Estimation of skeletal muscle mass in 4-year-old children using the D3-creatine dilution method.

BACKGROUND: Given limited experience in applying the creatine-(methyl-D3) (D3Cr) dilution method to measure skeletal muscle mass (SMM) in young children, the feasibility of deployment in a fielding setting and performance of the method was assessed in a cohort of 4-year-old children in Dhaka, Bangladesh. METHODS: Following D3Cr oral dose (10 mg) administration, single fasting urine samples were collected at 2-4 days (n = 100). Twenty-four-hour post-dose collections and serial spot urine samples on days 2, 3 and 4 were obtained in a subset of participants (n = 10). Urinary creatine, creatinine, D3Cr and D3-creatinine enrichment were analyzed by liquid chromatography-tandem mass spectrometry. Appendicular lean mass (ALM) was measured by dual-energy x-ray absorptiometry and grip strength was measured by a hand-held dynamometer. RESULTS: SMM was measured successfully in 91% of participants, and there were no adverse events. Mean ± SD SMM was greater than ALM (4.5 ± 0.4 and 3.2 ± 0.6 kg, respectively). Precision of SMM was low (intraclass correlation = 0.20; 95% CI: 0.02, 0.75; n = 10). Grip strength was not associated with SMM in multivariable analysis (0.004 kg per 100 g of SMM; 95% CI: -0.031, 0.038; n = 91). CONCLUSIONS: The D3Cr dilution method was feasible in a community setting. However, high within-child variability in SMM estimates suggests the need for further optimization of this approach. IMPACT: The D3-creatine (D3Cr) stable isotope dilution method was considered a feasible method for the estimation of skeletal muscle mass (SMM) in young children in a community setting and was well accepted among participants. SMM was weakly associated with both dual-energy x-ray absorptiometry-derived values of appendicular lean mass and grip strength. High within-child variability in estimated values of SMM suggests that further optimization of the D3Cr stable isotope dilution method is required prior to implementation in community research settings.

Prenatal Weight Change Trajectories and Perinatal Outcomes among Twin Gestations.

OBJECTIVE: Despite an increase in twin pregnancies in recent decades, the Institute of Medicine twin weight gain recommendations remain provisional and provide no guidance for the pattern or timing of weight change. We sought to characterize gestational weight change trajectory patterns and examine associations with birth outcomes in a cohort of twin pregnancies. STUDY DESIGN: Prenatal and delivery records were examined for 320 twin pregnancies from a maternal-fetal medicine practice in Austin, TX 2011-2019. Prenatal weights for those with >1 measured weight in the first trimester and ≥3 prenatal weights were included in analyses. Trajectories were estimated to 32 weeks (mean delivery: 33.7 ± 3.3 weeks) using flexible latent class mixed models with low-rank thin-plate splines. Associations between trajectory classes and infant outcomes were analyzed using multivariable Poisson or linear regression. RESULTS: Weight change from prepregnancy to delivery was 15.4 ± 6.3 kg for people with an underweight body mass index, 15.4 ± 5.8 kg for healthy weight, 14.7 ± 6.9 kg for overweight, and 12.5 ± 6.4 kg for obesity. Three trajectory classes were identified: low (Class 1), moderate (Class 2), or high gain (Class 3). Class 1 (24.7%) maintained weight for 15 weeks and then gained an estimated 6.6 kg at 32 weeks. Class 2 (60.9%) exhibited steady gain with 13.5 kg predicted total gain, and Class 3 (14.4%) showed rapid gain across pregnancy with 21.3 kg predicted gain. Compared to Class 1, Class 3 was associated with higher birth weight z-score (ß = 0.63, 95% confidence interval [CI]: 0.31,0.96), increased risk for large for gestational age (IRR = 5.60, 95% CI: 1.59, 19.67), and birth <32 weeks (IRR = 2.44, 95%CI: 1.10, 5.4) that was attenuated in sensitivity analyses. Class 2 was associated with moderately elevated birth weight z-score (ß = 0.24, 95%CI: 0.00, 0.48, p = 0.050). CONCLUSION: Gestational weight change followed a low, moderate, or high trajectory; both moderate and high gain patterns were associated with increased infant size outcomes. Optimal patterns of weight change that balance risk during the prenatal, perinatal, and neonatal periods require further investigation, particularly in high-risk twin pregnancies. KEY POINTS: · A majority gained weight below IOM twin recommendations.. · Three patterns of GWC across pregnancy were identified.. · Moderate or high GWC was associated with infant size..

Daily Intake of a Functional Synbiotic Yogurt Increases Calcium Absorption in Young Adult Women.

BACKGROUND: Foods containing both prebiotics and probiotics (synbiotics) might enhance calcium bioavailability. OBJECTIVES: We investigated the acute effect in young adult women on calcium absorption of consuming (185 mL) a synbiotic yogurt (SYN) containing inulin (4 g) and Lactobacillus rhamnosus GG (>1 × 107 CFU/mL) compared with a control yogurt (CON). METHODS: Adult normal-weight women (25.0 ± 3.5 y, n = 30) participated in a 3-wk crossover study testing daily consumption of SYN compared with CON. Habitual dietary intake, bone mineral density (BMD), calcium biomarkers, and serum 25-hydroxyvitamin D were measured at baseline. Calcium absorption was tested after each phase of the study using a 42Ca oral tracer. Cumulative tracer recovery was measured in 0-4-h,  0-24-h, and 0-36-h urine pools collected postdosing. The SYN/CON tracer ratio from the timed urine pools was the primary outcome. A beneficial response to SYN was defined as 0-36-h SYN/CON tracer ratio >1. RESULTS: Net 42Ca recovered increased over time in each of the SYN and CON urine pools postdosing (Friedman, P < 0.001), with a trend for higher 42Ca recovery in the 0-36-h urine pool postdosing in the SYN (1.14%) compared with the CON (0.90%) study (Wilcoxon, P = 0.07). For CON, the majority of total tracer was recovered in the 0-24-h pool (86%), whereas for SYN only 50% of total tracer was recovered in the 0-24-h pool (Friedman, P = 0.001). The SYN/CON tracer ratio in the 0-36-h pool (1.24) was >1 (Wilcoxon, P = 0.015). About two-thirds (n = 19) of women studied responded to the SYN treatment. Responders had higher vegetable intake (P = 0.03), tended to have higher potassium and calcium intakes (P ≤ 0.08), and had higher total body BMD (P = 0.09), than nonresponders. CONCLUSIONS: Short-term daily consumption of a synbiotic yogurt enhanced calcium absorption relative to a control yogurt in adult women. Given the observed time delays in tracer recovery, enhancement of calcium absorption likely occurred in the large intestine.The study was registered at clinicaltrials.gov (study registration ID: NCT03420716).

A Substantial Proportion of 6- to 12-Month-Old Infants Have Calculated Daily Absorbed Iron below Recommendations, Especially Those Who Are Breastfed.

OBJECTIVE: To calculate the amount of bioavailable iron consumed among 6- to 12- month-old infants considering differences in iron bioavailability among dietary iron sources and to compare this with current recommended intakes. STUDY DESIGN: We used the Feeding Infants and Toddlers Study database of dietary intakes from 2016 and the estimated bioavailability of dietary iron sources to evaluate the proportion of infants whose calculated total daily absorbed iron fell below physiologic requirements, that is, the recommended amount needed to fully support growth and erythropoiesis. RESULTS: The calculated daily iron absorption was below the recommended amount in 54.3% of infants evaluated ranging from 19.5% of 448 exclusively formula-fed infants, to 95.8% of 296 exclusively breastfed infants and 72.2% of 102 mixed fed infants. The calculated mean iron absorption of 6- to 9- month-old breastfed infants was 0.27 mg/day, far less than the estimated physiologic requirement of 0.69 mg/day. The most highly bioavailable iron, heme iron, was <12% of the contributor to total iron absorbed in breastfed infants. CONCLUSIONS: These data indicate a need for further education and public health policies to support increased iron intake in 6- to 12- month-old infants, emphasizing those receiving any breast milk. Exclusively formula-fed infants are at lower risk, but rates of low absorbed iron indicate that all infants may need monitoring for clinical evidence of low iron status. Consideration should be given to increasing the proportion of heme iron obtained from animal products in the diet where feasible.

Lessons Learned from Hereditary 1,25-Dihydroxyvitamin D-Resistant Rickets Patients on Vitamin D Functions.

We summarize here lessons learned from studies on skeletal and extra-skeletal functions of vitamin D in hereditary 1,25-dihydroxyvitamin D-resistant rickets (HVDRR) patients with a mutant, nonfunctioning vitamin D receptor (VDR). During childhood, HVDRR patients are dependent on intestinal VDR, demonstrate low intestinal fraction calcium absorption, and have a bone calcium accretion rate that leads to hypocalcemia and rickets. After puberty, there is recovery in intestinal calcium absorption and in bone calcium accretion and structure. HVDRR monocytes and lymphocytes show impairment in the expression of antimicrobial proteins and demonstrate a proinflammatory cytokine profile. However, HVDRR patients do not exhibit increased rates of infections or inflammatory diseases. Vitamin D deficiency is associated with asthmatic exacerbations. Surprisingly, HVDRR patients do not usually develop asthma. They have normal allergic tests and lung functions and are protected against provoked bronchial hyperactivity. HVDRR patients have decreased IL-5 levels in their exhaled breath condensate. Given that IL-5 is a key cytokine in the development of airway inflammation and hyperactivity and that VDR is important for IL-5 generation, it is plausible that low lung IL-5 protects HVDRR patients from asthma. Vitamin D metabolites have suppressive effects on the renin angiotensin system. However, no HVDRR patient showed hypertension or echocardiographic pathology, and their renin angiotensin metabolites were normal. The VDR is expressed throughout the reproductive system, suggesting a role in reproduction. However, the reproductive history of HVDRR patients is normal despite the lack of a normal VDR. HVDRR patients provide a unique opportunity to study the role of the VDR and the role of vitamin D in various human systems.

Vitamin D supplementation for term breastfed infants to prevent vitamin D deficiency and improve bone health.

BACKGROUND: Vitamin D deficiency is common worldwide, contributing to nutritional rickets and osteomalacia which have a major impact on health, growth, and development of infants, children and adolescents. Vitamin D levels are low in breast milk and exclusively breastfed infants are at risk of vitamin D insufficiency or deficiency. OBJECTIVES: To determine the effect of vitamin D supplementation given to infants, or lactating mothers, on vitamin D deficiency, bone density and growth in healthy term breastfed infants. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to 29 May 2020 supplemented by searches of clinical trials databases, conference proceedings, and citations. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs in breastfeeding mother-infant pairs comparing vitamin D supplementation given to infants or lactating mothers compared to placebo or no intervention, or sunlight, or that compare vitamin D supplementation of infants to supplementation of mothers. DATA COLLECTION AND ANALYSIS: Two review authors assessed trial eligibility and risk of bias and independently extracted data. We used the GRADE approach to assess the certainty of evidence. MAIN RESULTS: We included 19 studies with 2837 mother-infant pairs assessing vitamin D given to infants (nine studies), to lactating mothers (eight studies), and to infants versus lactating mothers (six studies). No studies compared vitamin D given to infants versus periods of infant sun exposure. Vitamin D supplementation given to infants: vitamin D at 400 IU/day may increase 25-OH vitamin D levels (MD 22.63 nmol/L, 95% CI 17.05 to 28.21; participants = 334; studies = 6; low-certainty) and may reduce the incidence of vitamin D insufficiency (25-OH vitamin D < 50 nmol/L) (RR 0.57, 95% CI 0.41 to 0.80; participants = 274; studies = 4; low-certainty). However, there was insufficient evidence to determine if vitamin D given to the infant reduces the risk of vitamin D deficiency (25-OH vitamin D < 30 nmol/L) up till six months of age (RR 0.41, 95% CI 0.16 to 1.05; participants = 122; studies = 2), affects bone mineral content (BMC), or the incidence of biochemical or radiological rickets (all very-low certainty). We are uncertain about adverse effects including hypercalcaemia. There were no studies of higher doses of infant vitamin D (> 400 IU/day) compared to placebo. Vitamin D supplementation given to lactating mothers: vitamin D supplementation given to lactating mothers may increase infant 25-OH vitamin D levels (MD 24.60 nmol/L, 95% CI 21.59 to 27.60; participants = 597; studies = 7; low-certainty), may reduce the incidences of vitamin D insufficiency (RR 0.47, 95% CI 0.39 to 0.57; participants = 512; studies = 5; low-certainty), vitamin D deficiency (RR 0.15, 95% CI 0.09 to 0.24; participants = 512; studies = 5; low-certainty) and biochemical rickets (RR 0.06, 95% CI 0.01 to 0.44; participants = 229; studies = 2; low-certainty). The two studies that reported biochemical rickets used maternal dosages of oral D3 60,000 IU/day for 10 days and oral D3 60,000 IU postpartum and at 6, 10, and 14 weeks. However, infant BMC was not reported and there was insufficient evidence to determine if maternal supplementation has an effect on radiological rickets (RR 0.76, 95% CI 0.18 to 3.31; participants = 536; studies = 3; very low-certainty). All studies of maternal supplementation enrolled populations at high risk of vitamin D deficiency. We are uncertain of the effects of maternal supplementation on infant growth and adverse effects including hypercalcaemia. Vitamin D supplementation given to infants compared with supplementation given to lactating mothers: infant vitamin D supplementation compared to lactating mother supplementation may increase infant 25-OH vitamin D levels (MD 14.35 nmol/L, 95% CI 9.64 to 19.06; participants = 269; studies = 4; low-certainty). Infant vitamin D supplementation may reduce the incidence of vitamin D insufficiency (RR 0.61, 95% CI 0.40 to 0.94; participants = 334; studies = 4) and may reduce vitamin D deficiency (RR 0.35, 95% CI 0.17 to 0.72; participants = 334; studies = 4) but the evidence is very uncertain. Infant BMC and radiological rickets were not reported and there was insufficient evidence to determine if maternal supplementation has an effect on infant biochemical rickets. All studies enrolled patient populations at high risk of vitamin D deficiency. Studies compared an infant dose of vitamin D 400 IU/day with varying maternal vitamin D doses from 400 IU/day to > 4000 IU/day. We are uncertain about adverse effects including hypercalcaemia. AUTHORS' CONCLUSIONS: For breastfed infants, vitamin D supplementation 400 IU/day for up to six months increases 25-OH vitamin D levels and reduces vitamin D insufficiency, but there was insufficient evidence to assess its effect on vitamin D deficiency and bone health. For higher-risk infants who are breastfeeding, maternal vitamin D supplementation reduces vitamin D insufficiency and vitamin D deficiency, but there was insufficient evidence to determine an effect on bone health. In populations at higher risk of vitamin D deficiency, vitamin D supplementation of infants led to greater increases in infant 25-OH vitamin D levels, reductions in vitamin D insufficiency and vitamin D deficiency compared to supplementation of lactating mothers. However, the evidence is very uncertain for markers of bone health. Maternal higher dose supplementation (≥ 4000 IU/day) produced similar infant 25-OH vitamin D levels as infant supplementation of 400 IU/day. The certainty of evidence was graded as low to very low for all outcomes.

Vitamin D in Preterm and Full-Term Infants.

Vitamin D is necessary for the active (transcellular) absorption of calcium and for skeletal health. Inadequate vitamin D in infants leads to increased risks of poor bone mineralization and ultimately rickets. Rickets is uncommon in full-term infants with a much higher risk in very premature infants. However, the primary cause of rickets in premature infants is a deficiency of calcium and phosphorus, not vitamin D. Available research, as well as most guidelines, recommend an intake of 400 IU daily of vitamin D as adequate for bone health in preterm and full-term infants. Higher doses have not been consistently shown to have specific clinical benefits for healthy infants. There are no strong data to support either routine testing of serum 25-hydroxyvitamin D or targeting high serum 25-hydroxyvitamin D levels (e.g., 30 ng/mL) in healthy preterm or full-term infants. Vitamin D is commonly provided to infants via drops for breastfed babies or via infant formula, although alternative dosing approaches exist for breastfed infants, which some families may prefer. These include the use of drops placed on the mother's breast, dissolvable doses, and high maternal doses (approximately 6,400 IU daily). Infant formula contains vitamin D, and most infants will reach an intake from formula of about 400 IU daily within the first 2 months of life if they are consuming routine cow milk-based formula. Although vitamin D toxicity is very uncommon, caution should be used to avoid extremely concentrated high doses found in some commercially available drops. Infants with liver or kidney disease may need special attention to vitamin D intake and status. Further research is needed to define the role of vitamin D in non-bone health outcomes of infants and to identify methods to enhance compliance with current recommendations for vitamin D intake in infants.

Using stable isotope tracers to study bone metabolism in children.

Skeletal mineralization is initiated in utero and continues throughout childhood and adolescence. During these key periods of the life cycle, calcium retention must increase significantly to provide sufficient mineral for bone deposition and skeletal growth. Stable calcium isotopes have served as a fundamental tool to non-invasively characterize the dynamic changes in calcium physiology that occur from infancy through adolescence. These approaches have helped define the dynamics of calcium absorption and utilization in healthy children and in children with chronic diseases. As data in this area have accumulated, new areas of emphasis are beginning to characterize the determinants of variability in mineral retention, the genetic determinants of bone turnover and calcium flux and the impact of the gut microbiome on whole body and niche specific calcium dynamics. Advances in these areas will help define calcium utilization in paediatric populations and provide information that may be useful in maximizing bone acquisition across this critical phase of the life cycle.

Generalized metabolic bone disease and fracture risk in Rothmund-Thomson syndrome.

Rothmund-Thomson syndrome (RTS) is a rare autosomal recessive disorder characterized by poikiloderma, small stature, sparse hair, skeletal abnormalities, increased risk of osteosarcoma, and decreased bone mass. To date, there has not been a comprehensive evaluation of the prevalence and extent of metabolic bone disease in RTS. Furthermore, the mechanisms that result in this phenotype are largely unknown. In this report, we provide a detailed evaluation of 29 individuals with RTS with respect to their metabolic bone status including bone mineral density, calcium kinetics studies, and markers of bone remodeling. We show that individuals with RTS have decreased areal bone mineral density. Additionally, we demonstrate that the presence of pathogenic variants in RECQL4 and low bone mineral density correlate with the history of increased risk of fractures. Using a RECQL4-deficient mouse model that recapitulates skeletal abnormalities seen in individuals with RTS, we demonstrate that generalized skeletal involvement is likely due to decreased osteogenesis. Our findings are clinically relevant as they may help in the risk stratification of patients with RTS and also in the identification of individuals who may benefit from additional surveillance and management of metabolic bone disease.

Enteral lactoferrin for the treatment of sepsis and necrotizing enterocolitis in neonates.

BACKGROUND: Neonatal sepsis and necrotizing enterocolitis (NEC) cause significant neonatal mortality and morbidity despite appropriate antibiotic therapy. Enhancing host defense and modulating inflammation by using lactoferrin as an adjunct to antibiotics in the treatment of sepsis, NEC, or both, may improve clinical outcomes. OBJECTIVES: The primary objective was to assess safety and efficacy of oral lactoferrin as an adjunct to antibiotics in the treatment of neonates with suspected or confirmed sepsis, NEC, or both. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2018, Issue 9), MEDLINE via PubMed, PREMEDLINE, (1966 to 20 September 2018) Embase (1980 to 20 September 2018), and CINAHL (1982 to 20 September 2018). We also searched clinical trial databases, conference proceedings, the reference lists of retried articles and clinical trials, and the authors' personal files. SELECTION CRITERIA: We included randomized or quasi-randomized controlled trials evaluating enteral lactoferrin (at any dose or duration), used as an adjunct to antibiotic therapy, compared with antibiotic therapy alone (with or without placebo) or other adjuncts to antibiotic therapy to treat neonates at any gestational age up to 44 weeks' postmenstrual age with confirmed or suspected sepsis or necrotizing enterocolitis (Bell's Stage II or III). DATA COLLECTION AND ANALYSIS: We used the standardized methods of Cochrane Neonatal for conducting a systematic review and for assessing the methodological quality of studies (neonatal.cochrane.org/en/index.html). The titles and the abstracts of studies identified by the search strategy were independently assessed by the two review authors and full text versions were obtained for assessment if necessary. Forms were designed to record trial inclusion/exclusion and data extraction. We used the GRADE approach to assess the quality of evidence. MAIN RESULTS: We did not identify any eligible trials evaluating lactoferrin for the treatment of neonatal sepsis or NEC. AUTHORS' CONCLUSIONS: Implications for practice: currently there is no evidence to support or refute the use of enteral lactoferrin, as an adjunct to antibiotic therapy, for the treatment of neonatal sepsis or necrotizing enterocolitis. IMPLICATIONS FOR RESEARCH: given the lack of efficacy of enteral lactoferrin for preventing late-onset sepsis and necrotizing enterocolitis, evaluation of enteral lactoferrin as an adjunctive agent for treatment of sepsis or necrotizing enterocolitis does not appear to be a research priority.

Oxytocin, a main breastfeeding hormone, prevents hypertension acquired in utero: A therapeutics preview.

Hypertension is a major risk factor for ischemic heart disease and stroke, leading causes of morbidity and death worldwide. Intrauterine growth restriction (IUGR), caused by an excess of glucocorticoid exposure to the fetus, produces an imbalance in oxidative stress altering many biochemical and epigenetic gene transcription processes exposing the fetus and neonate to the 'thrifty' phenotype and pervasive polymorphisms appearance damaging health, cognitive, and behavioral processes in later life. OT is a major regulator of oxidative stress radicals that plays a major role in neonatal maturation of the central nervous system and many peripheral tissues expressing oxytocin/oxytocin-receptor (OT/OTR) system in the early postnatal period. OT and OTR are damaged by IUGR and early stress. This review highlights the fact that hypertension is likely to be a legacy of preterm birth due to IUGR and failure to meet nutritional needs in early infancy when fed formula instead of breastfeeding or human milk.

Delaying Iron Therapy until 28 Days after Antimalarial Treatment Is Associated with Greater Iron Incorporation and Equivalent Hematologic Recovery after 56 Days in Children: A Randomized Controlled Trial.

BACKGROUND: Iron therapy begun concurrently with antimalarial treatment may not be well absorbed because of malaria-induced inflammation. Delaying the start of iron therapy may permit better iron absorption and distribution. OBJECTIVE: We compared erythrocyte iron incorporation in children who started iron supplementation concurrently with antimalarial treatment or 28 d later. We hypothesized that delayed iron supplementation would be associated with greater incorporation and better hematologic recovery. METHODS: We enrolled 100 children aged 6-59 mo with malaria and hemoglobin concentrations of 50.0-99.9 g/L who presented to Mulago Hospital, Kampala, into a randomized trial of iron therapy. All children were administered antimalarial treatment. Children with zinc protoporphyrin (ZPP) ≥80 µmol/mol heme were randomly assigned to start iron supplementation concurrently with the antimalarial treatment [immediate iron (I) group] or 28 d later [delayed iron (D) group]. All children were administered iron-stable isotope (57)Fe on day 0 and (58)Fe on day 28. We compared the percentage of iron incorporation at the start of supplementation (I group at day 0 compared with D group at day 28, aim 1) and hematologic recovery at day 56 (aim 2). RESULTS: The percentage of iron incorporation (mean ± SE) was greater at day 28 in the D group (16.5% ± 1.7%) than at day 0 in the I group (7.9% ± 0.5%; P < 0.001). On day 56, concentrations of hemoglobin and ZPP and plasma ferritin, soluble transferrin receptor (sTfR), hepcidin, and C-reactive protein did not differ between the groups. On day 28, the hemoglobin (mean ± SD) and plasma iron markers (geometric mean; 95% CI) reflected poorer iron status in the D group than in the I group at this intervening time as follows: hemoglobin (105 ± 15.9 compared with 112 ± 12.4 g/L; P = 0.04), ferritin (39.3 µg/L; 23.5, 65.7 µg/L compared with 79.9 µg/L; 58.3, 110 µg/L; P = 0.02), sTfR (8.9 mg/L; 7.4, 10.7 mg/L compared with 6.7 mg/L; 6.1, 7.5 mg/L; P = 0.01), and hepcidin (13.3 ng/mL; 8.3, 21.2 ng/mL compared with 38.8 ng/mL; 28.3, 53.3 ng/mL; P < 0.001). CONCLUSIONS: Delaying the start of iron improves incorporation but leads to equivalent hematologic recovery at day 56 in Ugandan children with malaria and anemia. These results do not demonstrate a clear, short-term benefit of delaying iron. This trial was registered at clinicaltrials.gov as NCT01754701.

Delayed Introduction of Parenteral Phosphorus Is Associated with Hypercalcemia in Extremely Preterm Infants.

BACKGROUND: Early parenteral nutrition (PN) provides essential macro- and micronutrients for extremely low birth weight (ELBW) infants <1000 g. Frequent cases of hypercalcemia [whole blood ionized calcium (iCa) > 1.45 mmol/L] in the first week of life while receiving PN solutions at our large quaternary center prompted investigation and 2 plan-do-study-act (PDSA) cycles to reduce rates of hypercalcemia. OBJECTIVE: We compared 2 cohorts of ELBW infants separated by PDSA cycles to evaluate and reduce the incidence of abnormal iCa concentration. METHODS: Data were recorded for 150 premature infants with mean birth weight of 726 ± 164 g, 48% male, and mean gestational age of 26 ± 2.1 wk. This process included an internal practice analysis and PDSA cycles monitored prospectively over 3 y. From December 2011 to September 2012, 66 infants received 0-1.2 mmol parenteral phosphorus supplementation/(kg ⋅ d) beginning at 72 h of life. In the second protocol, 84 infants born September 2012 to July 2013 received earlier phosphorus supplementation within 24 h of life. The peak whole blood iCa and serum phosphorus concentrations in the first week of life were monitored. RESULTS: Early introduction of phosphorus was significantly associated with a decreased mean peak iCa (1.64 ± 0.27 mmol/L to 1.50 ± 0.23 mmol/L, P = 0.001), and the incidence of severe hypercalcemia (iCa > 1.60 mmol/L) decreased from 50.0% to 21.4% (P = 0.002) in the first week of life. There was no difference in mortality, bronchopulmonary dysplasia, renal calcifications, seizures within 7 d of birth, brain calcifications, or intracranial hemorrhage between cohorts. CONCLUSION: Early introduction of phosphorus in PN solutions is associated with reduced incidence of whole blood iCa abnormalities in the first week of life and should be considered for ELBW infants. Ongoing evaluation of optimal mineral provision to this population after birth should be performed.

Oral lactoferrin for the prevention of sepsis and necrotizing enterocolitis in preterm infants.

BACKGROUND: Lactoferrin, a normal component of human colostrum and milk, can enhance host defense and may be effective in the prevention of sepsis and necrotizing enterocolitis (NEC) in preterm neonates. OBJECTIVES: Primary objective To assess the safety and effectiveness of oral lactoferrin in the prevention of sepsis and NEC in preterm neonates. Secondary objectives1. To determine the effects of oral lactoferrin used to prevent neonatal sepsis and/or NEC on duration of positive-pressure ventilation, development of chronic lung disease (CLD) or periventricular leukomalacia (PVL), length of hospital stay to discharge among survivors, and adverse neurological outcomes at two years of age or later.2. To determine the adverse effects of oral lactoferrin in the prophylaxis of neonatal sepsis and/or NEC.When data were available, we analyzed the following subgroups.1. Gestational age < 32 weeks and 32 to 36 weeks.2. Birth weight < 1000 g (extremely low birth weight (ELBW) infants) and birth weight < 1500 g (very low birth weight (VLBW) infants).3. Type of feeding: breast milk versus formula milk. SEARCH METHODS: We used the search strategy of the Cochrane Neonatal Review Group (CNRG) and updated our search in July 2014. We searched the databases Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, PREMEDLINE, EMBASE, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL), as well as trials registries and conference proceedings. SELECTION CRITERIA: Randomized controlled trials (RCTs) evaluating oral lactoferrin at any dose or duration to prevent sepsis or NEC in preterm neonates. DATA COLLECTION AND ANALYSIS: Review authors used standard methods of the CNRG. MAIN RESULTS: Four RCTs are included in this review. Oral lactoferrin supplementation decreased late-onset sepsis (typical risk ratio (RR) 0.49, 95% confidence interval (CI) 0.32 to 0.73; typical risk difference (RD) -0.09, 95% CI -0.14 to -0.04; number needed to treat for an additional beneficial outcome (NNTB) 11, 95% CI 7 to 25; four trials, 678 participants, moderate-quality evidence), NEC stage II or greater (typical RR 0.30, 95% CI 0.12 to 0.76; typical RD -0.05, 95% CI -0.08 to -0.01; NNTB 20, 95% CI 12.5 to 100; two studies, 505 participants, low-quality evidence), and "all-cause mortality" (typical RR 0.30, 95% CI 0.12 to 0.75; typical RD -0.05, 95% CI -0.08 to -0.01; NNTB 20, 95% CI 12.5 to 100; two studies, 505 participants, low-quality evidence).Oral lactoferrin supplementation with a probiotic decreased late-onset sepsis (RR 0.27, 95% CI 0.12 to 0.60; RD -0.13, 95% CI -0.19 to -0.06; NNTB 8, 95% CI 5 to 17; one study, 321 participants, low-quality evidence) and NEC stage II or greater (RR 0.04, 95% CI 0.00 to 0.62; RD -0.05, 95% CI -0.08 to -0.03; NNTB 20, 95% CI 12.5 to 33.3; one study, 496 participants, low-quality evidence), but not "all-cause mortality."Oral lactoferrin with or without probiotics decreased fungal sepsis but not chronic lung disease or length of hospital stay (from one study, low-quality evidence). No adverse effects were reported. Long-term neurological outcomes or periventricular leukomalacia was not evaluated. AUTHORS' CONCLUSIONS: Evidence of moderate to low quality suggests that oral lactoferrin prophylaxis with or without probiotics decreases late-onset sepsis and NEC stage II or greater in preterm infants without adverse effects. Completion of ongoing trials will provide evidence from more than 6000 preterm neonates and may enhance the quality of the evidence. Clarifications regarding optimum dosing regimens, type of lactoferrin (human or bovine), and long-term outcomes are still needed.

Randomized trial of human milk cream as a supplement to standard fortification of an exclusive human milk-based diet in infants 750-1250 g birth weight.

OBJECTIVE: To evaluate whether premature infants who received an exclusive human milk (HM)-based diet and a HM-derived cream supplement (cream) would have weight gain (g/kg/d) at least as good as infants receiving a standard feeding regimen (control). STUDY DESIGN: In a prospective noninferiority, randomized, unmasked study, infants with a birth weight 750-1250 g were randomly assigned to the control or cream group. The control group received mother's own milk or donor HM with donor HM-derived fortifier. The cream group received a HM-derived cream supplement if the energy density of the HM tested <20 kcal/oz using a near infrared HM analyzer. Infants were continued on the protocol until 36 weeks postmenstrual age. Primary outcomes included growth velocities and amount of donor HM-derived fortifier used. The hypothesis of noninferiority was established if the lower bound of the one-sided 95% CI for the difference in weight velocities exceeded -3 g/kg/day. RESULTS: There were no differences between groups in baseline demographics for the 78 infants studied except racial distribution (P = .02). The cream group (n = 39) had superior weight (14.0 ± 2.5 vs 12.4 ± 3.0 g/kg/d, P = .03) and length (1.03 ± 0.33 vs 0.83 ± 0.41 cm/wk, P = .02) velocity compared with the control group (n = 39). There were no significant differences in amount of fortifier used between study groups. The 1-sided 95% lower bound of the CI for the difference in mean velocity (cream-control) was 0.38 g/kg/d. CONCLUSIONS: Premature infants who received HM-derived cream to fortified HM had improved weight and length velocity compared with the control group. HM-derived cream should be considered an adjunctive supplement to an exclusive HM-based diet to improve growth rates in premature infants.

Hepcidin is the major predictor of erythrocyte iron incorporation in anemic African children.

Iron supplementation strategies in the developing world remain controversial because of fears of exacerbating prevalent infectious diseases. Understanding the conditions in which iron will be absorbed and incorporated into erythrocytes is therefore important. We studied Gambian children with either postmalarial or nonmalarial anemia, who were given oral iron supplements daily for 30 days. Supplements administered on days 1 and 15 contained the stable iron isotopes (57)Fe and (58)Fe, respectively, and erythrocyte incorporation was measured in blood samples drawn 14 days later. We investigated how the iron-regulatory hormone hepcidin and other inflammatory/iron-related indices, all measured on the day of isotope administration, correlated with erythrocyte iron incorporation. In univariate analyses, hepcidin, ferritin, C-reactive protein, and soluble transferrin receptor (sTfR) strongly predicted incorporation of (57)Fe given on day 1, while hepcidin, ferritin, and sTfR/log ferritin correlated with (58)Fe incorporation. In a final multivariate model, the most consistent predictor of erythrocyte isotope incorporation was hepcidin. We conclude that under conditions of competing signals (anemia, iron deficiency, and infection), hepcidin powerfully controls use of dietary iron. We suggest that low-cost point-of-care hepcidin assays would aid iron supplementation programs in the developing world.