Outcome in very preterm infants: a population-based study from a regional center in Austria.

Aim: To determine short-term morbidity and mortality rates in the first state-wide Austrian neonatal cohort and comparison to (inter)national data. Methods: Observational, population-based cohort study, analyzing data of preterm infants (<32 + 0 weeks of gestation) born between 2007 and 2020 (n = 501) in an Austrian state who were admitted to the neonatal intensive care unit. Outcome criteria were mortality, neonatal morbidities: bronchopulmonary dysplasia (BPD), severe necrotizing enterocolitis (NEC), severe intraventricular hemorrhage (IVH grades III-IV), severe retinopathy of prematurity (ROP grades III-V) and survival-free of major complications. Results: Overall survival rate was 95%, survival free of major complications was 79%. Prevalence for BPD was 11.2%, surgical NEC 4.0%, severe IVH 4.6%, and for severe ROP 2.6%, respectively. In the extremely low gestational age neonates (ELGAN) born <28 weeks of gestation (n = 158), survival was 88% and survival free of major complications 58.8%. Over time, mortality decreased significantly, predominantly driven by the improvement of infants born <28 week of gestation and survival free of major complications improved. Conclusions: This study demonstrates a very low mortality rate that decreases over time. Short-term morbidities and survival free of major complications do not differ from (inter)national data in a similar group of very preterm infants. Standard operating procedures, simulation trainings and accordance to international trials may improve patient care and surpass center case loads.

Psychomotor and Cognitive Outcome in Very Preterm Infants in Vorarlberg, Austria, 2007-2019.

AIM: The aim of this study was to analyze neurodevelopmental outcome of very and extremely preterm infants in Vorarlberg, Austria, accessed with neurodevelopmental testing, at the corrected age of 24 months. This article also compared these results with (inter)national data and analyzed the impact of perinatal parameters. METHODS: Population-based, retrospective multicenter study with data on very and extremely preterm infants born in Vorarlberg from 2007 to 2019 assessed with Bayley Scales of Infant Development (BSID-II/Bayley-III). RESULTS: Included were 264 infants with a mean age of 29.0 (± 2.1) weeks of gestational age and a mean birth weight of 1177 (± 328.26) g; 172 infants underwent a BSID-II, 92 a Bayley-III assessment. The psychomotor developmental index (PDI) and mental developmental index (MDI) showed mean scores of 99.6 (± 14.4) and 91 (± 20.4), respectively. Adverse outcomes (scores <70) were assessed in 4.2% for PDI and 15.5% for MDI. In the extremely preterm group (n = 79), results for mean PDI were 100.1 (± 16.8) and for mean MDI 88.4 (± 22.4). Accordingly, adverse outcomes were assessed in 5.1% for PDI and in 20.3% for MDI. In addition to bronchopulmonary dysplasia and intraventricular hemorrhage Grade 3-4, head circumference at birth and patent ductus arteriosus were also identified as risk factors for poor outcome. CONCLUSION: This study showed a remarkably good neurodevelopmental outcome in preterm infants with low rates of adverse outcome, similar to (inter)national reports, especially in the group of extremely preterm infants. Research is needed to explore the role of social factors and infants' environment, especially cognitive outcome and language skills.

Chorioamnionitis and neurodevelopmental outcome in very preterm infants from 2007 to 2017-a population-based study.

AIM: The study compares neurodevelopmental outcome at 24 months corrected age of very preterm infants exposed to chorioamnionitis and controls. Peripartal parameters which may influence outcome are also investigated. METHODS: In this observational population-based study, very preterm infants born between 2007 and 2017 were eligible (n = 466) and included if a histological placental examination and a complete neurodevelopmental assessment (Bayley Scale of Infant Development II or III) (n = 168) were performed. Secondary analyses were calculated to identify peripartal factors that significantly influence mental and psychomotor outcome. RESULTS: Included infants showed a mean MDI of 91.2 (SD = 20.7) and a mean PDI of 99.4 (SD = 14.8). Infants with (n = 71) and without (n = 97) chorioamnionitis did not statistically differ either with mean MDI (91.8 vs. 90.3 points; p = 0.29) or mean PDI (98.3 vs. 100.9 points; p = 0.81), even after controlling for gestational age, mean APGAR scores and administration of antenatal steroids. Bronchopulmonary dysplasia was identified as the most influential factor for both MDI (p = .024) and PDI (p = .004). CONCLUSION: We could not find an effect of chorioamnionitis on neurodevelopmental outcome of very preterm infants over an eleven-year period. Analysis shows that postnatal factors have higher impacts than does chorioamnionitis.

A Syrian patient with Steel syndrome due to compound heterozygous COL27A1 mutations with colobomata of the eye.

The joint occurrence of short stature, congenital dislocation of the hip, carpal coalition, dislocation of the radial head, cavus deformity, scoliosis, and vertebral anomalies was first described in 1993 by Steel et al. (OMIM #615155) in 23 children from Puerto Rico. The condition is caused by a deficient matrix protein, collagen type XXVII alpha 1 chain, due to bi-allelic loss of function mutations in the gene COL27A1. Outside of Puerto Rico, only four families have been described, in three of which the patients also had hearing loss. However, structural eye defects have not yet been reported in conjunction with this rare autosomal recessive syndrome. Here, we describe a 9-year-old girl born to nonconsanguineous Syrian parents with the characteristic features of Steel syndrome, including short stature, massive malalignment of large joints, kyphoscoliosis, hearing loss, and typical facial dysmorphism. However, she was also born with bilateral colobomata of the irides and choroido-retinae with unilateral affection of the macula. Whole exome sequencing identified two pathogenic compound heterozygous variants in COL27A1: c.93del, p.(Phe32Leufs*71) and c.3075del, p.(Lys1026Argfs*33). There was no discernible alternative cause for the colobomata. Our findings might indicate an association of this exceptionally rare disorder caused by COL27A1 mutations with developmental defects of the eye from the anophthalmia/microphthalmia/coloboma spectrum.

Effect of Sustained Inflations vs Intermittent Positive Pressure Ventilation on Bronchopulmonary Dysplasia or Death Among Extremely Preterm Infants: The SAIL Randomized Clinical Trial.

Importance: Preterm infants must establish regular respirations at delivery. Sustained inflations may establish lung volume faster than short inflations. Objective: To determine whether a ventilation strategy including sustained inflations, compared with standard intermittent positive pressure ventilation, reduces bronchopulmonary dysplasia (BPD) or death at 36 weeks' postmenstrual age without harm in extremely preterm infants. Design, Setting, and Participants: Unmasked, randomized clinical trial (August 2014 to September 2017, with follow-up to February 15, 2018) conducted in 18 neonatal intensive care units in 9 countries. Preterm infants 23 to 26 weeks' gestational age requiring resuscitation with inadequate respiratory effort or bradycardia were enrolled. Planned enrollment was 600 infants. The trial was stopped after enrolling 426 infants, following a prespecified review of adverse outcomes. Interventions: The experimental intervention was up to 2 sustained inflations at maximal peak pressure of 25 cm H2O for 15 seconds using a T-piece and mask (n = 215); standard resuscitation was intermittent positive pressure ventilation (n = 211). Main Outcome and Measures: The primary outcome was the rate of BPD or death at 36 weeks' postmenstrual age. There were 27 prespecified secondary efficacy outcomes and 7 safety outcomes, including death at less than 48 hours. Results: Among 460 infants randomized (mean [SD] gestational age, 25.30 [0.97] weeks; 50.2% female), 426 infants (92.6%) completed the trial. In the sustained inflation group, 137 infants (63.7%) died or survived with BPD vs 125 infants (59.2%) in the standard resuscitation group (adjusted risk difference [aRD], 4.7% [95% CI, -3.8% to 13.1%]; P = .29). Death at less than 48 hours of age occurred in 16 infants (7.4%) in the sustained inflation group vs 3 infants (1.4%) in the standard resuscitation group (aRD, 5.6% [95% CI, 2.1% to 9.1%]; P = .002). Blinded adjudication detected an imbalance of rates of early death possibly attributable to resuscitation (sustained inflation: 11/16; standard resuscitation: 1/3). Of 27 secondary efficacy outcomes assessed by 36 weeks' postmenstrual age, 26 showed no significant difference between groups. Conclusions and Relevance: Among extremely preterm infants requiring resuscitation at birth, a ventilation strategy involving 2 sustained inflations, compared with standard intermittent positive pressure ventilation, did not reduce the risk of BPD or death at 36 weeks' postmenstrual age. These findings do not support the use of ventilation with sustained inflations among extremely preterm infants, although early termination of the trial limits definitive conclusions. Trial Registration: clinicaltrials.gov Identifier: NCT02139800.

Doublesex and mab-3 related transcription factor 1 (DMRT1) is a sex-specific genetic determinant of childhood-onset asthma and is expressed in testis and macrophages.

BACKGROUND: Asthma is a disease affecting more boys than girls in childhood and more women than men in adulthood. The mechanisms behind these sex-specific differences are not yet understood. OBJECTIVE: We analyzed whether and how genetic factors contribute to sex-specific predisposition to childhood-onset asthma. METHODS: Interactions between sex and polymorphisms on childhood asthma risk were evaluated in the Multicentre Asthma Genetics in Childhood Study (MAGICS)/Phase II International Study of Asthma and Allergies in Childhood (ISAAC II) population on a genome-wide level, and findings were validated in independent populations. Genetic fine mapping of sex-specific asthma association signals was performed, and putatively causal polymorphisms were characterized in vitro by using electrophoretic mobility shift and luciferase activity assays. Gene and protein expression of the identified gene doublesex and mab-3 related transcription factor 1 (DMRT1) were measured in different human tissues by using quantitative real-time PCR and immunohistochemistry. RESULTS: Polymorphisms in the testis-associated gene DMRT1 displayed interactions with sex on asthma status in a population of primarily clinically defined asthmatic children and nonasthmatic control subjects (lowest P = 5.21 × 10(-6)). Replication of this interaction was successful in 2 childhood populations clinically assessed for asthma but showed heterogeneous results in other population-based samples. Polymorphism rs3812523 located in the putative DMRT1 promoter was associated with allele-specific changes in transcription factor binding and promoter activity in vitro. DMRT1 expression was observed not only in the testis but also in lung macrophages. CONCLUSION: DMRT1 might influence sex-specific patterns of childhood asthma, and its expression in testis tissue and lung macrophages suggests a potential involvement in hormone or immune cell regulation.

[The Fetal Tobacco Syndrome - A statement of the Austrian Societies for General- and Family Medicine (ÖGAM), Gynecology and Obstetrics (ÖGGG), Hygiene, Microbiology and Preventive Medicine (ÖGHMP), Pediatrics and Adolescence Medicine (ÖGKJ) as well as Pneumology (ÖGP)]. / Das Fetale Tabaksyndrom - Ein Statement der Österreichischen Gesellschaften für Allgemein- und Familienmedizin (ÖGAM), Gynäkologie und Geburtshilfe (ÖGGG), Hygiene, Mikrobiologie und Präventivmedizin (ÖGHMP), Kinder- und Jugendheilkunde (ÖGKJ) sowie Pneumologie (ÖGP).

Over more than 50 years, the nocuous effects of smoking in pregnancy on the fetus are well known. In the first years of science the focus was primarily on restricted fetal growth while in more recent years over 10.000 studies investigated the incomparably big sum of detrimental effects for the unborn's health. In this statement we want to present the recent scientific findings on this topic. The statement is aimed to show all doctors who treat pregnant women the present situation and evidence. In the beginning we give a short overview about the epidemiological situation in Europe. Then we present step by step the health effects with regards to pathophysiology and clinics. Furthermore the reader will learn about possibilities for smoking cessation in pregnancy. The problem of passive-smoking in pregnancy will be dealt with in a separate chapter. At present there is strong evidence that pregnant smoking has a detrimental effect on birth-weight, placenta-associated disease, stillbirth, sudden infant death syndrome (SIDS), childhood overweight, clefts, lung function, asthma, cardiovascular diseases and mental developmental disorders. These factors can be summarized by the term Fetal Tobacco Syndrome. There is supply for more studies for less investigated health effects. Pregnancy is a chance to stop smoking as most women show a high motivation in this period. Hence doctors of all disciplines should inform pregnant women about the detrimental effects of smoking on their unborn child and show them possibilities for smoking cessation.

Unifying candidate gene and GWAS Approaches in Asthma.

The first genome wide association study (GWAS) for childhood asthma identified a novel major susceptibility locus on chromosome 17q21 harboring the ORMDL3 gene, but the role of previous asthma candidate genes was not specifically analyzed in this GWAS. We systematically identified 89 SNPs in 14 candidate genes previously associated with asthma in >3 independent study populations. We re-genotyped 39 SNPs in these genes not covered by GWAS performed in 703 asthmatics and 658 reference children. Genotyping data were compared to imputation data derived from Illumina HumanHap300 chip genotyping. Results were combined to analyze 566 SNPs covering all 14 candidate gene loci. Genotyped polymorphisms in ADAM33, GSTP1 and VDR showed effects with p-values <0.0035 (corrected for multiple testing). Combining genotyping and imputation, polymorphisms in DPP10, EDN1, IL12B, IL13, IL4, IL4R and TNF showed associations at a significance level between p = 0.05 and p = 0.0035. These data indicate that (a) GWAS coverage is insufficient for many asthma candidate genes, (b) imputation based on these data is reliable but incomplete, and (c) SNPs in three previously identified asthma candidate genes replicate in our GWAS population with significance after correction for multiple testing in 14 genes.

Prenatal and postnatal treatment in cobalamin C defect.

OBJECTIVE: To evaluate prenatal treatment with hydroxycobalamin (OH-Cbl) in a pregnancy at risk for a severe form of the cobalamin C defect and postnatal treatment of the affected child. STUDY DESIGN: Observational study with non-randomized intervention. RESULTS: In contrast to reported pregnancies with affected fetuses in which maternal methylmalonic aciduria was found in the last trimester of pregnancy, there was no maternal methylmalonic aciduria in our case, given prenatal treatment with intramuscular OH-Cbl. We did not find that the concentration of odd long-chain fatty acids in cord blood erythrocytes reflects fetal methylmalonic academia. After birth, the infant was treated with intramuscular OH-Cbl and oral carnitine. Oral folate and betaine were added as adjunct therapy to decrease plasma total homocysteine. Because of inadequate metabolic control, a diet reduced in natural protein was introduced. The child had normal developmental milestones but had nystagmus, hyperpigmented retinopathy, and discrete truncal muscular hypotonia. CONCLUSIONS: Despite prenatal and postnatal treatment, adequate metabolic control, absence of metabolic crises, and normal developmental milestones, this patient with the cobalamin C defect had characteristic symptoms of the disease.

Loss of intrahepatic bile ducts: an important feature of familial hemophagocytic lymphohistiocytosis.

Familial hemophagocytic lymphohistiocytosis (FHL) is a rare, fatal disorder of early infancy. We report two siblings with FHL whose symptoms were dominated by hepatic failure. Both presented with sudden-onset fever and hepatosplenomegaly with progressive abnormalities of clinical biochemistry indices of liver function. One died of hepatorenal failure. The other underwent liver transplantation. Autopsy and explant liver displayed portal and periportal infiltrates of T lymphocytes and histiocytes; an activation of the hepatic mononuclear phagocytic system with focal hemophagocytosis; and almost complete loss of interlobular bile ducts. Paucity of bile ducts dominated in a pre-transplant liver biopsy specimen (and transiently obscured the diagnosis of FHL). Disease recurred in the allograft, again with lymphohistiocytic infiltration and destruction of interlobular bile ducts. Consequently the patient underwent haploidentical peripheral stem cell transplantation. This patient is alive 5 years later. Loss of bile ducts may be an important feature of hepatic involvement by FHL.

Successful treatment of ARDS and severe pulmonary hypertension in a child with Bordetella pertussis infection.

Infection with Bordetella pertussis can cause severe illness with neurological and pulmonary complications in children. Pulmonary hypertension is an early sign of potentially fatal disease and can cause failure of conventional respiratory therapy in severe acute respiratory distress syndrome (ARDS). We report a 4 1/2-year-old boy with B. pertussis infection who developed severe ARDS and pulmonary hypertension. Because of severe neurological signs the patient did not qualify for extracorporal membrane oxygenation (ECMO). After conventional ventilation, surfactant and high frequency oscillation ventilation (HFOV) failed, treatment with nitric oxide (NO) improved oxygenation, allowing recovery without the need for ECMO. The patient survived with few sequelae. Thus, this treatment may be an option in high-risk children who meet the criteria for ECMO but are excluded because of poor neurological status, as in our patient.

Congenital cystic lung disease: diagnostic and therapeutic considerations.

Congenital lung cysts such as congenital cystic adenomatoid malformation, pulmonary sequestration, congenital lobar emphysema, and bronchogenic cysts are rare but fascinating anomalies of lung development. While there are many similarities in terms of their presenting features, there are particular differences between the diagnostic groups that are important to highlight, especially in relationship to approaches to imaging and long-term outcome. A case of each entity is presented with an emphasis on the contemporary approach to diagnostic investigations and therapeutic options.