The 2005–06 chikungunya virus (CHIKV) outbreak in La Réunion suggested that mothers could transmit CHIKV to their neonates while viremic during the intrapartum period, and more than half of the infected neonates showed impaired neurodevelopment at two years of age. However, data sparsity precluded an overview of the developmental impact of vertical infection within the whole prenatal period. The current study assessed two-year old children born to mothers who were infected during the 2014 CHIKV outbreak in Grenada to determine the neurodevelopmental impact of perinatal CHIKV infection throughout gestation. Mother and child infection status were confirmed by serologic testing (IgG and IgM) for CHIKV. Cognitive, fine motor, gross motor, language and behavioral outcomes were assessed at two years of age on the INTERGROWTH-21^st Neurodevelopment Assessment (INTER-NDA). No differences in neurodevelopmental outcomes were observed between two-year-old children born to mothers infected with CHIKV during gestation (n = 149) and those born to mothers not infected with CHIKV (n = 161). No differences were found in INTER-NDA scores between children infected with CHIKV (n = 47) and children not infected with CHIKV (n = 592). Likewise, there were no differences between children infected with CHIKV post-partum (n = 19) versus children not infected with CHIKV (n = 592). Our findings suggest that children exposed and/or infected with CHIKV outside of the intrapartum period experience no significant neurodevelopmental delay at two years of age, as measured by the INTER-NDA, compared to their unexposed and/or uninfected peers. These results complement those of previous studies which showed a neurodevelopmental risk only for children infected during the intrapartum period, while the mother was highly viremic. These results might be reassuring for women of childbearing age and public health officials in CHIKV-endemic regions. The Chikungunya virus (CHIKV) can negatively impact fetal neurodevelopment and consequent neurocognitive functioning in young children. Studies from La Réunion island demonstrated that, compared to their uninfected counterparts, children infected by CHIKV during the intrapartum period were at increased risk for deficiencies in the frontal lobes where the language and coordination centers are located, as well as slight deficits in other neurocognitive skills like sociability, movement and posture. The current study assessed two-year old children born to mothers infected during the 2014 CHIKV outbreak in Grenada to determine the neurodevelopmental impact of perinatal infection throughout gestation. No differences in neurodevelopmental outcomes were observed between two-year-old children born to mothers infected with CHIKV during gestation and those born to mothers not infected with CHIKV, nor between children infected with CHIKV and children not infected with CHIKV. Our results support previous findings that a small proportion of children born in CHIKV-endemic regions are at risk as only mothers viremic during the intrapartum period are at risk of infecting their neonates. Healthcare providers in CHIKV-endemic regions may wish to monitor for CHIKV symptoms when pregnant women are near term. The relatively high symptomatic rate seen with CHIKV infection (75%) makes such monitoring feasible.

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.

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 ZIKVin 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).

Maternal infection with Zika virus (ZIKV) is associated with a distinct pattern of birth defects, known as congenital Zika syndrome (CZS). In ZIKV-exposed children without CZS, it is often unclear whether they were protected from in utero infection and neurotropism. Early neurodevelopmental assessment is essential for detecting neurodevelopmental delays (NDDs) and prioritizing at-risk children for early intervention. We compared neurodevelopmental outcomes between ZIKV-exposed and unexposed children at 1, 3 and 4 years to assess exposure-associated NDD risk. A total of 384 mother–child dyads were enrolled during a period of active ZIKV transmission (2016–2017) in Grenada, West Indies. Exposure status was based on laboratory assessment of prenatal and postnatal maternal serum. Neurodevelopment was assessed using the Oxford Neurodevelopment Assessment, the NEPSY^® Second Edition and Cardiff Vision Tests, at 12 (n = 66), 36 (n = 58) and 48 (n = 59) months, respectively. There were no differences in NDD rates or vision scores between ZIKV-exposed and unexposed children. Rates of microcephaly at birth (0.88% vs. 0.83%, p = 0.81), and childhood stunting and wasting did not differ between groups. Our results show that Grenadian ZIKV-exposed children, the majority of whom were without microcephaly, had similar neurodevelopmental outcomes to unexposed controls up to at least an age of 4 years.

• Congenital Zika Syndrome with microcephaly can present with focal seizures. • TeleEEG can augment epilepsy care in Zika-endemic resource limited settings. • A seizure questionnaire can prompt caregiver report of relevant seizure features.

Background: Adaptation of standardized early child development (ECD) assessments to low- and middle-income countries can be challenging because of culture-specific factors relating to language, content, context, and tool administration, and because the reliance of these tests on specialist healthcare professionals limits their scalability in low resource settings. Methods: We report the cross-cultural adaptation of an international, standardized ECD instrument, the INTERGROWTH-21st Project Neurodevelopment Assessment (INTER-NDA), measuring cognitive, language, motor and behavioural outcomes in 2-year-olds, from a UK-based English-speaking population to the English-speaking Caribbean. Children aged 22-30 months were recruited from a pre-existing randomized controlled neurodevelopment intervention study in Grenada, West Indies. Results: Eight of 37 INTER-NDA items (22%) were culturally and linguistically adapted for implementation in the Caribbean context. Protocol adherence across seven newly-trained non-specialist child development assessors was 89.9%; six of the seven assessors scored ≥80%. Agreement between the expert assessor and the non-specialist child development assessors was substantial (κ = 0.89 to 1.00 (95% CI [0.58, 1.00]). The inter-rater and test-retest reliability for non-specialist child development assessors was between κ = 0.99 -1.00 (95% CI [0.98, 0.99]) and κ = 0.76 - 1.00 (95% CI [0.33, 1.00]) across all INTER-NDA domains. Conclusions: The current study provides evidence to support the use of the adapted INTER-NDA by trained, non-specialist assessors to measure ECD prevalence in the English-speaking Caribbean. It also provides a methodological template for the adaptation of child developmental measures to cultural and linguistic contexts that conform to the cultural standards of the countries in which they are utilized to aid in the measurement of neurodevelopmental impairments (NDIs) in a variety of global clinical settings.