Neurodevelopmental Outcomes of Extremely Preterm Infants Fed Donor Milk or Preterm Infant Formula: A Randomized Clinical Trial.

Importance: Maternal milk feeding of extremely preterm infants during the birth hospitalization has been associated with better neurodevelopmental outcomes compared with preterm formula. For infants receiving no or minimal maternal milk, it is unknown whether donor human milk conveys similar neurodevelopmental advantages vs preterm formula. Objective: To determine if nutrient-fortified, pasteurized donor human milk improves neurodevelopmental outcomes at 22 to 26 months' corrected age compared with preterm infant formula among extremely preterm infants who received minimal maternal milk. Design, Setting, and Participants: Double-blind, randomized clinical trial conducted at 15 US academic medical centers within the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Infants younger than 29 weeks 0 days' gestation or with a birth weight of less than 1000 g were enrolled between September 2012 and March 2019. Intervention: Preterm formula or donor human milk feeding from randomization to 120 days of age, death, or hospital discharge. Main Outcomes and Measures: The primary outcome was the Bayley Scales of Infant and Toddler Development (BSID) cognitive score measured at 22 to 26 months' corrected age; a score of 54 (score range, 54-155; a score of ≥85 indicates no neurodevelopmental delay) was assigned to infants who died between randomization and 22 to 26 months' corrected age. The 24 secondary outcomes included BSID language and motor scores, in-hospital growth, necrotizing enterocolitis, and death. Results: Of 1965 eligible infants, 483 were randomized (239 in the donor milk group and 244 in the preterm formula group); the median gestational age was 26 weeks (IQR, 25-27 weeks), the median birth weight was 840 g (IQR, 676-986 g), and 52% were female. The birthing parent's race was self-reported as Black for 52% (247/478), White for 43% (206/478), and other for 5% (25/478). There were 54 infants who died prior to follow-up; 88% (376/429) of survivors were assessed at 22 to 26 months' corrected age. The adjusted mean BSID cognitive score was 80.7 (SD, 17.4) for the donor milk group vs 81.1 (SD, 16.7) for the preterm formula group (adjusted mean difference, -0.77 [95% CI, -3.93 to 2.39], which was not significant); the adjusted mean BSID language and motor scores also did not differ. Mortality (death prior to follow-up) was 13% (29/231) in the donor milk group vs 11% (25/233) in the preterm formula group (adjusted risk difference, -1% [95% CI, -4% to 2%]). Necrotizing enterocolitis occurred in 4.2% of infants (10/239) in the donor milk group vs 9.0% of infants (22/244) in the preterm formula group (adjusted risk difference, -5% [95% CI, -9% to -2%]). Weight gain was slower in the donor milk group (22.3 g/kg/d [95% CI, 21.3 to 23.3 g/kg/d]) compared with the preterm formula group (24.6 g/kg/d [95% CI, 23.6 to 25.6 g/kg/d]). Conclusions and Relevance: Among extremely preterm neonates fed minimal maternal milk, neurodevelopmental outcomes at 22 to 26 months' corrected age did not differ between infants fed donor milk or preterm formula. Trial Registration: ClinicalTrials.gov Identifier: NCT01534481.

Trends in ingredients added to infant formula: FDA's experiences in the GRAS notification program.

While human milk is considered the optimal source of nutrition for infants for the first six and twelve months of age, with continued benefit of breastfeeding with complementary foods, a safe alternative, nutritionally adequate to support infant growth and development, is necessary. In the United States, the Food and Drug Administration (FDA) establishes the requirements necessary to demonstrate the safety of infant formula within the framework of the Federal Food, Drug, and Cosmetic Act. FDA's Center for Food Safety and Applied Nutrition/Office of Food Additive Safety evaluates the safety and lawfulness of individual ingredients used in infant formula, whereas the Office of Nutrition and Food Labeling oversees the safety of infant formula. Most infant formula ingredients are either from sources with history of safe consumption by infants or are like components in human milk. Information demonstrating the regulatory status of all ingredients is required in submissions for new infant formulas, and ingredient manufacturers often use the Generally Recognized as Safe (GRAS) Notification program to establish ingredient regulatory status. We provide an overview of ingredients used in infant formula evaluated through the GRAS Notification program to highlight trends and discuss the data and information used to reach these GRAS conclusions.

Remembering Robert (Bob) Togasaki (1932-2019): A leader in Chlamydomonas genetics and in plant biology, as well as a teacher par excellence.

Robert (Bob) K. Togasaki was devoted to science and the people in the scientific community. He elucidated some of the most fundamental aspects of photosynthesis and carbon metabolism through classic genetic approaches and later using the tools of modern biotechnology. Along the way, he freely shared his ideas and enthusiasm with established scientists, junior researchers, graduate students, and even elementary students. His career trajectory led him to work with some of the leaders in the field, including the late Martin Gibbs and R. Paul Levine. His dedicated research has led to a more complete understanding of some of the core biochemical functions relating to photosynthesis of the green alga Chlamydomonas; this has included carbon-concentrating mechanisms, hydrogenases, and superoxide dismutase to name just a few. The focus of this Tribute is personal reminiscences by his postdoctoral advisor R. Paul Levine; his collaborators Teruo Ogawa, Jean-David Rochaix, Hidehiro Sakurai, Michael Seibert; and by his students William Belknap, Susan Carlson, Charlene Forest, Arthur Grossman, Gregory Katzman, Masahiko Kitayama, and Jon Suzuki. All remember Bob Togasaki for his intellect, dedication to science education, and his unwavering goodwill and optimism towards his fellow human beings.

Feeding Formula Eliminates the Necessity of Bacterial Dysbiosis and Induces Inflammation and Injury in the Paneth Cell Disruption Murine NEC Model in an Osmolality-Dependent Manner.

Necrotizing enterocolitis (NEC) remains a significant cause of morbidity and mortality in preterm infants. Formula feeding is a risk factor for NEC and osmolality, which is increased by the fortification that is required for adequate growth of the infant, has been suggested as a potential cause. Our laboratory has shown that Paneth cell disruption followed by induction of dysbiosis can induce NEC-like pathology in the absence of feeds. We hypothesized adding formula feeds to the model would exacerbate intestinal injury and inflammation in an osmolality-dependent manner. NEC-like injury was induced in 14-16 day-old C57Bl/6J mice by Paneth cell disruption with dithizone or diphtheria toxin, followed by feeding rodent milk substitute with varying osmolality (250-1491 mOsm/kg H2O). Animal weight, serum cytokines and osmolality, small intestinal injury, and cecal microbial composition were quantified. Paneth cell-disrupted mice fed formula had significant NEC scores compared to controls and no longer required induction of bacterial dysbiosis. Significant increases in serum inflammatory markers, small intestinal damage, and overall mortality were osmolality-dependent and not related to microbial changes. Overall, formula feeding in combination with Paneth cell disruption induced NEC-like injury in an osmolality-dependent manner, emphasizing the importance of vigilance in designing preterm infant feeds.

FDA regulatory approach to steviol glycosides.

Stevia rebaudiana (Bertoni) Bertoni, commonly known as stevia, is a plant native to South America that has been cultivated for hundreds of years. In 1995, FDA revised its import alert on stevia leaves and extracts to allow for their use as dietary ingredients in dietary supplements. In 2007, the Joint FAO/WHO Expert Committee on Food Additives established a safe level of intake and specifications for steviol glycosides that included a minimum purity of 95% of seven named steviol glycosides. In 2008, FDA responded without questions to a Generally Recognized as Safe (GRAS) notice for the use of highly purified steviol glycosides obtained from stevia leaves as a general purpose sweetener in food. Due to the existing import alert, FDA filed, evaluated, and has not objected to more than 50 GRAS notices for the use of various high-purity steviol glycosides as sweeteners in food. In this paper, we highlight FDA's practices for filing and evaluating GRAS notices for steviol glycosides. We also provide a summary of the data and information presented in GRAS notices for steviol glycosides in the GRAS Notification program. FDA has received a new wave of GRAS notices that include alternative biotechnological methods for production of steviol glycosides.

Physiological Approach to Sodium Supplementation in Preterm Infants.

OBJECTIVE: To implement and evaluate a clinical practice algorithm to identify preterm infants with sodium deficiency and guide sodium supplementation based on urine sodium concentrations. STUDY DESIGN: Urine sodium concentration was measured in infants born at 260/7 to 296/7 weeks' gestation at 2-week intervals. Sodium supplementation was based on the urine sodium algorithm. Growth and respiratory outcomes in this cohort were compared with a matched cohort cared for in our neonatal intensive care unit prior to algorithm implementation (2014-2015 cohort). RESULTS: Data were compared for 50 infants in the 2014-2015 cohort and 40 infants in the 2016 cohort. Urine sodium concentration met criteria for supplementation in 75% of the 2016 cohort infants within the first 4 weeks after birth. Average daily sodium intake was greater in the 2016 cohort compared with the 2014-2015 cohort (p < 0.05). Caloric, protein, and total fluid intakes were similar between cohorts. The change in weight Z-score between 2 and 8 weeks of age was significantly greater in the 2016 versus 2014-2015 cohort (0.32 ± 0.05 vs. -0.01 ± 0.08; p < 0.01). No impact on respiratory status at 28 days of age or 36 weeks of postmenstrual age was identified. CONCLUSION: Institution of a clinical practice algorithm to instruct clinicians on sodium supplementation in preterm infants may improve growth outcomes.

Preterm Infant Growth Velocity Calculations: A Systematic Review.

CONTEXT: Clinicians assess the growth of preterm infants and compare growth velocity using a variety of methods. OBJECTIVE: We determined the numerical methods used to describe weight, length, and head circumference growth velocity in preterm infants; these methods include grams/kilogram/day (g/kg/d), grams/day (g/d), centimeters/week (cm/week), and change in z scores. DATA SOURCES: A search was conducted in April 2015 of the Medline database by using PubMed for studies that measured growth as a main outcome in preterm neonates between birth and hospital discharge and/or 40 weeks' postmenstrual age. English, French, German, and Spanish articles were included. The systematic review was conducted by using Preferred Reporting Items for Systematic Reviews and Meta-analyses methods. STUDY SELECTION: Of 1543 located studies, 373 (24%) calculated growth velocity. DATA EXTRACTION: We conducted detailed extraction of the 151 studies that reported g/kg/d weight gain velocity. RESULTS: A variety of methods were used. The most frequently used method to calculate weight gain velocity reported in the 1543 studies was g/kg/d (40%), followed by g/d (32%); 29% reported change in z score relative to an intrauterine or growth chart. In the g/kg/d studies, 39% began g/kg/d calculations at birth/admission, 20% at the start of the study, 10% at full feedings, and 7% after birth weight regained. The kilogram denominator was not reported for 62%. Of the studies that did report the denominators, the majority used an average of the start and end weights as the denominator (36%) followed by exponential methods (23%); less frequently used denominators included birth weight (10%) and an early weight that was not birth weight (16%). Nineteen percent (67 of 355 studies) made conclusions regarding extrauterine growth restriction or postnatal growth failure. Temporal trends in head circumference growth and length gain changed from predominantly cm/wk to predominantly z scores. LIMITATIONS AND CONCLUSIONS: The lack of standardization of methods used to calculate preterm infant growth velocity makes comparisons between studies difficult and presents an obstacle to using research results to guide clinical practice.

Peripherally inserted central catheters optimize nutrient intake in moderately preterm infants.

BACKGROUND: While very preterm (<32 wk gestation) infants are routinely provided intensive nutritional support via central line, clinical practice varies for nutrient delivery in infants born moderately preterm (32-34 wk gestation). We sought to define the impact of nutritional support via peripherally inserted central catheter (PICC) on nutrient delivery in the first 2 wk of life and growth by discharge. METHODS: Data were extracted from the records of 187 infants born between 32 and 34 6/7 wk gestation and admitted to the University of Iowa Children's Hospital between April 2012 and December 2013. Records of all feedings, weights, and PICC placements were collected. The growth outcomes at discharge for infants who received nutrition via PICC were compared to those who did not. RESULTS: In the first week of life, newborns who received nutrition via PICC line received 17.6 more kilocalories (confidence interval (CI): 12.5-22.7, P < 0.001) and 1.2 more grams protein per kilogram body weight per day (CI: 0.9-1.4, P < 0.001) compared to control infants. By discharge, the PICC group had gained 302 g more body weight (P < 0.001). CONCLUSION: This study demonstrates superior nutrient intake and growth in the first 2 wk of life for infants who received nutrition via PICC line.

Regulatory status of caffeine in the United States.

This article summarizes the history of the regulation of caffeine, a key component of caffeine-containing energy drinks and other caffeine-containing energy products, in the United States. Caffeine as an ingredient in food has been regulated by the US Food and Drug Administration (FDA) since 1958, when the Food Additives Amendment to the Federal Food, Drug and Cosmetic Act was enacted. It is listed as a substance that is generally recognized as safe by experts for its intended use in cola-type beverages at levels not to exceed 200 parts per million. Here, the history of FDA evaluations of the safe use of, as well as consumer exposure to, caffeine in food in the United States is outlined. Finally, the FDA's current concerns about caffeine and caffeine-containing energy products are reported, along with the current activities to address those concerns.

Interventional strategies to promote appropriate growth.

Appropriate growth of premature infants can be defined as growth that is not associated with adverse consequences in the short and the long term. Growth failure is associated with neurocognitive impairment. The goal of nutritional management therefore is the achievement of appropriate growth by ensuring that nutrient intakes are maintained at all times at adequate levels. Many impediments stand in the way of this goal. Parenteral administration of nutrients must begin immediately at birth and needs to be continued until enteral nutrition is fully established. While nutritional support is provided by parenteral nutrition, gut priming, also beginning at birth, stimulates the immature gastrointestinal tract to undergo maturation. Human milk is the preferred agent for gut priming because it is more effective and safer than alternative agents. As a source of nutrients, however, human milk is incomplete for the premature infant and requires supplementation (fortification) with nutrients. At the authors' institution, commercial human milk fortifiers and additional sources of protein are being used in efforts to achieve appropriate growth. Data from the authors' institution indicate that nutrient intakes, especially intakes of protein, have improved in recent years and are approaching adequate levels. Accordingly, growth of infants has improved to the point where on average only a mild degree of postnatal growth failure is observed.

Early nutrition of very low birth weight infants.

In the past, initiation of nutritional support of very low birth weight (VLBW) infants was delayed because of concerns about the safety of nutrient administration. This contributed to the impairment of neurocognitive development that these infants often display later in life. Today there is consensus that nutritional support of VLBW infants must begin immediately at birth. Because of immaturity of the gastrointestinal tract, nutritional support initially relies mainly on parenteral nutrition. Trophic feedings, preferably in the form of human milk, are provided as a stimulus for maturation of the gastrointestinal tract. Once maturation has occurred, parenteral nutrition is phased out. Although the objective of nutritional support is to meet the needs of VLBW infants at all times, nutrient deficits, albeit of a modest size, continue to be the rule. Continuing efforts are necessary to eliminate the remaining nutrient deficits.

Genetic control of cell wall invertases in developing endosperm of maize.

We show here that the total invertase activity in developing seeds of maize is due to two cell wall invertase (CWI) genes, Incw1 and Incw2 (Mn1). Our previous results have shown that loss-of-function mutations at the Mn1 locus lead to the miniature-1 (mn1) seed phenotype, marked by a loss of >70% of seed weight at maturity. The mn1 seed mutant is, however, non-lethal presumably because it retains a residual low level, approximately 1%, of the total CWI activity relative to the Mn1 endosperm throughout seed development. Evidence here shows that the residual activity in the mn1 mutant is encoded by the Incw1 gene. RNA level analyses, especially quantitative real-time PCR studies, showed significant spatial and temporal heterogeneity in the expression of the two CWI genes in the developing endosperm. The Mn1-encoded Incw2 transcripts were seen at the highest levels in the basal region (the sugar unloading zone) during the early phase of cell division and elongation in the endosperm. In contrast, the highest levels of Incw1 transcripts were seen in the storage phase in both the upper (storage cells) and the lower parts of the endosperm. Protein and enzyme level analyses, however, appeared to show a lack of concordance with the RNA level of expression in both the Mn1 and mn1 endosperms, indicating a possibility of post-transcriptional control in the expression of these two genes. Collectively, the data suggest an important role for apoplastic cleavage of sucrose throughout the duration of seed development; and, of the two isoforms, the INCW2 appears to control metabolic flux of sugar utilization in the developing endosperm.

Current nutrition management of infants with chronic lung disease.

Preterm infants with lung disease present nutrition challenges to health care providers. Malnutrition is common, develops shortly after birth, and may continue into early childhood. Although there are many studies identifying the nutrient deficiencies in infants with chronic lung disease, few randomized trials have explored the effects of nutrition support on the prevention and treatment of chronic lung disease. The purpose of this article is to review current practices and ongoing controversies in the nutrition management of infants with chronic lung disease.

Aggressive nutrition of the very low birthweight infant.

We propose an approach to nutrition of the VLBW infant that aims at minimizing the interruption of nutrient uptake engendered by premature birth. Our approach is aggressive in that it goes beyond current practice in several key aspects. The gap in nutrient intakes between the proposed aggressive approach and current practice will most likely disappear over the next few years as today's aggressive practice becomes tomorrow's standard practice. As the gap diminishes, so will the threat that nutritional deprivation poses to growth and development of VLBW infants.

Gene expression studies on developing kernels of maize sucrose synthase (SuSy) mutants show evidence for a third SuSy gene.

Previous studies have identified two tissue- and cell-specific, yet functionally redundant, sucrose synthase (SuSy) genes, Sh1 and Sus1, which encode biochemically similar isozymes, SH1 and SUS1 (previously referred to as SS1 and SS2, respectively). Here we report evidence for a third SuSy gene in maize, Sus3, which is more similar to dicot than to monocot SuSys. RNA and/or protein blot analyses on developing kernels and other tissues show evidence of expression of Sus3, although at the lowest steady-state levels of the three SuSy gene products and without a unique pattern of tissue specificity. Immunoblots of sh1sus1-1 embryos that are either lacking or deficient for the embryo-specific SUS1 protein have shown a protein band which we attribute to the Sus3 gene, and may contribute to the residual enzyme activity seen in embryos of the double mutant. We also studied developing seeds of the double mutant sh1sus1-1, which is missing 99.5% of SuSy enzyme activity, for evidence of co-regulation of several genes of sugar metabolism. We found a significant reduction in the steady-state levels of Miniature-1 encoded cell wall invertase2, and Sucrose transporter (Sut) mRNAs in the double mutant, relative to the lineage-related sh1Sus1 and sh1Sus1 kernels. Down-regulation of the Mn1 gene was also reflected in significant reductions in cell wall invertase activity. Co-regulatory changes were not seen in the expression of Sucrose phosphate synthase, UDP-glucose pyrophosphorylase, and ADP-glucose pyrophosphorylase.