 20 minutes along with video recording of participant behavior time-locked to the EEG. vEEGs were interpreted independently by two pediatric epileptologists, who were blinded to ZIKV status, via telemedicine platform. Positive screening cases were referred to a local pediatrician for an epilepsy diagnostic evaluation. Epilepsy screens were positive in 2/71 EC (IR: 0.028; 95% CI: 0.003–0.098) and 0/71 UC. In both epilepsy-positive cases, questionnaire responses and interictal vEEGs were consistent with focal, rather than generalized, seizures. Both children met criteria for a clinical diagnosis of epilepsy and good seizure control was achieved with carbamazepine. Our results indicate that epilepsy rates are modestly elevated in EC. Given our small sample size, results should be considered preliminary. They support the use of epilepsy screening procedures in larger epidemiological studies of children with congenital ZIKV exposure, even in the absence of microcephaly, and provide guidance for conducting epilepsy surveillance in resource limited settings., Author summary Epilepsy is a clinical concern in children with Congenital Zika Syndrome and microcephaly; however, it is unknown whether epilepsy rates are elevated in normocephalic children with prenatal Zika virus exposure. We found a modest elevation of epilepsy rates in the first year of life of exposed, relative to unexposed, children, despite no other neurological manifestations. Seizures in exposed children had features of focal, rather than generalized, epilepsy and were well controlled with carbamazepine. Our findings suggest that epilepsy surveillance should be included in the neurodevelopmental assessment of children with prenatal Zika virus exposure, even in the absence of neurologic manifestations at birth.

Background While microcephaly is a significant adverse outcome of prenatal exposure to the Zika virus (ZIKV), subtle malformations of cortical development (MCD) have been observed in Zika-exposed children (ZEC), including delays in language, cognition, and motor domains, and visual acuity deficits. Interventions within the first 1,000 days of life can significantly improve developmental outcomes. This study examined a 12-week Responsive Caregiving Intervention on neurodevelopmental outcomes in 24-30-month-old ZEC. Methodology/Principal findings A randomized controlled trial was implemented in Grenada, West Indies using an existing ZIKV cohort surveillance study. When children in that study turned 24 months, baseline child neurodevelopmental measures and caregiver interviews were administered. Caregivers who agreed to participate in the 12-week Responsive Caregiving Intervention, implemented when children were 24–30 months of age, were randomly assigned to the Intervention or Waitlist Control group. Children in both groups were re-assessed on the neurodevelopmental measures post-intervention. Conclusions/Significance 233 children from the ZIKV surveillance study met inclusion criteria, of which n = 80 declined participation, n = 42 did not complete the Intervention, and n = 72 missed follow-up assessments given strict timelines in the study design. The final sample for analysis was N = 13 children in the Intervention group and N = 26 children in the Control group. A GEE model analysis showed significantly higher language (p = 0.021) and positive behaviour (p = 0.005) scores for children in the Intervention group compared to the Control group. The Intervention had a medium effect on child language (d = 0.66) and a large effect on positive behaviour (d = 0.83). A 12-week Responsive Caregiving Intervention Programme significantly improves language and positive behaviour scores in 30-month-old normocephalic children who were exposed to ZIKV in utero. The programme provides an option for mothers of ZIKV-exposed children who are seeking an evidence-based neurodevelopmental intervention regardless of known impact of the virus on cortical formation. Trial registration The study was registered with clinicaltrials.gov (NCT04697147).

Background: The Zika virus (ZIKV) targets neural stem cells in the developing brain. It remains unclear whether ZIKV-Exposed Children (ZEC) with no apparent neurological manifestations at birth were protected from ZIKV neurotropism during gestation or harbor subtle pathology that might disrupt neurodevelopment. In this prospective study, we tracked a cohort of normocephalic ZIKV-exposed children (NZEC) in parallel with normocephalic unexposed controls (UC) from birth to 30 months of age to determine whether NZEC show higher rates of neurodevelopmental delays relative to UC. Methods: A total of 384 pregnant women were recruited from public health centers in Grenada, West Indies and enrolled between April 2016 and March 2017, which was a period of active ZIKV transmission. Serum samples were collected from mothers during the prenatal and postnatal period and assessed for ZIKV antibodies using a plasmonic-gold platform. Infants were classified as NZEC if their mothers tested positive for ZIKV infection during pregnancy and they were normocephalic, as defined by World Health Organization Child Growth Standards. Children were classified as UC if their mothers tested negative for ZIKV infection during and following pregnancy. Outcome measures included the INTERGROWTH-21st Neurodevelopment Assessment (INTER-NDA) package and Cardiff Vision Tests, which were administered and scored by research staff blinded to participants’ exposure status. Findings: A total of 68 NZEC and 63 UC completed outcome measures between 22 to 30 months of age. There were no group differences in socio-demographics. Visual acuity deficits were apparent in NZEC in the absence of any other cognitive, motor, language, or behavioral delays. Interpretation: The presence of visual acuity deficits in NZEC suggests that the visual system may be selectively vulnerable in otherwise normally developing children. Continued neurocognitive surveillance of this cohort will address whether early vision problems place NZEC at risk for future deficits in visuo-spatial functions and learning disorders. Funding Statement: TWINDREF GSP-SRGI-18009 (KB); USAID AID-OAA-A-14-00028 (ADL), NIH R21HD093551-01 (RW, BL, MF), Stanford Maternal Child Health Research Institute (ADL). MF is supported by an Academic Clinical Fellowship in Paediatrics from the National Institute for Health Research, UK, to the University of Southampton. Declaration of Interests: None of the authors have any conflicts of interest to disclose. Ethics Approval Statement: Institutional Review Board approval was obtained at St George’s University (IRB#16061) and Stanford University (IRB#45242). Informed consent was obtained from all mothers who participated in this study. There was no financial compensation.