Marita de Waard

Effect of Donor Milk on Severe Infections and Mortality in Very Low-Birth-Weight Infants: The Early Nutrition Study Randomized Clinical Trial

IMPORTANCE Infections and necrotizing enterocolitis, major causes of mortality and morbidity in preterm infants, are reduced in infants fed their own mothers milk when compared with formula. When own mothers milk is not available, human donor milk is considered a good alternative, albeit an expensive one. However, most infants at modern neonatal intensive care units are predominantly fed with own mothers milk. The benefits of add-on donor milk over formula are not clear. OBJECTIVE To determine whether providing donor milk instead of formula as supplemental feeding whenever own mothers milk is insufficiently available during the first 10 days of life reduces the incidence of serious infection, necrotizing enterocolitis, and mortality. DESIGN, SETTINGS, AND PARTICIPANTS The Early Nutrition Study was a multicenter, double-blind randomized clinical trial in very low-birth-weight infants (birth weight <1500 g) admitted to 1 of 6 neonatal intensive care units in the Netherlands from March 30, 2012, through August 17, 2014. Intent-to-treat analysis was performed. INTERVENTIONS Infants received pasteurized donor milk or preterm formula during the first 10 days of life if own mothers milk was not (sufficiently) available. MAIN OUTCOMES AND MEASURES The primary end point was cumulative occurrence of serious infection (sepsis or meningitis), necrotizing enterocolitis, or mortality during the first 60 days of life. RESULTS A total of 930 infants were screened for inclusion; 557 were excluded, resulting in 373 infants (183 receiving donor milk and 190 receiving formula) who were evaluated by intent-to-treat analysis (median birth weight, 1066 g; mean gestational age, 28.4 weeks). Own mothers milk comprised 89.1% and 84.5% of total mean intake during the intervention period for the donor milk and formula groups, respectively. The incidence of the combined outcome was not different (85 [44.7%] [formula] vs 77 [42.1%] [donor milk]; mean difference, 2.6%; 95% CI, -12.7% to 7.4%). The adjusted hazard ratio was 0.87 (95% CI, 0.63-1.19; P = .37). CONCLUSIONS AND RELEVANCE In the current study, pasteurized donor milk and preterm formula as supplemental feeding during the first 10 days of life yielded similar short-term outcomes in very low-birth-weight infants regarding safety and efficacy when own mothers milk availability was insufficient. Future studies investigating longer duration of use of human donor milk on short-term and long-term outcomes are necessary. TRIAL REGISTRATION trialregister.nl Identifier: NTR3225.

Changes over lactation in breast milk serum proteins involved in the maturation of immune and digestive system of the infant

Here we provide data from shot-gun proteomics, using filtered-aided sample preparation (FASP), dimethyl labeling and LC–MS/MS, to quantify the changes in the repertoire of human milk proteins over lactation. Milk serum proteins were analyzed at week 1, 2, 3 4, 8, 16, and 24 in milk from four individual mothers. A total of 247 proteins were identified, of which 200 proteins were quantified. The data supplied in this article supports the accompanying publication (Zhang et al., 2006) [1]. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium (Vizcaíno et al., 2016) [2] via the PRIDE partner repository with the dataset identifier PXD003465.

Pasteurization Procedures for Donor Human Milk Affect Body Growth, Intestinal Structure, and Resistance against Bacterial Infections in Preterm Pigs

Background: Holder pasteurization (HP) destroys multiple bioactive factors in donor human milk (DM), and UV-C irradiation (UVC) is potentially a gentler method for pasteurizing DM for preterm infants.Objective: We investigated whether UVC-treated DM improves gut maturation and resistance toward bacterial infections relative to HP-treated DM.Methods: Bacteria, selected bioactive components, and markers of antioxidant capacity were measured in unpasteurized donor milk (UP), HP-treated milk, and UVC-treated milk (all from the same DM pool). Fifty-seven cesarean-delivered preterm pigs (91% gestation; ratio of males to females, 30:27) received decreasing volumes of parental nutrition (average 69 mL · kg-1 · d-1) and increasing volumes of the 3 DM diets (n = 19 each, average 89 mL · kg-1 · d-1) for 8-9 d. Body growth, gut structure and function, and systemic bacterial infection were evaluated.Results: A high bacterial load in the UP (6×105 colony forming units/mL) was eliminated similarly by HP and UVC treatments. Relative to HP-treated milk, both UVC-treated milk and UP showed greater activities of lipase and alkaline phosphatase and concentrations of lactoferrin, secretory immunoglobulin A, xanthine dehydrogenase, and some antioxidant markers (all P < 0.05). The pigs fed UVC-treated milk and pigs fed UP showed higher relative weight gain than pigs fed HP-treated milk (5.4% and 3.5%), and fewer pigs fed UVC-treated milk had positive bacterial cultures in the bone marrow (28%) than pigs fed HP-treated milk (68%) (P < 0.05). Intestinal health was also improved in pigs fed UVC-treated milk compared with those fed HP-treated milk as indicated by a higher plasma citrulline concentration (36%) and villus height (38%) (P < 0.05) and a tendency for higher aminopeptidase N (48%) and claudin-4 (26%) concentrations in the distal intestine (P < 0.08). The gut microbiota composition was similar among groups except for greater proportions of Enterococcus in pigs fed UVC-treated milk than in pigs fed UP and those fed HP-treated milk in both cecum contents (20% and 10%) and distal intestinal mucosa (24% and 20%) (all P < 0.05).Conclusions: UVC is better than HP treatment in preserving bioactive factors in DM. UVC-treated milk may induce better weight gain, intestinal health, and resistance against bacterial infections as shown in preterm pigs as a model for DM-fed preterm infants.

Glucocorticoid Programming in Very Preterm Birth

Very preterm (i.e., <32 weeks of gestation) infants admitted to the neonatal intensive care unit are compromised in their abilities to respond adequately to common threats like hemodynamic changes and reduced energy supplies, which is partly attributable to adrenocortical insufficiency. Conversely, later in life, these infants show features of increased glucocorticoid bioactivity, such as abdominal fat distribution, raised blood pressure, insulin resistance and diabetes mellitus type 2. It has been suggested that the very preterm newborn responds to the adverse postnatal environment with a sustained elevation in hypothalamus-pituitary-adrenal axis activity that persists beyond infancy. This has implications for subsequent growth, body composition, metabolism, neurodevelopment and, ultimately, long-term disease risk. The mechanisms underpinning these associations are not fully elucidated yet. This review gives a brief summary of studies that investigated adrenocortical function in very preterm newborns and how the axis changes with age, as a possible explanation for the association between prematurity and long-term outcome.

Programming of the Hypothalamus-Pituitary-Adrenal Axis by Very Preterm Birth

Background: Many very preterm (i.e., <32 weeks of gestation) newborns fail to mount an adequate adrenocortical response to stress or illness, termed relative adrenal insufficiency. Conversely, later in life these infants show features of increased glucocorticoid bioactivity, such as abdominal adiposity, insulin resistance, raised blood pressure, shorter stature and internalizing problem behavior. Summary: Studies suggested that very preterm newborns have impairments along multiple levels of the hypothalamus-pituitary-adrenal (HPA) axis. Among the impairment were defects in: (1) the pituitary responsiveness to exogenous corticotropin-releasing hormone, (2) 11β-hydroxylase activity, and (3) the interconversion between cortisol and inert cortisone. There is some evidence suggesting that later in life these infants have an increased basal secretion rate of cortisol and adrenal hyperandrogenism. However, the response to acute (psychosocial) stress was blunted rather than enhanced in them. The mechanisms explaining this switch in HPA axis activity are complex and not yet fully understood. Key Messages: Very preterm newborns have several impairments along the HPA axis that could impede an adequate adrenocortical response to stress or illness. Later in life, these infants are predisposed to increased HPA axis activity, which could partially explain their phenotype.

Stability of Cortisol and Cortisone in Human Breast Milk During Holder Pasteurization

ABSTRACT Human donor milk is the feeding of choice for preterm infants, when own mothers milk is not available. Holder pasteurization is necessary to secure the safety of donor milk, although it can affect milk quality by reduction of nutritional and bioactive components. Recently, research has focused on the potential role of breast milk glucocorticoids for infant development. At this moment, it is unknown whether pasteurization affects milk glucocorticoid levels. Therefore, we assessed whether Holder pasteurization, the most frequently used method nowadays, reduces breast milk cortisol and cortisone levels, using breast milk samples from 30 women who delivered at term. We found tight correlations between pre- and postpasteurization levels of cortisol (R2 = 0.99) and cortisone (R2 = 0.98), and good agreement in Passing and Bablok regression analysis. In conclusion, cortisol and cortisone in human term breast milk are not significantly affected by Holder pasteurization.

Low- versus High-Dose and Early versus Late Parenteral Amino-Acid Administration in Very-Low-Birth-Weight Infants: A Systematic Review and Meta-Analysis

Objectives: Providing parenteral amino acids to very-low-birth-weight infants during the first weeks of life is critical for adequate growth and neurodevelopment. However, there is no consensus about what dose is appropriate or when to initiate supplementation. As a result, daily practice varies among neonatal intensive care units. The objective of our study was to determine the effects of early parenteral amino-acid supplementation (within 24 h of birth) versus later initiation and high dose (>3.0 g/kg/day) versus a lower dose on growth and morbidities. Methods: A systematic review and meta-analysis of publications identified by searching PubMed, EMBASE, and Cochrane databases was conducted. Randomized controlled studies were eligible if information on growth was available. Results: The search identified 14 studies. No differences were observed in growth or morbidity after early or high-dose amino-acid supplementation, but for several outcomes, meta-analysis was not possible due to study heterogeneity. Initiation of amino acids within the first 24 h of life appeared to be safe and well tolerated, and leads more rapidly to a positive nitrogen balance. Conclusions: Administering a high dose (>3.0 g/kg/day) or an early dose (≤24 h) of parenteral amino acids is safe and well tolerated but does not offer significant benefits on growth. Further large-scale randomized controlled trials in preterm infants are needed to study the effects of early and high-dose amino acids on growth and morbidity more consistently and extensively.

Medication Use During Pregnancy and Lactation in a Dutch Population

Background: Medication use during pregnancy and lactation can be unavoidable, but knowledge on safety for the fetus or breastfed infant is limited among patients and healthcare providers. Research aim: This study aimed to determine (a) the prevalence of medication use in pregnant and lactating women in a tertiary academic center, (b) the types and safety of these medicines, and (c) the influence of medication use on initiation of breastfeeding. Methods: This study used a cross-sectional survey among women (N = 292) who underwent high-risk or low-risk deliveries. Data about their use of prescribed, over-the-counter, and homeopathic medication during pregnancy were obtained through a structured interview, followed by a questionnaire during lactation. Safety was classified according to the risk classification system from the Dutch Teratological Information Service. Results: Overall, 95.5% of participants used medication. One third of participants used at least one medicine with an unknown risk for the fetus. Teratogenic medication was used by 6.5% of participants, whereas 29.5% used medication with a (suspected) pharmacological effect on the fetus. Lactation was initiated by 258 (88.7%) participants, of which 84.2% used medication while breastfeeding. In 3.8% of participants, this medication was classified unsafe, but none used medication with an unknown risk. One-third of the nonlactating participants decided not to initiate breastfeeding because of medication use. In 70% of participants, this decision was appropriate. Conclusion: The prevalence of overall use of medication in Dutch pregnant and lactating women admitted to a tertiary center was high. There is an urgent need for pharmacometric studies for determination of the safe use of the most frequently used medicines during pregnancy or lactation.