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1.
Effects of the neonatal intensive care environment on circadian health and development of preterm infants.
Van Gilst, D, Puchkina, AV, Roelants, JA, Kervezee, L, Dudink, J, Reiss, IKM, Van Der Horst, GTJ, Vermeulen, MJ, Chaves, I
Frontiers in physiology. 2023;:1243162
Abstract
The circadian system in mammals ensures adaptation to the light-dark cycle on Earth and imposes 24-h rhythmicity on metabolic, physiological and behavioral processes. The central circadian pacemaker is located in the brain and is entrained by environmental signals called Zeitgebers. From here, neural, humoral and systemic signals drive rhythms in peripheral clocks in nearly every mammalian tissue. During pregnancy, disruption of the complex interplay between the mother's rhythmic signals and the fetal developing circadian system can lead to long-term health consequences in the offspring. When an infant is born very preterm, it loses the temporal signals received from the mother prematurely and becomes totally dependent on 24/7 care in the Neonatal Intensive Care Unit (NICU), where day/night rhythmicity is usually blurred. In this literature review, we provide an overview of the fetal and neonatal development of the circadian system, and short-term consequences of disruption of this process as occurs in the NICU environment. Moreover, we provide a theoretical and molecular framework of how this disruption could lead to later-life disease. Finally, we discuss studies that aim to improve health outcomes after preterm birth by studying the effects of enhancing rhythmicity in light and noise exposure.
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2.
Maternal iron status in early pregnancy and DNA methylation in offspring: an epigenome-wide meta-analysis.
Taeubert, MJ, de Prado-Bert, P, Geurtsen, ML, Mancano, G, Vermeulen, MJ, Reiss, IKM, Caramaschi, D, Sunyer, J, Sharp, GC, Julvez, J, et al
Clinical epigenetics. 2022;(1):59
Abstract
BACKGROUND Unbalanced iron homeostasis in pregnancy is associated with an increased risk of adverse birth and childhood health outcomes. DNA methylation has been suggested as a potential underlying mechanism linking environmental exposures such as micronutrient status during pregnancy with offspring health. We performed a meta-analysis on the association of maternal early-pregnancy serum ferritin concentrations, as a marker of body iron stores, and cord blood DNA methylation. We included 1286 mother-newborn pairs from two population-based prospective cohorts. Serum ferritin concentrations were measured in early pregnancy. DNA methylation was measured with the Infinium HumanMethylation450 BeadChip (Illumina). We examined epigenome-wide associations of maternal early-pregnancy serum ferritin and cord blood DNA methylation using robust linear regression analyses, with adjustment for confounders and performed fixed-effects meta-analyses. We additionally examined whether associations of any CpGs identified in cord blood persisted in the peripheral blood of older children and explored associations with other markers of maternal iron status. We also examined whether similar findings were present in the association of cord blood serum ferritin concentrations with cord blood DNA methylation. RESULTS Maternal early-pregnancy serum ferritin concentrations were inversely associated with DNA methylation at two CpGs (cg02806645 and cg06322988) in PRR23A and one CpG (cg04468817) in PRSS22. Associations at two of these CpG sites persisted at each of the follow-up time points in childhood. Cord blood serum ferritin concentrations were not associated with cord blood DNA methylation levels at the three identified CpGs. CONCLUSION Maternal early-pregnancy serum ferritin concentrations were associated with lower cord blood DNA methylation levels at three CpGs and these associations partly persisted in older children. Further studies are needed to uncover the role of these CpGs in the underlying mechanisms of the associations of maternal iron status and offspring health outcomes.
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3.
Maternal Iron Status in Pregnancy and Child Health Outcomes after Birth: A Systematic Review and Meta-Analysis.
Quezada-Pinedo, HG, Cassel, F, Duijts, L, Muckenthaler, MU, Gassmann, M, Jaddoe, VWV, Reiss, IKM, Vermeulen, MJ
Nutrients. 2021;(7)
Abstract
In pregnancy, iron deficiency and iron overload increase the risk for adverse pregnancy outcomes, but the effects of maternal iron status on long-term child health are poorly understood. The aim of the study was to systematically review and analyze the literature on maternal iron status in pregnancy and long-term outcomes in the offspring after birth. We report a systematic review on maternal iron status during pregnancy in relation to child health outcomes after birth, from database inception until 21 January 2021, with methodological quality rating (Newcastle-Ottawa tool) and random-effect meta-analysis. (PROSPERO, CRD42020162202). The search identified 8139 studies, of which 44 were included, describing 12,7849 mother-child pairs. Heterogeneity amongst the studies was strong. Methodological quality was predominantly moderate to high. Iron status was measured usually late in pregnancy. The majority of studies compared categories based on maternal ferritin, however, definitions of iron deficiency differed across studies. The follow-up period was predominantly limited to infancy. Fifteen studies reported outcomes on child iron status or hemoglobin, 20 on neurodevelopmental outcomes, and the remainder on a variety of other outcomes. In half of the studies, low maternal iron status or iron deficiency was associated with adverse outcomes in children. Meta-analyses showed an association of maternal ferritin with child soluble transferrin receptor concentrations, though child ferritin, transferrin saturation, or hemoglobin values showed no consistent association. Studies on maternal iron status above normal, or iron excess, suggest deleterious effects on infant growth, cognition, and childhood Type 1 diabetes. Maternal iron status in pregnancy was not consistently associated with child iron status after birth. The very heterogeneous set of studies suggests detrimental effects of iron deficiency, and possibly also of overload, on other outcomes including child neurodevelopment. Studies are needed to determine clinically meaningful definitions of iron deficiency and overload in pregnancy.
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4.
First week weight dip and reaching growth targets in early life in preterm infants.
Roelants, JA, Joosten, KFM, van der Geest, BMA, Hulst, JM, Reiss, IKM, Vermeulen, MJ
Clinical nutrition (Edinburgh, Scotland). 2018;(5):1526-1533
Abstract
BACKGROUND & AIMS Aggressive parenteral nutritional practices were implemented in clinical practice over a decade ago to prevent early growth retardation in preterm infants. We aimed to study adherence to current nutritional recommendations in a population of very preterm infants, and to evaluate growth in early life. METHODS Preterm infants (gestational age <30 weeks and birth weight <1500 g) were included in a prospective observational cohort study. Data on parenteral and enteral intake were collected on days 1-7, 14, 21 and 28 (d28) of life. Growth data were collected at birth, at moment of maximal weight loss (dip), and either at discharge from the neonatal intensive care unit or at d28, whichever came first. Nutritional intakes were compared to recommendations of current guidelines. The target growth rate was 15-20 g/kg/d. RESULTS Fifty-nine infants (63% male) were included. Median gestational age was 27 3/7 (interquartile range 25 6/7;28 4/7), and birth weight was 920 g (720;1200). Median macronutrient intakes were within or above the targets on all study days, but energy targets were not met before day 5. Median growth rates were 9.5 and 18.1 g/kg/d, when calculated from respectively birth and dip to discharge/d28. Eight (14%) versus 46 (78%) infants met the growth targets, when evaluated from respectively birth and dip to discharge/d28. CONCLUSIONS In this cohort, only energy intake up to day 5 was lower than recommended. Growth targets were achieved in the majority of the infants, but only when evaluated from dip onward, not from birth.
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5.
Effect of Donor Milk on Severe Infections and Mortality in Very Low-Birth-Weight Infants: The Early Nutrition Study Randomized Clinical Trial.
Corpeleijn, WE, de Waard, M, Christmann, V, van Goudoever, JB, Jansen-van der Weide, MC, Kooi, EM, Koper, JF, Kouwenhoven, SM, Lafeber, HN, Mank, E, et al
JAMA pediatrics. 2016;(7):654-61
Abstract
IMPORTANCE Infections and necrotizing enterocolitis, major causes of mortality and morbidity in preterm infants, are reduced in infants fed their own mother's milk when compared with formula. When own mother's 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 mother's 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 mother's 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 mother's 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 mother's 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 mother's 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.
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6.
Albumin synthesis in very low birth weight infants is enhanced by early parenteral lipid and high-dose amino acid administration.
Vlaardingerbroek, H, Schierbeek, H, Rook, D, Vermeulen, MJ, Dorst, K, Vermes, A, van Goudoever, JB, van den Akker, CHP
Clinical nutrition (Edinburgh, Scotland). 2016;(2):344-350
Abstract
BACKGROUND & AIMS Albumin is one of the most important plasma proteins and plays a key role in many physiologic processes, such as preserving colloid osmotic pressure, scavenging radicals, and binding and transporting bilirubin, hormones, and drugs. However, albumin concentrations are often low in preterm infants during the first days of life. We hypothesized that early parenteral lipid and high-dose amino acid (AA) administration to very low birth weight (VLBW) infants from birth onwards increases hepatic albumin synthesis rates. METHODS Inborn VLBW infants were randomized to receive from birth onwards either 2.4 g amino acids/(kg(·)d) (control group), 2.4 g amino acids/(kg(·)d) plus 2 g lipids/(kg(·)d) (AA + lipid group), or 3.6 g amino acids/(kg(·)d) plus 2 g lipids/(kg(·)d) (high AA + lipid group). On postnatal day 2, infants received a primed continuous infusion of [U-(13)C6,(15)N]leucine. Mass spectrometry was used to determine the fractional and absolute albumin synthesis rates (FSR and ASR, respectively). RESULTS In total, 28 infants (median gestational age 27 weeks (IQR 25-28), median birth weight 810 g (IQR 679-998) were studied. The median FSR was 6.5%/d in the control group, 10.6%/d in the AA group, and 12.3%/d in the high AA + lipid group, while the median was 84 mg/(kg(·)d) in the control group, 138 mg/(kg(·)d) in the AA group, and 160 mg/(kg(·)d) in the high AA + lipid group. CONCLUSION A group of VLBW infants given parenteral nutrition containing lipids and high-dose amino acids showed a higher rate of albumin synthesis compared to infants receiving no lipids and standard amounts of amino acids during the first two days of life.
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7.
Necrotising enterocolitis and mortality in preterm infants after introduction of probiotics: a quasi-experimental study.
Samuels, N, van de Graaf, R, Been, JV, de Jonge, RC, Hanff, LM, Wijnen, RM, Kornelisse, RF, Reiss, IK, Vermeulen, MJ
Scientific reports. 2016;:31643
Abstract
Evidence on the clinical effectiveness of probiotics in the prevention of necrotising enterocolitis (NEC) in preterm infants is conflicting and cohort studies lacked adjustment for time trend and feeding type. This study investigated the association between the introduction of routine probiotics (Lactobacillus acidophilus and Bifidobacterium bifidum; Infloran(®)) on the primary outcome 'NEC or death'. Preterm infants (gestational age <32 weeks or birth weight <1500 gram) admitted before (Jan 2008-Sep 2012; n = 1288) and after (Oct 2012-Dec 2014; n = 673) introduction of probiotics were compared. Interrupted time series logistic regression models were adjusted for confounders, effect modification by feeding type, seasonality and underlying temporal trends. Unadjusted and adjusted analyses showed no difference in 'NEC or death' between the two periods. The overall incidence of NEC declined from 7.8% to 5.1% (OR 0.63, 95% CI 0.42-0.93, p = 0.02), which was not statistically significant in the adjusted models. Introduction of probiotics was associated with a reduced adjusted odds for 'NEC or sepsis or death' in exclusively breastmilk-fed infants (OR 0.43, 95% CI 0.21-0.93, p = 0.03) only. We conclude that introduction of probiotics was not associated with a reduction in 'NEC or death' and that type of feeding seems to modify the effects of probiotics.
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8.
Safety and efficacy of early parenteral lipid and high-dose amino acid administration to very low birth weight infants.
Vlaardingerbroek, H, Vermeulen, MJ, Rook, D, van den Akker, CH, Dorst, K, Wattimena, JL, Vermes, A, Schierbeek, H, van Goudoever, JB
The Journal of pediatrics. 2013;(3):638-44.e1-5
Abstract
OBJECTIVE To assess the efficacy and safety of early parenteral lipid and high-dose amino acid (AA) administration from birth onwards in very low birth weight (VLBW, birth weight <1500 g) infants. STUDY DESIGN VLBW infants (n = 144; birth weight 862 ± 218 g; gestational age 27.4 ± 2.2 weeks) were randomized to receive 2.4 g of AA kg(-1) · d(-1) (control group), or 2.4 g AA kg(-1) · d(-1) plus 2-3 g lipids kg(-1) · d(-1) (AA + lipid group), or 3.6 g AA kg(-1) · d(-1) plus 2-3 g lipids kg(-1) · d(-1) (high AA + lipid group) from birth onwards. The primary outcome was nitrogen balance. The secondary outcomes were biochemical variables, urea rate of appearance, growth rates, and clinical outcome. RESULTS The nitrogen balance on day 2 was significantly greater in both intervention groups compared with the control group. Greater amounts of AA administration did not further improve nitrogen balance compared with standard AA dose plus lipids and was associated with high plasma urea concentrations and high rates of urea appearance. No differences in other biochemical variables, growth, or clinical outcomes were observed. CONCLUSIONS In VLBW infants, the administration of parenteral AA combined with lipids from birth onwards improved conditions for anabolism and growth, as shown by improved nitrogen balance. Greater levels of AA administration did not further improve the nitrogen balance but led to increased AA oxidation. Early lipid initiation and high-dose AA were well tolerated.
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9.
Resuscitation of very preterm infants with 30% vs. 65% oxygen at birth: study protocol for a randomized controlled trial.
Rook, D, Schierbeek, H, van der Eijk, AC, Longini, M, Buonocore, G, Vento, M, van Goudoever, JB, Vermeulen, MJ
Trials. 2012;:65
Abstract
BACKGROUND Resuscitation at birth with 100% oxygen is known to increase the oxidative burden with concomitant deleterious effects. Although fractions of inspired oxygen (FiO₂) < 100% are widely used in preterm infants, starting resuscitation at a (too) low FiO₂ may result in hypoxia. The objective of this study is to compare the safety and efficacy of resuscitating very preterm infants with an initial FiO2 of 30% versus 65%. METHODS/DESIGN In this double-blind, randomized controlled trial, 200 very preterm infants with a gestational age < 32 weeks will be randomized to start resuscitation after birth with either 30% or 65% oxygen. The FiO₂ will be adjusted based on oxygen saturation measured by pulse oximetry (SpO₂) and pulse rate (which should be over 100 beats per minute) in order to achieve a target SpO₂ of 88-94% at 10 min of life. The FiO₂ and pulse oximetry data will be continuously recorded.The primary outcome is survival without bronchopulmonary dysplasia, as assessed by a physiological test at 36 weeks postmenstrual age. The secondary outcomes include the time to achieve SpO₂ > 88%, Apgar score at 5 min, cumulative O₂ exposure, oxidative stress (as determined by glutathione synthesis and oxidative stress markers), retinopathy of prematurity, brain injury and neurodevelopmental outcome at 2 years of age.This study will provide insight into determining the appropriate initial FiO₂ to start resuscitation of very preterm infants. TRIAL REGISTRATION http://www.trialregister.nl, NTR243.
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10.
Majority of dietary glutamine is utilized in first pass in preterm infants.
van der Schoor, SR, Schierbeek, H, Bet, PM, Vermeulen, MJ, Lafeber, HN, van Goudoever, JB, van Elburg, RM
Pediatric research. 2010;(2):194-9
Abstract
Glutamine is a conditionally essential amino acid for very low-birth weight infants by virtue of its ability to play an important role in several key metabolic processes of immune cells and enterocytes. Although glutamine is known to be used to a great extent, the exact splanchnic metabolism in enterally fed preterm infants is unknown. We hypothesized that preterm infants show a high splanchnic first-pass glutamine metabolism and the primary metabolic fate of glutamine is oxidation. Five preterm infants (mean + or - SD birth weight 1.07 + or - 0.22 kg and GA 29 + or - 2 wk) were studied by dual tracer ([U-(13)C]glutamine and [(15)N(2)]glutamine) cross-over techniques on two study days (at postnatal week 3 + or - 1 wk). Splanchnic and whole-body glutamine kinetics were assessed by plasma isotopic enrichment of [U-(13)C]glutamine and [(15)N(2)]glutamine and breath (13)CO(2) enrichments. Mean fractional first-pass glutamine uptake was 73 + or - 6% and 57 + or - 17% on the study days. The splanchnic tissues contributed for a large part (57 + or - 6%) to the total amount of labeled carbon from glutamine retrieved in expiratory air. Dietary glutamine is used to a great extent by the splanchnic tissues in preterm infants and its carbon skeleton has an important role as fuel source.