Delivery-based criteria for empiric antibiotic administration among preterm infants.

OBJECTIVE: Determine impact of using delivery criteria to initiate antibiotics among very low birth weight (VLBW) and extremely low birth weight (ELBW) infants. STUDY DESIGN: Single site cohort study from 01/01/2009 to 01/31/2020. After 04/2017, infants delivered by Cesarean section, without labor or membrane rupture were categorized as low-risk for early-onset infection and managed without empiric antibiotics. We determined effect of this guideline by pre-post, and interrupted time-series analyses. RESULTS: After 04/2017, antibiotic initiation ≤3 days decreased among low-risk VLBW (62% vs. 13%, p < 0.001) and low-risk ELBW (88% vs. 21%, p < 0.001) infants. In time series analysis, guideline was associated with decreased initiation among low-risk ELBW infants. In contrast, low-risk VLBW infants demonstrated decreased antibiotic initiation throughout study period. Incidence of confirmed infection, death, or transfer ≤7 days age was unchanged. CONCLUSION: Delivery criteria may be used to optimize early antibiotic initiation among preterm infants without short-term increase in adverse outcomes.

Metabolic bone disease screening practices among U.S. neonatologists.

Preterm, low-birth-weight neonates are predisposed to metabolic bone disease (MBD). This survey aimed to assess screening, diagnostic, and treatment practices in U.S. level IIIB/IIIC neonatal intensive care units (NICUs). A 29-question anonymous online survey was e-mailed to American Academy of Pediatrics Perinatal Section members. 338 neonatologists, representing 246 IIIB/IIIC NICUs, responded. 86% reported MBD screening. Screening was primarily based on gestational age (71%), with thresholds <26 to <36 weeks. Other criteria included birth weight (64%), total parenteral nutrition duration (48%), X-ray findings (56%), diuretic use (41%), and exclusive breast-feeding (9.6%). Almost universally, diagnosis was based on elevated alkaline phosphatase, most commonly >500 U/L (58.6%). 52% used X-ray for diagnosis. Treatment included human milk fortification (83%), vitamin D (67%), calcium (65%), and phosphorus (65%) supplementation. Our survey confirms widespread awareness of MBD but highlights lack of consensus regarding definition, screening, and treatment. Further research is needed to develop and optimize strategies to prevent, recognize, and manage MBD.

Metabolic bone disease of prematurity.

Metabolic bone disease (MBD) of prematurity remains a significant problem for preterm, chronically ill neonates. The definition and recommendations for screening and treatment of MBD vary in the literature. A recent American Academy of Pediatrics Consensus Statement may help close the gap in institutional variation, but evidence based practice guidelines remain obscure due to lack of normative data and clinical trials for preterm infants. This review highlights mineral homeostasis physiology, current recommendations in screening and monitoring, prevention and treatment strategies, and an added perspective of a bone health team serving a high volume referral neonatal intensive care center.

Generalized arterial calcification of infancy and pseudoxanthoma elasticum can be caused by mutations in either ENPP1 or ABCC6.

Spontaneous pathologic arterial calcifications in childhood can occur in generalized arterial calcification of infancy (GACI) or in pseudoxanthoma elasticum (PXE). GACI is associated with biallelic mutations in ENPP1 in the majority of cases, whereas mutations in ABCC6 are known to cause PXE. However, the genetic basis in subsets of both disease phenotypes remains elusive. We hypothesized that GACI and PXE are in a closely related spectrum of disease. We used a standardized questionnaire to retrospectively evaluate the phenotype of 92 probands with a clinical history of GACI. We obtained the ENPP1 genotype by conventional sequencing. In those patients with less than two disease-causing ENPP1 mutations, we sequenced ABCC6. We observed that three GACI patients who carried biallelic ENPP1 mutations developed typical signs of PXE between 5 and 8 years of age; these signs included angioid streaks and pseudoxanthomatous skin lesions. In 28 patients, no disease-causing ENPP1 mutation was found. In 14 of these patients, we detected pathogenic ABCC6 mutations (biallelic mutations in eight patients, monoallelic mutations in six patients). Thus, ABCC6 mutations account for a significant subset of GACI patients, and ENPP1 mutations can also be associated with PXE lesions in school-aged children. Based on the considerable overlap of genotype and phenotype of GACI and PXE, both entities appear to reflect two ends of a clinical spectrum of ectopic calcification and other organ pathologies, rather than two distinct disorders. ABCC6 and ENPP1 mutations might lead to alterations of the same physiological pathways in tissues beyond the artery.

The angiogenic factor midkine is regulated by dexamethasone and retinoic acid during alveolarization and in alveolar epithelial cells.

BACKGROUND: A precise balance exists between the actions of endogenous glucocorticoids (GC) and retinoids to promote normal lung development, in particular during alveolarization. The mechanisms controlling this balance are largely unknown, but recent evidence suggests that midkine (MK), a retinoic acid-regulated, pro-angiogenic growth factor, may function as a critical regulator. The purpose of this study was to examine regulation of MK by GC and RA during postnatal alveolar formation in rats. METHODS: Newborn rats were treated with dexamethasone (DEX) and/or all-trans-retinoic acid (RA) during the first two weeks of life. Lung morphology was assessed by light microscopy and radial alveolar counts. MK mRNA and protein expression in response to different treatment were determined by Northern and Western blots. In addition, MK protein expression in cultured human alveolar type 2-like cells treated with DEX and RA was also determined. RESULTS: Lung histology confirmed that DEX treatment inhibited and RA treatment stimulated alveolar formation, whereas concurrent administration of RA with DEX prevented the DEX effects. During normal development, MK expression was maximal during the period of alveolarization from postnatal day 5 (PN5) to PN15. DEX treatment of rat pups decreased, and RA treatment increased lung MK expression, whereas concurrent DEX+RA treatment prevented the DEX-induced decrease in MK expression. Using human alveolar type 2 (AT2)-like cells differentiated in culture, we confirmed that DEX and cAMP decreased, and RA increased MK expression. CONCLUSION: We conclude that MK is expressed by AT2 cells, and is differentially regulated by corticosteroid and retinoid treatment in a manner consistent with hormonal effects on alveolarization during postnatal lung development.

Hormonal regulation of alveolarization: structure-function correlation.

BACKGROUND: Dexamethasone (Dex) limits and all-trans-retinoic acid (RA) promotes alveolarization. While structural changes resulting from such hormonal exposures are known, their functional consequences are unclear. METHODS: Neonatal rats were treated with Dex and/or RA during the first two weeks of life or were given RA after previous exposure to Dex. Morphology was assessed by light microscopy and radial alveolar counts. Function was evaluated by plethysmography at d13, pressure volume curves at d30, and exercise swim testing and arterial blood gases at both d15 and d30. RESULTS: Dex-treated animals had simplified lung architecture without secondary septation. Animals given RA alone had smaller, more numerous alveoli. Concomitant treatment with Dex + RA prevented the Dex-induced changes in septation. While the results of exposure to Dex + RA were sustained, the effects of RA alone were reversed two weeks after treatment was stopped. At d13, Dex-treated animals had increased lung volume, respiratory rate, tidal volume, and minute ventilation. On d15, both RA- and Dex-treated animals had hypercarbia and low arterial pH. By d30, the RA-treated animals resolved this respiratory acidosis, but Dex-treated animals continued to demonstrate blood gas and lung volume abnormalities. Concomitant RA treatment improved respiratory acidosis, but failed to normalize Dex-induced changes in pulmonary function and lung volumes. No differences in exercise tolerance were noted at either d15 or d30. RA treatment after the period of alveolarization also corrected the effects of earlier Dex exposure, but the structural changes due to RA alone were again lost two weeks after treatment. CONCLUSION: We conclude that both RA- and corticosteroid-treatments are associated with respiratory acidosis at d15. While RA alone-induced changes in structure andrespiratory function are reversed, Dex-treated animals continue to demonstrate increased respiratory rate, minute ventilation, tidal and total lung volumes at d30. Concomitant treatment with Dex + RA prevents decreased septation induced by Dex alone and results in correction of hypercarbia. However, these animals continue to have abnormal pulmonary function and lung volumes. Increased septation as a result of RA treatment alone is reversed upon discontinuation of treatment. These data suggest that Dex + RA treatment results in improved gas exchange likely secondary to normalized septation.