The QT_c-Bazett Interval in Former Very Preterm Infants in Adolescence and Young Adulthood is Not Different from Term-Born Controls

Introduction: Although relevant for precision pharmacovigilance, there are conflicting data on whether former preterm birth is associated with QTc-Bazett prolongation in later life. Methods: To explore QTc-Bazett interval differences between former preterm and/or extremely low birth weight (ELBW) cases and term-born controls in adolescence and young adulthood, we analyzed pooled individual data after a structured search on published cohorts. To test the absence of a QTc-Bazett difference, a non-inferiority approach was applied (one-sided, upper limit of the 95% confidence interval [CI] mean QTc-Bazett difference, 5 and 10 ms). We also investigated the impact of characteristics, either perinatal or at assessment, on QTc-Bazett in the full dataset (cases and controls). Data were reported as median and range. Results: The pooled dataset contained 164 former preterm and/or ELBW (cases) and 140 controls born full-term from three studies. The median QTc-Bazett intervals were 409 (335–490) and 410 (318–480) ms in cases and controls. The mean QTc-Bazett difference was 1 ms, with an upper 95% CI of 6 ms (p &gt; 0.05 and p &lt; 0.01 for 5 and 10 ms, respectively). In the full dataset, females had a significantly longer QTc-Bazett than males (415 vs. 401 ms; p &lt; 0.0001). Conclusions: QTc-Bazett intervals are not significantly different between former preterm and/or ELBW cases and term-born controls, and we rejected a potential prolongation &gt; 10 ms in cases. When prescribing QTc-prolonging drugs, pharmacovigilance practices in this subpopulation should be similar to the general public (NCT05243537).</p

Reshaping the preterm heart: shifting cardiac renin-angiotensin system towards cardioprotection in rats exposed to neonatal high-oxygen stress

Background: Approximately 10% of infants are born preterm. Preterm birth leads to short and long-term changes in cardiac shape and function. By using a rat model of neonatal high-oxygen (80%O2) exposure, mimicking the premature hyperoxic transition to the extrauterine environment, we revealed a major role of the renin-angiotensin system peptide Angio II (angiotensin II) and its receptor AT1 (angiotensin receptor type 1) on neonatal O2-induced cardiomyopathy. Here, we tested whether treatment with either orally active compounds of the peptides Angio-(1–7) or alamandine included in cyclodextrin could prevent postnatal cardiac remodeling and the programming of cardiomyopathy induced by neonatal high-O2 exposure. Methods: Sprague-Dawley pups were exposed to room air or 80% O2 from postnatal day 3 (P3) to P10. Neonatal rats were treated orally from P3 to P10 and assessed at P10 and P28. Left ventricular (LV) shapes were characterized by tridimensional computational atlases of ultrasound images in addition to histomorphometry. Results: At P10, high O2-exposed rats presented a smaller, globular and hypertrophied LV shape versus controls. Treatment with cyclodextrin–Angio-(1–7) significantly improved LV function in the O2-exposed neonatal rats and slightly changed LV shape. Cyclodextrin-alamandine and cyclodextrin–Angio-(1–7) treatments similarly reduced hypertrophy at P10 as well as LV remodeling and dysfunction at P28. Both treatments upregulated cardiac angiotensin-converting enzyme 2 in O2-exposed rats at P10 and P28. Conclusions: Our findings demonstrate LV remodeling changes induced by O2-stress and the potential benefits of treatments targeting the cardioprotective renin-angiotensin system axis, supporting the neonatal period as an important window for interventions aiming at preventing cardiomyopathy in people born preterm

Cancer risk in children and young adults born preterm: A systematic review and meta-analysis.

IntroductionRisk of developing a malignancy when born premature is unknown. We hypothesised that risk of certain cancers might be increased in youth born preterm versus term. We therefore performed a systematic review and meta-analysis to evaluate the incidence of malignancy in the context of preterm birth, according to various cancer types.MethodsThe study was designed per MOOSE and PRISMA guidelines. Articles were identified through November 2015. Observational studies exploring the association between childhood malignancy and birth characteristics were included. Of the 1658 records identified, 109 full text articles were evaluated for eligibility. Random effects meta-analyses were conducted on 10/26 studies retained; 95% confidence intervals were computed and adjusted following sensitivity analysis. Publication bias was evaluated using funnel plots, Begg's and Egger's tests.ResultsNo differences in risk of primary central nervous system tumor [OR 1.05; 95% CI 0.93-1.17, 5 studies, 580 cases] and neuroblastoma [OR 1.09; 95% CI 0.90-1.32, 5 studies, 211 cases] were observed in individuals born ConclusionsChildren born premature may be at increased risk for hepatoblastoma but there is no strong evidence of an increased risk of primary central nervous system tumours or neuroblastoma. There is insufficient evidence to conclude whether prematurity modulates the risk of other childhood cancers

Developmental programming of eNOS uncoupling and enhanced vascular oxidative stress in adult rats after transient neonatal oxygen exposure

International audienceThe authors have previously shown that neonatal hyperoxic stress leads to high blood pressure, impaired endothelium-mediated vasodilatation, and increased vascular production of superoxide anion by NAD(P)H oxidase in adulthood. However, it is unknown whether changes in nitric oxide (NO) production and/or bioinactivation prevail and whether NO synthase (NOS) is also a source of superoxide. The purpose of this study was to evaluate whether adult animals exposed to neonatal hyperoxic stress have impaired vascular NO production associated with NOS uncoupling participating to vascular superoxide production and vascular dysfunction. In adult male rats exposed to 80% oxygen from day 3 to 10 of life (H, n = 6) versus room air controls (CTRL, n = 6), vascular (aorta) NO production is decreased at baseline (CTRL: 21 +/- 1 vs. H: 16 +/- 2 4,5-diaminofluorescein diacetate fluorescence intensity arbitrary units; P < 0.05) and after carbachol stimulation (acetylcholine analog; CTRL: 26 +/- 2 vs. H: 18 +/- 2; P < 0.05). Pretreatment with L-arginine (CTRL: 32 +/- 4 vs. H: 31 +/- 5) and L-sepiapterine [analog of key NOS cofactor tetrahydro-L-biopterin (BH4)] (CTRL: 30 +/- 3 vs. H: 29 +/- 3) normalizes NO production after carbachol. L-Sepiapterine also normalizes impaired vasodilatation to carbachol. Vascular endothelial NO synthase (eNOS) immunostaining is reduced, whereas total eNOS protein expression is increased in H (CTRL: 0.76 +/- 0.08 vs. H: 1.76 +/- 0.21; P < 0.01). The significantly higher superoxide generation (CTRL: 20 +/- 2 vs. H: 28 +/- 3 hydroethidine fluorescence intensity arbitrary units; P < 0.05) is prevented by pretreatment with the eNOS inhibitor N-nitro-L-arginine methyl ester (CTRL: 21 +/- 4 vs. H: 22 +/- 4). Taken together, the current data indicate a role for eNOS uncoupling in enhanced vascular superoxide, impaired endothelium-mediated vasodilatation, and decreased NO production in adult animals with programmed elevated blood pressure after a brief neonatal oxygen exposure

Developmental programming of cardiovascular and metabolic diseases in adulthood: the role of neonatal oxygen exposure

International audienc

Neonatal exposure to high oxygen levels leads to impaired ischemia-induced neovascularization in adulthood

Abstract Adverse perinatal conditions can lead to developmental programming of cardiovascular diseases. Prematurely born infants are often exposed to high oxygen levels, which in animal models has been associated with endothelial dysfunction, hypertension, and cardiac remodeling during adulthood. Here we found that adult mice that have been transiently exposed to O2 after birth show defective neovasculariation after hindlimb ischemia, as demonstrated by impaired blood flow recovery, reduced vascular density in ischemic muscles and increased tissue damages. Ischemic muscles isolated from mice exposed to O2 after birth exhibit increased oxidative stress levels and reduced expression of superoxide dismutase 1 (SOD1) and vascular endothelial growth factor (VEGF). Pro-angiogenic cells (PACs) have been shown to have an important role for postnatal neovascularisation. We found that neonatal exposure to O2 is associated with reduced number of PACs in adults. Moreover, the angiogenic activities of both PACs and mature mouse aortic endothelial cells (MAECs) are significantly impaired in mice exposed to hyperoxia after birth. Our results indicate that neonatal exposure to high oxygen levels leads to impaired ischemia-induced neovascularization during adulthood. The mechanism involves deleterious effects on oxidative stress levels and angiogenic signals in ischemic muscles, together with dysfunctional activities of PACs and mature endothelial cells

Possible predictors of cardiorespiratory events after immunization in preterm neonates.

International audienceBACKGROUND: The influence of the first immunization on cardiorespiratory (CR) stability in very preterm infants is still a controversial subject. OBJECTIVES: To describe the changes induced by immunization on heart and respiratory rate variability (HRV-RRV) and to test a potential association between preimmunization profiles and postimmunization CR events. METHODS: Continuous 72-hour CR recordings and 2.5-hour polysomnographic recordings were performed on very preterm infants immunized after 7 weeks. The results are expressed as medians (interquartile ranges). RESULTS: Immunization was performed on 31 very preterm infants [28 weeks' gestation (26.9-29), birth weight: 965 g (795-1,105)], and was associated with an increased incidence (p < 0.01) of events lasting more than 10 s: bradycardia <80 bpm [2.2 (1.1-7) vs. 1.8 (1-4)/12 h], desaturation [17.6 (9.4-36.4) vs. 13.9 (7.7-33.8)/12 h] and associated bradycardia-desaturation [IB+D, 4.1 (1.4-7.3) vs. 2.4 (1-4.6)/12 h], with mild changes in HRV and no change in RRV. The changes in IB+D frequency were correlated with preimmunization IB+D frequency (r = 0.44, p < 0.05), HRV spectral parameter low frequency/high frequency ratio (LF/HF, r = 0.55, p < 0.01) and approximate entropy of HRV (r = -0.39, p < 0.05). CONCLUSION: The increase in CR events after the first immunization in very preterm infants was associated with: (1) sympathetic predominance in heart rate control (high LF/HF ratio), (2) abnormal oversimplification of HRV (low entropy) and (3) persistent respiratory rhythm control immaturity (high IB+D before vaccine)

Microvascular rarefaction and impaired angiogenesis precede elevation of blood pressure and vascular dysfunction in rats exposed to neonatal hyperoxic stress

National audienc