Longitudinal changes in the gut microbiome of infants on total parenteral nutrition.

BACKGROUND: Animal studies suggest that total parenteral nutrition (TPN) may alter bacterial colonization of the intestinal tract and contribute to complications. Progressive changes in gut microbiome of infants receiving TPN are not well understood. METHODS: Infants with and without TPN/soy lipid were enrolled in a prospective, longitudinal study. Weekly fecal samples were obtained for the first 4 weeks of life. High throughput pyrosequencing of 16S rDNA was used for compositional analysis of the gut microbiome. RESULTS: 47 infants were eligible for analyses, 25 infants received TPN, and 22 infants did not (control). Although similar between TPN and control groups in the first week, fecal bacterial alpha diversity was significantly lower in the TPN group compared to controls at week 4 (Shannon index 1.0 vs 1.5, P-value = 0.03). The TPN group had significantly lower Bacteroidetes and higher Verrucomicrobia abundance compared to controls (P-values < 0.05), and these differences became more pronounced over time. At the genus level, TPN was associated with lower abundance of Bacteroides and Bifidobacterium in all weeks. CONCLUSIONS: TPN is associated with significant loss of biodiversity and alterations in the pattern of gut microbial colonization of infants over time. TPN-associated dysbiosis may predispose infants to adverse NICU outcomes.

Kinetics of phytosterol metabolism in neonates receiving parenteral nutrition.

BACKGROUND: Phytosterols in soybean oil (SO) lipids likely contribute to parenteral nutrition-associated liver disease (PNALD) in infants. No characterization of phytosterol metabolism has been done in infants receiving SO lipids. METHODS: In a prospective cohort study, 45 neonates (36 SO lipid vs. 9 control) underwent serial blood sample measurements of sitosterol, campesterol, and stigmasterol. Mathematical modeling was used to determine pharmacokinetic parameters of phytosterol metabolism and phytosterol exposure. RESULTS: Compared to controls, SO lipid-exposed infants had significantly higher levels of sitosterol and campesterol (P < 0.01). During SO lipid infusion, sitosterol and campesterol reached half of steady-state plasma levels within 1.5 and 0.8 d, respectively. Steady-state level was highest for sitosterol (1.68 mg/dl), followed by campesterol (0.98 mg/dl), and lowest for stigmasterol (0.01 mg/dl). Infants born < 28 wk gestational age had higher sitosterol steady-state levels (P = 0.03) and higher area under the curve for sitosterol (P = 0.03) during the first 5 d of SO lipid (AUC5) than infants born ≥ 28 wk gestational age. CONCLUSION: Phytosterols in SO lipid accumulate rapidly in neonates. Very preterm infants receiving SO lipid have higher sitosterol exposure, and may have poorly developed mechanisms of eliminating phytosterols that may contribute to their vulnerability to PNALD.

A multicenter matched-cohort analysis of gastroschisis outcomes in infants born before 32 weeks gestation.

OBJECTIVE: To examine neonatal outcomes of infants with gastroschisis born <32 weeks' gestation compared to matched infants without gastroschisis. STUDY DESIGN: Retrospective matched-cohort analysis of infants with gastroschisis born <32 weeks' gestation at Children's Hospitals Neonatal Consortium (CHNC) NICUs from 2010 to 2022 compared to gestational age-matched controls. RESULTS: The study included 119 infants with gastroschisis and 357 matched infants; 60% of infants born 29-32 weeks, 23% born 26-28 weeks, and 16% born < 25 weeks. Mortality was not significantly different between groups (11% vs. 9%, p = 0.59). Preterm co-morbidities such as IVH, BPD, ROP, and PVL were similar, as were rates of surgical NEC. Infants with gastroschisis had longer hospital stays (92 vs. 67 days), higher CLABSI and UTIs, and were more likely to need feeding support at discharge. CONCLUSION: Compared to infants without gastroschisis, infants <32 weeks' gestation with gastroschisis had similar risks for inpatient mortality, NEC, and other preterm co-morbidities.

Assessing growth of infants with chylothorax receiving fortified skimmed human breast milk.

LEARNING OUTCOME: To learn how skimmed human milk (SHM) can be used in infants with chylothorax to support adequate weight gain and nutrition while receiving human milk. BACKGROUND: Traditional nutrition management for chylothorax is to limit long-chain triglycerides (LCTs) and provide a diet high in medium-chain triglycerides (MCTs). Transition from human milk to formula has been required to provide the ratio of MCT to LCT required to stop the accumulation of chyle. Although SHM may provide the right fat content for a baby with chylothorax, previous studies have shown slow growth in infants receiving SHM. OBJECTIVE: To demonstrate that infants receiving SHM fortified with high-MCT infant formula will have age appropriate growth without re-accumulation of chyle. DESIGN/METHODS: Between 2017 and 2019, term infants with the diagnosis of chylothorax who were previously receiving human milk and transitioned to fortified SHM were monitored for growth and reaccumulation of chyle. RESULTS: The six infants who were prescribed fortified SHM with high-MCT infant formula using standardized recipes did not show reaccumulation of chyle and showed positive weight gain in five of the six study patients. The infants gained a mean weight of 30.5 g/day (±19.5), and their weight z scores improved by a mean of +0.29 (±0.33). CONCLUSIONS: Fortified SHM is a safe treatment option that can provide adequate nutrition for the infant with chylothorax to gain weight appropriately for age.

Human induced pluripotent stem cell derived hepatocytes provide insights on parenteral nutrition associated cholestasis in the immature liver.

Parenteral nutrition-associated cholestasis (PNAC) significantly limits the safety of intravenous parenteral nutrition (PN). Critically ill infants are highly vulnerable to PNAC-related morbidity and mortality, however the impact of hepatic immaturity on PNAC is poorly understood. We examined developmental differences between fetal/infant and adult livers, and used human induced pluripotent stem cell-derived hepatocyte-like cells (iHLC) to gain insights into the contribution of development to altered sterol metabolism and PNAC. We used RNA-sequencing and computational techniques to compare gene expression patterns in human fetal/infant livers, adult liver, and iHLC. We identified distinct gene expression profiles between the human feta/infant livers compared to adult liver, and close resemblance of iHLC to human developing livers. Compared to adult, both developing livers and iHLC had significant downregulation of xenobiotic, bile acid, and fatty acid metabolism; and lower expression of the sterol metabolizing gene ABCG8. When challenged with stigmasterol, a plant sterol found in intravenous soy lipids, lipid accumulation was significantly higher in iHLC compared to adult-derived HepG2 cells. Our findings provide insights into altered bile acid and lipid metabolizing processes in the immature human liver, and support the use of iHLC as a relevant model system of developing liver to study lipid metabolism and PNAC.

NICU management and outcomes of infants with trisomy 21 without major anomalies.

OBJECTIVE: To describe how trisomy 21 affects neonatal intensive care management and outcomes of full-term infants without congenital anomalies. STUDY DESIGN: Retrospective cohort of full-term infants without anomalies with and without trisomy 21 admitted to Pediatrix NICUs from 2005 to 2012. We compared diagnoses, management, length of stay, and discharge outcomes. RESULTS: In all, 4623 infants with trisomy 21 and 606 770 infants without trisomy 21 were identified. One-third of infants in the NICU with and without trisomy 21 were full term without major anomalies. Trisomy 21 infants had more respiratory distress, thrombocytopenia, feeding problems, and pulmonary hypertension. They received respiratory support for a longer period of time and had a longer length of stay. CONCLUSION: One-third of infants with trisomy 21 admitted to the NICU are full term without major anomalies. Common diagnoses and greater respiratory needs place infants with trisomy 21 at risk for longer length of stay.

Outcomes of Infants With Home Tube Feeding: Comparing Nasogastric vs Gastrostomy Tubes.

BACKGROUND: The aim of this study was to determine the tube-related complications and feeding outcomes of infants discharged home from the neonatal intensive care unit (NICU) with nasogastric (NG) tube feeding or gastrostomy (G-tube) feeding. MATERIALS AND METHODS: We performed a chart review of 335 infants discharged from our NICU with home NG tube or G-tube feeding between January 2009 and December 2013. The primary outcome was the incidence of feeding tube-related complications requiring emergency department (ED) visits, hospitalizations, or deaths. Secondary outcome was feeding status at 6 months postdischarge. Univariate and multivariate analyses were conducted. RESULTS: There were 322 infants discharged with home enteral tube feeding (NG tube, n = 84; G-tube, n = 238), with available outpatient data for the 6-month postdischarge period. A total of 115 ED visits, 28 hospitalizations, and 2 deaths were due to a tube-related complication. The incidence of tube-related complications requiring an ED visit was significantly higher in the G-tube group compared with the NG tube group (33.6% vs 9.5%, P < .001). Two patients died due to a G-tube-related complication. By 6 months postdischarge, full oral feeding was achieved in 71.4% of infants in the NG tube group compared with 19.3% in the G-tube group ( P < .001). Type of feeding tube and percentage of oral feeding at discharge were significantly associated with continued tube feeding at 6 months postdischarge. CONCLUSION: Home NG tube feeding is associated with fewer ED visits for tube-related complications compared with home G-tube feeding. Some infants could benefit from a trial home NG tube feeding.

Potential Hepatotoxicities of Intravenous Fat Emulsions in Infants and Children.

Infants and children who depend on parenteral nutrition are among the most vulnerable to developing potentially devastating intestinal failure-associated liver disease. While the pathogenesis of intestinal failure-associated liver disease remains unclear, evidence for the contribution of fat emulsions to cholestasis and liver injury has rapidly increased in recent years. Data demonstrating the interaction among phytosterols, fatty acids, and antioxidants in cellular pathways that mediate bile flow and hepatic injury have led to the development of newer alternative fat emulsions. This article reviews recent studies that have provided insight into the potential hepatotoxicities of fat emulsions.

Influence of gestational age and birth weight in neonatal cholesterol response to total parenteral nutrition.

BACKGROUND: Premature and critically ill infants receiving total parenteral nutrition (TPN) are at risk for dyslipidemia, and altered cholesterol levels in early life may contribute to later cardiovascular risk. Data regarding plasma cholesterol response to TPN in young infants are lacking. OBJECTIVE: To determine the changes in plasma cholesterol levels during the first week of life in infants receiving TPN and a comparison group of infants who did not receive TPN during routine care. METHODS: In a prospective, pilot cohort study, 38 neonates (30 TPN vs. 8 No-TPN) underwent serial blood sampling during the first week of life. Gas chromatography-mass spectrometry was used to measure cholesterol in plasma and TPN administered to study participants. RESULTS: Baseline cholesterol level was similar between groups. In contrast to infants who did not receive TPN, cholesterol levels during the first week of life were significantly higher than baseline in infants receiving TPN (maximum cholesterol response 34% vs. 103% change from baseline, No-TPN vs. TPN, respectively, P = .036). After adjusting for cumulative cholesterol received by infants receiving TPN, maximum cholesterol response remained inversely related to gestational age and birth weight (P < .05). CONCLUSION: Plasma cholesterol significantly increases during the first week of life in neonates receiving TPN. A higher cholesterol response was induced by TPN in infants of lower gestational age and birth weight.

Investigating Sitosterolemia to Understand Lipid Physiology.

The cholesterol molecule is at the center of the pathophysiology of many vascular diseases. Whole-body cholesterol pools are maintained by a balance of endogenous synthesis, dietary absorption and elimination from our bodies. While the cellular aspects of cholesterol metabolism received significant impetus from the seminal work of Goldstein and Brown investigating LDL receptor trafficking, how dietary cholesterol was absorbed and eliminated was relatively neglected. The identification of the molecular defect a rare human disorder, Sitosterolemia, led to elucidation of a key mechanism of how we regulate the excretory pathway in the liver and in the intestine. Two proteins, ABCG5 and ABCG8, constitute a heterodimeric transporter that facilitates the extrusion of sterols from the cell into the biliary lumen, with a preference for xenosterols. This mechanism explained how dietary xenosterols are prevented from accumulating in our bodies. In addition, this disease has also highlighted the potential harm of xenosterols; macrothrombocytopenia, liver disease and endocrine disruption are seen when xenosterols accumulate. Mouse models of this disease suggest that there are more dramatic alterations of physiology, suggesting that these highly conserved mechanisms have evolved to prevent these xenosterols from accumulating in our bodies.

Risks and benefits of prophylactic cyclic parenteral nutrition in surgical neonates.

BACKGROUND: Cyclic parenteral nutrition (PN) is used for both the treatment and prevention of parenteral nutrition-associated liver disease (PNALD). Early initiation of prophylactic cyclic PN may not be well tolerated in young neonates. Our objective was to test the hypothesis that prophylactic cyclic PN initiated prior to the onset of hyperbilirubinemia is associated with younger age at initiation, lower bilirubin levels, and similar rates of adverse events compared to therapeutic cyclic PN initiated after established cholestasis in surgical neonates. METHODS: A retrospective review of infants with gastrointestinal disorders requiring surgical intervention who received cyclic PN 2006-2011 was performed. RESULTS: Of the 43 infants eligible for analysis, 23 received prophylactic and 20 received therapeutic cyclic PN. Infants in both groups were comparable in demographics, surgical diagnoses, and illness severity. At initiation of cyclic PN, infants with prophylactic cyclic PN were significantly younger in chronologic (P = .003) and postmenstrual age (P = .029). Prophylactic cyclic PN was associated with a significantly lower incidence of hyperbilirubinemia (P = .001), lower maximum conjugated bilirubin (P < .0001), and lower last checked conjugated bilirubin (P = .032) compared to the therapeutic cyclic PN. The incidence of hypoglycemia, hyperglycemia, and hypertriglyceridemia was similar for the 2 groups. CONCLUSIONS: There may be a potential benefit to initiating cyclic PN prior to the development of hyperbilirubinemia in surgical neonates. Early initiation of prophylactic cyclic PN does not appear to increase the risk for adverse events.