Search

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.

BACKGROUND: Near-infrared spectroscopy is used in the assessment of regional splanchnic oxygen saturation (rsSO2), but solid reference values are scarce. We aimed to establish reference values of rsSO2 for preterm infants during the first week after birth, both crude and modeled based on predictors.METHODS: We included infants with gestational age (GA) RESULTS: We included 220 infants. On day 1, the mean ± SD rsSO2 value was 48.2% ± 16.6. The nadir of rsSO2 was on day 4 (38.7% ± 16.6 smoothed line) to 5 (37.4%±17.3, actual data), after which rsSO2 increased to 44.2% ± 16.6 on day 7. The final model of the reference values of rsSO2 included the following coefficients: rsSO2 = 3.2 - 7.0 × PNA + 0.8 × PNA2 - 4.0 × SGA + 1.8 × GA.CONCLUSIONS: We established reference values of rsSO2 for preterm infants during the first week after birth. GA, PNA, and SGA affect these values and need to be taken into account.IMPACT: Regional splanchnic oxygen saturation is lower in infants with a lower gestational age and in small-for-gestational age infants. Regional splanchnic oxygen saturation decreases with a higher postnatal age until day 4 after birth and then increases until day 7 after birth. Gestational age, postnatal age, and small-for-gestational age status affect regional splanchnic oxygen saturation and need to be taken into account when interpreting regional splanchnic oxygen saturations using NIRS. Reference values for infant regional splanchnic oxygen saturation can be computed with a formula based on these variables, as provided by this study.

Background To systematically evaluate short-term efficacy of UCM versus other interventions in preterm infants. Methods Six engines were searched until February 2020 for randomized controlled trials (RCTs) assessing UCM versus immediate cord clamping (ICC), delayed cord clamping (DCC), or no intervention. Primary outcomes were overall mortality, intraventricular hemorrhage (IVH), and patent ductus arteriosus (PDA); secondary outcomes were need for blood transfusion, mean blood pressure (MBP), serum hemoglobin (Hb), and ferritin levels. Random-effects meta-analyses were used. Results Fourteen RCTs (n = 1708) were included. In comparison to ICC, UCM did not decrease mortality (RR 0.5, 95% CI 0.2-1.1), IVH (RR 0.7, 95% CI 0.5-1.0), or PDA (RR 1.0, 95% CI 0.7-1.5). However, UCM reduced need of blood transfusion (RR 0.5, 95% CI 0.3-0.9) and increased MBP (MD 2.5 mm Hg, 95% CI 0.5-4.5), Hb (MD 1.2 g/dL, 95% CI 0.8-1.6), and ferritin (MD 151.4 ng/dL, 95% CI 59.5-243.3). In comparison to DCC, UCM did not reduce mortality, IVH, PDA, or need of blood transfusion but increased MBP (MD 3.7, 95% CI 0.6-6.9) and Hb (MD 0.3, 95% CI -0.2-0.8). Only two RCTs had high risk of bias. Conclusions UCM did not decrease short-term clinical outcomes in comparison to ICC or DCC in preterm infants. Intermediate outcomes improved significantly with UCM. Impact In 14 randomized controlled trials (RCTs), umbilical cord milking (UCM) did not reduce mortality, intraventricular hemorrhage, or patent ductus arteriosus compared to immediate (ICC) or delayed cord clamping (DCC).UCM improved mean blood pressure and hemoglobin levels compared to ICC or DCC. In comparison to ICC, UCM reduced the need for blood transfusion.We updated searches until February 2020, stratified by type of control, and performed subgroup analyses.There was low quality of evidence about clinical efficacy of UCM. Most of RCTs had low risk of bias.UCM cannot be recommended as standard of care for preterm infants.

Background Indomethacin treatment for patent ductus arteriosus (PDA) is associated with acute kidney injury (AKI). Fenoldopam, a dopamine (DA) DA1-like receptor agonist dilates the renal vasculature and may preserve renal function during indomethacin treatment. However, limited information exists on DA receptor-mediated signaling in the ductus and fenoldopam may prevent ductus closure given its vasodilatory nature. Methods DA receptor expression in CD-1 mouse vessels was analyzed by qPCR and immunohistochemistry. Concentration-response curves were established using pressure myography. Pretreatment with SCH23390 (DA1-like receptor antagonist), phentolamine (α -adrenergic receptor antagonist) or indomethacin addressed mechanisms for DA-induced changes. Fenoldopam's effects on postnatal ductus closure were evaluated in vivo. Results DA1 receptors were expressed equally in ductus and aorta. High-dose DA induced modest vasoconstriction under newborn O2 conditions. Phentolamine inhibited DA-induced constriction, while SCH23390 augmented constriction, consistent with a vasodilatory role for DA1 receptors. Despite this, fenoldopam had little effect on ductus tone nor indomethacin- or O2-induced constriction and did not impair postnatal closure in vivo. Conclusion(s) DA receptors are present in the ductus but have limited physiologic effects. DA-induced ductus vasoconstriction is mediated via α-adrenergic pathways. The absence of DA1-mediated impairment of ductus closure supports the study of potential role for fenoldopam during PDA treatment.

Changes in systemic and cerebral hemodynamics in preterm infants during early transitional circulation are complex and may differ between infants with or without intraventricular hemorrhage (IVH). In total, 43 infants born at median (range) 25 + 5 (23 + 3–31) had continuous near-infrared spectroscopy (NIRS) monitoring of tissue oxygenation index (TOI) and cerebrovascular reactivity within the first 48 h of life. Measurements of left and right cardiac outputs (LVO, RVO) and patent ductus arteriosus (PDA) were collected at 6, 12, 24, and 48 h of life. LVO increased within the first 48 h in the IVH (P = 0.007) and no-IVH (P

Serum creatinine (SCr)- or urine output-based definitions of acute kidney injury (AKI) have important limitations in neonates. This study evaluates the diagnostic value of urinary biomarkers in very low-birth-weight (VLBW) infants receiving indomethacin for closure of a patent ductus arteriosus (PDA). Prospective cohort study in 14 indomethacin-treated VLBW infants and 18 VLBW infants without indomethacin as controls. Urinary biomarkers were measured before, during, and after indomethacin administration. Indomethacin therapy was associated with significantly higher SCr concentrations at 36, 84, and 120 h compared to controls. At 36 h, three indomethacin-treated patients met the criteria for neonatal modified Kidney Disease: Improving Global Outcomes (KDIGO) AKI. The product of urinary tissue inhibitor of metalloproteinase-2 and insulin-like growth factor-binding protein 7 ([TIMP-2]•[IGFBP7]) was significantly elevated in the AKI subgroup at 12 h (P

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 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 n = 307): infants intubated ≥10 days: OR (95% CI) = 2.41 (1.47–3.95)); infants intubated 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 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

IntroductionVery and extremely preterm infants frequently have brain injury-related long-term neurodevelopmental problems. Altered perfusion, for example, seen in the context of a hemodynamically significant patent ductus arteriosus (PDA), has been linked to injury of the immature brain. However, a direct relation with outcome has not been reviewed systematically.MethodsA systematic review was conducted to provide an overview of the value of different cerebral arterial blood flow parameters assessed by Doppler ultrasound, in relation to brain injury, to predict long-term neurodevelopmental outcome in preterm infants.ResultsIn total, 23 studies were included. Because of heterogeneity of studies, a meta-analysis of results was not possible. All included studies on resistance index (RI) showed significantly higher values in subjects with a hemodynamically significant PDA. However, absolute differences in RI values were small. Studies using Doppler parameters to predict brain injury and long-term neurodevelopmental outcome were inconsistent.DiscussionThere is no clear evidence to support the routine determination of RI or other Doppler parameters in the cerebral arteries to predict brain injury and long-term neurodevelopmental outcome in the preterm infant. However, there is evidence that elevated RI can point to the presence of a hemodynamically significant PDA.

In many preterm infants, the ductus arteriosus remains patent beyond the first few days of life. This prolonged patency is associated with numerous adverse outcomes, but the extent to which these adverse outcomes are attributable to the hemodynamic consequences of ductal patency, if at all, has not been established. Different treatment strategies have failed to improve short-term outcomes, with a paucity of data on the correct diagnostic and pathophysiological assessment of the patent ductus arteriosus (PDA) in association with long-term outcomes. Echocardiography is the selected method of choice for detecting a PDA, assessing the impact on the preterm circulation and monitoring treatment response. PDA in a preterm infant can result in pulmonary overcirculation and systemic hypoperfusion, Therefore, echocardiographic assessment should include evaluation of PDA characteristics, indices of pulmonary overcirculation with left heart loading conditions, and indices of systemic hypoperfusion. In this review, we provide an evidence-based overview of the current and emerging ultrasound measurements available to identify and monitor a PDA in the preterm infant. We offer indications and limitations for using Neonatologist Performed Echocardiography to optimize the management of a neonate with a PDA.

Postnatally, the immature left ventricle (LV) is subjected to high systemic afterload. Hypothesizing that LV pumping would change during transition–adaptation, we analyzed the LV in preterm infants (GA≤32+6), clinically stable or with a hemodynamically significant patent ductus arteriosus (hPDA) by applying a pump model. Pumping was characterized by EA (effective arterial elastance, reflecting afterload), EES (end-systolic LV elastance, reflecting contractility), EA/EES coupling ratios, descriptive EA:EES relations, and EA/EES graphs. Data calculated from echocardiography and blood pressure were analyzed by diagnosis (S group: clinically stable, no hPDA, n=122; hPDA group, n=53) and by periods (early transition: days of life 1–3; late transition: 4–7; and adaptation: 8–30). S group: LV pumping was characterized by an increased EA/EES coupling ratio of 0.65 secondary to low EES in early transition, a tandem rise of both EA and EES in late transition, and an EA/EES coupling ratio of 0.45 secondary to high EES in adaptation; hPDA group: time-trend analyses showed significantly lower EA (P

Perfusion index (PI) is a noninvasive measure of perfusion. ΔPI (difference between pre- and postductal PI) may identify hemodynamically significant PDA. However, studies are limited to brief and intermittent ΔPI sampling. Our objective is to assess the value of continuous high resolution ΔPI monitoring in the diagnosis of PDA. Continuous ΔPI monitoring in preterm infants was prospectively performed using two high-resolution pulse oximeters. Perfusion Index measures (ΔPI mean and variability, pre- and postductal PI) were analyzed over a 4-h period prior to echocardiography. A cardiologist blinded to the results evaluated for PDA on echocardiography. Linear mixed regression models were utilized for analyses. We obtained 31 echocardiography observations. Mean ΔPI (−0.23 vs. 0.16; P < 0.05), mean pre-PI (0.86 vs. 1.26; P < 0.05), and ΔPI variability (0.39 vs. 0.61; P = 0.05) were lower in infants with PDA compared to infants without PDA at the time of echocardiography. Mean ΔPI, ΔPI variability, and mean pre-PI measured 4 h prior to echocardiography detect PDA in preterm infants. PI is dynamic and should be assessed continuously. Perfusion index is a promising bedside measurement to identify PDA in preterm infants.

Background To test the hypothesis that dopamine is associated with impaired cerebral autoregulation (ICA) in a dose-dependent fashion. Methods Non a priori designed secondary analysis of a prospectively enrolled cohort study subjects 0.5. Results Twenty-three of 61 subjects (38%) required dopamine. Time spent with ICA was 23% in dopamine-exposed subjects vs. 14% in those not exposed (p = 0.0001). On the epoch level, time spent with ICA was 15%, 29%, 34%, 37%, and 23% in epochs with dopamine titration of 0, 1–5, 6–10, 11–15, and 16–20 μg/kg/min, respectively. Using mixed-effect modeling, ICA for each dopamine titration was significantly higher than unexposed times when controlling for gestation, presence of a patent ductus arteriosus, day of life, MAP less than gestational age, and illness severity score (p

The ductus arteriosus (DA) is probably the most intriguing vessel in postnatal hemodynamic transition. DA patency in utero is an active state, in which prostaglandin E2 (PGE2) and nitric monoxide (NO), play an important role. Since the DA gets programmed for postnatal closure as gestation advances, in preterm infants the DA frequently remains patent (PDA). PGE2 exposure programs functional postnatal closure by inducing gene expression of ion channels and phosphodiesterases and anatomical closure by inducing intimal thickening. Postnatally, oxygen inhibits potassium and activates calcium channels, which ultimately leads to a rise in intracellular calcium concentration consequently inducing phosphorylation of the myosin light chain and thereby vasoconstriction of the DA. Since ion channel expression is lower in preterm infants, oxygen induced functional vasoconstriction is attenuated in comparison with full term newborns. Furthermore, the preterm DA is more sensitive to both PGE2 and NO compared to the term DA pushing the balance toward less constriction. In this review we explain the physiology of DA patency in utero and subsequent postnatal functional closure. We will focus on the pathobiology of PDA in preterm infants and the (un)intended effect of antenatal exposure to medication on both fetal and neonatal DA vascular tone.

BackgroundPatent 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.MethodsWe 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.ResultsResults 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.ConclusionWe conclude that these pathways may play an important role during both development and postnatal DA closure and warrant further investigation.

Cerebral development may be impaired in fetuses with congenital cardiovascular malformations, particularly hypoplastic left heart syndrome (HLHS) and aortopulmonary transposition (APT). The decreased cerebral arterial pusatility index observed in some of these fetuses led to the belief that cerebral vascular resistance was reduced as a result of arterial hypoxemia and cerebral hypoxia is thought to be responsible for impaired cerebral growth. However, other hemodynamic factors could affect pulsatility index. I propose that cerebral blood flow is reduced in fetuses with HLHS and that reduced glucose, rather than oxygen, delivery interferes with cerebral development. This is based on the fact that most of these fetuses do not have lactate accumulation in the brain.In fetuses with APT, umbilical venous blood, containing oxygen and glucose derived across the placenta, is distributed to the lungs and lower body; venous blood, with low oxygen and glucose content, is delivered to the ascending aorta and brain. Oxygen and glucose delivery may further be reduced by decreased cerebral blood flow resulting from run-off of aortic blood through the ductus arteriosus to the pulmonary circulation during diastole. In APT fetuses, lack of lactate in the brain also supports my proposal that glucose deficiency interferes with cerebral development.

To determine associations of low superior vena cava (SVC) flow (≤55 ml/kg/min) and low right ventricular output (RVO) (≤150 ml/kg/min) in preterm infants. An observational study in infants

The glucocorticosteroid betamethasone is routinely administered prior to anticipated preterm birth to enhance lung maturation. While betamethasone also increases fetal pulmonary blood flow and reduces pulmonary vascular resistance (PVR), we investigated whether alterations in right ventricular (RV) function and ductal characteristic impedance (Zc) additionally contributed to rises in pulmonary flow. Anesthetized preterm fetal lambs with (n = 10) or without (n = 8) betamethasone pretreatment were instrumented with a pulmonary trunk micromanometer and ductus arteriosus and left pulmonary artery (PA) flow probes to calculate Zc, and obtain RV output and hydraulic power. Betamethasone (1) increased systolic and pulse arterial pressures (P ≤ 0.04), heart rate (P = 0.02), and lowered PVR (P = 0.04), (2) increased mean (P = 0.008) and systolic (P = 0.004), but not diastolic PA flow or PA Zc, (3) increased ductal Zc (P

Early identification of infants at risk for complications from patent ductus arteriosus (PDA) may improve treatment outcomes. The aim of this study was to identify biochemical markers associated with persistence of PDA, and with failure of pharmacological treatment for PDA, in extremely preterm infants. Infants born at 22–27 weeks’ gestation were included in this prospective study. Blood samples were collected on the second day of life. Fourteen biochemical markers associated with factors that may affect PDA closure were analyzed and related to persistent PDA and to the response of pharmacological treatment with ibuprofen. High levels of B-type natriuretic peptide, interleukin-6, -8, -10, and -12, growth differentiation factor 15 and monocyte chemotactic protein 1 were associated with persistent PDA, as were low levels of platelet-derived growth factor. High levels of erythropoietin were associated with both persistent PDA and failure to close PDA within 24 h of the last dose of ibuprofen. High levels of inflammatory markers were associated with the persistence of PDA. High levels of erythropoietin were associated with both the persistence of PDA and failure to respond to pharmacological treatment.

BACKGROUND Preterm infants are at risk for white matter (WM) injury and adverse neurodevelopmental outcomes. METHODS Serial diffusion tensor magnetic resonance imaging data were obtained from very preterm infants (N = 78) born

Apnea of prematurity (AOP) is a common and pervasive problem in very low birth weight infants. Methylxanthines were reported >40 years ago to be an effective therapy and, by the early 2000s, caffeine had become the preferred methylxanthine because of its wide therapeutic index, excellent bioavailability, and longer half-life. A clinical trial to address unresolved questions and toxicity concerns, completed in 2004, confirmed significant benefits of caffeine therapy, including shorter duration of intubation and respiratory support, reduced incidence of chronic lung disease, decreased need for treatment of patent ductus arteriosus, reduced severity of retinopathy of prematurity, and improved motor and visual function. Cohort studies have now further delineated the benefits of initiation of therapy before 3 days postnatal age, and of higher maintenance doses to achieve incremental beneficial effects. This review summarizes the pivotal and in particular the most recent studies that have established the safety and efficacy of caffeine therapy for AOP and other respiratory and neurodevelopmental outcomes. Caffeine has a very favorable benefit-to-risk ratio, and has become one of the most prescribed and cost-effective pharmacotherapies in the NICU.

Insights image for exploration of potential biochemical markers for persistence of patent ductus arteriosus in preterm infants at 22-27 weeks' gestation : [published in Pediatric Research volume 86, page 413 (2019)]

BACKGROUND Tandem mass spectrometry has been proposed as a method of diagnosing or predicting the development of common complex neonatal diseases. Our objective was to identify metabolites associated with common complications of prematurity. METHODS We performed a retrospective analysis of medical data and metabolite measurements from routine neonatal screening on 689 preterm (

BackgroundPatent ductus arteriosus (PDA) is a common complication seen in preterm infants. Indomethacin is routinely used to treat PDA. Evidence suggests that the response of indomethacin is highly heritable. This study investigated the association between single-nucleotide polymorphisms (SNPs) in CYP2C9 and the closure of PDA in response to indomethacin.MethodsSix SNPs in CYP2C9 were analyzed for association with indomethacin response. A case-control analysis was performed among neonates who responded to indomethacin (responders) and among those who required surgical ligation (non-responders). Independent transmission disequilibrium tests were performed among parent-child trios of responders and non-responders.ResultsThe G allele of rs2153628 was associated with increased odds of response to indomethacin in the case-control analysis (odds ratios (OR): 1.918, 95% confidence interval (CI): 1.056, 3.483). Among indomethacin responders, the G allele of rs2153628 and the T allele of rs1799853 were overtransmitted from the parents to their child (OR: 2.667, 95% CI: 1.374, 5.177 and OR: 2.375, 95% CI: 1.040, 5.425, respectively), consistent with the case-control analysis.ConclusionWe identified an association between two SNPs in CYP2C9, rs2153628 and rs1799853, and indomethacin response for the treatment of PDA. These findings suggest that response to indomethacin in the closure of PDA may be influenced by polymorphisms associated with altered indomethacin metabolism.

We examined recent trends and interhospital variation in use of indomethacin, ibuprofen, and surgical ligation for patent ductus arteriosus (PDA) in very-low-birth-weight (VLBW) infants. Included in this retrospective study of the Pediatric Hospital Information System database were 13,853 VLBW infants from 19 US children’s hospitals, admitted at age < 3 d between 1 January 2005 and 31 December 2014. PDA management and in-hospital outcomes were examined for trends and variation. PDA was diagnosed in 5,719 (42%) VLBW infants. Cyclooxygenase inhibitors and/or ligation were used in 74% of infants with PDA overall, however studied hospitals varied greatly in PDA management. Odds of any cyclooxygenase inhibitor or surgical treatment for PDA decreased 11% per year during the study period. This was temporally associated with improved survival but also with increasing bronchopulmonary dysplasia, periventricular leukomalacia, retinopathy of prematurity, and acute renal failure in unadjusted analyses. There was no detectable correlation between hospital-specific changes in PDA management and hospital-specific changes in outcomes of preterm birth during the study period. Use of cyclooxygenase inhibitors and ligation for PDA in VLBW infants decreased over a 10-y period at the studied hospitals. Further evidence is needed to assess the impact of this change in PDA management.

Near-infrared spectroscopy (NIRS) may assist with characterization of a hemodynamically significant patent ductus arteriosus (hsPDA) by measuring cerebral and renal saturation (Csat and Rsat) levels. We hypothesized that Csat and Rsat in preterm infants with an hsPDA would be decreased compared to those with no PDA or nonsignificant PDA. This non a-priori designed study retrospectively investigated clinical and ECHO characteristics of preterm infants

Patent ductus arteriosus (PDA) is a common life-threatening complication among premature infants. Although cyclooxygenase inhibitors are frequently used to treat PDA, as they inhibit the synthesis of prostaglandin E(2), the most potent vasodilator in the ductus arteriosus (DA), their efficacy is often limited. As thromboxane A(2) (TXA(2)) induces vascular contraction via the TXA(2) receptor (TP), we hypothesized that TP stimulation would promote DA closure.To measure the inner diameter of the vessels, a rapid whole-body freezing method was used.Injection of the selective TP agonists U46619 and I-BOP constricted the fetal DA at embryonic day 19 (e19) and e21 in a dose-dependent manner. Of note, U46619 also exerted a vasoconstrictive effect on two different types of postnatal PDA models: premature PDA and hypoxia-induced PDA. We also found that U46619 constricted the ex vivo DA ring to a greater extent than it constricted the ex vivo aorta. Furthermore, we found that U46619 at lower concentrations (up to 0.05 mg/g of body weight) had a minimal vasoconstrictive effect on other vessels and did not induce microthrombosis in the pulmonary capillary arteries.Low-dose TP stimulation constricts the DA with minimal adverse effects at least in rat neonates and our results could point to an alternative potent vasoconstrictor for PDA.

Infants and children with repaired congenital diaphragmatic hernia (CDH) often continue to show delayed growth and development that may be, in part, secondary to unrecognized persistence of increased pulmonary vascular resistance (PVR). Data were reviewed from all patients ages 6–36 mo with repaired CDH who underwent cardiac catheterization from 2007 to 2010 and were compared to data from a control population of patients undergoing percutaneous closure of a patent ductus arteriosus (PDA). Indexed pulmonary blood flow (Qp), mean pulmonary artery pressure (mPAP), pulmonary capillary wedge pressure (PCWP), and PVR were examined. Data from 8 CDH patients and 10 control patients were examined. The mPAP (22.5 ± 3.33 vs. 18.2 ± 4.13 mm Hg) and PVR (3.66 ± 0.79 vs. 1.22 ± 0.4 iwU (indexed Wood’s units)) were both significantly elevated in the CDH population, whereas the Qp (4.08 ± 1.43 vs. 6.82 ± 1.46 l/min/m2) was significantly lower in this population. There was no significant difference in pulmonary capillary wedge pressure (PCWP). Less than half of the CDH patients had signs of pulmonary hypertension (PH) on echocardiogram. Our data suggest that children who are ages 6–36 mo with repaired CDH have significantly increased PVR compared with controls and early consideration of cardiac catheterization may be warranted.

The ductus arteriosus (DA), a fetal arterial shunt vessel between the proximal descending aorta and the pulmonary artery, closes shortly after birth. Initial functional closure as a result of the DA's smooth muscle contraction is followed by definite anatomical closure. The latter involves several complex mechanisms like endothelial cushion formation and smooth muscle cell migration resulting in fibrosis and sealing of the vessel. These complex steps indicate highly specialized functions of the DA vascular smooth muscle cells (VSMCs), endothelial cells, and fibroblasts. Herein, we describe a new reproducible method for isolating VSMCs, endothelial cells, and fibroblasts of high viability from fetal rat DA using immunomagnetic cell sorting. Purity of the different cell cultures was assessed by immunohistochemistry and flow cytometry and ranged between 85 and 94%. The capability of the VSMCs to react to hypoxic stimuli was assessed by intracellular calcium and ATP measurements and by VEGF mRNA expression analysis. VSMCs respond to hypoxia with decreases in intracellular calcium concentrations and ATP levels, whereas VEGF mRNA expression increased 3.2-fold. The purified vessel-specific different cell types are suitable for subsequent gene expression profiling and functional studies and provide important tools for improving our understanding of the complex processes involved in the closure of the DA.

Ibuprofen-induced ductus closure improves pulmonary mechanics and increases alveolar surface area in premature baboons compared with baboons with a persistent patent ductus arteriosus (PDA). Ibuprofen-treatment has no effect on the expression of genes that regulate pulmonary inflammation but does increase the expression of alpha-ENaC (the transepithelial sodium channel that is critical for alveolar water clearance). Although ligation eliminates the PDA, it does not improve pulmonary mechanics or increase alveolar surface area. We used preterm baboons (delivered at 67% of term gestation and ventilated for 14 days) to study whether the lack of beneficial effects, following PDA ligation, might be due to alterations in pulmonary gene expression. We found no differences in Ventilation or Oxygenation Indices between animals that were ligated (n=7) on day of life 6 and those that had a persistent PDA (n=12) during the entire 14 days study. In contrast with no intervention, PDA ligation produced a significant increase in the expression of genes involved with pulmonary inflammation (COX-2, TNF-alpha, and CD14), and a significant decrease in alpha-ENaC sodium channel expression. We speculate that these changes may decrease the rate of alveolar fluid clearance and contribute to the lack of improvement in pulmonary mechanics after PDA ligation.

Ibuprofen is an effective pharmacological intervention for closure of a patent ductus arteriosus in preterm infants, and is an alternative to surgical ligation; however it is not certain whether ibuprofen treatment is associated with adverse effects on the brain. Therefore, this study examined neuropathological outcomes of ibuprofen therapy for a patent ductus arteriosus. Fetal baboons were delivered at 125-days of gestation (dg, term ~185dg) by caesarean section, given surfactant and ventilated for 14-days with positive pressure ventilation. Baboons were randomly allocated to receive either ibuprofen (PPV + ibuprofen, n=8) or no therapy (PPV, n=5). Animals were euthanased on day 14 and brains assessed for cerebral growth, development and neuropathology. Body and brain weights, the total volume of the brain and the surface folding index (measure of brain growth) were not different (p>0.05) between PPV + ibuprofen-treated and PPV animals. There was no difference (p>0.05) in the number of myelin basic protein-immunoreactive oligodendrocytes, glial fibrillary acid protein-immunoreactive astrocytes or Iba1-immunoreactive macrophages/microglia in the forebrain. No overt cerebellar alterations were observed in either group. Ibuprofen treatment for patent ductus arteriosus closure in the preterm baboon neonate is not associated with any increased risk of neuropathology or alterations to brain growth and development.

The original version of this article contained an error in the legend of Fig. 3, which incorrectly read:Figure 3. a The patterns of arterial saturation (SaO2; orange), and rScO2 (blue) and mean arterial blood pressure (MABP; red) of an extremely preterm infant on postnatal day 1. The initial rScO2 values were very low (red box). These low values seemed to be associated with PaCO2 values below 30 mmHg (brown squares; starting at 24 mmHg. SaO2 and MABPs values were always normal. When PaCO2 values increased above values of 30 mmHg (brown arrow) the rScO2 increased and eventually normalized. b The patterns of rScO2 (blue) and mean arterial blood pressure (MABP; red) of a very preterm girl, starting on postnatal day 1, was especially marked by a steep decrease in cerebral oxygenation (rScO2; red box) to very low values (

Furosemide increases prostaglandin production and may be associated with patent ductus arteriosus (PDA). We aimed to clarify the in vivo ductus-dilating effects of furosemide in neonatal rats. Near-term rat pups delivered by a cesarean section were housed at 33 degrees C. After a rapid whole-body freezing, the DA diameter was measured using a microscope and a micrometer. Pregnant rats (gestational day 21) were s.c. injected with furosemide 4 h before delivery, and the neonatal DA was examined 0, 15, 30, 60, and 120 min after birth. Furosemide was also s.c. injected into 60-min-old rats and the DA diameter was examined 30, 60, and 120 min later. The control rats showed a rapid postnatal DA constriction (diameter: 0.80 and 0.08 mm at 0 and 60 min after birth, respectively). Prenatally administered furosemide delayed postnatal DA closure (0.36 mm at 60 min after birth). Furosemide injection in 60-min-old rats dilated the constricted DA at 60 min (0.25 versus 0.02 mm in the controls). Indomethacin inhibited furosemide-induced DA dilatation. Furosemide delays DA closure and dilates the constricted DA in neonatal rats. If furosemide has similar effects in human preterm neonates, caution may be warranted in its use in the treatment of infants with PDA.

A patent ductus arteriosus is due in large part to increased sensitivity of the premature ductus to PGE2. After PGE2 stimulation, cAMP concentrations are higher in the immature than in the mature ductus. cAMP concentrations depend on the rates of adenyl cyclase production and phosphodiesterase (PDE)-mediated degradation. We used ductus from immature (n = 25) and mature (n = 21) fetal sheep to investigate whether a developmental increase in PDE activity could explain the diminished cAMP accumulation that follows PGE2 stimulation in the mature ductus. With advancing gestation, mRNA expression of the smooth muscle PDE isoforms (PDE1A, 1B, 1C, 3A, 3B, 4D, and 5A) increased in the ductus as did their hydrolytic activities. Selective inhibitors of PDE1, PDE3, and PDE4 relaxed the mature and immature ductus in the presence of inhibitors of prostaglandin and nitric oxide production. The mature ductus required higher concentrations of each of the PDE inhibitors to inhibit its tension to the same extent as in the immature ductus. There were no developmental changes in PDE expression in the fetal aorta. In conclusion, we observed a developmental increase in cAMP and cGMP PDE activity that contributes to the decreased sensitivity of the late-gestation ductus arteriosus to vasodilators like PGE2.

Premature newborn baboons [125 d (67%) gestation], exposed to a moderate-size patent ductus arteriosus (PDA) [pulmonary-to-systemic blood-flow-ratio (Qp/Qs) = 1.8] for 14 d, have impaired pulmonary function and arrested alveolar development and surface area when compared with age matched fetuses (140 d gestation). Pharmacologic closure of the PDA reduces the detrimental effects of preterm delivery on pulmonary function and surface area. We used preterm baboons (delivered at 125 d gestation and ventilated for 14 d) to study the effects of surgical PDA ligation on pulmonary function and alveolar surface area. After ligation (on day of life 6), ligated animals had lower Qp/Qs ratios [Qp/Qs (ligated, n = 10) = 1.00 +/- 0.04; (nonligated, n = 12) = 2.05 +/- 0.17; mean +/- SD] and higher systemic blood pressures than nonligated control animals. Ventilation and oxygenation indices did not differ between the groups, during either the pre- or postoperative periods. Alveolar surface area measurements were made by digital image analysis and compared with measurements made from fetal lungs at 125 d (n = 6) and 140 d (n = 7) gestation. PDA ligation failed to improve the postnatal arrest in alveolar surface area. In contrast with pharmacologic closure of the PDA, surgical closure failed to improve either pulmonary function or alveolar surface area in baboons with a moderate PDA shunt.

Studies have been performed to describe the significance of genetic polymorphisms in complications associated with disturbed perinatal adaptation. Due to the large number of interacting factors, the results of classic statistical methods are often inconsistent. The random forest technique (RFT) is a robust nonparametric statistical approach that overcomes this problem through the calculation of the importance of each factor. We used RFT to reanalyze the importance of 24 genetic polymorphisms in the classification of preterm infants (birth weight, 680-1460 g, n = 100) to affected and unaffected groups according to the presence of acute perinatal complications. The accuracy of classification was between 0.5 and 0.8 for each complication when only birth data were considered. However, when genetic polymorphisms with the highest importance scores (ISs) were included in the analysis, the accuracy of classification according overall morbidity, necrotizing enterocolitis (NEC), acute renal failure (ARF), infant respiratory distress syndrome (IRDS), cardiac failure (CF), and patent ductus arteriosus (PDA) improved from 0.69, 0.60, 0.70, 0.72, 0.68, and 0.57 to 0.77, 0.70, 0.76, 0.77, 0.76, and 0.64, respectively. Our findings suggest that genetic polymorphisms identified by RFT as predictors may improve the risk assessment of preterm infants. RFT is a suitable tool to develop risk factor patterns in this population.

Patent ductus arteriosus (DA) is the second most common congenital heart defect, the incidence of which is increased in premature infants, although mechanisms responsible are not clear. Our previous studies with genetic or pharmacological inactivation of cyclooxygenase-2 (COX-2) in mice, emphasized the importance of this enzyme in normal DA closure. The current study was designed to determine whether reduced COX-2 expression contributes to patent DA in preterm mice. Real-time PCR analysis indicated that COX-2 expression in the fetal mouse DA significantly increased with advancing gestational age. Furthermore, we observed a significant induction in COX-2 expression in the DA at 3 h after birth at full-term gestation. In contrast, COX-2 expression was significantly attenuated in the DA of preterm neonatal mice. DA closure was incomplete in preterm mice at 3 h postpartum, a time-point when the DA of full-term neonates was completely remodeled. Additionally, COX-2 expression was significantly attenuated in the DA of mice deficient in the prostanoid receptor EP4, which also show a patent DA phenotype, suggesting the importance of this receptor for the induction of COX-2 required for DA closure. Overall, these studies suggest that attenuated expression of COX-2 may contribute to increased patent DA at preterm gestation.

Persistent ductus arteriosus (PDA) is a common cardiovascular anomaly in children caused by the pathologic persistence of the left sixth pharyngeal arch artery. The inbred Brown-Norway (BN) rat presents with increased vascular fragility due to an aortic elastin deficit resulting from decreased elastin synthesis. The strikingly high prevalence of PDA in BN rats in a pilot study led us to investigate this vascular anomaly in 12 adolescent BN rats. In all BN rats, a PDA was observed macroscopically, whereas a ligamentum arteriosum was found in adult controls. The macroscopic appearance of the PDA was tubular (n = 2), stenotic (n = 8), or diverticular (n = 2). The PDA had the structure of a muscular artery with intimal thickening. In the normal closing ductus of the neonatal controls, the media consisted of layers of smooth muscle cells (SMCs) intermingled with layers of elastin. The intima was thin and poor in elastin. By contrast, the media of PDA in BN rats elastin lamellae were absent and the intima contained many elastic fibers. The abnormal distribution of elastin in the PDA of BN rats suggests that impaired elastin metabolism is related to the persistence of the ductus and implicates a genetically determined factor that may link the PDA with aortic fragility.

Programmed proliferative degeneration of the human fetal ductus arteriosus (DA) in preparation for its definite postnatal closure has a large developmental variability and is controlled by several signaling pathways, most prominently by prostaglandin (PG) metabolism. Numerous studies in various mammalian species have shown interspecies and developmental differences in ductal protein expression of cyclooxygenase (COX) isoforms and PG E receptor subtypes (EP1-4). We examined COX1, COX2, and EP4 receptor protein expression immunohistochemically in 57 human fetal autopsy DA specimens of 11-38 wk of gestation. According to their histologic maturity, specimens were classified into four stages using a newly designed maturity score that showed that histologic maturity of the DA was not closely related to gestational age. COX1 expression was found in all DA regions and rose steadily during development. COX2 staining remained weak throughout gestation. EP4 receptor staining increased moderately during gestation and was limited to the intima and media. In conclusion, histologic maturity classification helps to address developmentally regulated processes in the fetal DA. Concerning prostaglandin metabolism our findings are in line with animal studies, which assigned COX1 the predominant role in the DA throughout gestation. EP4 receptor presumably plays a key role for active patency of the human DA in the third trimester.

The voltage-gated potassium channels (Kv) are partially responsible for the contraction/relaxation of blood vessels in response to changes in the Po(2) level. The present study determined the expression of Kvbeta1 and four oxygen-sensitive Kvalpha subunits (Kv1.2, Kv1.5, Kv2.1, and Kv9.3) in the ductus arteriosus (DA), the aorta (Ao), and the pulmonary artery (PA) in porcine neonates immediately after birth. We cloned three Kvbeta1 transcript variants (Kvbeta1.2, Kvbeta1.3, and Kvbeta1.4), Kv1.2, Kv1.5, and Kv9.3 from piglets. Three Kvbeta1 transcripts, Kv1.2, Kv1.5, and Kv9.3, encode predicted proteins of 401, 408, 202, 499, 600, and 491 residues. These Kv showed a high degree of sequence conservation with the corresponding Kv in human. Northern and quantitative real-time PCR (qr-PCR) analyses showed that Kvbeta1.2 expression was high in the DA and Ao but low in the PA. Kv1.5 expression was high in the Ao and PA but low in the DA. Expression of Kvbeta1.3, Kvbeta1.4, Kv1.2, Kv2.1, and Kv9.3 was low in these blood vessels. The inactivation property of Kvbeta1.2 against Kv1.5 was confirmed using Xenopus laevis oocytes. Our findings suggest that the molecular basis for the differential electrophysiological characteristics including opposing response to oxygen in the DA and the PA are partially due to diversity in expression of Kv1.5 and Kvbeta1.2 subunits. The high expression of Kvbeta1.2 and relatively low expression of Kv1.5 in the DA might be partially responsible for the ductal closure after birth.

Studies in premature animals suggest that 1) prolonged tight constriction of the ductus arteriosus is necessary for permanent anatomic closure and 2) endogenous nitric oxide (NO) and prostaglandins both play a role in ductus patency. We hypothesized that combination therapy with an NO synthase (NOS) inhibitor [NG-monomethyl-l-arginine (l-NMMA)] and indomethacin would produce tighter ductus constriction than indomethacin alone. Therefore, we conducted a phase I and II study of combined treatment with indomethacin and l-NMMA in newborns born at