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ObjectiveWe performed a multicenter study of preterm infants, who were about to undergo patent ductus arteriosus ligation, to determine whether echocardiographic indices of impaired myocardial performance were associated with subsequent development of catecholamine-resistant hypotension following ligation.Study designA standardized treatment approach for hypotension was followed at each center. Infants were considered to have catecholamine-resistant hypotension if their dopamine infusion was > 15 μg kg(-1)min(-1). Echocardiograms and cortisol measurements were obtained between 6 and 14 h after the ligation (prior to the presence of catecholamine-resistant hypotension).ResultForty-five infants were enrolled, 10 received catecholamines (6 were catecholamine-responsive and 4 developed catecholamine-resistant hypotension). Catecholamine-resistant hypotension was not associated with decreased preload, shortening fraction or ventricular output. Infants with catecholamine-resistant hypotension had significantly lower levels of systemic vascular resistance and postoperative cortisol concentration.ConclusionWe speculate that low cortisol levels and impaired vascular tone may have a more important role than impaired cardiac performance in post-ligation catecholamine-resistant hypotension.

Rationale: Nitric oxide (NO) plays an important role in lung development and perinatal lung function, and pulmonary NO synthases (NOS) are decreased in bronchopulmonary dysplasia (BPD) following preterm birth. Fetal estradiol levels increase during late gestation and estradiol up-regulates NOS, suggesting that after preterm birth estradiol deprivation causes attenuated lung NOS resulting in impaired pulmonary function.Objective: To test the effects of postnatal estradiol administration in a primate model of BPD over 14 days after delivery at 125 days of gestation (term = 185 d).Methods: Cardiopulmonary function was assessed by echocardiography and whole body plethysmography. Lung morphometric and histopathologic analyses were performed, and NOS enzymatic activity and abundance were measured.Measurements and Main Results: Estradiol caused an increase in blood pressure and ductus arteriosus closure. Expiratory resistance and lung compliance were also improved, and this occurred before spontaneous ductal closure. Furthermore, both oxygenation and ventilation indices were improved with estradiol, and the changes in lung function and ventilatory support requirements persisted throughout the study period. Whereas estradiol had negligible effect on indicators of lung inflammation and on lung structure assessed after the initial 14 days of ventilatory support, it caused an increase in lung neuronal and endothelial NOS enzymatic activity.Conclusions: In a primate model of BPD, postnatal estradiol treatment had favorable cardiovascular impact, enhanced pulmonary function, and lowered requirements for ventilatory support in association with an up-regulation of lung NOS. Estradiol may be an efficacious postnatal therapy to improve lung function and outcome in preterm infants. [ABSTRACT FROM AUTHOR]

Background: A patent ductus arteriosus (DA) promotes fetal development. However, the DA must close immediately after birth. Prostaglandin E[2] (PGE[2]) is the most important factor in the regulation of DA tone during fetal development. This eicosanoid is generated through the activities of cyclooxygenases-1 (COX-1) and -[2] (COX-[2]) and mediates its effects by interacting with G protein-coupled E-prostanoid (EP) receptors EP[1], EP[2], EP[3], and EP[4].Objective: This article summarizes the role of COX-1 and -[2] and PGE[2] receptors in fetal and neonatal DA tone.Methods: A MEDLINE search was performed of the English-language literature, using the terms ductus arteriosus, PGE[2], and lamb.Results: The DA is less responsive to PGE[2] in neonates than in fetuses. EP receptor subtypes [2] to [4] are expressed equivalently in fetal DA. Stimulation of all [3] receptor subtypes relaxes the DA. In the DA of newborns delivered at full term, EP[2] remains unchanged, EP[4] decreases, and changes in EP[3] expression are equivocal. The DA is less responsive to PGE[2] in newborns than in fetuses. The EP[4] receptor may represent a possible therapeutic target for regulating DA tone in premature newborns. An EP[2] agonist might be useful for maintaining DA patency in neonates and children with certain congenital heart diseases.Conclusions: COX-1 is the predominant isoenzyme in fetal DA, whereas COX-[2] is upregulated in the DA immediately following birth. More research on patent DA and the role of preterm labor versus cesarean delivery is needed, as well as comparisons of the efficacy of selective EP-receptor targeting and enzymatic inhibition of COX and PGE[2] synthetases. [ABSTRACT FROM AUTHOR]

Background: Antenatal corticosteroids decrease the incidence of severe intraventricular hemorrhage (grades 3, 4) in preterm infants. It is unclear whether their beneficial effects on intraventricular hemorrhage wane with time (as occurs in neonatal respiratory distress) and if repeat courses can restore this effect. Previous randomized controlled trials of betamethasone retreatment found no benefit on severe intraventricular hemorrhage rates. However, the trials may have included an insufficient number of infants at risk for intraventricular hemorrhage to be able to adequately address this question. Severe intraventricular hemorrhages occur almost exclusively in infants born at <28 weeks' gestation, whereas only 7% (0%-16%) of the retreatment trials' populations were <28 weeks' gestation., Objective: This study aimed to determine if the risk for severe intraventricular hemorrhage in infants delivered at <28 weeks' gestation increases when the betamethasone treatment-to-delivery interval increases beyond 9 days and to determine if betamethasone retreatment before delivery decreases the rate of hemorrhage., Study Design: This was an observational study that examined the incidence of intraventricular hemorrhage before (epoch 1) and after (epoch 2) a practice change that encouraged obstetricians to retreat pregnant women still at high risk for delivery before 28 weeks' gestation when >9 days elapsed from the first dose of betamethasone. Multivariable analyses with logistic regression using generalized estimating equation techniques were conducted to examine the rates of intraventricular hemorrhage among 410 infants <28 weeks' gestation who were either delivered between 1 to 9 days (n=290) after the first 2-dose betamethasone course or ≥10 days (and eligible for retreatment) after the first course (n=120)., Results: After adjusting for potential confounding variables, infants who were delivered ≥10 days after a single betamethasone course had an increased risk for either severe intraventricular hemorrhage alone or the combined outcome severe intraventricular hemorrhage or death before 4 days (odds ratio, 2.8; 95% confidence interval, 1.2-6.6) when compared with infants who were delivered between 1 and 9 days after betamethasone. Among the 120 infants who were delivered ≥10 days after the first dose of betamethasone, 64 (53%) received a second or retreatment course of antenatal betamethasone. The severe intraventricular hemorrhage rate in infants whose mothers received a second or retreatment course of betamethasone was similar to the rate among infants who delivered within 1 to 9 days and significantly lower than among those who delivered ≥10 days without retreatment (odds ratio, 0.10; 95% confidence interval, 0.02-0.65). Following the change in guidelines, the rate of retreatment in infants who were delivered ≥10 days after the first betamethasone course (and before 28 weeks) increased from epoch 1 to epoch 2 (25% to 87%; P<.001) and the rate of severe intraventricular hemorrhage decreased from 22% to 0% (P<.001). In contrast, the rate of severe intraventricular hemorrhage among infants who were delivered 1 to 9 days after the initial betamethasone dose (who were not eligible for retreatment) did not change between epochs 1 and 2 (12% and 11%, respectively)., Conclusion: Although betamethasone's benefits on severe intraventricular hemorrhage appear to wane after the first dose, retreatment with a second course seems to restore its beneficial effects. Encouraging earlier retreatment of women at high risk for delivery before 28 weeks was associated with a lower rate of severe intraventricular hemorrhages among infants delivered at <28 weeks' gestation., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: To determine if prophylactic indomethacin (PINDO) decreases serious pulmonary hemorrhages in infants <28 weeks., Study Design: Intention-to-treat analysis of 615 consecutively admitted infants during four alternating protocol-driven epochs of PINDO or expectant patent ductus arteriosus (PDA) management., Results: 41/615 (6.7%) developed serious pulmonary hemorrhage at 2 (1, 3) days (median (IQR)). In unadjusted and adjusted multivariable models, infants born in a PINDO epoch had significantly lower incidences of pulmonary hemorrhage and pulmonary hemorrhage or death before 7 days. There were less moderate/large PDA during PINDO epochs. The associations between PINDO and pulmonary hemorrhage and pulmonary hemorrhage/death were no longer significant when presence of a PDA was included in the analyses. There was no apparent association between PINDO epochs and the incidence of serious intraventricular hemorrhages., Conclusion: Even though PINDO no longer appears to affect the incidence of sIVH it still is associated with a lower incidence of pulmonary hemorrhage., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Objective: To determine if intestinal perforations before 14 days (either spontaneous (SIP) or necrotizing enterocolitis-induced) are increased when infants who received antenatal betamethasone shortly before birth are treated with prophylactic indomethacin (PINDO)., Study Design: Observational study of 475 infants <28 week's gestation assigned to either a PINDO-protocol (n = 231) or expectant management protocol (n = 244) during consecutive protocol epochs., Results: Intestinal perforations before 14 days occurred in 33/475 (7%). In unadjusted and adjusted models, we found no associations between PINDO-protocol and intestinal perforations. PINDO-protocol did not increase intestinal perforations or SIP-alone even when given to infants who received betamethasone <7 or <2 days before delivery. 213/231 (92%) PINDO-protocol infants actually received indomethacin. The results were unchanged when examined just in those who received indomethacin., Conclusion: In our study, early intestinal perforations and SIP-alone were not increased when PINDO was used by protocol in infants who received antenatal betamethasone shortly before birth., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: The aim of the study was to determine whether prolonged exposure to a moderate/large patent ductus arteriosus left-to-right shunt (PDA) increases the risk of late (beyond 36 weeks) pulmonary hypertension (BPD-PH) and pulmonary vascular disease (BPD-PVD) during the neonatal hospitalization in preterm infants (<28 weeks' gestation) with bronchopulmonary dysplasia (BPD)., Methods: All infants requiring respiratory support ≥36 weeks had systematic echocardiographic evaluations for BPD-PH at planned intervals. Infants were classified as having either flow-associated BPD-PH (BPD-flow-PH) or BPD-PVD., Results: 256 infants survived ≥36 weeks: 105 had NO BPD (were off respiratory support by 36 weeks); 151 had BPD. 22/151 had BPD-PH (12/22 had BPD-flow-PH from a PDA that persisted beyond 36 weeks; 10/22 had BPD-PVD). Moderate/large PDA shunts that persisted beyond 36 weeks were significantly associated with an increased incidence of BPD-PH due to BPD-flow-PH. We found no association between the duration of PDA exposure and the incidence of BPD-PVD., Conclusions: Moderate/large PDA shunts increase the risk of flow-associated BPD-PH when present beyond 36 weeks. Although term infants with PDA-congenital heart disease can develop pulmonary vascular remodeling and PVD after months of PDA exposure, we found no echocardiographic evidence in preterm infants that prolonged PDA exposure increases the incidence of BPD-PVD during the neonatal hospitalization., Impact: In our study, preterm infants (<28 weeks' gestation) with bronchopulmonary dysplasia (BPD) had a 15% incidence of pulmonary hypertension (PH) beyond 36 weeks' postmenstrual age as a comorbidity. Moderate/large patent ductus arteriosus (PDA) shunts increased the risk of flow-associated PH when present beyond 36 weeks. Although months of prolonged PDA exposure can cause pulmonary vascular remodeling and pulmonary vascular disease (PVD) in term infants with PDA-congenital heart disease, we found no echocardiographic evidence for an association between the duration of PDA exposure and the incidence of late PVD during the neonatal hospitalization in preterm infants with BPD., (© 2023. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

A persistent left-to-right shunt through a patent ductus arteriosus (PDA) increases the rate of pulmonary hydrostatic fluid filtration, impairs pulmonary mechanics, and prolongs the need for respiratory support. Infants with a moderate/large PDA shunt that persists for more than 7-14 days are at increased risk for developing bronchopulmonary dysplasia (BPD) if they also require invasive ventilation for more than 10 days. In contrast, infants who require invasive ventilation for less than 10 days have similar rates of BPD no matter how long they are exposed to a moderate/large PDA shunt. Although pharmacologic PDA closure decreases the risk of abnormal early alveolar development in preterm baboons that are ventilated for 2 weeks, the findings from recent randomized controlled trials, as well as a quality improvement project, suggest that routine early targeted pharmacologic treatments, as currently employed, do not appear to alter the incidence of BPD in human infants., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: To determine if prophylactic indomethacin (PINDO) decreases death or bronchopulmonary dysplasia-grades 2 and 3 (death/BPD) in newborns <25 weeks., Study Design: Intention-to-treat, cohort-controlled study of 106 infants admitted during three alternating epochs of PINDO or Expectant patent ductus arteriosus (PDA) management., Results: At 7-8 days 85% of Expectant Management epoch infants had a moderate/large PDA (median exposure was 23 days). Among PINDO epoch infants only 24% still had a PDA at 7-8 days. There were no significant differences in the incidence of death/BPD or of secondary outcomes (BPD, death, necrotizing enterocolitis/spontaneous perforations, or intraventricular hemorrhage (grades 3 or 4)) in either unadjusted or adjusted comparisons between infants born in a PINDO epoch and those born in the Expectant Management epoch., Conclusion: Despite being at high risk for PDA-related morbidities, PINDO did not appear to alter the rates of our primary and secondary outcomes in infants <25 weeks., (© 2022. The Author(s).)

Background: DNA polymorphisms in PTGIS and TFAP2B have been identified as risk factors for patent ductus arteriosus (PDA) in a population composed of preterm infants with European genetic ancestry but not in more genetically diverse populations., Goal: To determine if the effects of TFAP2B and PTGIS polymorphisms on ductus arteriosus (DA) gene expression differ based on genetic ancestry., Methods: DA from 273 human second trimester fetuses were genotyped for TFAP2B and PTGIS polymorphisms and for polymorphisms distributing along genetic ancestry lines. RT-PCR was used to measure the RNA expression of 49 candidate genes involved with DA closure., Results: Seventeen percent of the DA analyzed were of European ancestry. In multivariable regression analyses we found consistent associations between four PDA-related TFAP2B polymorphisms (rs2817399(A), rs987237(G), rs760900(C), and rs2817416(C)) and expression of the following genes: EPAS1, CACNB2, ECE1, KCNA2, ATP2A3, EDNRA, EDNRB, BMP9, and BMP10, and between the PTGIS haplotype rs493694(G)/rs693649(A) and PTGIS and NOS3. These changes only occurred in DA with European ancestry. No consistent positive or negative associations were found among DA samples unless an interaction between the polymorphisms and genetic ancestry was taken into account., Conclusion: PTGIS and TFAP2B polymorphisms were associated with consistent changes in DA gene expression when present in fetuses with European ancestry., Impact: DNA polymorphisms in PTGIS and TFAP2B have been identified as risk factors for patent ductus arteriosus (PDA) in a population composed primarily of preterm infants with European genetic ancestry but not in more genetically diverse populations. The same PTGIS and TFAP2B polymorphisms are associated with changes in ductus gene expression when present in ductus from fetuses with European genetic ancestry. No consistent associations with gene expression can be found unless an interaction between the polymorphisms and genetic ancestry is taken into account., (© 2021. The Author(s).)

Patent ductus arteriosus is the most common cardiovascular condition in preterm infants. There is a significant uncertainty about when and how to close ductus arteriosus in preterm infants due to a high spontaneous closure rate even in very immature preterm infants. Diagnosis and management of patent ductus arteriosus remain a challenge for both neonatologists and pediatric cardiologists. Researchers have tried to define a balance between an expectant approach and active treatment in selected infants. This review aimed to focus on the pathophysiology and management of patent ductus arteriosus and to make suggestions about approaches that might eliminate the association of morbidities with patent ductus arteriosus.

Background: An increased risk for bronchopulmonary dysplasia (BPD) exists when moderate-to-large patent ductus arteriosus shunts (hsPDA) persist beyond 14 days., Goal: To examine the interaction between prolonged exposures to tracheal ventilation (≥10 days) and hsPDA on the incidence of BPD in infants <28 weeks gestation., Study Design: Predefined definitions of prolonged ventilation (≥10 days), hsPDA (≥14 days), and BPD (room air challenge test at 36 weeks) were used to analyze deidentified data from the multicenter TRIOCAPI RCT in a secondary analysis of the trial., Results: Among 307 infants who survived >14 days, 41 died before 36 weeks. Among survivors, 93/266 had BPD. The association between BPD and hsPDA depended on the length of intubation. In multivariable analyses, prolonged hsPDA shunts were associated with increased BPD (odds ratio (OR) (95% confidence interval (CI)) = 3.00 (1.58-5.71)) when infants required intubation for ≥10 days. In contrast, there was no significant association between hsPDA exposure and BPD when infants were intubated <10 days (OR (95% CI) = 1.49 (0.98-2.26)). A similar relationship between prolonged hsPDA and length of intubation was found for BPD/death (n = 307): infants intubated ≥10 days: OR (95% CI) = 2.41 (1.47-3.95)); infants intubated <10 days: OR (95% CI) = 1.37 (0.86-2.19))., Conclusions: Moderate-to-large PDAs were associated with increased risks of BPD and BPD/death-but only when infants required intubation ≥10 days., Impact: Infants with a moderate-to-large hsPDA that persist beyond 14 days are only at risk for developing BPD if they also receive prolonged tracheal ventilation for ≥10 days. Infants who receive less ventilatory support (intubation for <10 days) have the same incidence of BPD whether the ductus closes shortly after birth or whether it persists as a moderate-to-large shunt for several weeks. Early PDA closure may be unnecessary in infants who require short durations of intubation since the PDA does not seem to alter the incidence of BPD in infants who require intubation for <10 days., (© 2021. The Author(s).)

In the PDA-TOLERATE trial, persistent (even for several weeks) moderate to large patent ductus arteriosus (PDA) was not associated with an increased risk of BPD when the infant required <10 days of intubation. However, in infants requiring intubation for ≥10 days, prolonged PDA exposure (≥11 days) was associated with an increased risk of moderate/severe BPD., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: To examine the relationship between intestinal perforations (caused by either spontaneous perforation (SIP) or necrotizing enterocolitis (NEC)) and the outcome "death due to intestinal perforation"., Methods: Multivariable logistic regression analyses were used to compare infants <28 weeks' gestation with SIP (n = 32) and perforated-NEC (n = 45) for the outcome perforation-related death., Results: In univariate analyses the incidence of death due to perforation was higher among infants with perforated-NEC (36%) than infants with SIP (13%). However, infants with perforated-NEC were more likely to be older than 10 days and have bacteremia/fungemia with non-coagulase-negative staphylococci (non-CONS) organisms than infants with SIP. After adjusting for confounding the only variable that was significantly associated with mortality due to perforation was the presence of non-CONS bacteremia/fungemia at the onset of perforation., Conclusions: The apparent association between death and perforated-NEC could be explained by the higher incidence of non-CONS bacteremia/fungemia among infants with perforated-NEC.

Objective: To determine if the need for mechanical ventilation alters the association between prolonged patent ductus arteriosus (PDA) exposure and bronchopulmonary dysplasia (grades 2 and 3) (BPD)., Study Design: Observational study of 407 infants (<28 weeks' gestation) with echocardiograms performed at planned intervals., Results: Twelve percent (48/407) of study infants had BPD (grades 2 and 3). In a multivariable regression model, exposure to a moderate-to-large PDA shunt for ≥7 days was associated with an increased risk of BPD (grades 2 and 3) (from 16 to 35%: aRD = 19% (6, 32%), p < 0.005) when infants required ≥10 days of intubation (n = 170). In contrast, there was no significant association between prolonged PDA exposure and BPD when infants required ≤9 days of intubation (aRD = 4%) (-1, 10%) (n = 237)., Conclusions: Moderate-to-large PDAs are associated with an increased risk of BPD-but only when infants require intubation ≥10 days.

Objective: This study was aimed to examine the relationship between duration of infant exposure to a moderate-to-large patent ductus arteriosus (PDA) shunt and the risk of developing bronchopulmonary dysplasia (BPD) or death before 36 weeks (BPD/death)., Study Design: Infants <28 weeks' gestation who survived ≥7 days ( n  = 423) had echocardiograms performed on day 7 and at planned intervals., Results: In multivariable regression models, BPD/death did not appear to be increased until infants had been exposed to a moderate-to-large PDA for at least 7-13 days: OR (95%CI) (referent = closed or small PDA): moderate-to-large PDA exposure for <7 days: 0.38 (range, 0.10-1.46); for 7 to 13 days = 2.12 (range, 1.04-4.32); for ≥14 days = 3.86 (range, 2.15-6.96). Once the threshold of 7 to 13 days had been reached, additional exposure (≥14 days) did not significantly add to the increased incidence of BPD/death: (referent exposure = 7-13 days) exposure for 14 to 27 days = 1.34 (range, 0.52-3.45); for 28 to 48 days = 2.34 (range, 0.88-6.19); for ≥49 days = 1.80 (range. 0.59-5.47). A similar relationship was found for the outcome of BPD-alone., Conclusion: Infants < 28 weeks' gestation required at least 7 to 13 days of exposure to a moderate-to-large PDA before a significant increase in the incidence of BPD/death was apparent. Once this threshold was reached additional exposure to a moderate-to-large PDA did not significantly add to the increased incidence of BPD/death., Competing Interests: None declared., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

The PDA: TO LEave it alone or Respond And Treat Early trial compared the effects of 2 strategies for treatment of patent ductus arteriosus (PDA) in infants <28 0/7  weeks of gestation; however 137 potentially eligible infants were not recruited and received treatment of their PDA outside the PDA-TOLERATE trial due to "lack-of-physician-equipoise" (LPE). Despite being less mature and needing more respiratory support, infants with LPE had lower rates of mortality than enrolled infants. Infants with LPE treated before day 6 had lower rates of late respiratory morbidity than infants with LPE treated ≥day 6. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01958320., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Aims: To identify clinical andgenetic factors associated with indomethacin treatment failure in preterm neonates with patent ductus arteriosus (PDA). Patients & Methods: This is a multicenter cohort study of 144 preterm infants (22-32 weeks gestational age) at three centers who received at least one treatment course of indomethacin for PDA. Indomethacin failure was defined as requiring subsequent surgical intervention. Results: In multivariate analysis, gestational age (AOR 0.76, 95% CI 0.60-0.96), surfactant use (AOR 9.77, 95% CI 1.15-83.26), and CYP2C9*2 (AOR 3.74; 95% CI 1.34-10.44) were each associated with indomethacin failure. Conclusion: Age, surfactant use, and CYP2C9*2 influence indomethacin treatment outcome in preterm infants with PDA. This combination of clinical and genetic factors may facilitate targeted indomethacin use for PDA.

Objective: To evaluate the effectiveness of drugs used to constrict patent ductus arteriosus (PDA) in newborns < 28 weeks., Methods: We performed a secondary analysis of the multi-center PDA-TOLERATE trial (NCT01958320). Infants with moderate-to-large PDAs were randomized 1:1 at 8.1 ± 2.1 days to either Drug treatment (n = 104) or Conservative management (n = 98). Drug treatments were assigned by center rather than within center (acetaminophen: 5 centers, 27 infants; ibuprofen: 7 centers, 38 infants; indomethacin: 7 centers, 39 infants)., Results: Indomethacin produced the greatest constriction (compared with spontaneous constriction during Conservative management): RR (95% CI) = 3.21 (2.05-5.01)), followed by ibuprofen = 2.03 (1.05-3.91), and acetaminophen = 1.33 (0.55-3.24). The initial rate of acetaminophen-induced constriction was 27%. Infants with persistent moderate-to-large PDA after acetaminophen were treated with indomethacin. The final rate of constriction after acetaminophen ± indomethacin was 60% (similar to the rate in infants receiving indomethacin-alone (62%))., Conclusion: Indomethacin was more effective than acetaminophen in producing ductus constriction.

It is generally accepted that intrauterine growth restriction (IUGR) increases morbidity and mortality among very preterm neonates. However, evidence is hampered by the widespread practice of using the terms small for gestational age (SGA) and IUGR as synonyms. We conducted a systematic review of studies reporting on the association between IUGR/SGA and patent ductus arteriosus (PDA). PubMed/MEDLINE and EMBASE databases were searched. Of 993 studies reviewed, 47 (50,790 infants) were included. Studies were combined using a random effects model and sources of heterogeneity were determined by subgroup and meta-regression analyses. Meta-analysis of all included studies showed a significantly reduced risk of PDA in the SGA/IUGR group with an odds ratio (OR) of 0.82, and a 95% confidence interval (CI) of 0.70 to 0.96 ( p = 0.015). Of the 47 studies, only 7 used a definition for growth restriction that went beyond birth weight (BW) for gestational age (GA). When pooled, meta-analysis could not demonstrate a significant effect size (OR 1.31, 95% CI 0.75 to 2.27, p = 0.343). Moreover, the significantly reduced risk of PDA was found in the 25 studies defining SGA as BW <10th percentile (OR 0.81, 95% CI 0.66 to 0.98, p = 0.032), but not in the 6 studies defining SGA as BW <3rd (OR 1.09, 95% CI 0.70 to 1.71, p = 0.694), or in the 27 studies using a more refined definition of PDA (i.e., hemodynamically significant PDA or PDA requiring treatment, OR 0.87, 95% CI 0.72 to 1.04, p = 0.133). In addition, we found that GA was significantly higher in the SGA/IUGR group (18 studies, mean difference 0.63 weeks, 95% CI 0.24 to 1.03, p = 0.002). Meta-regression analysis confirmed the correlation between this difference in GA and PDA risk. In summary, we observed marked heterogeneity across studies in the definition of growth restriction and PDA, and we found differences between the control and growth-restricted groups in relevant baseline characteristics, such as GA. Therefore, our meta-analysis could not provide conclusive evidence on the association between growth restriction and PDA.

Objective: To compare early routine pharmacologic treatment of moderate-to-large patent ductus arteriosus (PDA) at the end of week 1 with a conservative approach that requires prespecified respiratory and hemodynamic criteria before treatment can be given., Study Design: A total of 202 neonates of <28 weeks of gestation age (mean, 25.8 ± 1.1 weeks) with moderate-to-large PDA shunts were enrolled between age 6 and 14 days (mean, 8.1 ± 2.2 days) into an exploratory randomized controlled trial., Results: At enrollment, 49% of the patients were intubated and 48% required nasal ventilation or continuous positive airway pressure. There were no differences between the groups in either our primary outcome of ligation or presence of a PDA at discharge (early routine treatment [ERT], 32%; conservative treatment [CT], 39%) or any of our prespecified secondary outcomes of necrotizing enterocolitis (ERT, 16%; CT, 19%), bronchopulmonary dysplasia (BPD) (ERT, 49%; CT, 53%), BPD/death (ERT, 58%; CT, 57%), death (ERT,19%; CT, 10%), and weekly need for respiratory support. Fewer infants in the ERT group met the rescue criteria (ERT, 31%; CT, 62%). In secondary exploratory analyses, infants receiving ERT had significantly less need for inotropic support (ERT, 13%; CT, 25%). However, among infants who were ≥26 weeks gestational age, those receiving ERT took significantly longer to achieve enteral feeding of 120 mL/kg/day (median: ERT, 14 days [range, 4.5-19 days]; CT, 6 days [range, 3-14 days]), and had significantly higher incidences of late-onset non-coagulase-negative Staphylococcus bacteremia (ERT, 24%; CT,6%) and death (ERT, 16%; CT, 2%)., Conclusions: In preterm infants age <28 weeks with moderate-to-large PDAs who were receiving respiratory support after the first week, ERT did not reduce PDA ligations or the presence of a PDA at discharge and did not improve any of the prespecified secondary outcomes, but delayed full feeding and was associated with higher rates of late-onset sepsis and death in infants born at ≥26 weeks of gestation., Trial Registration: ClinicalTrials.gov: NCT01958320., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Although studies involving preterm infants ≤34 weeks gestation report a decreased incidence of patent ductus arteriosus after antenatal betamethasone, studies involving younger gestation infants report conflicting results., Methods: We used preterm baboons, mice, and humans (≤27 6/7 weeks gestation) to examine betamethasone's effects on ductus gene expression and constriction both in vitro and in vivo., Results: In mice, betamethasone increased the sensitivity of the premature ductus to the contractile effects of oxygen without altering the effects of other contractile or vasodilatory stimuli. Betamethasone's effects on oxygen sensitivity could be eliminated by inhibiting endogenous prostaglandin/nitric oxide signaling. In mice and baboons, betamethasone increased the expression of several developmentally regulated genes that mediate oxygen-induced constriction (K + channels) and inhibit vasodilator signaling (phosphodiesterases). In human infants, betamethasone increased the rate of ductus constriction at all gestational ages. However, in infants born ≤25 6/7 weeks gestation, betamethasone's contractile effects were only apparent when prostaglandin signaling was inhibited, whereas at 26-27 weeks gestation, betamethasone's contractile effects were apparent even in the absence of prostaglandin inhibitors., Conclusions: We speculate that betamethasone's contractile effects may be mediated through genes that are developmentally regulated. This could explain why betamethasone's effects vary according to the infant's developmental age at birth.

A persistent left-to-right shunt through a patent ductus arteriosus (PDA) increases the rate of hydrostatic fluid filtration into the lung's interstitium, impairs pulmonary mechanics, and prolongs the need for mechanical ventilation. In preclinical trials, pharmacologic PDA closure leads to improved alveolarization and minimizes the impaired postnatal alveolar development that is the pathologic hallmark of bronchopulmonary dysplasia (BPD). Although routine prophylactic treatment of a PDA on the day of birth does not appear to offer any more protection against BPD than delaying treatment for 2-3 days, recent evidence from quality improvement trials suggests that early pharmacologic treatment decreases the incidence of BPD compared with a treatment approach that exposes infants to a moderate-to-large PDA shunt for the first 7-10 days after birth. After the first week, routine pharmacologic treatment (compared with continued PDA exposure) no longer appears to alter the course of BPD development. Evidence from epidemiologic, preclinical, and randomized controlled trials demonstrate that early ductus ligation is an independent risk factor for the development of BPD., (Copyright © 2018. Published by Elsevier Inc.)

DA closure is crucial for the transition from fetal to neonatal life. This closure is supported by changes to the DA's signaling and structural properties that distinguish it from neighboring vessels. Examining transcriptional differences between these vessels is key to identifying genes or pathways responsible for DA closure. Several microarray studies have explored the DA transcriptome in animal models but varied experimental designs have led to conflicting results. Thorough transcriptomic analysis of the human DA has yet to be performed. A clear picture of the DA transcriptome is key to guiding future research endeavors, both to allow more targeted treatments in the clinical setting, and to understand the basic biology of DA function. In this review, we use a cross-species cross-platform analysis to consider all available published rodent microarray data and novel human RNAseq data in order to provide high priority candidate genes for consideration in future DA studies., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: To determine whether prophylactic indomethacin (PINDO) has more or less morbidity than delayed conservative management of the moderate-to-large patent ductus arteriosus (PDA)., Study Design: We performed a prospective double cohort controlled study of infants delivered at ≤27 6/7 weeks gestation (n = 397). From January 2005 through April 2011, all infants were treated with PINDO (n = 247). From May 2011 through August 2016, no infant was treated with indomethacin until at least 8 postnatal days (conservative epoch, n = 150). Echocardiograms were performed on day 7 and at planned intervals until the PDA was small or closed. A single neonatologist prospectively collected all data., Results: The incidence of moderate-to-large PDA on day 7 and duration of exposure to moderate-to-large PDA were significantly less in the PINDO epoch (incidence = 10%, median = 2 days) than the conservative epoch (incidence = 67%, median = 14 days). Ligation rates were low in both epochs (PINDO = 14%, conservative = 5%). In multivariate analyses, PINDO infants had a significantly lower incidence of bronchopulmonary dysplasia (BPD) (risk ratio = 0.68, CI: 0.46-0.89) and BPD or death (risk ratio= 0.78, CI: 0.62-0.95) than conservative infants. There were no differences between the epochs in death, intraventricular hemorrhage grades 3 and 4, necrotizing enterocolitis, or retinopathy of prematurity receiving treatment. The effects of PINDO on BPD and BPD or death were no longer significant when analyses were adjusted for presence of a moderate-to-large PDA on day 7. The significant effects of PINDO were independent of whether or not a ligation was performed., Conclusions: PINDO decreases BPD and BPD or death compared with delayed conservative PDA management. These effects are mediated by closure of the PDA., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: To determine whether a moderate-to-large patent ductus arteriosus (PDA) is responsible for vasopressor-dependent hypotension, occurring at the end of the first postnatal week., Study Design: We performed a retrospective, double cohort controlled study of infants delivered at ≤27 +6 weeks' gestation (n = 313). From January 2004 through April 2011, all infants were treated with prophylactic indomethacin ([PINDO] epoch). From May 2011 through December 2015, no infant was treated with indomethacin until at least 8 postnatal days (conservative epoch). Echocardiograms were performed on postnatal days 6 or 7. Hypotension was managed by a predefined protocol. The primary outcome was the incidence of dopamine-dependent hypotension, defined as having received at least 6 µg/kg/min dopamine for at least 24 hours during postnatal days 4-7., Results: As expected, the incidence of moderate-to-large PDA at the end of the first week differed significantly between epochs (PINDO = 8%; conservative = 64%). In multivariate analyses, infants in the PINDO epoch had a significantly lower incidence of vasopressor-dependent hypotension (11%) than infants in the conservative epoch (21%; OR = 0.40, 95% CI 0.20-0.82). Infants in the PINDO epoch also required less mean airway pressure, had a lower respiratory severity score, and lower mode of ventilation score than infants in the conservative epoch during postnatal days 4-7. The effects of PINDO on both the incidence of vasopressor-dependent hypotension and the need for respiratory support were no longer significant when analyses were adjusted for "presence or absence of a moderate-to-large PDA.", Conclusion: PINDO decreases vasopressor-dependent hypotension and the need for respiratory support at the end of the first postnatal week. These effects are mediated by closure of the PDA., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: To examine the effects of antenatal steroids on severe intraventricular hemorrhage (IVH) in infants born during the IVH vulnerable period (<28 weeks gestational age) and to evaluate rates of IVH correlated with the time interval between treatment or retreatment and birth., Study Design: A total of 429 infants (<28 weeks gestation), who delivered ≥24 hours after the first betamethasone (BMZ) course (2 doses), were divided into groups based on the interval between the first course of BMZ and delivery: <10 days or ≥10 days. The primary outcome was severe IVH. Multiple regression analyses were performed to adjust for potential confounders., Results: Three hundred ninety-two infants delivered after a single BMZ course (312 delivered <10 days; 80 ≥10 days). The incidence of severe IVH was 17% for infants delivered ≥10 days and 7% for those delivered <10 days after a single BMZ course (aOR 4.16; 95% CI 1.59-10.87, P = .004); 37 infants (born ≥10 days from the first BMZ course) received a second/rescue BMZ course. The incidence of severe IVH among infants receiving a second/rescue course was 8%, which was similar to the incidence among infants born <10 days (aOR 1.7; 95% CI 0.41-6.6, P = .48)., Conclusions: In infants born before 28 weeks gestation, delivery ≥10 days from the first BMZ course is associated with a higher incidence of severe IVH; a second/rescue course may reverse this effect., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Patent ductus arteriosus (PDA) in the newborn is the most common congenital heart anomaly and is significantly more common in preterm infants. Contemporary pharmacological treatment is effective in only 70-80% of the cases. Moreover, indomethacin or ibuprofen, which are used to close a PDA may be accompanied by serious side effects in premature infants. To explore the novel molecular pathways, which may be involved in the maturation and closure of the ductus arteriosus (DA), we used fetal and neonatal sheep to test the hypothesis that maturational development of DA is associated with significant alterations in specific mRNA expression., Methods: We conducted oligonucleotide microarray experiments on the isolated mRNA from DA and ascending aorta from three study groups (premature fetus-97 ± 0 d, near-term fetus-136 ± 0.8 d, and newborn lamb-12 ± 0 h). We compared the alterations in mRNA expression in DA and aorta to identify genes specifically involved in DA maturation., Results: Results demonstrate significant changes in wingless-integrin1, thrombospondin 1, receptor activator of nuclear factor-kappa B, nitric oxide synthase, and retinoic acid receptor activation signaling pathways., Conclusion: We conclude that these pathways may play an important role during both development and postnatal DA closure and warrant further investigation.

Objective: To discover a predictor, that could be used at least 3 to 4 weeks' before discharge, to identify infants who would need home oxygen therapy. We hypothesized that infants requiring a high level of respiratory support at 34 weeks' postmenstrual age (PMA) would require home oxygen., Study Design: Single center retrospective study of 143 infants less than 28 weeks' gestation. We determined when infants weaned from each level of respiratory support (mechanical ventilation, nasal continuous airway pressure [nCPAP] or biphasic positive pressure, nasal cannula flow ≥ 2 L/min, nasal cannula flow < 2 L/min or no respiratory support). Our primary outcome was need for home oxygen., Result: Infants who required nCPAP at 34 weeks' PMA had a 100% positive predictive value for home oxygen therapy., Conclusion: Higher levels of respiratory support at 34 weeks' PMA can predict the need for home oxygen and is useful in preparing patients and families for discharge., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Objective: To identify genes affected by advancing gestation and racial/ethnic origin in human ductus arteriosus (DA)., Study Design: We collected 3 sets of DA tissue (n = 93, n = 89, n = 91; total = 273 fetuses) from second trimester pregnancies. We examined four genes, with DNA polymorphisms that distribute along racial lines, to identify "Caucasian" and "non-Caucasian" DA. We used real time polymerase chain reaction to measure RNA expression of 48 candidate genes involved in functional closure of the DA, and used multivariable regression analyses to examine the relationships between advancing gestation, "non-Caucasian" race, and gene expression., Results: Mature gestation and non-Caucasian race are significant predictors for identifying infants who will close their patent DA when treated with indomethacin. Advancing gestation consistently altered gene expression in pathways involved with oxygen-induced constriction (eg, calcium-channels, potassium-channels, and endothelin signaling), contractile protein maturation, tissue remodeling, and prostaglandin and nitric oxide signaling in all 3 tissue sets. None of the pathways involved with oxygen-induced constriction appeared to be altered in "non-Caucasian" DA. Two genes, SLCO2A1 and NOS3, (involved with prostaglandin reuptake/metabolism and nitric oxide production, respectively) were consistently decreased in "non-Caucasian" DA., Conclusions: Prostaglandins and nitric oxide are the most important vasodilators opposing DA closure. Indomethacin inhibits prostaglandin production, but not nitric oxide production. Because decreased SLCO2A1 and NOS3 expression can lead to increased prostaglandin and decreased nitric oxide concentrations, we speculate that prostaglandin-mediated vasodilation may play a more dominant role in maintaining the "non-Caucasian" patent DA, making it more likely to close when inhibited by indomethacin., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Several cohort studies have shown an association between low platelet counts in the first day(s) of life and patent ductus arteriosus (PDA) in preterm infants. However, these results have not been confirmed by other studies., Objective: To perform a meta-analysis of all the studies addressing the relationship between platelet counts in the first day(s) of life and PDA in preterm infants., Methods: PubMed/MEDLINE and EMBASE were searched from their inception until December 2014. Results from 11 cohort studies involving 3,479 preterm infants (gestational age <32 weeks) were pooled using random-effects modeling., Results: Meta-analysis showed a significant positive association between PDA and platelet counts <150 × 10(9)/l [6 studies, risk ratio (RR) = 1.215, 95% CI: 1.027-1.436], between PDA and platelet counts <100 × 10(9)/l (5 studies, RR = 1.255, 95% CI: 1.034-1.525), and between significant PDA (SPDA) and platelet counts <100 × 10(9)/l (5 studies, RR = 1.254, 95% CI: 1.021-1.540). The association between SPDA and platelet counts <150 × 10(9)/l was not statistically significant (6 studies, RR = 1.289, 95% CI: 0.925-1.795). Pooled standard differences in mean platelet counts between infants with and without PDA/SPDA were not statistically different., Conclusion: This meta-analysis reveals a marginal but significant association between low platelet counts in the first day(s) of life and PDA/SPDA in very preterm infants. This association needs to be confirmed in prospective studies., (© 2015 S. Karger AG, Basel.)

Optimal management of the patent ductus arteriosus (PDA) in the premature infant remains controversial. Despite considerable historical and physiological data indicating that a persistent PDA may be harmful, robust evidence of long-term benefits or harms from treatment is lacking. This has been equated to a lack of benefit but is also a reflection of the fact that most clinical trials were designed to assess the effects of short-term (2-8 days) rather than prolonged exposure to a PDA. No clinical trials have been designed to assess the effects of prolonged exposure of persistent PDA on morbidity and mortality of very premature infants in the era of antenatal corticosteroids, surfactant and non-invasive respiratory support. Further research is required, but new insights and novel therapies are evolving, which will allow greater individual patient assessment, understanding of risk and optimisation of treatment. In this paper, we review the current literature, evidence for treatment options, including a non-interventional approach, and research directions for infants <28 weeks' gestational age., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objective: To test the hypothesis that an impaired adrenal response to stress might play a role in the hypotension that follows patent ductus arteriosus (PDA) ligation., Study Design: We performed a multicenter study of infants born at <32 weeks' gestation who were about to undergo PDA ligation. Serum adrenal steroids were measured 3 times: before and after a cosyntropin (1.0 μg/kg) stimulation test (performed before the ligation), and at 10-12 hours after the ligation. A standardized approach for diagnosis and treatment of postoperative hypotension was followed at each site. A modified inotrope score (1 × dopamine [μg/kg/min] + 1 × dobutamine) was used to monitor the catecholamine support an infant received. Infants were considered to have catecholamine-resistant hypotension if their greatest inotrope score was >15., Results: Of 95 infants enrolled, 43 (45%) developed hypotension and 14 (15%) developed catecholamine-resistant hypotension. Low postoperative cortisol levels were not associated with the overall incidence of hypotension after ligation. However, low cortisol levels were associated with the refractoriness of the hypotension to catecholamine treatment. In a multivariate analysis: the OR for developing catecholamine-resistant hypotension was OR 36.6, 95% CI 2.8-476, P = .006. Low cortisol levels (in infants with catecholamine-resistant hypotension) were not attributable to adrenal immaturity or impairment; their cortisol precursor concentrations were either low or unchanged, and their response to cosyntropin was similar to infants without catecholamine-resistant hypotension., Conclusion: Infants with low cortisol concentrations after PDA ligation are likely to develop postoperative catecholamine-resistant hypotension. We speculate that decreased adrenal stimulation, rather than an impaired adrenal response to stimulation, may account for the decreased production., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: To examine the relationship between the cause or severity of hypotension and the development of severe ROP (sROP) (≥stage 3 or stage 2 with plus disease in zone I or II)., Study Design: Infants (<28 weeks' gestation, n = 242) were observed for hypotension and treated with a standardized hypotension-treatment protocol. Hypotension was classified as resulting from one of the following causes: (1) culture-positive infection and/or necrotizing enterocolitis; (2) patent ductus arteriosus ligation; or (3) "idiopathic" (no cause identified other than prematurity), and as being either dopamine responsive or dopamine resistant. Cortisol levels were measured for infants with dopamine-resistant hypotension. Eye examinations were performed until the retinopathy of prematurity resolved or the vasculature matured. Multivariable logistic regression analysis was performed to determine the relationship between the cause/severity of hypotension and sROP., Results: Overall, 66% of infants developed hypotension (41% were dopamine responsive and 25% were dopamine resistant). sROP developed in 19% of infants. "Idiopathic" dopamine-resistant hypotension was the only cause significantly related to sROP. Of the infants with dopamine-resistant hypotension, 66% had low serum cortisol (≤10 μg/dL). Low cortisol, in the presence of dopamine-resistant hypotension, was significantly associated with sROP and accounted for the relationship between "idiopathic" hypotension and sROP. When low cortisol was included in statistical models, other known risk factors, such as immature gestation, were no longer significantly related to sROP., Conclusion: Low cortisol, in the presence of dopamine-resistant hypotension, has the greatest magnitude of association with sROP., (Copyright © 2013 Mosby, Inc. All rights reserved.)

A persistent left-to-right shunt through a patent ductus arteriosus (PDA) increases the rate of hydrostatic fluid filtration into the lung's interstitium, impairs pulmonary mechanics, and prolongs the need for mechanical ventilation. In preclinical trials, pharmacologic PDA closure leads to improved alveolarization and minimizes the impaired postnatal alveolar development that is the pathologic hallmark of the "new bronchopulmonary dysplasia (BPD)". Although early pharmacologic closure of the PDA decreases the incidence of pulmonary hemorrhage, intraventricular hemorrhage, and the need for PDA ligation, there is little evidence from controlled, clinical trials to support or refute a causal role for the PDA in the development of BPD. However, evidence from epidemiologic, preclinical, and randomized controlled clinical trials demonstrate that early ductus ligation is an independent risk factor for the development of BPD and may directly contribute to the neonatal morbidities it is trying to prevent., (Copyright © 2013 Elsevier Inc. All rights reserved.)