The impact of exclusive human milk diet on short-term growth of very preterm infants.

OBJECTIVES: The impact of exclusive human milk diet (EHMD) on postnatal growth remains controversial. This study aims to investigate the association between EHMD and short-term growth. METHODS: This multicenter retrospective study aims to compare growth between the EHMD and non-EHMD groups among infants <32 weeks of gestation. Primary outcomes include weight, length, and head circumference growth trajectories between birth and 34 weeks postmenstrual age. Sensitivity and subgroup analyses were performed. RESULTS: An EHMD was independently associated with poorer length growth, especially in infants born at ≥28 weeks' gestation or those exposed to hypertensive disorders of pregnancy. While initiating fortification at <26 kcal/oz on an EHMD showed inferior growth, initiating fortification at ≥26 kcal/oz was associated with improved weight growth, and similar length and head circumference growth when compared to the non-EHMD group. CONCLUSIONS: An EHMD with initial fortification at ≥26 kcal/oz may be implemented to avoid bovine milk exposure while sustaining comparable growth.

Perceptions and impact of patient reviews: a survey of academic dermatologists.

BACKGROUND: Patient reviews (PRs) have emerged as a method to assess patient experiences with healthcare in order to improve the quality of care. Both institutional and third-party organizations collect quantitative data and comments from these patient surveys, usually accessible to the public for review. Our study examined dermatologists' perceptions of PRs and assessed their impact on dermatologists. METHODS: A survey was sent to the Association of Professors of Dermatology listserv (response rate 30%). RESULTS: Most respondents disagreed with the statements that PRs are good for doctors (63%), good for patients (58%), helpful for doctors (58%), or that high PRs indicate being a good doctor (65%). The majority disagreed that PRs should be available publicly (60%). Respondents agreed that PRs contribute to depersonalization (60%), energy depletion or exhaustion (55%), added stress at work (70%), negativism/cynicism about work (60%), and diminished professional efficacy (29%). Self-identified female respondents were more likely to agree that PRs added stress to work compared to self-identified males (66% vs. 42%, P < 0.05). CONCLUSIONS: Overall, these findings suggest that PRs may negatively impact dermatologists' well-being and perceived stress levels.

The association between antenatal corticosteroids exposure and postnatal growth in infants born between 23 and 29 weeks of gestation.

OBJECTIVE: To assess the association between antenatal corticosteroids exposure and postnatal growth in infants born at 23-29 weeks' gestation. STUDY DESIGN: This retrospective study used data from the Pediatrix Clinical Data Warehouse. Maternal-infant dyads from 2018 to 2020 were included. Inverse propensity weighting (IPW) was applied to balance pre-treatment confounders. Primary outcomes included postnatal weight, length, and head circumference growth trajectory percentiles. RESULT: The unadjusted cohort consisted of 11,912 dyads. After IPW adjustment, there were 23,231 dyads. Exposed infants showed higher postnatal trajectory percentiles for weight (by 3.4%), length (by 1.8%), and head circumference (by 2.5%) when compared to non-exposed infants. The positive association between antenatal corticosteroids and postnatal growth was only observed in infants not exposed to preeclampsia/eclampsia/HELLP syndrome or without fetal growth restriction. CONCLUSION: Antenatal corticosteroids exposure is associated with better postnatal growth. The study is limited by its retrospective nature.

When the Unknown Is Unknowable: Confronting Diagnostic Uncertainty.

The neonatology literature often refers to medical uncertainty and specifically the challenges of predicting morbidity for extremely premature infants, who can have widely varying outcomes. Less has been written about situations in which diagnoses are simply unknown or unattainable. This case highlights the importance of communication amidst uncertainty from a lack of knowledge about aspects of a patient's condition. Using epidemiologic and clinical reasoning, the authors challenge the assumption that diagnostic uncertainty must necessarily portend prognostic uncertainty. When physicians' quest for a diagnosis becomes burdensome and detrimental to the infant's quality of life, this should be abandoned and replaced by focusing on prognosis. The authors focus on the shift of the physician's role toward one of support, assisting the family in ascribing meaning to the dying experience. By focusing on prognosis and support, communication can proceed with more clarity, understanding, and empathy.

A comparative study of postnatal anthropometric growth in very preterm infants and intrauterine growth.

Most growth references for very preterm infants were developed using measurements taken at birth, and were thought to represent intrauterine growth. However, it remains unclear whether the goal of approximating an intrauterine growth rate as stated by the American Academy of Pediatrics is attainable by very preterm infants. Using real-world measurement data from very preterm infants born between 2010 through 2020, we develop models to characterize the patterns of postnatal growth, and compare them to intrauterine growth. By assessing the weight growth rate, we show three phases of postnatal growth not evident in intrauterine growth. Furthermore, postnatal length and head circumference growth exhibit a slow rate after birth, followed by an acceleration. Collectively, postnatal and intrauterine growth are distinctly different. Although postnatal growth models do not represent optimal growth of very preterm infants, they can serve as a practical tool for clinical assessment of growth and for nutrition research.

Comparison of Adverse Clinical Outcomes in Children Hospitalized for Myocarditis with and Without COVID-19.

We used a nationally representative database of the US, which included 1995 myocarditis cases, among whom 620 children had COVID-19. While the risk of in-hospital mortality was not higher, illness severity and length of hospital stay were higher in patients with myocarditis and COVID-19 than those without COVID-19.

Impact of congenital heart disease on outcomes among pediatric patients hospitalized for COVID-19 infection.

BACKGROUND: COVID-19 infection is generally regarded as an acute self-limiting illness in children, but it can cause significant morbidity and mortality in both healthy and high-risk children. There are limited data on the outcomes of children with congenital heart disease (CHD) and COVID-19. This study aimed to examine the risks of mortality, in-hospital cardiovascular and non-cardiovascular complications in this patient population. METHODS: We analyzed data from hospitalized pediatric patients from 2020 using the nationally representative National Inpatient Sample (NIS). Children hospitalized for COVID-19 were included, and weighted data were used to compare in-hospital mortality and morbidities between children with and without CHD. RESULTS: Out of 36,690 children admitted with a diagnosis of COVID-19 infection(ICD-10 code:U07.1 and B97.29) during calendar year 2020, 1240 (3.4%) had CHD. The risk of mortality in children with CHD was not significantly higher than those without CHD(1.2% vs. 0.8%, p = 0.50), with adjusted OR (aOR) of 1.7 (95% CI: 0.6-5.3). Tachyarrhythmias and heart block were more likely in CHD children with an aOR of 4.2 (95% CI: 1.8-9.9) and aOR of 5.0 (95% CI: 2.4-10.8), respectively. Similarly, respiratory failure [aOR = 2.0 (1.5-2.8)], respiratory failure requiring non-invasive mechanical ventilation [aOR = 2.7 (1.4-5.2)] and invasive mechanical ventilation [aOR = 2.6 (1.6-4.0)], and acute kidney injury [aOR = 3.4 (2.2-5.4)] were all significantly higher among patients with CHD. Median length of hospital stay in children with CHD was longer than those without CHD [5 days (IQR: 2-11) vs. 3 days (IQR: 2-5), p = < 0.001]. CONCLUSIONS: Children with CHD hospitalized with COVID-19 infection were at increased risk of serious cardiovascular and non-cardiovascular adverse clinical outcomes. They also had increased length of hospital stay and utilization of healthcare resources.

Oxygenation index in the first three weeks of life is a predictor of bronchopulmonary dysplasia grade in very preterm infants.

BACKGROUND: The new bronchopulmonary dysplasia (BPD) grading system was developed based on its correlation with long-term respiratory and neurodevelopmental outcomes and may provide better personalized prognostication. Identifying early-life predictors for accurate BPD grade prediction may allow interventions to be tailored to individual needs. This study aimed to assess whether oxygenation index (OI) dynamics in the first three weeks of life are a predictor of BPD grade. METHODS: A single-center retrospective study was performed. Generalized additive mixed modeling was used to model OI trajectories for each BPD grade subgroup. A multinomial regression model was then developed to quantify the association between OI dynamics and BPD grade. RESULTS: Two hundred fifty-four infants were identified for inclusion in the trajectory modeling. A total of 6,243 OI data points were available for modeling. OI trajectory estimates showed distinct patterns in the three groups, most prominent during the third week of life. The average daily OI change was -0.33 ± 0.52 (n = 85) in the No-BPD group, -0.04 ± 0.75 (n = 82) in the Low-Grade BPD group, and 0.22 ± 0.65 (n = 75) in the High-Grade BPD group (p < 0.001). A multinomial regression analysis showed the initial OI value and the average daily OI change both independently correlated with BPD grade outcomes after adjusting for birth gestation, birth weight z-score, sex, and the duration of invasive ventilation. CONCLUSION: Early-life OI dynamics may be a useful independent marker for BPD grade prediction. Prospective studies may be warranted to further validate the findings.

The association between bronchopulmonary dysplasia grade and risks of adverse neurodevelopmental outcomes among preterm infants born at less than 30 weeks of gestation.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is a multifactorial disease with neurodevelopmental implications. This study aims to quantify the risks of adverse neurodevelopmental outcomes for each BPD grade among preterm infants born at less than 30 weeks' gestation. METHODS: We retrospectively studied infants who received care in our institution until at least 36 weeks postmenstrual age and had a formal neurodevelopmental assessment in our infant follow-up clinic using the Bayley Scales for Infant and Toddler Development (BSID). We assessed the association between BPD grade and adverse neurodevelopmental outcomes using descriptive statistics and regression models. RESULTS: Two hundred and fifty infants, including 89 (35.6%), 87 (34.8%), 65 (20.6%), and 9 (3.6%) with No BPD, Grade 1, Grade 2, and Grade 3 BPD, were included in the study. Small for gestational age, late pulmonary hypertension, dexamethasone administration, and adverse neurodevelopmental outcomes were more common as BPD grade increased. In a logistic regression analysis, Grades 2 and 3, but not Grade 1, BPD were associated with increased odds of a composite adverse neurodevelopmental outcome by 2.7 and 7.2 folds, respectively. A BSID domain-specific analysis showed that higher grades were associated with lower scores in the cognitive, gross motor, and fine motor domains. CONCLUSIONS: Grades 2 and 3 BPD, but not Grade 1, correlate with risks of adverse neurodevelopmental outcomes at a grade-dependent manner in our single-center cohort retrospective study. Further validation using a multi-center large cohort is warranted.

Developing a machine learning-based tool to extend the usability of the NICHD BPD Outcome Estimator to the Asian population.

The NICHD BPD Outcome Estimator uses clinical and demographic data to stratify respiratory outcomes of extremely preterm infants by risk. However, the Estimator does not have an option in its pull-down menu for infants of Asian descent. We hypothesize that respiratory outcomes in extreme prematurity among various racial/ethnic groups are interconnected and therefore the Estimator can still be used to predict outcomes in infants of Asian descent. Our goal was to apply a machine learning approach to assess whether outcome prediction for infants of Asian descent is possible with information hidden in the prediction results using White, Black, and Hispanic racial/ethnic groups as surrogates. We used the three racial/ethnic options in the Estimator to obtain the probabilities of BPD outcomes for each severity category. We then combined the probability results and developed three respiratory outcome prediction models at various postmenstrual age (PMA) by a random forest algorithm. We showed satisfactory model performance, with receiver operating characteristics area under the curve of 0.934, 0.850, and 0.757 for respiratory outcomes at PMA 36, 37, and 40 weeks, respectively, in the testing data set. This study suggested an interrelationship among racial/ethnic groups for respiratory outcomes among extremely preterm infants and showed the feasibility of extending the use of the Estimator to the Asian population.

Machine learning for prediction of bronchopulmonary dysplasia-free survival among very preterm infants.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is one of the most common and serious sequelae of prematurity. Prompt diagnosis using prediction tools is crucial for early intervention and prevention of further adverse effects. This study aims to develop a BPD-free survival prediction tool based on the concept of the developmental origin of BPD with machine learning. METHODS: Datasets comprising perinatal factors and early postnatal respiratory support were used for initial model development, followed by combining the two models into a final ensemble model using logistic regression. Simulation of clinical scenarios was performed. RESULTS: Data from 689 infants were included in the study. We randomly selected data from 80% of infants for model development and used the remaining 20% for validation. The performance of the final model was assessed by receiver operating characteristics which showed 0.921 (95% CI: 0.899-0.943) and 0.899 (95% CI: 0.848-0.949) for the training and the validation datasets, respectively. Simulation data suggests that extubating to CPAP is superior to NIPPV in BPD-free survival. Additionally, successful extubation may be defined as no reintubation for 9 days following initial extubation. CONCLUSIONS: Machine learning-based BPD prediction based on perinatal features and respiratory data may have clinical applicability to promote early targeted intervention in high-risk infants.

Impaired Cell Cycle Progression and Self-Renewal of Fetal Neural Stem and Progenitor Cells in a Murine Model of Intrauterine Growth Restriction.

Individuals with intrauterine growth restriction (IUGR) are at an increased risk for neurodevelopmental impairment. Fetal cortical neurogenesis is a time-sensitive process in which fetal neural stem cells (NSCs) follow a distinct pattern of layer-specific neuron generation to populate the cerebral cortex. Here, we used a murine maternal hypoxia-induced IUGR model to study the impact of IUGR on fetal NSC development. In this model, timed-pregnant mice were exposed to hypoxia during the active stage of neurogenesis, followed by fetal brain collection and analysis. In the IUGR fetal brains, we found a significant reduction in cerebral cortical thickness accompanied by decreases in layer-specific neurons. Using EdU labeling, we demonstrated that cell cycle progression of fetal NSCs was delayed, primarily observed in the G2/M phase during inward interkinetic nuclear migration. Following relief from maternal hypoxia exposure, the remaining fetal NSCs re-established their neurogenic ability and resumed production of layer-specific neurons. Surprisingly, the newly generated neurons matched their control counterparts in layer-specific marker expression, suggesting preservation of the fetal NSC temporal identity despite IUGR effects. As expected, the absolute number of neurons generated in the IUGR group remained lower compared to that in the control group due to a reduced fetal NSC pool size as a result of cell cycle defect. Transcriptome analysis identified genes related to energy expenditure and G2/M cell cycle progression being affected by maternal hypoxia-induced IUGR. Taken together, maternal hypoxia-induced IUGR is associated with a defect in cell cycle progression of fetal NSCs, and has a long-term impact on offspring cognitive development.

Assessment of social factors influencing hospitalization cost of US preterm newborns, 2016.

BACKGROUND AND OBJECTIVE: Preterm newborn (PTN) care is costly in the US, and the preterm birth (PTB) rate has not seen substantial improvement. PTB remains a significant public health issue because of risks of adverse health outcomes and the associated economic burden. Assessing factors leading to high hospital cost is imperative in order to ease economic burden associated with PTB. Social factors influencing hospitalization cost for PTN have not been studied extensively. This study aims to examine the contributions of hospital type, race/ethnicity, and median household income quartile to the cost of the PTN's initial hospitalization after birth. MATERIALS AND METHODS: Data used in this study originated from the 2016 Healthcare Cost and Utilization Project Kids' Inpatient Database (KID) which provided the most recent national records of pediatric hospitalization in the US. International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes P07.2x and P07.3x were used to identify birth gestational age (GA) in complete weeks. Q00-Q99 codes were used to identify congenital anomalies. Data records reflecting hospitalization of newborns without congenital anomalies were extracted to estimate total cost in 2016. Analysis of factors influencing total cost was performed on the subset of newborns that were in-born and with birth GA from 24 to 36 weeks. Total hospital cost was calculated by multiplying total charges and cost-to-charge ratios. Per-diem cost was calculated by dividing total hospital cost by length of stay. Linear regression modeling was performed using weighted data, and the best model was selected using the Akaike information criteria. RESULTS: Hospitalization cost for PTNs, who constituted 7.6% of all studied newborns, comprised 45% of total newborn hospitalization cost. PTNs in freestanding children's hospitals had significantly higher total cost compared to non-children's teaching and non-teaching hospitals. The cost difference was GA-dependent. The latter two hospital types reported similar cost for PTNs. Although race/ethnicity and median household income quartile were related, the two covariates had independent effects on total hospitalization cost. A model built to assess the roles of covariates in the association between GA and total hospitalization cost found that all three covariates independently affected total cost when controlling for one another, with hospital type also showing an interaction effect with GA. CONCLUSIONS: Hospitalization cost is highly influenced by hospital type, race/ethnicity, and median household income quartile. The modifiable aspects of these factors may be further dissected and targeted in order to ease the burden of high hospitalization cost associated with PTB.

In-Hospital Outcomes in Fontan Completion Surgery According to Age.

Actual timing of the Fontan operation is variable. Our aim was to evaluate the impact of age at the time of Fontan operation on mortality and clinical outcome and characterize patients with worse outcomes. We conducted a retrospective, cross-sectional study on the Fontan operation using nationally representative databases from 2003 to 2016 and categorized the patient into 1 of 5 groups according to their age at the time of surgery: <2, 2, 3, 4, and ≥5 years. Survey-weighted logistic regression models were used to compare the outcomes of the different age groups. A total of 6,647 children underwent the Fontan completion procedure during the study period with median age 3 (interquartile range 2 to 4) years. The in-hospital mortality was 2.1%. In logistic regression models, in-hospital mortality, respiratory failure, acute kidney injury, chylothorax, arrhythmias, and sudden cardiac arrest were similar among the 5 age groups. Compared with children >2 years, those <2 years were less likely to be admitted for surgery on an elective basis (73.5% vs 90.4%, p <0.001), more likely to have chromosomal anomalies (2.7% vs 1.7%), and more likely to have repair of atrioventricular valves (8.5% vs 6.0%, p = 0.027). Mortality was higher in those with an underlying atrioventricular septal defect (AVSD) adjusted odds ratio 4.3 (2.4 to 7.9, p <0.001). Repair of AV valves was more common in the AVSD group compared with those in non-AVSD (14.3% vs 5.5%, p <0.001). In conclusion, age at Fontan completion does not adversely affect the in-hospital outcomes. Our focus should be on optimizing essential factors that are crucial for successful Fontan completion.

Sex differences in postnatal weight gain trajectories of extremely preterm newborns.

OBJECTIVE: Both postnatal growth and sex play a crucial role in long-term outcomes of extremely preterm newborns (EPNs), but the relationship between sex and postnatal growth is not clear. This study aims to assess sex differences in weight trajectories. STUDY DESIGN: Weight data in the first 200 days of life from 4327 EPNs were used for generalized additive mixed modeling. We considered gestational age and sex as fixed-effects, and included random intercepts and random slopes for postnatal age. We assessed interactions between fixed-effects and postnatal age. RESULTS: Male EPNs had higher predicted weight trajectories than females. Weight z-score trajectories decreased in both sexes before term-equivalent age comparably, but females showed faster increases afterward. Although weight gain velocity was comparable between both sexes, weight gain velocity in male EPNs was lower compared to the corresponding reference values from the 2013 Fenton growth charts, which explained slower z-score rises. CONCLUSION: Sex disparity exists in postnatal weight gain trajectories of EPNs after reaching the term-equivalent age.

Machine Learning for Mortality Prediction in Pediatric Myocarditis.

Background: Pediatric myocarditis is a rare disease. The etiologies are multiple. Mortality associated with the disease is 5-8%. Prognostic factors were identified with the use of national hospitalization databases. Applying these identified risk factors for mortality prediction has not been reported. Methods: We used the Kids' Inpatient Database for this project. We manually curated fourteen variables as predictors of mortality based on the current knowledge of the disease, and compared performance of mortality prediction between linear regression models and a machine learning (ML) model. For ML, the random forest algorithm was chosen because of the categorical nature of the variables. Based on variable importance scores, a reduced model was also developed for comparison. Results: We identified 4,144 patients from the database for randomization into the primary (for model development) and testing (for external validation) datasets. We found that the conventional logistic regression model had low sensitivity (~50%) despite high specificity (>95%) or overall accuracy. On the other hand, the ML model struck a good balance between sensitivity (89.9%) and specificity (85.8%). The reduced ML model with top five variables (mechanical ventilation, cardiac arrest, ECMO, acute kidney injury, ventricular fibrillation) were sufficient to approximate the prediction performance of the full model. Conclusions: The ML algorithm performs superiorly when compared to the linear regression model for mortality prediction in pediatric myocarditis in this retrospective dataset. Prospective studies are warranted to further validate the applicability of our model in clinical settings.

Quantifying Fetal Reprogramming for Biomarker Development in the Era of High-Throughput Sequencing.

Gestational hypertensive disorders continue to threaten the well-being of pregnant women and their offspring. The only current definitive treatment for gestational hypertensive disorders is delivery of the fetus. The optimal timing of delivery remains controversial. Currently, the available clinical tools do not allow for assessment of fetal stress in its early stages. Placental insufficiency and fetal growth restriction secondary to gestational hypertensive disorders have been shown to have long-term impacts on offspring health even into their adulthood, becoming one of the major focuses of research in the field of developmental origins of health and disease. Fetal reprogramming was introduced to describe the long-lasting effects of the toxic intrauterine environment on the growing fetus. With the advent of high-throughput sequencing, there have been major advances in research attempting to quantify fetal reprogramming. Moreover, genes that are found to be differentially expressed as a result of fetal reprogramming show promise in the development of transcriptional biomarkers for clinical use in detecting fetal response to placental insufficiency. In this review, we will review key pathophysiology in the development of placental insufficiency, existing literature on high-throughput sequencing in the study of fetal reprogramming, and considerations regarding research design from our own experience.