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.

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.

Feeding preterm infants today for later metabolic and cardiovascular outcomes.

Preterm birth continues to contribute disproportionately to neonatal morbidity and subsequent physical and neurodevelopmental disabilities. Epidemiologic studies have described additional long-term health consequences of preterm birth such as an increased risk of hypertension and insulin resistance in adult life. It is not known whether the influence of infant and childhood growth rates and early nutrition on long-term outcomes is the same or different among preterm infants and neonates with intrauterine growth restriction. Our goal is to review the effects of fetal growth, postnatal growth, and early nutrition on long-term cardiovascular and metabolic outcomes in preterm infants. Present evidence suggests that even brief periods of relative undernutrition during a sensitive period of development have significant adverse effects on later development. Our review suggests that growth between birth and expected term and 12-18 months post-term has no significant effect on later blood pressure and metabolic syndrome, whereas reduced growth during hospitalization significantly impacts later neurodevelopment. In contrast, growth during late infancy and childhood appears to be a major determinant of later metabolic and cardiovascular well being, which suggests that nutritional interventions during this period are worthy of more study. Our review also highlights the paucity of well-designed, controlled studies in preterm infants of the effects of nutrition during hospitalization and after discharge on development, the risk of developing hypertension, or insulin resistance.

Effects of early postnatal growth restriction and subsequent catch-up growth on body composition, insulin sensitivity, and behavior in neonatal rats.

BACKGROUND: Early postnatal growth retardation with subsequent catch-up growth is common in preterm infants. We describe a model of ex utero (postnatal) growth retardation followed by varying degrees of catch-up growth in the neonatal rat. METHODS: Newborn CD rat pups were randomized to litters of 10 (NN, normal then normal intake) or 16 (R, restricted intake). On day 10, R pups were further randomized to litters of 6 (RC, restricted then catch-up intake), 10 (RN, restricted then normal intake), or 16 (RR, restricted then restricted intake). Body weight, body composition, insulin sensitivity, biochemistry, and learning (passive avoidance test) were assessed. RESULTS: Growth was significantly lower in the R than the NN group. Subsequently, the RC group caught up with the NN group but had higher fat mass; the RN group showed partial catch-up but body composition similar to that of the NN group. Insulin sensitivity did not differ between groups. Learning behavior was significantly better in the NN than the three R groups, and in the RC group than the RR or RN groups. CONCLUSION: Early postnatal growth retardation is associated with poorer medium-term growth and poorer developmental outcome. Increased catch-up growth is associated with improved developmental outcome but with increased body adiposity, without any significant effect on glucose homeostasis.

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.

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.

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.

Adiposity is not altered in preterm infants fed with a nutrient-enriched formula after hospital discharge.

To determine whether adiposity was altered, body size (weight, length) and composition, determined by dual energy x-ray absorptiometry, were examined in preterm infants fed with a nutrient enriched (A, n=56), a term infant (B, n=57) or the nutrient enriched (discharge and term) plus the term formula (term and 6 mo; C, n=26), and a group of breast-fed preterm infants (D, n=25) at hospital discharge, 3, 6, and 12 mo corrected age. The results were analyzed using standard statistics. One hundred sixty-four infants (birth weight=1406+/-248 g, GA=31+/-1.7 wk) were studied. All infants underwent "catch-up," but weight and length were greater in infants in group A compared with groups B, C, or D. More rapid and complete "catch-up" was paralleled by increased total nonfat and fat mass (g) but not percentage of fat mass. Changes in fat mass (g) were primarily explained by increased fat accretion on the legs. More rapid and complete "catch-up" growth, therefore, reflected increased nonfat and peripheral fat mass. These data do not support the hypothesis of increased or central adiposity in infants fed a nutrient-enriched formula after hospital discharge.

Perturbed zinc homeostasis in rural 3-5-y-old Malawian children is associated with abnormalities in intestinal permeability attributed to tropical enteropathy.

Tropical enteropathy and zinc deficiency are major public health problems worldwide. Tropical enteropathy is characterized by reduced mannitol absorption with normal or increased lactulose absorption when a dual sugar absorption test is administered, the results of which are reported as the lactulose:mannitol ratio (L:M). Zinc homeostasis is quantified with a dual stable isotope test. This study tested the hypothesis that endogenous fecal zinc (EFZ) was correlated with the L:M. A dual sugar absorption test and dual stable isotope test were performed on 25 asymptomatic Malawian children aged 3-5 y at risk for tropical enteropathy and zinc deficiency. EFZ and net zinc retention were estimated and correlated with the L:M. Twenty-two children (88%) had an abnormal L:M (L:M>0.10), and the L:M was 0.24+/-0.10 (mean+/-SD). EFZ was 1.68+/-1.06 mg/d, a quantity greater than is seen in healthy populations from the developed world. EFZ was positively correlated with the L:M (r=0.62, p<0.001). Net zinc retention (0.67+/-1.6 mg/d) was negatively correlated with the L:M (r=-0.47, p=0.02). This suggests that perturbed zinc homeostasis is associated with subclinical enteropathy in these children.

Orange but not apple juice enhances ferrous fumarate absorption in small children.

OBJECTIVE: Ferrous fumarate is a common, inexpensive iron form increasingly used instead of ferrous sulfate as a food iron supplement. However, few data exist as to whether juices enhance iron absorption from ferrous fumarate. SUBJECTS AND METHODS: We studied 21 children, ages 4.0 to 7.9 years using a randomized crossover design. Subjects consumed a small meal including a muffin containing 4 mg Fe as ferrous fumarate and either apple (no ascorbic acid) or orange juice (25 mg ascorbic acid). They were separately given a reference dose of Fe (ferrous sulfate) with ascorbic acid. RESULTS: Iron absorption increased from 5.5% +/- 0.7% to 8.2% +/- 1.2%, P < 0.001 from the muffins given with orange juice compared with muffins given with apple juice. The absorption of ferrous fumarate given with orange juice and enhancement of absorption by the presence of juice were significantly positively related to height, weight, and age (P < 0.01 for each). Although iron absorption from ferrous fumarate given with apple juice was significantly inversely associated with the (log transformed) serum ferritin, the difference in absorption between juice types was not (P > 0.9). CONCLUSIONS: These data demonstrate an overall benefit to iron absorption from ferrous fumarate provided with orange juice. The effect was age related such that in children older than 6 years of age, there was a nearly 2-fold increase in iron absorption from ferrous fumarate given with orange juice.

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.

Meals and dephytinization affect calcium and zinc absorption in Nigerian children with rickets.

Nutritional rickets resulting from calcium insufficiency is common in Nigeria and high dietary phytate is thought to inhibit calcium and zinc absorption. We compared the effects of a high-phytate meal and enzymatic dephytinization on calcium and zinc absorption in Nigerian children with and without rickets. Nineteen children with rickets and 15 age-matched control children, aged 2-10 y, were given calcium (600 mg/d) and ergocalciferol (1250 microg/wk). After 6 wk, calcium and zinc absorption were measured in both groups with and without maize porridge using stable isotopes. One week later, absorption measurements were repeated to assess the effects of enzymatic dephytinization and fermentation of the maize porridge. The phytate concentration of maize porridge (3.87 +/- 0.38 g/kg wet weight) was reduced by enzymatic dephytinization (2.83 +/- 0.41 g/kg; P < 0.001) but not by fermentation (3.35 +/- 0.27 g/kg; P = 0.08). Calcium and zinc absorption were unaffected by the presence of rickets or by fermentation of maize porridge. Calcium absorption was greater with a meal (61.3 +/- 25.1%) than without (27.8 +/- 14.6%; P < 0.001). Zinc absorption was lower with a meal (16.2 +/- 8.0%) than without (63.4 +/- 23.9%; P < 0.001). Enzymatic dephytinization increased relative zinc absorption from a meal by 101 +/- 81% (P < 0.001) but did not affect calcium absorption. Rickets was not associated with impaired calcium or zinc absorption. Calcium absorption was enhanced by maize porridge, but zinc absorption was reduced. Enzymatic dephytinization increased zinc absorption. Multiple strategies may be required to optimize calcium and zinc absorption in deficient populations.

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.

Magnesium retention in 12 to 48 month-old children.

OBJECTIVES: In adults, adaptation to changes in magnesium intake is largely due to changes in fractional magnesium absorption and urinary magnesium excretion. We sought to examine whether these homeostatic mechanism also occurred in young children. METHODS: Children, 12-48 m old were studied (n=30). They were adapted to a home diet representative of their usual magnesium intake for 7 d then admitted for a stable isotope study. Children received 5 mg Mg-25 intravenously, and 10 mg Mg-26 orally (5 mg with breakfast and 5 mg with lunch). Magnesium absorption was calculated from the relative fractional excretion of the oral and intravenous isotopes in the urine samples. Endogenous fecal magnesium absorption was calculated in a subgroup from the fecal and urinary excretion of the intravenous tracer. RESULTS: Magnesium intake (mean +/- SD; 106 +/- 25 mg/d) was significantly greater than the Estimated Average Requirement (EAR) described by the Institute of Medicine in the US (65 mg/d, p < 0.0001). Across the range of intake studied, fractional magnesium absorption was significantly (P = 0.0383) but weakly (r(2) = 0.144) related to magnesium intake. Absolute magnesium absorption (the product of fractional absorption and intake) significantly increased as intake increased (r(2) = 0.566, P < 0.0001). Urinary magnesium excretion was unrelated to magnesium intake (r(2) = 0.036, P = 0.31). Endogenous fecal magnesium excretion tended to increase as magnesium intake increased (r(2) = 0.312, P = 0.12). Magnesium retention (absolute absorption minus urinary and fecal losses) was positive in 26 of the 30 subjects studied, and was linearly related to magnesium intake (r(2) = 0.157, P = 0.0304). A magnesium intake of 52-78 mg/d would appear to be required to meet the needs for absorbed magnesium for half the children at this age range, suggesting that the current EAR is broadly appropriate. CONCLUSIONS: In young children, consuming magnesium intakes typical of the US population, fractional magnesium absorption is a major site of magnesium homeostasis, but magnesium retention increased linearly across the intake range studied. Our results support at EAR for magnesium of 55-80 mg/d and an RDA of 70-100 mg/d.