Reducing umbilical catheter migration rates by using a novel securement device.

OBJECTIVE: This study evaluates the effectiveness of a novel device, LifeBubble, in reducing umbilical cord catheter (UC) migration and associated complications in neonates. STUDY DESIGN: A retrospective review was performed at Oregon Health & Science University's NICU (2019-2021) to compare standard adhesive securement with LifeBubble. The primary outcomes were UC migration, discontinuation due to malposition, and CLABSI incidence. Differences between groups were statistically analyzed and logistic regression used to adjust for potential confounders. RESULTS: Among 118 neonates (57 LifeBubble, 61 adhesive), LifeBubble significantly reduced migration of any UC > 1 vertebral body (12.3% vs. 55.7%), including UVC migration (5.3% vs. 39.3%) and UAC migration (7.0% vs 23.0%), as well as UVC discontinuation due to malposition (5.6% vs 37.7%). The number needed to treat (NNT) to prevent one instance of UVC discontinuation is 4. CONCLUSION: LifeBubble effectively reduces UC migration and premature discontinuation, indicating its potential to enhance neonatal care and safety.

Oxygenation Fluctuations Associated with Severe Retinopathy of Prematurity: Insights from a Multimodal Deep Learning Approach.

Purpose: Retinopathy of prematurity (ROP) is one of the leading causes of blindness in children. Although the role of oxygen in the pathophysiology of ROP is well established, a precise understanding of the dynamic relationship between oxygen exposure ROP incidence and severity is lacking. The purpose of this study was to evaluate the correlation between time-dependent oxygen variables and the onset of ROP. Design: Retrospective cohort study. Participants: Two hundred thirty infants who were born at a single academic center and met the inclusion criteria were included. Infants are mainly born between January 2011 and October 2022. Methods: Patient data were extracted from electronic health records (EHRs), with sufficient time-dependent oxygen data. Clinical outcomes for ROP were recorded as none/mild or moderate/severe (defined as type II or worse). Mixed-effects linear models were used to compare the 2 groups in terms of dynamic oxygen variables, such as daily average and the coefficient of variation (COV) fraction of inspired oxygen (FiO2). Support vector machine (SVM) and long-short-term memory (LSTM)-based multimodal models were trained with fivefold cross-validation to predict which infants would develop moderate/severe ROP. Gestational age (GA), birth weight, and time-dependent oxygen variables were used to develop predictive models. Main Outcome Measures: Model cross-validation performance was evaluated by computing the mean area under the receiver operating characteristic (AUROC) curve, precision, recall, and F1 score. Results: We found that both daily average and COV of FiO2 were associated with more severe ROP (adjusted P < 0.001). With fivefold cross-validation, the multimodal LSTM models had higher performance than the best static models (SVM using GA and 3 average FiO2 features) and SVM models trained on GA alone (mean AUROC = 0.89 ± 0.04 vs. 0.86 ± 0.05 vs. 0.83 ± 0.04). Conclusions: The development of severe ROP might not only be influenced by oxygen exposure but also by its fluctuation, which provides direction for future study of pathophysiological factors associated with severe ROP development. Additionally, we demonstrated that multimodal neural networks can be a method to extract useful information from time-series data, which may be a valuable methodology for the investigation of other diseases using EHR data. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Carnitine-Acylcarnitine Translocase Deficiency Masked by Extreme Prematurity.

Carnitine-acylcarnitine translocase (CACT) deficiency is a rare disorder of long chain fatty acid oxidation with a very high mortality rate due to cardiomyopathy or multiorgan failure. We present the course of a very premature infant with early onset CACT deficiency complicated by multiple episodes of necrotizing enterocolitis, sepsis, and liver insufficiency, followed by eventual demise. The complications of prematurity, potentiated by the overlay of CACT deficiency, contributed to the difficulty of reaching the ultimate diagnosis of CACT deficiency.

Premature monochorionic monoamniotic twins have lower lung compliance at birth than matched dichorionic diamniotic twins.

BACKGROUND: Premature infants are born with immature lungs that demonstrate abnormal pulmonary function with differences in passive respiratory system compliance and resistance, and functional residual capacity. To our knowledge, no studies have evaluated differences in neonatal pulmonary function based on the type of twin gestation, or chorionicity. Given the effect of chorionicity on outcomes, we aimed to study the effect of twin type, monochorionic monoamniotic (MCMA) vs dichorionic diamniotic (DCDA), on neonatal early pulmonary function tests. METHODS: In this prospective cohort study, 5 sets of DCDA twins were matched to 5 sets of MCMA twins on gestational age at delivery, latency from antenatal corticosteroid exposure, birthweight, race and gender. Mean values were compared for passive respiratory system compliance and resistance, functional residual capacity, and tidal volume. RESULTS: MCMA infants had a significantly lower compliance (0.64 vs 1.25 mL/cm H2O /kg; p = 0.0001) and significantly higher resistance (0.130 vs 0.087 cm H2O /mL/sec; p = 0.0003) than DCDA infants. Functional residual capacity was lower for MCMA than DCDA infants (17.5 vs 23.4 mL/kg; p = 0.17). Further, 80% of MCMA infants required intubation for surfactant administration compared to 20% of DCDA infants, indicating the clinical significance of these objective measures. CONCLUSIONS: Due to the matched case-control design, causality cannot be established. However, we speculate that these differences in lung function may derive from differential exposure to preterm labor and endogenous maternal corticosteroid exposure. Further study is necessary to establish the true causal relationship.

Perioperative Improvement in Pulmonary Function in Infants with Congenital Diaphragmatic Hernia.

OBJECTIVE: The objective of this study was to compare serial changes in pulmonary function in contemporary infants with congenital diaphragmatic hernia managed with a gentle ventilation approach. STUDY DESIGN: Observational cohort, single-center study of infants ≥350/7 weeks gestation at delivery with congenital diaphragmatic hernia. Functional residual capacity (FRC), passive respiratory compliance, and passive respiratory resistance were measured presurgical and postsurgical repair and within 2 weeks of discharge. A 1-way analysis of variance for repeated measures was used to evaluate the change in FRC, passive respiratory compliance, and passive respiratory resistance over these repeated measures. RESULTS: Twenty-eight infants were included in the analysis with a mean gestational age of 38.3 weeks and birth weight of 3139 g. We found a significant increase in FRC across the 3 time points (mean in mL/kg [SD]: 10.9 [3.6] to 18.5 [5.2] to 24.2 [4.4]; P < .0001). There was also a significant increase in passive respiratory compliance and decrease in passive respiratory resistance. In contrast to a previous report, there were survivors in the current cohort with a preoperative FRC of <9 mL/kg. The mean FRC measured at discharge was in the range considered within normal limits. Sixteen infants had prenatal measurements of the lung-to-head ratio, but there was no relationship between the lung-to-head ratio and preoperative or postoperative FRC measurements. CONCLUSIONS: Infants with congenital diaphragmatic hernia demonstrate significant increases in FRC and improvements in respiratory mechanics measured preoperatively and postoperatively and at discharge. We speculate these improvements are due to the surgical resolution of the mechanical obstruction to lung recruitment and that after achieving preoperative stability, repair should not be delayed given these demonstrable postoperative improvements.

Let's Talk about Dex: When do the Benefits of Dexamethasone for Prevention of Bronchopulmonary Dysplasia Outweigh the Risks?

Bronchopulmonary dysplasia (BPD) is the most common complication of extreme prematurity and carries increased respiratory morbidity into childhood and adulthood. Systemic administration of dexamethasone during the preterm period has been shown to decrease the incidence of BPD in this population. However, enthusiasm about its use has been tempered by early evidence that suggested potential adverse neurodevelopmental outcomes. More recent studies suggest that the timing, dosing, and duration of therapy may have a significant impact on the safety and efficacy of dexamethasone administration and that side effects and harms may be minimized if its use is appropriately targeted. Focusing on studies published since the 2010s American Academy of Pediatrics (AAP) statement on dexamethasone, this review seeks to examine the evidence from recent clinical trials to present the current state of knowledge regarding the systemic dexamethasone administration to prevent BPD in extremely premature infants and how dose, duration, and timing might impact its safety and efficacy in this vulnerable population.

Bifidobacteriumlongum subsp. infantis EVC001 Administration Is Associated with a Significant Reduction in the Incidence of Necrotizing Enterocolitis in Very Low Birth Weight Infants.

OBJECTIVE: To assess the effects of Bifidobacteriumlongum subsp. infantis EVC001 (Binfantis EVC001) administration on the incidence of necrotizing enterocolitis (NEC) in preterm infants in a single level IV neonatal intensive care unit (NICU). STUDY DESIGN: Nonconcurrent retrospective analysis of 2 cohorts of very low birth weight (VLBW) infants not exposed and exposed to Binfantis EVC001 probiotic at Oregon Health & Science University from 2014 to 2020. Outcomes included NEC incidence and NEC-associated mortality, including subgroup analysis of extremely low birth weight (ELBW) infants. Log-binomial regression models were used to compare the incidence and risk of NEC-associated outcomes between the unexposed and exposed cohorts. RESULTS: The cumulative incidence of NEC diagnoses decreased from 11.0% (n = 301) in the no EVC001 (unexposed) cohort to 2.7% (n = 182) in the EVC001 (exposed) cohort (P < .01). The EVC001 cohort had a 73% risk reduction of NEC compared with the no EVC001 cohort (adjusted risk ratio, 0.27; 95% CI, 0.094-0.614; P < .01) resulting in an adjusted number needed to treat of 13 (95% CI, 10.0-23.5) for Binfantis EVC001. NEC-associated mortality decreased from 2.7% in the no EVC001 cohort to 0% in the EVC001 cohort (P = .03). There were similar reductions in NEC incidence and risk for ELBW infants (19.2% vs 5.3% [P < .01]; adjusted risk ratio, 0.28; 95% CI, 0.085-0.698 [P = .02]) and mortality (5.6% vs 0%; P < .05) in the 2 cohorts. CONCLUSIONS: In this observational study of 483 VLBW infants, Binfantis EVC001 administration was associated with significant reductions in the risk of NEC and NEC-related mortality. Binfantis EVC001 supplementation may be considered safe and effective for reducing morbidity and mortality in the NICU.

Single-Examination Risk Prediction of Severe Retinopathy of Prematurity.

BACKGROUND AND OBJECTIVES: Retinopathy of prematurity (ROP) is a leading cause of childhood blindness. Screening and treatment reduces this risk, but requires multiple examinations of infants, most of whom will not develop severe disease. Previous work has suggested that artificial intelligence may be able to detect incident severe disease (treatment-requiring retinopathy of prematurity [TR-ROP]) before clinical diagnosis. We aimed to build a risk model that combined artificial intelligence with clinical demographics to reduce the number of examinations without missing cases of TR-ROP. METHODS: Infants undergoing routine ROP screening examinations (1579 total eyes, 190 with TR-ROP) were recruited from 8 North American study centers. A vascular severity score (VSS) was derived from retinal fundus images obtained at 32 to 33 weeks' postmenstrual age. Seven ElasticNet logistic regression models were trained on all combinations of birth weight, gestational age, and VSS. The area under the precision-recall curve was used to identify the highest-performing model. RESULTS: The gestational age + VSS model had the highest performance (mean ± SD area under the precision-recall curve: 0.35 ± 0.11). On 2 different test data sets (n = 444 and n = 132), sensitivity was 100% (positive predictive value: 28.1% and 22.6%) and specificity was 48.9% and 80.8% (negative predictive value: 100.0%). CONCLUSIONS: Using a single examination, this model identified all infants who developed TR-ROP, on average, >1 month before diagnosis with moderate to high specificity. This approach could lead to earlier identification of incident severe ROP, reducing late diagnosis and treatment while simultaneously reducing the number of ROP examinations and unnecessary physiologic stress for low-risk infants.

Quantification of Early Neonatal Oxygen Exposure as a Risk Factor for Retinopathy of Prematurity Requiring Treatment.

Purpose: Retinopathy of prematurity (ROP) is a leading cause of childhood blindness related to oxygen exposure in premature infants. Since oxygen monitoring protocols have reduced the incidence of treatment-requiring ROP (TR-ROP), it remains unclear whether oxygen exposure remains a relevant risk factor for incident TR-ROP and aggressive ROP (A-ROP), a severe, rapidly progressing form of ROP. The purpose of this proof-of-concept study was to use electronic health record (EHR) data to evaluate early oxygen exposure as a predictive variable for developing TR-ROP and A-ROP. Design: Retrospective cohort study. Participants: Two hundred forty-four infants screened for ROP at a single academic center. Methods: For each infant, oxygen saturations and fraction of inspired oxygen (FiO2) were extracted manually from the EHR until 31 weeks postmenstrual age (PMA). Cumulative minimum, maximum, and mean oxygen saturation and FiO2 were calculated on a weekly basis. Random forest models were trained with 5-fold cross-validation using gestational age (GA) and cumulative minimum FiO2 at 30 weeks PMA to identify infants who developed TR-ROP. Secondary receiver operating characteristic (ROC) curve analysis of infants with or without A-ROP was performed without cross-validation because of small numbers. Main Outcome Measures: For each model, cross-validation performance for incident TR-ROP was assessed using area under the ROC curve (AUC) and area under the precision-recall curve (AUPRC) scores. For A-ROP, we calculated AUC and evaluated sensitivity and specificity at a high-sensitivity operating point. Results: Of the 244 infants included, 33 developed TR-ROP, of which 5 developed A-ROP. For incident TR-ROP, random forest models trained on GA plus cumulative minimum FiO2 (AUC = 0.93 ± 0.06; AUPRC = 0.76 ± 0.08) were not significantly better than models trained on GA alone (AUC = 0.92 ± 0.06 [P = 0.59]; AUPRC = 0.74 ± 0.12 [P = 0.32]). Models using oxygen alone showed an AUC of 0.80 ± 0.09. ROC analysis for A-ROP found an AUC of 0.92 (95% confidence interval, 0.87-0.96). Conclusions: Oxygen exposure can be extracted from the EHR and quantified as a risk factor for incident TR-ROP and A-ROP. Extracting quantifiable clinical features from the EHR may be useful for building risk models for multiple diseases and evaluating the complex relationships among oxygen exposure, ROP, and other sequelae of prematurity.

Trajectories of Lung Function in Infants and Children: Setting a Course for Lifelong Lung Health.

For healthy individuals, it is increasingly accepted that lung function follows along an individual percentile established early in life and that the level of maximal function reached as a young adult can affect the subsequent development of lung disease that occurs with the normal aging process. This emphasizes the need to maximize early lung function. The trajectories of lung function are at least partially established by perinatal factors, including prematurity and in utero exposures (tobacco exposure, nutrition, inflammation, etc), although they can also be affected by a variety of additional factors and exposures throughout the life span. Whether lung function trajectories can be impacted or reset if established under suboptimal conditions is an unanswered question, offering new avenues for research. In this review, we will summarize important articles outlining lung function trajectories and linking pediatric lung function tests to adult lung function tests decades later. We will focus on perinatal factors and outline progress and opportunities for further investigation into the potential ability to reset trajectories to impact long-term lung health.

The window of improved neonatal respiratory compliance after rescue antenatal steroids.

OBJECTIVE: To evaluate whether premature infants delivered ≤7 days after rescue antenatal steroid treatment (ideal treatment) have increased passive respiratory compliance compared to those delivered >7 days after treatment (remote treatment). METHODS: Secondary analysis of a randomized trial of rescue antenatal steroids on respiratory compliance. Infants in the treatment group were stratified by the interval between rescue antenatal steroids and delivery. We then compared the respiratory compliance in the ideal vs. remote groups. RESULTS: Forty-four women (56 infants) received rescue antenatal steroids. Forty-nine infants had evaluable respiratory compliance measurements, with 27 (GA 30.1 weeks, BW 1362 g) "ideally" treated, and 22 (GA 33.8 weeks, BW 2248 g) "remotely" treated. Respiratory compliance was significantly higher for the ideal compared to the remote group (1.32 vs. 1.06 mL/cm H2O/kg; p = 0.037). CONCLUSION: Infants treated with rescue antenatal steroids have a significantly higher respiratory compliance if delivery occurs within 7 days after treatment.

Pulmonary Function at Hospital Discharge in Preterm Infants Randomized to a Single Rescue Course of Antenatal Steroids.

OBJECTIVE: To compare the pulmonary function, measured at birth and at hospital discharge, of infants whose mothers had been randomized to a single rescue course of antenatal steroids versus those whose mothers had been randomized to placebo. STUDY DESIGN: This study involved follow-up at hospital discharge of subjects of a randomized, double-blinded trial. In the original trial, pregnant women at ≥14 days after their initial course of antenatal steroids and <34 weeks' gestation were randomized to rescue antenatal steroids (44 mothers, 56 infants) or placebo (41 mothers, 57 infants). Passive respiratory compliance (Crs), passive respiratory resistance, and functional residual capacity were measured in all infants at birth and again at discharge to evaluate changes in pulmonary mechanics over time. Statistical analyses were based on intention to treat. RESULTS: We previously reported that compared with infants in the placebo group, infants in the rescue antenatal steroids group had a higher mean Crs value measured within 72 hours of birth (1.21 vs 1.01 mL/cm H2O/kg; P < .05). Here we show that the Crs benefit in the antenatal steroids group was sustained until discharge. Infants in the placebo group demonstrated improvement in Crs such that by discharge, there was no difference in mean Crs between the rescue antenatal steroids and placebo groups (1.18 vs 1.22 mL/cm H2O/kg). CONCLUSIONS: Rescue antenatal steroids significantly increased Crs measured within 72 hours of birth, and this increase was sustained until hospital discharge. Preterm infants in the placebo group demonstrated a decreased initial Crs compared with the rescue antenatal steroids group, but achieved a comparable Crs by the time of discharge. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00669383.

Relationship between acute kidney injury and brain MRI findings in asphyxiated newborns after therapeutic hypothermia.

BACKGROUND: We hypothesized that acute kidney injury (AKI) in asphyxiated neonates treated with therapeutic hypothermia would be associated with hypoxic-ischemic lesions on brain magnetic resonance imaging (MRI). METHODS: Medical records of 88 cooled neonates who had had brain MRI were reviewed. All neonates had serum creatinine assessed before the start of cooling; at 24, 48, and 72 h through cooling; and then on day 5 or 7 of life. A neonatal modification of the Kidney Disease: Improving Global Outcomes guidelines was used to classify AKI. MRI images were evaluated by a neuroradiologist masked to outcomes. Outcome of interest was abnormal brain MRI at 7-10 d of life. RESULTS: AKI was found in 34 (39%) of 88 neonates, with 15, 7, and 12 fulfilling criteria for stages 1, 2, and 3, respectively. Brain MRI abnormalities related to hypoxia-ischemia were present in 50 (59%) newborns. Abnormal MRI was more frequent in infants from the AKI group (AKI: 25 of 34, 73% vs. no AKI: 25 of 54, 46%; P = 0.012; odds ratio (OR) = 3.2; 95% confidence interval (CI) = 1.3-8.2). Multivariate analysis identified AKI (OR = 2.9; 95% CI = 1.1-7.6) to be independently associated with the primary outcome. CONCLUSION: AKI is independently associated with the presence of hypoxic-ischemic lesions on postcooling brain MRI.

Lucinactant for the prevention of respiratory distress syndrome in premature infants.

Respiratory distress syndrome (RDS) is the leading cause of neonatal morbidity and mortality in premature infants. It is caused by surfactant deficiency and lung immaturity. Lucinactant is a synthetic surfactant containing sinapultide, a bioengineered peptide mimic of surfactant-associated protein B. A meta-analysis of clinical trials demonstrates that lucinactant is as effective as animal-derived surfactants in preventing RDS in premature neonates, and in vitro studies suggest it is more resistant to oxidative and protein-induced inactivation. Its synthetic origin confers lower infection and inflammation risks as well other potential benefits, which may make lucinactant an advantageous alternative to its animal-derived counterparts, which are presently the standard treatment for RDS.

Acute kidney injury in asphyxiated newborns treated with therapeutic hypothermia.

OBJECTIVE: To test the hypothesis that acute kidney injury (AKI) would be independently associated with increased morbidity and mortality. STUDY DESIGN: A total of 96 consecutively cooled infants were reviewed retrospectively. Modified Acute Kidney Injury Network criteria were used to classify AKI based on absolute rise in serum creatinine (SCr) level from a previous trough (stage I, rise in SCr of 0.3 mg/dL or SCr 150-<200%; stage II, rise in SCr of 200-<300%; stage III, rise in SCr of ≥300%, SCr 2.5 mg/dL, or dialysis). Outcomes were mortality, duration of neonatal intensive care unit (NICU) stay, and duration of mechanical ventilation. RESULTS: AKI occurred in 36 of 96 infants (38%). Overall mortality was 7% and was higher for those with AKI, with the difference approaching statistical significance (14% vs 3% in those without AKI; P = .099). Patients with AKI stayed longer in the NICU (mean, 15.4 ± 9.3 days vs 11 ± 5.9 days; P = .014) and required prolonged mechanical ventilation (mean, 9.7 ± 5.9 days vs 4.8 ± 3.7 days; P < .001). On multivariate analysis, AKI remained predictive of prolonged duration of mechanical ventilation and prolonged NICU stay. CONCLUSION: We used the Acute Kidney Injury Network definition for AKI in asphyxiated newborns undergoing therapeutic hypothermia to demonstrate that the incidence of AKI remains high, but lower than rates published before the advent of therapeutic hypothermia. We highlight the importance of recognizing AKI in asphyxiated newborns undergoing therapeutic hypothermia, along with the potential benefits of early recognition.

Wnt4 overexpression disrupts normal testicular vasculature and inhibits testosterone synthesis by repressing steroidogenic factor 1/beta-catenin synergy.

Genetic studies in mice suggest that Wnt4 signaling antagonizes expression of male hormones and effectively blocks male development in the female embryo. We recently identified an XY intersex patient carrying a chromosomal duplication of the WNT4 locus and proposed that this patient's feminization arises from an increased dosage of WNT4. To test this hypothesis, a transgenic mouse was generated with a large genomic P1 containing the human WNT4. Although a complete male to female intersex phenotype was not observed in WNT4 transgenic male mice, a dramatic reduction in steroidogenic acute regulatory protein was detected consistent with the marked reduction in serum and testicular androgen levels. Furthermore, a mild reduction of germ cells and a disorganized vascular system were observed in testes of WNT4 transgenic males. Consistent with these in vivo data, Wnt4 repressed steroidogenesis in adrenocortical and Leydig cell lines, as evidenced by reduced progesterone secretion and 3beta-hydroxysteroid dehydrogenase activity. In vitro studies showed that Wnt4 antagonizes the functional synergy observed between the major effector of the Wnt signaling pathway, beta-catenin and steroidogenic factor 1, and chromatin immunoprecipitation showed that Wnt4 attenuates recruitment of beta-catenin to the steroidogenic acute regulatory protein promoter. Our findings suggest a model in which Wnt4 acts as an anti-male factor by disrupting recruitment of beta-catenin at or near steroidogenic factor 1 binding sites present in multiple steroidogenic genes.

Familial mutation in the testis-determining gene SRY shared by an XY female and her normal father.

In humans, mutations in the testis-determining gene SRY result in XY sex reversal with pure gonadal dysgenesis (PGD). However, only about 10-15% of the cases of PGD can be explained by mutations within the SRY open reading frame, suggesting the existence of other sex-determining genes. Although SRY is known to bind and bend DNA, its target and mode of action remain elusive. Here, we describe a novel mutation in SRY at codon 127, resulting in a tyrosine (Y) to phenylalanine (F) substitution in the protein. This sequence variant was found not only in the XY female patient but also in her father, who is a phenotypically normal male. However, this Y127F variant was not found in the SRY sequences of 93 other randomly chosen males. This substitution affects a highly conserved tyrosine residue in the HMG box of SRY, in which two de novo mutations have been described previously in XY females with PGD. Furthermore, electromobility shift studies demonstrate that SRY protein harboring the Y127F variant is incapable of binding consensus SRY binding sites in vitro. Taken together, these data suggest that the Y127F variant is a novel mutation with functional consequences and not simply a polymorphism. The allelic variant of SRY transmitted in this family and shared by both a phenotypic female (proband) and a phenotypic male (proband's father) emphasizes the importance of modifier genes in the sex determination pathway.