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BACKGROUND: The use of cerebral oximetry monitoring in the care of extremely preterm infants is increasing. However, evidence that its use improves clinical outcomes is lacking. METHODS: In this randomized, phase 3 trial conducted at 70 sites in 17 countries, we assigned extremely preterm infants (gestational age, <28 weeks), within 6 hours after birth, to receive treatment guided by cerebral oximetry monitoring for the first 72 hours after birth or to receive usual care. The primary outcome was a composite of death or severe brain injury on cerebral ultrasonography at 36 weeks' postmenstrual age. Serious adverse events that were assessed were death, severe brain injury, bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis, and late-onset sepsis. RESULTS: A total of 1601 infants underwent randomization and 1579 (98.6%) were evaluated for the primary outcome. At 36 weeks' postmenstrual age, death or severe brain injury had occurred in 272 of 772 infants (35.2%) in the cerebral oximetry group, as compared with 274 of 807 infants (34.0%) in the usual-care group (relative risk with cerebral oximetry, 1.03; 95% confidence interval, 0.90 to 1.18; P = 0.64). The incidence of serious adverse events did not differ between the two groups. CONCLUSIONS: In extremely preterm infants, treatment guided by cerebral oximetry monitoring for the first 72 hours after birth was not associated with a lower incidence of death or severe brain injury at 36 weeks' postmenstrual age than usual care. (Funded by the Elsass Foundation and others; SafeBoosC-III ClinicalTrials.gov number, NCT03770741.).
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Lactente Extremamente Prematuro , Doenças do Prematuro , Oximetria , Humanos , Lactente , Recém-Nascido , Lesões Encefálicas/diagnóstico por imagem , Lesões Encefálicas/etiologia , Displasia Broncopulmonar/etiologia , Circulação Cerebrovascular , Doenças do Prematuro/diagnóstico , Doenças do Prematuro/mortalidade , Doenças do Prematuro/terapia , Oximetria/métodos , Cérebro , Ultrassonografia , Retinopatia da Prematuridade/etiologia , Enterocolite Necrosante/etiologia , Sepse Neonatal/etiologiaRESUMO
INTRODUCTION: Using pre-procedure analgesia with the risk of apnoea may complicate the Less Invasive Surfactant Administration (LISA) procedure or reduce the effect of LISA. METHODS: The NONA-LISA trial (ClinicalTrials.gov, NCT05609877) is a multicentre, blinded, randomised controlled trial aiming at including 324 infants born before 30 gestational weeks, meeting the criteria for surfactant treatment by LISA. Infants will be randomised to LISA after administration of fentanyl 0.5-1 mcg/kg intravenously (fentanyl group) or isotonic saline solution intravenously (saline group). All infants will receive standardised non-pharmacological comfort care before and during the LISA procedure. Additional analgesics will be provided at the clinician's discretion. The primary outcome is the need for invasive ventilation, meaning mechanical or manual ventilation via an endotracheal tube, for at least 30 min (cumulated) within 24 h of the procedure. Secondary outcomes include the modified COMFORTneo score during the procedure, bronchopulmonary dysplasia at 36 weeks, and mortality at 36 weeks. DISCUSSION: The NONA-LISA trial has the potential to provide evidence for a standardised approach to relief from discomfort in preterm infants during LISA and to reduce invasive ventilation. The results may affect future clinical practice. IMPACT: Pre-procedure analgesia is associated with apnoea and may complicate procedures that rely on regular spontaneous breathing, such as Less Invasive Surfactant Administration (LISA). This randomised controlled trial addresses the effect of analgesic premedication in LISA by comparing fentanyl with a placebo (isotonic saline) in infants undergoing the LISA procedure. All infants will receive standardised non-pharmacological comfort. The NONA-LISA trial has the potential to provide evidence for a standardised approach to relief from discomfort or pain in preterm infants during LISA and to reduce invasive ventilation. The results may affect future clinical practice regarding analgesic treatment associated with the LISA procedure.
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BACKGROUND: Neurodevelopmental disorders are the most common and distressful comorbidities associated with congenital heart defects (CHD). Head circumference at birth (HC), a proxy for prenatal cerebral growth, is an established risk factor for neurodevelopmental disorders. METHODS AND RESULTS: In a nationwide cohort, we included all 924 422 liveborn Danish singletons, 1997 to 2011. CHD was present in 5519. The association between CHD and growth indices was analyzed by multivariable linear regression, adjusted for potential confounders. We report mean differences in gestational age-specific z scores in comparison with the general population. CHD was associated with lower HC z scores, -0.10 (95% confidence interval [CI], -0.13 to -0.08). Several CHD subtypes were associated with smaller HC, eg, hypoplastic left heart syndrome, -0.39 (95% CI, -0.58 to -0.21); common arterial trunk, -0.41 (95% CI, -0.74 to -0.09); and major ventricular septal defects, -0.25 (95% CI, -0.35 to -0.15). Other single-ventricle defects, transposition of the great arteries, tetralogy of Fallot, and anomalous pulmonary venous return, were also associated with smaller HC. Transposition of the great arteries was associated with smaller HC relative to birth weight, -0.26 (95% CI, -0.39 to -0.13). Major ventricular septal defects were associated with larger HC relative to birth weight. The results were consistent under various conditions, eg, when siblings of infants with CHD (n=5311) or infants with other major malformations (n=24 974) were used as the reference. CONCLUSIONS: Several subtypes of CHD were associated with smaller HC. The associations with major ventricular septal defects, common arterial trunk, and anomalous pulmonary venous return have not previously been described. Only infants with transposition of the great arteries had smaller HC relative to birth weight.
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Encéfalo/embriologia , Encéfalo/crescimento & desenvolvimento , Desenvolvimento Fetal/fisiologia , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/epidemiologia , Adulto , Estudos de Coortes , Dinamarca/epidemiologia , Feminino , Humanos , Recém-Nascido , Masculino , GravidezRESUMO
BACKGROUND: Congenital heart defects (CHDs) have been associated with placental anomalies. The nature and the consequences of this association remain poorly understood. We aimed to estimate the associations between all major subtypes of CHD and placental weight at birth, and the association between placental weight and measures of both overall and cerebral growth in fetuses with CHD, as well. METHODS: We included all 924 422 liveborn Danish singletons, 1997 to 2011. CHD was present in 7569. We compared mean differences in placental weight z score between newborns with CHD and newborns without CHD by multivariable linear regression adjusted for potential confounders. RESULTS: CHD was associated with a mean z score difference of -0.04 (95% confidence interval, -0.07 to -0.02). Some subtypes were associated with smaller placental size at birth: tetralogy of Fallot, -0.45 (95% confidence interval, -0.58 to -0.31); double-outlet right ventricle, -0.48 (95% confidence interval, -0.87 to -0.10); major ventricular septal defects, -0.41 (95% confidence interval, -0.52 to -0.29). Placental weight z score was associated with birth weight and head circumference z scores in all subtypes. In the 3 mentioned subtypes, the mean deviations from the population mean head circumference and birth weight z scores were reduced by up to 66% with adjustment for placental weight z score. CONCLUSIONS: Three subtypes of CHD were associated with lower placental weight, and placental weight was associated with measures of both overall growth and cerebral growth in fetuses with all subtypes of CHD. In certain subtypes, the described deviations in fetal growth were reduced by up to two-thirds after adjustment for placental weight z score.
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Peso ao Nascer , Desenvolvimento Fetal/fisiologia , Cardiopatias Congênitas/epidemiologia , Placenta/fisiopatologia , Feminino , Humanos , Recém-Nascido , Masculino , GravidezRESUMO
OBJECTIVES: To estimate the association between congenital heart defects (CHD) and indices of fetal growth in Down and 22q11.2 deletion syndromes. STUDY DESIGN: We established 2 Danish nationwide cohorts of newborn singletons with either Down syndrome (n = 670) or 22q11.2 deletion syndrome (n = 155), born 1997-2011. In both cohorts, we analyzed the association between CHD, CHD severity, and indices of fetal growth by multivariable linear regression adjusted for potential confounders. We report mean differences in gestational age specific z-scores compared with newborns without CHD. RESULTS: Down syndrome and 22q11.2 deletion syndrome were both associated with lower mean birth weight and head circumference z-scores. We found no association between CHD or CHD severity and indices of fetal growth. In Down syndrome, the association between any CHD and the mean difference in head circumference z-score was 0.03 (95% CI -0.12, 0.18), and the estimate regarding birth weight z-score was 0.09 (95% CI -0.08, 0.25). The corresponding estimates in 22q11.2 deletion syndrome were 0.00 (95% CI -0.33, 0.32) and -0.09 (95% CI -0.45, 0.26). CONCLUSIONS: We found no association between CHD and fetal growth measures in newborns with Down syndrome or 22q11.2 deletion syndrome. Thus, in certain subtypes of CHD, the contribution of genetic factors to prenatal growth impairment may be more important than circulatory disturbances.
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Síndrome de DiGeorge/embriologia , Síndrome de Down/embriologia , Desenvolvimento Fetal , Cardiopatias Congênitas/embriologia , Peso ao Nascer , Cefalometria , Feminino , Desenvolvimento Fetal/genética , Desenvolvimento Fetal/fisiologia , Cabeça/anatomia & histologia , Cabeça/embriologia , Humanos , Recém-Nascido , Modelos Lineares , Masculino , Sistema de Registros , Índice de Gravidade de DoençaRESUMO
The prevalence of the 22q11.2 duplication is unknown in children with cardiovascular malformations (CVMs). As most individuals with the duplication are detected in the search for other conditions, especially the 22q11.2 deletion, CVMs associated with the duplication are subject to referral bias. We circumvented this bias by investigating the prevalence of the 22q11.2 duplication in a population-based cohort of children with CVMs. The study population was defined as children born in 2000-2008, who were registered in the Danish National Patient Registry with a diagnosis of CVM from one of the two national university departments of pediatric cardiology. Sensitive multiplex ligation-dependent probe amplification was performed on dried blood spot samples from each individual's neonatal screening test. The study population consisted of 2,952 children with CVMs, 2,424 of whom were eligible for genetic testing; 13 individuals (0.5% [0.3-0.9%]) carried the duplication. Nine individuals (69%) had not previously been tested for a copy number variation on chromosome 22q11.2 in the clinical setting for children with CVMs. We conclude that 22q11.2 duplication is rare in children with CVMs, and is primarily found in malformations that are also associated with the 22q11.2 deletion.
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Duplicação Cromossômica , Cromossomos Humanos Par 22 , Vigilância da População , Criança , Estudos de Coortes , Dinamarca , Ligação Genética , Humanos , Recém-NascidoRESUMO
Deletion of chromosome 22q11.2 is considered one of the most frequent genetic causes of cardiovascular malformations. It is frequently associated with conotruncal malformations, but may also be present among patients with nonconotruncal malformations. The aim of the present study was to establish the prevalence of the 22q11.2 deletion in an unselected population-based cohort of children with various cardiovascular malformations. The study population was defined as children born in 2000-2008 who were registered in the Danish National Patient Registry with a diagnosis of cardiovascular malformation from one of the two national departments of pediatric cardiology. Sensitive multiplex ligation-dependent probe amplification was performed on dried blood spot samples from each individual's neonatal screening test. Of 2,952 children with cardiovascular malformations, 2,478 were eligible for genetic testing. A total of 46 individuals (1.9% [1.4-2.5%]) carried the deletion, with the highest prevalence among individuals registered with interrupted aortic arch (22% [11-40]). The most frequent diagnoses among individuals carrying the deletion were tetralogy of Fallot (n = 15) and ventricular septal defect (n = 15). One in four cases had not been diagnosed in the usual clinical setting. The prevalence of 22q11.2 deletions in an unselected population-based cohort of children with cardiac malformations was 1.9% [1.4-2.5%]. Genetic testing of every individual registered with a conotruncal malformation would have achieved a diagnostic sensitivity of 70% in the present cohort. Prospective studies outlining testing recommendations in children with ventricular septal defect are warranted.
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Anormalidades Cardiovasculares/genética , Deleção Cromossômica , Cromossomos Humanos Par 22 , Vigilância da População , Criança , Dinamarca , HumanosRESUMO
INTRODUCTION: No consensus exists regarding the ability to detect the 22q11 deletion syndrome based on clinical assessment. Traditionally, diagnosis depends on clinical referral. Thus, individuals with typical manifestations are easily identified, but when manifestations are atypical or subclinical, diagnosis may be delayed or even missed. The aim of the present literature review was to evaluate the validity of clinical assessment as a method of predicting 22q11.2 deletions in individuals with congenital cardiac malformations. METHODS: We identified 14 studies in which clinical assessment was blinded to the result from the genetic analysis. RESULTS: Among 1458 patients, 159 (11% [9-13%]) carried the 22q11.2 deletion. The clinicians correctly identified 110 (69% [62-76%]) of them, whereas 49 (31% [24-38%]) would have remained undiagnosed if genetic screening had not been performed. Sensitivity, specificity, predictive value of positive and negative tests ranged from 0-100%, 43-100%, 7-100%, and 79-100%, respectively. CONCLUSIONS: Clinical assessment identifies less than 3/4 patients with a 22q11.2 deletion, whereas more than 1/4 remain undiagnosed if genetic tests are not performed on a routine basis. In this review, we found that clinical assessment is not suited for detecting individuals to be tested for 22q11.2 deletions.
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Deleção Cromossômica , Cromossomos Humanos Par 22/genética , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/genética , Testes Genéticos , Coração/fisiopatologia , Cardiopatias Congênitas/fisiopatologia , Humanos , Miocárdio/metabolismo , Miocárdio/patologia , Sensibilidade e EspecificidadeRESUMO
INTRODUCTION: The present study was conducted to establish the positive predictive value of congenital cardiac malformation diagnoses registered in the Danish National Patient Registry (NPR), thereby exploring whether the NPR can serve as a valid tool for epidemiologic studies of congenital cardiac malformations. MATERIALS AND METHODS: The study population comprised every individual born from 2000 to 2008 who was registered in the NPR with a congenital cardiac malformation diagnosis and treated at one of the two national departments of pediatric cardiology. Positive predictive values were established comparing NPR information with the clinical record of each individual. RESULTS: A total of 2952 patients with a total of 3536 diagnoses were eligible for validation. Review of their clinical records unveiled no patient without cardiac malformation. In 98% (98%-99%) of the cases, the NPR diagnosis could be found as the discharge diagnosis in the patient's clinical record, and in 90% (89%-91%) of the cases the NPR diagnosis was considered a true reflection of the patient's actual malformation. CONCLUSIONS: Our study verifies that the present study population retrieved from the NPR is a valid tool for epidemiological research within the topic of congenital cardiac malformations, given that the research question is not dependent on a fully established sensitivity of the NPR. Precautions should be made regarding cardiac malformations characterized by low prevalence or poor predictive values, and the reported validity should not be extrapolated beyond the study period.
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22q11 deletion syndrome is one of the most frequent syndromes with an estimated prevalence of 1:2000-4000 live births. The syndrome is known to be associated with congenital cardiac malformations, hypocalcaemia and immunodeficiency. We present two cases with rhinopharyngeal insufficiency, cognitive impairment, developmental delay and behavioural problems. These symptoms are even more often associated with the syndrome than the former manifestations. Early diagnosis is important to prevent complications and provide proper support to patient and family.
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Síndrome de DiGeorge/genética , Pré-Escolar , Síndrome de DiGeorge/complicações , Síndrome de DiGeorge/diagnóstico , Diagnóstico Precoce , Feminino , Variação Genética/genética , Humanos , Lactente , Recém-Nascido , Fenótipo , Apoio SocialRESUMO
The 22q11 deletion syndrome, which is caused by a 1.5- to 3.0-megabase hemizygous deletion in chromosome 22q11.2, has a prevalence of 1/2000 to 1/4000. However, the syndrome presents with highly variable phenotypes and thus may be underestimated among Danish newborns. To establish a true incidence of 22q11.2 deletions among certain manifestations, eg, congenital heart disease, on selected Danes, a multiplex ligation-dependant probe amplification (MLPA) analysis was designed. The analysis was planned to be performed on DNA extracted from dried blood spot samples (DBSS) obtained from Guthrie cards collected during neonatal screening programs. However, the DNA concentration necessary for a standard MLPA analysis (20 ng) could not be attained from DBSS, and a novel MLPA design was developed to permit for analysis on limited amounts of DNA (2 ng). A pilot study is reported here that validates the new MLPA design using nine patients diagnosed with the 22q11.2 deletion and 101 controls. All deletions were identified using DNA extracted from DBSS, and no copy number variations were detected in the controls, resulting in a specificity and sensitivity of 100%. It is thereby concluded that the novel MLPA probe design is successful and reliable using minimal amounts of DNA. This allows for use of DBSS samples in a retrospective study of 22q11.2 deletion among certain manifestations associated with DiGeorge Syndrome.
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Deleção Cromossômica , Cromossomos Humanos Par 22/genética , Recém-Nascido , Técnicas de Amplificação de Ácido Nucleico/métodos , Criança , DNA/análise , DNA/genética , Variações do Número de Cópias de DNA , Dinamarca , Humanos , Recém-Nascido/sangue , Programas de Rastreamento/métodosRESUMO
22q11 deletion syndrome (formerly named CATCH22, DiGeorge, Velo-Cardio-Facial, Caylor, Kinouchi and Shprintzen syndrome) occurs in approximately 1/2000 to 4000 children. The genetic lesion is remarkably uniform, occurring mainly as 3 or 1.5 MB deletions in the 22q11.2 region. However, the clinical manifestations are variable and manifestation in several organ systems often occur. In this review we describe the various manifestations of the syndrome. Finally, we suggest strategies for diagnosing, evaluating and organizing the treatment for Danish patients with this syndrome.