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"lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1695403323002345?idApp=UINPBA00005H" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2341287923002880?idApp=UINPBA00005H" "url" => "/23412879/0000010000000001/v1_202401141514/S2341287923002880/v1_202401141514/en/main.assets" ] "en" => array:21 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Original Article</span>" "titulo" => "Neurodevelopmental outcomes in congenital heart disease: Usefulness of biomarkers of brain injury" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "13" "paginaFinal" => "24" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Laia Vega Puyal, Elisa Llurba, Queralt Ferrer, Paola Dolader Codina, Olga Sánchez García, Alba Montoliu Ruiz, Joan Sanchez-de-Toledo" "autores" => array:7 [ 0 => array:4 [ "nombre" => "Laia" "apellidos" => "Vega Puyal" "email" => array:1 [ 0 => "laia.vega@quironsalud.es" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Elisa" "apellidos" => "Llurba" "referencia" => array:4 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] 2 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "aff0020" ] 3 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">e</span>" "identificador" => "aff0025" ] ] ] 2 => array:3 [ "nombre" => "Queralt" "apellidos" => "Ferrer" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">e</span>" "identificador" => "aff0025" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">f</span>" "identificador" => "aff0030" ] ] ] 3 => array:3 [ "nombre" => "Paola" "apellidos" => "Dolader Codina" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">e</span>" "identificador" => "aff0025" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">f</span>" "identificador" => "aff0030" ] ] ] 4 => array:3 [ "nombre" => "Olga" "apellidos" => "Sánchez García" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] 5 => array:3 [ "nombre" => "Alba" "apellidos" => "Montoliu Ruiz" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">f</span>" "identificador" => "aff0030" ] ] ] 6 => array:3 [ "nombre" => "Joan" "apellidos" => "Sanchez-de-Toledo" "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">g</span>" "identificador" => "aff0035" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">h</span>" "identificador" => "aff0040" ] 2 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">i</span>" "identificador" => "aff0045" ] ] ] ] "afiliaciones" => array:9 [ 0 => array:3 [ "entidad" => "Hospital Universitario Dexeus, Grupo Quironsalud, Barcelona, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Women and Perinatal Health Research Group, Institut d’Investigació Biomèdica Sant Pau (IIB SANT PAU), Barcelona. Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Primary Care Interventions to Prevent Maternal and Child Chronic Diseases of Perinatal and Developmental Origin Network (RICORS-SAMID) (RD21/0012), Instituto de Salud Carlos III, Madrid, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Departmento de Obstetricia y Ginecología, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain" "etiqueta" => "d" "identificador" => "aff0020" ] 4 => array:3 [ "entidad" => "Universitat Autònoma de Barcelona (UAB), Barcelona, Spain" "etiqueta" => "e" "identificador" => "aff0025" ] 5 => array:3 [ "entidad" => "Hospital Universitario Vall d’Hebrón. Servicio de Cardiología Pediátrica, Barcelona. Spain" "etiqueta" => "f" "identificador" => "aff0030" ] 6 => array:3 [ "entidad" => "Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain" "etiqueta" => "g" "identificador" => "aff0035" ] 7 => array:3 [ "entidad" => "iCare4Kids Research Group, Institud de Recerca Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain" "etiqueta" => "h" "identificador" => "aff0040" ] 8 => array:3 [ "entidad" => "Department of Critical Care Medicine, Universityy of Pittsburgh, Pittsburgh, PA, United States" "etiqueta" => "i" "identificador" => "aff0045" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Neurodesarrollo a los dos años en cardiopatía congénita: utilidad pronóstica de los marcadores de daño cerebral" ] ] "resumenGrafico" => array:2 [ "original" => 1 "multimedia" => array:5 [ "identificador" => "fig0015" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => false "mostrarDisplay" => true "figura" => array:1 [ 0 => array:4 [ "imagen" => "fx1.jpeg" "Alto" => 741 "Ancho" => 1333 "Tamanyo" => 223262 ] ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">The mortality associated with congenital heart disease (CHD) has decreased in the past few decades. More than 85% of affected patients survive to adulthood. This increase in survival has evinced the associated comorbidities that have a negative impact on quality of life.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Neurodevelopmental abnormalities are currently the most frequent comorbidity found in school-aged children with CHD.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Acute neurologic events (ANEs) or neurologic complications are among the most feared comorbidities in patients with CHD, but their role as predictors of long-term neurodevelopmental outcomes has not been clearly established.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Neurodevelopmental disorders have a multifactorial aetiology, with prenatal, neonatal and perioperative factors contributing to long-term neurologic outcomes.<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4–6</span></a> In recent decades, the usefulness of various instruments and measures for the early prediction of poor neurologic outcomes has been investigated, including the association of biomarkers of brain injury with the development of neurologic events and abnormalities in the long term.<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7,8</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">We present the results of a study designed to identify risk factors for neurodevelopmental disorders in newborns with CHD treated with cardiac surgery. The objectives of the study were: (a) to determine the incidence of ANEs in patients with complex CHD treated with cardiac surgery, (b) to assess neurodevelopmental outcomes at age 2 years in a cohort of children with complex CHD treated with cardiac surgery and (c) to assess the usefulness of biomarkers of brain injury measured in the cardiac surgery perioperative period to predict the occurrence of ANEs in the postoperative period and poor neurodevelopmental outcomes.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Patients and methods</span><p id="par0020" class="elsevierStylePara elsevierViewall">We conducted a prospective observational study of newborns who received a prenatal diagnosis of CHD and treated with cardiac surgery within 1 year post birth at the Hospital Universitari Vall d’Hebrón. The enrolment period lasted 4 years (2012–2016 for pregnant women and 2013–2017 for infants). We excluded cases of foetal death, antenatal detection of genetic disorders and of CHD associated with other major congenital anomalies.</p><p id="par0025" class="elsevierStylePara elsevierViewall">The studied cohort is part of a multicentre study that recruited and assessed pregnant women with healthy foetuses and foetuses with CHD, the methodology of which has been described in a previous publication.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> We analysed demographic, clinical, laboratory and treatment-related variables, documented postoperative complications and measured serum markers of brain injury. The neurodevelopmental assessment was conducted at age 2 years by means of the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III).</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Clinical and demographic variables</span><p id="par0030" class="elsevierStylePara elsevierViewall">We collected data on clinical and laboratory variables in the postnatal and perioperative period: sex, gestational age, preterm birth, anthropometric measurements, weight and height circumference percentiles and <span class="elsevierStyleItalic">z</span> scores, type of surgical repair, age at time of surgery, scores in surgical mortality risk scales, duration of extracorporeal circulation (ECC) and genetic disorders diagnosed after birth. Every newborn underwent a postnatal ultrasound examination to confirm the prenatal diagnosis. Infants were classified into 4 groups based on the cardiac anatomy and physiology (univentricular [UV] or biventricular [BV]) and whether there were lesions obstructing systemic blood (systemic obstruction: SO vs no SO). They were also classified in 3 groups based on the degree of cyanosis: (1) no cyanosis, (2) moderate neonatal cyanosis (cyanotic defect other than transposition of the great arteries [TGA]) and (3) cyanosis associated with TGA, as previously done by other authors.<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5,8,10</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Treatments, complications and acute neurologic events</span><p id="par0035" class="elsevierStylePara elsevierViewall">We collected variables pertaining to postoperative care, received treatment and postoperative complications including ANEs. We documented the mortality risk score at admission to the intensive care unit (ICU), the duration of mechanical ventilation, the use of vasoactive drugs, the length of stay in the ICU, the length of stay in hospital, the need for extracorporeal membrane oxygenation (ECMO) after surgery, complications in the postoperative period and postoperative mortality.</p><p id="par0040" class="elsevierStylePara elsevierViewall">We defined ANE as intracranial bleeding, stroke, venous sinus thrombosis, seizures (clinical, electrographic or both) or brain death. The diagnosis of ANE was based on the findings of imaging tests ordered as the care team considered necessary. We did not include temporal changes in the definition of ANE. When available, diagnostic images were compared with previous imaging to verify the timing of development of the radiological features.</p><p id="par0045" class="elsevierStylePara elsevierViewall">We documented suspected or confirmed postnatal diagnoses of genetic disorders and their association with neurodevelopmental outcomes, whether or not the association had been described in the previous literature.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Biomarkers of brain injury</span><p id="par0050" class="elsevierStylePara elsevierViewall">We analysed the levels of 2 biomarkers of brain injury: S100 calcium-binding protein B (S100B) and neuron-specific enolase (NSE). Blood samples were collected at 4 time points: (1) immediately after birth (cord blood), (2) immediately before surgery, (3) at admission to the ICU after surgery and (5) at 24 h from admission to the ICU after surgery. The samples were collected from central venous or arterial catheters already in place, extracting the minimum necessary volume (EDTA collection tube, 0.5 mL). Samples were processed by separating the plasma through centrifugation at 1400 <span class="elsevierStyleItalic">g</span> for 10 min at 4 °C, and frozen immediately after for storage at −80 °C until testing. Enzyme-linked immunosorbent assays (ELISAs) were performed in duplicate with commercial kits (BlueGene Biotech CO. Ltd, Shanghai, China). The minimum detection limits in the assays were 50 pg/mL for S100B and 0.5 ng/mL for NSE.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Follow-up neurodevelopmental assessment</span><p id="par0055" class="elsevierStylePara elsevierViewall">We analysed the scores in the neurodevelopmental assessment conducted at age 2 years (Bayley-III). The Bayley-III scales assess 5 developmental domains: cognition, language, social-emotional, motor and adaptive behaviour. It yields scores based on the answers or behaviour of the child that are transformed into scaled and composite scores for age. The results are scaled to a metric a mean of 100 points, and a standard deviation (SD) of 15 points and a range of 40–160 points. For each domain, values of less than 85 points are indicative of developmental delay and are classified as mild (1–2 SDs below mean), moderate (2–3 SDs below mean) and severe (<3 SDs below mean).</p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Data handling and analysis</span><p id="par0060" class="elsevierStylePara elsevierViewall">The data were entered in an ad hoc database. The results were analysed and interpreted jointly by the research team and the research support unit of the hospital.</p><p id="par0065" class="elsevierStylePara elsevierViewall">We described the characteristics of the sample using absolute frequencies and percentages for qualitative variables and the mean and SD or median and interquartile range (IQR) for quantitative variables.</p><p id="par0070" class="elsevierStylePara elsevierViewall">Qualitative data were compared with the χ<span class="elsevierStyleSup">2</span> test or Fisher exact test, and quantitative data with the Kruskal-Wallis test. We assessed the association of variables with the Spearman correlation coefficient (<span class="elsevierStyleItalic">r</span>). We considered results with <span class="elsevierStyleItalic">P</span> values of less than 0.05 statistically significant. The statistical analysis was conducted with the software package Stata, version 15.1 (StataCorp. 2017. Stata Statistical Software: Release 15. College Station, TX: StataCorp LLC)</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Ethical approval and consent to participation</span><p id="par0075" class="elsevierStylePara elsevierViewall">The study was approved by the ethics committee of the hospital on February 13, 2014 (PR (AMI) 317/2012). All pregnant women included in the study signed the informed consent form for participation in the study.</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Results</span><p id="par0080" class="elsevierStylePara elsevierViewall">The initial sample included 96 pregnant women carrying foetuses with a diagnosis of CHD. Four were excluded during pregnancy: 2 due to prenatal diagnosis of a genetic disorder, 1 due to foetal death and 1 due to transfer to a different hospital. In the 92 offspring of the remaining pregnant women, the diagnosis of CHD was confirmed after birth, and 86 were eligible for surgical management. Of these 86, 2 died before the surgery, and the 84 remaining infants who underwent surgery within 1 year of birth were included in the analysis (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0085" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> presents the CHD diagnoses confirmed after birth. The most frequent form of CHD was transposition of the great arteries (TGA, 29 patients), followed by coarctation of the aorta with or without hypoplastic left heart (17 patients), tetralogy of Fallot with pulmonary atresia (16 patients) and atrioventricular septal defect (8 patients). <a class="elsevierStyleCrossRefs" href="#tbl0010">Tables 2A and 2B</a> present distribution of CHD cases into 4 groups based on anatomy and in 3 groups based on the degree of cyanosis.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Postnatal and perioperative clinical variables</span><p id="par0090" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0020">Table 3</a> presents the results for the overall sample and by CHD anatomy group.</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><p id="par0095" class="elsevierStylePara elsevierViewall">Six patients (7.1% of the total) were born preterm, and all had a biventricular anatomy. There were no differences in the sex distribution, mean gestational age, weight or head circumference between the groups of patients classified according to heart anatomy. Most patients (69.1%) were operated within 28 days post birth.</p><p id="par0100" class="elsevierStylePara elsevierViewall">In the group with univentricular anatomy, a higher proportions of patients required vasoactive drugs or postoperative ECMO (11.8% vs 0%) and the mortality was higher (29% vs 0%), and the subset with SO had significantly longer stays in the ICU (38.5 days [23−60] vs 19 days [9−29.5]; <span class="elsevierStyleItalic">P</span> = .04), increased need of vasoactive support (maximal VIS, 61.5 [20−66] vs 19 <a class="elsevierStyleCrossRefs" href="#bib0050">[10–32]</a>; <span class="elsevierStyleItalic">P</span> = .01), with a higher proportion requiring ECMO after surgery (16.7% vs 2.4%; <span class="elsevierStyleItalic">P</span> = .04) and a higher mortality (66.67% vs 5.95%; <span class="elsevierStyleItalic">P</span> < .01) (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). Ten patients (12% of the total) received a genetic syndrome diagnosis after birth, either confirmed or highly suspected and awaiting confirmation.</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Complications and acute neurologic events</span><p id="par0105" class="elsevierStylePara elsevierViewall">The general complications and the ANEs developed by the patients are presented in <a class="elsevierStyleCrossRef" href="#tbl0025">Tables 4</a> (entire cohort) and <a class="elsevierStyleCrossRef" href="#tbl0030">5</a> (by CHD anatomy group). We found no differences between groups in the variables under study, except for the use of insulin for management of hyperglycaemia, which was more frequent in the group with biventricular anatomy without SO.</p><elsevierMultimedia ident="tbl0025"></elsevierMultimedia><elsevierMultimedia ident="tbl0030"></elsevierMultimedia><p id="par0110" class="elsevierStylePara elsevierViewall">The postoperative mortality was 5.9%, corresponding to 5 patients, all of who had univentricular anatomy, and 4 of who had SO.</p><p id="par0115" class="elsevierStylePara elsevierViewall">As regards the neurologic complications detected in the cohort, 13 ANEs were detected in the cohort. Two of them were diagnosed in 2 different patients before surgery.</p><p id="par0120" class="elsevierStylePara elsevierViewall">Eleven ANEs were diagnosed after surgery in 9 patients: 5 ischaemic strokes, 3 episodes of seizures, 1 venous sinus thrombosis, 1episode of severe extra-axial haemorrhage and 1 case of severe hypoxic-ischaemic encephalopathy resulting in brain death). Of the 9 patients that experienced postoperative ANEs (10.7%), 6 were operated in the neonatal period (9.5 days [7.5–12.5]) and 1 at 36 days post birth.</p><p id="par0125" class="elsevierStylePara elsevierViewall">There were no differences in the incidence of ANE between anatomical groups; on the other hand, postoperative ANEs were more frequent in the moderate cyanosis group (26.1% vs 10.7%; <span class="elsevierStyleItalic">P</span> = .04). Two patients who experienced ANEs died.</p><p id="par0130" class="elsevierStylePara elsevierViewall">During the follow-up, 5 patients required antiepileptic drugs, 3 experienced postoperative ischaemic strokes and 1 was diagnosed with a genetic syndrome characterised by heart disease, epilepsy and neurodevelopmental delay. All 5 had a biventricular anatomy.</p><p id="par0135" class="elsevierStylePara elsevierViewall">The incidence of ANEs was higher patients who required ECMO after surgery compared to all other patients (100% vs 9.76%; <span class="elsevierStyleItalic">P</span> = .01), and both of these patients died.</p><p id="par0140" class="elsevierStylePara elsevierViewall">Of the patients that experienced and survived cardiac arrest in the postoperative period (n = 6), 3 had ANEs and 1 died from the neurologic complication.</p><p id="par0145" class="elsevierStylePara elsevierViewall">The incidence of ANE was greater in patients with moderate cyanosis (no TGA), patients who required ECMO after surgery and patients who had cardiac arrest in the immediate postoperative period. We did not find significant differences in incidence based on gestational age, birth weight or head circumference, a high STAT score, the minutes of ECC, the maximal VIS at 24 h, the Pediatric Risk of Mortality score (PRISM III) or other variables.</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Biomarkers of brain injury</span><p id="par0150" class="elsevierStylePara elsevierViewall">In the analysis of the levels of the two biomarkers, we found detectable levels in cord blood (S100B, 48.27 [16.89–171.12]; NSE, 0.46 [0.42−0.53]). The levels of S100B increased after surgery compared to the preoperative period, with greater values in the immediate postoperative period and a decreasing trend observed by 24 h after surgery (136.19 [72.68−211.14] vs 169.90 [67.5–284.07] vs 162.75 [62.12−278.10]; <span class="elsevierStyleItalic">P</span> ≤ .01). The levels of NSE did not increase after surgery compared to before (0.88 [0.73−1.06] vs 0.86 [0.70−0.98] vs 0.62 [0.54−0.86]; <span class="elsevierStyleItalic">P</span> = .241).</p><p id="par0155" class="elsevierStylePara elsevierViewall">The levels of the biomarkers at the different time points by CHD group can be found in <a class="elsevierStyleCrossRef" href="#tbl0035">Table 6</a>. Levels of S100B increased significantly in the immediate postoperative period in patients with SO (in both the BV and UV groups). We did not find significant differences at the other perioperative time points or between the other CHD categories.</p><elsevierMultimedia ident="tbl0035"></elsevierMultimedia><p id="par0160" class="elsevierStylePara elsevierViewall">The levels of S100B were higher in the immediate postoperative period in patients that experience ANEs after surgery compared to patients who did not (284.07 [167.74–483.50] vs 164.54 [67.50–273.01]; <span class="elsevierStyleItalic">P</span> = .20), but the difference was not statistically significant; the levels of NSE were similar in patients who had ANEs and the rest of the patients (0.75 [0.75−0.76]) vs 0.87 [0.70−0.98]; <span class="elsevierStyleItalic">P</span> = .578).</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Long-term follow-up</span><p id="par0165" class="elsevierStylePara elsevierViewall">Five of the 84 patients died during the follow-up, and another 5 were lost to follow-up. Of the 74 remaining patients, 55 (74%) were evaluated at 2 years with the Bayley-III. The median scores in each of the 5 domains of the test were all within the normal range (85−115) (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>).</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0170" class="elsevierStylePara elsevierViewall">Thirty-eight patients had normal scores (≥ 85) in the cognition, motor and language domains; 30 had normal scores in every domain in the test. Of the patients who had an abnormal score in at least one domain, 16 had a low score in only one domain. There were 9 patients with scores below the normal range in 2 or more domains. Of the 6 patients with abnormal scores in 3 or more domains, 4 had neonatal cyanosis of moderate or high degree, 2 had UV anatomy, and 1 who had abnormal scores in all 5 domains had been diagnosed with a genetic syndrome associated with abnormal neurodevelopment.</p><p id="par0175" class="elsevierStylePara elsevierViewall">We obtained a total of 260 scores for the assessed domains in the 55 patients (all patients underwent assessment of at least 3 domains and up to a total possible maximum of 5); 43 of the 260 scores were below the normal range, of which 27 indicated mild delay, 13 moderate delay and 3 severe delay.</p><p id="par0180" class="elsevierStylePara elsevierViewall">Patients with UV anatomy scored lower in the cognition, motor, language and adaptive behaviour domains, and the difference was statistically significant in the motor assessment (89.5 [85–97] vs 103 [94–121]; <span class="elsevierStyleItalic">P</span> = .02).</p><p id="par0185" class="elsevierStylePara elsevierViewall">We did not find significant differences when we compared the scores of patients based on the degree of cyanosis (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>).</p><p id="par0190" class="elsevierStylePara elsevierViewall">Patients who experienced an ANE had scores lower than normal in at least 1 domain of the Bayley-III (2 of these patients had low scores in 3 or more domains), although the differences compared to patients without ANEs were not statistically significant: cognition (95 [81–105] vs 110 [95–130]; <span class="elsevierStyleItalic">P</span> = .5; language (79 [78–94] vs 91 [86–115]; <span class="elsevierStyleItalic">P</span> = .5); motor (91 [85–91] vs 100 [91–118]; <span class="elsevierStyleItalic">P</span> = .13); socioemotional (100 [90–110] vs 100 [90–115]; <span class="elsevierStyleItalic">P</span> = .8) and adaptive behaviour (82 [75−25; 89.25] vs 98 [85–106]; <span class="elsevierStyleItalic">P</span> = .07), as can be seen in <a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>.</p><p id="par0195" class="elsevierStylePara elsevierViewall">Patients with epilepsy had significantly lower scores in the motor assessment (100 [91–118] vs 53.5 [46–61]; <span class="elsevierStyleItalic">P</span> = .02).</p><p id="par0200" class="elsevierStylePara elsevierViewall">Patients who survived an episode of cardiac arrest after surgery had lower scores compared to patients who did not experience cardiac arrest in 4 of the 5 domains: cognition (82.5 [67.5–101.25] vs 110 [97.5–1032.25]; <span class="elsevierStyleItalic">P</span> ≤ .01), language (82.5 [77.75–88] vs 95.5 [86–115]; <span class="elsevierStyleItalic">P</span> ≤ .01); motor (89.5 [81.25–100] vs 100 [92.5−118]; <span class="elsevierStyleItalic">P</span> ≤ .01) and adaptive behaviour (76.5 [71.75–81.25] vs 98 [85–106]; <span class="elsevierStyleItalic">P</span> ≤ .01).</p><p id="par0205" class="elsevierStylePara elsevierViewall">Patients with a suspected or confirmed genetic disorder scored lower in all domains, with significantly lower scores in the language, motor and adaptive behaviour domains. The scores in this group were the following, compared to those of patients without a genetic diagnosis: language, 74 [57.5–83] vs 92.5 [83–115] (<span class="elsevierStyleItalic">P</span> = .006); motor, 76 [52–98.6] vs 100 [91–118] (<span class="elsevierStyleItalic">P</span> = .0057); adaptive behaviour, 59 [47–77] vs 98 [84–106] (<span class="elsevierStyleItalic">P</span> = .007); cognition, 77.5 [55–105] vs 110 [95–130] (<span class="elsevierStyleItalic">P</span> = .051); socioemotional, 85 [55–100] vs 100 [90–110] (<span class="elsevierStyleItalic">P</span> = .069).</p><p id="par0210" class="elsevierStylePara elsevierViewall">Excluding the patients with genetic syndromes from the analysis, 21 patients had scores below 85 in at least one domain, with 15 scoring low in one domain, 2 in two domains and 4 in three domains. Nine patients had language delay (mild in 7, moderate in 2), 9 had delays in adaptive behaviour (mild in 5, moderate in 4), 5 cognitive delay (mild in all), 4 delay in socioemotional development (mild in all) and 3 in motor development (mild in 2, moderate in 1).</p><p id="par0215" class="elsevierStylePara elsevierViewall">We analysed the correlation between the measured levels of the markers of brain injury at each time point and the scores of the patients in the different domains of the Bayley-III. There was a correlation between higher levels of S100B in the immediate postoperative period and lower scores in the domains of cognition (<span class="elsevierStyleItalic">r</span> = 0.336 [0.023−0.589]; <span class="elsevierStyleItalic">P</span> = .036), language (<span class="elsevierStyleItalic">r</span> = 0.337 [0.020−0.593]; <span class="elsevierStyleItalic">P</span> = .038) and motor development (<span class="elsevierStyleItalic">r</span> = 0.424 [0.125−0.652]; <span class="elsevierStyleItalic">P</span> ≤ .01). We did not find a correlation between the level of NSE at the different perioperative time points and the scores in the Bayley-III domains.</p><p id="par0220" class="elsevierStylePara elsevierViewall">Thus, we found less favourable scores in the Bayley-III in patients who experienced ANEs in the postoperative period, although the difference with the scores of patients without ANEs was not statistically significant. In our cohort, patients with CHD operated in the first year of life had lower scores in the Bayley-III scales if they had a univentricular cardiac anatomy, received a diagnosis of genetic disorder, suffered and survived cardiac arrest in the postoperative period and had elevated levels of S100B in the immediate postoperative period.</p></span></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Discussion</span><p id="par0225" class="elsevierStylePara elsevierViewall">In the studied cohort of newborns with CHD managed with cardiac surgery and followed up from the foetal period, we found that at age 2 years, more than half of assessed patients had normal overall neurodevelopmental outcomes, which was consistet with the recent literature.<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11–14</span></a> However, 45.4% of the patients had scores of less than 85 in at least one of the five domains of the Bayley-III scales and 31% have low scores in the cognition, language or motor domains. In addition, 34.5% of the total had abnormal scores in 1 or 2 neurodevelopmental domains and 10.9% in 3 or more domains.</p><p id="par0230" class="elsevierStylePara elsevierViewall">It is estimated that 30%–50% of patients with complex CHD exhibit neurodevelopmental abnormalities ranging from mild cognitive delay to severe executive dysfunction.<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2,8,15</span></a> At present, learning difficulties are the most prevalent heath problem in school-aged patients with CHD.<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2,11,16–19</span></a></p><p id="par0235" class="elsevierStylePara elsevierViewall">In our study, all patients who died after surgery had UV anatomy and 80% had LFOT. Consistent with the previous literature, postoperative severity (measured with the PRISM-III risk of mortality score) was greater in patients with UV anatomy, who had longer lengths of stay and had a greater need for vasoactive support and ECMO compared to the rest of the sample.<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">16,20,21</span></a></p><p id="par0240" class="elsevierStylePara elsevierViewall">Patients with UV anatomy had lower scores in the Bayley-III scales; specifically, they had poorer scores compared to the rest of the patients in the cognitive, language, motor and adaptive behaviour assessments. On the other hand, we did not find statistically significant differences based on the degree of cyanosis.</p><p id="par0245" class="elsevierStylePara elsevierViewall">In our cohort, newborns with a genetic syndrome diagnosis had lower scores in the Bayley-III scales, as previously reported.<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6,22,23</span></a> Although there is solid evidence supporting the inclusion of genetic testing in routine management protocols, it is not routinely performed in our region.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a></p><p id="par0250" class="elsevierStylePara elsevierViewall">Patients with postoperative ANEs had lower scores in the cognition, motor and adaptive behaviour domains, as previously described,<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">24–29</span></a> although in our cohort these differences were not statistically significant. Younger age at the time of surgery was associated with an increased risk of ANE, and cardiac arrest after surgery was associated with an increased mortality and poorer neurodevelopmental outcomes.</p><p id="par0255" class="elsevierStylePara elsevierViewall">The analysis of biomarkers of brain injury revealed an increase in the levels of S100B in the immediate postoperative period, as reported in other case series,<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7,8,30,31</span></a> although in our study, this increase was not significantly associated with the probability of ANEs after surgery.</p><p id="par0260" class="elsevierStylePara elsevierViewall">Elevation of S100B levels in adults has been associated with stroke, an increase in mortality and in length of stay, delirium, poorer neuropsychiatric outcomes and memory impairment after cardiac surgery.<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">32,33</span></a> In the paediatric population, elevation of S100B has been observed in patients with neurologic complications managed with ECMO,<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> after extracorporeal surgery<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> and in the context of perinatal asphyxia or head trauma with intracranial lesions.<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a></p><p id="par0265" class="elsevierStylePara elsevierViewall">In the correlation analysis, higher levels of S100B in the immediate postoperative period appeared to be associated with poorer scores in the cognition, language and motor domains of the Bayley-III scales at age 2 years. The evidence on the predictive value of S100B in the paediatric population is scarce compared to the adult population, but we did find studies that found a correlation between higher values of S100B after head trauma and poor neurologic outcomes<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a> and higher values of S100B after cardiac surgery in patients with CHD and poorer neurodevelopmental outcomes.<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8,30</span></a></p><p id="par0270" class="elsevierStylePara elsevierViewall">In our cohort, the levels of NSE did not increase after surgery, contrary to what has been observed in other case series.<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7,30,31,33</span></a> In adults who underwent coronary bypass surgery and after cardiac arrest, NSE is a reliable predictor of adverse neurologic outcomes,<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> in the paediatric age group, it has been found useful as a marker of brain injury in samples of cerebrospinal fluid from newborns with hypoxic/ischaemic encephalopathy managed with hypothermia.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> In our study, we did not find an association of NSE with postoperative ANEs or poorer early neurodevelopmental outcomes.</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Limitations</span><p id="par0275" class="elsevierStylePara elsevierViewall">The small size of some of the subgroups, especially the UV group, and the mortality within this subgroup, have affected the overall neurodevelopmental assessment results, although this has also reflected the greater medical complexity of this type of defects.</p><p id="par0280" class="elsevierStylePara elsevierViewall">We conducted a descriptive analysis due to the small number of patients in some of the subgroups, which did not allow performance of a multivariate analysis free of bias, and we expect to be able to carry out such an analysis in future studies conducted in larger samples.</p><p id="par0285" class="elsevierStylePara elsevierViewall">Neurodevelopmental disorders evolve through time, and some develop at older ages and cannot be detected in early neurodevelopmental assessments. Patients with operated CHD need to remain in follow-up and undergo neurodevelopmental assessments at older ages to ensure detection of potential abnormalities.</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Conclusion</span><p id="par0290" class="elsevierStylePara elsevierViewall">Although the average scores in the neurodevelopmental assessment at age 2 years of patients with a prenatal diagnosis of CHD who underwent surgical repair in the first year of life were within the normal range, one in three patients had abnormal results in the motor, language and cognition assessments.</p><p id="par0295" class="elsevierStylePara elsevierViewall">In our study, patients with genetic disorders and patients with univentricular heart anatomy had poorer neurodevelopmental outcomes at age 2 years compared to the rest of the cohort. Acute neurologic events during the postoperative period could contribute to poorer neurodevelopmental outcomes at age 2 years.</p><p id="par0300" class="elsevierStylePara elsevierViewall">In this cohort, the highest levels of S100B in the immediate postoperative period occurred in patients with poorer neurodevelopmental outcomes at age 2 years. Further research is needed to elucidate the value of postoperative S100B levels for prediction of unfavourable neurodevelopmental outcomes in patients with complex CHD.</p><p id="par0305" class="elsevierStylePara elsevierViewall">The early identification of genetic syndromes and postoperative ANEs and the delivery of standardised and personalised care for infants with univentricular CHD are important to improve long-term neurodevelopmental outcomes.</p><p id="par0310" class="elsevierStylePara elsevierViewall">The neurobehavioural follow-up of patients with CHD should be standardised to progress toward an integrative care model aimed at promoting healthy development and improve quality of life in these patients and their famil