Modeling Developmental Changes in Caffeine Clearance Considering Differences between Pre- and Postnatal Period.

Taguchi et al. reported that postmenstrual age (PMA) is a promising factor in describing and understanding the developmental change of caffeine (CAF) clearance. The aim of the present study was to quantify how developmental changes occur and to determine the effect of the length of the gestational period on CAF clearance. We performed a nonlinear mixed effect model (NONMEM) analysis and evaluated the fit of six models. A total of 115 samples were obtained from 52 patients with a mean age of 34.3 ± 18.2 d. The median values of gestational age (GA) and postnatal age (PNA) were 196 and 31 d, respectively. Serum CAF levels corrected for dose per body surface area (BSA) (C/D ratioBSA) were dependent on PMA rather than PNA, which supports the findings of a previous study. NONMEM analysis provided the following final model of oral clearance: CL/F = 0.00603∙WT∙∙0.877GA ≤ 196 L/h. This model takes into account developmental changes during prenatal and postnatal periods separately. The model successfully described the variation in clearance of CAF. Our findings suggest that the dosage of CAF in preterm infants should be determined based not only on body weight (WT) but also on both PNA and GA.

Pharmacokinetic Variability of Caffeine in Routinely Treated Preterm Infants: Preliminary Considerations on Developmental Changes of Systemic Clearance.

The purpose of this study was to clarify the variability of serum concentrations of caffeine (CAF) in preterm infants, and to deliberate on a better explanation for developmental changes of systemic clearance during the neonatal period. Forty-nine serum samples were obtained from 23 preterm neonates (age, 34.1 ± 18.8 d), and additive blood sampling was conducted periodically for 10 of the 23 patients after discontinuation of CAF treatment. The concentrations of CAF and its major metabolites were determined by liquid chromatography-tandem mass spectrometory. The serum concentrations of CAF were within therapeutic levels (5-25 µg/mL) in 37 samples and exceeded 25 µg/mL in the rest of the 12 samples, although no sample was in the toxic range (> 50 µg/mL). The inter- and intra-individual variability of the concentration to dose (C/D) ratio corrected for body surface area (BSA) was more negatively associated with postmenstrual age (PMA) rather than postnatal age (PNA). The serum concentrations of major metabolites were much smaller than those of CAF throughout the study, suggesting that the contribution of hepatic metabolism to drug elimination was small in the preterm infants under 241 d of PMA. The mean values for elimination half-life and oral clearance estimated in the 10 patients were 124.6 ± 44.6 h and 2.26 ± 0.73 mL/min/1.73 m2, respectively. Consequently, we confirmed that the exposure to CAF was considerably variable and provided additive insight that the C/D ratio corrected for patient's BSA and PMA are promising for describing and understanding the developmental change of clearance in preterm infants.

Treatment of retinopathy of prematurity (ROP) outside International Classification of ROP (ICROP) guidelines.

AIM: To evaluate the incidence and clinical indications for which eyes were treated for retinopathy of prematurity (ROP) outside the guidelines set by International Classification of ROP (ICROP). METHODS: Medical records of the patients treated at a single tertiary care ophthalmology hospital for ROP from January 2016 to December 2019 were retrospectively analysed to evaluate the indications for which they were treated. RESULTS: Out of 241 eyes, 33 eyes (13.7%) were treated outside the guidelines. The reasons for the treatment outside the guidelines were structural changes (n = 24, 72.7%), persistent stage 3 ROP that did not show any sign of regression for 6 weeks (n = 7, 21.2%) and active ROP with fellow eye being treated (n = 2, 6.1%). The recorded specific structural changes were tangential traction with temporal vessel straightening concerning for macular distortion and ectopia (n = 5, 15.2%), and stage 3 neovascularisation or ridge with anteroposterior traction with risk of progression to stage 4 disease (n = 19, 57.6%). Pre-plus disease was present in 11 eyes (33.3%).After the treatment, ROP stages regressed and retinal vessels grew either until the ora or at least into zone III in all the treated eyes. None of the eyes showed worsening of structural changes after treatment. The mean follow-up of the patients was 12.4 ± 11.7 months. CONCLUSION: Experts occasionally recommend treatment in eyes with disease milder than type 1 ROP. This study may help paediatric retinal practitioners in decision-making in borderline cases.

Ranibizumab injection and laser photocoagulation to treat type 1 retinopathy of prematurity after 40 weeks post menstrual age: a retrospective case series study.

BACKGROUND: Type 1 retinopathy of prematurity (ROP) is occasionally observed in preterm infants after the postmenstrual age (PMA) of 40 weeks; however, evidence-based treatment guidelines are largely lacking. In this study, we report the clinical characteristics of preterm infants with type 1 ROP at PMA of > 40 weeks and compare the treatment outcomes of intravitreal ranibizumab (IVR) and laser therapy. METHODS: Twenty-seven eyes of 14 infants, primarily treated for type 1 ROP after 40 weeks PMA by IVR (17 eyes in 9 infants) or by laser photocoagulation (10 eyes in 5 infants) were included in this retrospective analysis. The preoperative fundus characteristics and the structural outcomes and additional treatment after 6 months were analyzed. RESULTS: Of the 27 eyes, 20 eyes (74%) had zone II stage 3 plus disease (+) ROP and 7 eyes had zone II stage 2 + ROP. Seventeen (63%) eyes showed thick fibrous ridges. After primary treatment at 40-48 weeks PMA, ROP regression was observed in a similar proportion of eyes in the IVR and laser groups (88% vs. 70%; p = 0.326); complete vascularization was observed in 24% eyes in the IVR group. Compared to laser group, a higher proportion of eyes in IVR group received additional treatment (IVR group 76% vs. laser group 30%; p = 0.040), for unresolved peripheral avascularity in 11 eyes and ROP progression with fibrotic contraction in 2 eyes after primary IVR. CONCLUSION: Preterm infants with type 1 ROP at > 40 weeks PMA displayed enhanced fibrotic proliferation. Both primary IVR and laser effectively promote ROP regression. Primary IVR cannot guarantee full retinal vascularization but is associated with a risk of fibrotic contraction.

The effect of enteral bolus feeding on regional intestinal oxygen saturation in preterm infants is age-dependent: a longitudinal observational study.

BACKGROUND: The factors that determine the effect of enteral feeding on intestinal perfusion after preterm birth remain largely unknown. We aimed to determine the effect of enteral feeding on intestinal oxygen saturation (rintSO2) in preterm infants and evaluated whether this effect depended on postnatal age (PNA), postmenstrual age (PMA), and/or feeding volumes. We also evaluated whether changes in postprandial rintSO2 affected cerebral oxygen saturation (rcSO2). METHODS: In a longitudinal observational pilot study using near-infrared spectroscopy we measured rintSO2 and rcSO2 continuously for two hours on postnatal Days 2 to 5, 8, 15, 22, 29, and 36. We compared preprandial with postprandial values over time using multi-level analyses. To assess the effect of PNA, PMA, and feeding volumes, we performed Wilcoxon signed-rank tests or logistic regression analyses. To evaluate the effect on rcSO2, we also used logistic regression analyses. RESULTS: We included 29 infants: median (range) gestational age 28.1 weeks (25.1-30.7) and birth weight 1025 g (580-1495). On Day 5, rintSO2 values decreased postprandially: mean (SE) 44% (10) versus 35% (7), P = .01. On Day 29, rintSO2 values increased: 44% (11) versus 54% (7), P = .01. Infants with a PMA ≥ 32 weeks showed a rintSO2 increase after feeding (37% versus 51%, P = .04) whereas infants with a PMA < 32 weeks did not. Feeding volumes were associated with an increased postprandial rintSO2 (per 10 mL/kg: OR 1.63, 95% CI, 1.02-2.59). We did not find an effect on rcSO2 when rintSO2 increased postprandially. CONCLUSIONS: Our study suggests that postprandial rintSO2 increases in preterm infants only from the fifth week after birth, particularly at PMA ≥ 32 weeks when greater volumes of enteral feeding are tolerated. We speculate that at young gestational and postmenstrual ages preterm infants are still unable to increase intestinal oxygen saturation after feeding, which might be essential to meet metabolic demands. TRIAL REGISTRATION: For this prospective longitudinal pilot study we derived patients from a larger observational cohort study: CALIFORNIA-Trial, Dutch Trial Registry NTR4153 .

Outcomes and prognostic factors for aggressive posterior retinopathy of prematurity following initial treatment with intravitreal ranibizumab.

BACKGROUND: This study sought to identify factors associated with retinal detachment and retreatment of aggressive posterior retinopathy of prematurity (APROP) initially treated with intravitreal ranibizumab (IVR) injection as well as the efficacy of IVR treatment. METHODS: This was a retrospective study. A total of 83 preterm infants (160 eyes) diagnosed with APROP who were primarily treated with IVR were included. The 160 eyes were divided into two groups based on the anatomic outcomes. Group A included 35 eyes that developed retinal detachment, and Group B included 125 eyes without retinal detachment. The following patient factors were retrospectively reviewed: gender, gestational age (GA), birth weight (BW), postmenstrual age (PMA) at first treatment, iris neovascularizations, retinal hemorrhage, neutrophil and lymphocyte counts before the first intravitreal injection, neutrophil-to-lymphocyte ratio (NLR), anatomical outcomes, additional treatment and follow-up time. Three dummy variables were created as dependent variables based on the methods of retreatment. The possible risk factors for APROP were evaluated, and statistical analyses included univariate and multivariate logistic regression. RESULTS: A total of 160 eyes from 83 preterm infants (56 males and 27 females) underwent initial IVR treatment with a follow-up time of 17.17 ± 10.54 months. Thirty-five of the 160 (21.9%) eyes progressed to retinal detachment, and 82 of the 125 (65.6%) non-retinal detachment eyes needed retreatment, with favorable anatomical outcomes. The disease improved approximately 1.5 ± 1.2 weeks after the first IVR treatment. The mean recurrence period of APROP was approximately 7.5 ± 6.9 weeks after the first IVR treatment. Multiple logistic regression analysis revealed postmenstrual age (P < 0.001) and neutrophil count (P = 0.009) as the most significant factors for retinal detachment in APROP. Retinal hemorrhage (P = 0.007) and BW (P = 0.04) were most significantly associated with APROP recurrence and retreatment. CONCLUSIONS: IVR injection is an effective treatment for APROP. In this study, older postmenstrual age and low neutrophil count were identified as risk factors for retinal detachment in APROP. In addition, retinal hemorrhage and low BW were significantly associated with recurrence and retreatment in non-retinal detachment APROP. Thus, patients with a lower BW, older postmenstrual age, low neutrophil count and retinal hemorrhage should be reexamined in a timely and more frequent manner.

Comparing different methods of human breast milk fortification using measured v. assumed macronutrient composition to target reference growth: a randomised controlled trial.

The variable content of human breast milk suggests that its routine fortification may result in sub-optimal nutritional intakes and growth. In a pragmatic trial, we randomised infants born below 30 weeks of gestation to either the intervention (Igp) of fortifying milk on measured composition according to birth weight criteria and postmenstrual age (PMA) or our routine practice (RPgp) of fortifying on assumed milk composition to target 3·8-4·4 g protein/kg per d and 545-629 kJ/kg per d. Milk composition was measured using the MIRIS® Human Milk Analyser. Percentage fat mass (%FM) was measured using PEA POD (COSMED). The effects of macronutrient intakes and clinical variables on growth were assessed using mixed model analysis. Mean measured protein content (1·6 g/100 ml) was higher than the assumed value (1·4 g/100 ml), often leading to lower amounts of fortifier added to the milk of intervention infants. At discharge (Igp v. RPgp), total protein (3·2 (SD 0·3) v. 3·4 (SD 0·4) g; P=0·067) and energy (456 (SD 39) v. 481 (SD 48) kJ; P=0·079) intakes from all nutrition sources, weight gain velocity (11·4 (SD 1·4) v. 12·1 (SD 1·6) g/kg per d; P=0·135) and %FM (13·7 (SD 3·6) v.13·6 (SD 3·5) %; P=0·984) did not significantly differ between groups. A protein intake >3·4 g/kg per d reduced %FM by 2%. Nutrition and growth was not improved by targeting milk fortification according to birth weight criteria and PMA using measured milk composition, compared with routine practice. Targeting fortification on measured composition is labour intensive, requiring frequent milk sampling and precision measuring equipment, perhaps reasons for its limited practice. Guidance around safe upper levels of milk fortification is needed.

Ocular blood flow values measured by laser speckle flowgraphy correlate with the postmenstrual age of normal neonates.

PURPOSE: To evaluate the relationships between optic nerve head (ONH) blood flow by laser speckle flowgraphy (LSFG), and postmenstrual age and body weight in normal neonates. METHODS: During their normal sleep, we studied 24 infants (postmenstrual age, 248-295 days) whose ocular blood flow could be measured three consecutive times. While the subjects slept in the supine position, three mean blur rate (MBR) values of the ONH were obtained: the MBR-A (mean of all values), MBR-V (vessel mean) and MBR-T (tissue mean) in the ONH. With regard to eye diseases, no retinopathy of prematurity (ROP) was observed, and no severe systemic diseases requiring treatment were noted in the subjects. Pearson's correlation coefficients were used to determine the relationship between the MBR-A, -V, -T and postmenstrual age (days) and body weight (g). RESULTS: Postmenstrual age was significantly correlated with MBR-A (r = 0.64, p = 0.0007), MBR-V (r = 0.62, p = 0.0012) and MBR-T (r = 0.62, p = 0.0012). However, the body weight was not correlated with the MBR (MBR-A: r = 0.37, p = 0.07, MBR-V: r = 0.31, p = 0.14, MBR-T: r = 0.38, p = 0.06). CONCLUSIONS: Our results clarified that the values of ocular blood flow measured by LSFG correlate with the postmenstrual age of normal neonates.

Brain microstructural development at near-term age in very-low-birth-weight preterm infants: an atlas-based diffusion imaging study.

At near-term age the brain undergoes rapid growth and development. Abnormalities identified during this period have been recognized as potential predictors of neurodevelopment in children born preterm. This study used diffusion tensor imaging (DTI) to examine white matter (WM) microstructure in very-low-birth-weight (VLBW) preterm infants to better understand regional WM developmental trajectories at near-term age. DTI scans were analyzed in a cross-sectional sample of 45 VLBW preterm infants (BW≤1500g, GA≤32weeks) within a cohort of 102 neonates admitted to the NICU and recruited to participate prior to standard-of-care MRI, from 2010 to 2011, 66/102 also had DTI. For inclusion in this analysis, 45 infants had DTI, no evidence of brain abnormality on MRI, and were scanned at PMA ≤40weeks (34.7-38.6). White matter microstructure was analyzed in 19 subcortical regions defined by DiffeoMap neonatal brain atlas, using threshold values of trace <0.006mm(2)s(-1) and FA >0.15. Regional fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were calculated and temporal-spatial trajectories of development were examined in relation to PMA and brain region location. Posterior regions within the corona radiata (CR), corpus callosum (CC), and internal capsule (IC) demonstrated significantly higher mean FA values compared to anterior regions. Posterior regions of the CR and IC demonstrated significantly lower RD values compared to anterior regions. Centrally located projection fibers demonstrated higher mean FA and lower RD values than peripheral regions including the posterior limb of the internal capsule (PLIC), cerebral peduncle, retrolenticular part of the IC, posterior thalamic radiation, and sagittal stratum. Centrally located association fibers of the external capsule had higher FA and lower RD than the more peripherally-located superior longitudinal fasciculus (SLF). A significant relationship between PMA-at-scan and FA, MD, and RD was demonstrated by a majority of regions, the strongest correlations were observed in the anterior limb of the internal capsule, a region undergoing early stages of myelination at near-term age, in which FA increased (r=.433, p=.003) and MD (r=-.545, p=.000) and RD (r=-.540, p=.000) decreased with PMA-at-scan. No correlation with PMA-at-scan was observed in the CC or SLF, regions that myelinate later in infancy. Regional patterns of higher FA and lower RD were observed at this near-term age, suggestive of more advanced microstructural development in posterior compared to anterior regions within the CR, CC, and IC and in central compared to peripheral WM structures. Evidence of region-specific rates of microstructural development was observed. Temporal-spatial patterns of WM microstructure development at near-term age have important implications for interpretation of near-term DTI and for identification of aberrations in typical developmental trajectories that may signal future impairment.

Pulmonary outcome in former preterm, very low birth weight children with bronchopulmonary dysplasia: a case-control follow-up at school age.

OBJECTIVE: To assess and compare long-term pulmonary outcomes in former preterm-born, very low birth weight (VLBW) children with and without bronchopulmonary dysplasia (BPD) born in the surfactant era. STUDY DESIGN: Pulmonary function tests (ie, spirometry, body plethysmography, and gas transfer testing) were performed in children with a history of VLBW and BPD (n = 28) and compared with a matched preterm-born VLBW control group (n = 28). Medical history was evaluated by questionnaire. RESULTS: At time of follow-up (mean age, 9.5 years), respiratory symptoms (36% vs 8%) and receipt of asthma medication (21% vs 0%) were significantly more frequent in the preterm-born children with previous BPD than in those with no history of BPD. The children with a history of BPD had significantly lower values for forced expiratory volume in 1 second (z-score -1.27 vs -0.4; P = .008), forced vital capacity (z-score -1.39 vs -0.71 z-score; P = .022), and forced expiratory flow rate at 50% of forced vital capacity (z-score -2.21 vs -1.04; P = .048) compared with the preterm control group. CONCLUSION: Preterm-born children with a history of BPD are significantly more likely to have lung function abnormalities, such as airway obstruction and respiratory symptoms, at school age compared with preterm-born children without BPD.

Alterations in brain structure and neurodevelopmental outcome in preterm infants hospitalized in different neonatal intensive care unit environments.

OBJECTIVE: To evaluate associations between neonatal intensive care unit (NICU) room type (open ward and private room) and medical outcomes; neurobehavior, electrophysiology, and brain structure at hospital discharge; and developmental outcomes at 2 years of age. STUDY DESIGN: In this prospective longitudinal cohort study, we enrolled 136 preterm infants born <30 weeks gestation from an urban, 75-bed level III NICU from 2007-2010. Upon admission, each participant was assigned to a bedspace in an open ward or private room within the same hospital, based on space and staffing availability, where they remained for the duration of hospitalization. The primary outcome was developmental performance at 2 years of age (n = 86 infants returned for testing, which was 83% of survivors) measured using the Bayley Scales of Infant and Toddler Development, 3rd Edition. Secondary outcomes were: (1) medical factors throughout the hospitalization; (2) neurobehavior; and (3) cerebral injury and maturation (determined by magnetic resonance imaging and electroencephalography). RESULTS: At term equivalent age, infants in private rooms were characterized by a diminution of normal hemispheric asymmetry and a trend toward having lower amplitude integrated electroencephalography cerebral maturation scores (P = .02; ß = -0.52 [CI -0.95, -0.10]). At age 2 years, infants from private rooms had lower language scores (P = .006; ß = -8.3 [CI -14.2, -2.4]) and a trend toward lower motor scores (P = .02; ß = -6.3 [CI -11.7, -0.99]), which persisted after adjustment for potential confounders. CONCLUSION: These findings raise concerns that highlight the need for further research into the potential adverse effects of different amounts of sensory exposure in the NICU environment.

Quantitative Electroencephalography in Term Neonates During the Early Postnatal Period Across Various Sleep States.

Background: Neonatal sleep is pivotal for their growth and development, yet manual interpretation of raw images is time-consuming and labor-intensive. Quantitative Electroencephalography (QEEG) presents significant advantages in terms of objectivity and convenience for investigating neonatal sleep patterns. However, research on the sleep patterns of healthy neonates remains scarce. This study aims to identify QEEG markers that distinguish between different neonatal sleep cycles and analyze QEEG alterations across various sleep stages in relation to postmenstrual age. Methods: From September 2023 to February 2024, full-term neonates admitted to the neonatology department at the Obstetrics and Gynecology Hospital of Fudan University were enrolled in this study. Electroencephalographic (EEG) recordings were obtained from neonates aged 37-42 weeks, within 1-7 days post-birth. The ROC curve was employed to evaluate QEEG features related to amplitude, range EEG (rEEG), spectral density, and connectivity across different sleep stages. Furthermore, regression analyses were performed to investigate the association between these QEEG characteristics and postmenstrual age. Results: The alpha frequency band's spectral_diff_F3 emerged as the most potent discriminator between active sleep (AS) and quiet sleep (QS). In distinguishing AS from wakefulness (W), the theta frequency's spectral_diff_C4 was the most effective, whereas the delta frequency's spectral_diff_P4 excelled in differentiating QS from W. During AS and QS phases, there was a notable increase in entropy within the delta frequency band across all monitored brain regions and in the spectral relative power within the theta frequency band, correlating with postmenstrual age (PMA). Conclusion: Spectral difference showcases the highest discriminative capability across awake and various sleep states. The observed patterns of neonatal QEEG alterations in relation to PMA are consistent with the maturation of neonatal sleep, offering insights into the prediction and evaluation of brain development outcomes.

Exploring the Association of Male Sex With Adverse Outcomes in Severe Bronchopulmonary Dysplasia: A Retrospective, Multicenter Cohort Study.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is a significant contributor to morbidity and death in infants who are born premature. Male sex is an independent risk factor for the development of BPD. However, whether male sex is associated with adverse outcomes that occur after formal diagnosis of severe BPD prior to hospital discharge remains unclear. RESEARCH QUESTION: Is male sex associated with a higher risk of adverse outcomes in infants with established severe BPD? STUDY DESIGN AND METHODS: A retrospective, multicenter cohort study of infants enrolled in the BPD Collaborative Registry from January 1, 2015, to June 29, 2022, was performed. Demographics, clinical characteristics, and outcomes were stratified by sex (ie, male vs female). Regression modeling was used to estimate the association of sex with the primary composite outcome of death or tracheostomy at hospital discharge. RESULTS: We identified 1,156 infants with severe BPD, defined at 36 weeks postmenstrual age by the National Institutes of Health 2001 consensus definition. The cohort was predominantly male (59% male infants, 41% female infants). However, rates of mechanical ventilation at 36 weeks postmenstrual age (ie, type 2 severe BPD) did not differ by sex. Overall mortality rates within the cohort were low (male infants, 5.3%; female infants, 3.6%). The OR of death or tracheostomy for male-to-female infants was 1.0 (95% CI, 0.7-1.5). INTERPRETATION: Our results lead us to speculate that, although sex is an important variable that contributes to the development and pathogenesis of severe BPD, it does not appear to be associated with adverse outcomes in this cohort of infants with established disease. The surprising results raise important questions surrounding the temporal role of biological sex in the development of severe BPD and its progression during the neonatal ICU stay. As we explore the phenotypes and endotypes of BPD, it is imperative to consider how sex modulates the disease from birth through hospital discharge.

Prenatal substance exposure: neurobiologic organization at 1 month.

OBJECTIVE: To examine the autonomic nervous system and neurobehavioral response to a sustained visual attention challenge in 1-month-old infants with prenatal substance exposure. STUDY DESIGN: We measured heart rate, respiratory sinus arrhythmia, and neurobehavior during sustained visual orientation tasks included in the Neonatal Intensive Care Unit Network Neurobehavioral Scale in 1129 1-month-old infants with prenatal substance exposure. Four groups were compared: infants with prenatal cocaine and opiate exposure, infants with cocaine exposure, infants with opiate exposure, and infants with exposure to other substances (ie, alcohol, marijuana, and tobacco). RESULTS: The infants with prenatal exposure to both cocaine and opiates had the highest heart rates and lowest levels of respiratory sinus arrhythmia during a sustained visual attention challenge compared with the other 3 groups. Infants with prenatal cocaine and opiate exposure had poorer quality of movement and more hypertonicity during the Neonatal Intensive Care Unit Network Neurobehavioral Scale examination. They also had more nonoptimal reflexes and stress/abstinence signs compared with infants with prenatal exposure to cocaine only and those with prenatal exposure to alcohol, tobacco, and marijuana. CONCLUSION: Problems with arousal regulation were identified in infants with prenatal substance exposure. Autonomic dysregulation has been implicated as a mechanism by which these difficulties occur. Our results suggest that infants with prenatal exposure to both cocaine and opiates have the greatest autonomic response to the challenge of a sustained visual attention task, possibly putting these infants at risk for problems associated with physiologic and behavioral regulation, a necessary prerequisite for early learning.

Targeting 2.5 versus 4 g/kg/day of amino acids for extremely low birth weight infants: a randomized clinical trial.

OBJECTIVE: To compare the effect of 2.5 vs 4 g/kg/d of amino acid (AA) in parenteral nutrition of extremely low birth weight infants on metabolic tolerance, short-term growth, and neurodevelopment. STUDY DESIGN: One hundred thirty-one infants with birth weight between 500 and 1249 g were randomized to 2.5 (standard AA [SAA] group) or 4 (high AA [HAA] group) g/kg/d AA intake, with equal nonprotein energy. The primary outcome was body size at 36 weeks. RESULTS: One hundred thirty-one patients were randomized and 114 analyzed (58 SAA group and 56 HAA group). Study groups had similar demographics and clinical characteristics. Elevated blood urea (BU >70 mg/dL = BU nitrogen >32.6 mg/dL) occurred in 24% vs 59% (P = .000) and hyperglycemia (>175 mg/dL) in 34% vs 11% (P = .003) of the SAA and HAA patients, respectively. Body weight, length, and head circumference at 36 weeks and 2 years were similar between groups. Bayley Scales of Infant and Toddler Development, Third Edition score was 94 ± 13 in the SAA group and 97 ± 15 in the HAA group (P = .35). CONCLUSIONS: The HAA group had higher BU levels and better glucose control. An extra 8 g/kg of AA over the first 10 days of life did not improve growth and neurodevelopment.

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.

[Decreased Serum Copper Concentrations by Zinc Administration in Preterm Infants with Hypozincemia Are Associated with a Lower Postmenstrual Age: A Single-center Retrospective Observational Study].

Copper is one of the essential trace elements in humans, and its deficiency causes various diseases. Zinc acetate dihydrate is administered to treat hypozincemia in preterm infants; however, zinc inhibits the gastrointestinal absorption of copper, which may cause copper deficiency. To safely treat hypozincemia in preterm infants, we retrospectively analyzed the factors reducing serum copper concentrations when zinc is administered to preterm infants with hypozincemia. Seventy preterm infants were included in the present study. Serum zinc and copper concentrations, doses, and other clinical characteristics were retrieved from electronic medical records. The administration of zinc acetate dihydrate decreased serum copper concentrations in 21 out of 70 patients. In comparisons between the two groups with and without a decrease in serum copper concentrations, significant differences were observed in postmenstrual age (34.9 and 35.9 weeks, respectively) and serum zinc concentrations (62.0 and 58.0 µg/dL, respectively) at the start of the zinc acetate dihydrate treatment. A logistic regression analysis identified postmenstrual age as a significant factor decreasing serum copper concentrations. In the ROC curve, the cut-off value for postmenstrual age for a decrease in serum copper concentrations was 34.143 weeks. The present results suggest that when zinc acetate dihydrate is administered to preterm infants with a low postmenstrual age who are at higher risk of decreased serum copper concentrations, particularly to those with a postmenstrual age <34 weeks, it is important to consider copper deficiency and periodically measure serum copper concentrations.

Impact of Illness Severity and Interventions on Successful Weaning from Nasal CPAP in Very Preterm Neonates: An Observational Study.

This study aims to identify clinical variables that could affect successful weaning from nasal continuous positive airway pressure (NCPAP) in very preterm infants. Infants born at a gestational age (GA) of <32 weeks were retrospectively enrolled. Weaning from NCPAP was initiated when the infants were clinically stable. In the univariate analysis, GA, birth weight, body weight (BW) z-score at the time of successful NCPAP weaning, intubation, total duration of intubation, respiratory distress syndrome grade, APGAR score at the 1 and 5 min, initial shock, anemia, bronchopulmonary dysplasia, number of blood transfusions, total duration of dopamine use, administration of more than two doses of surfactant, use of aminophylline, use of a diuretic, and total duration of total parenteral nutrition were significantly associated with postmenstrual age (PMA) at the time of successful NCPAP weaning. Multivariate analysis showed that the total duration of intubation, bronchopulmonary dysplasia, and administration of more than two doses of surfactant were positively associated with PMA at the time of successful NCPAP weaning. A reverse association was noted between BW z-score and PMA at the time of successful NCPAP weaning. Sufficient nutrition and avoidance of further ventilator-induced lung injury could decrease NCPAP duration in very preterm infants.

Postnatal administration of systemic steroids increases severity of retinopathy in premature infants.

BACKGROUND: Postnatal systemic steroids are known to increase the risk of developing retinopathy of prematurity (ROP). However, whether the total dosage and type of postnatal systemic steroids are related to the development and severity of ROP in premature infants remains unclear. This study was conducted to identify the risk factors for ROP and investigate the relationship between photocoagulation (PC)-demanding severe ROP and the postnatal dosage of any type of systemic steroids. METHODS: A total of 75 infants born at <28 weeks of postmenstrual age (PMA) were enrolled. The number of PC procedures for ROP was evaluated as the objective variable. This study analyzed the following independent variables: gestational age; birth weight; sex; Apgar scores; duration of mechanical ventilation; duration of nasal intermittent positive pressure ventilation; mean saturation and mean oxygen concentration administration until 36 weeks of PMA; total accumulation dosage of hydrocortisone, dexamethasone, and systemic steroids; dosage number of times of erythropoietin; total dosage of red cell concentrates (RCC); incidence of necrotizing enterocolitis (NEC) and focal intestinal perforation; sepsis; bronchopulmonary dysplasia (BPD); and intraventricular hemorrhage (IVH). Logistic regression was used to estimate the relative risk (odds ratio (OR)) associated with risk factors for PC-demanding severe ROP. RESULTS: Compared with infants in the non-PC group, PC-treated infants had younger gestational age, longer mechanical ventilation periods, and higher dosage of systemic steroids and dexamethasone. Multivariate logistic regression analysis revealed total dosage of systemic steroids as the only risk factor for PC-demanding severe ROP. Based on receiver operating characteristic (ROC) curve analysis, a cutoff value of 8.95 mg/kg of postnatal systemic steroid administration was identified as a useful marker to predict PC-demanding severe ROP. CONCLUSION: By focusing on the method of systemic steroid administration and avoiding excessive doses for infants born at <28 weeks of PMA, preventing the development of severe ROP is possible.

Sex-Specific Long-Term Trends in Length of Hospital Stay, Postmenstrual Age at Discharge, and Survival in Very Low Birth Weight Infants.

INTRODUCTION: In very low birth weight (<1,500 g, VLBW) infants, morbidity and mortality have decreased substantially during the past decades, and both are known to be lower in girls than in boys. In this study, we assessed sex-specific changes over time in length of hospital stay (LOHS) and postmenstrual age at discharge (PAD), in addition to survival in VLBW infants. METHODS: This is a single-center retrospective cohort analysis based on quality assurance data of VLBW infants born from 1978 to 2018. Estimation of sex-specific LOHS over time was based on infants discharged home from neonatal care or deceased. Estimation of sex-specific PAD over time was based on infants discharged home exclusively. Analysis of in-hospital survival was performed for all VLBW infants. RESULTS: In 4,336 of 4,499 VLBW infants admitted from 1978 to 2018 with complete data (96.4%), survival rates improved between 1978-1982 and 1993-1997 (70.8 vs. 88.3%; hazard ratio (HR) 0.20, 95% confidence interval 0.14, 0.30) and remained stable thereafter. Boys had consistently higher mortality rates than girls (15 vs. 12%, HR 1.23 [1.05, 1.45]). Nonsurviving boys died later compared to nonsurviving girls (adjusted mean survival time 23.0 [18.0, 27.9] vs. 20.7 [15.0, 26.3] days). LOHS and PAD assessed in 3,166 survivors displayed a continuous decrease over time (1978-1982 vs. 2013-2018: LOHS days 82.9 [79.3, 86.5] vs. 60.3 [58.4, 62.1] days); PAD 40.4 (39.9, 40.9) vs. 37.4 [37.1, 37.6] weeks). Girls had shorter LOHS than boys (69.4 [68.0, 70.8] vs. 73.0 [71.6, 74.4] days) and were discharged with lower PAD (38.6 [38.4, 38.8] vs. 39.2 [39.0, 39.4] weeks). DISCUSSION/CONCLUSIONS: LOHS and PAD decreased over the last 40 years, while survival rates improved. Male sex was associated with longer LOHS, higher PAD, and higher mortality rates.