Early Respiratory Physiotherapy versus an Individualized Postural Care Program for Reducing Mechanical Ventilation in Preterm Infants: A Randomised Controlled Trial.

BACKGROUND: Tactile stimulation manoeuvres stimulate spontaneous breathing in preterm newborns. The aim of this study is to evaluate the effect of early respiratory physiotherapy on the need for mechanical ventilation during the first week of life in preterm infants with respiratory failure. METHODS: This is a monocentric, randomised controlled trial. Preterm infants (gestational age ≤ 30 weeks) not intubated in the delivery room and requiring non-invasive respiratory support at birth were eligible for the study. The intervention group received early respiratory physiotherapy, while the control group received only a daily physiotherapy program (i.e., modifying the infant's posture in accordance with the patient's needs). RESULTS: between October 2019 and March 2021, 133 preterm infants were studied, 68 infants in the study group and 65 in routine care. The study group showed a reduction in the need for mechanical ventilation (not statistically significant) and a statistically significant reduction in hemodynamically significant patent ductus arteriosus with respect to the control group (19/68 (28%) vs. 35/65 (54%), respectively, p = 0.03). CONCLUSIONS: early respiratory physiotherapy in preterm infants requiring non-invasive respiratory support at birth is safe and has proven to be protective against haemodynamically significant PDA.

Differences in Cerebral Tissue Oxygenation in Preterm Neonates Receiving Adult or Cord Blood Red Blood Cell Transfusions.

Importance: Repeated transfusions in preterm neonates with anemia of prematurity replace fetal hemoglobin (HbF) with adult Hb (HbA), which has a low oxygen affinity. The reduction of HbF is associated with a higher incidence of retinopathy of prematurity (ROP). Objective: To assess whether HbF and HbA are differently associated with cerebral tissue oxygenation in preterm neonates. Design, Setting, and Participants: This cohort study was a single-center, pilot study on cerebral oxygenation kinetics in preterm neonates with a gestational age between 24.0 weeks and 27.9 weeks who were admitted to the neonatal intensive care unit of Policlinico Universitario A. Gemelli IRCCS from December 27, 2021, to May 15, 2023. This study was ancillary to the ongoing, double-blind, multicenter Umbilical or Adult Donor Red Blood Cells in Extremely Low Gestational Age Neonates and Retinopathy of Prematurity (BORN) randomized clinical trial. The BORN trial outcome was ROP severity in neonates randomized to receive standard packed red blood cell (PRBC) transfusions obtained from RBCs of adult donors (A-RBCs) or from cord blood (CB-RBCs). According to standard procedures at the institute's neonatal intensive care unit, patients concurrently received continuous cerebral near-infrared spectroscopy (NIRS) monitoring. This cohort study was not prespecified in the trial protocol. Exposure: Transfusion with A-RBCs or CB-RBCs. Main Outcomes and Measures: The main outcome was the kinetics of cerebral regional oxygen saturation (crSO2) and cerebral fraction of tissue oxygen extraction (cFTOE) associated with A-RBC or CB-RBC transfusions. Cerebral NIRS monitoring was performed by neonatologists and nurses, who were blinded to the PRBC type. The NIRS monitoring was conducted starting with the blood product order, during transfusion, and for the subsequent 24 hours after transfusion completion. The mean treatment effects of A-RBCs or CB-RBCs were quantified using a linear mixed model for repeated measures. Results: Of 23 randomized neonates, 17 (11 male [64.7%]; median gestational age at birth, 25.6 weeks [IQR, 25.3-26.1 weeks]) with a median birth weight of 840 g (IQR, 580-900 g) were included in the study; NIRS was evaluated for 42 transfusion episodes, of which 22 were A-RBCs and 20 were CB-RBCs. Globally considering all posttransfusion time points, the overall crSO2 covariate-adjusted mean after CB-RBC transfusions was 5.27% lower (95% CI, 1.20%-9.34%; P = .01) than that after A-RBC transfusions, while the cFTOE after CB-RBC transfusions was 6.18% higher (95% CI, 1.66%-10.69%; P = .009) than that after A-RBCs. Conclusions and Relevance: The findings of this cohort study suggest that A-RBC transfusions may be associated with more oxygen delivery to cerebral tissues of preterm neonates than transfusions from CB-RBCs. This finding may explain the previously observed association between low HbF and high ROP risk. It also suggests that use of CB to meet the RBC transfusion needs of neonates with a gestational age of less than 28 weeks may protect cerebral tissues from overexposure to oxygen.

Allogenic Cord Blood Transfusion in Preterm Infants.

Repeated red blood cell (RBC) transfusions in preterm neonates cause the progressive displacement of fetal hemoglobin (HbF) by adult hemoglobin. The ensuing increase of oxygen delivery may result at the cellular level in a dangerous condition of hyperoxia, explaining the association between low-HbF levels and retinopathy of prematurity or bronchopulmonary dysplasia. Transfusing preterm neonates with RBC concentrates obtained from allogeneic umbilical blood is a strategy to increase hemoglobin concentration without depleting the physiologic HbF reservoir. This review summarizes the mechanisms underlying a plausible beneficial impact of this strategy and reports clinical experience gathered so far in this field.

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.

Transfusion-Free Survival Predicts Severe Retinopathy in Preterm Neonates.

Repeated red blood cell (RBC) transfusions are thought to increase the risk for retinopathy of prematurity (ROP), likely due to a critical fetal hemoglobin (HbF) reduction. In this study, we investigated if the postmenstrual age (PMA) of neonates at transfusion influences the risk for ROP. We estimated the cumulative transfusion-free survival (TFS) in a series of 100 preterm neonates receiving one or more RBC units. TFS was calculated by censoring patients at first transfusion and expressing the time between birth and transfusion as either PMA or postnatal day. Then, we investigated if TFS predicted the occurrence of severe ROP, defined as ROP stage 3 or higher. We found that neonates with severe ROP displayed a significantly shorter TFS expressed according to their PMA (p = 0.001), with similar TFS according to postnatal days. At receiver operating characteristic (ROC) curve analysis, receiving an RBC unit before week 28 of PMA predicted severe ROP with a sensitivity of 64% and a specificity of 78%. In addition, receiving a second RBC unit before the PMA of 29 weeks predicted severe ROP with a sensitivity of 75% and a specificity of 69%. At multivariate analysis, PMA at the second transfusion was even more informative than at first transfusion and outperformed all other variables in predicting severe ROP, with an odds ratio of 4.554 (95% CI 1.332-15.573, p = 0.016). Since HbF decrease is greater after multiple RBC transfusions, it is conceivable that neonates receiving more than one unit before the PMA of 29 weeks may be exposed to a greater disturbance of retinal vascularization. Any strategy aimed at preventing the critical HbF decrease at this low age might potentially reduce the risk for severe ROP.

Effects of early respiratory physiotherapy on spontaneous respiratory activity of preterm infants: study protocol for a randomized controlled trial.

BACKGROUND: Tactile maneuvers stimulating spontaneous respiratory activity in preterm infants are recommended since birth, but data on how and how often these maneuvers are applied in clinical practice are unknown. In the last years, most preterm newborns with respiratory failure are preferentially managed with non-invasive respiratory support and by stimulating spontaneous respiratory activity from the delivery room and in neonatal intensive care unit (NICU), in order to avoid the risks of intubation and prolonged mechanical ventilation. METHODS: Preterm infants with gestational age < 31 weeks not intubated in the delivery room and requiring non-invasive respiratory support at birth will be eligible for the study. They will be randomized and allocated to one of two treatment groups: (1) the study group infants will be subject to the technique of respiratory facilitation within the first 24 h of life, according to the reflex stimulations, by the physiotherapist. The newborn is placed in supine decubitus and a slight digital pressure is exerted on a hemithorax. The respiratory facilitation technique will be performed for about three minutes and repeated for a total of 4/6 times in sequence, three times a day until spontaneous respiratory activity is achieved; thus, no respiratory support is required; (2) the control group infants will take part exclusively in the individualized postural care program. They will perform the technique of respiratory facilitation and autogenous drainage. OBJECTIVE: To evaluate the efficacy of early respiratory physiotherapy in reducing the incidence of intubation and mechanical ventilation in the first week of life (primary outcome). DISCUSSION: The technique of respiratory facilitation is based on reflex stimulations, applied early to preterm infant. Slight digital pressure is exerted on a "trigger point" of each hemithorax, to stimulate the respiratory activity with subsequent increase of the ipsilateral pulmonary minute ventilation and to facilitate the contralateral pulmonary expansion. This mechanism will determine the concatenation of input to all anatomical structures in relation to the area being treated, to promote spontaneous respiratory activity and reducing work of breathing, avoiding or minimizing the use of invasive respiratory support. TRIAL REGISTRATION: UMIN-CTR Clinical Trial UMIN000036066. Registered on March 1, 2019. Protocol 1. https://www.umin.ac.jp/ctr.

Infectious complications in neonatal transfusion: Narrative review and personal contribution.

Neonates and prematures are among the most transfused categories of patients. Adverse reactions due to transfusions, such as transfusion-transmitted infections, can affect the rest of their lives. In this systematic review, we revised the literature concerning transfusion-transmitted infection in neonates. We reported case-reports and case-series previously published and we integrated these data with our experience at local neonatal intensive care unit. Moreover, we illustrated strategies for mitigating transfusion-transmitted infections, including donor selection and testing, pathogen inactivation technologies and combined approaches, as for Cytomegalovirus infection, integrating leukoreduction and identification of seronegative donors.

Allogeneic cord blood transfusions prevent fetal haemoglobin depletion in preterm neonates. Results of the CB-TrIP study.

Repeated red blood cell (RBC) transfusions in preterm neonates are associated with poor outcome and increased risk for prematurity-associated diseases. RBC transfusions cause the progressive replacement of fetal haemoglobin (HbF) by adult haemoglobin (HbA). We monitored HbF levels in 25 preterm neonates until 36 weeks of post-menstrual age (PMA); patients received RBC units from allogeneic cord blood (cord-RBCs) or from adult donors (adult-RBCs), depending on whether cord-RBCs were available. Primary outcome was HbF level at PMA of 32 weeks. Twenty-three neonates survived until this age: 14 received no transfusions, two only cord-RBCs, three only adult-RBCs and four both RBC types. HbF levels in neonates transfused with cord-RBCs were significantly higher than in neonates receiving adult-RBCs (P < 0·0001) or both RBC types (P < 0·0001). Superimposable results were obtained at PMA of 36 weeks. Every adult-RBCs transfusion increased the risk for an HbF in the lowest quartile by about 10-fold, whereas this effect was not evident if combined adult- and cord-RBCs were evaluated. Overall, these data show that transfusing cord-RBCs can limit the HbF depletion caused by conventional RBC transfusions. Transfusing cord blood warrants investigation in randomised trials as a strategy to mitigate the severity of retinopathy of prematurity (NCT03764813).

Rotating-disc micro-solid phase extraction of F2-isoprostanes from maternal and cord plasma by using oxidized buckypaper as sorbent membrane.

This paper describes the development of an original micro-solid phase extraction device and its evaluation for the isolation of F2-isoprostanes (F2-IsoPs) from cord and maternal plasma samples. The unit is very simple and consists in a rotating disc (1.8 cm diameter) of oxidized buckypaper (BP), enwrapped in a polypropylene mesh pouch. Even if the selected F2-IsoPs have logP and pKa values that make them suitable candidates for their sorption on BP, several parameters were optimized to maximize recoveries: time of adsorption and desorption; stirring speed; volume, pH and ionic strength of the sample; type, volume, and fractions of the elution solvent; oxidation grade of BP. Among all, the last one was crucial in affecting extraction yields because of the analyte interactions with polar functionalities, introduced by a preliminary oxidative acid treatment. The investigation established the optimal oxidation time and highlighted the pros and cons of the acid activation step. All extracts were analyzed by means of liquid chromatography-tandem mass spectrometry (LC-MS/MS). Validation was performed according to the main FDA guidelines for bioanalytical methods. Depending on the spike level and analyte, recoveries ranged between 30 and 120% with precision and accuracy values lower than 20%. Quantitative analysis was accomplished by matrix-matched calibration curves whose determination coefficients were higher than 0.95. Lower limit of quantitation (LLOQ) spanned the range 2.45-6.77 µg L-1. The validated method was applied to the analysis of eight pairs of mother/child plasma samples, revealing the presence of 8-iso-15-keto-PGF2α and 8-iso-PGE2 at a concentration of about 10 µg L-1 in most cord plasma samples of preterm newborns.

Umbilical cord blood as a source for red-blood-cell transfusion in neonatology: a systematic review.

The prevention and treatment of anaemia in newborn patients made tremendous progress in the last decades. However, red-blood-cell (RBC) transfusions remain unavoidable in many neonates candidate to surgery and especially in preterm infants. In particular, anaemia occurring in neonates born at extremely low gestational age is actually severe and frequently requires transfusions. Several approaches have been explored to prevent or even to reduce the threshold and the frequency of RBC transfusions. Among these, umbilical cord blood (UCB) collection and processing to obtain RBC components for autologous or allogeneic transfusion have been extensively investigated. In this systematic review, we revised the literature concerning the use of UCB for either autologous or allogeneic transfusion purposes and we illustrated the rationale for a transfusion therapy tailored to extremely preterm neonates, based on RBC concentrates from allogeneic UCB donations.

Effect of Early Expressed Human Milk on Insulin-Like Growth Factor 1 and Short-Term Outcomes in Preterm Infants.

AIMS: Preterm breast milk contains high levels of bioactive components, including insulin-like growth factor 1 (IGF-1), that are reduced by Holder pasteurization. Animal studies have shown that milk-borne IGF-1 is likely absorbed intact in a bioactive form by the intestines. The aim of this study was to assess if early non-pasteurized expressed breast milk nutrition may affect IGF-1 plasma levels in premature infants. We also investigated the possible association between early expressed milk nutrition and short-term outcomes. METHODS: Fifty-two preterm infants with gestational age < 31 weeks were divided into two groups according to expressed breast milk intake (< or ≥ 50 mL/Kg/day) until 32 weeks of postmenstrual age when blood sampling for IGF-1 analysis was performed. RESULTS: In our population, early expressed breast milk does not affect IGF-1 plasma levels (p 0.48). An association was observed between early expressed milk nutrition and a lower incidence of bronchopulmonary dysplasia, sepsis, feeding intolerance, need for parenteral nutrition and length of hospitalization. CONCLUSIONS: Contrary to the results in some animal studies, our results did not seem to show that early expressed breast milk can help to maintain postnatal IGF-1 near foetal levels in preterm infants. The observed protective effect of expressed breast milk on short-term outcomes can be the starting point for further study of the effects of non-pasteurized human milk in preterm infants.

Allogeneic umbilical cord blood red cell concentrates: an innovative blood product for transfusion therapy of preterm infants.

BACKGROUND: Preterm infants often receive blood transfusions early in life. In this setting, umbilical cord blood (UCB) might be safer than adult blood (A) with respect to infectious and immunologic threats. OBJECTIVES: To evaluate, as a first objective, the feasibility of fulfilling transfusion needs of preterm infants with allogeneic UCB red blood cell (RBC) concentrates and, as a secondary objective, to assess the safety of allogeneic cord blood transfusions. METHODS: At the Neonatal Intensive Care Unit and the UNICATT Cord Blood Bank of 'A. Gemelli' Hospital in Rome, a prospective study was carried out over a 1-year period, enrolling newborns with gestational age ≤30 weeks and/or birth weight ≤1,500 g requiring RBC transfusions within the first 28 days of life. At first transfusion, patients were assigned to receive UCB-RBCs or A-RBCs depending on the availability of ABO-Rh(D)-matched UCB-RBC units. The same regimen (UCB-RBC or A-RBC units) was thereafter maintained, unless ABO-Rh(D)-matched UCB-RBC units were not available. RESULTS: Overall, 23 UCB-RBC units were transfused to 9 patients; the requests for UCB-RBC units were met in 45% of patients at the first transfusion and in 78% at the subsequent transfusions. At a median follow-up of 57 days (range 6-219), no acute or delayed transfusion-related adverse events occurred. Hematocrit gain after transfusion and time intervals between transfusions were similar in the UCB-RBC and A-RBC group, as well. CONCLUSIONS: Transfusing allogeneic UCB-RBC units in preterm infants appears a feasible and safe approach, although the transfusion needs of our study population were not completely covered. More data are necessary to validate this novel transfusion practice.

Longitudinal assessment of perceptual-motor abilities in pre-school preterm children.

OBJECTIVE: To verify the value of early perceptual-motor assessment in preterms. METHODS: The M-ABC2 was performed below the age 3 years-4 months and 1 year later. RESULTS: At 4 years children showed a significant improvement in the scores and reduced rate of refusals. CONCLUSION: Early findings may be related to delayed maturation.

Intravitreal bevacizumab versus laser treatment in type 1 retinopathy of prematurity: report on fluorescein angiographic findings.

PURPOSE: To compare the structural outcome at 9 months of eyes treated with intravitreal injection of bevacizumab with fellow eyes treated with conventional laser photoablation in zone I type 1 retinopathy of prematurity (ROP). DESIGN: Single randomized controlled trial. PARTICIPANTS: All inborn babies with type 1 zone I ROP at a single institution were included in the study. One eye was randomized to receive an intravitreal injection of 0.5 mg bevacizumab; the fellow eye received conventional laser photoablation. METHODS: Digital fundus photographs and fluorescein angiography (FA) using the RetCam (Clarity Medical Systems Inc., Pleasanton, CA) were performed before treatment and 9 months after treatment. MAIN OUTCOME MEASURES: Presence of retinal and choroidal abnormalities on FA at 9 months. RESULTS: Thirteen infants were enrolled; 1 died 3 months after birth. One laser-treated eye progressed to stage 5 retinal detachment. The remaining 23 eyes had favorable structural results at the 9-month follow-up and provided FA results. At 9 months of age, all eyes treated with a bevacizumab injection were noted to have abnormalities at the periphery (large avascular area, abnormal branching, shunt) or the posterior pole (hyperfluorescent lesion, absence of foveal avascular zone). These posterior and peripheral lesions were not observed in the majority of the lasered eyes. CONCLUSIONS: This study documents significant vascular and macular abnormalities of eyes in the bevacizumab group. Long-lasting implications of these abnormalities for visual function of the child need to be studied.

Feasibility of transferring intensive cared preterm infants from incubator to open crib at 1600 grams.

BACKGROUND: Ability to maintain a normal body temperature in an open crib is an important physiologic competency generally requested to discharge preterm infants from the hospital. The aim of this study is to assess the feasibility of an early weaning protocol from incubator in preterm newborns in a Neonatal Intensive Care Unit. METHODS: 101 infants with birth weight < 1600 g were included in this feasibility study. We compared 80 newborns successfully transferred from an incubator to open crib at 1600 g with 21 infants transferred at weight ≥ 1700 g. The primary outcome was to evaluate feasibility of the protocol and the reasons for the eventual delay. Secondary outcomes were the identification of factors that would increase the likelihood of early weaning, the impact of an earlier weaning on discharge timing, and the incidence of adverse outcomes. Newborns in the study period were then compared with an historical control group with similar characteristics. RESULTS: Early weaning was achieved in 79.2% of infants without significant adverse effects on temperature stability or weight gain. Delayed weaning was mainly due to the need of respiratory support. Gestational age affected the likelihood of early weaning (OR 1.7282 95% CI: 1.3071 - 2.2850). In the multivariate linear regression, early weaning reduced length of stay (LOS) by 25.8 days (p < 0.0001). CONCLUSIONS: Preterm infants can be weaned successfully from an incubator to an open crib at weight as low as 1600 grams without significant adverse effect. Early weaning significantly reduces LOS in preterm newborns.

Perceptual-motor abilities in pre-school preterm children.

BACKGROUND: Several studies report a high percentage of premature infants presenting perceptual motor difficulties at school age. The new version of the Movement Assessment Battery for Children allows the assessment of perceptual-motor abilities in children from the age of 3years. AIMS: To evaluate early perceptual-motor abilities in prematurely born children below the age of 4years. STUDY DESIGN: The Movement Assessment Battery for Children 2nd edition was administered to 105 low-risk prematurely born children (<32weeks gestation) and in a control group of 105 term-born children matched for age and sex. All children were assessed between the age of 3years and 3years-11months. RESULTS: 63 children (60%) had total scores above the 15th percentile, 15 (14.3%) had scores between the 5th and the 15th percentile, and 13 (12.4%) below the 5th percentile. The remaining 14 children (13.3%) refused to perform or to complete the test. The difference between preterm and control group was significant for total scores, Manual Dexterity and Aiming and Catching scores. In the preterm group there was a correlation between age at testing, total scores and Aiming and Catching subscores. The Movement ABC-2 subscores were significantly lower in children born below 29weeks. CONCLUSION: Perceptual-motor difficulties can already be detected on the assessment performed before the age of 4years. Prematurely born children assessed between 3years and 3years-3months appeared to have more difficulties in performing the test than the older ones or their age matched term-born peers. These findings support the possibility of a delayed maturation in the younger age group.