Human Milk Fortification for Very Preterm Infants: Toward Optimal Nutrient Delivery, Neonatal Intensive Care Unit Growth, and Long-Term Outcomes.

Human milk is the preferred diet for very preterm infants due to short-term and long-term benefits for health and neurodevelopment. Fortification of human milk is required to deliver sufficient nutrients to attain recommended growth targets during the neonatal hospitalization. Intrinsic variability in human milk composition poses a challenge in clinical practice because some infants fail to meet recommended nutrient intakes even with existing approaches of standard (fixed-dose) and adjustable fortification. Individually targeted fortification is an emerging strategy to minimize nutrition delivery gaps through application of point-of-care human milk analysis and has potential to improve growth and related outcomes.

Health inequities start early in life, even before birth: Why race-specific fetal and neonatal growth references disadvantage Black infants.

Clinicians and researchers use published standards to assess and classify the size and growth of the fetus and newborn infant. Fetal growth is slower on average in Black fetuses as compared with White fetuses, and existing standards differ in whether they are race-specific or not. Here, we apply a health equity lens to the topic of fetal and newborn growth assessment by critically appraising two widely available growth standards. We conclude that using race-based standards is not well-justified and could perpetuate or even worsen inequities in perinatal health outcomes. We therefore recommend that neonatal and perinatal providers remove race from the assessment of fetal and newborn size.

Associations of Macronutrient Intake Determined by Point-of-Care Human Milk Analysis with Brain Development among very Preterm Infants.

Point-of-care human milk analysis is now feasible in the neonatal intensive care unit (NICU) and allows accurate measurement of macronutrient delivery. Higher macronutrient intakes over this period may promote brain growth and development. In a prospective, observational study of 55 infants born at <32 weeks' gestation, we used a mid-infrared spectroscopy-based human milk analyzer to measure the macronutrient content in repeated samples of human milk over the NICU hospitalization. We calculated daily nutrient intakes from unfortified milk and assigned infants to quintiles based on median intakes over the hospitalization. Infants underwent brain magnetic resonance imaging at term equivalent age to quantify total and regional brain volumes and fractional anisotropy of white matter tracts. Infants in the highest quintile of energy intake from milk, as compared with the lower four quintiles, had larger total brain volume (31 cc, 95% confidence interval [CI]: 5, 56), cortical gray matter (15 cc, 95%CI: 1, 30), and white matter volume (23 cc, 95%CI: 12, 33). Higher protein intake was associated with larger total brain (36 cc, 95%CI: 7, 65), cortical gray matter (22 cc, 95%CI: 6, 38) and deep gray matter (1 cc, 95%CI: 0.1, 3) volumes. These findings suggest innovative strategies to close nutrient delivery gaps in the NICU may promote brain growth for preterm infants.

Human Milk and Preterm Infant Brain Development: A Narrative Review.

PURPOSE: To review and synthesize the literature on human milk and structural brain development and injury in preterm infants, focusing on the application of quantitative brain magnetic resonance imaging (MRI) in this field. METHODS: For this narrative review, we searched PubMed for articles published from 1990 to 2021 that reported observational or interventional studies of maternal milk or donor milk in relation to brain development and/or injury in preterm infants assessed with quantitative MRI at term equivalent age. Studies were characterized with respect to key aspects of study design, milk exposure definition, and MRI outcomes. FINDINGS: We identified 7 relevant studies, all of which were observational in design and published between 2013 and 2021. Included preterm infants were born at or below 33 weeks' gestation. Sample sizes ranged from 22 to 377 infants. Exposure to human milk included both maternal and donor milk. No study included a full-term comparison group. Main MRI outcome domains were white matter integrity (assessed with diffusion tensor imaging, resting state functional connectivity, or semiautomated segmentation of white matter abnormality) and total and regional brain volumes. Studies revealed that greater exposure to human milk versus formula was associated with favorable outcomes, including more mature and connected cerebral white matter with less injury and larger regional brain volumes, notably in the deep nuclear gray matter, amygdala-hippocampus, and cerebellum. No consistent signature effect of human milk exposure was found; instead, the beneficial associations were regional and tissue-specific neuroprotective effects on the areas of known vulnerability in the preterm infant. IMPLICATIONS: Evidence to date suggests that human milk may protect the preterm infant from the white matter injury and dysmaturation to which this population is vulnerable. Brain MRI at term equivalent age is emerging as a useful tool to investigate the effects of human milk on the preterm brain. When grounded in neurobiological knowledge about preterm brain injury and development, this approach holds promise for allowing further insight into the mechanisms and pathways underlying beneficial associations of human milk with neurodevelopmental outcomes in this population and in the investigation of specific milk bioactive components with neuroprotective or neurorestorative potential.

Clinical Characteristics and Breastfeeding Outcomes in Term Dyads Following In-Hospital Supplementation with Pasteurized Donor Human Milk or Formula.

Background: Pasteurized donor human milk (PDHM) supplementation for healthy infants is an emerging practice. Little is known about demographics or breastfeeding outcomes for dyads whose mothers choose PDHM versus formula. Research Aims: To identify relationships between in-hospital supplementation choice and (1) dyad characteristics and breastfeeding intent, and (2) breastfeeding outcomes at 1 month. Materials and Methods: This exploratory prospective cohort study surveyed healthy dyads requiring medically indicated supplementation. Participants completed questionnaires including demographics, breastfeeding intent, and self-efficacy during hospitalization, and self-efficacy and lactation outcomes at 1 month. Results: Of 39 participants, 24 (62%) supplemented with formula and 15 (38%) with PDHM. Formula dyads were more likely than PDHM dyads to have a delivery body mass index (BMI) ≥30 kg/m2 (58% versus 20%, p = 0.02), and less likely to have attained greater than a college degree (33% versus 7%, p = 0.02); formula dyads also reported lower breastfeeding intent scores (12.0 versus 15.5, p = 0.002). Breastfeeding self-efficacy scores were similar but decreased for both groups over 1 month. At 1 month, mothers who chose formula were more likely to continue to provide breast milk to their infants (84% versus 72%). Direct breastfeeding rates were similar (72% versus 68%); of participants directly breastfeeding at 1 month, PDHM dyads were 1.5 times more likely to provide maternal expressed milk. Conclusions: Differences in maternal education, BMI, and breastfeeding intent were found between feeding groups. Results suggest an association between PDHM choice and initial breastfeeding intent and breastfeeding self-efficacy and provision of maternal expressed milk at 1 month.

Human Milk Hormone Intake in the First Month of Life and Physical Growth Outcomes in Preterm Infants.

CONTEXT: Human milk contains hormones that regulate metabolism. Extrauterine growth restriction remains common among preterm infants, but the effect of ingesting milk hormones on preterm infant growth is poorly understood. OBJECTIVE: To quantify associations of longitudinal exposure to leptin, adiponectin, and insulin in milk with physical growth of preterm infants. DESIGN/METHODS: In 50 preterm neonates (median gestational age 29.4 weeks), we sampled maternal milk on day-of-life 7, 14, 21, and 28 and measured hormone levels in whole milk by ELISA. Milk leptin levels were available for a subset of 18 infants. We calculated milk hormone doses by multiplying the hormone level by the milk volume ingested on each day and estimated the area under the curve (AUC) to reflect longitudinal exposure. We analyzed associations of milk hormone exposure with growth outcomes in generalized estimated equations. MAIN OUTCOME MEASURES: Weight gain velocity and z-scores in weight, length, head circumference, and body mass index at 36 weeks' postmenstrual age (PMA). RESULTS: Higher leptin intake was associated with greater weight gain (2.17g/kg/day [95% CI, 1.31, 3.02]) and weight z-score at 36 weeks' PMA (0.30 [0.08, 0.53] higher z-score per tertile). Higher adiponectin intake was associated with greater length z-score (0.41 [0.13, 0.69]), however, this association was nullified after adjustment of protein and calorie intake. Higher adiponectin was associated with smaller head circumference z-score (-0.36 [-0.64, -0.07]). Insulin was not associated with growth outcomes. CONCLUSIONS: Milk leptin and adiponectin exposures may affect growth of preterm infants. The long-term effects of milk hormones warrant further investigation.

Telomere length shortening in hospitalized preterm infants: A pilot study.

Leukocyte telomere length is a biomarker of aging-related health risks. Hospitalized preterm infants frequently experience elevated oxidative stress and inflammation, both of which contribute to telomere shortening. Our aim was to examine changes in telomere length during neonatal intensive care unit (NICU) hospitalization in a cohort of preterm infants <32 weeks' gestation. We conducted a longitudinal study of 10 infants (mean gestational age 27 weeks, range 23.5 to 29, at birth). We isolated DNA from dried blood spots and used Real Time Quantitative PCR to measure relative leukocyte telomere length in triplicate at three time points for each participant. From birth to discharge, infants experienced an average decline in relative telomere length of 0.021 units per week (95% CI -0.040, -0.0020; p = 0.03), after adjustment for gestational age at birth. Our results suggest a measurable decline in telomere length during NICU hospitalization. We speculate that telomere length change may convey information about NICU exposures that carry short- and long-term health risks.

Preterm infant nutrition and growth with a human milk diet.

Human milk is the preferred enteral diet for preterm infants. It provides macronutrients, micronutrients, and bioactive factors that support physical growth and neurodevelopment. Challenges of the human milk diet include the variability in its composition and a need for fortification to mirror placental nutrient delivery and prevent extrauterine growth restriction. Various strategies exist to attain target nutrient provision and optimize growth, including leveraging new technology for point-of-care human milk analysis. When maternal milk is unavailable or in short supply, pasteurized donor human milk is the preferred alternative. Infants fed donor milk may have slower weight gain than those fed exclusively maternal milk or formula, whereas infants fed fortified maternal milk have similar weight gain to preterm formula-fed infants. Future directions include more rigorous characterization of the variation in human milk, further investigation of the clinical benefits of non-nutrient bioactive factors in milk, and novel approaches to optimize fortification.

Growth and Clinical Outcomes of Very Low-Birth-Weight Infants Receiving Acidified vs Nonacidified Liquid Human Milk Fortifiers.

BACKGROUND: Liquid human milk fortifiers are used commonly in neonatal intensive care. Use of an acidified HMF (A-HMF) is associated with transient metabolic acidosis, but whether growth outcomes differ between infants fed A-HMF vs nonacidified HMF (NA-HMF) remains unknown. METHODS: Retrospective cohort study of 255 infants born at <33 weeks' gestation and ≤1500 g who were receiving ≥75% fortified human milk on day of life 14, in a level III neonatal intensive care unit (NICU) from May 2015 to December 2018. Infants born before October 2017 (n = 165) received A-HMF, whereas infants born after October 2017 (n = 90) received NA-HMF. We used logistic regression to estimate odds of metabolic acidosis (serum bicarbonate <16 mEq/L in the first 21 days of life) in infants receiving A-HMF vs NA-HMF and linear mixed models to compare the mean size at discharge (weight, length, head z-scores) by HMF type. We adjusted models for confounders and accounted for the nonindependence of multiple births. RESULTS: Median gestational age was 28.7 weeks (range, 22.6-32.9) and birth weight 1.1 kg (range, 0.4-1.5). Infants receiving A-HMF had higher adjusted odds of metabolic acidosis than infants receiving NA-HMF (adjusted odds ratio, 2.7; 95% CI, 1.2-6.2). There were no differences between groups in size z-scores at discharge. CONCLUSIONS: In human-milkfed, very-low-birthweight infants, fortification with liquid A-HMF may contribute to metabolic acidosis in the first month of life, but this practice does not appear to impair growth through NICU discharge, compared with fortification with NA-HMF.

Association of Poor Postnatal Growth with Neurodevelopmental Impairment in Infancy and Childhood: Comparing the Fetus and the Healthy Preterm Infant References.

OBJECTIVES: To compare the classification of preterm postnatal poor growth using healthy preterm vs fetal growth references and to examine associations with neurodevelopmental impairment in infancy and childhood. STUDY DESIGN: We included 613 infants born at <33 weeks of gestation. Using the INTERGROWTH-21st (healthy-preterm growth) reference and the Fenton and Olsen (fetal growth) references, we classified poor growth as a decline in z-score from birth to term-equivalent >0.8 SD (weight), >1 SD (head), and >2 SD (length). We used generalized estimating equations to estimate aOR for neurodevelopmental impairment at 18 months and 7 years of corrected age, comparing infants with and without poor growth by each reference, accounting for multiple births and covariates. RESULTS: The prevalence of poor growth was higher with INTERGROWTH-21st than with fetal references for all measurements. Agreement was higher between the Fenton and Olsen (fetal) growth references (0.72-0.81) than between INTERGROWTH-21st and fetal references (0.41-0.59). Poor growth by fetal references (but not by INTERGROWTH-21st) was associated with low neurodevelopmental scores in infancy and childhood. Poor weight gain using the Fenton reference was associated with 18-month Mental Developmental Index <85 (aOR 1.6, 95%CI: 1.1, 2.4) whereas poor weight gain by the INTERGROWTH-21st reference was not (aOR 1.0, 95%CI: 0.6, 1.7). Poor linear growth by the Olsen reference, but not INTERGROWTH-21st, was associated with 7-year verbal intelligence quotient <70 (aOR 3.5, 95%CI: 1.1, 12.7). CONCLUSIONS: Poor neonatal growth categorized using fetal references showed stronger associations with long term neurodevelopment than poor growth categorized using the INTERGROWTH-21st standards.

Updates on Assessment and Monitoring of the Postnatal Growth of Preterm Infants.

Assessing and monitoring the physical growth of preterm infants is fundamental to NICU care. The goals of nutritional care are to approximate the growth and body composition of the healthy fetus and to support optimal brain development while minimizing future cardiometabolic risk. Both poor and excessive growth predict adverse long-term health outcomes. Growth curves are clinical tools used to assess the preterm infant's growth status. Several growth curves for preterm infants were developed in the past decade. To use them effectively, clinicians need to understand how each growth curve was developed; the underlying reference population; intended use; and strengths and limitations. Intrauterine growth curves are references that use size at birth to represent healthy fetal growth. These curves serve 2 purposes-to assign size classifications at birth and to monitor postnatal growth. The INTERGROWTH-21 st preterm postnatal growth standards were developed to compare the postnatal growth of preterm infants to that of healthy preterm infants rather than the fetus. Individualized weight growth curves account for the water weight loss that frequently occurs after birth. In addition, body mass index (BMI) curves are now available. In this review, we discuss the main characteristics of growth curves used for preterm infants as well as the use of percentiles, z scores, and their change over time to evaluate size and growth status. We also review the differences in body composition between preterm infants at term-equivalent age and term-born infants and the potential role of monitoring proportionality of growth using BMI curves.

NIH workshop on human milk composition: summary and visions.

Nationally representative data from mother-child dyads that capture human milk composition (HMC) and associated health outcomes are important for advancing the evidence to inform federal nutrition and related health programs, policies, and consumer information across the governments in the United States and Canada as well as in nongovernment sectors. In response to identified gaps in knowledge, the National Institute of Diabetes and Digestive and Kidney Diseases of the NIH sponsored the "Workshop on Human Milk Composition-Biological, Environmental, Nutritional, and Methodological Considerations" held 16-17 November 2017 in Bethesda, Maryland. Through presentations and discussions, the workshop aimed to 1) share knowledge on the scientific need for data on HMC; 2) explore the current understanding of factors affecting HMC; 3) identify methodological challenges in human milk (HM) collection, storage, and analysis; and 4) develop a vision for a research program to develop an HMC data repository and database. The 4 workshop sessions included 1) perspectives from both federal agencies and nonfederal academic experts, articulating scientific needs for data on HMC that could lead to new research findings and programmatic advances to support public health; 2) information about the factors that influence lactation and/or HMC; 3) considerations for data quality, including addressing sampling strategies and the complexities in standardizing collection, storage, and analyses of HM; and 4) insights on how existing research programs and databases can inform potential visions for HMC initiatives. The general consensus from the workshop is that the limited scope of HM research initiatives has led to a lack of robust estimates of the composition and volume of HM consumed and, consequently, missed opportunities to improve maternal and infant health.

NICU Diet, Physical Growth and Nutrient Accretion, and Preterm Infant Brain Development.

Half of very preterm infants experience neurodevelopmental impairments after NICU discharge. These adverse outcomes result in part from abnormal brain development and injury that occur during the NICU hospitalization. Although many factors influence infant brain development, nutritional determinants are of particular interest because they are highly modifiable within clinical care. Physical growth of preterm infants in the NICU continues to lag behind the reference fetus, suggesting reduced nutrient accretion during a critical period for brain development. Nutrient accretion is driven by intake of specific nutrients such as macro- and micronutrients as well as non-nutritional factors such as systemic inflammation. Most often, anthropometric indicators, such as weight, length, and head circumference, are used as proxies for nutrient accretion. A limitation of weight is that it does not differentiate the healthy growth of specific organs and tissues from excess fat accumulation. Body length provides information about skeletal growth, and linear growth stunting predicts neurodevelopmental impairment. Head circumference is only a crude proxy for brain size. More recently, application of new technologies such as air displacement plethysmography and magnetic resonance imaging has allowed the direct estimation of lean tissue accretion and brain growth in the NICU. These newer techniques can facilitate research to improve our understanding of the links among the NICU diet, inflammation, physical growth, and brain development. These new measures may also be relevant within clinical care to identify infants who may benefit from specific interventions to enhance nutrient accretion and brain development.

Prevalence and Trends in Donor Milk Use in the Well-Baby Nursery: A Survey of Northeast United States Birth Hospitals.

BACKGROUND AND OBJECTIVES: Pasteurized donor human milk ("donor milk") is an alternative to formula for supplementation of breastfed infants. We conducted a survey to determine (1) prevalence, trends, and hospital-level correlates of donor milk use for healthy newborns in the northeast United States and (2) clinician knowledge and opinions regarding this practice. METHODS: We conducted parallel surveys of clinicians (88% nurse and/or lactation consultant) at (1) all birth hospitals in Massachusetts (MA) and (2) all birth hospitals served by a northeast United States milk bank. We asked about hospital use of donor milk for newborns ≥35 weeks' gestation and receiving Level I care in well nursery, hospital-related factors we hypothesized would be associated with this practice, and clinician knowledge and opinions about donor milk use. RESULTS: 35/46 (76%) of MA birth hospitals and 51/69 (74%) of hospitals served by the milk bank responded; 71 unique hospitals were included. Twenty-nine percent of MA birth hospitals and 43% of hospitals served by the milk bank reported using donor milk for healthy newborns. Hospitals that used donor milk for healthy newborns had higher exclusive breastfeeding at hospital discharge than hospitals that did not (77% versus 56%, p = 0.02). Eighty-three percent of respondents agreed or strongly agreed that using donor milk is an effective way to increase the hospital's exclusive breastfeeding rate. CONCLUSIONS: Many northeast United States birth hospitals currently use donor milk for healthy newborns. This practice is associated with higher exclusive breastfeeding at hospital discharge. Relationships with breastfeeding after discharge and related outcomes are unknown.

Donor Milk Utilization for Healthy Infants: Experience at a Single Academic Center.

BACKGROUND: Banked donor milk (BDM) has historically been used as an alternative to formula for preterm infants. Recently, BDM has been endorsed by two national organizations for use in healthy infants. We sought to quantify utilization trends and characteristics of mothers and their healthy newborns who received BDM during their postpartum stay between 2013 and 2016 at a single academic medical center. MATERIALS AND METHODS: In this observational study, we used a clinical log to identify all infants who received BDM in the well-baby nursery between July 2013 and June 2016. From this log, we abstracted data on the numbers of babies who received BDM, the quantity of BDM provided, and indications for usage. We also collected clinical data from the medical records of a subset of corresponding mothers and infants. RESULTS: BDM utilization increased over time in healthy infants, with 0.04% of infants before July 2014 receiving BDM compared with 4.7% in July 2015 to June 2016. During the same periods, the number of bottles provided per infant also increased, from 0.6 bottles per infant to 4.6 bottles per infant. The most common indications for providing BDM were parent/caregiver request (19%) and excessive weight loss/dehydration (17%). CONCLUSION: At our center, the use of BDM for healthy infants increased substantially over the study period. More research is urgently needed to understand the repercussions of this practice on resource utilization as well as short- and long-term breastfeeding and health outcomes.

Neurodevelopmental outcomes and nutritional strategies in very low birth weight infants.

The developing brain of the very low birth weight (VLBW) infant is highly sensitive to effects of the nutritional milieu during the neonatal hospitalization and after discharge. Strategies to optimize nutritional care play an important role in reducing long-term neurodevelopmental morbidities in this population. Currently available interventions to ensure that the unique nutrient requirements of the VLBW infant are met include various dietary fortification strategies and parenteral nutrition. In this article, we review evidence regarding nutritional strategies and their beneficial effects on neurodevelopment in VLBW infants. We also highlight gaps in current knowledge and areas of current investigation that hold promise for improving nutritional care and long-term outcomes.