Sleep in children from northeastern Brazil with congenital Zika syndrome: assessment using polysomnography.

STUDY OBJECTIVES: We performed this study to describe the characteristics of sleep in children with congenital Zika syndrome through polysomnographic assessment. METHODS: Polysomnography with neurological setup and capnography was performed. Respiratory events were scored according to American Academy of Sleep Medicine criteria. Children were classified based on neuroclinical examination as having corticospinal plus neuromuscular abnormalities or exclusively corticospinal abnormalities. Neuroradiological classification was based on imaging exams, with children classed as having supratentorial plus infratentorial abnormalities or exclusively supratentorial abnormalities. RESULTS: Of 65 children diagnosed with congenital Zika syndrome, sleep apnea was present in 23 children (35.4%), desaturation in 26 (40%), and snoring in 13 (20%). The most prevalent apnea type was central in 15 children (65.2%), followed by obstructive apnea in 5 (21.7%) and mixed type in 3 (13%). The average of the lowest saturation recorded was slightly below normal (89.1 ± 4.9%) and the mean partial pressure of end-tidal carbon dioxide value was normal. Periodic leg movements were present in 48 of 65 children. Lower ferritin levels were observed in 84.6% of children. Palatine and pharyngeal tonsils (adenoids) were small in most children and not associated with the presence of obstructive apnea. Ventriculomegaly and subcortical and nucleus calcification were the most frequent neuroimaging findings. Supratentorial and infratentorial anomalies were present in 26.7% (16 of 60) and exclusively supratentorial changes in 73.3% (44 of 60). In the neuroclinical classification, isolated corticospinal changes were more frequent and the mean peak in capnography was lower in this group. There was no difference regarding the presence of apnea for children in the neuroclinical and neuroradiological classification groups. CONCLUSIONS: Sleep disorders were frequent in children with congenital Zika syndrome, with central sleep apnea being the main finding. CITATION: Brandão Marquis V, de Oliveira Melo A, Pradella-Hallinan M, et al. Sleep in children from northeastern Brazil with congenital Zika syndrome: assessment using polysomnography. J Clin Sleep Med. 2023;19(10):1759-1767.

Out-of-pocket expenditures associated with congenital zika syndrome in Brazil: an analysis of household health spending / Gastos out-of-pocket associados à síndrome congênita do vírus Zika no Brasil: uma análise dos gastos domiciliares em saúde

Objective: The study aims to estimate catastrophic health expenditures associated with the diagnosis and follow-up treatment of Congenital Zika Syndrome (CZS) in children affected during the 2015-2016 epidemic in Brazil. Catastrophic health expenditures are defined as health spending that exceeds a predefined proportion of the household's total expenditures, exposing family members to financial vulnerability. Methods: Ninety-six interviews were held in the cities of Fortaleza and Rio de Janeiro in a convenience sample, using a questionnaire on sociodemographic characteristics and private household expenditures associated with the syndrome, which also allowed estimating catastrophic expenditures resulting from care for CZS. Results: Most of the mothers interviewed in the study were brown, under 34 years of age, unemployed, and reported a monthly family income of two minimum wages or less. Spending on medicines accounted for 77.6% of the medical expenditures, while transportation and food were the main components of nonmedical expenditures, accounting for 79% of this total. The affected households were largely low-income and suffered catastrophic expenditures due to the disease. Considering the family income metric, in 41.7% of the households, expenses with the child's disease exceeded 10% of the household income. Conclusion: Public policies should consider the financial and healthcare needs of these families to ensure adequate support for individuals affected by CZS.

Objetivo: O estudo tem como objetivo estimar os gastos catastróficos em saúde associados ao diagnóstico e acompanhamento do tratamento da síndrome congênita do Zika (SCZ) em crianças afetadas durante a epidemia de 2015-2016 no Brasil. Gastos catastróficos em saúde são definidos como gastos com saúde que excedem uma proporção predefinida dos gastos totais do domicílio, expondo os membros da família à vulnerabilidade financeira. Métodos: Foram realizadas 96 entrevistas nas cidades de Fortaleza e Rio de Janeiro numa amostra de conveniência, por meio de questionário sobre características sociodemográficas e gastos privados domiciliares associados à síndrome, o que também permitiu estimar gastos catastróficos decorrentes do cuidado à SCZ. Resultados: A maioria das mães entrevistadas no estudo era parda, com menos de 34 anos, desempregada e com renda familiar mensal igual ou inferior a dois salários mínimos. Os gastos com medicamentos representaram 77,6% dos gastos médicos, enquanto transporte e alimentação foram os principais componentes dos gastos não médicos, respondendo por 79% desse total. Os domicílios afetados eram, em grande parte, de baixa renda e sofreram gastos catastróficos devido à doença. Considerando a métrica de renda familiar, em 41,7% dos domicílios, os gastos com a doença da criança ultrapassaram 10% da renda familiar. Conclusão: As políticas públicas devem considerar as necessidades financeiras e de saúde dessas famílias para garantir o suporte adequado aos indivíduos acometidos pela SCZ.

Assessment of the feasibility of Juntos: A support programme for families of children affected by Congenital Zika Syndrome.

Background: The 2015-16 Zika epidemic resulted in thousands of children born with congenital Zika syndrome (CZS). In Brazil, gaps in the health system often caused parents to be left with insufficient information and support. Consequently, we developed and piloted Juntos - a participatory support programme which aims to improve knowledge, capacities and build support networks for caregivers of children with CZS.   Methods: Six caregiver groups received the programme between August 2017 and June 2018: three in Rio de Janeiro and three in Bahia. We assessed the feasibility of Juntos against six of the eight areas of a feasibility framework described by Bowen et al. to consider whether Juntos 'could work'. These areas were: acceptability, demand, implementation, practicality, adaptation and limited efficacy. We used mixed methods including: 1) baseline and end-line questionnaires completed by all group participants; 2) in-depth interviews with 18 participants, seven facilitators and three key stakeholders; 3) participant focus group discussions after each session; 4) researchers session observation; and 5) recording programme costs.  Results: 37/48 (77%) enrolled families completed both questionnaires. Acceptability and demand were noted as high, based on participant responses to interview questions, focus group feedback and satisfaction scores. Potential for implementation and practicality were also demonstrated through interviews with facilitators and key stakeholders and analysis of project documents. Two groups included caregivers of children with non-Zika related developmental disabilities, showing potential for adaptability. Self-reported quality of life scores increased in caregivers between baseline and end-line, as did the dimensions of family relationships and daily activities in the Pediatric Quality of Life Inventory (PEDS QL) Family Impact Module, showing limited efficacy.   Conclusions: The programme showed feasibility according to Bowen's framework. However, further research of scale up, particularly in the areas of integration, expansion and limited efficacy are needed to ascertain if the programme is effective.

Deficiência e transferência de renda diante da síndrome congênita do Zika vírus: um estudo sobre a Medida Provisória 894/2019 / Discapacidad y transferencia de renta ante el síndrome congénito del zika virus: un estudio sobre la medida provisional 894/2019 / Disability and income transfer in relation to congenital Zika syndrome: a study of provisional measure 894/2019

Desde 2015, a Síndrome Congênita do Zika Vírus (SCZV) marca o cenário brasileiro, extrapolando o campo da Saúde Pública com demandas da proteção social. Considerando a intersecção entre pobreza, deficiência e marcos da seguridade social, examina-se a Medida Provisória 894, que prevê renda mensal vitalícia para as crianças acometidas. Com o objetivo discutir o instrumento à luz dos marcos da seguridade social no recorte da transferência de renda não condicionada para as pessoas com deficiência (PcD) no Brasil, realizou-se um estudo qualitativo mediante análise de documentos públicos e revisão de literatura. As respostas estatais não produziram impacto na insuficiência de renda porque voltaram-se inicialmente para atender à situação emergencial, recorrendo às políticas preexistentes, e culminaram na substituição entre modalidades de transferência de renda - o Benefício de Prestação Continuada para Pensão Vitalícia -, revelando fragilização da proteção social integral. (AU)

Desde 2015 el Síndrome Congénito del Zika Virus (SCZV) marca el escenario brasileño, extrapolando el campo de la salud pública con demandas de la protección social. Considerando la intersección entre pobreza, discapacidad y marcos de la seguridad social, se examina la Medida Provisional 894 que prevé renta mensual vitalicia para los niños afectados. Con el objetivo de discutir el instrumento a la luz de los marcos de la seguridad social en el recorte de la transferencia de renta no condicionada para las Personas con Discapacidad (PcD) en Brasil, se realizó un estudio cualitativo mediante análisis de documentos públicos y revisión de literatura. Las respuestas estatales no causaron impacto en la insuficiencia de renta porque inicialmente se enfocaron para atender la situación de emergencia recurriendo a las políticas preexistentes y que culminaron en la substitución entre modalidades de transferencia de renta, el Beneficio de Prestación Continua para Pensión Vitalicia, revelando la fragilización de la protección social integral. (AU)

Since 2015, Congenital Zika Syndrome (CZS) has been a feature of the Brazilian context and has moved beyond public health to demands for social protection. Given the intersection between poverty, disability and the social security framework, we examine Provisional Measure 894, which provides a lifetime monthly income for affected children. We conduct a qualitative study, analysing public documents and reviewing the literature, in order to discuss this instrument in the light of social security frameworks for unconditional cash transfers for People with Disabilities (PwD) in Brazil. State responses did not have an impact on income insufficiencies, since they were initially intended to respond to emergency situations and referred to pre-existing policies; this culminated in an income transfer modality, the Continuous Cash Benefit, being replaced by a Lifetime Pension, demonstrating a weakening of comprehensive social protection. (AU)

Examining the Association of Socioeconomic Position with Microcephaly and Delayed Childhood Neurodevelopment among Children with Prenatal Zika Virus Exposure.

Increased rates of Zika virus have been identified in economically deprived areas in Brazil at the population level; yet, the implications of the interaction between socioeconomic position and prenatal Zika virus exposure on adverse neurodevelopmental outcomes remains insufficiently evaluated at the individual level. Using data collected between September 2015 and September 2019 from 163 children with qRT-PCR and/or IgM-confirmed prenatal exposure to Zika virus participating in a prospective cohort study in Rio de Janeiro, Brazil (NCT03255369), this study evaluated the relationships of socioeconomic indicators with microcephaly at birth and Bayley-III neurodevelopmental scores during the early life course. Adjusted logistic regression models indicated increased odds of microcephaly in children born to families with lower household income (OR, 95% CI: 3.85, 1.43 to 10.37) and higher household crowding (OR, 95% CI: 1.83, 1.16 to 2.91), while maternal secondary and higher education appeared to have a protective effect for microcephaly compared to primary education (OR, 95% CI: 0.33, 0.11 to 0.98 and 0.10, 0.03 to 0.36, respectively). Consistent with these findings, adjusted linear regression models indicated lower composite language (-10.78, 95% CI: -19.87 to -1.69), motor (-10.45, 95% CI: -19.22 to -1.69), and cognitive (-17.20, 95% CI: -26.13 to -8.28) scores in children whose families participated in the Bolsa Família social protection programme. As such, the results from this investigation further emphasise the detrimental effects of childhood disadvantage on human health and development by providing novel evidence on the link between individual level socioeconomic indicators and microcephaly and delayed early life neurodevelopment following prenatal Zika virus exposure.

Two Sides of a Coin: a Zika Virus Mutation Selected in Pregnant Rhesus Macaques Promotes Fetal Infection in Mice but at a Cost of Reduced Fitness in Nonpregnant Macaques and Diminished Transmissibility by Vectors.

Although fetal death is now understood to be a severe outcome of congenital Zika syndrome, the role of viral genetics is still unclear. We sequenced Zika virus (ZIKV) from a rhesus macaque fetus that died after inoculation and identified a single intrahost substitution, M1404I, in the ZIKV polyprotein, located in nonstructural protein 2B (NS2B). Targeted sequencing flanking position 1404 in 9 additional macaque mothers and their fetuses identified M1404I at a subconsensus frequency in the majority (5 of 9, 56%) of animals and some of their fetuses. Despite its repeated presence in pregnant macaques, M1404I has occurred rarely in humans since 2015. Since the primary ZIKV transmission cycle is human-mosquito-human, mutations in one host must be retained in the alternate host to be perpetuated. We hypothesized that ZIKV I1404 increases viral fitness in nonpregnant macaques and pregnant mice but is less efficiently transmitted by vectors, explaining its low frequency in humans during outbreaks. By examining competitive fitness relative to that of ZIKV M1404, we observed that ZIKV I1404 produced lower viremias in nonpregnant macaques and was a weaker competitor in tissues. In pregnant wild-type mice, ZIKV I1404 increased the magnitude and rate of placental infection and conferred fetal infection, in contrast to ZIKV M1404, which was not detected in fetuses. Although infection and dissemination rates were not different, Aedes aegypti mosquitoes transmitted ZIKV I1404 more poorly than ZIKV M1404. Our data highlight the complexity of arbovirus mutation-fitness dynamics and suggest that intrahost ZIKV mutations capable of augmenting fitness in pregnant vertebrates may not necessarily spread efficiently via mosquitoes during epidemics.IMPORTANCE Although Zika virus infection of pregnant women can result in congenital Zika syndrome, the factors that cause the syndrome in some but not all infected mothers are still unclear. We identified a mutation that was present in some ZIKV genomes in experimentally inoculated pregnant rhesus macaques and their fetuses. Although we did not find an association between the presence of the mutation and fetal death, we performed additional studies with ZIKV with the mutation in nonpregnant macaques, pregnant mice, and mosquitoes. We observed that the mutation increased the ability of the virus to infect mouse fetuses but decreased its capacity to produce high levels of virus in the blood of nonpregnant macaques and to be transmitted by mosquitoes. This study shows that mutations in mosquito-borne viruses like ZIKV that increase fitness in pregnant vertebrates may not spread in outbreaks when they compromise transmission via mosquitoes and fitness in nonpregnant hosts.

Health demands and care of children with congenital Zika syndrome and their mothers in a Brazilian state.

BACKGROUND: A Zika virus (ZIKV) infection outbreak occurred in Brazil in 2015, accompanied by a marked increase in the number of newborns presenting with microcephaly and other neurological disorders. This characteristic set of birth defects was later termed congenital Zika syndrome (CZS). The therapeutic itinerary of mothers and children infected by ZIKV can be determined by several factors, including the relationship established with existing healthcare services. Here, we aimed to describe and analyze the extent to which children with CZS, born from 2015 to 2018 in the state of Mato Grosso do Sul, Brazil, and their mothers were treated according to the guidelines established by the Brazilian Ministry of Health. METHODS: This was a descriptive cross-sectional study that considered all children (and respective mothers) with confirmed or suspected CZS born in Mato Grosso do Sul. Children and their mothers were identified based on all suspected or confirmed cases of congenital anomalies in Mato Grosso do Sul that were reported to the Registry of Public Health Events. We analyzed data on the epidemiological profile of mother-child pairs and the care received by them. Data were summarized using statistical descriptive analysis. RESULTS: We showed that most mothers were white women (57%) with low income. Among pregnant women, 73% had a diagnosis of fever caused by ZIKV infection at a primary health care institution (PHCI), but only 36% received the necessary information regarding the risk of CZS. Over a third (36%) of the mothers did not receive guidance about childcare follow-up and 73% did not receive guidance regarding the availability of social support after childbirth. Gaps in medical care were observed mainly in pregnant women treated at a PHCI. Specialized assistance for children was adequate in most cases. Psychosocial support was not made available to women throughout their therapeutic itineraries. CONCLUSIONS: Here, we identified gaps in the care of families and children with disabilities, which can have an important impact on their quality of life. Beyond protocols, practical interventions must cover all the needs that arise throughout the therapeutic itineraries not only of children but also of pregnant women and mothers.

Congenital Zika Syndrome-Assessing the Need for a Family Support Programme in Brazil.

The Zika outbreak in Brazil caused congenital impairments and developmental delays, or Congenital Zika Syndrome (CZS). We sought to ascertain whether a family support programme was needed and, if so, could be adapted from the Getting to Know Cerebral Palsy programme (GTKCP) designed for children with cerebral palsy (CP). We conducted a systematic review of the needs of families of children with CZS or CP in low- and middle-income countries and reviewed the findings of the Social and Economic Impact of Zika study. We undertook a scoping visit to three facilities offering services to children with CZS in Brazil to understand potential utility and adaptability of GTKCP. The literature review showed that caregivers of children with CZS experience challenges in mental health, healthcare access, and quality of life, consistent with the CP literature. The scoping visits demonstrated that most support provided to families was medically orientated and while informal support networks were established, these lacked structure. Caregivers and practitioners expressed an eagerness for more structure community-based family support programmes. A support programme for families of children with CZS in Brazil appeared relevant and needed, and may fill an important gap in the Zika response.

How do mothers feel? Life with children with congenital Zika syndrome.

OBJECTIVE: To describe the repercussions, from the perspectives of caregiver mothers, of confirmed congenital Zika syndrome (CZS) in their offspring. METHODS: A descriptive-exploratory study with a qualitative approach was carried out in the state of Espírito Santo in southeastern Brazil, with 25 women who had a child diagnosed with CZS. RESULTS: Emerging themes from the content analysis were grouped into two categories: (1) inequalities experienced by mothers, including social inequality, poverty, and gender inequality; (2) the impact of a child with CZS on mothering, including feelings at the time of diagnosis, maternal isolation and mental health, experiences of stigma and prejudice, and exhausting itineraries searching for therapeutic care. CONCLUSION: The repercussions of CZS were a huge burden on already vulnerable women, and social inequalities and poverty were important markers in the mothers' reports. Many of the families affected by CZS already lived in precarious social conditions and these conditions were exacerbated further. Robust public and social policies to support these mothers need effective implementation given that babies born with CZS need long-term care and support.

Análise de dimensões do acesso à saúde das crianças com Síndrome Congênita de Zika (SCZ) na Região Metropolitana do Rio de Janeiro / Dimensional analysis of access to health of children with Congenital Zika Syndrome (CZS) in the Metropolitan Region of Rio de Janeiro

Resumo Desde 2015 a população brasileira vive com as repercussões da epidemia de Zika, levantando o debate sobre as dificuldades de diagnóstico e acesso aos cuidados para crianças com Síndrome Congênita do Zika. As regiões Nordeste e Sudeste foram as mais atingidas, desafiando-nos a caracterizar o acesso à saúde das crianças portadoras da Síndrome Congênita do Zika nessas regiões. O objetivo deste artigo é analisar a disponibilidade e a acessibilidade dos serviços de saúde para a reabilitação das crianças com Síndrome Congênita do Zika na Região Metropolitana do Rio de Janeiro. A metodologia consistiu no mapeamento dos casos de Síndrome Congênita do Zika entre 2015 e 2017 na Região Metropolitana do Rio de Janeiro por bairros de residência e relacionados com a localização das unidades de reabilitação indicadas no Protocolo da Secretaria de Estado de Saúde do Rio de Janeiro. Como resultado foram identificados 202 casos de Síndrome Congênita do Zika na Região Metropolitana do Rio de Janeiro no período de 2015 a 2017. A região teve 85% de todos os casos do estado do Rio de Janeiro, o município do Rio de Janeiro concentrou 63% dos casos. A acessibilidade nesse município é a melhor se comparada com os demais da região metropolitana, dado que é a capital do estado e concentra grande parte dos serviços especializados em saúde materno-infantil.

Abstract Since 2015, the Brazilian population has lived with the repercussions of the Zika epidemic, raising the debate on the difficulties of diagnosis and access to care for children with Congenital Zika Syndrome (CZS). The Northeast and Southeast regions were the hardest hit, challenging us to characterize the access to health of children with ZCS in these regions. The aim of this paper is to analyse the availability and accessibility of health services for the rehabilitation of children with CZS in the Rio de Janeiro Metropolitan Region (RMRJ). The methodology consisted of mapping the cases of CZS between 2015 and 2017 in RJRM by neighbourhoods of residence and related to the location of rehabilitation units indicated in the Protocol of the Rio de Janeiro State Secretariat of Health (SES/RJ). As a result, 202 cases of CZS were identified in the RMRJ from 2015 to 2017. The RMRJ had 85% of all cases in the state of Rio de Janeiro, the municipality of Rio de Janeiro concentrated 63% of the cases. Accessibility in this municipality is better compared to the others in the RMRJ, as it is the state capital and concentrates most of the specialized services in maternal and child health.

ZikaPLAN: addressing the knowledge gaps and working towards a research preparedness network in the Americas.

Zika Preparedness Latin American Network (ZikaPLAN) is a research consortium funded by the European Commission to address the research gaps in combating Zika and to establish a sustainable network with research capacity building in the Americas. Here we present a report on ZikaPLAN`s mid-term achievements since its initiation in October 2016 to June 2019, illustrating the research objectives of the 15 work packages ranging from virology, diagnostics, entomology and vector control, modelling to clinical cohort studies in pregnant women and neonates, as well as studies on the neurological complications of Zika infections in adolescents and adults. For example, the Neuroviruses Emerging in the Americas Study (NEAS) has set up more than 10 clinical sites in Colombia. Through the Butantan Phase 3 dengue vaccine trial, we have access to samples of 17,000 subjects in 14 different geographic locations in Brazil. To address the lack of access to clinical samples for diagnostic evaluation, ZikaPLAN set up a network of quality sites with access to well-characterized clinical specimens and capacity for independent evaluations. The International Committee for Congenital Anomaly Surveillance Tools was formed with global representation from regional networks conducting birth defects surveillance. We have collated a comprehensive inventory of resources and tools for birth defects surveillance, and developed an App for low resource regions facilitating the coding and description of all major externally visible congenital anomalies including congenital Zika syndrome. Research Capacity Network (REDe) is a shared and open resource centre where researchers and health workers can access tools, resources and support, enabling better and more research in the region. Addressing the gap in research capacity in LMICs is pivotal in ensuring broad-based systems to be prepared for the next outbreak. Our shared and open research space through REDe will be used to maximize the transfer of research into practice by summarizing the research output and by hosting the tools, resources, guidance and recommendations generated by these studies. Leveraging on the research from this consortium, we are working towards a research preparedness network.

Development and assessment of the feasibility of a Zika family support programme: a study protocol.

The Zika virus outbreak in Brazil in 2015 affected thousands of people. Zika is now known to cause congenital malformations leading to impairments and developmental delays in affected children, including Congenital Zika Syndrome (CZS). Children with CZS have complex care needs. Caregivers require significant levels of support to meet these needs, and there are large gaps in healthcare services. This study aims to develop, pilot and assess the feasibility and scalability of a community-based Family Support Programme for caregivers of children with CZS. The programme is adapted from the Getting to Know Cerebral Palsy (GTKCP) programme for the context of CZS in Brazil. GTKCP is a 10-session programme held with 6-10 caregivers in the local community. It includes practical, educational, peer-support and psychosocial aspects, which aim to improve confidence and capacity to care for a child with CP, and quality of life and empowerment of caregivers. The research project contains four components: Ascertaining need for the caregiver programme: a mixed-methods approach that included two literature reviews, interviews with key stakeholders in country, and incorporation of findings from the Social and Economic Impact of Zika study.Adapting GTKCP for the context of CZS and Brazil: undertaken with guidance from technical experts.Pilot testing the intervention: deliver the 10-session programme to one group of caregivers of children with CZS in Rio de Janeiro and another in Greater Salvador.Update the manual through fast-track learning from participant and facilitator feedback. Assessing the feasibility of the intervention for scale up: deliver the updated programme to two groups each in Rio de Janeiro and Greater Salvador, and evaluate the acceptability, demand, implementation, practicality, adaptation, integration, expansion, and limited efficacy, through questionnaires, direct observation, semi-structured interviews and cost calculation. The project has ethics approval in both the UK and Brazil.

Social and economic impacts of congenital Zika syndrome in Brazil: Study protocol and rationale for a mixed-methods study.

Global concern broke out in late 2015 as thousands of children in Brazil were born with microcephaly, which was quickly linked to congenital infection with Zika virus (ZIKV). ZIKV is now known to cause a wider spectrum of severe adverse outcomes-congenital Zika syndrome (CZS)-and also milder impairments. This study aimed to explore the social and economic impacts of CZS in Brazil. Data was collected through mixed methods across two settings: Recife City and Jaboatão dos Guararapes in Pernambuco State (the epicentre of the epidemic), and the city of Rio de Janeiro (where reports of ZIKV infection and CZS were less frequent). Data was collected May 2017-January 2018. Ethical standards were adhered to throughout the research. In-depth qualitative interviews were conducted with: mothers and other carers of children with CZS (approximately 30 per setting), pregnant women (10-12 per setting), men and women of child-bearing age (16-20 per setting), and health professionals (10-12 per setting). Thematic analysis was undertaken independently by researchers from at least two research settings, and these were shared for feedback. A case-control study was undertaken to quantitatively explore social and economic differences between caregivers of a child with CZS (cases) and caregivers with an unaffected child (controls). We aimed to recruit 100 cases and 100 controls per setting, from existing studies. The primary caregiver, usually the mother, was interviewed using a structured questionnaire to collect information on: depression, anxiety, stress, social support, family quality of life, health care and social service use, and costs incurred by families. Multivariable logistic regression analyses were used to compare outcomes for cases and controls. Costs incurred as a result of CZS were estimated from the perspective of the health system, families and society. Modelling was undertaken to estimate the total economic burden of CZS from those three perspectives.