Sex-Specific Effects of Nutritional Supplements for Infants Born Early or Small: An Individual Participant Data Meta-Analysis (ESSENCE IPD-MA) I-Cognitive Function and Metabolic Risk.

Neonatal nutritional supplements are widely used to improve growth and development but may increase risk of later metabolic disease, and effects may differ by sex. We assessed effects of supplements on later development and metabolism. We searched databases and clinical trials registers up to April 2019. Participant-level data from randomised trials were included if the intention was to increase macronutrient intake to improve growth or development of infants born preterm or small-for-gestational-age. Co-primary outcomes were cognitive impairment and metabolic risk. Supplementation did not alter cognitive impairment in toddlers (13 trials, n = 1410; adjusted relative risk (aRR) 0.88 [95% CI 0.68, 1.13]; p = 0.31) or older ages, nor alter metabolic risk beyond 3 years (5 trials, n = 438; aRR 0.94 [0.76, 1.17]; p = 0.59). However, supplementation reduced motor impairment in toddlers (13 trials, n = 1406; aRR 0.76 [0.60, 0.97]; p = 0.03), and improved motor scores overall (13 trials, n = 1406; adjusted mean difference 1.57 [0.14, 2.99]; p = 0.03) and in girls not boys (p = 0.03 for interaction). Supplementation lowered triglyceride concentrations but did not affect other metabolic outcomes (high-density and low-density lipoproteins, cholesterol, fasting glucose, blood pressure, body mass index). Macronutrient supplementation for infants born small may not alter later cognitive function or metabolic risk, but may improve early motor function, especially for girls.

Sex-Specific Effects of Nutritional Supplements for Infants Born Early or Small: An Individual Participant Data Meta-Analysis (ESSENCE IPD-MA) II: Growth.

Neonatal nutritional supplements may improve early growth for infants born small, but effects on long-term growth are unclear and may differ by sex. We assessed the effects of early macronutrient supplements on later growth. We searched databases and clinical trials registers from inception to April 2019. Participant-level data from randomised trials were included if the intention was to increase macronutrient intake to improve growth or development of infants born preterm or small-for-gestational-age. Co-primary outcomes were cognitive impairment and metabolic risk. Supplementation did not alter BMI in childhood (kg/m2: adjusted mean difference (aMD) -0.11[95% CI -0.47, 0.25], p = 0.54; 3 trials, n = 333). Supplementation increased length (cm: aMD 0.37[0.01, 0.72], p = 0.04; 18 trials, n = 2008) and bone mineral content (g: aMD 10.22[0.52, 19.92], p = 0.04; 6 trials, n = 313) in infancy, but not at older ages. There were no differences between supplemented and unsupplemented groups for other outcomes. In subgroup analysis, supplementation increased the height z-score in male toddlers (aMD 0.20[0.02, 0.37], p = 0.03; 10 trials, n = 595) but not in females, and no significant sex interaction was observed (p = 0.21). Macronutrient supplementation for infants born small may not alter BMI in childhood. Supplementation increased growth in infancy, but these effects did not persist in later life. The effects did not differ between boys and girls.

Longitudinal measures of maternal vitamin D and neonatal body composition.

BACKGROUND/OBJECTIVES: Vitamin D status has been associated with fetal growth and offspring's bone mass in some observational studies. We characterize the trajectory of total maternal serum 25-hydroxyvitamin D [25(OH)D] concentration by race and examine whether vitamin D status is associated with neonatal anthropometry and body composition as assessed by dual energy X-ray absorptiometry (DXA). SUBJECTS/METHODS: Three longitudinal pregnancy samples from the Memphis site of the Calcium for Preeclampsia Prevention trial (1992-1995) were used. Racial differences in total 25(OH)D trajectories (n = 343 women) were tested using an interaction term between blood draw gestational week and race in linear mixed-effects models. Linear regression and linear mixed-effects models estimated the adjusted associations between total 25(OH)D concentration with neonatal anthropometry and body composition (n = 252 with DXA) including interactions with infant sex and serum calcium. RESULTS: Total 25(OH)D concentration increased with gestational age, but its trajectory over pregnancy did not differ between African-American and Caucasian women. Deficient maternal vitamin D (25(OH)D concentration <20 ng/ml) was associated with lower neonatal total bone mineral density (ß -0.009 g/cm2; 95% CI -0.016, -0.002). Among male newborns, deficiency was also associated with lower lean mass (-217 g; -391, -43) and birthweight (-308 g; -540, -76). Deficient maternal vitamin D was also associated with lower ponderal index (ß -2.3 kg/m3; 95% CI -4.0, -0.5) among those in the lowest calcium tertile. CONCLUSION: Vitamin D deficiency during pregnancy is associated with lower bone density and smaller size at birth in certain subgroups suggesting its importance in fetal development.

Human Milk Fortifiers Do Not Meet the Current Recommendation for Nutrients in Very Low Birth Weight Infants.

BACKGROUND: Use of multinutrient fortifiers is standard of care for small preterm infants fed exclusively human milk. However, adequacy of human milk fortifiers (HMFs) to meet the recommended intake for macronutrients and micronutrients is now known. MATERIALS AND METHODS: Nutrient content of human milk fortified according to manufacturer's recommendations was compared at isocaloric levels for 1 human milk-based (HMF-A), 2 bovine milk protein-based (HMF-B, HMF-C), and 2 preterm infant formulas (PTF-B, PTF-C). In addition, 4 multivitamin supplements were compared. RESULTS: At 130 kcal/kg, intake of macronutrients was similar to the recommendation, although deficient and excess intake of micronutrient occurred with all fortifiers. Four to 9 micronutrients were absent in HMF or PTF (biotin, choline, inositol, carnitine, taurine, molybdenum, iodine, selenium, or chromium). For the remainder, HMF resulted in deficient intake for 1-13 micronutrients, occurring most frequently with HMF-A. Excess micronutrients (3-15 at <50% and 1-3 at 109%-437%) occurred with all HMF and most frequently with HMF-B and HMF-C. At 150 kcal/kg, deficient intake improved but generally remained below recommendation, while excess intake became exaggerated. PTF and multivitamin formulations do not fully compensate for the deficiencies and can result in extremely high micronutrient intake. CONCLUSIONS: At the recommended energy intake for very low birth weight infants, many micronutrients are absent or are present in grossly inadequate amounts, and several micronutrients are in excess. Reformulation of HMF is urgently needed since PTF or multivitamin supplement only partially corrects some deficiencies while providing some nutrients in excess.

Lack of Effect of Graded Doses of Vitamin D on Bone Metabolism of Breastfed Infants.

OBJECTIVE: A range of doses of supplemental vitamin D has been shown to be effective in preventing rickets in breastfed infants, but the effect of different doses of vitamin D on bone metabolism and mineral content has not been delineated. METHODS: In a randomized trial, breastfed infants received from 2 to 9 months daily supplements of vitamin D in doses of 200 IU/d, 400 IU/d, 600 IU/d or 800 IU/d. Measures of bone metabolism (plasma) were determined periodically and bone mineral content (DXA) was determined at study entry and at the end of winter when infants were 5.5 to 9 months old. The main findings have been reported; here we report findings related to bone metabolism. RESULTS: There were no consistent meaningful effects of vitamin D dose on markers of bone metabolism. Some markers showed changes with age. Bone mineral content increased with age but showed no effect of vitamin D dose. CONCLUSION: Vitamin D in daily doses from 200 IU/d to 800 IU/d had no measurable effect on bone mineral content or bone metabolism of breastfed infants.

Human milk and neurodevelopment in children with very low birth weight: a systematic review.

Human milk (HM) contains critical nutrients and possibly other neurotrophic factors that could benefit the less developed brain of preterm infants, particularly those with very low birth weight (VLBW). This study aims to systematically review the original studies to determine whether there is a reproducible independent effect of HM feeding on neurodevelopment outcome in preterm VLBW infants. Search of seven databases (PubMed, Cochrane, CINAHL, Embase, Proquest Research Library, Google Scholar, and Web of Science) identified 24 original studies. Each study was evaluated by two authors independently for 8 non-nutritive (study design, target population, a priori power calculation, adjustment for baseline growth status, postnatal complication, other confounders, observer blinding to feeding status, effect size) and 5 nutritive (definition and duration of HM intake, use of HM fortifier, source of HM data, infant formula used) methodology parameters, and consistency and directness of outcome measures. Thirteen reports of preterm infants with wide ranges of birth weights were excluded as none provided sufficient data to delineate the effects of HM feeding on developmental outcome of subjects with VLBW. Eleven reports included only VLBW children and 7 studies were reviewed after elimination of preliminary data from same cohort or lack of appropriate standardized testing or control group. These 7 studies (n = 18 to 704, median 219) were performed at <3 years (3 studies) and at 5 to 11 years (4 studies). Six studies were secondary analysis of data from other studies. Each study met or only partially met 4 to 10 methodological parameters. VLBW children with no neurological impairment fed HM achieved normal or low normal range of test scores. Formula feeding using older formulations was associated with a lower subtest score in 4 studies. There is no randomized clinical trial comparing the neurodevelopment outcome of HM versus formula or minimal HM feeding that included only children with VLBW. The role of HM in the neurodevelopment and cognitive function of VLBW children needs reassessment with high quality studies in the context of current formulations of HM fortifier and preterm formula.

Bone densitometry in infants and young children: the 2013 ISCD Pediatric Official Positions.

Infants and children <5 yr were not included in the 2007 International Society for Clinical Densitometry Official Positions regarding Skeletal Health Assessment of Children and Adolescents. To advance clinical care of very young children, the International Society for Clinical Densitometry 2013 Position Development Conference reviewed the literature addressing appropriate methods and skeletal sites for clinical dual-energy X-ray absorptiometry (DXA) measurements in infants and young children and how results should be reported. DXA whole-body bone mineral content and bone mineral density for children ≥3 yr and DXA lumbar spine measurements for infants and young children 0-5 yr were identified as feasible and reproducible. There was insufficient information regarding methodology, reproducibility, and reference data to recommended forearm and femur measurements at this time. Appropriate methods to account for growth delay when interpreting DXA results for children <5 yr are currently unknown. Reference data for children 0-5 yr at multiple skeletal sites are insufficient and are needed to enable interpretation of DXA measurements. Given the current scarcity of evidence in many areas, it is likely that these positions will change over time as new data become available.

Vitamin D and skeletal growth and development.

Vitamin D is critical to bone mineral metabolism and to the growth and development of the skeleton. Optimizing vitamin D status could be one of the cornerstones to optimize skeletal growth and achieving the maximum peak bone mass soon after the completion of adolescence. Maximizing peak bone mass is considered to be the key to primary prevention of osteoporosis. There is controversy, however, about what constitutes a healthy vitamin D status based on the most abundant circulating metabolite of vitamin D, namely 25 hydroxyvitamin D (25 OHD) in plasma or serum; and even the value of 25 OHD that should be used to define vitamin D deficiency. We reviewed the recent data on circulating 25 OHD concentrations and its relationship with skeletal growth in apparently healthy children and in those with nutritional vitamin D deficiency.

An algorithm to detect adverse drug reactions in the neonatal intensive care unit.

Critically ill newborns in neonatal intensive care units (NICUs) are at greater risk of developing adverse drug reactions (ADRs). Differentiation of ADRs from reactions associated with organ dysfunction/immaturity is difficult. Current ADR algorithm scoring was established arbitrarily without validation in infants. The study objective was to develop a valid and reliable algorithm to identify ADRs in the NICU. Algorithm development began with a 24-item questionnaire for data collection on 100 previously suspected ADRs. Five pediatric pharmacologists independently rated cases as definite, probable, possible, and unlikely ADRs. Consensus "gold standard" was reached via teleconference. Logistic regression and iterative C programs were used to derive the scoring system. For validation, 50 prospectively collected ADR cases were assessed by 3 clinicians using the new algorithm and the Naranjo algorithm. Weighted kappa and intraclass correlation coefficient (ICC) were used to compare validity and reliability of algorithms. The new algorithm consists of 13 items. Kappa and ICC of the new algorithm were 0.76 and 0.62 versus 0.31 and 0.43 for the Naranjo algorithm. The new algorithm developed using actual patient data is more valid and reliable than the Naranjo algorithm for identifying ADRs in the NICU population. Because of the relatively small and nonrandom samples, further refinement and additional testing are needed.

Ethnic differences in the accumulation of fat and lean mass in late gestation.

OBJECTIVES: Lower birth weight within the normal range predicts adult chronic diseases, but the same birth weight in different ethnic groups may reflect different patterns of tissue development. Neonatal body composition was investigated among non-Hispanic Caucasians and African Americans, taking advantage of variability in gestational duration to understand growth during late gestation. METHODS: Air displacement plethysmography assessed fat and lean body mass among 220 non-Hispanic Caucasian and 93 non-Hispanic African American neonates. The two ethnic groups were compared using linear regression. RESULTS: At 36 weeks of gestation, the average lean mass of Caucasian neonates was 2,515 g vs. that of 2,319 g of African American neonates (difference, P = 0.02). The corresponding figures for fat mass were 231 and 278 g, respectively (difference, P = 0.24). At 41 weeks, the Caucasians were 319 g heavier in lean body mass (P < 0.001) but were also 123 g heavier in fat mass (P = 0.001). The slopes for lean mass vs. gestational week were similar, but the slope of fat mass was 5.8 times greater (P = 0.009) for Caucasian (41.0 g/week) than for African American neonates (7.0 g/week). CONCLUSIONS: By 36 weeks of gestation, the African American fetus developed similar fat mass and less lean mass compared with the Caucasian fetus. Thereafter, changes in lean mass among the African American fetus with increasing gestational age at birth were similar to the Caucasian fetus, but fat accumulated more slowly. We hypothesize that different ethnic fetal growth strategies involving body composition may contribute to ethnic health disparities in later life.

The relationship of newborn adiposity to fetal growth outcome based on birth weight or the modified neonatal growth assessment score.

OBJECTIVES: (1) Develop reference ranges of neonatal adiposity using air displacement plethysmography. (2) Use new reference ranges for neonatal adiposity to compare two different methods of evaluating neonatal nutritional status. METHODS: Three hundred and twenty-four normal neonates (35-41 weeks post-menstrual age) had body fat (%BF) and total fat mass (FM, g) measured using air displacement plethysmography shortly after delivery. Results were stratified for 92 of these neonates with corresponding fetal biometry using two methods for classifying nutritional status: (1) population-based weight percentiles; and (2) a modified neonatal growth assessment score (m(3)NGAS(51)). RESULTS: At the 50th percentile, %BF varied from 7.7% (35 weeks) to 11.8% (41 weeks), while the corresponding 50th percentiles for total FM were 186-436 g. Among the subset of 92 neonates, no significant differences in adiposity were found between small for gestational age (SGA), appropriate for gestational age (AGA), and large for gestational age (LGA) groups using population-based weight standards. Classification of the same neonates using m(3)NGAS(51) showed significant differences in mean %BF between corresponding groups. CONCLUSIONS: Population-based weight criteria for neonatal nutritional status can lead to misclassifications on the basis of adiposity. A neonatal growth assessment score, that considers the growth potential of several anatomic parameters, appears to more effectively classify under- and over-nourished newborns.

Bone ultrasound velocity in neonates with intrauterine growth deficit reflects a growth continuum.

Both bone mass by densitometry and speed of sound (SOS) from quantitative ultrasound of the bone (QUS) are directly related to bone strength. However, reports of lower bone mass but higher SOS in neonates with intrauterine growth deficit lead to apparent contradictory conclusions on bone strength. Three groups of infants were studied: small for gestation (SGA) with birth weights ≤10th percentile for gestation and 2 control groups with appropriate birth weights (11th to 90th percentile) for gestation (AGA): matched to SGA group for gestation and birth weight, respectively. SOS was measured with a commercial QUS instrument (Sunlight Omnisense 7000, Sunlight Medical Ltd, Tel Aviv, Israel) and 2 manufacturer supplied ultrasound probes (CS and CR) for small bones. The SGA group had significantly (p<0.01) higher SOS compared with weight matched but gestational less matured control group by an average of 54m/s with the CS probe and 80m/s with the CR probe but not significantly different from gestation-matched AGA group. SOS values from both probes were significantly correlated (r=0.71-0.91) but were significantly different between probes. Probe failure occurred with both probes. We conclude that QUS SOS values in SGA neonates are a reflection of a continuum of intrauterine maturation of the skeleton.

An outbreak of carbapenem-resistant Acinetobacter baumannii infection in a neonatal intensive care unit: investigation and control.

OBJECTIVE: To investigate the mode of transmission of and assess control measures for an outbreak of carbapenem-resistant (multidrug-resistant) Acinetobacter baumannii infection involving 6 premature infants. DESIGN: An outbreak investigation based on medical record review was performed for each neonate during the outbreak (from November 2008 through January 2009) in conjunction with an infection control investigation. SETTING: A 36-bed, level 3 neonatal intensive care unit in a university-affiliated teaching hospital in Detroit, Michigan. INTERVENTIONS: Specimens were obtained for surveillance cultures from all infants in the unit. In addition, geographic cohorting of affected infants and their nursing staff, contact isolation, re-emphasis of adherence to infection control practices, environmental cleaning, and use of educational modules were implemented to control the outbreak. RESULTS: Six infants (age, 10-197 days) with multidrug-resistant A. baumannii infection were identified. All 6 infants were premature (gestational age, 23-30 weeks) and had extremely low birth weights (birth weight, 1000 g or less). Conditions included conjunctivitis (2 infants), pneumonia (4 infants), and bacteremia (1 infant). One infant died of causes not attributed to infection with the organism; the remaining 5 infants were discharged home. All surveillance cultures of unaffected infants yielded negative results. CONCLUSIONS: The spread of multidrug-resistant A. baumannii infection was suspected to be due to staff members who spread the pathogen through close contact with infants. Clinical staff recognition of the importance of multidrug-resistant A. baumannii recovery from neonatal intensive care unit patients, geographic cohorting of infected patients, enhanced infection control practices, and staff education resulted in control of the spread of the organism.

Effect of subcutaneous fat on quantitative bone ultrasound in chicken and neonates.

Bone quantitative ultrasound generated speed of sound (SOS) is a marker of bone strength. However, critical evaluation of its validity for use in small bones is extremely limited, and SOS data may not be consistent with data obtained from dual energy x ray absorptiometry, another marker of bone strength. We report the SOS values pre and postinjection of s.c. fat using a chicken bone model; and in large for gestation and appropriate for gestation neonates to determine the influence of s.c. fat. Average SOS were lowered for the chicken bones postfat injection by 36 m/s (CS probe) and 58 m/s (CR probe), and in large for gestation group by 75 m/s (CS probe) and 51 m/s (CR probe) (p = 0.03-0.004 paired t test) although SOS measurements from each probe are significantly correlated within the large (r = 0.78) and appropriate (r = 0.83) for gestation group. Failed SOS measurements occurred significantly more frequently in the postinjection studies regardless of the probe used in the chicken bone model and for the CS probe in large for gestation neonates. The lowered bone quantitative ultrasound measurements in large for gestation neonates is likely a measurement artifact from increased s.c. fat.

Quantitative bone US measurements in neonates and their mothers.

BACKGROUND: Factors that affect quantitative ultrasound (QUS) bone measurements have not been clearly defined for all clinical populations. OBJECTIVE: To determine some technical and clinical aspects that may affect QUS bone measurement in the neonate-maternal dyad. MATERIALS AND METHODS: Speed of sound (SOS) was measured at the radius and tibia using a commercial multisite axial transmission QUS instrument and three manufacturer-provided probes (CS, CR and CM). RESULTS: The study included 183 singleton neonates and 159 mothers. The type of probe, weight and edema significantly affected SOS measurements. In infants, the CS and CR probes measured SOS consistently at the tibia but not the radius. Gestational age was predictive of SOS from the CS probe and remained significant when race, gender, and birth weight were included. None of these parameters predicted SOS when using the CR probe. Maternal SOS at the radius and tibia was correlated with the CM probe. Maternal SOS was predicted by age but not by gravid status, number of living children, or race. There was no consistent correlation between maternal-infant dyad SOS measurements. CONCLUSIONS: Axial transmission SOS of bone varies with probe and site and is affected by technical and clinical factors. Valid data depend on documentation of the probes used and the clinical population studied.

Developmental variations in plasma leptin, leptin soluble receptor and their molar ratio in healthy infants.

BACKGROUND: Leptin and its soluble receptor (sOB-R) are important to regulation of body composition but there are no data on the developmental variations in these plasma variables and their relationship with body composition measurements, METHODS: Weight, length, and body composition (bone, fat and lean mass) by dual energy absorptiometry, and plasma variables were measured in healthy infants at 2, 4, 8 and 12 months. RESULTS: 15 whites and 29 African Americans (21 males and 23 females) with mean birth weight 3357 +/- 45 (SEM) g and gestation of 39.3 +/- 0.17 weeks were studied. The overall Z score for weight, length and weight for length during the study were 0.00 +/- 0.15, -0.08 +/- 0.11 and 0.12 +/- 0.14 respectively. With increasing age, plasma leptin (1.0 to 18.2, median 5.5 ng/mL) and sOB-R:leptin molar ratio (10.1 to 247.4, median 59.9) were lowered (r = -0.47, p < 0.01; and r = -0.37, p < 0.05 respectively), best predicted by weight Z score and percentage of fat mass, and higher in African American and female. Presence of body composition measurements eliminated the race and gender effect on the plasma variables. Plasma sOB-R (49.5 to 173.9, median 81.3 ng/mL) did not change significantly with age and was correlated and predicted only by body composition measurements. CONCLUSION: In healthy growing infants, plasma leptin but not sOB-R decreases with age. Gender, race and anthropometric measurements are additional physiological determinants predictive of plasma leptin and the receptor:ligand ratio. However, body composition is the only variable that can predict plasma leptin and its soluble receptor and the receptor: ligand ratio; and body composition measurements eliminated the race and gender effect on these plasma variables.