Genotypic-Phenotypic Correlations of Hereditary Hyperferritinemia-Cataract Syndrome: Case Series of Three Brazilian Families.

Hereditary hyperferritinemia-cataract syndrome (HHCS) is a rare, frequently misdiagnosed, autosomal dominant disease caused by mutations in the FTL gene. It causes bilateral pediatric cataract and hyperferritinemia without iron overload. The objective of this case series, describing three Brazilian families, is to increase awareness of HHCS, as well as to discuss possible phenotypic interactions with concurrent mutations in HFE, the gene associated with autosomal recessive inheritance hereditary hemochromatosis. Whole-exome sequencing was performed in eight individuals with HHCS from three different families, as well as one unaffected member from each family for trio analysis-a total of eleven individuals. Ophthalmological and clinical genetic evaluations were conducted. The likely pathogenic variant c.-157G>A in FTL was found in all affected individuals. They presented slowly progressing bilateral cataract symptoms before the age of 14, with a phenotype of varied bilateral diffuse opacities. Hyperferritinemia was present in all affected members, varying from 971 ng/mL to 4899 ng/mL. There were two affected individuals with one concurrent pathogenic variant in HFE (c.187C>G, p.H63D), who were also the ones with the highest values of serum ferritin in our cohort. Few publications describe individuals with pathogenic mutations in both FTL and HFE genes, and further studies are needed to assess possible phenotypic interactions causing higher values of hyperferritinemia.

Discordant Zika Virus Findings in Twin Pregnancies Complicated by Antenatal Zika Virus Exposure: A Prospective Cohort.

BACKGROUND: There are limited data on the natural history of antenatal Zika virus (ZIKV) exposure in twin pregnancies, especially regarding intertwin concordance of prenatal, placental, and infant outcomes. METHODS: This prospective cohort study included twin pregnancies referred to a single institution from September 2015 to June 2016 with maternal ZIKV. Polymerase chain reaction (PCR) testing of maternal, placental, and neonatal samples was performed. Prenatal ultrasounds were completed for each twin, and histomorphologic analysis was performed for each placenta. Abnormal neonatal outcome was defined as abnormal exam and/or abnormal imaging. Two- to three-year follow-up of infants included physical exams, neuroimaging, and Bayley-III developmental assessment. RESULTS: Among 244 pregnancies, 4 twin gestations without coinfection were identified. Zika virus infection occurred at 16-33 weeks gestation. Zika virus PCR testing revealed discordance between dichorionic twins, between placentas in a dichorionic pair, between portions of a monochorionic placenta, and between a neonate and its associated placenta. Of the 8 infants, 3 (38%) had an abnormal neonatal outcome. Of 6 infants with long-term follow-up, 3 (50%) have demonstrated ZIKV-related abnormalities. CONCLUSIONS: Neonatal PCR testing, placental findings, and infant outcomes can be discordant between co-twins with antenatal ZIKV exposure. These findings demonstrate that each twin should be evaluated independently for vertical transmission.

The Role of Amniocentesis in the Diagnosis of Congenital Zika Syndrome.

There are limited data on amniocentesis as a diagnostic tool for congenital Zika syndrome. Here we report on a prospective cohort of 16 women with suspected Zika virus infection in a highly endemic area, and discuss the role of amniocentesis in the prenatal diagnosis of fetal Zika infection.

Zika Virus Infection in Pregnant Women in Rio de Janeiro.

BACKGROUND: Zika virus (ZIKV) has been linked to central nervous system malformations in fetuses. To characterize the spectrum of ZIKV disease in pregnant women and infants, we followed patients in Rio de Janeiro to describe clinical manifestations in mothers and repercussions of acute ZIKV infection in infants. METHODS: We enrolled pregnant women in whom a rash had developed within the previous 5 days and tested blood and urine specimens for ZIKV by reverse-transcriptase-polymerase-chain-reaction assays. We followed women prospectively to obtain data on pregnancy and infant outcomes. RESULTS: A total of 345 women were enrolled from September 2015 through May 2016; of these, 182 women (53%) tested positive for ZIKV in blood, urine, or both. The timing of acute ZIKV infection ranged from 6 to 39 weeks of gestation. Predominant maternal clinical features included a pruritic descending macular or maculopapular rash, arthralgias, conjunctival injection, and headache; 27% had fever (short-term and low-grade). By July 2016, a total of 134 ZIKV-affected pregnancies and 73 ZIKV-unaffected pregnancies had reached completion, with outcomes known for 125 ZIKV-affected and 61 ZIKV-unaffected pregnancies. Infection with chikungunya virus was identified in 42% of women without ZIKV infection versus 3% of women with ZIKV infection (P<0.001). Rates of fetal death were 7% in both groups; overall adverse outcomes were 46% among offspring of ZIKV-positive women versus 11.5% among offspring of ZIKV-negative women (P<0.001). Among 117 live infants born to 116 ZIKV-positive women, 42% were found to have grossly abnormal clinical or brain imaging findings or both, including 4 infants with microcephaly. Adverse outcomes were noted regardless of the trimester during which the women were infected with ZIKV (55% of pregnancies had adverse outcomes after maternal infection in the first trimester, 52% after infection in the second trimester, and 29% after infection in the third trimester). CONCLUSIONS: Despite mild clinical symptoms in the mother, ZIKV infection during pregnancy is deleterious to the fetus and is associated with fetal death, fetal growth restriction, and a spectrum of central nervous system abnormalities. (Funded by Ministério da Saúde do Brasil and others.).

Retinopathy of prematurity screening and treatment cost in Brazil.

OBJECTIVE: To assess the additional cost of incorporating the detection and treatment of retinopathy of prematurity (ROP) into neonatal care services of Brazil's Unified Health System (SUS). METHODS: A deterministic decision-tree simulation model was built to estimate the direct costs of screening for and treating ROP in neonatal intensive-care units (NICUs), based on data for 869 preterm infants with birth weight less than 1 500 g examined in six governmental NICUs in the capital city of Rio de Janeiro, where coverage was 52% and 8% of infants were treated. All of the parameters from this study were extrapolated to Brazilian newborn estimates in 2010. Costs of screening and treatment were estimated considering staff, equipment and maintenance, and training based on published data and expert opinion. A budget impact analysis was performed considering the population of preterm newborns, screening coverage, and the incidence of treatable ROP. One- and two-way sensitivity analyses were performed. RESULTS: In Rio de Janeiro, unit costs per newborn were US$ 18 for each examination, US$ 398 per treatment, and US$ 29 for training. The estimated cost of ROP diagnosis and treatment for all at-risk infants NICUs was US$ 80 per infant. The additional cost to the SUS for one year would be US$ 556 640 for a ROP program with 52% coverage, increasing to US$ 856 320 for 80% coverage, and US$ 1.07 million or 100% coverage. CONCLUSIONS: The results of this study indicate that providing ROP care is affordable within the framework of the SUS in Brazil, and might be feasible elsewhere in Latin America, considering the evidence of the effectiveness of ROP treatment and the social benefits achieved.

The cost of genetic diagnosis of suspected hereditary pediatric cataracts with whole-exome sequencing from a middle-income country perspective: a mixed costing analysis.

Up to 25% of pediatric cataract cases are inherited. There is sparse information in the literature regarding the cost of whole-exome sequencing (WES) for suspected hereditary pediatric cataracts. Molecular diagnosis of suspected hereditary pediatric cataracts is important for comprehensive genetic counseling. We performed a partial economic evaluation with a mixed costing analysis, using reimbursement data and microcosting approach with a bottom-up technique to estimate the cost of using WES for genetic diagnosis of suspected hereditary pediatric cataracts from the perspective of the Brazilian governmental health care system. One hundred and ten participants from twenty-nine families in Rio de Janeiro (RJ) were included. Costs of consumables, staff and equipment were calculated. Two scenarios were created: (1) The reference scenario included patients from RJ with suspected hereditary pediatric cataracts plus two family members. (2) The alternative scenario considered other genetic diseases, resulting in 5,280 exams per month. Sensitivity analysis was also performed. In the reference scenario, the total cost per exam was 700.09 United States dollars (USD), and in the alternative scenario, the total cost was 559.23 USD. The cost of WES alone was 527.85 USD in the reference scenario and 386.98 USD in the alternative scenario. Sensitivity analysis revealed that the largest costs were associated with consumables in both scenarios. Economic evaluations can help inform policy decisions, especially in middle-income countries such as Brazil.

Current practices and profiles of ophthalmologists involved in retinopathy of prematurity care in Brazil.

Retinopathy of prematurity (ROP) care in Brazil varies in availability of resources and infrastructure. A cross-sectional survey was conducted among ophthalmologists of the Brazilian ROP Group (BRA-ROP) to assess the profiles and practices of ophthalmologists involved in ROP care. A total of 78 responses of BRA-ROP participants (79%) were included. Participants were mostly retina experts (64.1%), female (65.4%), and over 40 years of age (60.2%). Eighty-six percent reported following Brazil's ROP screening criteria. Retinal imaging is available to 16.9% of respondents; fluorescein angiography, to 1.4%. For ROP stage 3 zone II (with plus disease), laser treatment was the preferred treatment (78.9%); for aggressive ROP, anti-VEGF was favored (66.2%). There were significant regional differences in treatment choice. Not all respondents continued to follow treated patients after discharge from the neonatal intensive care unit, highlighting an aspect of ROP care in need of improvement.

Capacity building of nurses providing neonatal care in Rio de Janeiro, Brazil: methods for the POINTS of care project to enhance nursing education and reduce adverse neonatal outcomes.

BACKGROUND: Increased survival of preterm infants in developing countries has often been accompanied by increased morbidity. A previous study found rates of severe retinopathy of prematurity varied widely between different neonatal units in Rio de Janeiro. Nurses have a key role in the care of high-risk infants but often do not have access to ongoing education programmes. We set out to design a quality improvement project that would provide nurses with the training and tools to decrease neonatal mortality and morbidity. The purpose of this report is to describe the methods and make the teaching package (POINTS of care--six modules addressing Pain control; optimal Oxygenation; Infection control; Nutrition interventions; Temperature control; Supportive care) available to others. METHODS/DESIGN: Six neonatal units, caring for 40% of preterm infants in Rio de Janeiro were invited to participate. In Phase 1 of the study multidisciplinary workshops were held in each neonatal unit to identify the neonatal morbidities of interest and to plan for data collection. In Phase 2 the teaching package was developed and tested. Phase 3 consisted of 12 months data collection utilizing a simple tick-sheet for recording. In Phase 4 (the Intervention) all nurses were asked to complete all six modules of the POINTS of care package, which was supplemented by practical demonstrations. Phase 5 consisted of a further 12 months data collection. In Phase 1 it was agreed to include inborn infants with birthweight ≤ 1500 g or gestational age of ≤ 34 weeks. The primary outcome was death before discharge and secondary outcomes included retinopathy of prematurity and bronchopulmonary dysplasia. Assuming 400-450 infants in both pre- and post-intervention periods the study had 80% power at p = < 0.05 to detect an increase in survival from 68% to 80%; a reduction in need for supplementary oxygen at 36 weeks post menstrual age from 11% to 5.5% and a reduction in retinopathy of prematurity requiring treatment from 7% to 2.5%. DISCUSSION: The results of the POINTS of Care intervention will be presented in a separate publication. TRIAL REGISTRATION: Current Controlled Trials: ISRCTN83110114.

Cost-Utility Analysis of Wide-Field Imaging as an Auxiliary Technology for Retinopathy of Prematurity Care in Brazil.

Purpose: To evaluate the cost-utility of wide-field imaging (WFI) as a complementary technology for retinopathy of prematurity (ROP) screening from the Brazilian Unified Health System's perspective. Introduction: ROP is one of the leading causes of avoidable childhood blindness worldwide, especially in middle-income countries. The current ROP screening involves indirect binocular ophthalmoscopy (IBO) by ROP expert ophthalmologists. However, there is still insufficient ROP screening coverage. An alternative screening strategy is the combination of WFI with IBO. Methods: A cost-utility analysis was performed using a deterministic decision-tree simulation model to estimate incremental cost-utility for ROP care. Two screening strategies were compared: (1) IBO and (2) combination of WFI of all eligible preterm infants and IBO for type 2 ROP or worse and for non-readable images. Eligible population included preterm infants <32 weeks of gestational age or birth weight equal to or <1,500 g. The temporal horizon was lifetime. Visual outcome data was converted to utility, and the health benefits were estimated on quality-adjusted life-years (QALY). Incremental cost per QALY gained was calculated from the health system perspective. Costs were estimated considering equipment, maintenance, consumables, and staff. A micro-costing approach was used for WFI. Two technician nurses were trained for imaging execution and had their time evaluated. Two ROP expert ophthalmologists had their time evaluated for imaging reading. One-way sensitivity analysis and probabilistic sensitivity analysis were performed. Results: Combined screening strategy resulted in a cost-effective program considering 90% ROP screening coverage. Costs per examination: (1) screening with IBO: US dollar (US $) 34.36; (2) screening with combination: US $58.20; (3) laser treatment: US $642.09; (4) long-term follow-up: ranged from US $69.33 to 286.91, based on the infant's visual function. Incremental cost per QALY gained was US $1,746.99/QALY per infant screened with the combination strategy. One-way sensitivity analysis resulted in cost-effectiveness for all parameters. Probabilistic sensitivity analyses yielded a 100% probability of combination being cost-effective in a willingness-to-pay threshold of US $1,800/QALY. Conclusion: The combined strategy for ROP screening was cost-effective. It enhances access for appropriate ROP care in middle-income countries and dminishes opportunity costs for ophthalmologists.

Novel Mutation in CRYBB3 Causing Pediatric Cataract and Microphthalmia.

Up to 25% of pediatric cataract cases are inherited, with half of the known mutant genes belonging to the crystallin family. Within these, crystallin beta B3 (CRYBB3) has the smallest number of reported variants. Clinical ophthalmological and genetic-dysmorphological evaluation were performed in three autosomal dominant family members with pediatric cataract and microphthalmia, as well as one unaffected family member. Peripheral blood was collected from all participating family members and next-generation sequencing was performed. Bioinformatics analysis revealed a novel missense variant c.467G>A/p.Gly156Glu in CRYBB3 in all family members with childhood cataract. This variant is classified as likely pathogenic by ACMG, and no previous descriptions of it were found in ClinVar, HGMD or Cat-Map. The only other mutation previously described in the fifth exon of CRYBB3 is a missense variant that causes a change in amino acid from the same 156th amino acid to arginine and has been associated with pediatric cataract and microphthalmia. To the best of our knowledge, this is the first time the c.467G>A/p.Gly156Glu variant is reported and the second time a mutation in CRYBB3 has been associated with microphthalmia.

Why Did ZIKV Perinatal Outcomes Differ in Distinct Regions of Brazil? An Exploratory Study of Two Cohorts.

The Zika virus (ZIKV) epidemic in Brazil occurred in regions where dengue viruses (DENV) are historically endemic. We investigated the differences in adverse pregnancy/infant outcomes in two cohorts comprising 114 pregnant women with PCR-confirmed ZIKV infection in Rio de Janeiro, Southeastern Brazil (n = 50) and Manaus, in the north region of the country (n = 64). Prior exposure to DENV was evaluated through plaque reduction neutralizing antibody assays (PRNT 80) and DENV IgG serologies. Potential associations between pregnancy outcomes and Zika attack rates in the two cities were explored. Overall, 31 women (27%) had adverse pregnancy/infant outcomes, 27 in Rio (54%) and 4 in Manaus (6%), p < 0.001. This included 4 pregnancy losses (13%) and 27 infants with abnormalities at birth (24%). A total of 93 women (82%) had evidence of prior DENV exposure, 45 in Rio (90%) and 48 in Manaus (75%). Zika attack rates differed; the rate in Rio was 10.28 cases/10,000 and in Manaus, 0.6 cases/10,000, p < 0.001. Only Zika attack rates (Odds Ratio: 17.6, 95% Confidence Interval 5.6-55.9, p < 0.001) and infection in the first trimester of pregnancy (OR: 4.26, 95% CI 1.4-12.9, p = 0.011) were associated with adverse pregnancy and infant outcomes. Pre-existing immunity to DENV was not associated with outcomes (normal or abnormal) in patients with ZIKV infection during pregnancy.

Overlapping Spectrum of Retinochoroidal Scarring in Congenital Zika Virus and Toxoplasmosis Infections.

BACKGROUND AND OBJECTIVE: Antenatal Zika virus (ZIKV) or toxoplasmosis infections may present with isolated eye abnormalities with absence of other apparent birth defects. The purpose of this article is to discuss the overlapping spectrum of clinical presentation and retinochoroidal scarring in congenital ZIKV and toxoplasmosis infections. PATIENTS AND METHODS: Prenatal ultrasound abnormalities seen from antenatal ZIKV and toxoplasmosis infections overlap and may include intracranial calcifications, microcephaly, and intrauterine growth restriction. The clinical spectrum of both infections in less severely affected infants and children may include nonspecific neurological impairment such as developmental delay and seizures. RESULTS: Inherent limitations in serological testing pose additional barriers in establishing a diagnosis. Retinal pigment epithelium (RPE) mottling in ZIKV infection can occur in isolation or adjacent to retinochoroidal atrophy. In contrast, RPE mottling outside of the borders of retinochoroidal atrophy is not typically seen in toxoplasmosis. To date, postnatal reactivation of congenital eye lesions as seen in toxoplasmosis have not been reported with ZIKV infection. CONCLUSIONS: As children infected with congenital ZIKV grow older, subclinical eye abnormalities may be indistinguishable from toxoplasmosis. Brazil has had high prevalence of both diseases with long-term information available on toxoplasmosis only. Surveillance guidelines for asymptomatic eye abnormalities will likely evolve. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:779-784.].

Delayed childhood neurodevelopment and neurosensory alterations in the second year of life in a prospective cohort of ZIKV-exposed children.

We report neurodevelopmental outcomes in 216 infants followed since the time of PCR-confirmed maternal Zika virus (ZIKV) infection in pregnancy during the Rio de Janeiro epidemic of 2015-2016 (refs. 1,2). Neurodevelopment was assessed by Bayley Scales of Infant and Toddler Development, third edition (Bayley-III; cognitive, language and motor domains) in 146 children and through neurodevelopment questionnaires/neurological examinations in 70 remaining children. Complete eye exams (n = 137) and hearing assessments (n = 114) were also performed. Below-average neurodevelopment and/or abnormal eye or hearing assessments were noted in 31.5% of children between 7 and 32 months of age. Among children assessed by Bayley-III, 12% scored below -2 s.d. (score <70; a score of 100 ± 2 s.d. is the range) in at least one domain; and 28% scored between -1 and -2 s.d. in any domain (scores <85-70). Language function was most affected, with 35% of 146 children below average. Improved neurodevelopmental outcomes were noted in female children, term babies, children with normal eye exams and maternal infection later in pregnancy (P = 0.01). We noted resolution of microcephaly with normal neurodevelopment in two of eight children, development of secondary microcephaly in two other children and autism spectrum disorder in three previously healthy children in the second year of life.

Association of Prenatal Ultrasonographic Findings With Adverse Neonatal Outcomes Among Pregnant Women With Zika Virus Infection in Brazil.

Importance: Congenital Zika virus infection causes a spectrum of adverse birth outcomes, including severe birth defects of the central nervous system. The association of prenatal ultrasonographic findings with adverse neonatal outcomes, beyond structural anomalies such as microcephaly, has not been described to date. Objective: To determine whether prenatal ultrasonographic examination results are associated with abnormal neonatal outcomes in Zika virus-affected pregnancies. Design, Setting, and Participants: A prospective cohort study conducted at a single regional referral center in Rio de Janeiro, Brazil, from September 1, 2015, to May 31, 2016, among 92 pregnant women diagnosed during pregnancy with Zika virus infection by reverse-transcription polymerase chain reaction, who underwent subsequent prenatal ultrasonographic and neonatal evaluation. Exposures: Prenatal ultrasonography. Main Outcomes and Measures: The primary outcome measure was composite adverse neonatal outcome (perinatal death, abnormal finding on neonatal examination, or abnormal finding on postnatal neuroimaging). Secondary outcomes include association of specific findings with neonatal outcomes. Results: Of 92 mother-neonate dyads (mean [SD] maternal age, 29.4 [6.3] years), 55 (60%) had normal results and 37 (40%) had abnormal results on prenatal ultrasonographic examinations. The median gestational age at delivery was 38.6 weeks (interquartile range, 37.9-39.3). Of the 45 neonates with composite adverse outcome, 23 (51%) had normal results on prenatal ultrasonography. Eleven pregnant women (12%) had a Zika virus-associated finding that was associated with an abnormal result on neonatal examination (adjusted odds ratio [aOR], 11.6; 95% CI, 1.8-72.8), abnormal result on postnatal neuroimaging (aOR, 6.7; 95% CI, 1.1-38.9), and composite adverse neonatal outcome (aOR, 27.2; 95% CI, 2.5-296.6). Abnormal results on middle cerebral artery Doppler ultrasonography were associated with neonatal examination abnormalities (aOR, 12.8; 95% CI, 2.6-63.2), postnatal neuroimaging abnormalities (aOR, 8.8; 95% CI, 1.7-45.9), and composite adverse neonatal outcome (aOR, 20.5; 95% CI, 3.2-132.6). There were 2 perinatal deaths. Abnormal findings on prenatal ultrasonography had a sensitivity of 48.9% (95% CI, 33.7%-64.2%) and a specificity of 68.1% (95% CI, 52.9%-80.1%) for association with composite adverse neonatal outcomes. For a Zika virus-associated abnormal result on prenatal ultrasonography, the sensitivity was lower (22.2%; 95% CI, 11.2%-37.1%) but the specificity was higher (97.9%; 95% CI, 88.7%-99.9%). Conclusions and Relevance: Abnormal results on prenatal ultrasonography were associated with adverse outcomes in congenital Zika infection. The absence of abnormal findings on prenatal ultrasonography was not associated with a normal neonatal outcome. Comprehensive evaluation is recommended for all neonates with prenatal Zika virus exposure.

Eye Findings in Infants With Suspected or Confirmed Antenatal Zika Virus Exposure.

: media-1vid110.1542/5804915134001PEDS-VA_2018-1104Video Abstract OBJECTIVES: To characterize ophthalmic manifestations of confirmed or suspected antenatal Zika virus (ZIKV) exposure. METHODS: Infants with antenatal ZIKV exposure were referred for evaluation during the 2015-2016 Rio de Janeiro outbreak. Mothers with symptomatic ZIKV infection during pregnancy and/or infants with microcephaly or other findings that were suggestive of suspected antenatal exposure were tested with reverse transcriptase polymerase chain reaction (RT-PCR). Complete eye examinations were performed by pediatric ophthalmologists between January 2016 and February 2017. The main outcome measure was eye abnormalities in RT-PCR-positive and suspected (ie, not tested or RT-PCR-negative) antenatal ZIKV cases. RESULTS: Of 224 infants, 189 had RT-PCR testing performed. Of 189 patients, 156 had positive RT-PCR results in their blood, urine, and/or placenta. Of 224 infants, 90 had central nervous system (CNS) abnormalities, including microcephaly (62 infants). Eye abnormalities were present in 57 of 224 (25.4%) infants. Optic nerve (44 of 57; 77.2%) and retina abnormalities (37 of 57; 64.9%) were the most common. The group with suspected ZIKV infection (68 infants) had proportionally more eye (36.8% vs 20.5%; P = .022) and CNS abnormalities (68.3% vs 28.1%; P = .008), likely because of referral patterns. Eye abnormalities consistent with ZIKV infection were clinically comparable in both RT-PCR-positive and unconfirmed groups, including 4 RT-PCR-positive infants of 5 without any CNS abnormalities. CONCLUSIONS: Similar eye manifestations were identified regardless of laboratory confirmation. Well-appearing infants were also found to have eye abnormalities. Therefore, all infants born after ZIKV outbreaks should be universally screened for eye abnormalities.

Visual function in infants with antenatal Zika virus exposure.

PURPOSE: To report the findings of a cross-sectional study of visual function in infants with confirmed or suspected antenatal Zika virus (ZIKV) infection seen at a single referral center in Rio de Janeiro. METHODS: Infants were examined following the ZIKV outbreak period at Instituto Fernandes Figueira/FIOCRUZ. Visual function was considered abnormal if an infant could not fix and follow a standardized high-contrast target (10 cm) by 3-6 months of age. Visual function and associations with structural eye abnormalities, central nervous system (CNS) abnormalities, microcephaly, and nystagmus were assessed. Sensitivity and specificity of screening criteria for structural eye abnormalities was assessed. RESULTS: A total of 173 infants met inclusion criteria. Abnormal visual function was found in 52 infants (30.0%) and was significantly associated with eye abnormalities (40/52; OR = 44.2; 95% CI, 16.6-117.6), CNS abnormalities (50/52; OR = 64.0; 95% CI, 14.7-277.6), microcephaly (44/52; OR = 31.5; 95% CI, 12.7-77.8), and nystagmus (26/52; OR = 120.0; 95% CI, 15.6-924.5). Using microcephaly as screening criteria for the detection of eye abnormalities provided a sensitivity of 88.9% (95% CI, 76.0-96.3) and specificity of 82.8% (95% CI, 75.1-88.9). Using both abnormal visual function and microcephaly increased sensitivity to 100% (95% CI, 92.1-100.0) and decreased specificity to 80.5% (95% CI, 72.5-86.9). CONCLUSIONS: Infants with suspected antenatal ZIKV infection and reduced visual function should be referred to an ophthalmologist. Visual function assessments are helpful in screening for antenatal ZIKV exposure in resource-limited settings and can identify infants who may benefit from visual habilitation.

Screening Criteria for Ophthalmic Manifestations of Congenital Zika Virus Infection.

Importance: Current guidelines recommend screening eye examinations for infants with microcephaly or laboratory-confirmed Zika virus infection but not for all infants potentially exposed to Zika virus in utero. Objective: To evaluate eye findings in a cohort of infants whose mothers had polymerase chain reaction-confirmed Zika virus infection during pregnancy. Design, Setting, and Participants: In this descriptive case series performed from January 2 through October 30, 2016, infants were examined from birth to 1 year of age by a multidisciplinary medical team, including a pediatric ophthalmologist, from Fernandes Figueira Institute, a Ministry of Health referral center for high-risk pregnancies and infectious diseases in children in Rio de Janeiro, Brazil. Participants: Mother-infant pairs from Rio de Janeiro, Brazil, who presented with suspected Zika virus infection during pregnancy were referred to our institution and had serum, urine, amniotic fluid, or placenta samples tested by real-time polymerase chain reaction for Zika virus. Main Outcomes and Measures: Description of eye findings, presence of microcephaly or other central nervous system abnormalities, and timing of infection in infants with confirmed Zika virus during pregnancy. Eye abnormalities were correlated with central nervous system findings, microcephaly, and the timing of maternal infection. Results: Of the 112 with polymerase chain reaction-confirmed Zika virus infection in maternal specimens, 24 infants (21.4%) examined had eye abnormalities (median age at first eye examination, 31 days; range, 0-305 days). Ten infants (41.7%) with eye abnormalities did not have microcephaly, and 8 (33.3%) did not have any central nervous system findings. Fourteen infants with eye abnormalities (58.3%) were born to women infected in the first trimester, 8 (33.3%) in the second trimester, and 2 (8.3%) in the third trimester. Optic nerve and retinal abnormalities were the most frequent findings. Eye abnormalities were statistically associated with microcephaly (odds ratio [OR], 19.1; 95% CI, 6.0-61.0), other central nervous system abnormalities (OR, 4.3; 95% CI, 1.6-11.2), arthrogryposis (OR, 29.0; 95% CI, 3.3-255.8), and maternal trimester of infection (first trimester OR, 5.1; 95% CI, 1.9-13.2; second trimester OR, 0.5; 95% CI, 0.2-1.2; and third trimester OR, 0.3; 95% CI, 0.1-1.2). Conclusions and Relevance: Eye abnormalities may be the only initial finding in congenital Zika virus infection. All infants with potential maternal Zika virus exposure at any time during pregnancy should undergo screening eye examinations regardless of the presence or absence of central nervous system abnormalities.

Retinopathy of prematurity in 7 neonatal units in Rio de Janeiro: screening criteria and workload implications.

OBJECTIVES: The goals were to determine optimal screening criteria for retinopathy of prematurity (ROP) in 7 neonatal units in Rio de Janeiro, Brazil, and to explore the workload implications of applying different criteria. METHODS: Infants with birth weights of < or = 2000 g or gestational age of <37 weeks were examined by 3 ophthalmologists in 7 of the largest units in Rio de Janeiro, during a 34-month period. ROP was classified by using the international classification, and laser treatment was given to infants developing type 1 ROP. RESULTS: A total of 3437 (87%) of 3953 eligible infants were examined, of whom 124 (3.6% [range: 2.1%-7.8%]) were treated. Eleven infants were treated for aggressive posterior ROP. Appropriate screening criteria for the 2 NICUs with high survival rates (ie, > or =80% among infants with birth weights of <1500 g) would be < or =1500 g or <32 weeks. For NICUs with low survival rates (ie, <80%), appropriate criteria would be < or =1500 g or < or =35 weeks. UK, US, and previous Brazilian criteria would all miss infants needing treatment. CONCLUSIONS: ROP programs in Brazil should use the wider criteria of < or =1500 g or < or =35 weeks until further evidence-based criteria become available, although this would mean a slight increase in workload across the city, compared with use of the narrower criteria in the better units. Whether survival rates can be used as a proxy to indicate screening criteria requires further investigation.

Retinopathy of prematurity screening and treatment cost in Brazil / Costo de la detección y el tratamiento de la retinopatía de la prematuridad en el Brasil

OBJECTIVE: To assess the additional cost of incorporating the detection and treatment of retinopathy of prematurity (ROP) into neonatal care services of Brazil's Unified Health System (SUS). METHODS: A deterministic decision-tree simulation model was built to estimate the direct costs of screening for and treating ROP in neonatal intensive-care units (NICUs), based on data for 869 preterm infants with birth weight less than 1 500 g examined in six governmental NICUs in the capital city of Rio de Janeiro, where coverage was 52% and 8% of infants were treated. All of the parameters from this study were extrapolated to Brazilian newborn estimates in 2010. Costs of screening and treatment were estimated considering staff, equipment and maintenance, and training based on published data and expert opinion. A budget impact analysis was performed considering the population of preterm newborns, screening coverage, and the incidence of treatable ROP. One- and two-way sensitivity analyses were performed. RESULTS: In Rio de Janeiro, unit costs per newborn were US$ 18 for each examination, US$ 398 per treatment, and US$ 29 for training. The estimated cost of ROP diagnosis and treatment for all at-risk infants NICUs was US$ 80 per infant. The additional cost to the SUS for one year would be US$ 556 640 for a ROP program with 52% coverage, increasing to US$ 856 320 for 80% coverage, and US$ 1.07 million or 100% coverage. CONCLUSIONS: The results of this study indicate that providing ROP care is affordable within the framework of the SUS in Brazil, and might be feasible elsewhere in Latin America, considering the evidence of the effectiveness of ROP treatment and the social benefits achieved.

OBJETIVO: Evaluar el costo adicional de incorporar la detección y el tratamiento de la retinopatía de la prematuridad (RP) en los servicios de atención neonatal del Sistema Único de Salud (SUS) del Brasil. MÉTODOS: Se estableció un modelo de simulación determinístico en forma de árbol de decisión para calcular los costos directos del tamizaje y el tratamiento de la RP en las unidades de cuidados intensivos neonatales (UCIN), con base en los datos correspondientes a 869 lactantes prematuros con un peso al nacer inferior a 1 500 g examinados en seis UCIN gubernamentales de Rio de Janeiro, capital del estado del mismo nombre, donde la cobertura fue de 52% y se trató a un 7% de los lactantes. Todos los parámetros de este estudio se extrapolaron a los cálculos de recién nacidos brasileños correspondientes al año 2010. Se calcularon los costos de la detección y el tratamiento, teniendo en cuenta el personal, el equipo y la capacitación, con base en los datos publicados y la opinión de los expertos. Se llevó a cabo un análisis de la repercusión presupuestaria considerando la población de recién nacidos prematuros, la cobertura del tamizaje y la incidencia de RP susceptible de tratamiento. Se realizaron análisis de sensibilidad en uno y dos sentidos. RESULTADOS: En Rio de Janeiro, los costos unitarios por recién nacido fueron de US$ 18 por cada examen, US$ 398 por tratamiento y US$ 29 por capacitación. El costo calculado del diagnóstico y el tratamiento de la RP en todos los lactantes en situación de riesgo de las UCIN fue de US$ 80 por lactante. El costo anual adicional para el SUS de un programa de RP con una cobertura de 52% sería de US$ 556 640, y ascendería a US$ 856 320 para una cobertura de 80%, y a US$ 1,07 millones si la cobertura fuera de 100%. CONCLUSIONES: Los resultados de este estudio indican que, teniendo en cuenta los datos probatorios de la eficacia del tratamiento de la RP y los beneficios sociales obtenidos, la prestación de asistencia a la RP es asequible en Brasil en el marco del SUS y podría ser factible en otros lugares de América Latina.