Impact of Docosahexaenoic acid supplementation on proinflammatory cytokines release and the development of Necrotizing enterocolitis in preterm Neonates: A randomized controlled study.

INTRODUCTION: Preterm neonates have under-developed immune-regulatory system; consequently, there is a risk for developing chronic inflammation. Necrotizing enterocolitis (NEC) is an acute devastating neonatal intestinal inflammatory disorder. Due to the obscure multifactorial etiology, early diagnosis and effective treatment of NEC are limited. Consequently, effective strategies in the prevention of NEC, including nutritional approaches, are critically needed. The current study was conducted to assess the potential immunomodulatory effect of Docosahexaenoic Acid (DHA) supplementation in preterm neonates at neonatal intensive care unit (NICU) and subsequently its effect on preventing or reducing NEC incidence. METHODS: This was a prospective randomized controlled study. A total of 67 neonates, with gestational age equal or less than 32 weeks at birth and weight less than or equal 1500 g, were randomly assigned to either DHA group or the control group. Modified Bell's staging criteria for NEC was used as an objective tool for diagnosis and staging of NEC. Levels of Interleukin 1 beta (IL-1ß) were measured at baseline and after 10 days. Mortality and NICU length of stay (LOS) were also monitored. RESULTS: Thirty neonates of each group completed the study. A statistically significant difference was observed between the two groups regarding diagnosis and staging of NEC (p = 0.0001). There was also a statistically significant difference between DHA group 22(73.3), 95% CI [55.9, 86.5] and the control group 8 (26.7), 95% CI [13.5, 44.1] in the percentage change in IL-1ß levels (p = 0.0001).A statistically significant association was found between IL and 1 ß change and NEC diagnosis (p = 0.001). NICU LOS was significantly lower among DHA group 21.63 ± 6.67 compared to the control group 25.07 ± 4.67 (p = 0.025). Mortality n (%) among the control group 4 (11.8) was higher than DHA group 3 (9.1), however, no significant difference was detected (p = 1.0). CONCLUSION: Findings of this study suggest that enteral DHA supplementation can reduce NEC incidence in preterm neonates through its immunoregulatory effect that modulates production of regulatory cytokines.Trial registration: Registered at clinical trials.gov (NCT03700957), 6 October 2018.

Neonatologist-performed point-of-care abdominal ultrasound: What have we learned so far?

This review describes the sonographic appearances of the neonatal bowel in Necrotising enterocolitis. It compares these findings to those seen in midgut-Volvulus, obstructive intestinal conditions such as milk-curd obstruction, and slow gut motility in preterm infants on continuous positive airway pressure (CPAP)-CPAP belly syndrome. Point-of-care bowel ultrasound is also helpful in ruling out severe and active intestinal conditions, reassuring clinicians when the diagnosis is unclear in a non-specific clinical presentation where NEC cannot be excluded. As NEC is a severe disease, it is often over-diagnosed, mainly due to a lack of reliable biomarkers and clinical presentation similar to sepsis in neonates. Thus, the assessment of the bowel in real-time would allow clinicians to determine the timing of re-initiation of feeds and would also be reassuring based on specific typical bowel characteristics visualised on the ultrasound.

The role of neutrophil extracellular traps in necrotizing enterocolitis.

Necrotizing enterocolitis (NEC) continues to be one of the most common causes of mortality and morbidity in preterm infants. Although not fully elucidated, studies suggest that prematurity, formula feeding, imbalanced vascular supply, and altered bacterial colonization play major roles in the pathogenesis of NEC. NEC is characterized by increased cytokine release and leukocyte infiltration. Recent data from preterm infants and animal models of NEC suggest that neutrophil extracellular traps (NETs) are released in intestinal tissue. The contribution of NETs in the pathogenesis and/or prevention/treatment of this disease continues to be controversial. Here, we review the available data on NETs release in NEC in human patients and in different NEC models, highlighting their potential contribution to pathology and resolution of inflammation. Here, we review the available data on NETs release in NEC in human patients and the different NEC models, highlighting their potential contribution to pathology or resolution of inflammation.

Suppression of Bile Acid Synthesis in a Preterm Infant Receiving Prolonged Parenteral Nutrition.

Bile acid metabolism is altered in neonates on parenteral nutrition (PN), predisposing them to parenteral nutrition-associated liver disease. Cholesterol 7α-hydroxylase (CYP7A1), the rate-limiting enzyme in the bile acid synthesis pathway, is repressed by fibroblast growth factor 19 (FGF19) and phytosterols (PS). We describe a case of a preterm infant who developed necrotizing enterocolitis (NEC) and received exclusive PN for over 2 months. Our objective was to serially assess CYP7A1 activity and plasma FGF19 and PS concentrations in this infant case compared to five healthy preterm infants. We found that CYP7A1 activity increased during the first 2 weeks of life in control infants but was undetectable in the infant case. FGF19 concentrations were high at birth in all infants and subsequently declined and did not differ between the case and control infants. As expected, PS concentrations were elevated in the infant case and continued to increase despite lipid minimization. In conclusion, CYP7A1 activity was gradually upregulated in healthy preterm infants but remained suppressed in the infant requiring prolonged PN. Preterm infants also had elevated FGF19 concentrations at birth, which decreased with advancing postnatal age.

Systemic Factors Associated with a Thinner Choroid in Preterm Infants.

Purpose: To identify systemic health factors associated with a thinner choroid, which has been hypothesized as a cause of poor visual outcomes in low-birth weight infants. Design: The prospective, observational Study of Eye Imaging in Preterm Infants (BabySTEPS) enrolled infants recommended for retinopathy of prematurity screening based on the American Association of Pediatrics guidelines. Participants: Infants who underwent imaging with investigational handheld OCT at 36 ± 1 weeks' postmenstrual age (PMA) as part of BabySTEPS. Methods: Average choroidal thickness was measured across the central subfoveal 1 mm. We concurrently collected maternal and infant clinical health data. Univariate and multivariate linear regression analyses were performed to evaluate factors associated with choroidal thickness. The left and right eyes showed similar thicknesses, so their average was used for analysis. Main Outcomes Measures: Association between infant health factors and subfoveal choroidal thickness. Results: Subfoveal choroidal thickness was measurable in 82 of 85 infants and 94% of eyes. Mean choroidal thickness was 231 ± 78 µm. In the univariate analysis, a thinner choroid was associated with decreased growth velocity (P < 0.001), lower birth weight (P < 0.001), smaller head circumference (P < 0.001), younger gestational age (P = 0.01), the presence of patent ductus arteriosus (P = 0.05), sepsis or necrotizing enterocolitis (P = 0.03), bronchopulmonary dysplasia (P = 0.03), pulmonary interstitial emphysema (P = 0.002), more days on oxygen support (P < 0.001), and being on oxygen support at 36 weeks (P < 0.001) and at the time of imaging (P < 0.001). In the multivariate analysis, growth velocity (P = 0.002) and oxygen support at the time of OCT imaging (P = 0.004) remained associated with a thinner choroid. Conclusions: A thinner choroid is associated independently with growth velocity and receiving oxygen support at 36 ± 1 weeks PMA. This suggests that choroidal development in preterm infants may be related to growth rate in the first weeks of life and the prolonged use of supplemental oxygen. Longitudinal studies are needed to assess differences in choroidal thickness before 36 weeks PMA and to assess their impact on visual outcomes.

Impact of 1% chlorhexidine gluconate bathing and emollient application on bacterial pathogen colonization dynamics in hospitalized preterm neonates - A pilot clinical trial.

BACKGROUND: Chlorhexidine gluconate (CHG) body washes and emollient application may modulate bacterial pathogen colonization and prevent neonatal hospital-acquired infections. METHODS: This pilot, non-randomized, open-label trial, enrolled preterm neonates (1000-1500g; day 1-3 of life) at a tertiary hospital in Cape Town, South Africa. Participants were sequentially allocated to 4 trial arms (n=20 each): 1% aqueous CHG (CHG), 1% CHG plus emollient (CHG+EM), emollient only (EM) and standard of care (SOC: no antiseptic/emollient). Trial treatment/s were applied daily for 10 days (d) post-enrolment, documenting neonatal skin condition score. Anterior nose, neck, umbilical and perianal swabs for bacterial culture were collected at d1, d3, d10 and d16 post-enrolment, (±1 day), reporting pathogen acquisition rates and semi-quantitative bacterial colony counts. (ClinicalTrials.gov identifier: NCT03896893; trial status: closed). FINDINGS: Eighty preterm neonates (mean gestational age 30 weeks [SD 2]) were enrolled between 4 March and 26 August 2019. The bacterial pathogen acquisition rate (comparing d1 and d16 swabs) varied from 33·9% [95%CI 22·9-47·0] at the umbilicus, 39·3% [95%CI 27·6-52·4] at the neck, to 71·4% [95%CI 58·5-81·7] at both the nose and perianal region. At d10, CHG babies had reduced bacterial density detected from neck, umbilicus, and perianal swabs compared to other groups (see Table 3). Following intervention cessation, colonization density was similar across all trial arms, but S. aureus colonization was more prevalent among EM and CHG+EM babies. Neonatal skin condition score improved in babies receiving emollient application (EM: -0·87 [95%CI 0·69-1·06] and CHG+EM: -0·73 [0·45-0·99]), compared to the SOC and CHG arms (Table 2); no CHG-related skin reactions occurred. INTERPRETATION: Bacterial colonization density was significantly reduced in babies receiving 1% CHG washes but colonization levels rebounded rapidly post-intervention. Emollient application improved skin condition but was associated with higher rates of S. aureus colonization. FUNDING: South African Medical Research Council; National Institutes of Health (TW010682).

The influence of the gut microbiota on the bioavailability of oral drugs.

Due to its safety, convenience, low cost and good compliance, oral administration attracts lots of attention. However, the efficacy of many oral drugs is limited to their unsatisfactory bioavailability in the gastrointestinal tract. One of the critical and most overlooked factors is the symbiotic gut microbiota that can modulate the bioavailability of oral drugs by participating in the biotransformation of oral drugs, influencing the drug transport process and altering some gastrointestinal properties. In this review, we summarized the existing research investigating the possible relationship between the gut microbiota and the bioavailability of oral drugs, which may provide great ideas and useful instructions for the design of novel drug delivery systems or the achievement of personalized medicine.

Idiopathic pneumoperitoneum without gastrointestinal perforation in a low-birth weight infant: A rare type of air leak syndrome.

Neonatal free air on X-ray images is generally due to intestinal perforation, and requires surgical intervention. However, some cases without intestinal perforation show free air on X-ray images. Pneumoperitoneum without perforation is caused by an air leak syndrome. We present here the case of a low-birth-weight infant with free air on X-ray images, who had no evidence of intestinal perforation intraoperatively.

Toll-Like Receptor-Mediated Intestinal Inflammatory Imbalance in the Pathogenesis of Necrotizing Enterocolitis.

Necrotizing enterocolitis (NEC) remains the leading cause of death from gastrointestinal disease in premature infants and attacks the most fragile patients at a time when they appear to be the most stable. Despite significant advances in our overall care of the premature infant, NEC mortality remains stubbornly high. There is no specific treatment for NEC beyond broad-spectrum antibiotics and intestinal resection, and current efforts have focused on preventive strategies. Over the past decade, we have proposed a unifying hypothesis to explain the pathogenesis of NEC in premature infants that suggests that NEC develops in response to an imbalance between exaggerated proinflammatory signaling in the mucosa of the premature gut leading to mucosal injury, which is not countered effectively by endogenous repair processes, and in the setting of impaired mesenteric perfusion leads to intestinal ischemia and disease development. One of the most important pathways that mediates the balance between injury and repair in the premature intestine, and that plays a key role in NEC pathogenesis, is Toll-like receptor 4 (TLR4), which recognizes lipopolysaccharide on gram-negative bacteria. This review focuses on the role that the TLR4-mediated imbalance between proinflammatory and anti-inflammatory signaling in the premature intestinal epithelium leads to the development of NEC, and will explore how an understanding of the role of TLR4 in NEC pathogenesis has led to the identification of novel preventive or treatment approaches for this devastating disease.

The cerebral hemodynamic response to phonetic changes of speech in preterm and term infants: The impact of postmenstrual age.

Higher brain dysfunction, such as language delay, is a major concern among preterm infants. Cerebral substrates of cognitive development in preterm infants remain elusive, partly because of limited methods. The present study focuses on hemodynamic response patterns for brain function by using near-infrared spectroscopy. Specifically, the study investigates gestational differences in the hemodynamic response pattern evoked in response to phonetic changes of speech and cerebral hemispheric specialization of the auditory area in preterm infants (n = 60) and term infants (n = 20). Eighty neonates born between 26 and 41 weeks of gestational age (GA) were tested from 33 to 41 weeks of postmenstrual age (PMA). We analyzed the hemodynamic response pattern to phonemic and prosodic contrasts for multiple channels on temporal regions and the laterality index of the auditory area. Preterm infants younger than 39 weeks of PMA showed significantly atypical hemodynamic patterns, with an inverted response shape. Partial correlation analysis of the typicality score of hemodynamic response revealed a significant positive correlation with PMA. The laterality index of preterm infants from 39 weeks of PMA demonstrated a tendency rightward dominance for prosodic changes similar to term infants. We provide new evidence that alterations in hemodynamic regulation and the functional system for phonemic and prosodic processing in preterm infants catch up by their projected due dates.

Host-Gut Microbiota Crosstalk in Intestinal Adaptation.

Short-bowel syndrome represents the most common cause of intestinal failure and occurs when the remaining intestine cannot support fluid and nutrient needs to sustain adequate physiology and development without the use of supplemental parenteral nutrition. After intestinal loss or damage, the remnant bowel undergoes multifactorial compensatory processes, termed adaptation, which are largely driven by intraluminal nutrient exposure. Previous studies have provided insight into the biological processes and mediators after resection, however, there still remains a gap in the knowledge of more comprehensive mechanisms that drive the adaptive responses in these patients. Recent data support the microbiota as a key mediator of gut homeostasis and a potential driver of metabolism and immunomodulation after intestinal loss. In this review, we summarize the emerging ideas related to host-microbiota interactions in the intestinal adaptation processes.

Organic Solute Transporter α-ß Protects Ileal Enterocytes From Bile Acid-Induced Injury.

BACKGROUND & AIMS: Ileal bile acid absorption is mediated by uptake via the apical sodium-dependent bile acid transporter (ASBT), and export via the basolateral heteromeric organic solute transporter α-ß (OSTα-OSTß). In this study, we investigated the cytotoxic effects of enterocyte bile acid stasis in Ostα-/- mice, including the temporal relationship between intestinal injury and initiation of the enterohepatic circulation of bile acids. METHODS: Ileal tissue morphometry, histology, markers of cell proliferation, gene, and protein expression were analyzed in male and female wild-type and Ostα-/- mice at postnatal days 5, 10, 15, 20, and 30. Ostα-/-Asbt-/- mice were generated and analyzed. Bile acid activation of intestinal Nrf2-activated pathways was investigated in Drosophila. RESULTS: As early as day 5, Ostα-/- mice showed significantly increased ileal weight per length, decreased villus height, and increased epithelial cell proliferation. This correlated with premature expression of the Asbt and induction of bile acid-activated farnesoid X receptor target genes in neonatal Ostα-/- mice. Expression of reduced nicotinamide adenine dinucleotide phosphate oxidase-1 and Nrf2-anti-oxidant responsive genes were increased significantly in neonatal Ostα-/- mice at these postnatal time points. Bile acids also activated Nrf2 in Drosophila enterocytes and enterocyte-specific knockdown of Nrf2 increased sensitivity of flies to bile acid-induced toxicity. Inactivation of the Asbt prevented the changes in ileal morphology and induction of anti-oxidant response genes in Ostα-/- mice. CONCLUSIONS: Early in postnatal development, loss of Ostα leads to bile acid accumulation, oxidative stress, and a restitution response in ileum. In addition to its essential role in maintaining bile acid homeostasis, Ostα-Ostß functions to protect the ileal epithelium against bile acid-induced injury. NCBI Gene Expression Omnibus: GSE99579.

Human Fetal-Derived Enterospheres Provide Insights on Intestinal Development and a Novel Model to Study Necrotizing Enterocolitis (NEC).

BACKGROUND & AIMS: Untreated necrotizing enterocolitis (NEC) can lead to massive inflammation resulting in intestinal necrosis with a high mortality rate in preterm infants. Limited access to human samples and relevant experimental models have hampered progress in NEC pathogenesis. Earlier evidence has suggested that bacterial colonization of an immature and developing intestine can lead to an abnormally high inflammatory response to bacterial bioproducts. The aim of our study was to use human fetal organoids to gain insights into NEC pathogenesis. METHODS: RNA sequencing analysis was performed to compare patterns of gene expression in human fetal-derived enterospheres (FEnS) and adult-derived enterospheres (AEnS). Differentially expressed genes were analyzed using computational techniques for dimensional reduction, clustering, and gene set enrichment. Unsupervised cluster analysis, Gene Ontology, and gene pathway analysis were used to predict differences between gene expression of samples. Cell monolayers derived from FEnS and AEnS were evaluated for epithelium function and responsiveness to lipopolysaccharide and commensal bacteria. RESULTS: Based on gene expression patterns, FEnS clustered according to their developmental age in 2 distinct groups: early and late FEnS, with the latter more closely resembling AEnS. Genes involved in maturation, gut barrier function, and innate immunity were responsible for these differences. FEnS-derived monolayers exposed to either lipopolysaccharide or commensal Escherichia coli showed that late FEnS activated gene expression of key inflammatory cytokines, whereas early FEnS monolayers did not, owing to decreased expression of nuclear factor-κB-associated machinery. CONCLUSIONS: Our results provide insights into processes underlying human intestinal development and support the use of FEnS as a relevant human preclinical model for NEC. Accession number of repository for expression data: GSE101531.

Probiotics supplementation and length of hospital stay in neonates with gastrointestinal surgery.

Any manipulation on open bowel causes interventional impact on gut microbiome, and surgical stress triggers bacterial translocation; thus, it will be fundamental to determine gut microbiome after surgery. Monitoring dynamic changes in microbiome of post-surgical infants who received probiotics and placebo could provide with important information about gut colonization and potential bacterial overgrowth. The purpose of this study is to assess the effect of probiotics supplementation on length of hospital stay, duration of parenteral nutrition, and feed tolerance in neonates after gastrointestinal surgery.

Gastrointestinal Organoids: Understanding the Molecular Basis of the Host-Microbe Interface.

In recent years, increasing attention has been devoted to the concept that microorganisms play an integral role in human physiology and pathophysiology. Despite this, the molecular basis of host-pathogen and host-symbiont interactions in the human intestine remains poorly understood owing to the limited availability of human tissue, and the biological complexity of host-microbe interactions. Over the past decade, technological advances have enabled long-term culture of organotypic intestinal tissue derived from human subjects and from human pluripotent stem cells, and these in vitro culture systems already have shown the potential to inform our understanding significantly of host-microbe interactions. Gastrointestinal organoids represent a substantial advance in structural and functional complexity over traditional in vitro cell culture models of the human gastrointestinal epithelium while retaining much of the genetic and molecular tractability that makes in vitro experimentation so appealing. The opportunity to model epithelial barrier dynamics, cellular differentiation, and proliferation more accurately in specific intestinal segments and in tissue containing a proportional representation of the diverse epithelial subtypes found in the native gut greatly enhances the translational potential of organotypic gastrointestinal culture systems. By using these tools, researchers have uncovered novel aspects of host-pathogen and host-symbiont interactions with the intestinal epithelium. Application of these tools promises to reveal new insights into the pathogenesis of infectious disease, inflammation, cancer, and the role of microorganisms in intestinal development. This review summarizes research on the use of gastrointestinal organoids as a model of the host-microbe interface.

Prolonged Absence of Mechanoluminal Stimulation in Human Intestine Alters the Transcriptome and Intestinal Stem Cell Niche.

BACKGROUND & AIMS: For patients with short-bowel syndrome, intestinal adaptation is required to achieve enteral independence. Although adaptation has been studied extensively in animal models, little is known about this process in human intestine. We hypothesized that analysis of matched specimens with and without luminal flow could identify new potential therapeutic pathways. METHODS: Fifteen paired human ileum samples were collected from children aged 2-20 months during ileostomy-reversal surgery after short-segment intestinal resection and diversion. The segment exposed to enteral feeding was denoted as fed, and the diverted segment was labeled as unfed. Morphometrics and cell differentiation were compared histologically. RNA Sequencing and Gene Ontology Enrichment Analysis identified over-represented and under-represented pathways. Immunofluorescence staining and Western blot evaluated proteins of interest. Paired data were compared with 1-tailed Wilcoxon rank-sum tests with a P value less than .05 considered significant. RESULTS: Unfed ileum contained shorter villi, shallower crypts, and fewer Paneth cells. Genes up-regulated by the absence of mechanoluminal stimulation were involved in digestion, metabolism, and transport. Messenger RNA expression of LGR5 was significantly higher in unfed intestine, accompanied by increased levels of phosphorylated signal transducer and activator of transcription 3 protein, and CCND1 and C-MYC messenger RNA. However, decreased proliferation and fewer LGR5+, OLFM4+, and SOX9+ intestinal stem cells (ISCs) were observed in unfed ileum. CONCLUSIONS: Even with sufficient systemic caloric intake, human ileum responds to the chronic absence of mechanoluminal stimulation by up-regulating brush-border enzymes, transporters, structural genes, and ISC genes LGR5 and ASCL2. These data suggest that unfed intestine is primed to replenish the ISC population upon re-introduction of enteral feeding. Therefore, the elucidation of pathways involved in these processes may provide therapeutic targets for patients with intestinal failure. RNA sequencing data are available at Gene Expression Omnibus series GSE82147.

ZnT2-Mediated Zinc Import Into Paneth Cell Granules Is Necessary for Coordinated Secretion and Paneth Cell Function in Mice.

BACKGROUND & AIMS: Defects in Paneth cell (PC) function are associated with microbial dysbiosis and intestinal inflammation. PC granules contain antimicrobial peptides, cytokines, and substantial stores of zinc (Zn). We hypothesized that Zn, transported into the granule through the Zn transporter (ZnT)2, is critical for signature PC functions. METHODS: ZnT2 was localized to PC granules using immunofluorescence and sucrose gradient fractionation in wild-type (wt) mice, and consequences of ZnT2 loss were characterized in ZnT2 knockout (ZnT2ko) mice. Terminal ilea were harvested for immunofluorescence, electron microscopy, and fluorescent imaging with the Zn reporter Zinpyr-1. Alterations in fecal microbiota were characterized using 16s ribosomal RNA sequencing. PC degranulation, bacterial translocation, cytokine response to Escherichia coli endotoxin lipopolysaccharide, crypt viability after exposure to the oxidant monochloramine (NH2Cl), and bactericidal activity of luminal contents of terminal ilea against enteropathogenic E coli were assessed. RESULTS: ZnT2 was localized to the membrane of PC granules. In ZnT2ko mice, spontaneous degranulation was observed more frequently than among wt mice. Secretory granules were hypodense with less active lysozyme, and there was evidence of autophagosome accumulation and granule degradation in PCs from ZnT2ko mice. Gut microbiota of ZnT2ko mice were enriched in Bacteroidales S24-7 and relatively depleted of species commonly found in wt mice. Evidence of PC dysfunction in ZnT2ko mice included impaired granule secretion and increased inflammatory response to lipopolysaccharide, less bactericidal activity, and greater susceptibility to cell death from NH2Cl. CONCLUSIONS: ZnT2 is critical for Zn import into PC granules, and the inability to import Zn leads to profound defects in PC function and uncoordinated granule secretion.

Introduction for the special issue on "Tissue Barriers in Inflammation".

This issue of Tissue Barriers contains the inaugural special issue devoted to recent advances in barrier function of endothelial and epithelial cells. We used this opportunity to invite experts in vascular endothelial cell biology and epithelial cell biology to comment on critical questions and problems in permeability of organ and tissue barriers, and to provide insight into common areas in these fields, namely how these cells maintain homeostasis and response to injury and infection. To complement these reviews, this issue also contains four research articles that explore specific questions related respiratory and intestinal epithelial cell function.

The role of intestinal epithelial barrier function in the development of NEC.

The intestinal epithelial barrier plays an important role in maintaining host health. Breakdown of intestinal barrier function is known to play a role in many diseases such as infectious enteritis, idiopathic inflammatory bowel disease, and neonatal inflammatory bowel diseases. Recently, increasing research has demonstrated the importance of understanding how intestinal epithelial barrier function develops in the premature neonate in order to develop strategies to promote its maturation. Optimizing intestinal barrier function is thought to be key to preventing neonatal inflammatory bowel diseases such as necrotizing enterocolitis. In this review, we will first summarize the key components of the intestinal epithelial barrier, what is known about its development, and how this may explain NEC pathogenesis. Finally, we will review what therapeutic strategies may be used to promote optimal development of neonatal intestinal barrier function in order to reduce the incidence and severity of NEC.

Calcitriol treatment in metabolic bone disease of prematurity with elevated parathyroid hormone: A preliminary study.

OBJECTIVE: To describe the association of calcitriol treatment with the change in parathyroid hormone (PTH) and biochemical markers of bone disease in infants with metabolic bone disease of prematurity (MBD) and secondary hyperparathyroidism. STUDY DESIGN: This retrospective chart review examined serum intact PTH, serum calcium (Ca), serum phosphorus (P), serum alkaline phosphatase (APA), urine calcium/creatinine (UCa/Cr), and tubular reabsorption of phosphate (TRP) in 32 infants prior to and following calcitriol treatment for MBD with PTH >100 pg/ml. 25-hydroxyvitamin D concentrations were recorded. RESULTS: Following calcitriol treatment, PTH decreased from median (min/max) 220 (115/593) to 25 (3/259) pg/ml, p < 0.001; Ca increased from 9.9 (8.9/10.7) to 10.3 (9.7/11.3) mg/dl, p < 0.001; P increased from 4.3 (2.7/6.4) to 5.4 (2.9/7.4) mg/dl, p = 0.001; and TRP increased from 81 (59/98) to 91.5 (78/98) %, p = 0.03. APA did not differ pre-treatment: 616 (209/1193) vs. post-treatment 485 (196/1229) U/L, p = 0.12. Vitamin D deficiency was not present. Hypercalcemia with hypercalciuria occurred in 3/32 subjects, all normalized after dose reduction. CONCLUSION: Improvements in MBD markers and lack of serious adverse effects suggest calcitriol may be a treatment option in infants with MBD and secondary hyperparathyroidism.