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.

Effect of Enteral Protein Amount on Growth and Health Outcomes in Very-Low-Birth-Weight Preterm Infants: Phase II of the Pre-B Project and an Evidence Analysis Center Systematic Review.

Adequate protein intake by very-low-birth-weight preterm infants (≤1,500 g at birth) is essential to optimize growth and development. The estimated needs for this population are the highest of all humans, however, the recommended intake has varied greatly over the past several years. A literature search was conducted in PubMed, Embase, CINAHL (Cumulative Index to Nursing and Allied Health Literature), and Cochrane Central databases to identify randomized controlled trials evaluating the effect of prescribed protein intake and identified outcomes. Articles were screened by 2 reviewers, risk of bias was assessed, data were synthesized quantitatively and narratively, and each outcome was separately graded for certainty of evidence. The literature search retrieved 25,384 articles and 2 trials were included in final analysis. No trials were identified that evaluated effect of protein amount on morbidities or mortality. Moderate certainty evidence found a significant difference in weight gain when protein intake of greater than 3.5 g/kg/day from preterm infant formula was compared with lower intakes. Low-certainty evidence found no evidence of effect of protein intake of 2.6 vs 3.1 vs 3.8 g/kg/day on length, head circumference, skinfold measurements, or mid-arm circumference. Low-certainty evidence found some improvement in development measures when higher protein intake of 3.8 vs 3.1 vs 2.6 g/kg/day were compared. Low-certainty evidence found no significant difference in bone mineral content when these protein intakes were compared. No studies were identified that compared protein intake greater than 4.0 g/kg/day. This systematic review found that protein intake between 3.5 and 4.0 g/kg/day promotes weight gain and improved development.

Exclusive Maternal Milk Compared With Exclusive Formula on Growth and Health Outcomes in Very-Low-Birthweight Preterm Infants: Phase II of the Pre-B Project and an Evidence Analysis Center Systematic Review.

As part of the Pre-B Project, a systematic review was conducted to evaluate associations between exclusive maternal milk (≥75%) intake and exclusive formula intake and growth and health outcomes in very-low-birthweight (VLBW) preterm infants. The protocols from the Academy of Nutrition and Dietetics' Evidence Analysis Center and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist were followed. Thirteen observational studies were included; 11 studies reported data that could be synthesized in a pooled analysis. The evidence is very uncertain (very low quality) about the effect of exclusive maternal milk on all outcomes due to observational study designs and risk of selection, performance, detection, and reporting bias in most of the included studies. Very-low-quality evidence suggested that providing VLBW preterm infants with exclusive maternal milk was not associated with mortality, risk of necrotizing enterocolitis, sepsis, or developing bronchopulmonary dysplasia, as compared with exclusive preterm formula, but exclusive maternal milk was associated with a lower risk of retinopathy of prematurity (very low certainty). Results may change when additional studies are conducted. There was no difference in weight, length, and head circumference gain between infants fed fortified exclusive maternal milk and infants receiving exclusive preterm formula; however, weight and length gain were lower in infants fed non-fortified exclusive maternal milk. Given the observational nature of human milk research, cause-and-effect evidence was lacking for VLBW preterm infants. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=86829, PROSPERO ID: CRD42018086829.

Developmental regulation of the gut-liver (FGF19-CYP7A1) axis in neonates.

Introduction: Fibroblast growth factor 19 (FGF19) is a gut-derived hormone that regulates the expression of CYP7A1, the rate-limiting enzyme in bile acid (BA) synthesis pathway. Dysregulation of the FGF19-CYP7A1 (gut-liver) axis is associated with cholestatic liver disease. Infants, especially preterm infants and those with intestinal failure are at high risk for developing cholestatic liver disease. The activity of the gut-liver axis has not been characterized in this population. Our objective was to assess relationships between circulating FGF19 concentrations and CYP7A1 activity in neonates.Materials and methods: Plasma samples were obtained longitudinally from term and preterm infants (22-41-week gestation) hospitalized in a neonatal intensive care unit. Infants with congenital and acquired gastrointestinal disorders were excluded. Plasma levels of 7α-hydroxy-4-cholesten-3-one (C4), a marker of CYP7A1 activity, were quantified using HPLC-MS/MS. Plasma FGF19 concentrations were quantified by ELISA. Data were analyzed using linear regression models and structural equation modeling.Results: One hundred eighty-one plasma samples were analyzed from 62 infants. C4 concentrations were undetectable prior to 30 weeks' gestation and, thereafter, increased with advancing gestational age and with volume of enteral feeds. They did not correlate with serum FGF19 concentrations, which decreased with advancing gestational age and volume of enteral feeds.Discussion: The activity of CYP7A1, the rate-limiting BA synthetic enzyme in adults, is developmentally regulated and undetectable in newborns less than 30 weeks' gestation. FGF19 concentrations do not correlate with CYP7A1 activity, suggesting that the gut-liver axis is not functional in infants. High FGF19 concentrations at birth in infants less than 37 weeks' gestation is a novel finding, and its source and role in preterm infants warrants further investigation.Rationale: The intestinal hormone, fibroblast growth factor 19 (FGF19), is a major regulator of CYP7A1, the rate limiting enzyme in bile acid (BA) synthesis. Recently, dysregulation of the gut-liver (FGF19-CYP7A1) axis has been implicated in adult cholestatic liver disease, and animal studies have shown that exogenous FGF19 protects against liver injury. Given the therapeutic potential related to this signaling pathway, we sought to characterize the association between CYP7A1 and FGF19 in term and preterm infants. We conducted a prospective, observational study that measured in vivo CYP7A1 activity and FGF19 concentrations in 62 term and preterm infants (n = 181 samples). We found that CYP7A1 activity is developmentally regulated; its activity is undetectable prior to 30 weeks' gestation and increases with advancing gestational age and volume of enteral feeds. Contrary to expectation, we demonstrated that FGF19 is expressed at birth in preterm infants and decreases over time, even as enteral feeds increase. Using structural equation modeling, we were able to show that CYP7A1 activity does not correlate with FGF19 concentrations. Our results suggest that the gut-liver axis is not upregulated in preterm and term infants and that neonates with cholestatic liver disease will unlikely benefit from supplemental FGF19. We also report novel findings of elevated FGF19 concentrations in preterm infants at birth and speculate that there may be an extra-intestinal source of FGF19 that is developmentally expressed in these infants.

Accuracy of preterm infant weight gain velocity calculations vary depending on method used and infant age at time of measurement.

BACKGROUND: We examined preterm infants' weight gain velocity (WGV) to determine how much calculation methods influences actual WGV during the first 28 days of life. METHODS: WGV methods (Average 2-point, Exponential 2-point, Early 1-point, and Daily) were calculated weekly and for various start times (birth, nadir, regain, day 3 and day 7) to 28 days of age for 103 preterm < 1500 gram infants, with daily weights. RESULTS: Range of WGV estimates decreased 10-22 g/kg/day to 15.5-15.8 g/kg/day when the Early 1-point method and the postnatal weight loss phase were excluded. WGV were lower when the postnatal weight loss was included and higher using the early method. WGV calculations beginning at day 7 did not differ from calculations beginning at the nadir. CONCLUSIONS: Variations in WGV calculations were large enough to create difficulties for comparing results between studies and translating research to practice. We recommend that the postnatal weight loss phase be excluded from WGV calculations and clinical studies report weight nadir and weights at day 7 and 28 to allow adequate comparison and translation of findings in clinical practice. The Average2pt method may be easier to calculate at bedside, so we recommend it be used in clinical settings and research summaries. The Early1pt method should not be used to summarize WGV for research.

Time interval for preterm infant weight gain velocity calculation precision.

Calculation of weight gain velocity is used to guide nutrition and fluid management practices in neonatal intensive care units. Calculations over short time periods may be more responsive to management changes, but less precise. Weight gain velocity calculated over 5 to 7+ days have lower variability and less noise than shorter periods.

Essential Fatty Acid Deficiency with SMOFlipid Reduction in an Infant with Intestinal Failure-Associated Liver Disease.

Multicomponent lipid emulsions, such as SMOFlipid, contain intermediate amounts of essential fatty acids (EFAs) compared with traditional soybean-oil based lipid emulsions and 100% fish-oil lipid emulsions. We describe the development of moderate EFA deficiency (EFAD) and slow weight gain in an infant with intestinal failure-associated liver disease managed with SMOFlipid reduction (1 g/kg/d). Once SMOFlipid dosage was increased (2-3 g/kg/d), EFA levels normalized, adequate growth resumed, and the infant's cholestasis resolved. We recommend avoiding lipid reduction of SMOFlipid, which not only increases the risk for EFAD, but also is unnecessary given that cholestasis can be reversed on conventional doses of SMOFlipid.

Preterm Infant Growth Velocity Calculations: A Systematic Review.

CONTEXT: Clinicians assess the growth of preterm infants and compare growth velocity using a variety of methods. OBJECTIVE: We determined the numerical methods used to describe weight, length, and head circumference growth velocity in preterm infants; these methods include grams/kilogram/day (g/kg/d), grams/day (g/d), centimeters/week (cm/week), and change in z scores. DATA SOURCES: A search was conducted in April 2015 of the Medline database by using PubMed for studies that measured growth as a main outcome in preterm neonates between birth and hospital discharge and/or 40 weeks' postmenstrual age. English, French, German, and Spanish articles were included. The systematic review was conducted by using Preferred Reporting Items for Systematic Reviews and Meta-analyses methods. STUDY SELECTION: Of 1543 located studies, 373 (24%) calculated growth velocity. DATA EXTRACTION: We conducted detailed extraction of the 151 studies that reported g/kg/d weight gain velocity. RESULTS: A variety of methods were used. The most frequently used method to calculate weight gain velocity reported in the 1543 studies was g/kg/d (40%), followed by g/d (32%); 29% reported change in z score relative to an intrauterine or growth chart. In the g/kg/d studies, 39% began g/kg/d calculations at birth/admission, 20% at the start of the study, 10% at full feedings, and 7% after birth weight regained. The kilogram denominator was not reported for 62%. Of the studies that did report the denominators, the majority used an average of the start and end weights as the denominator (36%) followed by exponential methods (23%); less frequently used denominators included birth weight (10%) and an early weight that was not birth weight (16%). Nineteen percent (67 of 355 studies) made conclusions regarding extrauterine growth restriction or postnatal growth failure. Temporal trends in head circumference growth and length gain changed from predominantly cm/wk to predominantly z scores. LIMITATIONS AND CONCLUSIONS: The lack of standardization of methods used to calculate preterm infant growth velocity makes comparisons between studies difficult and presents an obstacle to using research results to guide clinical practice.

Post-discharge formula feeding in preterm infants: A systematic review mapping evidence about the role of macronutrient enrichment.

BACKGROUND & AIMS: Preterm infants are a heterogeneous group and many accumulate growth deficits before and after initial hospital discharge. Although this is associated with worse cognitive outcome, recent meta-analyses suggest that nutrient fortification of breast milk, or the use of nutrient and energy rich formulae after discharge exert little effect on growth and neurodevelopment. However, the complexity of study design, inclusion criteria and outcome parameters, combined with differences in formula composition mean that meta-analysis may overlook important effects of differing interventions in sub-groups. METHODS: We systematically identified evidence and mapped the information on Participants, Intervention, Comparator, and Outcome (PICO) from 31 published studies illustrating the marked heterogeneity in study design and interventions next to outcomes on (quality of) growth and neurodevelopment. RESULTS: Despite significant heterogeneity in study design, we found that nutrient enriched diets after discharge show no negative effects but frequently improve growth parameters at some point in the course of the study, in particular for boys. The data indicates that when energy requirements are adequate, increased protein results in increased growth and lean mass (LM) accretion; In particular, higher protein to energy ratios lead to increased lean mass accretion, and increased head circumference (HC) at one year. However, improvements in neurodevelopmental outcome were rarely seen. CONCLUSION: This comprehensive evidence mapping approach to the field provides a broad but detailed overview of the currently available evidence. Furthermore, we identified key gaps in existing knowledge on the role of nutrient enrichment in the post-discharge period.

Postnatal growth failure in very low birthweight infants born between 2005 and 2012.

BACKGROUND: Postnatal growth restriction is common in preterm infants and is associated with long-term neurodevelopmental impairment. Recent trends in postnatal growth restriction are unclear. METHODS: Birth and discharge weights from 25,899 Californian very low birthweight infants (birth weight 500-1500 g, gestational age 22-32 weeks) who were born between 2005 and 2012 were converted to age-specific Z-scores and analysed using multivariable modelling. RESULTS: Birthweight Z-score did not change between 2005 and 2012. However, the adjusted discharge weight Z-score increased significantly by 0.168 Z-scores (0.154, 0.182) over the study period, and the adjusted fall in weight Z-score between birth and discharge decreased significantly between those dates (by 0.016 Z-scores/year). The proportion of infants who were discharged home below the 10th weight-for-age centile or had a fall in weight Z-score between birth and discharge of >1 decreased significantly over time. The comorbidities most associated with poorer postnatal growth were medical or surgical necrotising enterocolitis, isolated gastrointestinal perforation and severe retinopathy of prematurity, which were associated with an adjusted mean reduction in discharge weight Z-score of 0.24, 0.57, 0.46 and 0.32, respectively. Chronic lung disease was not a risk factor after accounting for length of stay. CONCLUSIONS: Postnatal, but not prenatal, growth improved among very low birthweight infants between 2005 and 2012. Neonatal morbidities including necrotising enterocolitis, gastrointestinal perforations and severe retinopathy of prematurity have significant negative effects on postnatal growth.

Catch-Up Growth: Basic Mechanisms.

The neuroendocrine model of catch-up growth has been well studied in a number of animal models. During nutritional inadequacy, which invariably precedes catch-up growth, growth hormone (GH) levels increase under the influence of the oxygenic 'hunger signal' ghrelin. This increase in GH would usually be accompanied by an increase in IGF-1. However, malnutrition also induces the nutritionally responsive proteins sirtuin 1 (SIRT1) and fibroblast growth factor 21 (FGF21) that block GH signal transduction in the liver by blocking the JAK/STAT pathway, limiting IGF-1 production. The result is that GH's action is shifted from hepatic effects to effects in other tissues (for example muscle and adipose) and shifted away from IGF-1-mediated effects and towards GH-mediated effects. Once nutrients become more available, SIRT1 and FGF21 levels, and hepatic GH sensitivity return to normal, and production of IGF-1 resumes. This shifts GH signaling away from GH-mediated effects, and towards IGF-1-mediated effects both in the liver and in other tissues. It presumably leads to greatly increased IGF-1 signaling that would have been expected without the prior episode of nutritional inadequacy. Although much work remains to be done, it does appear that ghrelin is increased in in utero and postnatal malnutrition, that elevations in ghrelin may be prolonged after malnutrition resolves, and that higher ghrelin levels are associated with increased rates of catch-up growth. Prolonged increases in circulating ghrelin and GH, combined with a rapid return in hepatic GH sensitivity would provide an elegant mechanism to drive catch-up growth after periods of nutritional insufficiency.

Effects of postnatal growth restriction and subsequent catch-up growth on neurodevelopment and glucose homeostasis in rats.

BACKGROUND: There is increasing evidence that poor growth of preterm infants is a risk factor for poor long-term development, while the effects of early postnatal growth restriction are not well known. We utilized a rat model to examine the consequences of different patterns of postnatal growth and hypothesized that early growth failure leads to impaired development and insulin resistance. Rat pups were separated at birth into normal (N, n = 10) or restricted intake (R, n = 16) litters. At d11, R pups were re-randomized into litters of 6 (R-6), 10 (R-10) or 16 (R-16) pups/dam. N pups remained in litters of 10 pups/dam (N-10). Memory and learning were examined through T-maze test. Insulin sensitivity was measured by i.p. insulin tolerance test and glucose tolerance test. RESULTS: By d10, N pups weighed 20% more than R pups (p < 0.001). By d15, the R-6 group caught up to the N-10 group in weight, the R-10 group showed partial catch-up growth and the R-16 group showed no catch-up growth. All R groups showed poorer scores in developmental testing when compared with the N-10 group during T-Maze test (p < 0.05). Although R-16 were more insulin sensitive than R-6 and R-10, all R groups were more glucose tolerant than N-10. CONCLUSION: In rats, differences in postnatal growth restriction leads to changes in development and in insulin sensitivity. These results may contribute to better elucidating the causes of poor developmental outcomes in human preterm infants.

Childhood growth patterns following congenital heart disease.

INTRODUCTION: Prenatal and early postnatal growth are known to be abnormal in patients with CHD. Although adult metabolic risk is associated with growth later in childhood, little is known of childhood growth in CHD. PATIENTS AND METHODS: Retrospective data were collected on 551 patients with coarctation of the aorta, hypoplastic left heart syndrome, single ventricle physiology, tetralogy of Fallot, transposition of the great arteries, or ventricular septal defects. Weight, height, and body mass index data were converted to Z-scores. Body size at 2 years and growth between 2 and 20 years, 2 and 7 years, and 8 and 15 years were compared with Normative data using a sequential series of mixed-effects linear models. RESULTS: A total of 4660 weight, 2989 height, and 2988 body mass index measurements were analysed. Body size at 2 years of age was affected by cardiac diagnosis and gender. Abnormal growth was frequent and varied depending on cardiac diagnosis, gender, and the time period considered. The most abnormal patterns were seen in patients with tetralogy of Fallot, hypoplastic left heart syndrome, or single ventricle physiology. Potentially high-risk growth, a combination of small body size at 2 years and rapid subsequent growth, was seen in several groups. CONCLUSIONS: Childhood and adolescent growth patterns were gender- and lesion-specific. Several lesions were associated with abnormal patterns of childhood growth known to be associated with an increased risk of adult adiposity or metabolic risk in other populations. Further information is needed on the long-term metabolic risks of survivors of CHD.

Zinc and copper requirements in preterm infants: an examination of the current literature.

BACKGROUND: Zinc and copper are essential for preterm infants, but recommended requirements from different groups vary widely. Recommended zinc intakes have steadily increased over the years. Although this would be expected to impair copper absorption, recommended copper intakes have not risen in parallel. OBJECTIVES: To systematically review the literature on zinc and copper retention in preterm infants; to examine the effect on zinc intake on copper retention; and to estimate the zinc and copper intakes required to meet the levels of zinc and copper retention required for normal growth. DESIGN: Studies reporting zinc and/or copper retention in preterm infants (<36 weeks of gestation) during the first 120 days of life were identified using PubMed. Only studies reporting net retention were included. RESULTS: Fourteen studies on zinc retention reporting data on 45 different groups were identified. Eleven studies (32 groups) were identified reporting copper retention. Zinc retention was significantly higher at higher zinc intakes, and higher in formula-based diets than in human milk based diets. Zinc intakes of between 1.8-2.4 mg/kg/d (from formula based diets) and 2.3-2.4 mg/kg/d (from human-milk based diets) were required to achieve adequate zinc retention. Copper retention was significantly positively correlated with copper intake and significantly negatively correlated with zinc intake. At the zinc intakes suggested previously (1.8-2.4, 2.3-2.4 mg/kg/d), copper intakes of between 200 and 250 mcg/kg/d are required to ensure adequate copper retention. CONCLUSIONS: Our results support the higher zinc intakes recommended in recent guidelines. However, they suggest that recommended copper intakes have not kept pace with increasing zinc intakes, and that preterm infants may need higher copper intakes than currently recommended.