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 S100ß, 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% CI -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% CI 0.14 to 0.99)) but not in boys (ALLO n=18 (32%) vs CONT n=15 (25%); RR 1.4 (95% CI 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% CI 12.1 to 26.9) in the ALLO group versus 32.2 pg/mL (95% CI 22.7 to 45.7) in the CONT group (geometric mean difference -16.4 (95% CI -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.

Management and prevention of neonatal anemia: current evidence and guidelines.

Neonatal anemia is a common disorder, particularly in (very) preterm neonates. Management of neonatal anemia is based principally on red blood cell (RBC) transfusion. Although the use of blood products is nowadays widespread in neonatal medicine, evidence on the potential benefit is extremely limited. Recent studies suggest that RBC transfusions in newborns may be associated with an increased risk for necrotizing enterocolitis, transfer of infectious agents and negative effects on neurodevelopmental outcome. Whether the benefits of RBC transfusions outweigh the risks is controversial and requires further studies. In this review, we summarize the current evidence on the management of neonatal anemia and compare the various international guidelines. In addition, we discuss the various strategies to prevent neonatal anemia and reduce the need for RBC transfusions and discuss important trials currently enrolling patients to improve the management in neonatal anemia.

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 (<32 weeks gestation) with thrombocytopaenia is lower when using a liberal platelet-transfusion guideline compared with a restrictive guideline. STUDY DESIGN: A retrospective cohort study comparing the incidence of IVH in very premature infants with thrombocytopaenia (platelet count <150×10(9)/l) admitted between 2007 and 2008 to two neonatal intensive care unit in The Netherlands. The restrictive platelet-transfusion unit (N=353 infants <32 weeks gestation) transfused only in case of active haemorrhage and a platelet count <50×10(9)/l. The liberal-transfusion unit (N=326 infants <32 weeks gestation) transfused according to predefined platelet count thresholds. Primary outcome was the incidence and severity of IVH in infants with thrombocytopaenia in both units. 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<0.001). The incidence of IVH in infants with thrombocytopaenia in the restrictive-transfusion and liberal-transfusion units was 30% (44/145) and 29% (41/141), respectively (p=0.81). The incidence of severe IVH (grade 3 or 4) in the restrictive-transfusion and liberal-transfusion units was 8% (12/145) and 11% (16/141), respectively (p=0.38). 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.

[Revision of the guideline 'Blood transfusion': for the newborn]. / Revisie van de richtlijn 'bloedtransfusie': voor pasgeborenen.

The large majority (> 90%) of very premature infants and newborn infants with haemolysis receive one or more red blood cell (RBC) transfusions. Up to 35% of newborn infants have thrombocytopenia (platelet count < 150 x 109/l). Following an unambiguous blood transfusion guideline leads to decrease in the number of transfusions given. The necessity for RBC transfusions can be diminished by use of diagnostic tests, micro-analysis techniques and delay of umbilical cord clamping (waiting for 30 seconds to 3 minutes after birth). Newborn infants with a gestational age < 32 weeks or birth weight < 1500 g must receive irradiated and Parvovirus-B19 safe blood products until 6 months post-term. It is still unclear whether lower Hb values and thrombocyte counts can be accepted as a transfusion limit without negative effect on the (neurological) long term outcomes and without increase in risk of intraventricular bleeding.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

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

BACKGROUND: 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). METHODS: 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. RESULTS: 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).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). CONCLUSION: 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.

A clinical study on the feasibility of autologous cord blood transfusion for anemia of prematurity.

BACKGROUND: The objective was to investigate the use of autologous red blood cells (RBCs) derived from umbilical cord blood (UCB), as an alternative for allogeneic transfusions in premature infants admitted to a tertiary neonatal center. STUDY DESIGN AND METHODS: UCB collection was performed at deliveries of less than 32 weeks of gestation and processed into autologous RBC products. Premature infants requiring a RBC transfusion were randomly assigned to an autologous or allogeneic product. The primary endpoint was an at least 50 percent reduction in allogeneic transfusion needs. RESULTS: Fifty-seven percent of the collections harvested enough volume (> or =15 mL) for processing. After being processed, autologous products (> or =10 mL/kg) were available for 36 percent of the total study population and for 27 percent of the transfused infants and could cover 58 percent (range, 25%-100%) of the transfusion needs within the 21-day product shelf life. Availability of autologous products depended most on the gestational age. Infants born between 24 and 28 weeks had the lowest availability (17%). All products, however, would be useful in view of their high (87%) transfusion needs. Availability was highest (48%) for the infants born between 28 and 30 weeks. For 42 percent of the infants with transfusion needs in this group, autologous products were available. For the infants born between 30 and 32 weeks, autologous products were available for 36 percent of the infants. Transfusion needs in this group were, however, much lower (19%) compared to the other gestational groups. CONCLUSION: Autologous RBCs derived from UCB could not replace 50 percent of allogeneic transfusions due to the low UCB volumes collected and subsequent low product availability.

The use of blood products in perinatal medicine.

Fetal and neonatal medicine is a field with many new procedures and techniques. An increasing number of centres worldwide give intrauterine transfusions, which are considered to be standard-of-care treatment for severe fetal anaemia. The survival of very prematurely born neonates, in particular of a gestational age of <28 weeks, has greatly improved over the last decade but almost all these children need transfusions. Although in many cases such blood transfusions are life saving, randomized, controlled studies investigating appropriate indications, transfusion volume and type of blood product have not been performed. Most of the protocols used are expert based.

Potential use of autologous umbilical cord blood red blood cells for early transfusion needs of premature infants.

BACKGROUND: This prospective study investigated whether the odds of receiving a red blood cell (RBC) transfusion in premature infants can be predicted at birth and for whom of these infants harvesting of umbilical cord blood (UCB) for autologous transfusion within 30 days after birth would be worthwhile. STUDY DESIGN AND METHODS: Characteristics were evaluated from 288 premature infants with a gestational age between 24 and 36 weeks and who were admitted to our neonatal center. In 144 (63%) of these infants UCB collection was attempted and the early transfusion needs could be compared with the amount of UCB available for transfusion. RESULTS: Sixty-nine of 114 (61%) inborn infants with a gestational age of less than 32 weeks received one or more RBC transfusions of 10 mL per kg within 30 days after birth. Apgar score at 1 minute of less than 6 and gestational age of less than 32 weeks were independently associated with the chance of receiving a transfusion in this group. In 31 of 69 (46%) infants, at least 15 mL of UCB per kg of birth weight was collected and in 28 of 69 (41%) this would have been sufficient to cover their early transfusion needs. CONCLUSION: The decision to collect UCB for postnatal transfusion can be made just after labor, based on Apgar score and gestational age. The collection of UCB is most effective and efficient for premature infants between 29 and 31 weeks of gestation. For infants less than 29 weeks of gestation, the technical aspects of UCB collection need improvement. This pilot study requires a prospective clinical study to evaluate the proportion of premature infants that can be fully or substantially supported with autologous UCB.