Postnatal vitamin D supplementation is standard of care in neonates and preterm infants. Despite routine supplementation of vitamin D, a wide range of complications related to vitamin D deficiency ...has been described in the literature. Since standard vitamin D supplementation might be not sufficient in preterm infants with a genetic predisposition for vitamin D deficiency, we investigated the outcome of preterm infants with regard to their genetic estimated vitamin D levels.
Preterm infants with a birth weight below 1500 grams were included in the German Neonatal Network at the time of their birth and tested at the age of five. The vitamin D level was genetically calculated based on three single nucleotide polymorphisms (SNPs: rs12794714, rs7944926 and rs2282679) which alter vitamin D synthesis pathways. Specific alleles of these polymorphisms are validated markers for low plasma vitamin D levels. Outcome data were based on baseline data at the time of birth, typical complications of prematurity, body measurements at the age of five and occurrence of bone fractures. T-test and Fisher's exact test were used for statistical comparison.
According to their genetic predisposition, 1,924 preterm infants were divided into groups of low (gsVitD < 20. Percentile), intermediate and high vitamin D level estimates. Low genetic vitamin D level estimates could not be shown to be associated with any adverse outcome measures examined. The analyses covered data on aforementioned determinants.
Low genetic vitamin D level estimates could not be shown to be associated with previously described adverse outcome in preterm infants.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Regulatory T cells (Tregs) are important for the ontogenetic control of immune activation and tissue damage in preterm infants. However, the role of Tregs for the development of bronchopulmonary ...dysplasia (BPD) is yet unclear. The aim of our study was to characterize CD4+ CD25+ forkhead box protein 3 (FoxP3)+ Tregs in peripheral blood of well-phenotyped preterm infants (
= 382; 23 + 0 - 36 + 6 weeks of gestational age) with a focus on the first 28 days of life and the clinical endpoint BPD (supplemental oxygen for longer than 28 days of age). In a subgroup of preterm infants, we characterized the immunological phenotype of Tregs (
= 23). The suppressive function of Tregs on CD4+CD25- T cells was compared in preterm, term and adult blood. We observed that extreme prematurity was associated with increased Treg frequencies which peaked in the second week of life. Independent of gestational age, increased Treg frequencies were noted to precede the development of BPD. The phenotype of preterm infant Tregs largely differed from adult Tregs and displayed an overall naïve Treg population (CD45RA+/HLA-DR-/Helios+), especially in the first days of life. On day 7 of life, a more activated Treg phenotype pattern (CCR6+, HLA-DR+, and Ki-67+) was observed. Tregs of preterm neonates had a higher immunosuppressive capacity against CD4+CD25- T cells compared to the Treg compartment of term neonates and adults. In conclusion, our data suggest increased frequencies and functions of Tregs in preterm neonates which display a distinct phenotype with dynamic changes in the first weeks of life. Hence, the continued abundance of Tregs may contribute to sustained inflammation preceding the development of BPD. Functional analyses are needed in order to elucidate whether Tregs have potential as future target for diagnostics and therapeutics.
Abstract Background Very-low-birth-weight infants (VLBWI) are frequently delivered by cesarean section (CS). However, it is unclear at what gestational age the benefits of spontaneous delivery ...outweigh the perinatal risks, i.e. intraventricular hemorrhage (IVH) or death. Objectives To assess the short-term outcome of VLBWI on IVH according to mode of delivery in a population-based cohort of the German Neonatal Network (GNN). Study design A total cohort of 2203 singleton VLBWI with a birth weight < 1500 g and gestational age between 22 0/7 and 36 6/7 weeks born and discharged between 1st of January 2009 and 31st of December 2015 was available for analysis. VLBWI were stratified into three categories according to mode of delivery: (1) planned cesarean section (n = 1381), (2) vaginal delivery (n = 632) and (3) emergency cesarean section (n = 190). Outcome was assessed in univariate and logistic regression analyses. Results Prevalence of IVH was significantly higher in the vaginal delivery (VD) (26.6%) and emergency CS group (31.1%) as compared to planned CS (17.2%), respectively. In a logistic regression analysis including known risk factors for IVH, vaginal delivery (OR 1.725 1.325 −2.202, p ≤ 0.001) and emergency cesarean section (OR 1.916 1.338 −2.746, p ≤ 0.001) were independently associated with IVH risk. In the subgroup of infants > 30 weeks of gestation prevalence for IVH was not significantly different in VD and planned CS (5.3% vs. 4.4%). Conclusions Our observational data demonstrate that elective cesarean section is associated with a reduced risk of IVH in preterm infants <30 weeks gestational age when presenting with preterm labor.
Aim
In animal studies, aminoglycosides induced ductus arteriosus relaxation in a dose‐dependent fashion. We tested the hypothesis that antibiotic treatment of preterm infants with aminoglycosides is ...associated with higher rates of surgical patent ductus arteriosus (PDA) closure.
Methods
Preterm infants (birthweight <1000 grams or gestational age <29 weeks) enrolled in 62 German neonatal intensive care units (NICUs) were analysed. NICUs were stratified according to the use of aminoglycosides as first‐line antibiotics.
Results
Baseline data were not different when NICUs using aminoglycosides (n = 9965 infants) were compared to NICUs using other antibiotics (n = 1948 infants). Rates of surgical PDA closure were 5.9% for NICUs using aminoglycosides; 6.2% for units using gentamicin; and 5.0% for NICUs using tobramycin compared to 4.1% in NICUs using other antibiotics (P < .001, P < .001 and P = .140, respectively, Fisher's exact test). Indomethacin and ibuprofen use was more common in NICUs using aminoglycosides (41% vs 33%, P < .001, Fisher's exact test). Gentamicin trough levels were higher in NICUs with surgical closure rates above the mean (median 2.0 µg/mL, inter‐quartile range 0.8‐4.0 µg/mL vs 1.2 µg/mL, IQR 0.8‐1.7, P < .001, Mann‐Whitney U test).
Conclusion
First‐line antibiotic treatment of preterm infants with aminoglycosides was associated with higher rates of surgical PDA closure.
Abstract
Background
Respiratory distress syndrome is the main cause of mortality and morbidity in preterm infants. “Less invasive surfactant administration” (LISA), which describes intratracheal ...surfactant administration to spontaneously breathing infants via a small diameter tube, is recommended as the first-line treatment in preterm infants with more than 30% supplemental oxygen. Prophylactic use of LISA in preterm infants with less than 30% supplemental oxygen was not tested in randomised controlled trials yet, and long-term outcome data of the procedure are scarce.
Methods
Preterm infants with a gestational age between 25 weeks + 0 days and 28 weeks + 6 days who are breathing spontaneously on continuous positive airway pressure with supplemental oxygen at or below 30% in the first hour of life will be randomised to a prophylactic LISA treatment with 100–200 mg surfactant intratracheally per kilogramme bodyweight (intervention group) or will continue the continuous positive airway pressure treatment (control group). Participants will have follow-up until age 5 years. At that time, the children will be tested by spirometry, and forced expiratory volume within 1-s
z
-scores will be compared between the intervention and control groups as the primary outcome parameter of the trial. Secondary endpoints include additional lung function parameters, endurance, motor development, intelligence, and sensitivity for infectious lung diseases. Short-term safety assessment will be done after completed enrolment (
n
= 698) and discharge of all infants. This safety assessment will include in-hospital mortality and short-term complications.
Discussion
Robust data concerning the possible long-term benefits of prophylactic LISA treatment are lacking. The current observational data from the German Neonatal Network indicate that approximately 50% of preterm infants with supplemental oxygen at or below 30% within the first hour of life are treated with LISA. The pro.LISA trial will provide short- and long-term outcomes of preterm infants receiving prophylactic treatment and will clarify if prophylactic treatment should be given to all preterm infants or if the current practice of selective treatment if supplemental oxygen exceeds 30% is more appropriate.
Trial registration
German Clinical Trials Register DRKS00028086. Prospectively registered on 8 February 2022.
Associations of APOE genotypes with intracerebral hemorrhage (ICH) in preterm infants were previously described. In adults, APOE-ε4 genotype has been proposed as susceptibility factor for impaired ...recovery after cerebral insult. We here aim to determine APOE genotype-specific neurological consequences of neonatal ICH at school age.
In this multicenter observational cohort study, very low birth weight (<1500 g, <32 weeks gestational age) children were studied for cerebral palsy (CP) after ultrasound diagnosed ICH stratified by APOE genotype. Follow-up examination was done at the age of 5 to 6 years. Study personnel were blinded for perinatal information and complications. Participants were born between January 1, 2009 and December 31, 2013 and enrolled in the German Neonatal Network. Of 8022 infants primarily enrolled, 2467 children were invited for follow-up between January 1, 2014 and December 31, 2019. Univariate analyses and multivariate logistic regression models were used to assess the impact of APOE genotype (APOE-ε2, APOE-ε3, APOE-ε4) on CP after ICH.
Two thousand two hundred fifteen children participated at follow-up, including 363 children with ultrasound diagnosed neonatal ICH. In univariate analyses of children with a history of ICH, APOE-ε3 carriers had lower frequencies of CP (n=33/250; 13.2 95% CI, 9.4%-17.8%), as compared to APOE-ε2 (n=15/63; 23.8 14.6%-35.3%,
=0.037) and -ε4 carriers (n=31/107; 29.0 21.0%-38.0%,
<0.001), respectively. Regression models revealed an association of APOE-ε4 genotype and CP development (odds ratio, 2.77 1.44-5.32,
=0.002) after ICH. Notably, at low-grade ICH (grade I) APOE-ε4 expression resulted in an increased rate of CP (n=6/39; 15.4 6.7-29.0) in comparison to APOE-ε3 (n=2/105; 1.9 0.4%-6.0%,
=0.002).
APOE-ε4 carriers have an increased risk for long-term motor deficits after ICH. We assume an effect even after low-grade neonatal ICH, but more data are needed to clarify this issue.
Sepsis is regarded as a risk factor for brain injury in preterm infants. We herein hypothesize that extremely low birth weight infants (ELBWI, birth weight <1,000 g) having survived recurrent blood ...culture-proven late-onset sepsis (LOS) episodes are more likely to have an adverse long-term neurologic outcome.
In a large multicenter observational study of ELBWI ≤28 6/7 weeks, we evaluated the impact of recurrent LOS (blood culture-proven, after day 7 of life) on development at 5-6 years. Neurodevelopment, behavior, and motor qualities were tested by blinded investigators. Univariate and logistic regression analyses were performed.
The cohort consisted of 1343 ELBWI including 1,080 infants without LOS, 186 infants with one LOS, and 77 with recurrent LOS, i.e., 55 infants with two and 22 infants with three LOS episodes. After Bonferroni-Holm correction, multiple logistic regression analysis revealed recurrent sepsis to be significantly associated with adverse motor development (critical MABC-2 testing: 3.3 1.5-7.3, p = 0.003, pB = 0.012), whereas no significant impact of recurrent LOS was found on intelligence quotient and behavioral difficulties. Odds of having critical motor testing results for infants with recurrent LOS were 1.7 times (95% confidence interval 1.4-2.3) that of infants with one LOS.
Recurrent sepsis in preterm infants is associated with adverse long-term motor development. However, infants with recurrent infections are also more likely to have preterm-related complications, and reasons for a worse neurodevelopmental outcome remain to be elucidated.
Vancomycin is an extensively used anti-infective drug in neonatal ICUs. However, exposure-toxicity relationships have not been clearly defined.
To evaluate the risk profile for hearing deficits in ...vancomycin-exposed very-low-birthweight infants (VLBWI).
In a large cohort study of the German Neonatal Network (GNN; n = 16 967 VLBWI) we assessed the association of vancomycin treatment and pathological hearing tests at discharge and at 5 year follow-up. We performed audits on vancomycin exposure, drug levels, dose adjustments and exposure to other ototoxic drugs in a subgroup of 1042 vancomycin-treated VLBWI.
In the GNN cohort, 28% (n = 4739) were exposed to IV vancomycin therapy. In multivariable logistic regression analysis, vancomycin exposure proved to be independently associated with pathological hearing test at discharge (OR 1.18, 95% CI 1.03-1.34, P = 0.016). Among vancomycin-treated infants, a cumulative vancomycin dose above the upper quartile (>314 mg/kg bodyweight) was associated with pathological hearing test at discharge (OR 2.1, 95% CI 1.21-3.64, P = 0.009), whereas a vancomycin cumulative dose below the upper quartile was associated with a reduced risk of pathological tone audiometry results at 5 years of age (OR 0.29, 95% CI 0.1-0.8, P = 0.02, n = 147).
Vancomycin exposure in VLBWI is associated with an increased, dose-dependent risk of pathological hearing test results at discharge and at 5 years of age. Prospective studies on long-term hearing impairment are needed.
Aim
To determine the regional cerebral tissue oxygenation saturation (rcSO2) in a group of infants requiring less invasive surfactant administration (LISA) as compared to infants with continuous ...positive airway pressure (CPAP) only.
Methods
In preterm infants with a gestational age 26 0/7‐31 6/7 weeks, we conducted an observational study using near‐infrared spectroscopy (NIRS) in the first 120 hours of life.
Results
We analysed the data of 22 infants who never received surfactant (CPAP), 22 infants had LISA and CPAP (LISA) and 6 infants received surfactant via endotracheal tube (ETT). Four infants had both surfactant application modes including six LISA applications. In total, there were 32 successful LISA applications but 44 attempts; 13/44 (30%) of LISA attempts resulted in a 20% decrease of rcSO2. During the first 120 hours of life, rcSO2 values of CPAP were similar to those of infants in the LISA group, that is median rcSO2 values 90% vs 85%, respectively (P = .126). Episodes with rcSO2 values <65% were 0.4% in the CPAP group as compared to 4.8% in the LISA group (P < .001).
Conclusion
Our observational data indicate that rcSO2 values of infants in the LISA group were similar to the CPAP group.
To determine if survival rates of preterm infants receiving active perinatal care improve over time.
The German Neonatal Network is a cohort study of preterm infants with birth weight <1500 g. All ...eligible infants receiving active perinatal care are registered. We analysed data of patients discharged between 2011 and 2016.
43 German level III neonatal intensive care units (NICUs).
8222 preterm infants with a gestational age between 22/0 and 28/6 weeks who received active perinatal care.
Participating NICUs were grouped according to their specific survival rate from 2011 to 2013 to high (percentile >P75), intermediate (P25-P75) and low (<P25) survival. We compared these survival rates with data in 2014-2016.
Death by any cause before discharge.
Total survival increased from 85.8% in 2011-2013 to 87.4% in 2014-2016. This increase was due to reduced mortality of NICUs with low survival rates in 2011-2013. Survival increased in these centres from 53% to 64% in the 22-24 weeks strata and from 73% to 84% in the 25-26 weeks strata.
Our data support previous reports that active perinatal care of very immature infants improves outcomes at the border of viability and survival rates at higher gestational ages. The high total number of surviving infants below 24 weeks of gestation challenges national recommendations exclusively referring to gestational age as the single criterion for providing active care. However, more data are needed before recommendations for parental counselling should be reconsidered.
Approval by the local institutional review board for research in human subjects of the University of Lübeck (file number 08-022) and by the local ethic committees of all participating centres has been given.
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