Neurodevelopment in Children Exposed to Zika in utero: Clinical and Molecular Aspects.

Five years after the identification of Zika virus as a human teratogen, we reviewed the early clinical manifestations, collectively called congenital Zika syndrome (CZS). Children with CZS have a very poor prognosis with extremely low performance in motor, cognitive, and language development domains, and practically all feature severe forms of cerebral palsy. However, these manifestations are the tip of the iceberg, with some children presenting milder forms of deficits. Additionally, neurodevelopment can be in the normal range in the majority of the non-microcephalic children born without brain or eye abnormalities. Vertical transmission and the resulting disruption in development of the brain are much less frequent when maternal infection occurs in the second half of the pregnancy. Experimental studies have alerted to the possibility of other behavioral outcomes both in prenatally infected children and in postnatal and adult infections. Cofactors play a vital role in the development of CZS and involve genetic, environmental, nutritional, and social determinants leading to the asymmetric distribution of cases. Some of these social variables also limit access to multidisciplinary professional treatment.

Prevalence and diagnostic accuracy of microcephaly in a pediatric cohort in Brazil: a retrospective cross-sectional study

Abstract Objective We sought to describe the prevalence of microcephaly and to compare the different cutoff points established by the Brazilian Ministry of Health at various times during a Zika virus epidemic. As a secondary aim, we investigated the possible etiology of the microcephaly. Method This retrospective study utilized newborn participants in the Zika Cohort Study Jundiaí. Newborns from the Zika Cohort Study Jundiaí with an accurate gestational age determination and complete anthropometric data were analyzed, and microcephaly was diagnosed according to the INTERGROWTH-21st curve. At delivery, fluids were tested for specific antibodies and for viruses. Brain images were evaluated for microcephaly. Receiver Operating Characteristic curves were plotted to define the accuracy of different cutoff points for microcephaly diagnosis. Results Of 462 eligible newborns, 19 (4.1%) were positive for microcephaly. Cutoff points corresponding to the curves of the World Health Organization yielded the best sensitivity and specificity. Three of the microcephaly cases (15.8%) were positive for Zika virus infections; nine (47.4%) had intrauterine growth restriction; one had intrauterine growth restriction and was exposed to Zika virus; three had a genetic syndrome (15.8%); and three had causes that had not been determined (15.8%). Conclusions Microcephaly prevalence was 4.1% in this study. Cutoff values determined by the World Health Organization had the highest sensitivity and specificity in relation to the standard IG curve. The main reason for microcephaly was intrauterine growth restriction. All possible causes of microcephaly must be investigated to allow the best development of an affected baby.

Development, Reliability, and Testing of a New Rating Scale for Neonatal Encephalopathy.

OBJECTIVE: To develop and test the Neonatal Encephalopathy-Rating Scale (NE-RS), a new rating scale to grade the severity of neonatal encephalopathy (NE) within the first 6 hours after birth. STUDY DESIGN: A 3-phase process was conducted: (1) design of a comprehensive scale that would be specific, sensitive, brief, and unsophisticated; (2) evaluation in a cohort of infants with neonatal encephalopathy and healthy controls; and (3) validation with brain magnetic resonance imaging findings and outcome at 2 years of age. RESULTS: We evaluated the NE-RS in 54 infants with NE and 28 healthy infants. The NE-RS had excellent internal consistency (Cronbach alpha coefficient: 0.93 [95% CI 0.86-0.94]) and reliability (intraclass correlation coefficient in the NE cohort 0.996 [95% CI 0.993-0.998; P < .001]). Alertness, posture, motor response, and spontaneous activity were the top discriminators for degrees of NE. The cut-off value for mild vs moderate NE was 8 points (area under the curve [AUC] 0.99, 95% CI 0.85-1.00) and for moderate vs severe NE, 30 points (AUC 0.93, 95% CI 0.81-0.99). The NE-RS was significantly correlated with the magnetic resonance imaging score (Spearman Rho 0.77, P < .001) and discriminated infants who had an adverse outcome (AUC 0.91, 95% CI 0.83-0.99, sensitivity 0.82, specificity 0.81, positive predictive value 0.87, negative predictive value 0.74). CONCLUSIONS: The NE-RS is reliable and performs well in reflecting the severity of NE within the first 6 hours after birth. This tool could be useful when assessing clinical criteria for therapeutic hypothermia in NE.

Hypoxic Ischemic Encephalopathy in Units Reporting to the Ibero-American Society of Neonatology Network: Prevalence and Mortality.

INTRODUCTION: Hypoxic ischemic encephalopathy is a neurological condition occurring immediately after birth following a perinatal asphytic episode. Therapeutic hypothermia is a safe and effective intervention to reduce mortality and major disability in survivors. In Latin America, perinatal asphyxia is a major problem, but no data are available characterizing its current situation in the region or the impact of hypoxic ischemic encephalopathy on its management. OBJECTIVE: Understand the prevalence, mortality and use of therapeutic hypothermia in newborns at ≥36 weeks gestational age with hypoxic ischemic encephalopathy admitted to neonatal units reporting to the Ibero-American Society of Neonatology Network. METHODS: The Ibero-American Society of Neonatology Network groups various neonatology centers in Latin America that share information and collaborate on research and medical care. We evaluated data on newborns with ≥36 weeks gestational age reported during 2019. Each unit received a guide with definitions and questions based on the Society's 7th Clinical Consensus. Evaluated were encephalopathy frequency and severity, Apgar score, need for resuscitation at birth, use of therapeutic hypothermia and clinical evolution at discharge. Our analysis includes descriptive statistics and comparisons made using the chi-square test. RESULTS: We examined reports of 2876 newborns from 33 units and 6 countries. In 2849 newborns with available data, hypoxic encephalopathy prevalence was 5.1% (146 newborns): 27 (19%) mild, 36 (25%) moderate, 43 (29%) severe, and 40 (27%) of unknown intensity. In those with moderate and severe encephalopathy, frequencies of Apgar scores ≤3 at the first minute (p = 0.001), Apgar scores ≤3 at the fifth minute (p ⟨0.001) and advanced resuscitation (p = 0.007) were higher. Therapeutic hypothermia was performed in only 13% of newborns (19). Neonatal mortality from encephalopathy was 42% (61). CONCLUSIONS: Hypoxic ischemic encephalopathy is a neonatal condition that results in high mortality and severe neurological sequelae. In this study, the overall prevalence was 5.1% with a mortality rate of 42%. Although encephalopathy was moderate or severe in 54% of reported cases, treatment with hypothermia was not performed in 87% of newborns. These data reflect a regional situation that requires urgent action.

[Current status of Therapeutic Hypothermia in Hypoxic-Ischemic Encephalopathy]. / Estado actual de la Hipotermia Terapéutica en la Encefalopatía Hipóxico-Isquémica.

Therapeutic hypothermia (TH) has been the standard treatment for neonatal Hypoxic-Ischemic En cephalopathy (HIE) for more than a decade. This therapy has been one of the best studied treatments in neonatal medicine, moving from preclinical models to patient application. Its implementation has been accompanied by the development of neuromonitoring, neonatal neurology as a specific area of expertise, and the intense search for new neuroprotective strategies. This article provides an update on the clinical scope of this therapy, with emphasis on the problems of our geographic region. In addition, some additional strategies that can improve the therapeutic efficacy of TH are reviewed, as well as controversial aspects in its application and some future perspectives in the care of neonates with HIE.

Prevalence and diagnostic accuracy of microcephaly in a pediatric cohort in Brazil: a retrospective cross-sectional study.

OBJECTIVE: We sought to describe the prevalence of microcephaly and to compare the different cutoff points established by the Brazilian Ministry of Health at various times during a Zika virus epidemic. As a secondary aim, we investigated the possible etiology of the microcephaly. METHOD: This retrospective study utilized newborn participants in the Zika Cohort Study Jundiaí. Newborns from the Zika Cohort Study Jundiaí with an accurate gestational age determination and complete anthropometric data were analyzed, and microcephaly was diagnosed according to the INTERGROWTH-21st curve. At delivery, fluids were tested for specific antibodies and for viruses. Brain images were evaluated for microcephaly. Receiver Operating Characteristic curves were plotted to define the accuracy of different cutoff points for microcephaly diagnosis. RESULTS: Of 462 eligible newborns, 19 (4.1%) were positive for microcephaly. Cutoff points corresponding to the curves of the World Health Organization yielded the best sensitivity and specificity. Three of the microcephaly cases (15.8%) were positive for Zika virus infections; nine (47.4%) had intrauterine growth restriction; one had intrauterine growth restriction and was exposed to Zika virus; three had a genetic syndrome (15.8%); and three had causes that had not been determined (15.8%). CONCLUSIONS: Microcephaly prevalence was 4.1% in this study. Cutoff values determined by the World Health Organization had the highest sensitivity and specificity in relation to the standard IG curve. The main reason for microcephaly was intrauterine growth restriction. All possible causes of microcephaly must be investigated to allow the best development of an affected baby.

[Cerebral sinovenous thrombosis in a newborn with mutation of MTHFR C677T treated with enoxaparin]. / Trombosis senovenosa cerebral en un recién nacido con mutación MTHFR C677T tratado con enoxaparina.

INTRODUCTION: Neonatal cerebral sinovenous thrombosis (CSNT) is a rare and generally serious con dition about which there is little knowledge of the responsible pathophysiological mechanisms and, although controversial, it has been suggested that genetic thrombophilia may play a role in its patho genesis. Out of concern for intracranial bleeding, the anticoagulant treatment with low-molecular- weight heparin is controversial. CLINICAL CASE: Full-term newborn who presented at eight days of life breastfeeding rejection, clonic seizures, and locomotor hypoactivity. The MRI neuroimaging showed a CSNT involving multiple venous sinuses, a right thalamic hemorrhagic infarction, and venous con gestion in frontal white matter. Thrombophilia study highlighted a homozygous MTHFR C677T mutation. Treatment with low-molecular-weight heparin was associated with repermeabilization of the superior sagittal sinus after 23 days of starting therapy. CONCLUSIONS: The clinical presentation of CSNT in the neonate is nonspecific, probably related to the extent and severity of the injury and the development of associated complications, such as venous hemorrhagic infarctions and intraparenchymal or intraventricular hemorrhage. These complications are detected through ultrasound or MRI, and they should make us suspect a CSNT. In this experience, the anticoagulant treatment proved to be safe and prevents thrombus propagation.

Trombosis senovenosa cerebral en un recién nacido con mutación MTHFR C677T tratado con enoxaparina / Cerebral sinovenous thrombosis in a newborn with mutation of MTHFR C677T treated with enoxaparin

Resumen: Introducción: La trombosis senovenosa cerebral neonatal (TSVC), es una patología rara y generalmente grave, de la cual se conoce poco sobre los mecanismos fisiopatológicos responsables y, aunque controvertido, se ha sugerido que la trombofilia genética, puede desempeñar un rol en la patogénesis. Debido a los temores de un sangrado intracraneal el tratamiento anticoagulante con heparina de bajo peso mole cular es controvertido. Objetivo: presentar un recién nacido con una trombosis senovenosa cerebral neonatal, discutir los factores de riesgo trombofílico, y el manejo con heparina de bajo peso molecu lar de la trombosis venosa cerebral. Caso Clínico: Recién nacido de término que debutó a los 8 días de vida con convulsiones clónicas, rechazo al pecho más hipoactividad motora. La neuroimagen con RM mostró una TSVC involucrando múltiples senos venosos, un infarto hemorrágico talámico dere cho y congestión venosa de la sustancia blanca frontal. El estudio de trombofilia puso de relieve una mutación homocigota del gen MTHFR C677T. El tratamiento con heparina de bajo peso molecular se asoció a repermeabilización del seno sagital superior a los 23 días de iniciada la terapia. Conclusio nes: La presentación clínica de la TSVC en el neonato es inespecífica, probablemente en relación con la extensión y gravedad de la lesión y el desarrollo de complicaciones asociadas, como infartos he morrágicos venosos intraparenquimatosos o hemorragia intraventricular. Estas complicaciones son detectables mediante Ecografia o Resonancia Magnética, y deben hacer sospechar una TSVC. En esta experiencia el tratamiento anticoagulante mostró ser seguro y prevenir la extensión de la trombosis.

Abstract: Introduction: Neonatal cerebral sinovenous thrombosis (CSNT) is a rare and generally serious con dition about which there is little knowledge of the responsible pathophysiological mechanisms and, although controversial, it has been suggested that genetic thrombophilia may play a role in its patho genesis. Out of concern for intracranial bleeding, the anticoagulant treatment with low-molecular- weight heparin is controversial. Objective: To present a case of a newborn with neonatal CSNT, to analyze the thrombophilic risk factors, and the management of cerebral venous thrombosis with low-molecular-weight heparin. Clinical Case: Full-term newborn who presented at eight days of life breastfeeding rejection, clonic seizures, and locomotor hypoactivity. The MRI neuroimaging showed a CSNT involving multiple venous sinuses, a right thalamic hemorrhagic infarction, and venous congestion in frontal white matter. Thrombophilia study highlighted a homozygous MTHFR C677T mutation. Treatment with low-molecular-weight heparin was associated with repermeabilization of the superior sagittal sinus after 23 days of starting therapy. Conclusions: The clinical presentation of CSNT in the neonate is nonspecific, probably related to the extent and severity of the injury and the development of associated complications, such as venous hemorrhagic infarctions and intraparenchymal or intraventricular hemorrhage. These complications are detected through ultrasound or MRI, and they should make us suspect a CSNT. In this experience, the anticoagulant treatment proved to be safe and prevents thrombus propagation.

Neuron-Specific Enolase in Cerebrospinal Fluid Predicts Brain Injury After Sudden Unexpected Postnatal Collapse.

BACKGROUND: Biomarkers of brain injury with high predictive value in newborns in critical neurological status are increasingly required. Neuron-specific enolase in cerebrospinal fluid has been shown to be highly predictive in newborns with perinatal hypoxic-ischemic encephalopathy, but its utility has not been examined in sudden unexpected postnatal collapse. PURPOSE: We analyzed whether the levels of neuron-specific enolase in cerebrospinal fluid can be a useful biomarker to estimate the severity of brain injury in neonates after a sudden unexpected postnatal collapse. METHODS: This is a prospective observational study of near-term infants who were consecutively admitted with sudden unexpected postnatal collapse in two neonatal intensive care units during a nine-year period. Variables were collected and analyzed regarding the perinatal period, clinical course, severity of encephalopathy, amplitude-integrated encephalography, magnetic resonance imaging findings, and outcome. Neuron-specific enolase in cerebrospinal fluid samples were obtained in 18 infants with sudden unexpected postnatal collapse between 12 and 72 hours after the collapse and compared with those of 29 controls. RESULTS: The levels of neuron-specific enolase in cerebrospinal fluid were higher in patients than in controls (P < 0.001). Levels of neuron-specific enolase in cerebrospinal fluid in infants with sudden unexpected postnatal collapse were significantly higher in patients who presented severe encephalopathy, seizures, abnormal amplitude-integrated encephalography background, or brain injury on magnetic resonance imaging. Receiver operator characteristic curve analysis revealed a neuron-specific enolase in cerebrospinal fluid cutoff value of maximum predictive accuracy of 61 ng/mL (area under the curve, 1.0; sensitivity, specificity, positive predictive value, and negative predictive value, 100%) for identifying infants who died or had adverse outcomes. CONCLUSIONS: Levels of neuron-specific enolase in cerebrospinal fluid obtained between 12 and 72 hours after a sudden unexpected postnatal collapse event seem to be a useful biomarker for identifying newborns with severe brain injury and for predicting outcome.

Variations in the number of births by day of the week, and morbidity and mortality in very-low-birth-weight infants / Variações no número de partos por dia da semana e morbidez e mortalidade em neonatos com muito baixo peso ao nascer

Abstract Objective: To know the distribution of births of very low birth weight infants by day of the week, and whether this distribution affects the morbidity and mortality in this group of patients. Methods: This was a retrospective analysis of data collected prospectively in the Spanish SEN1500 network (2002-2011). Outborn infants, patients with major congenital anomalies, and those who died in the delivery room were excluded. Births were grouped into "weekdays" and "weekends." A multivariate logistic regression analysis was conducted to evaluate the independent effect of the birth moment on outcomes, and Cox regression for survival. Results: Out of a total of 27,205 very low birth weight infants born at and/or admitted to the participating centers, 22,961 (84.4%) met inclusion criteria. A reduction of 24% in the number of births was observed during the "weekends" compared with "weekdays". In the raw analysis, patients born on weekends exhibited higher morbidity and mortality (mortality rate: 14.2% vs. 16.5%, p < 0.001), but differences were no longer significant after adjusting for confounding factors. Conclusions: The present results suggest that current care practices reduce the proportion of births during the weekends and tend to cluster some high-risk births during this period, increasing crude morbidity and mortality. However, after adjusting for confounding factors, the differences disappear, suggesting that overall care coverage in these centers is appropriate.

Resumo Objetivo: Conhecer a distribuição dos partos de neonatos com muito baixo peso ao nascer durante a semana e se essa distribuição afeta a morbidez e a mortalidade nesse grupo de pacientes. Método: Esta é uma análise retrospectiva de dados coletados prospectivamente na rede espanhola SEN1500 (2002-2011). Foram excluídos neonatos nascidos em outro local, pacientes com grandes anomalias congênitas e pacientes falecidos na sala de parto. Os partos foram agrupados em "Dias úteis" e "Final de semana". Foi realizada uma análise de regressão logística multivariada para avaliar o efeito independente do parto sobre os resultados e uma regressão de Cox para avaliar a sobrevida. Resultados: Do total de 27.205 neonatos com muito baixo peso ao nascer nascidos e/ou internados nos centros participantes, 22.961 (84,4%) atenderam aos critérios de inclusão. Houve uma redução de 24% no número de partos no "Final de semana" em comparação com os "Dias úteis". Na análise bruta, os pacientes nascidos em finais de semana apresentaram maior morbidez e mortalidade (Taxa de mortalidade: 14,2% em comparação a 16,5%, p < 0,001), porém as diferenças não eram mais significativas após o ajuste aos fatores de confusão. Conclusões: Nossos resultados sugerem que as práticas atuais de atendimento reduzem a proporção de partos em finais de semana e tendem a agrupar alguns partos de alto risco nesse período, aumentando a morbidez e mortalidade brutas. Contudo, após o ajuste aos fatores de risco, as diferenças desaparecem, sugerindo que a cobertura de atendimento geral em nossos centros é adequada.

Variations in the number of births by day of the week, and morbidity and mortality in very-low-birth-weight infants.

OBJECTIVE: To know the distribution of births of very low birth weight infants by day of the week, and whether this distribution affects the morbidity and mortality in this group of patients. METHODS: This was a retrospective analysis of data collected prospectively in the Spanish SEN1500 network (2002-2011). Outborn infants, patients with major congenital anomalies, and those who died in the delivery room were excluded. Births were grouped into "weekdays" and "weekends." A multivariate logistic regression analysis was conducted to evaluate the independent effect of the birth moment on outcomes, and Cox regression for survival. RESULTS: Out of a total of 27,205 very low birth weight infants born at and/or admitted to the participating centers, 22,961 (84.4%) met inclusion criteria. A reduction of 24% in the number of births was observed during the "weekends" compared with "weekdays". In the raw analysis, patients born on weekends exhibited higher morbidity and mortality (mortality rate: 14.2% vs. 16.5%, p<0.001), but differences were no longer significant after adjusting for confounding factors. CONCLUSIONS: The present results suggest that current care practices reduce the proportion of births during the weekends and tend to cluster some high-risk births during this period, increasing crude morbidity and mortality. However, after adjusting for confounding factors, the differences disappear, suggesting that overall care coverage in these centers is appropriate.

Efficacy of passive hypothermia and adverse events during transport of asphyxiated newborns according to the severity of hypoxic-ischemic encephalopathy / Eficácia da hipotermia passiva e eventos adversos durante o transporte de recém-nascidos asfixiados de acordo com a gravidade da encefalopatia hipóxico-isquêmica

Abstract Objective To determine if the efficacy of passive hypothermia and adverse events during transport are related to the severity of neonatal hypoxic-ischemic encephalopathy. Methods This was a retrospective study of 67 infants with hypoxic-ischemic encephalopathy, born between April 2009 and December 2013, who were transferred for therapeutic hypothermia and cooled during transport. Results Fifty-six newborns (84%) were transferred without external sources of heat and 11 (16%) needed an external heat source. The mean temperature at departure was 34.4 ± 1.4 °C and mean transfer time was 3.3 ± 2.0 h. Mean age at arrival was 5.6 ± 2.5 h. Temperature at arrival was between 33 and 35 °C in 41 (61%) infants, between 35 °C and 36.5 °C in 15 (22%) and <33 °C in 11 (16%). Infants with severe hypoxic-ischemic encephalopathy had greater risk of having an admission temperature < 33 °C (OR: 4.5; 95% CI: 1.1-19.3). The severity of hypoxic-ischemic encephalopathy and the umbilical artery pH were independent risk factors for a low temperature on admission (p < 0.05). Adverse events during transfer, mainly hypotension and bleeding from the endotracheal tube, occurred in 14 infants (21%), with no differences between infants with moderate or severe hypoxic-ischemic encephalopathy. Conclusion The risk of overcooling during transport is greater in newborns with severe hypoxic-ischemic encephalopathy and those with more severe acidosis at birth. The most common adverse events during transport are related to physiological deterioration and bleeding from the endotracheal tube. This observation provides useful information to identify those asphyxiated infants who require closer clinical surveillance during transport.

Resumo Objetivo Determinar se a eficácia da hipotermia passiva e eventos adversos durante o transporte estão relacionados à gravidade da encefalopatia hipóxico-isquêmica neonatal. Métodos Estudo retrospectivo de 67 neonatos com encefalopatia hipóxico-isquêmica (nascidos entre abril de 2009 e dezembro de 2013) transferidos para hipotermia terapêutica e resfriados durante o transporte. Resultados Foram transportados 56 recém-nascidos (84%) sem fontes externas de calor e 11 (16%) precisaram de uma fonte externa de calor. A temperatura média na saída foi de 34,4 ± 1,4 °C e o tempo médio de transporte foi de 3,3 ± 2,0 horas. A idade média na chegada foi de 5,6 ± 2,5 horas. A temperatura na chegada ficou entre 33-35 °C em 41 (61%) neonatos, entre 35°-36,5 °C em 15 (22%) e < 33 °C em 11 (16%). Neonatos com encefalopatia hipóxico-isquêmica grave apresentaram maior risco de temperatura < 33 °C na internação (RC 4,5; IC de 95% 1,1-19,3). A gravidade da encefalopatia hipóxico-isquêmica e o pH da artéria umbilical foram fatores de risco independentes para uma baixa temperatura na internação (p < 0,05). Eventos adversos durante o transporte, principalmente hipotensão e sangramento do tubo endotraqueal, ocorreram em 14 neonatos (21%), sem diferenças entre neonatos com encefalopatia hipóxico-isquêmica moderada ou grave. Conclusão O risco de super-resfriamento durante o transporte é maior em recém-nascidos com encefalopatia hipóxico-isquêmica grave e naqueles com acidose mais grave no nascimento. Os eventos adversos mais comuns durante o transporte estão relacionados a deterioração fisiológica e sangramento do tubo endotraqueal. Essa observação fornece informações úteis para identificar neonatos asfixiados que exigem maior vigilância clínica durante o transporte.

Efficacy of passive hypothermia and adverse events during transport of asphyxiated newborns according to the severity of hypoxic-ischemic encephalopathy.

OBJECTIVE: To determine if the efficacy of passive hypothermia and adverse events during transport are related to the severity of neonatal hypoxic-ischemic encephalopathy. METHODS: This was a retrospective study of 67 infants with hypoxic-ischemic encephalopathy, born between April 2009 and December 2013, who were transferred for therapeutic hypothermia and cooled during transport. RESULTS: Fifty-six newborns (84%) were transferred without external sources of heat and 11 (16%) needed an external heat source. The mean temperature at departure was 34.4±1.4°C and mean transfer time was 3.3±2.0h. Mean age at arrival was 5.6±2.5h. Temperature at arrival was between 33 and 35°C in 41 (61%) infants, between 35°C and 36.5°C in 15 (22%) and <33°C in 11 (16%). Infants with severe hypoxic-ischemic encephalopathy had greater risk of having an admission temperature<33°C (OR: 4.5; 95% CI: 1.1-19.3). The severity of hypoxic-ischemic encephalopathy and the umbilical artery pH were independent risk factors for a low temperature on admission (p<0.05). Adverse events during transfer, mainly hypotension and bleeding from the endotracheal tube, occurred in 14 infants (21%), with no differences between infants with moderate or severe hypoxic-ischemic encephalopathy. CONCLUSION: The risk of overcooling during transport is greater in newborns with severe hypoxic-ischemic encephalopathy and those with more severe acidosis at birth. The most common adverse events during transport are related to physiological deterioration and bleeding from the endotracheal tube. This observation provides useful information to identify those asphyxiated infants who require closer clinical surveillance during transport.

The phenotypic spectrum of congenital Zika syndrome.

In October 2015, Zika virus (ZIKV) outbreak the Brazilian Ministry of Health (MoH). In response, the Brazilian Society of Medical Genetics established a task force (SBGM-ZETF) to study the phenotype of infants born with microcephaly due to ZIKV congenital infection and delineate the phenotypic spectrum of this newly recognized teratogen. This study was based on the clinical evaluation and neuroimaging of 83 infants born during the period from July, 2015 to March, 2016 and registered by the SBGM-ZETF. All 83 infants had significant findings on neuroimaging consistent with ZIKV congenital infection and 12 had confirmed ZIKV IgM in CSF. A recognizable phenotype of microcephaly, anomalies of the shape of skull and redundancy of the scalp consistent with the Fetal Brain Disruption Sequence (FBDS) was present in 70% of infants, but was most often subtle. In addition, features consistent with fetal immobility, ranging from dimples (30.1%), distal hand/finger contractures (20.5%), and feet malpositions (15.7%), to generalized arthrogryposis (9.6%), were present in these infants. Some cases had milder microcephaly or even a normal head circumference (HC), and other less distinctive findings. The detailed observation of the dysmorphic and neurologic features in these infants provides insight into the mechanisms and timings of the brain disruption and the sequence of developmental anomalies that may occur after prenatal infection by the ZIKV.

A Population-Based Study on Congenital Disorders of Protein N- and Combined with O-Glycosylation Experience in Clinical and Genetic Diagnosis.

OBJECTIVE: To describe the clinical, biochemical, and genetic features of patients with congenital disorders of glycosylation (CDG) identified in Spain during the last 20 years. STUDY DESIGN: Patients were selected among those presenting with multisystem disease of unknown etiology. The isoforms of transferrin and of ApoC3 and dolichols were analyzed in serum; phosphomannomutase and mannosephosphate isomerase activities were measured in fibroblasts. Conventional or massive parallel sequencing (customized panel or Illumina Clinical-Exome Sequencing TruSight One Gene Panel) was used to identify genes and mutations. RESULTS: Ninety-seven patients were diagnosed with 18 different CDG. Eighty-nine patients had a type 1 transferrin profile; 8 patients had a type 2 transferrin profile, with 6 of them showing an alteration in the ApoC3 isoform profile. A total of 75% of the patients had PMM2-CDG presenting with a heterogeneous mutational spectrum. The remaining patients showed mutations in any of the following genes: MPI, PGM1, GFPT1, SRD5A3, DOLK, DPGAT1, ALG1, ALG6, RFT1, SSR4, B4GALT1, DPM1, COG6, COG7, COG8, ATP6V0A2, and CCDC115. CONCLUSION: Based on literature and on this population-based study of CDG, a comprehensive scheme including reported clinical signs of CDG is offered, which will hopefully reduce the timeframe from clinical suspicion to genetic confirmation. The different defects of CDG identified in Spain have contributed to expand the knowledge of CDG worldwide. A predominance of PMM2 deficiency was detected, with 5 novel PMM2 mutations being described.

Clinical, biochemical, and neuroimaging findings predict long-term neurodevelopmental outcome in symptomatic congenital cytomegalovirus infection.

OBJECTIVE: To evaluate clinical, biochemical, and neuroimaging findings as predictors of neurodevelopmental outcome in patients with symptomatic congenital cytomegalovirus (CMV). STUDY DESIGN: The study cohort comprised 26 patients with symptomatic congenital CMV born between 1993 and 2009 in a single center. Absolute and weight deficit-adjusted head circumference were considered. Cerebrospinal fluid (CSF) investigations included standard cytochemical analysis, determination of beta2-microglobulin (ß2-m), neuron-specific enolase, and CMV DNA detection. Neuroimaging was classified according to a validated scoring system comprising calcifications, ventriculomegaly, and atrophy, with findings graded from 0 to 3. Systematic long-term neurodevelopmental assessment included motor function, cognition, behavior, hearing, vision, and epilepsy. Sequelae were graded as mild/absent, moderate, or severe; adverse outcome was defined as death or moderate to severe disability. RESULTS: Three children died. The mean age at follow-up of the survivors was 8.7 ± 5.3 years (range, 19 months to 18.0 years). Neonatal findings showing a significant association with adverse outcome were relative microcephaly, CSF ß2-m concentrations, and grade 2-3 neuroimaging abnormalities (P < .05). Receiver operator characteristic curve analysis indicated that the most accurate single factor for predicting unfavorable outcome was CSF ß2-m >7.9 mg/L (area under the curve, 0.84 ± 0.08; sensitivity, 69%; specificity, 100%). The combination of CSF ß2-m >7.9 mg/L and moderate-severe neuroimaging alterations improved predictive ability (area under the curve, 0.92 ± 0.06; sensitivity, 87%; specificity, 100%). CONCLUSION: Adjusted head circumference, CSF ß2-m level, and neuroimaging studies have prognostic significance for neurodevelopmental outcome in newborns with congenital CMV. A combination of early findings improves the predictive value.