Thrombocytopenia in neonates and the risk of intraventricular hemorrhage: a retrospective cohort study

<p>Abstract</p> <p>Background</p> <p>The overall prevalence of thrombocytopenia in neonates admitted to neonatal intensive care units ranges from 22 to 35%. There are only a few small studies that outline the relationship between the severity of thrombocytopenia and the risk of bleeding. This makes it difficult to form an evidence-based threshold for platelet transfusions in neonatal patients. The aim of this study was to determine the prevalence of thrombocytopenia in a tertiary neonatal intensive care unit and to study the relation between thrombocytopenia and the risk of intraventricular hemorrhage (IVH).</p> <p>Methods</p> <p>We performed a retrospective cohort study of all patients with thrombocytopenia admitted to our neonatal tertiary care nursery between January 2006 and December 2008. Patients were divided into 4 groups according to the severity of thrombocytopenia: mild (100-149 × 10⁹/L), moderate (50-99 × 10⁹/L), severe (30-49 × 10⁹/L) or very severe (< 30 × 10⁹/L). The primary outcome was IVH ≥ grade 2. Pearson's chi-squared and Fischer's exact tests were used for categorical data. ANOVA, logistic regression analysis and multivariate linear regression were used for comparisons between groups and for confounding factors.</p> <p>Results</p> <p>The prevalence of thrombocytopenia was 27% (422/1569). Risk of IVH ≥ grade 2 was 12% (48/411) in neonates with versus 5% (40/844) in neonates without thrombocytopenia (p < 0.01). After multivariate linear regression analysis, risk of IVH ≥ grade 2 in the subgroups of thrombocytopenic infants was not significantly different (p = 0.3).</p> <p>After logistic regression analysis the difference in mortality rate in neonates with and without thrombocytopenia was not significant (p = 0.4). Similarly, we found no difference in mortality rate in the subgroups of neonates with thrombocytopenia (p = 0.7).</p> <p>Conclusion</p> <p>Although IVH ≥ grade 2 occurs more often in neonates with thrombocytopenia, this relation is independent of the severity of thrombocytopenia. Prospective studies should be conducted to assess the true risk of hemorrhage depending on underlying conditions. Randomized controlled trials are urgently needed to determine a safe lower threshold for platelet transfusions.</p

Long-term outcome in relationship to neonatal transfusion volume in extremely premature infants: a comparative cohort study

<p>Abstract</p> <p>Background</p> <p>In premature born infants red blood cell (RBC) transfusions have been associated with both beneficial and detrimental sequels. Upon RBC transfusion, improvement in cerebral blood flow and oxygenation have been observed, while a more liberal transfusion policy may be associated with a better developmental outcome. The effect of the transfusion volume on long-term outcome is not known.</p> <p>Methods</p> <p>Observational follow-up study of a cohort of extremely premature born infants, treated in 2 neonatal intensive care units using a different transfusion volume (15 ml/kg in Unit A and 20 ml/kg in Unit B). The primary outcome was a composite of post discharge mortality, neuromotor developmental delay, blindness or deafness, evaluated at a mean corrected age (CA) of 24 months related to the transfusion volume/kg bodyweight administered during the postnatal hospital stay.</p> <p>Results</p> <p>Despite the difference in transfusion volume in clinically comparable groups of infants, they received a similar number of transfusions (5.5 ± 3.2 versus 5.5 ± 2.3 respectively in Unit A and B). The total transfused volume in unit A was 79 ± 47 ml/kg and 108 ± 47 ml/kg in unit B (p = 0.02). Total transfused RBC volume per kg bodyweight was not an independent predictor of the composite outcome (p = 0.96, OR 1.0 (CI 0.9-1.1).</p> <p>Conclusion</p> <p>There was no relationship between the composite outcome at 24 months CA and transfusion volume received during the post natal hospital stay. As there was no clinical advantage of the higher transfusion volume, a more restrictive volume will reduce total transfusion volume and donor exposure. Future research on the optimal transfusion volume per event to extreme preterm infants should include larger, prospective studies with a longer follow-up period through to childhood or even adolescence.</p

Antenatal allopurinol for reduction of birth asphyxia induced brain damage (ALLO-Trial); a randomized double blind placebo controlled multicenter study

<p>Abstract</p> <p>Background</p> <p>Hypoxic-ischaemic encephalopathy is associated with development of cerebral palsy and cognitive disability later in life and is therefore one of the fundamental problems in perinatal medicine. The xanthine-oxidase inhibitor allopurinol reduces the formation of free radicals, thereby limiting the amount of hypoxia-reperfusion damage. In case of suspected intra-uterine hypoxia, both animal and human studies suggest that maternal administration of allopurinol immediately prior to delivery reduces hypoxic-ischaemic encephalopathy.</p> <p>Methods/Design</p> <p>The proposed trial is a randomized double blind placebo controlled multicenter study in pregnant women at term in whom the foetus is suspected of intra-uterine hypoxia.</p> <p>Allopurinol 500 mg IV or placebo will be administered antenatally to the pregnant woman when foetal hypoxia is suspected. Foetal distress is being diagnosed by the clinician as an abnormal or non-reassuring foetal heart rate trace, preferably accompanied by either significant ST-wave abnormalities (as detected by the STAN-monitor) or an abnormal foetal blood scalp sampling (pH < 7.20).</p> <p>Primary outcome measures are the amount of S100B (a marker for brain tissue damage) and the severity of oxidative stress (measured by isoprostane, neuroprostane, non protein bound iron and hypoxanthine), both measured in umbilical cord blood. Secondary outcome measures are neonatal mortality, serious composite neonatal morbidity and long-term neurological outcome. Furthermore pharmacokinetics and pharmacodynamics will be investigated.</p> <p>We expect an inclusion of 220 patients (110 per group) to be feasible in an inclusion period of two years. Given a suspected mean value of S100B of 1.05 ug/L (SD 0.37 ug/L) in the placebo group this trial has a power of 90% (alpha 0.05) to detect a mean value of S100B of 0.89 ug/L (SD 0.37 ug/L) in the 'allopurinol-treated' group (z-test_2-sided). Analysis will be by intention to treat and it allows for one interim analysis.</p> <p>Discussion</p> <p>In this trial we aim to answer the question whether antenatal allopurinol administration reduces hypoxic-ischaemic encephalopathy in neonates exposed to foetal hypoxia.</p> <p>Trial registration number</p> <p>Clinical Trials, protocol registration system: NCT00189007</p

Thrombocytopaenia and intraventricular haemorrhage in very premature infants:a tale of two cities

Objective To study whether the incidence of intraventricular haemorrhage (IVH) in very premature infants ( Study design A retrospective cohort study comparing the incidence of IVH in very premature infants with thrombocytopaenia (platelet count Results The number of infants with thrombocytopaenia that received a platelet transfusion was significantly lower in the restrictive-transfusion unit compared with the liberal-transfusion unit, 15% (21/145) versus 31% (41/141), (p Conclusion In the restrictive-transfusion unit, the rate of platelet transfusions was significantly lower, but the incidence and severity of IVH was similar to the liberal-transfusion unit

Efficacy and safety of switching from intravenous to oral antibiotics (amoxicillin–clavulanic acid) versus a full course of intravenous antibiotics in neonates with probable bacterial infection (RAIN): a multicentre, randomised, open-label, non-inferiority trial

Background: Switching from intravenous antibiotic therapy to oral antibiotic therapy among neonates is not yet practised in high-income settings due to uncertainties about exposure and safety. We aimed to assess the efficacy and safety of early intravenous-to-oral antibiotic switch therapy compared with a full course of intravenous antibiotics among neonates with probable bacterial infection. Methods: In this multicentre, randomised, open-label, non-inferiority trial, patients were recruited at 17 hospitals in the Netherlands. Neonates (postmenstrual age ≥35 weeks, postnatal age 0–28 days, bodyweight ≥2 kg) in whom prolonged antibiotic treatment was indicated because of a probable bacterial infection, were randomly assigned (1:1) to switch to an oral suspension of amoxicillin 75 mg/kg plus clavulanic acid 18·75 mg/kg (in a 4:1 dosing ratio, given daily in three doses) or continue on intravenous antibiotics (according to the local protocol). Both groups were treated for 7 days. The primary outcome was cumulative bacterial reinfection rate 28 days after treatment completion. A margin of 3% was deemed to indicate non-inferiority, thus if the reinfection rate in the oral amoxicillin–clavulanic acid group was less than 3% higher than that in the intravenous antibiotic group the null hypothesis would be rejected. The primary outcome was assessed in the intention-to-treat population (ie, all patients who were randomly assigned and completed the final follow-up visit on day 35) and the per protocol population. Safety was analysed in all patients who received at least one administration of the allocated treatment and who completed at least one follow-up visit. Secondary outcomes included clinical deterioration and duration of hospitalisation. This trial was registered with ClinicalTrials.gov, NCT03247920, and EudraCT, 2016-004447-36. Findings: Between Feb 8, 2018 and May 12, 2021, 510 neonates were randomly assigned (n=255 oral amoxicillin–clavulanic group; n=255 intravenous antibiotic group). After excluding those who withdrew consent (n=4), did not fulfil inclusion criteria (n=1), and lost to follow-up (n=1), 252 neonates in each group were included in the intention-to-treat population. The cumulative reinfection rate at day 28 was similar between groups (one [<1%] of 252 neonates in the amoxicillin–clavulanic acid group vs one [<1%] of 252 neonates in the intravenous antibiotics group; between-group difference 0 [95% CI –1·9 to 1·9]; pnon-inferiority<0·0001). No statistically significant differences were observed in reported adverse events (127 [50%] vs 113 [45%]; p=0·247). In the intention-to-treat population, median duration of hospitalisation was significantly shorter in the amoxicillin–clavulanic acid group than the intravenous antibiotics group (3·4 days [95% CI 3·0–4·1] vs 6·8 days [6·5–7·0]; p<0·0001). Interpretation: An early intravenous-to-oral antibiotic switch with amoxicillin–clavulanic acid is non-inferior to a full course of intravenous antibiotics in neonates with probable bacterial infection and is not associated with an increased incidence of adverse events. Funding: The Netherlands Organization for Health Research and Development, Innovatiefonds Zorgverzekeraars, and the Sophia Foundation for Scientific Research

Maternal allopurinol administration during suspected fetal hypoxia: a novel neuroprotective intervention? A multicentre randomised placebo controlled trial

Objective To determine whether maternal allopurinol treatment during suspected fetal hypoxia would reduce the release of biomarkers associated with neonatal brain damage. Design A randomised double-blind placebo controlled multicentre trial. Patients We studied women in labour at term with clinical indices of fetal hypoxia, prompting immediate delivery. Setting Delivery rooms of 11 Dutch hospitals. Intervention When immediate delivery was foreseen based on suspected fetal hypoxia, women were allocated to receive allopurinol 500 mg intravenous (ALLO) or placebo intravenous (CONT). Main outcome measures Primary endpoint was the difference in cord 510013, a tissue-specific biomarker for brain damage. Results 222 women were randomised to receive allopurinol (ALLO, n=111) or placebo (CONT, n=111). Cord S100ss was not significantly different between the two groups: 44.5 pg/mL (IQR 20.2-71.4) in the ALLO group versus 54.9 pg/mL (IQR 26.8-94.7) in the CONT group (difference in median -7.69 (95% Cl -24.9 to 9.52)). Post hoc subgroup analysis showed a potential treatment effect of allopurinol on the proportion of infants with a cord S100ss value above the 75th percentile in girls (ALLO n=5 (12%) vs CONT n=10 (31%); risk ratio (RR) 0.37 (95% Cl 0.14 to 0.99)) but not in boys (ALLO n=18 (32%) vs CONT n=15 (25%); RR 1.4(95% Cl 0.84 to 2.3)). Also, cord neuroketal levels were significantly lower in girls treated with allopurinol as compared with placebo treated girls: 18.0 pg/mL (95% Cl 12.1 to 26.9) in the ALLO group versus 32.2 pg/mL (95% Cl 22.7 to 45.7) in the CONT group (geometric mean difference 16.4(95% Cl 24.6 to 1.64)). Conclusions Maternal treatment with allopurinol during fetal hypoxia did not significantly lower neuronal damage markers in cord blood. Post hoc analysis revealed a potential beneficial treatment effect in girls. Trial registration number NCT00189007, Dutch Trial Register NTR1383

Daily intranasal palivizumab to prevent respiratory syncytial virus infection in healthy preterm infants: a phase 1/2b randomized placebo-controlled trialResearch in context

Summary: Background: Mucosal administration of monoclonal antibodies (mAbs) against respiratory pathogens is a promising alternative for systemic administration because lower doses are required for protection. Clinical development of mucosal mAbs is a highly active field yet clinical proof-of-concept is lacking. Methods: In this investigator-initiated, double-blind, randomized placebo-controlled trial, we evaluated intranasal palivizumab for the prevention of RSV infection in preterm infants (Dutch Trial Register NTR7378 and NTR7403). We randomized infants 1:1 to receive intranasal palivizumab (1 mg/mL) or placebo once daily during the RSV season. Any RSV infection was the primary outcome and RSV hospitalization was the key secondary outcome. The primary outcome was analyzed with a mixed effect logistic regression on the modified intention-to-treat population. Findings: We recruited 268 infants between Jan 14, 2019 and Jan 28, 2021, after which the trial was stopped for futility following the planned interim analysis. Adverse events were similar in both groups (22/134 (16.4%) palivizumab arm versus 26/134 (19.4%) placebo arm). There were 6 dropouts and 168 infants were excluded from the efficacy analyses due to absent RSV circulation during the SARS-CoV-2 pandemic. Any RSV infection was similar in infants in both groups (18/47 (38.3%) palivizumab arm versus 11/47 (23.4%) placebo arm; aOR 2.2, 95% CI 0.7–6.5). Interpretation: Daily intranasal palivizumab did not prevent RSV infection in late preterm infants. Our findings have important implications for the clinical development of mucosal mAbs, namely the necessity of timely interim analyses and further research to understand mucosal antibody half-life. Funding: Funded by the Department of Pediatrics, University Medical Centre Utrecht, the Netherlands