Insulin-like growth factor-1 and insulin-like growth factor binding protein-3 as early predictors of growth, body composition, and neurodevelopment in preterm infants.

OBJECTIVE: To investigate the relationship between insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding protein 3 (IGFBP-3) and long-term growth, body composition, and neurodevelopment in preterm infants. STUDY DESIGN: Prospective data were collected from ≤32 weeks gestational age infant cohort (N = 50). IGF-1 and IGFBP-3 concentrations were measured at 1 week (early) and 35 weeks (late) post-menstrual age (PMA). Growth, body composition, and neurodevelopment outcomes were measured at 4 and 12 months PMA. Relationships were measured by linear regression analysis. RESULTS: Early IGFBP-3 concentration was positively associated with neurodevelopment at 12 months PMA. Early IGF-1 concentration was positively associated with weight at 4 months PMA, head circumference at 12 months PMA, and body mass index at 12 months PMA. Late IGFBP-3 concentration was positively associated with weight at 4 months PMA. CONCLUSION: Further investigation of these associations may lead to novel biomarkers and/or treatments to optimize health outcomes in preterm infants.

Body composition after implementation of an enhanced parenteral nutrition protocol in the neonatal intensive care unit: a randomised pilot trial.

BACKGROUND: Very low birthweight (VLBW) infants are at risk for growth failure and poor neurodevelopment. Optimised parenteral nutrition may help promote optimal growth and development, but concerns that provision of enhanced nutrition may contribute to increased early adiposity and later metabolic disease remain. AIM: To determine associations between provision of an early enhanced parenteral nutrition protocol or standard parenteral nutrition protocol and growth and body composition for VLBW preterm infants in the neonatal intensive care unit. SUBJECTS: This is a secondary analysis of data from a clinical trial aimed at assessing the feasibility and safety of randomising VLBW preterm infants to Standard (n = 45) or Intervention (n = 42) parenteral nutrition groups between August 2017 and June 2019. METHODS: We evaluated associations between weekly infant growth and body composition measurements from n = 55 infants (Standard = 29, Intervention = 26) that were clinically stable enough to have body composition measurements taken before discharge using mixed effects linear regression models. RESULT: No statistically significant associations between nutrition group and infant growth or body composition measures were observed (p >.05). CONCLUSION: In this pilot trial, enhanced parenteral nutrition in the first week of life was not associated with significant differences in infant growth or body composition during hospitalisation.

An exploratory study of clinical factors associated with IGF-1 and IGFBP-3 in preterm infants.

BACKGROUND: Despite advances in parenteral nutrition, postnatal growth failure in very low birthweight (VLBW) preterm infants is common and associated with chronic health problems. Insulin-like growth factor 1 (IGF-1) is positively associated with improved infant growth, but factors which promote IGF-1 levels in this population have not been clearly identified. The objective of this study was to explore early factors that influence IGF-1 in VLBW preterm infants. METHODS: VLBW infants were enrolled into a prospective, randomized controlled nutrition trial (N = 87). Outcome measures included IGF-1 and IGFBP-3 levels measured at 35 weeks PMA. Linear regression analyses tested the relationships between candidate clinical predictors and levels of IGF-1 and IGFBP-3. RESULTS: Higher protein intake, longer duration of parenteral nutrition, and lower IGFBP-3 levels at 1 week of life were associated with lower IGF-1 levels at 35 weeks PMA. Neither early markers of insulin resistance nor degree of illness were associated with IGF-1 levels at 35 weeks PMA. CONCLUSION: Optimization of early nutrient intake, and attention to route of delivery, may have a lasting influence on IGF-1/IGFBP-3, and in turn, long-term health outcomes. IMPACT: In very low birthweight preterm infants, early protein intake, duration of parenteral nutrition, and insulin-like growth factor binding protein 3 (IGFBP-3) levels at 1 week of life are positively associated with insulin-like growth factor 1 (IGF-1) levels at 35 weeks postmenstrual age. Data from this study highlight the influence of early nutrition on components of the endocrine axis in preterm infants. Strategies aimed at early initiation of enteral nutrition, as well as optimizing composition of parenteral nutrition, may bolster hormones involved in promoting preterm infant growth.

Importance of human milk for infants in the clinical setting: Updates and mechanistic links.

INTRODUCTION: Human milk (HM) is the optimal source of nutrition for infants and has been implicated in multiple aspects of infant health. Although much of the existing literature has focused on the individual components that drive its nutrition content, examining HM as a biological system is needed for meaningful advancement of the field. Investigation of the nonnutritive bioactive components of HM and the maternal, infant, and environmental factors which affect these bioactives is important to better understand the importance of HM provision to infants. This information may inform care of clinical populations or infants who are critically ill, hospitalized, or who have chronic diseases and may benefit most from receiving HM. METHODS: In this narrative review, we reviewed literature examining maternal and infant influences on HM composition with a focus on studies published in the last 10 years that were applicable to clinical populations. RESULTS: We found multiple studies examining HM components implicated in infant immune and gut health and neurodevelopment. Additional work is needed to understand how donor milk and formula may be used in situations of inadequate maternal HM. Furthermore, a better understanding of how maternal factors such as maternal genetics and metabolic health influence milk composition is needed. CONCLUSION: In this review, we affirm the importance of HM for all infants, especially clinical populations. An understanding of how HM composition is modulated by maternal and environmental factors is important to progress the field forward with respect to mechanistic links between HM biology and infant health outcomes.

Enhanced Parenteral Nutrition Is Feasible and Safe in Very Low Birth Weight Preterm Infants: A Randomized Trial.

OBJECTIVE: The objective of this study was to determine the feasibility and safety of enhanced early (PN) (early initiation of intralipids and faster advancement of glucose infusion rate) during the first week of life for very low birth weight (VLBW) preterm infants. METHODS: 90 VLBW preterm infants (<32 weeks gestational age at birth) admitted to the University of Minnesota Masonic Children's Hospital between August 2017 and June 2019 were included. Enrolled infants were stratified by gestational age-groups and randomized to either the enhanced nutrition protocol (intervention group) or the standard PN protocol (standard group). Welch's two-sample t tests were used to investigate differences in calorie and protein intake, insulin use, days of hyperglycemia, hyperbilirubinemia, and hypertriglyceridemia, and proportion of bronchopulmonary dysplasia, necrotizing enterocolitis, and death between groups. RESULTS: Intervention and standard groups were similar in baseline characteristics. The intervention group received higher weekly mean caloric intake (102.6 [SD 24.9] kcal/kg/day versus 89.7 [SD 30.2] kcal/kg/day; p = 0.001) and higher mean caloric intake on days of life 2-4 (p < 0.05 for all). Both groups received the recommended protein intake (≥4 g/kg/day). There were no significant differences in safety or feasibility outcomes between groups (all p values >0.12). CONCLUSION: Utilization of an enhanced nutrition protocol during the first week of life resulted in increased caloric intake and was feasible with no evidence of harm. Follow-up of this cohort is needed to determine if enhanced PN will result in improved growth and neurodevelopment.

Randomized Trial of Early Enhanced Parenteral Nutrition and Later Neurodevelopment in Preterm Infants.

Retrospective studies indicate that the parenteral provision of calories, proteins, and lipids in the first week of life is associated with improved later neurodevelopment. We aimed to determine whether infants randomized to an enhanced parenteral nutrition protocol had improved developmental outcomes at 4, 12, or 24 months corrected age (CA). In total, 90 preterm infants (<32 weeks gestational age and <1500 g) were randomized to receive enhanced parenteral nutrition (PN) or standard PN during the first week of life. The enhanced group received a higher glucose infusion rate and intralipids. Neurodevelopmental outcomes included pattern-reversal visually evoked potentials (VEP) at 4 months CA (n = 33) and the Bayley Scales of Infant Development (BSID) at 12 (n = 46) and 24 (n = 29) months CA. P100 latency was longer in the intervention group, indicating slower processing speed (145 vs. 178 ms, p = 0.01). This association did not hold in multivariable analysis adjusting for potentially confounding variables. BSID scores were not associated with enhanced PN. Higher enteral energy and protein intake regardless of randomization group were associated with faster processing speed at 4 months CA (p ≤ 0.02 for both). Enhanced early PN was not associated with improved neurodevelopment; however, first-week enteral caloric and protein intake were associated with improved speed of processing.

Gestational Diabetes Mellitus Is Associated with Differences in Human Milk Hormone and Cytokine Concentrations in a Fully Breastfeeding United States Cohort.

It is unclear whether gestational diabetes mellitus (GDM) alters breast milk composition. We prospectively examined associations of GDM status with concentrations of six potentially bioactive elements (glucose, insulin, C-reactive protein (CRP), interleukin-6 (IL-6), leptin, and adiponectin) in human milk. These were measured at both 1 and 3 months postpartum in 189 fully breastfeeding women. Mixed-effects linear regression assessed GDM status-related differences in these milk bioactives, adjusting for demographics, maternal factors, and diet. At 1 and 3 months postpartum, milk CRP was higher (1.46 ± 0.31 ng/mL; p < 0.001 and 1.69 ± 0.31 ng/mL; p < 0.001) in women with GDM than in women without GDM, whereas milk glucose (−5.23 ± 2.22 mg/dL; p = 0.02 and −5.70 ± 2.22; p = 0.01) and milk insulin (−0.38 ± 0.17 µIU/mL; p = 0.03 and −0.53 ± 0.17; p = 0.003) were lower in women with GDM. These significant associations remained similar after additional adjustment for maternal weight status and its changes. No difference was found for milk IL-6, leptin, and adiponectin. There was no evidence of association between these milk bioactive compounds and 1 h non-fasting oral glucose challenge serum glucose in the women without GDM. This prospective study provides evidence that potentially bioactive elements of human milk composition are altered in women with GDM.

Gestational Diabetes Mellitus Is Associated with Altered Abundance of Exosomal MicroRNAs in Human Milk.

PURPOSE: Human milk (HM) is a unique biological fluid that is enriched with a variety of factors, including microRNAs (miRNAs) that potentially provide both short- and long-term benefits to the infants. miRNAs are packaged within exosomes, making them bioavailable to infants. Gestational diabetes mellitus (GDM) may affect the abundance of exosomal miRNAs in HM, providing a mechanism for growth and adiposity variation in infants of mothers with GDM in early life. Therefore, the purposes of this study were to examine the impact of GDM on select miRNAs (miRNA-148a, miRNA-30b, miRNA-let-7a, and miRNA-let-7d) involved in metabolism and to examine the association of these miRNAs with measures of infant body composition in the first 6 months of life. METHODS: Milk samples were collected from a cohort of 94 mothers (62 mothers without GDM and 32 mothers with GDM) matched on body mass index strata at 1 month post partum. miRNA abundance was measured by real-time polymerase chain reaction. Linear regression models were used to examine potential differences in miRNA abundance in women with and without GDM, testing associations between miRNA abundance and infant growth and body composition measures from 1 to 6 months. FINDINGS: The abundances of miRNA-148a, miRNA-30b, miRNA-let-7a, and miRNA-let-7d were reduced in milk from mothers with GDM. Independent of GDM status, higher maternal diet quality was associated with increased abundance of each of the measured miRNAs. miRNA-148a was negatively associated with infant weight, percentage of body fat, and fat mass, whereas miRNA-30b was positively associated with infant weight and fat mass at 1 month of age. There was no association of milk miRNA-148a and miRNA-30b with infant weight at 1 month of age or with body composition measures at 3 months of age; however, miRNA-148a was negatively associated with infant weight at 6 months of age. IMPLICATIONS: If supported by randomized dietary supplementation or other intervention trials, HM miRNAs may be a therapeutic target to mitigate risk of metabolic outcomes in offspring of women with GDM.

Maternal Psychological Distress and Lactation and Breastfeeding Outcomes: a Narrative Review.

PURPOSE: Despite recommendations from the World Health Organization and the American Academy of Pediatrics to exclusively breastfeed infants for their first 6 months of life, 75% of women do not meet exclusive breastfeeding guidelines, and 60% do not meet their own breastfeeding goals. Numerous observational studies have linked maternal psychological distress (eg, perceived stress, anxiety, and depression) with nonoptimal breastfeeding outcomes, such as decreased proportion and duration of exclusive breastfeeding. The physiological mechanisms underlying these associations, however, remain unclear. METHODS: For this narrative review, we evaluated the evidence of relationships between maternal psychological distress and lactation and breastfeeding outcomes in pregnancy and post partum and the possible physiological mechanisms that facilitate these relationships. We searched PubMed using the following terms: stress, anxiety, depression, breastfeeding, and lactation. Additional search by hand was conducted to ensure a thorough review of the literature. FINDINGS: Among the studies examined, methods used to assess maternal psychological distress were not uniform, with some studies examining perceived distress via a variety of validated tools and others measuring biological measures of distress, such as cortisol. Evidence supports a role for psychological distress in multiple breastfeeding outcomes, including delayed secretory activation and decreased duration of exclusive breastfeeding. One physiological mechanism proposed to explain these relationships is that psychological distress may impair the release of oxytocin, a hormone that plays a critical role in milk ejection during lactation. Continued impairment of milk ejection may lead to decreased milk production because of incomplete emptying of the breast during each feed. Maternal distress may also yield elevated levels of serum cortisol and decreased insulin sensitivity, which are associated with decreased milk production. The relationship between psychological distress and breastfeeding is likely to be bidirectional, however, in that breastfeeding appears to reduce maternal distress, again possibly via effects on the pleasure or reward pathway and calming effects of oxytocin on the mother. This finding suggests that interventions to support lactation and breastfeeding goals in women who score high on measures of psychological distress would be beneficial for both maternal and infant well-being. IMPLICATIONS: Evidence to date suggests that maternal psychological distress may impair lactation and breastfeeding outcomes, but stronger study designs and rigorous assessment methods are needed. A better understanding of the physiological mechanisms leading to impaired lactation may assist in the development of early interventions for mothers experiencing distress. In addition, stress-reducing programs and policies should be investigated for their potential to improve breastfeeding outcomes.

Human Milk Glucose, Leptin, and Insulin Predict Cessation of Full Breastfeeding and Initiation of Formula Use.

Objective: We aimed to investigate prospective associations between milk bioactives related to metabolic health (glucose, insulin, leptin, C reactive protein [CRP], and interleukin 6 [IL-6]) and incident formula initiation at 3 and 6 months postpartum. Design: This study included 363 mother-infant dyads who were fully breastfed at 1 month and participated in the prospective Mothers and Infants Linked for Healthy Growth study from pregnancy to 6 months postpartum. Associations between milk glucose, leptin, insulin, CRP, and IL-6 at 1 and 3 months and incident formula feeding (FF) at 3 and 6 months, respectively, were tested using multiple logistic regression, adjusting for numerous potential confounders such as maternal age and prepregnancy body mass index. Results: At 3 months postpartum, 1-month glucose (odds ratio [OR] 0.45 [95% confidence interval (CI): 0.27-0.75], p ≤ 0.01) and smaller decreases in glucose from 1 to 3 months (OR 0.51 [95% CI: 0.28-0.92], p = 0.03) were associated with lower odds of FF, whereas 1-month leptin (OR 2.30 [95% CI: 1.30-4.07], p < 0.01) and larger increase in insulin (OR 1.86 [95% CI: 1.23-2.81], p < 0.01) and leptin (OR 2.17 [95% CI: 1.29-3.68], p < 0.01) from 1 to 3 months were associated with increased odds of FF. At 6 months, insulin increases (OR 2.08 [95% CI: 1.03-4.17], p = 0.04) were associated with higher odds of FF. Conclusions: In a cohort of women with established lactation, 1-month milk glucose, insulin, and leptin predicted initiation of FF at 3 months. Early milk composition may provide a window into mammary gland function, allowing identification of women at risk of not meeting their breastfeeding goals.

Ultrasound measurements of abdominal muscle thickness are associated with postmenstrual age at full oral feedings in preterm infants: A preliminary study.

BACKGROUND: A premature infant's discharge from the neonatal intensive care unit (NICU) is dependent on factors such as respiratory stability, adequate growth, and the ability to consume oral feeds. Once infants have achieved respiratory stability, a tool that can better predict age at discharge is desirable. Thus, we conducted a secondary data analysis to assess the association between ultrasound measurements of abdominal muscle thickness and postmenstrual age (PMA) at full oral feedings. METHODS: Forty-nine (n = 49) healthy, premature infants (mean gestational age = 32 weeks) were recruited from the NICU. Anthropometric measurements and ultrasound measurements of the rectus abdominis were conducted when infants were medically stable. Fat-free mass (FFM) was obtained using air displacement plethysmography. The relationship between ultrasound measurements of muscle thickness and PMA at full oral feedings was assessed using linear regression analysis. The relationship between FFM z-scores and PMA at full oral feedings was also assessed for comparison. RESULTS: When adjusting for gestational age at birth, PMA at measurement, days of positive pressure respiratory support, weight, and length, ultrasound measurements of abdominal muscle thickness were independently, negatively associated with PMA at full oral feedings (ß estimate: -0.71, P = .03). CONCLUSION: Preliminary results suggest infants with greater abdominal muscle thickness may reach full oral feedings at an earlier PMA (nearly 1 week per millimeter). Thus, ultrasound measurements of abdominal muscle thickness may be helpful in assessing readiness for discharge in healthy preterm infants. Further research is needed for development and validation of a prediction equation.

Maternal Dietary Intake of Total Fat, Saturated Fat, and Added Sugar Is Associated with Infant Adiposity and Weight Status at 6 mo of Age.

BACKGROUND: Whether current dietary guidelines are appropriate for pregnancy and lactation has not been well studied. Many women of reproductive age are not meeting recommendations for dietary components such as fat, added sugar, and fiber. OBJECTIVES: To assess associations between maternal dietary components during pregnancy and lactation and infant growth and adiposity at 6 mo of age. METHODS: Mother-infant dyads (n = 349) from the prospective, observational Mothers and Infants Linked for Healthy Growth study were included (100% fully breastfed for 1 mo; 75% to 6 mo). Daily intake of fat, fiber, and added sugar was obtained using the National Cancer Institute Diet History Questionnaire II during the third trimester of pregnancy and at 1 and 3 mo postpartum. Furthermore, intakes were categorized as meeting/exceeding 2015-2020 Dietary Guidelines for Americans. Multiple linear regression models adjusted for numerous potential confounders tested relations between dietary components and infant adiposity (via DXA) and growth parameters. Regression coefficients (ß) for continuous variables were expressed per SD to allow for comparison of effect sizes. RESULTS: Maternal intake of total fat and saturated fat was positively associated with infant percent body fat (%BF) (ß: 0.84 per SD, P = 0.04; ß: 0.96 per SD, P = 0.01, respectively). Added sugar intake was positively associated with infant weight-for-length z score (ß: 0.16 per SD, P = 0.02), and excessive added sugar intake was positively associated with %BF at 6 mo (ß: 0.75 per SD, P = 0.05). CONCLUSIONS: In a predominantly fully breastfeeding cohort of women, maternal intake of fat and added sugar during pregnancy and lactation were associated with small increases in infant adiposity and relative weight at 6 mo. Additional research is needed to determine if these relations persist later in infancy and if such elevations in adiposity are important for long-term obesity risk.

Infant sex differences in human milk intake and composition from 1- to 3-month post-delivery in a healthy United States cohort.

BACKGROUND: Macronutrient composition of human milk differs by infant sex, but few studies have examined sex differences in other milk components, or their potential modification by maternal body mass index (BMI). AIM: We compared milk intake and human milk hormone and cytokine concentrations at 1- and 3-month post-delivery and tested infant sex by maternal BMI (OW/OB vs. NW) interactions. SUBJECTS AND METHOD: Data were analysed for 346 mother-infant dyads in the Mothers and Infants Linked for Healthy Growth (MILk) Study at 1- and 3-month post-delivery. Infant milk intake was estimated by the change in infant weight after test feedings. Concentrations of glucose, insulin, leptin, adiponectin, interleukin-6 (IL-6), and C-reactive protein (CRP) were measured using ELISA. Multivariable linear regression and linear mixed models were used to estimate sex main effects and their interaction with maternal BMI. RESULTS: Mean glucose concentration at 1 month was 2.62 mg/dl higher for male infants, but no difference at 3 months was observed. Milk intake and concentrations for the other milk components were similar for males and females at both time points. Associations with infant sex did not differ significantly by maternal BMI. CONCLUSIONS: Among healthy United States mother-infant dyads, appetite, and growth-regulating factors in human milk did not differ significantly by infant sex.

Diagnosing clinical malnutrition: Perspectives from the past and implications for the future.

This review, intended for both researchers and clinicians, provides a history of the definition of clinical malnutrition. Despite global efforts, we remain without one clear, objective, internationally accepted definition; clarity in this regard will ultimately improve our evaluation and monitoring of nutritional status to achieve optimal patient outcomes. In this review we explore the development of the term malnutrition and its diagnosis and application in the setting of acute and chronic disease. We begin in the second century A.D. with the work of the Greek physician Galen who is credited as the first to apply the term marasmus to characterize three categories of malnutrition, which are surprisingly similar to components of current international definitions. We then highlight significant developments over the next 2000 years culminating in our current application of the clinical diagnosis of malnutrition. A perspective on historical practices may inform current efforts toward a global definition and diagnosis of malnutrition.

Preoperative Pectoralis Muscle Quantity and Attenuation by Computed Tomography Are Novel and Powerful Predictors of Mortality After Left Ventricular Assist Device Implantation.

BACKGROUND: Skeletal muscle mass decreases in end-stage heart failure and is predictive of clinical outcomes in several disease states. Skeletal muscle attenuation and quantity as quantified on preoperative chest computed tomographic scans may be predictive of mortality after continuous flow (CF) left ventricular assist device (LVAD) implantation. METHODS AND RESULTS: A single-center continuous flow-LVAD database (n=354) was used to identify patients with chest computed tomographies performed in the 3 months before LVAD implantation (n=143). Among patients with computed tomography data available, unilateral pectoralis muscle mass indexed to body surface area and attenuation (approximated by mean Hounsfield units [PHUm]) were measured in each patient with a high intrarater and inter-rater reliability (intraclass correlation coefficients 0.98 and 0.97, respectively). Multivariate Cox regression analyses were performed, censoring at cardiac transplantation, to assess the impact of preoperative pectoralis muscle index and pectoralis muscle mean Hounsfield unit on survival after LVAD implantation. Each unit increase in pectoralis muscle index was associated with a 27% reduction in the hazard of death after LVAD (adjusted hazard ratio, 0.73; 95% confidence interval, 0.58-0.92; P=0.007). Each 5-U increase in pectoralis muscle mean Hounsfield unit was associated with a 22% reduction in the hazard of death after LVAD (adjusted hazard ratio, 0.78; 95% confidence interval, 0.68-0.89; P<0.0001). Pectoralis muscle index and pectoralis muscle mean Hounsfield unit outperformed other traditional measures in the data set, including the HeartMate II risk score. CONCLUSIONS: Pectoralis muscle size and attenuation were powerful predictors of outcomes after LVAD implantation in this data set. This one time, repeatable, internal assessment of patient substrate added valuable prognostic information that was not available on standard preoperative testing.