Two-year neurodevelopmental outcome in children born extremely preterm:the EPI-DAF study

OBJECTIVE: In 2010, the Dutch practice regarding initiation of active treatment in extremely preterm infants was lowered from 25 completed weeks' to 24 completed weeks' gestation. The nationwide Extremely Preterm Infants - Dutch Analysis on Follow-up Study was set up to provide up-to-date data on neurodevelopmental outcome at 2 years' corrected age (CA) after this guideline change. Design: National cohort study. PATIENTS: All live born infants between 240/7 weeks' and 266/7 weeks' gestational age who were 2 years' CA in 2018-2020. MAIN OUTCOME MEASURE: Impairment at 2 years' CA, based on cognitive score (Bayley-III-NL), neurological examination and neurosensory function. RESULTS: 651 of 991 live born infants (66%) survived to 2 years' CA, with data available for 554 (85%). Overall, 62% had no impairment, 29% mild impairment and 9% moderate-to-severe impairment (further defined as neurodevelopmental impairment, NDI). The percentage of survivors with NDI was comparable for infants born at 24 weeks', 25 weeks' and 26 weeks' gestation. After multivariable analysis, severe brain injury and low maternal education were associated with higher odds on NDI. NDI-free survival was 48%, 67% and 75% in neonatal intensive care unit (NICU)-admitted infants at 24, 25 and 26 weeks' gestation, respectively. CONCLUSIONS: Lowering the threshold has not been accompanied by a large increase in moderate-to-severely impaired infants. Among live-born and NICU-admitted infants, an increase in NDI-free survival was observed from 24 weeks' to 26 weeks' gestation. This description of a national cohort with high follow-up rates gives an accurate description of the range of outcomes that may occur after extremely preterm birth

Neurodevelopmental outcome at 5.5 years in Dutch preterm infants born at 24–26 weeks’ gestational age: the EPI-DAF study

Objective After lowering the Dutch threshold for active treatment from 25 to 24 completed weeks’ gestation, survival to discharge increased by 10% in extremely preterm live born infants. Now that this guideline has been implemented, an accurate description of neurodevelopmental outcome at school age is needed. Design Population-based cohort study. Setting All neonatal intensive care units in the Netherlands. Patients All infants born between 240/7 and 266/7 weeks’ gestation who were 5.5 years’ corrected age (CA) in 2018–2020 were included. Main outcome measures Main outcome measure was neurodevelopmental outcome at 5.5 years. Neurodevelopmental outcome was a composite outcome defined as none, mild or moderate-to-severe impairment (further defined as neurodevelopmental impairment (NDI)), using corrected cognitive score (Wechsler Preschool and Primary Scale of Intelligence Scale-III-NL), neurological examination and neurosensory function. Additionally, motor score (Movement Assessment Battery for Children-2-NL) was assessed. All assessments were done as part of the nationwide, standardised follow-up programme. Results In the 3-year period, a total of 632 infants survived to 5.5 years’ CA. Data were available for 484 infants (77%). At 5.5 years’ CA, most cognitive and motor (sub)scales were significantly lower compared with the normative mean. Overall, 46% had no impairment, 36% had mild impairment and 18% had NDI. NDI-free survival was 30%, 49% and 67% in live born children at 24, 25 and 26 weeks’ gestation, respectively (p<0.001). Conclusions After lowering the threshold for supporting active treatment from 25 to 24 completed weeks’ gestation, a considerable proportion of the surviving extremely preterm children did not have any impairment at 5.5 years’ CA

Neonatal cholestasis, hyperferritinemia, hypoglycemia and deafness:a diagnostic challenge

Neonatal conjugated hyperbilirubinemia is a diagnostic challenge. A full term, small for gestational age boy presented with cholestasis, hypoglycemia, hyperferritinemia and severe bilateral deafness. Diagnostic work-up revealed two hereditary diseases: alpha-1-antitrypsin deficiency (PI*ZZ genotype) and autosomal recessive deafness type 3 (compound heterozygous MYO15A gene mutation). In addition, we found late hypoglycemia on full enteral feeding which complicated this case. Hyperferritinemia is an uncommon finding in newborn cholestasis without liver failure

Placing <i>Ureaplasma</i> within the Context of Bronchopulmonary Dysplasia Endotypes and Phenotypes

Different pathophysiological pathways (endotypes), leading to very preterm birth may result in distinct clinical phenotypes of bronchopulmonary dysplasia (BPD). Ureaplasma is a unique player in the pathogenesis of BPD. The interaction between factors inherent to Ureaplasma (virulence, bacterial load, duration of exposure), and to the host (immune response, infection clearance, degree of prematurity, respiratory support, concomitant infections) may contribute to BPD development in a variable manner. The data reviewed herein support the hypothesis that Ureaplasma, as a representative of the infectious/inflammatory endotype, may produce pulmonary damage predominantly in parenchyma, interstitium, and small airways. In contrast, Ureaplasma may have a very limited role in the pathogenesis of the vascular phenotype of BPD. In addition, if Ureaplasma is a key factor in BPD pathogenesis, its eradication by macrolides should prevent BPD. However, various meta-analyses do not show consistent evidence that this is the case. The limitations of current definitions and classifications of BPD, based on respiratory support needs instead of pathophysiology and phenotypes, may explain this and other failures in strategies aimed to prevent BPD. The precise mechanisms through which Ureaplasma infection leads to altered lung development and how these pathways can result in different BPD phenotypes warrant further investigation

Endotypes of Prematurity and Phenotypes of Bronchopulmonary Dysplasia:Toward Personalized Neonatology

Bronchopulmonary dysplasia (BPD), the chronic lung disease of prematurity, is increasingly recognized as the consequence of a pathological reparative response of the developing lung to both antenatal and postnatal injury. According to this view, the pathogenesis of BPD is multifactorial and heterogeneous with different patterns of antenatal stress (endotypes) that combine with varying postnatal insults and might distinctively damage the development of airways, lung parenchyma, interstitium, lymphatic system, and pulmonary vasculature. This results in different clinical phenotypes of BPD. There is no clear consensus on which are the endotypes of prematurity but the combination of clinical information with placental and bacteriological data enables the identification of two main pathways leading to birth before 32 weeks of gestation: (1) infection/inflammation and (2) dysfunctional placentation. Regarding BPD phenotypes, the following have been proposed: parenchymal, peripheral airway, central airway, interstitial, congestive, vascular, and mixed phenotype. In line with the approach of personalized medicine, endotyping prematurity and phenotyping BPD will facilitate the design of more targeted therapeutic and prognostic approaches

Endotypes of Prematurity and Phenotypes of Bronchopulmonary Dysplasia: Toward Personalized Neonatology

Bronchopulmonary dysplasia (BPD), the chronic lung disease of prematurity, is increasingly recognized as the consequence of a pathological reparative response of the developing lung to both antenatal and postnatal injury. According to this view, the pathogenesis of BPD is multifactorial and heterogeneous with different patterns of antenatal stress (endotypes) that combine with varying postnatal insults and might distinctively damage the development of airways, lung parenchyma, interstitium, lymphatic system, and pulmonary vasculature. This results in different clinical phenotypes of BPD. There is no clear consensus on which are the endotypes of prematurity but the combination of clinical information with placental and bacteriological data enables the identification of two main pathways leading to birth before 32 weeks of gestation: (1) infection/inflammation and (2) dysfunctional placentation. Regarding BPD phenotypes, the following have been proposed: parenchymal, peripheral airway, central airway, interstitial, congestive, vascular, and mixed phenotype. In line with the approach of personalized medicine, endotyping prematurity and phenotyping BPD will facilitate the design of more targeted therapeutic and prognostic approaches

Patent Ductus Arteriosus and Bronchopulmonary Dysplasia-Associated Pulmonary Hypertension:A Bayesian Meta-Analysis

IMPORTANCE: Bronchopulmonary dysplasia (BPD) is often associated with pulmonary vascular disease and secondary pulmonary hypertension (PH). The pathogenesis of BPD-associated PH (BPD-PH) is complex and involves prenatal and postnatal factors that disrupt pulmonary vascular development, and patent ductus arteriosus (PDA) is a factor potentially associated with risk of BPD-PH that has been identified in very recent studies. OBJECTIVE: To explore the association of PDA with BPD-PH using a bayesian model-averaged (BMA) meta-analysis of studies. DATA SOURCES: PubMed and Embase were searched up to April 2023. Key search terms included BPD and PH. STUDY SELECTION: Studies examining infants with gestational age 32 weeks or less and reporting data on PDA and risk of BPD-PH. DATA EXTRACTION AND SYNTHESIS: This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and the Meta-Analysis of Observational Studies in Epidemiology reporting guidelines. Two independent reviewers extracted data, with a third reviewer checking for accuracy and completeness. Data pooling and effect size calculations were performed by BMA. MAIN OUTCOMES AND MEASURES: The primary outcome was BPD-PH. BMA was used to calculate Bayes factors (BFs). The BF10 is the ratio of the probability of the data under the alternative hypothesis (H1, association of PDA with BPD-HP) over the probability of the data under the null hypothesis (H0). RESULTS: A total of 32 studies (8513 infants) were included. BMA showed that the evidence in favor of H1 was weak for any PDA (BF10?=?2.90; 10 studies), moderate for hemodynamically significant PDA (BF10?=?3.77; 3 studies), and extreme for surgically ligated or catheter-occluded PDA (BF10?=?294.9; 16 studies). In contrast, the evidence in favor of H0 was weak for medically treated PDA (BF10?=?0.55; 6 studies). In addition, BMA found strong evidence in favor of H1 when prolonged exposure to PDA was analyzed as a dichotomous variable (BF10?=?11.80; 6 studies) and extreme evidence (BF10?=?113.60; 3 studies) when PDA exposure time was analyzed as a continuous variable. CONCLUSIONS AND RELEVANCE: In this bayesian meta-analysis, the data suggest that prolonged exposure to PDA might be associated with increased risk of pulmonary vascular disease in extremely preterm infants. This highlights the need to monitor for PH in high-risk preterm infants with prolonged exposure to PDA and to incorporate PH risk into clinical decisions regarding PDA management

Tobacco Smoking During Pregnancy Is Associated With Increased Risk of Moderate/Severe Bronchopulmonary Dysplasia:A Systematic Review and Meta-Analysis

Epidemiological evidence and animal studies support that intrauterine exposure to tobacco smoke disturbs lung development and has a negative effect in the pulmonary health of the offspring. Individual studies suggest an association between fetal exposure to maternal smoking and risk of developing bronchopulmonary dysplasia (BPD). However, this association has not yet been systematically investigated. We aimed to conduct a systematic review of studies reporting on tobacco smoking during pregnancy as potential risk factor for BPD. PubMed/MEDLINE and EMBASE databases were searched. BPD was defined as requirement of supplemental oxygen on postnatal day 28 (BPD28; all BPD), at the postmenstrual age (PMA) of 36 weeks (BPD36; moderate/severe BPD), or as requirement of more than 30% oxygen and/or positive pressure at 36 weeks PMA (severe BPD). Pooled risk ratios (RR) and 95% confidence intervals (CI) were calculated using a random-effects model. Of 2,894 potentially relevant studies, 33 met the inclusion criteria. The included studies evaluated 171,772 infants and included 30,445 cases of exposure to maternal smoking and 25,340 cases of BPD of any severity. Meta-analysis showed a significant association between tobacco smoking during pregnancy and BPD36 (17 studies, RR 1.126, 95% CI 1.008-1.259, p = 0.036), but could not demonstrate a significant association between tobacco smoking during pregnancy and BPD28 (16 studies, RR 1.021, 95% CI 0.924-1.129, p = 0.681), or severe BPD (3 studies, RR 1.143, 95% CI 0.528-2.478, p = 0.734). In conclusion, our data suggest that tobacco smoking during pregnancy increases the risk of moderate/severe BPD. Our results highlight the detrimental effects of tobacco smoking and reinforce the hypothesis of the involvement of prenatal insults in the etiopathogenesis of BPD

Tobacco Smoking During Pregnancy Is Associated With Increased Risk of Moderate/Severe Bronchopulmonary Dysplasia: A Systematic Review and Meta-Analysis

Epidemiological evidence and animal studies support that intrauterine exposure to tobacco smoke disturbs lung development and has a negative effect in the pulmonary health of the offspring. Individual studies suggest an association between fetal exposure to maternal smoking and risk of developing bronchopulmonary dysplasia (BPD). However, this association has not yet been systematically investigated. We aimed to conduct a systematic review of studies reporting on tobacco smoking during pregnancy as potential risk factor for BPD. PubMed/MEDLINE and EMBASE databases were searched. BPD was defined as requirement of supplemental oxygen on postnatal day 28 (BPD28; all BPD), at the postmenstrual age (PMA) of 36 weeks (BPD36; moderate/severe BPD), or as requirement of more than 30% oxygen and/or positive pressure at 36 weeks PMA (severe BPD). Pooled risk ratios (RR) and 95% confidence intervals (CI) were calculated using a random-effects model. Of 2,894 potentially relevant studies, 33 met the inclusion criteria. The included studies evaluated 171,772 infants and included 30,445 cases of exposure to maternal smoking and 25,340 cases of BPD of any severity. Meta-analysis showed a significant association between tobacco smoking during pregnancy and BPD36 (17 studies, RR 1.126, 95% CI 1.008-1.259, p = 0.036), but could not demonstrate a significant association between tobacco smoking during pregnancy and BPD28 (16 studies, RR 1.021, 95% CI 0.924-1.129, p = 0.681), or severe BPD (3 studies, RR 1.143, 95% CI 0.528-2.478, p = 0.734). In conclusion, our data suggest that tobacco smoking during pregnancy increases the risk of moderate/severe BPD. Our results highlight the detrimental effects of tobacco smoking and reinforce the hypothesis of the involvement of prenatal insults in the etiopathogenesis of BPD

Survival and causes of death in extremely preterm infants in the Netherlands

Objective In the Netherlands, the threshold for offering active treatment for spontaneous birth was lowered from 25 +0 to 24 +0 weeks' gestation in 2010. This study aimed to evaluate the impact of guideline implementation on survival and causes and timing of death in the years following implementation. Design National cohort study, using data from the Netherlands Perinatal Registry. Patients The study population included all 3312 stillborn and live born infants with a gestational age (GA) between 24 0/7 and 26 6/7 weeks born between January 2011 and December 2017. Infants with the same GA born between January 2007 and December 2009 (N=1400) were used as the reference group. Main outcome measures Survival to discharge, as well as cause and timing of death. Results After guideline implementation, there was a significant increase in neonatal intensive care unit (NICU) admission rate for live born infants born at 24 weeks' GA (27%-69%, p<0.001), resulting in increased survival to discharge in 24-week live born infants (13%-34%, p<0.001). Top three causes of in-hospital mortality were necrotising enterocolitis (28%), respiratory distress syndrome (19%) and intraventricular haemorrhage (17%). A significant decrease in cause of death either complicated or caused by respiratory insufficiency was seen over time (34% in 2011-2014 to 23% in 2015-2017, p=0.006). Conclusions Implementation of the 2010 guideline resulted as expected in increased NICU admissions rate and postnatal survival of infants born at 24 weeks' GA. In the years after implementation, a shift in cause of death was seen from respiratory insufficiency towards necrotising enterocolitis and sepsis