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.

Association between endotypes of prematurity and pharmacological closure of patent ductus arteriosus: A systematic review and meta-analysis.

Introduction: Endotypes leading to very and extremely preterm birth are clustered into two groups: infection/inflammation and dysfunctional placentation. We conducted a systematic review of observational studies exploring the association between these two endotypes and the pharmacological closure of patent ductus arteriosus (PDA) induced by cyclooxygenase (COX) inhibitors. Chorioamnionitis represented the infectious-inflammatory endotype, while dysfunctional placentation proxies were hypertensive disorders of pregnancy (HDP) and small for gestational age (SGA) or intrauterine growth restriction. Methods: PubMed/Medline and Embase databases were searched. The random-effects odds ratio (OR) and 95% confidence interval (CI) were calculated for each association. We included 30 studies (12,639 infants). Results: Meta-analysis showed a significant association between exposure to HDP and increased rate of pharmacological closure of PDA (17 studies, OR 1.41, 95% CI 1.10-1.81, p = 0.006). In contrast, neither chorioamnionitis (13 studies, OR 0.75, 95% CI 0.47-1.18, p = 0.211) nor SGA (17 studies, OR 1.20, 95% CI 0.96-1.50, p = 0.115) were significantly associated with the response to therapy. Subgroup analyses showed that the higher response to COX inhibitors in the HDP group was significant for indomethacin (OR 1.568, 95% CI 1.147-2.141, p = 0.005) but not for ibuprofen (OR 1.107, 95% CI 0.248-4.392, p = 0.894) or for the studies using both drugs (OR 1.280, 95% CI 0.935-1.751, p = 0.124). However, meta-regression showed that this difference between the drugs was not statistically significant (p = 0.404). Discussion/Conclusion: Our data suggest that the pathologic condition that triggers prematurity may alter the response to pharmacological treatment of PDA. The DA of infants exposed to HDP appears to be more responsive to COX inhibitors.

Sex Differences in Patent Ductus Arteriosus Incidence and Response to Pharmacological Treatment in Preterm Infants: A Systematic Review, Meta-Analysis and Meta-Regression.

A widely accepted concept in perinatal medicine is that boys are more susceptible than girls to complications of prematurity. However, whether this 'male disadvantage of prematurity' also involves persistent patent ductus arteriosus (PDA) has been scarcely investigated. Our aim was to conduct a systematic review and meta-analysis on studies addressing sex differences in the risk of developing PDA among preterm infants. We also investigated whether the response to pharmacological treatment of PDA differs between boys and girls. PubMed/Medline and Embase databases were searched. The random-effects male/female risk ratio (RR) and 95% confidence interval (CI) were calculated. We included 146 studies (357,781 infants). Meta-analysis could not demonstrate sex differences in risk of developing any PDA (37 studies, RR 1.03, 95% CI 0.97 to 1.08), hemodynamically significant PDA (81 studies, RR 1.00, 95% CI 0.97 to 1.02), or in the rate of response to pharmacological treatment (45 studies, RR 1.01, 95% CI 0.98 to 1.04). Subgroup analysis and meta-regression showed that the absence of sex differences was maintained over the years and in different geographic settings. In conclusion, both the incidence of PDA in preterm infants and the response rate to pharmacological treatment of PDA are not different between preterm boys and girls.

Plasma Amino Acid Concentrations at Birth and Patent Ductus Arteriosus in Very and Extremely Preterm Infants.

Background: Amino acids are increasingly recognized as bioactive molecules in numerous physiological and pathophysiological pathways. The non-essential amino acid glutamate is vasoactive in the rat ductus arteriosus (DA) and a decrease in its levels within the 1st days of life has been associated with the presence of patent DA (PDA) in extremely preterm infants. However, these findings have not been confirmed in other studies. Objective: To investigate the possible association between amino acid concentrations in the 1st day of life and the presence of PDA in a cohort of 121 newborns with gestational age (GA) below 30 weeks and birth weight (BW) below 1,500 g. Methods: Plasma samples were collected 6-12 h after birth and amino acid concentrations were determined by tandem mass spectrometry. Besides PDA, we analyzed the potential association of amino acid concentrations with infant sex, small for GA (SGA, defined as BW < third percentile), antenatal corticosteroids, chorioamnionitis, and preeclampsia. Group differences were analyzed by ANOVA adjusted for GA and BW. A Bonferroni significance threshold of P < 0.0024 was used to correct for multiple testing. Results: PDA was found in 48 of the 121 infants examined. We observed higher mean levels of glutamate in infants with PDA (147.0 µmol/L, SD 84.0) as compared with those without (106.7 µmol/L, SD 49.1, P = 0.0006). None of the other amino acid concentrations in the PDA group reached the level of statistical significance that was pre-set to correct for multiple comparisons. Glutamate levels were not significantly affected by infant sex, being SGA, or by exposure to antenatal corticosteroids, clinical chorioamnionitis, or preeclampsia. Conclusion: Our study not only does not confirm the previous findings of low glutamate levels in preterm infants with PDA, but we have even found elevated glutamate concentrations associated with PDA. Nevertheless, despite the high statistical significance, the difference in glutamate levels may lack clinical significance or may be an epiphenomenon associated with the particular clinical condition of infants with PDA.

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.

Risk of Necrotizing Enterocolitis Associated With the Single Nucleotide Polymorphisms VEGF C-2578A, IL-18 C-607A, and IL-4 Receptor α-Chain A-1902G: A Validation Study in a Prospective Multicenter Cohort.

The etiology of necrotizing enterocolitis (NEC) is multifactorial and an underlying genetic predisposition to NEC is increasingly being recognized. A growing number of studies identified single nucleotide polymorphisms (SNPs) of selected genes with potential biological relevance in the development of NEC. However, few of these genetic studies have been replicated in validation cohorts. We aimed to confirm in a cohort of 358 preterm newborns (gestational age <30 weeks, 26 cases of NEC ≥ Bell stage II) the association with NEC of three candidate SNPs: the vascular endothelium growth factor (VEGF) C-2578A polymorphism (rs699947), the interleukin (IL)-18 C-607A polymorphism (rs1946518), and the IL-4 receptor α-chain (IL-4Rα) A-1902G polymorphism (rs1801275). We observed that allele and genotype frequencies of the three SNPs did not significantly differ between the infants with and without NEC. In contrast, the minor G-allele of the IL-4Rα A-1902G polymorphism was significantly less frequent in the group of 51 infants with the combined outcome NEC or death before 34 weeks postmenstrual age than in the infants without the outcome (0.206 vs. 0.331, P = 0.01). In addition, a significant negative association of the G-allele with the combined outcome NEC or death was found using the dominant (adjusted odds ratio, aOR: 0.44, 95% CI 0.21-0.92), recessive (aOR 0.15, 95% CI 0.03-0.74), and additive (aOR 0.46, 95% CI 0.26-0.80) genetic models. In conclusion our study provides further evidence that a genetic variant of the IL-4Rα gene may contribute to NEC.

Is the C242T Polymorphism of the CYBA Gene Linked with Oxidative Stress-Associated Complications of Prematurity?

The C242T polymorphism of CYBA (cytochrome B-245 alpha chain), the gene encoding the p22phox subunit of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, has been linked to several conditions in which oxidative stress plays a pathogenic role. We investigated in a cohort of 451 preterm infants [gestational age (GA) ≤30 weeks] the association of the polymorphism with the risk of developing neonatal respiratory distress syndrome (RDS), retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD), necrotizing enterocolitis, patent ductus arteriosus, or intraventricular hemorrhage. We observed a significant association of the TT/CT genotype with RDS [odds ratio (OR) 2.34, 95% confidence interval (95% CI) 1.28-3.90], ROP (OR 1.72, 95% CI 1.05-2.80), and BPD (OR 1.60, 95% CI 1.05-2.43). When this dominant model was adjusted to account for GA, birth weight, and sex, it remained significant for the three outcomes. This study is the first to address the association of a polymorphism related to the NADPH family with oxidative stress-related complications of prematurity. Since p22phox is essential for reactive oxygen species production by NADPH oxidase, we hypothesize that genetic variations in the protein may lead to differences in susceptibility to oxidative stress-induced damage in preterm infants. Antioxid. Redox Signal. 27, 1432-1438.

Association between the p.Thr1406Asn polymorphism of the carbamoyl-phosphate synthetase 1 gene and necrotizing enterocolitis: A prospective multicenter study.

The p.Thr1406Asn (rs1047891) polymorphism of the carbamoyl-phosphate synthetase 1 (CPS1) gene has been linked to functional consequences affecting the downstream availability of the nitric oxide precursor L-arginine. L-arginine concentrations are decreased in preterm infants with necrotizing enterocolitis (NEC). In this multicenter prospective study, we investigated the association of the p.Thr1406Asn polymorphism with NEC in 477 preterm infants (36 cases of NEC) from 4 European neonatal intensive care units (Maastricht, Las Palmas de Gran Canaria, Mantova, and Milan). Allele and genotype frequencies of the p.Thr1406Asn polymorphism did not significantly differ between the infants with and without NEC. In contrast, the minor A-allele was significantly less frequent in the group of 64 infants with the combined outcome NEC or death before 34 weeks of corrected gestational age than in the infants without the outcome (0.20 vs. 0.31, P = 0.03). In addition, a significant negative association of the A-allele with the combined outcome NEC or death was found using the dominant (adjusted odds ratio, aOR: 0.54, 95% CI 0.29-0.99) and the additive (aOR 0.58, 95% CI 0.36-0.93) genetic models. In conclusion, our study provides further evidence that a functional variant of the CPS1 gene may contribute to NEC susceptibility.

Plasma levels of dimethylarginines in preterm very low birth weight neonates: its relation with perinatal factors and short-term outcome.

Endogenously produced inhibitors of nitric oxide (NO) synthase, in particular asymmetric dimethylarginine (ADMA), are currently considered of importance in various disease states characterized by reduced NO availability. We investigated the association between plasma levels of ADMA, symmetric dimethylarginine (SDMA), L-arginine, and citrulline and perinatal factors and outcome in 130 preterm (gestational age ≤ 30 weeks) very low birth weight (VLBW, < 1500 g) infants. Plasma samples were collected 6-12 h after birth. We did not find significant correlations between ADMA, SDMA, L-arginine, and citrulline levels and gestational age or birth weight. However, the arginine:ADMA ratio (AAR, a better indicator of NO availability than either arginine or ADMA separately) was positively correlated with gestational age. ADMA and arginine levels were not significantly different between males and females but males showed a negative correlation between ADMA levels and gestational age. Perinatal factors such as preeclampsia, chrorioamnionitis, prolonged rupture of membranes, or form of delivery did not significantly alter dimethylarginine levels or AAR. In contrast, the AAR was significantly reduced in the infants with respiratory distress, mechanical ventilation, and systemic hypotension Therefore, our data suggest that altered NO availability may play a role in the respiratory and cardiovascular adaptation in preterm VLBW infants.

Isoprostanes in fetal and neonatal health and disease.

Isoprostanes are prostaglandin-like bioactive molecules generated via nonenzymatic peroxidation of lipid membrane-derived arachidonic acid by free radicals and reactive oxygen species. Their cognate receptors, biological actions, and signaling pathways are poorly understood. Aside from being sensitive and specific biomarkers of oxidative stress, E- and F-ring isoprostanes have important biological functions and likely mediate many of the disease-related pathological changes for which they are used as indicators. The biochemical pathways involved in isoprostane formation, their pathogenetic relevance to adult disease states, and their biological function are addressed. Developmentally, plasma and tissue content data show that isoprostane levels are highest during fetal and early neonatal life, when compared with adults. As such, the available data suggesting that isoprostanes play an important biological role, as well as possibly actively participate in the regulation of pulmonary vascular tone and the transition from fetal to postnatal life, are here reviewed. Lastly, the association between isoprostanes and certain neonatal clinical conditions is addressed. Although its existence has been recognized for almost 20 years, little is known about the critical importance of isoprostanes during fetal life and immediate neonatal period. This review is an attempt to bridge this knowledge gap.