Stool and urine trefoil factor 3 levels: associations with symptoms, intestinal permeability, and microbial diversity in irritable bowel syndrome.

Previously we showed that urine trefoil factor 3 (TFF3) levels were higher in females with irritable bowel syndrome (IBS) compared to non-IBS females. To assess if TFF3 is associated with symptoms and/or reflect alterations in gastrointestinal permeability and gut microbiota in an IBS population, we correlated stool and urine TFF3 levels with IBS symptoms, intestinal permeability, stool microbial diversity and relative abundance of predominant bacterial families and genera. We also tested the relationship of stool TFF3 to urine TFF3, and compared results based on hormone contraception use. Samples were obtained from 93 females meeting Rome III IBS criteria and completing 4-week symptom diaries. TFF3 levels were measured by ELISA. Permeability was assessed with the urine lactulose/mannitol (L/M) ratio. Stool microbiota was assessed using 16S rRNA. Stool TFF3, but not urine TFF3, was associated positively with diarrhoea and loose stool consistency. Higher stool TFF3 was also associated with lower L/M ratio and microbial diversity. Of the 20 most abundant bacterial families Mogibacteriaceae and Christensenellaceae were inversely related to stool TFF3, with only Christensenellaceae remaining significant after multiple comparison adjustment. There were no significant relationships between stool or urine TFF3 levels and other symptoms, nor between stool and urine levels. In premenopausal females, urine TFF3 levels were higher in those reporting hormone contraception. Collectively these results suggest that higher stool TFF3 levels are associated with IBS symptoms (loose/diarrhoeal stools), lower gut permeability, and altered stool bacteria composition (decreased diversity and decreased Christensenellaceae), which further suggests that TFF3 may be an important marker of host-bacteria interaction.

Review article: the physiological effects and safety of peppermint oil and its efficacy in irritable bowel syndrome and other functional disorders.

BACKGROUND: Peppermint oil has been used for centuries as a treatment for gastrointestinal ailments. It has been shown to have several effects on gastrointestinal physiology relevant to clinical care and management. AIM: To review the literature on peppermint oil regarding its metabolism, effects on gastrointestinal physiology, clinical use and efficacy, and safety. METHODS: We performed a PubMed literature search using the following terms individually or in combination: peppermint, peppermint oil, pharmacokinetics, menthol, oesophagus, stomach, small intestine, gallbladder, colon, transit, dyspepsia, nausea, abdominal pain, and irritable bowel syndrome. Full manuscripts evaluating peppermint oil that were published through 15 July 2017 were reviewed. When evaluating therapeutic indications, only randomised clinical trials were included. References from selected manuscripts were used if relevant. RESULTS: It appears that peppermint oil may have several mechanisms of action including: smooth muscle relaxation (via calcium channel blockade or direct enteric nervous system effects); visceral sensitivity modulation (via transient receptor potential cation channels); anti-microbial effects; anti-inflammatory activity; modulation of psychosocial distress. Peppermint oil has been found to affect oesophageal, gastric, small bowel, gall-bladder, and colonic physiology. It has been used to facilitate completion of colonoscopy and endoscopic retrograde cholangiopancreatography. Placebo controlled studies support its use in irritable bowel syndrome, functional dyspepsia, childhood functional abdominal pain, and post-operative nausea. Few adverse effects have been reported in peppermint oil trials. CONCLUSION: Peppermint oil is a natural product which affects physiology throughout the gastrointestinal tract, has been used successfully for several clinical disorders, and appears to have a good safety profile.

Relationships of abdominal pain, reports to visceral and temperature pain sensitivity, conditioned pain modulation, and heart rate variability in irritable bowel syndrome.

BACKGROUND: Irritable bowel syndrome (IBS) is a heterogeneous condition with a number of pathophysiological mechanisms that appear to contribute to symptom chronicity. One of these is altered pain sensitivity. METHODS: Women between ages 18-45 were recruited the community. Of those enrolled, 56 had IBS and 36 were healthy control (HC) women. Participants completed questionnaires, kept a 4-week symptom diary and had a 12-h Holter placed to assess nighttime heart rate variability including high frequency power (HF), low frequency power (LF), and total power (TP). At mid-follicular phase approximately 80% of women completed a thermal pain sensitivity test with conditioned pain modulation and visceral pain sensitivity using a water load symptom provocation (WLSP) test. KEY RESULTS: As expected, daily abdominal pain was significantly higher in the IBS compared to HC group. There were no differences between the bowel pattern subgroups (IBS-diarrhea [IBS-D], IBS-constipation plus mixed [IBS-CM]). Thermal pain sensitivity did not differ between the IBS and the HC groups, but was significantly higher in the IBS-CM group than the IBS-D group. In the WLSP test, the IBS group experienced significantly more symptom distress than HCs and the IBS-CM group was higher than the IBS-D group. Heart rate variability indicators did not differ between the groups or IBS subgroups. Daily abdominal pain was positively correlated with LF and TP in the IBS group. CONCLUSIONS & INFERENCES: Despite similar levels of abdominal pain in IBS, the IBS-CM group demonstrated greater sensitivity to both thermal and visceral testing procedures.

Bristol Stool Form Scale reliability and agreement decreases when determining Rome III stool form designations.

BACKGROUND: Rater reproducibility of the Bristol Stool Form Scale (BSFS), which categorizes stools into one of seven types, is unknown. We sought to determine reliability and agreement by individual stool type and when responses are categorized by Rome III clinical designation as normal or abnormal (constipation or diarrhea). METHODS: Thirty-four gastroenterology providers from three institutions rated 35 stool photographs using the BSFS. Twenty rerated the photographs. KEY RESULTS: 1190 individual stool type ratings were completed. Though only four photographs had absolute agreement (all Type 1 or Type 7), general agreement was high with 1132 (95.1%) of ratings being within one category type of the modal rating. Inter-rater and intra-rater reliability of the BSFS by individual stool type was excellent with intraclass correlations of 0.88 (95% CI: 0.86-0.90, p < 0.001) and 0.89 (95% CI: 0.86-0.91, p < 0.001), respectively. However, agreement decreased when using Rome III designations with 13 (37%) photographs having significantly diverging classifications (semi-interquartile range = 0.5). These 13 photographs were rated by the majority of raters as either type 2 vs type 3 or type 5 vs type 6 stools, representing the boundaries of normal vs abnormal stools. Inter-rater and intra-rater reliability of the BSFS by Rome III clinical categorization decreased with intraclass correlations of 0.75 (95% CI: 0.69-0.81, p < 0.001) and 0.65 (95% CI: 0.49-0.81, p < 0.001), respectively. CONCLUSIONS & INFERENCES: The Bristol Stool Form Scale has excellent reliability and agreement when used to rate individual stool type by raters. However, BSFS reliability and agreement decreases when determining Rome III stool form categories.

Randomised clinical trial: gut microbiome biomarkers are associated with clinical response to a low FODMAP diet in children with the irritable bowel syndrome.

BACKGROUND: A low fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAP) diet can ameliorate symptoms in adult irritable bowel syndrome (IBS) within 48 h. AIM: To determine the efficacy of a low FODMAP diet in childhood IBS and whether gut microbial composition and/or metabolic capacity are associated with its efficacy. METHODS: In a double-blind, crossover trial, children with Rome III IBS completed a 1-week baseline period. They then were randomised to a low FODMAP diet or typical American childhood diet (TACD), followed by a 5-day washout period before crossing over to the other diet. GI symptoms were assessed with abdominal pain frequency being the primary outcome. Baseline gut microbial composition (16S rRNA sequencing) and metabolic capacity (PICRUSt) were determined. Metagenomic biomarker discovery (LEfSe) compared Responders (≥50% decrease in abdominal pain frequency on low FODMAP diet only) vs. Nonresponders (no improvement during either intervention). RESULTS: Thirty-three children completed the study. Less abdominal pain occurred during the low FODMAP diet vs. TACD [1.1 ± 0.2 (SEM) episodes/day vs. 1.7 ± 0.4, P < 0.05]. Compared to baseline (1.4 ± 0.2), children had fewer daily abdominal pain episodes during the low FODMAP diet (P < 0.01) but more episodes during the TACD (P < 0.01). Responders were enriched at baseline in taxa with known greater saccharolytic metabolic capacity (e.g. Bacteroides, Ruminococcaceae, Faecalibacterium prausnitzii) and three Kyoto Encyclopedia of Genes and Genomes orthologues, of which two relate to carbohydrate metabolism. CONCLUSIONS: In childhood IBS, a low FODMAP diet decreases abdominal pain frequency. Gut microbiome biomarkers may be associated with low FODMAP diet efficacy. ClinicalTrials.gov identifier: NCT01339117.

Agreement between prospective diary data and retrospective questionnaire report of abdominal pain and stooling symptoms in children with irritable bowel syndrome.

BACKGROUND: In functional gastrointestinal disorders, patient recall of symptoms drives diagnostic decisions and evaluation of treatment response, and research conclusions about potential treatments. In pediatrics, parent report also impacts assessment and care. Hence, identifying methods for accurately capturing patient and parent report of irritable bowel syndrome (IBS) symptoms is important. This study evaluated correspondence between retrospective questionnaire (parent and child report) and prospective diary data for children and adolescents with IBS. METHODS: Participants included 50 children/adolescents with IBS per Rome III criteria. Children completed a 2-week pain and stool diary. Children and parents subsequently completed a 2-week recall questionnaire, reporting number of pain days, maximum pain, days without bowel movement, and days with diarrhea during the diary interval. Intraclass correlation coefficients and Bland-Altman plots assessed agreement. KEY RESULTS: For pain and days without bowel movement, overall agreement between child recall questionnaire and child diary was strong, although under conditions likely to facilitate agreement and with individual variation observed. Parent recall and child diary were less concordant, and agreement about diarrhea was poor for parent and child. Age did not significantly correlate with agreement. CONCLUSIONS & INFERENCES: Child questionnaire with short recall interval may be a reasonable approximation for diary data, although this varies by individual and replication/investigation of lengthier recall are needed. Relying on parent questionnaire does not appear a suitable proxy, and recall of stool form by both parent and child appears more problematic. These results combined with existing literature support use of diary data whenever possible.

Gastric emptying scintigraphy results in children are affected by age, anthropometric factors, and study duration.

BACKGROUND: A standardized 4-h adult-based gastric emptying scintigraphy (GES) protocol is increasingly being used in children to evaluate for gastroparesis. We sought to determine the effect of age, anthropometrics, and study duration on GES results using this protocol in children. METHODS: Retrospective review of children who underwent a 4-h solid-meal GES study at a tertiary care center. GES results and anthropometric data (e.g., weight, stature, body surface area [BSA]) were systematically captured. KEY RESULTS: Of 216 children, 188 (87%) were able to complete the study meal. Children unable to complete the meal were younger and smaller. In multivariate analysis, only increasing BSA was identified as being positively associated with ability to complete the meal (odds ratio: 19.7; p < 0.001). Of those completing the meal, 48 (26%) had delayed emptying (4-h retention value >10%). These children were significantly younger and smaller than those with normal emptying. In multivariate analysis of those completing the meal, only increasing BSA (odds ratio: 0.26; p = 0.006) was identified as being negatively associated with delayed emptying. There was a progressive increase in the positive predictive value for identification of delayed gastric emptying as the duration of the study increased (0.25, 0.60, and 0.71 at 1, 2, and 3 h, respectively) using the 4-hr value as a comparator. CONCLUSIONS & INFERENCES: Young children have more difficulty completing the GES meal. Childhood gastric retention is affected by age and anthropometric factors, primarily BSA. The standardized 4-h GES protocol may need to take these factors into account in children.

Neuroimmune interactions at different intestinal sites are related to abdominal pain symptoms in children with IBS.

BACKGROUND: Neuroimmune interactions and inflammation have been proposed as factors involved in sensory-motor dysfunction and symptom generation in adult irritable bowel syndrome (IBS) patients. In children with IBS and healthy controls, we measured ileocolonic mast cell infiltration and fecal calprotectin and evaluated the relationships between these parameters and abdominal pain symptoms and stooling pattern. METHODS: Irritable bowel syndrome patients diagnosed according to Pediatric Rome III criteria and healthy controls kept a 2-week pain/stooling diary. Ileocolonic mucosal mast cells (MC) and MC in close proximity to nerve fibers (MC-NF) were identified immunohistochemically and quantified. Fecal calprotectin concentration was measured. KEY RESULTS: 21 IBS patients and 10 controls were enrolled. The MC-NF count was significantly higher in the ileum (p = 0.01), right colon (p = 0.04), and left colon (p < 0.001) of IBS patients compared with controls. No differences in fecal calprotectin concentration were noted. Abdominal pain intensity score correlated with ileal MC count (r(s) = 0.47, p = 0.030) and right colon MC-NF count (r(s) = 0.52, p = 0.015). In addition, children with IBS with >3 abdominal pain episodes/week had greater ileal (p = 0.002) and right colonic (p = 0.01) MC counts and greater ileal (p = 0.05) and right colonic (p = 0.016) MC-NF counts than children with less frequent pain. No relationship was found between MC and MC-NF and fecal calprotectin or stooling pattern. CONCLUSIONS & INFERENCES: Mast cells-nerve fibers counts are increased in the ileocolonic mucosa of children with IBS. Mast cells and MC-NF counts are related to the intensity and frequency of abdominal pain.

The interpretation of Rome III criteria and method of assessment affect the irritable bowel syndrome classification of children.

BACKGROUND: Paediatric classification of irritable bowel syndrome (IBS) is complicated by the potential discrepancy between parent and child report and by the interpretation of pain-stool relations in the Rome III classification system. AIM: To compare IBS classification by diary and by child and parent respondents. METHODS: Children (ages 7-10 years, n = 90) with recurrent abdominal pain and their parents completed IBS symptom questionnaires and 2-week pain and stool diaries. Diaries were coded with two algorithms, one defining stool changes individually and one defining changes normatively. Proportions of dichotomous classifications (IBS vs. not IBS) between pairs of classification methods/respondents were evaluated using Chi-squared tests (χ²) to determine whether coding methods were significantly related, the degree of inclusiveness, and whether differences in classification were randomly distributed. RESULTS: Individual and normative diary classifications were congruent in 62% of cases, but the individual method classified more children with IBS, 53% vs. 18%. Parent and child questionnaire reports were not correlated. The normative diary classifications and parent questionnaire were the most congruent pair of methods (76% of cases). CONCLUSIONS: Poor congruence among methods suggests that Rome III IBS criteria need better specification, and efforts to improve parent-child agreement are necessary.

Diagnostic yield of oesophagogastroduodenoscopy in children with abdominal pain.

BACKGROUND: Abdominal pain is the most common indication for oesophagogastroduodenoscopy (OGD) in children. However, existing studies examining the diagnostic outcomes of OGD in children with abdominal pain are limited. AIM: To examine the diagnostic yield of OGD with biopsy in the evaluation of abdominal pain and to describe the endoscopic and histological findings in patients undergoing OGD for abdominal pain of unclear aetiology. METHODS: We performed a retrospective cross-sectional cohort study in children under 18 years of age who had OGD for the primary indication of abdominal pain, at Texas Children's Hospital and Children's Hospital of The King's Daughters from 1 January 2002 to 30 June 2005. RESULTS: Overall, OGD was diagnostic in 454 (38.1%) of the 1191 procedures, including reflux oesophagitis (23%, n = 271), Helicobacter pylori infections (5%, n = 55), peptic ulcers (3%, n = 32), eosinophilic oesophagitis (2%, n = 25), celiac disease (1%, n = 9) and Crohn's disease (0.5%, n = 7). Male gender, older age, elevated C-reactive protein and vomiting were associated with increased diagnostic yield. CONCLUSIONS: Our findings suggest that OGD is valuable for the evaluation of chronic abdominal pain in children, with a diagnostic yield of 38%. The majority of alarm symptoms and routine laboratory tests are not significantly associated with diagnostic yield.

Effect of enteral administration of insulin on intestinal development and feeding tolerance in preterm infants: a pilot study.

OBJECTIVE: To determine in a pilot study whether enteral administration of insulin to preterm infants (26-29 weeks of gestational age) would enhance gastrointestinal development and reduce feed intolerance without adverse effects. DESIGN: Eight preterm infants were given 4 U/kg/day insulin enterally from 4 to 28 days of age. Lactase activity was measured at 28 days of age, while measures of feed intolerance were made throughout the hospital stay. The results were compared with those of a matched historical cohort of 80 preterm infants. SETTING: Tertiary care, university affiliated hospital. MAIN OUTCOME MEASURES: Lactase activity and feed intolerance. RESULTS: No adverse effects, such as hypoglycaemia, were observed after administration of insulin. The infants who received insulin had higher lactase activity and less feed intolerance than the controls (30% shorter time to full enteral feeds; fewer gastric residuals per infant). CONCLUSION: These preliminary data suggest that enteral insulin administration may be of benefit in reducing feed intolerance in preterm infants. A randomised, blinded trial is warranted.

Effects of age, feeding regimen, and glucocorticoids on catecholamine and cortisol excretion in preterm infants.

BACKGROUND: The sympathoadrenal system is important in maintaining normal physiologic functioning in infants and increased output also can reflect stress. We sought to determine the effects of age, feeding regimen, and glucocorticoids on catecholamine and cortisol excretion in preterm infants and to assess whether a particular strategy of feeding enhanced sympathoadrenal development or was stressful. METHODS: Preterm infants (26-30 wk gestation; n = 171) were assigned randomly to begin trophic feedings from day 4 through 14 (trophic group) or to start feedings at day 15 (standard group) with feedings administered either by bolus every 3 hours (bolus) or continuously over 24 hours (continuous). At 10, 28, 40, 50, and 60 days of age, urine was collected continuously for 6 hours for measurement of catecholamines (norepinephrine, epinephrine, dopamine), cortisol, and creatinine. Data were available for 98 infants. RESULTS: Norepinephrine excretion increased with postnatal age. The increase with age was significantly greater in the trophic group compared with that in the standard group. Epinephrine excretion did not change with age, and there were no differences between trophic and standard groups. Dopamine excretion increased with age but was similar between trophic and standard groups (borderline significantly greater in the trophic group). Cortisol excretion increased with age and also was similar between trophic and standard groups. There was no effect on catecholamine or cortisol excretion of bolus vs continuous feedings, antenatal or postnatal corticosteroids, gestational age at birth, age at which full feedings were attained, or use of human milk compared with preterm formula. CONCLUSIONS: The greatest determinant of catecholamine and cortisol excretion is postnatal age. Feeding method, type of feeding, and glucocorticoid administration in the amounts customarily used have little significant effect on catecholamine or cortisol excretion. The apparent link between early feeding and norepinephrine (and possibly dopamine) excretion warrants further investigation.

Characterization of the developmental stages of sucking in preterm infants during bottle feeding.

It is acknowledged that the difficulty many preterm infants have in feeding orally results from their immature sucking skills. However, little is known regarding the development of sucking in these infants. The aim of this study was to demonstrate that the bottle-feeding performance of preterm infants is positively correlated with the developmental stage of their sucking. Infants' oral-motor skills were followed longitudinally using a special nipple/bottle system which monitored the suction and expression/compression component of sucking. The maturational process was rated into five primary stages based on the presence/absence of suction and the rhythmicity of the two components of sucking, suction and expression/compression. This five-point scale was used to characterize the developmental stage of sucking of each infant. Outcomes of feeding performance consisted of overall transfer (percent total volume transferred/volume to be taken) and rate of transfer (ml/min). Assessments were conducted when infants were taking 1-2, 3-5 and 6-8 oral feedings per day. Significant positive correlations were observed between the five stages of sucking and postmenstrual age, the defined feeding outcomes, and the number of daily oral feedings. Overall transfer and rate of transfer were enhanced when infants reached the more mature stages of sucking. We have demonstrated that oral feeding performance improves as infants' sucking skills mature. In addition, we propose that the present five-point sucking scale may be used to assess the developmental stages of sucking of preterm infants. Such knowledge would facilitate the management of oral feeding in these infants.

New developments in total parenteral nutrition for children.

The field of parenteral nutrition continues to evolve along two major paths: prevention of complications and refining of nutritional needs. Parenteral nutrition-associated liver disease remains a vexing problem. No single factor is to blame; rather, it requires a number of "hits." In the infant, the liver disease primarily appears to be related to prematurity of bile flow and production, infection, lack of enteral feedings, and most recently appreciated, perhaps free radicals. We are able to meet the nutritional needs of our patients, but our knowledge of actual nutritional requirements remains incomplete. Future studies need to define better appropriate intakes and to rigorously test the utility of proposed nutrients such as glutamine.

Feeding tolerance in premature infants fed fortified human milk.

BACKGROUND: To evaluate feeding tolerance in premature infants immediately after the addition of human milk fortifier (HMF) to their expressed human milk diet. METHODS: Data on milk intake, feeding tolerance, and related assessments and growth milestones from a prospective study of feeding strategies in premature infants were analyzed. The database was searched for the first day HMF was added to the feeding of infants receiving human milk exclusively. The following assessments were tabulated for the 5 days before and the 5 days after the addition of HMF: milk intake, the number of episodes of abdominal distension, gastric residual volume (GRV) more than 2 ml/kg and more than 50% of the volume fed in the prior 3 hours. bile-stained gastric residual, emesis or regurgitation, blood in the stool, the number of abdominal radiographs, the number of episodes of apnea and bradycardia, changes in findings in the clinical examination, and the number of hours feeding was withheld. The time to achieve full tube feeding, complete oral feeding, and hospital discharge were recorded. RESULTS: Seventy-six exclusively human milk-fed premature infants (birth weight, 1065+/-18 g; gestational age, 27+/-0.1 weeks; mean +/- SEM) who received HMF beginning 22+/-0.8 days of age were evaluated. There were significant increases in milk intake and in the number of episodes of GRV more than 2 ml/kg and emesis after the addition of HMF. There were no differences in the number of hours feeding was withheld or any other assessment after the addition of HMF. Infants with increases in GRV more than 2 ml/kg and/or emesis after the addition of HMF were not more likely to be delayed in the time to achieve full tube feeding, complete oral feeding, or hospital discharge than infants who did not experience these events. CONCLUSION: These data suggest that, when all feeding and related assessments and the time to achieve important growth milestones are considered, the addition of HMF does not adversely affect the outcome of the premature infant.

Feeding strategies for premature infants: beneficial outcomes of feeding fortified human milk versus preterm formula.

BACKGROUND: In a large-scale study of feeding strategies in premature infants (early vs later initiation of enteral feeding, continuous vs bolus tube-feeding, and human milk vs formula), the feeding of human milk had more effect on the outcomes measured than any other strategy studied. Therefore, this report describes the growth, nutritional status, feeding tolerance, and health of participating premature infants who were fed fortified human milk (FHM) in comparison with those who were fed exclusively preterm formula (PF). METHODS: Premature infants were assigned randomly in a balanced two-way design to early (gastrointestinal priming for 10 days) versus late initiation of feeding (total parenteral nutrition only) and continuous infusion versus intermittent bolus tube-feeding groups. The type of milk was determined by parental choice and infants to receive their mother's milk were randomized separately from those to receive formula. The duration of the study spanned the entire hospitalization of the infant. To evaluate human milk versus formula feeding, we compared outcomes of infants fed >50 mL. kg-1. day-1 of any human milk (averaged throughout the hospitalization) with those of infants fed exclusively PF. Growth, feeding tolerance, and health status were measured daily. Serum indices of nutritional status were measured serially, and 72-hour nutrient balance studies were conducted at 6 and 9 weeks postnatally. RESULTS: A total of 108 infants were fed either >50 mL. kg-1. day-1 human milk (FHM, n = 62) or exclusively PF (n = 46). Gestational age (28 +/- 1 weeks each), birth weight (1.07 +/- 0.17 vs 1.04 +/- 0.19 kg), birth length and head circumference, and distribution among feeding strategies were similar between groups. Infants fed FHM were discharged earlier (73 +/- 19 vs 88 +/- 47 days) despite significantly slower rates of weight gain (22 +/- 7 vs 26 +/- 6 g. kg-1. day-1), length increment (0.8 +/- 0.3 vs 1.0 +/- 0.3 cm. week-1), and increment in the sum of five skinfold measurements (0.86 +/- 0.40 vs 1.23 +/- 0.42 mm. week-1) than infants fed PF. The incidence of necrotizing enterocolitis and late-onset sepsis was less in the FHM group. Overall, there were no differences in any measure of feeding tolerance between groups. Milk intakes of infants fed FHM were significantly greater than those fed PF (180 +/- 13 vs 157 +/- 10 mL. kg-1. day-1). The intakes of nitrogen and copper were higher and magnesium and zinc were lower in group FHM versus PF. Fat and energy absorption were lower and phosphorus, zinc, and copper absorption were higher in group FHM versus PF. The postnatal retention (balance) surpassed the intrauterine accretion rate of nitrogen, phosphorus, magnesium, zinc, and copper in the FHM group, and of nitrogen, magnesium, and copper in the PF group. CONCLUSIONS: Although the study does not allow a comparison of FHM with unfortified human milk, the data suggest that the unique properties of human milk promote an improved host defense and gastrointestinal function compared with the feeding of formula. The benefits of improved health (less sepsis and necrotizing enterocolitis) associated with the feeding of FHM outweighed the slower rate of growth observed, suggesting that the feeding of FHM should be promoted actively in premature infants.