Cord blood transfusions in extremely low gestational age neonates to reduce severe retinopathy of prematurity: results of a prespecified interim analysis of the randomized BORN trial.

BACKGROUND: Preterm infants are at high risk for retinopathy of prematurity (ROP), with potential life-long visual impairment. Low fetal hemoglobin (HbF) levels predict ROP. It is unknown if preventing the HbF decrease also reduces ROP. METHODS: BORN is an ongoing multicenter double-blinded randomized controlled trial investigating whether transfusing HbF-enriched cord blood-red blood cells (CB-RBCs) instead of adult donor-RBC units (A-RBCs) reduces the incidence of severe ROP (NCT05100212). Neonates born between 24 and 27 + 6 weeks of gestation are enrolled and randomized 1:1 to receive adult donor-RBCs (A-RBCs, arm A) or allogeneic CB-RBCs (arm B) from birth to the postmenstrual age (PMA) of 31 + 6 weeks. Primary outcome is the rate of severe ROP at 40 weeks of PMA or discharge, with a sample size of 146 patients. A prespecified interim analysis was scheduled after the first 58 patients were enrolled, with the main purpose to evaluate the safety of CB-RBC transfusions. RESULTS: Results in the intention-to-treat and per-protocol analysis are reported. Twenty-eight patients were in arm A and 30 in arm B. Overall, 104 A-RBC units and 49 CB-RBC units were transfused, with a high rate of protocol deviations. A total of 336 adverse events were recorded, with similar incidence and severity in the two arms. By per-protocol analysis, patients receiving A-RBCs or both RBC types experienced more adverse events than non-transfused patients or those transfused exclusively with CB-RBCs, and suffered from more severe forms of bradycardia, pulmonary hypertension, and hemodynamically significant patent ductus arteriosus. Serum potassium, lactate, and pH were similar after CB-RBCs or A-RBCs. Fourteen patients died and 44 were evaluated for ROP. Ten of them developed severe ROP, with no differences between arms. At per-protocol analysis each A-RBC transfusion carried a relative risk for severe ROP of 1.66 (95% CI 1.06-2.20) in comparison with CB-RBCs. The area under the curve of HbF suggested that HbF decrement before 30 weeks PMA is critical for severe ROP development. Subsequent CB-RBC transfusions do not lessen the ROP risk. CONCLUSIONS: The interim analysis shows that CB-RBC transfusion strategy in preterm neonates is safe and, if early adopted, might protect them from severe ROP. TRIAL REGISTRATION: Prospectively registered at ClinicalTrials.gov on October 29, 2021. Identifier number NCT05100212.

Direct breastfeeding: Predictive factors and possible effects on neurodevelopment in very preterm infants.

BACKGROUND: the importance of sucking milk directly at the mother's breast is often underestimated and many aspects of direct breastfeeding of very preterm infants are not investigated. AIM: The primary endpoint of the study was to identify maternal and infant clinical predictors of direct breastfeeding in a cohort of infants born at <32 weeks of gestation or weighing <1500 g. The secondary endpoint was to evaluate the possible effects of direct breastfeeding on infant neurodevelopment. STUDY DESIGN: Seventy-two infants born between July 2018 and December 2019 were divided into the subgroup that were directly breastfed (n = 42) and not directly breastfed (n = 30) at discharge. Maternal and infant characteristics were compared, and differences were analysed. RESULTS: Logistic regression analysis demonstrated that the percentage of maternal milk taken during hospitalization, maternal age, and weight (z-score) at discharge were positively correlated with the likelihood of direct breastfeeding at discharge. Direct breastfeeding was not correlated with the cognitive score at 24 months corrected age. CONCLUSIONS: Direct breastfeeding at discharge is more probable in infants of older mothers who receive more breastmilk and who experience greater weight gain. Direct breastfeeding is not correlated with the cognitive score at 24 months corrected age.

A structured programme to promote breastfeeding improved the rates in very preterm infants at discharge.

AIM: We developed the Promotion of Breastfeeding (PROBREAST) programme and evaluated what effect it had on the breastfeeding rate in infants born at less than 32 weeks of gestation or weighing ≤1500 grams. METHODS: We compared the breastfeeding rate in two cohorts of patients who were born before (n = 72; January 2017 to June 2018) and after (n = 80; July 2018 to December 2019) the application of the programme. Moreover, we compared the correlation between type of feeding at discharge and post-discharge breastfeeding rate, between exclusive breastfeeding, postnatal growth and neurodevelopment. RESULTS: Infants in the PROBREAST group had an exclusive breastfeeding rate at discharge higher (42 vs. 16%, p < 0.001) than that in the historical control group. Exclusive breastfeeding was negatively correlated with weight z-score at discharge, but not at 12 and 24 months corrected age, and was positively correlated with cognitive score at 24 months corrected age. CONCLUSION: The application of a structured programme for the promotion of breastfeeding improved the breastfeeding rate in very preterm infants. We demonstrated that exclusive breastfeeding at discharge improved their neurodevelopment without impairing growth.

Carboxyhemoglobin as biomarker of late-onset sepsis in preterm infants.

Carboxyhemoglobin (COHb) is considered a biomarker of oxidative stress and previous studies reported an increase in COHb levels in preterm infants who develop late-onset sepsis (LOS). Our aim was to assess the correlation between COHb levels and the risk for LOS development. We retrospectively studied 100 preterm infants, 50 in the LOS and 50 in the no LOS group. COHb levels were measured on the day of diagnosis of the first episode of LOS, 3, 2, and 1 days before and 1 and 4 days after the onset of LOS. Logistic regression analysis showed that a higher level of COHb 2 days before the diagnosis of LOS increases the risk for LOS development (OR 12.150, 95% Cl 1.311-12.605; P = 0.028). A COHb level of 1.55% measured 2 days before the diagnosis of LOS is the best predictive threshold for LOS with a sensitivity of 70% and a specificity of 70%.    Conclusion: Increased levels of COHb may predict the diagnosis of LOS in very preterm infants with a good accuracy. If further studies confirm our findings, this easy-to-measure biomarker could provide neonatologists with another tool for monitoring and early diagnosis of sepsis in high-risk patients. What is Known: • Carboxyhemoglobin (COHb) is a biomarker of oxidative stress. • Previous studies reported an increase in COHb levels in preterm infants who develop late-onset sepsis (LOS). What is New: • COHb levels increased two days before the diagnosis of LOS and this increase was associated with the risk for developing LOS. • ROC curve analysis for COHb measured two days before the diagnosis of LOS showed that 1.55% is the best predictive threshold for LOS with a sensitivity of 70% and a specificity of 70%.

Carboxyhemoglobin as biomarker of prematurity complications.

BACKGROUND: Carboxyhemoglobin (COHb) is considered a biomarker of oxidative stress and previous studies suggest a correlation between its blood level and prematurity complications. Our aim in this study was to assess the correlation between COHb levels and the risk for bronchopulmonary dysplasia (BPD), intraventricular hemorrhage (IVH), and retinopathy of prematurity (ROP). METHODS: We retrospectively studied 178 preterm infants with gestational age of 27.0 ± 1.5 weeks, among which 121 (68 %) had BPD, 43 (24 %) IVH, and 33 (19 %) ROP. COHb levels measured during the first seven days of life were recorded. RESULTS: Logistic regression analysis showed that higher levels of COHb on the seventh day of life increases the risk for moderate-to-severe BPD (OR 4.552, 95 % Cl 1.220-16.997; P = 0.024), while higher levels of COHb on the fourth day of life increases the risk for grade 2-4 IVH (OR 5.537, 95 % Cl 1.602-19.134; P = 0.007). CONCLUSIONS: COHb measured in the first week of life can contribute to predicting the risk for BPD and IVH, but not for ROP, in very preterm infants. Since COHb can be readily measured, its assessment can be useful in clinical practice for early identification of preterm infants at high risk for oxidative stress related complications.

Diagnostic Performance and Patient Outcomes With C-Reactive Protein Use in Early-Onset Sepsis Evaluations.

OBJECTIVES: To determine performance of C-reactive protein (CRP) in the diagnosis of early-onset sepsis, and to assess patient outcomes with and without routine use of CRP. STUDY DESIGN: This was a retrospective cohort study of infants admitted to 2 neonatal intensive care units. CRP was used routinely in early-onset sepsis evaluations during 2009-2014; this period was used to determine CRP performance at a cut-off of ≥10 mg/L in diagnosis of culture-confirmed early-onset sepsis. Routine CRP use was discontinued during 2018-2020; outcomes among infants admitted during this period were compared with those in 2012-2014. RESULTS: From 2009 to 2014, 10 134 infants were admitted; 9103 (89.8%) had CRP and 7549 (74.5%) had blood culture obtained within 3 days of birth. CRP obtained ±4 hours from blood culture had a sensitivity of 41.7%, specificity 89.9%, and positive likelihood ratio 4.12 in diagnosis of early-onset sepsis. When obtained 24-72 hours after blood culture, sensitivity of CRP increased (89.5%), but specificity (55.7%) and positive likelihood ratio (2.02) decreased. Comparing the periods with (n = 4977) and without (n = 5135) routine use of CRP, we observed lower rates of early-onset sepsis evaluation (74.5% vs 50.5%), antibiotic initiation (65.0% vs 50.8%), and antibiotic prolongation in the absence of early-onset sepsis (17.3% vs 7.2%) in the later period. Rate and timing of early-onset sepsis detection, transfer to a greater level of care, and in-hospital mortality were not different between periods. CONCLUSIONS: CRP diagnostic performance was not sufficient to guide decision-making in early-onset sepsis. Discontinuation of routine CRP use was not associated with differences in patient outcomes despite lower rates of antibiotic administration.

Enteral and Parenteral Treatment with Caffeine for Preterm Infants in the Delivery Room: A Randomised Trial.

BACKGROUND: Early treatment with caffeine in the delivery room (DR) has been proposed to decrease the need for mechanical ventilation (MV) by limiting episodes of apnoea and improving respiratory mechanics in preterm infants. Our aim was to verify the hypothesis that intravenous or enteral administration of caffeine can be performed in the preterm infant in the DR. METHODS: Infants with 25±0-29±6 weeks of gestational age were enrolled and randomised to receive 20 mg/kg of caffeine citrate intravenously, via the umbilical vein, or enterally, through an orogastric tube, within 10 min of birth. Caffeine blood level was measured at 60 ± 15 min after administration and 60 ± 15 min before the next dose (5 mg/kg). The primary endpoint was evaluation of the success rate of intravenous and enteral administration of caffeine in the DR. RESULTS: Nineteen patients were treated with intravenous caffeine and 19 with enteral caffeine. In all patients the procedure was successfully performed. Peak blood level of caffeine 60 ± 15 min after administration in the DR was found to be below the therapeutic range (5 µg/mL) in 25 % of samples and above the therapeutic range in 3%. Blood level of caffeine 60 ± 15 min before administration of the second dose was found to be below the therapeutic range in 18% of samples. CONCLUSIONS: Intravenous and enteral administration of caffeine can be performed in the DR without interfering with infants' postnatal assistance. Some patients did not reach the therapeutic range, raising the question of which dose is the most effective to prevent MV. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT04044976; EudraCT number 2018-003626-91.

BORN study: a multicenter randomized trial investigating cord blood red blood cell transfusions to reduce the severity of retinopathy of prematurity in extremely low gestational age neonates.

BACKGROUND: Extremely low gestational age neonates (ELGANs, i.e., neonates born before 28 weeks of gestation) are at high risk of developing retinopathy of prematurity (ROP), with potential long-life visual impairment. Due to concomitant anemia, ELGANs need repeated red blood cell (RBC) transfusions. These produce a progressive replacement of fetal hemoglobin (HbF) by adult hemoglobin (HbA). Furthermore, a close association exists between low levels of HbF and severe ROP, suggesting that a perturbation of the HbF-mediated oxygen release may derange retinal angiogenesis and promote ROP. METHODS/DESIGN: BORN (umBilical blOod to tRansfuse preterm Neonates) is a multicenter double-blinded randomized controlled trial in ELGANs, to assess the effect of allogeneic cord blood RBC transfusions (CB-RBCs) on severe ROP development. Recruitment, consent, and randomization take place at 10 neonatology intensive care units (NICUs) of 8 Italian tertiary hospitals. ELGANs with gestational age at birth comprised between 24+0 and 27+6 weeks are randomly allocated into two groups: (1) standard RBC transfusions (adult-RBCs) (control arm) and (2) CB-RBCs (intervention arm). In case of transfusion need, enrolled patients receive transfusions according to the allocation arm, unless an ABO/RhD CB-RBC is unavailable. Nine Italian public CB banks cooperate to make available a suitable amount of CB-RBC units for all participating NICUs. The primary outcome is the incidence of severe ROP (stage 3 or higher) at discharge or 40 weeks of postmenstrual age, which occurs first. DISCUSSION: BORN is a groundbreaking trial, pioneering a new transfusion approach dedicated to ELGANs at high risk for severe ROP. In previous non-randomized trials, this transfusion approach was proven feasible and able to prevent the HbF decrease in patients requiring multiple transfusions. Should the BORN trial confirm the efficacy of CB-RBCs in reducing ROP severity, this transfusion strategy would become the preferential blood product to be used in severely preterm neonates. TRIAL REGISTRATION: ClinicalTrials.gov NCT05100212. Registered on October 29, 2021.

Feasibility, Reproducibility and Reference Ranges of Left Atrial Strain in Preterm and Term Neonates in the First 48 h of Life.

Left atrial strain (LAS) is the most promising technique for assessment of diastolic dysfunction but few data are available in neonates. Our aim was to assess feasibility and reproducibility, and to provide reference ranges of LAS in healthy neonates in the first 48 h of life. We performed one echocardiography in 30 neonates to assess feasibility and develop a standard protocol for image acquisition and analysis. LAS reservoir (LASr), conduit (LAScd) and contraction (LASct) were measured. We performed echocardiography at 24 and 48 h of life in an unrelated cohort of 90 neonates. Median (range) gestational age and weight of the first cohort were 34.4 (26.4-40.2) weeks and 2075 (660-3680) g. LAS feasibility was 96.7%. Mean (SD) gestational age and weight of the second cohort were 34.2 (3.8) weeks and 2162 (833) g. Mean (SD) LASr significantly increased from 24 to 48 h: 32.9 (3.2) to 36.8 (4.6). Mean (SD) LAScd and LASct were stable: -20.6 (8.0) and -20.8 (9.9), -11.6 (4.9) and -13.5 (6.4). Intra and interobserver intraclass correlation coefficient for LASr, LAScd and LASct were 0.992, 0.993, 0.986 and 0.936, 0.938 and 0.871, respectively. We showed high feasibility and reproducibility of LAS in neonates and provided reference ranges.

Cerebral and splanchnic oxygenation during automated control of inspired oxygen (FiO2 ) in preterm infants.

OBJECTIVES: Our aim in this study was to assess the effect of the Predictive Intelligent Control of Oxygenation (PRICO® ) system on cerebral (rSO2 C) and splanchnic (rSO2 S) oxygenation in a cohort of preterm infants with frequent desaturations. METHODS: Twenty infants with gestational age <32 weeks (n = 20) were assigned in random sequence to 12 h of automated or manual adjustment of FiO2 . Over this period, they were studied continuously by near-infrared spectroscopy (NIRS). RESULTS: We found that rSO2 C [68.0% (60.5%-74.7%) vs. 68.5% (62%-72%); p = .824] and rSO2 S [27.0% (17.3%-45.7%) vs. 27.0% (15%-53%); p = .878] were similar during automatic and manual control of FiO2 . Time spent with SpO2 90%-95% was higher during the automatic than manual control of FiO2 , while time spent with SpO2 <80% or >95% was lower. CONCLUSIONS: Automated control of FiO2 with PRICO® system did not improve brain and splanchnic oxygenation in comparison with manual control in a cohort of preterm infants, but it significantly decreased SpO2 fluctuations and limited the duration of both hypoxemia and hyperoxemia.

Supraventricular tachycardias in the first year of life: what is the best pharmacological treatment? 24 years of experience in a single centre.

BACKGROUND: Supraventricular tachycardias (SVTs) are common in the first year of life and may be life-threatening. Acute cardioversion is usually effective, with both pharmacological and non-pharmacological procedures. However, as yet no international consensus exists concerning the best drug required for a stable conversion to sinus rhythm (maintenance treatment). Our study intends to describe the experience of a single centre with maintenance drug treatment of both re-entry and automatic SVTs in the first year of life. METHODS: From March 1995 to April 2019, 55 patients under one year of age with SVT were observed in our Centre. The SVTs were divided into two groups: 45 re-entry and 10 automatic tachycardias. As regards maintenance therapy, in re-entry tachycardias, we chose to start with oral flecainide and in case of relapses switched to combined treatment with beta-blockers or digoxin. In automatic tachycardias we first administered a beta-blocker, later combined with flecainide or amiodarone when ineffective. RESULTS: The patients' median follow-up time was 35 months. In re-entry tachycardias, flecainide was effective as monotherapy in 23/45 patients (51.1%) and in 20/45 patients (44.4%) in combination with nadolol, sotalol or digoxin (overall 95.5%). In automatic tachycardias, a beta-blocker alone was effective in 3/10 patients (30.0%), however, the best results were obtained when combined with flecainide: overall 9/10 (90%). CONCLUSIONS: In this retrospective study on pharmacological treatment of SVTs under 1 year of age the combination of flecainide and beta-blockers was highly effective in long-term maintenance of sinus rhythm in both re-entry and automatic tachycardias.

TREC and KREC in very preterm infants: reference values and effects of maternal and neonatal factors.

OBJECTIVE: T-cell receptor excision circles (TREC) and kappa-deleting recombination excision circles (KREC) assays have been used for severe combined immunodeficiencies newborn screening (NBS). We assessed TREC and KREC NBS values in preterm infants and investigated if perinatal characteristics affect their values. METHODS: We performed a retrospective study collecting data from TREC and KREC NBS database and from mothers' and infants' medical charts. RESULTS: TREC and KREC values were lower in preterm infants born at 23-31 or 32-36 weeks of gestation than in term infants. Gestational age <28 weeks of gestation, leukopenia, and hypertensive disorders of pregnancy lowered TREC. Hypertensive disorders of pregnancy lowered KREC and intrapartum fever >38 °C increased it. Low TREC and KREC values were not associated to the risk of developing early-onset sepsis and late-onset sepsis. CONCLUSION: TREC and KREC levels are lower in preterm than term infants, but this did not increase the risk of neonatal sepsis.

Effect on splanchnic oxygenation of breast milk, fortified breast milk, and formula milk in preterm infants.

BACKGROUND: Enteral feeding induces mesenteric hemodynamic changes in preterm infants, which may vary according to the milk used. Our aim in this study was to evaluate changes of splanchnic regional oxygenation (rSO2S) measured by near-infrared spectroscopy (NIRS) in infants fed with mother's own milk (MOM), fortified human milk (FHM), or preterm formula (PTF). METHODS: Infants born at 25-31 weeks of gestational age (n = 54) received a bolus of MOM, FHM, or PTF. rSO2S and splanchnic fractional oxygen extraction ratio (FOES) were recorded 60 min before (T0), and 30 min (T1) and 120 min (T2) after the beginning of bolus feeding. RESULTS: In the MOM group, rSO2S and FOES did not change during the study period. In the FBM group, rSO2S decreased from T0 to T1 and increased from T1 to T2, while FOES changed in reverse. In the PTF group, rSO2S decreased from T0 to T1 and from T1 to T2, while FOES changed in reverse. CONCLUSIONS: Splanchnic oxygenation was not affected by MOM feeding, was transiently decreased by FBM feeding, and was persistently decreased by PTF. These results suggest that preterm infants who received PTF has higher splanchnic tissue oxygen extraction compared to those who received MOM or FBM. IMPACT: Human milk feeding is associated to a lower splanchnic energy expenditure than preterm formula feeding. Fortified human milk transiently increases splanchnic energy expenditure. Preterm formula should be used only in the absence of human milk.

Study protocol: treatment with caffeine of the very preterm infant in the delivery room: a feasibility study.

INTRODUCTION: Early treatment with caffeine in the delivery room has been proposed to decrease the need for mechanical ventilation (MV) by limiting episodes of apnoea and improving respiratory mechanics in preterm infants. Thus, the purpose of this feasibility study is to verify the hypothesis that intravenous or enteral administration of caffeine can be performed in the preterm infant in the delivery room. METHODS AND ANALYSIS: In this multicentre prospective study, infants with 25+0-29+6 weeks of gestational age will be enrolled and randomised to receive 20 mg/kg of caffeine citrate intravenously, via the umbilical vein, or enterally, through an orogastric tube, within 10 min of birth. Caffeine plasma level will be measured at 60±15 min after administration and 60±15 min before the next dose (5 mg/kg). The primary endpoint will be evaluation of the success rate of intravenous and enteral administration of caffeine in the delivery room. Secondary endpoints will be the comparison of success rate of intravenous versus oral administration and the evaluation of the need for MV in treated infants. In the absence of previous references, we arbitrarily decided to study 20 infants treated with intravenous caffeine and 20 infants treated with enteral caffeine. Primary endpoint will be evaluated measuring the success rate of intravenous and enteral caffeine administration which will be considered a success when it is followed by the achievement of the caffeine therapeutic level (8-25 µg/mL) 60±15 min before administration of the second dose. ETHICS AND DISSEMINATION: The study has been approved by the Italian Medicines Agency (AIFA: AIFA/RSC/P/32755) and by Comitato Etico Pediatrico Regione Toscana. The results will be published in peer-reviewed academic journals. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier NCT04044976; EudraCT number 2018-003626-91.

Neonatal Cerebellar Hemorrhage and Facial Nerve Palsy: An Unusual Association.

Cerebellar hemorrhage is rare in term newborns and is most often seen after traumatic birth. Lifelong sequelae include motor and cognitive impairment. We report the uncommon case of a late preterm infant born by spontaneous delivery who showed right peripheral facial palsy at 24 hours of life. Cranial ultrasound showed lateral ventricles dilatation and a diffuse hyperechoic round lesion in the right cerebellar hemisphere. The computed tomography scan confirmed a hemorrhagic lesion in the right cerebellar hemisphere and in the vermis with midline shift and intraventricular bleeding. Ommaya reservoir was inserted and used for a few days. The facial palsy gradually recovered to a complete remission after 6 weeks. Follow-up examinations at 12 and 18 months evidenced infant's delayed motor function, hyperreflexia, tremors, and speech delay.

Erratum: Neonatal Cerebellar Hemorrhage and Facial Nerve Palsy: An Unusual Association.

[This corrects the article DOI: 10.1055/s-0040-1715162.][This corrects the article DOI: 10.1055/s-0040-1715162.].