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.

Early-life nutrition is associated with processing speed at age 5 in children born preterm with very low birth weight.

OBJECTIVE: Processing speed is suboptimal among preterm-born children which is of concern as it is a foundational skill supporting higher-level cognitive functions. The study objective was to evaluate associations between early-life nutrition and processing speed in childhood. METHODS: Macronutrient and human milk (mother's own, donor) intakes from 137 children born preterm with very low birth weight enrolled in a nutrition feeding trial were included. Processing speed was evaluated at age 5 using the Wechsler Preschool and Primary Scale of Intelligence-fourth edition Processing Speed Index. Associations between early-life nutrition and processing speed were explored through linear regression. RESULTS: Children had a mean (standard deviation [SD]) birth gestational age of 28.1 (2.5) weeks, weight of 1036 (260) g and 52% were male. The mean (SD) assessment age was 5.7 (0.2) years. Sex-dependent relationships were identified between first postnatal month protein, lipid and energy intakes and processing speed at 5 years. For females, lower protein (per 0.1 g/kg/d: -0.88, 95% confidence interval [CI]: -1.53, -0.23; p = 0.01) and energy (per 10 kcal/kg/d: -2.38, 95% CI: -4.70, -0.05; p = 0.03) intakes were related to higher processing speed scores. Mother's milk provision was positively associated (per 10% increase: 0.80, 95% CI: 0.22, 1.37; p = 0.01) and donor milk was negatively associated (per 10% increase: -1.15, 95% CI: -2.22, -0.08; p = 0.04) with processing speed scores; no sex differences were observed. CONCLUSIONS: First postnatal month nutrition was related to processing speed at age 5 in children born preterm with very low birth weight. Early-life nutrition that supports processing speed may be leveraged to improve later cognitive outcomes for this vulnerable population.

Extrauterine growth restriction in very-low-birthweight infants: prevalence and concordance according to Fenton, Olsen, and INTERGROWTH-21st growth charts in a multicenter Spanish cohort.

Multiple criteria and growth references have been proposed for extrauterine growth restriction (EUGR). We hypothesized that these may impact the diagnosis of EUGR. The objective was to evaluate the prevalence of EUGR with its different definitions and the concordance according to Fenton, Olsen, and INTERGROWTH-21st in very-low-birthweight (VLBW) infants. This is an observational, retrospective, and multicenter study including VLBW infants from the Spanish SEN1500 Network from 2011 to 2020. Patients with major congenital anomalies, embryopathies, and gestational age less than 24 weeks were excluded. EUGR prevalence was calculated at discharge with cross-sectional, longitudinal, "true" cross-sectional, and "true" longitudinal definitions. Concordance was assessed with Fleiss' kappa coefficient. 23582 VLBW infants from 77 NICUs were included. In total, 50.4% were men with a median of gestational age of 29 (4) weeks. The prevalence of EUGR (cross-sectional, longitudinal, and "true") was variable for weight, length, and head circumference. Overall, the prevalence was higher with Fenton and lower with Olsen (cross-sectional and "true" cross-sectional) and INTERGROWTH-21st (longitudinal and "true" longitudinal). Agreement among the charts by weight was good only for cross-sectional EUGR and moderate for longitudinal, "true" cross-sectional, and "true" longitudinal. Concordance was good or very good for EUGR by length and head circumference.Conclusions: The prevalence of EUGR with the most commonly used definitions was variable in the cohort. Agreement among growth charts was moderate for all the definitions of EUGR by weight except cross-sectional and good or very good for length and head circumference. The choice of reference chart can impact the establishment of the diagnosis of EUGR. What is known: • EUGR has been defined in the literature and daily practice considering weight, length and head circumference with multiple criteria (cross-sectional, longitudinal, and "true" definition) • Different growth charts have been used for EUGR diagnosis What is new: • Prevalence of EUGR is variable depending on the definition and growth chart used in our cohort of VLBW infants • For the most frequently EUGR criteria used, traditionally considering weight, concordance among Fenton, Olsen and INTERGROWTH-21st growth charts is only moderate for all the definitions of EUGR by weight except cross-sectional definition. Concordance among the charts is good or very good for the different criteria of EUGR by head circumference and length.

Noise or sound management in the neonatal intensive care unit for preterm or very low birth weight infants.

BACKGROUND: Infants in the neonatal intensive care unit (NICU) are subjected to different types of stress, including sounds of high intensity. The sound levels in NICUs often exceed the maximum acceptable level recommended by the American Academy of Pediatrics, which is 45 decibels (dB). Hearing impairment is diagnosed in 2% to 10% of preterm infants compared to only 0.1% of the general paediatric population. Bringing sound levels under 45 dB can be achieved by lowering the sound levels in an entire unit; by treating the infant in a section of a NICU, in a 'private' room, or in incubators in which the sound levels are controlled; or by reducing sound levels at the individual level using earmuffs or earplugs. By lowering sound levels, the resulting stress can be diminished, thereby promoting growth and reducing adverse neonatal outcomes. This review is an update of one originally published in 2015 and first updated in 2020. OBJECTIVES: To determine the benefits and harms of sound reduction on the growth and long-term neurodevelopmental outcomes of neonates. SEARCH METHODS: We used standard, extensive Cochrane search methods. On 21 and 22 August 2023, a Cochrane Information Specialist searched CENTRAL, PubMed, Embase, two other databases, two trials registers, and grey literature via Google Scholar and conference abstracts from Pediatric Academic Societies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) or quasi-RCTs in preterm infants (less than 32 weeks' postmenstrual age (PMA) or less than 1500 g birth weight) cared for in the resuscitation area, during transport, or once admitted to a NICU or stepdown unit. We specified three types of intervention: 1) intervention at the unit level (i.e. the entire neonatal department), 2) at the section or room level, or 3) at the individual level (e.g. hearing protection). DATA COLLECTION AND ANALYSIS: We used the standardised review methods of Cochrane Neonatal to assess the risk of bias in the studies. We used the risk ratio (RR) and risk difference (RD), with their 95% confidence intervals (CIs), for dichotomous data. We used the mean difference (MD) for continuous data. Our primary outcome was major neurodevelopmental disability. We used GRADE to assess the certainty of the evidence. MAIN RESULTS: We included one RCT, which enroled 34 newborn infants randomised to the use of silicone earplugs versus no earplugs for hearing protection. It was a single-centre study conducted at the University of Texas Medical School in Houston, Texas, USA. Earplugs were positioned at the time of randomisation and worn continuously until the infants were 35 weeks' postmenstrual age (PMA) or discharged (whichever came first). Newborns in the control group received standard care. The evidence is very uncertain about the effects of silicone earplugs on the following outcomes. • Cerebral palsy (RR 3.00, 95% CI 0.15 to 61.74)and Mental Developmental Index (MDI) (Bayley II) at 18 to 22 months' corrected age (MD 14.00, 95% CI 3.13 to 24.87); no other indicators of major neurodevelopmental disability were reported. • Normal auditory functioning at discharge (RR 1.65, 95% CI 0.93 to 2.94) • All-cause mortality during hospital stay (RR 2.07, 95% CI 0.64 to 6.70; RD 0.20, 95% CI -0.09 to 0.50) • Weight (kg) at 18 to 22 months' corrected age (MD 0.31, 95% CI -1.53 to 2.16) • Height (cm) at 18 to 22 months' corrected age (MD 2.70, 95% CI -3.13 to 8.53) • Days of assisted ventilation (MD -1.44, 95% CI -23.29 to 20.41) • Days of initial hospitalisation (MD 1.36, 95% CI -31.03 to 33.75) For all outcomes, we judged the certainty of evidence as very low. We identified one ongoing RCT that will compare the effects of reduced noise levels and cycled light on visual and neural development in preterm infants. AUTHORS' CONCLUSIONS: No studies evaluated interventions to reduce sound levels below 45 dB across the whole neonatal unit or in a room within it. We found only one study that evaluated the benefits of sound reduction in the neonatal intensive care unit for hearing protection in preterm infants. The study compared the use of silicone earplugs versus no earplugs in newborns of very low birth weight (less than 1500 g). Considering the very small sample size, imprecise results, and high risk of attrition bias, the evidence based on this research is very uncertain and no conclusions can be drawn. As there is a lack of evidence to inform healthcare or policy decisions, large, well designed, well conducted, and fully reported RCTs that analyse different aspects of noise reduction in NICUs are needed. They should report both short- and long-term outcomes.

Novel growth reference ImaGrow differed from existing charts for preterm children aged 0-2 years.

AIM: This study aimed to address the critical need for more accurate growth reference charts for preterm infants, with a particular focus on low- and very low-birth-weight infants. METHODS: The subjects were recruited at a single tertiary centre. The cohort comprised singleton and twin infants born before 37 weeks of gestation, with data collected from 2000 to 2016. Standardised measurements of body parameters were recorded in this mixed longitudinal survey. LMS method was utilised for data analysis. Statistical analysis was performed using SPSS Statistics Version 21. The validation with another new cohort was executed. RESULTS: A total of 1781 infants (52.5% boys) met the inclusion criteria. The median gestational age at birth was 30 weeks, with a median birth weight of 1350 grams. The main findings included the construction of ImaGrow charts for low- and very low-birth-weight infants and significant differences in growth trajectories compared to Fenton+WHO charts. CONCLUSION: Our comprehensive growth references, ImaGrow, are based on a long-term auxological assessment of preterm infants and differ from charts derived from size-at-birth standards or charts for term babies. These charts have significant implications for clinical practice in monitoring and assessing the growth of preterm infants.

Controlled Trial of Two Incremental Milk-Feeding Rates in Preterm Infants.

BACKGROUND: Observational data have shown that slow advancement of enteral feeding volumes in preterm infants is associated with a reduced risk of necrotizing enterocolitis but an increased risk of late-onset sepsis. However, data from randomized trials are limited. METHODS: We randomly assigned very preterm or very-low-birth-weight infants to daily milk increments of 30 ml per kilogram of body weight (faster increment) or 18 ml per kilogram (slower increment) until reaching full feeding volumes. The primary outcome was survival without moderate or severe neurodevelopmental disability at 24 months. Secondary outcomes included components of the primary outcome, confirmed or suspected late-onset sepsis, necrotizing enterocolitis, and cerebral palsy. RESULTS: Among 2804 infants who underwent randomization, the primary outcome could be assessed in 1224 (87.4%) assigned to the faster increment and 1246 (88.7%) assigned to the slower increment. Survival without moderate or severe neurodevelopmental disability at 24 months occurred in 802 of 1224 infants (65.5%) assigned to the faster increment and 848 of 1246 (68.1%) assigned to the slower increment (adjusted risk ratio, 0.96; 95% confidence interval [CI], 0.92 to 1.01; P = 0.16). Late-onset sepsis occurred in 414 of 1389 infants (29.8%) in the faster-increment group and 434 of 1397 (31.1%) in the slower-increment group (adjusted risk ratio, 0.96; 95% CI, 0.86 to 1.07). Necrotizing enterocolitis occurred in 70 of 1394 infants (5.0%) in the faster-increment group and 78 of 1399 (5.6%) in the slower-increment group (adjusted risk ratio, 0.88; 95% CI, 0.68 to 1.16). CONCLUSIONS: There was no significant difference in survival without moderate or severe neurodevelopmental disability at 24 months in very preterm or very-low-birth-weight infants with a strategy of advancing milk feeding volumes in daily increments of 30 ml per kilogram as compared with 18 ml per kilogram. (Funded by the Health Technology Assessment Programme of the National Institute for Health Research; SIFT Current Controlled Trials number, ISRCTN76463425.).

Biomarkers of ageing in New Zealand VLBW young adults and controls.

BACKGROUND: There is individual variation in physiological ageing. Former very low birthweight (VLBW; birthweight < 1500 g) young adults may have less satisfactory measurements on some physiological parameters than term controls. We hypothesized that a summation score of physiological biomarkers that change with age would show VLBW adults to have a more advanced physiologic age than controls. METHODS: VLBW adults (229; 71% survivors of a national VLBW cohort) and term-born controls (100) were clinically assessed at 26-30 years. Ten measured physiological biomarkers were selected and measurements converted to z-scores using normative reference data. Between-group comparisons were tested for statistical significance for individual biomarker z-scores and a summation score. RESULTS: Nine of 10 biomarkers showed a mean z-score suggestive of older physiological age in the VLBW group versus controls. The observed mean difference in the summation score was highly significant (p < 0.001), representing a mean shift of 0.47 SD in the distribution of test scores for VLBW relative to controls. CONCLUSIONS: Utilizing a 10-biomarker score, VLBW young adults have a score indicative of poorer physiological functioning than term-born controls. Repeating these measures after an interval could provide insights into the comparative pace of ageing between VLBW and term-born adults. IMPACT: A summation score of 10 physiological biomarkers that are known to change with age shows that former very low birthweight adults have significantly poorer physiological functioning by the end of their third decade than term-born controls. This result adds to existing literature showing very preterm and very low birthweight young adults often have physiological and metabolic test results that are less satisfactory than those from term controls, despite mostly being in the normal range for age; for instance, higher systolic blood pressure. Although the pace of ageing in later years is yet to be established, the implications of this study are that preventative measures and lifestyle choices that impact on physiological ageing might have even greater importance for very preterm and very low birthweight graduates.

Racial and socioeconomic disparities in breast milk feedings in US neonatal intensive care units.

Very low birth weight (VLBW; <1500 g birth weight) infants are substantially more likely to be born to black than to non-black mothers, predisposing them to potentially preventable morbidities that increase the risk for costly lifelong health problems. Mothers' own milk (MOM) may be considered the ultimate "personalized medicine" since milk composition and bioactive components vary among mothers and multiple milk constituents provide specific protection based on shared exposures between mother and infant. MOM feedings reduce the risks and associated costs of prematurity-associated morbidities, with the greatest reduction afforded by MOM through to NICU discharge. Although black and non-black mothers have similar lactation goals and initiation rates, black VLBW infants are half as likely to receive MOM at NICU discharge in the United States. Black mothers are significantly more likely to be low-income, single heads of household and have more children in the home, increasing the burden of MOM provision. Although rarely considered, the out-of-pocket and opportunity costs associated with providing MOM for VLBW infants are especially onerous for black mothers. When MOM is not available, the NICU assumes the costs of inferior substitutes for MOM, contributing further to disparate outcomes. Novel strategies to mitigate these disparities are urgently needed. IMPACT: Mother's own milk exemplifies personalized medicine through its unique biologic activity. Hospital factors and social determinants of health are associated with mother's own milk feedings for very low-birth-weight infants in the neonatal intensive care unit. Notably, out-of-pocket and opportunity costs associated with providing mother's own milk are borne by mothers. Conceptualizing mother's own milk feedings as an integral part of NICU care requires consideration of who bears the costs of MOM provision-the mother or the NICU?

Short versus long feeding interval for bolus feedings in very preterm infants.

BACKGROUND: There is presently no certainty about the ideal feeding intervals for preterm infants. Shorter feeding intervals of, for example, two hours, have the theoretical advantage of allowing smaller volumes of milk. This may have the potential to reduce the incidence and severity of gastro-oesophageal reflux. Longer feeding intervals have the theoretical advantage of allowing more gastric emptying between two feeds. This potentially provides periods of rest (and thus less hyperaemia) for an immature digestive tract. OBJECTIVES: To determine the safety of shorter feeding intervals (two hours or shorter) versus longer feeding intervals (three hours or more) and to compare the effects in terms of days taken to regain birth weight and to achieve full feeding. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to run comprehensive searches in CENTRAL (2020, Issue 6) and Ovid MEDLINE and Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Daily and Versions, and CINAHL on 25 June 2020. We searched clinical trials databases and the reference lists of retrieved articles for randomised controlled trials (RCTs) and quasi-RCTs. SELECTION CRITERIA: We included RCTs and quasi-RCTs comparing short (e.g. one or two hours) versus long (e.g. three or four hours) feeding intervals in preterm infants of any birth weight, all or most of whom were less than 32 weeks' gestation. Infants could be of any postnatal age at trial entry, but eligible infants should not have received feeds before study entry, with the exception of minimal enteral feeding. We included studies of nasogastric or orogastric bolus feeding, breast milk or formula, in which the feeding interval is the intervention. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. We used the GRADE approach to assess the certainty of evidence. Our primary outcomes were days taken to achieve full enteral feeding and days to regain birth weight. Our other outcomes were duration of hospital stay, episodes of necrotising enterocolitis (NEC) and growth during hospital stay (weight, length and head circumference). MAIN RESULTS: We included four RCTs, involving 417 infants in the review. One study involving 350 infants is awaiting classification. All studies compared two-hourly versus three-hourly feeding interval. The risk of bias of the included studies was generally low, but all studies had high risk of performance bias due to lack of blinding of the intervention. Three studies were included in meta-analysis for the number of days taken to achieve full enteral feeding (351 participants). The mean days to achieve full feeds was between eight and 11 days. There was little or no difference in days taken to achieve full enteral feeding between two-hourly and three-hourly feeding, but this finding was of low certainty (mean difference (MD) ‒0.62, 95% confidence interval (CI) ‒1.60 to 0.36). There was low-certainty evidence that the days taken to regain birth weight may be slightly longer in infants receiving two-hourly feeding than in those receiving three-hourly feeding (MD 1.15, 95% CI 0.11 to 2.20; 3 studies, 350 participants). We are uncertain whether shorter feeding intervals have any effect on any of our secondary outcomes including the duration of hospital stay (MD ‒3.36, 95% CI ‒9.18 to 2.46; 2 studies, 207 participants; very low-certainty evidence) and the risk of NEC (typical risk ratio 1.07, 95% CI 0.54 to 2.11; 4 studies, 417 participants; low-certainty evidence). No study reported growth during hospital stay. AUTHORS' CONCLUSIONS: The low-certainty evidence we found in this review suggests that there may be no clinically important differences between two- and three-hourly feeding intervals. There is insufficient information about potential feeding complications and in particular NEC. No studies have looked at the effect of other feeding intervals and there is no long-term data on neurodevelopment or growth.

Single-course antenatal corticosteroids is related to faster growth in very-low-birth-weight infant.

BACKGROUND: Antenatal corticosteroids (ACS) treatment is critical to support survival and lung maturation in preterm infants, however, its effect on feeding and growth is unclear. Prior preterm delivery, it remains uncertain whether ACS treatment should be continued if possible (repeated course ACS), until a certain gestational age is reached. We hypothesized that the association of single-course ACS with feeding competence and postnatal growth outcomes might be different from that of repeated course ACS in very-low-birth-weight preterm infants. METHODS: A multicenter retrospective cohort study was conducted in very-low-birth-weight preterm infants born at 23-37 weeks' gestation in South China from 2011 to 2014. Data on growth, nutritional and clinical outcomes were collected. Repeated course ACS was defined in this study as two or more courses ACS (more than single-course). Infants were stratified by gestational age (GA), including GA < 28 weeks, 28 weeks ≤ GA < 32 weeks and 32 weeks ≤ GA < 37 weeks. Multiple linear regression and multilevel model were applied to analyze the association of ACS with feeding and growth outcomes. RESULTS: A total of 841 infants were recruited. The results, just in very-low-birth-weight preterm infants born at 28-32 weeks' gestation, showed both single and repeated course of ACS regimens had shorter intubated ventilation time compared to non-ACS regimen. Single-course ACS promoted the earlier application of amino acid and enteral nutrition, and higher rate of weight increase (15.71; 95%CI 5.54-25.88) than non-ACS after adjusting for potential confounding factors. No associations of repeated course ACS with feeding, mean weight and weight increase rate were observed. CONCLUSIONS: Single-course ACS was positively related to feeding and growth outcomes in very-low-birth-weight preterm infants born at 28-32 weeks' gestation. However, the similar phenomenon was not observed in the repeated course of ACS regimen.

The effect of postnatal corticosteroids on growth parameters in infants with bronchopulmonary dysplasia.

OBJECTIVES: Corticosteroids are administered to ventilator dependent infants with bronchopulmonary dysplasia (BPD) to improve respiratory function and facilitating extubation. Acutely, however, growth impairment can occur as a side effect of such therapy. We aimed to determine the effect of corticosteroids on postnatal growth during the entire neonatal intensive care unit (NICU) admission. METHODS: A whole population study of extremely preterm infants with BPD was undertaken. Corticosteroid therapy was classified as treatment with dexamethasone or hydrocortisone for a least five consecutive days. Growth was calculated as the difference in weight and head circumference z-score from birth to discharge. RESULTS: Six thousand, one hundred and four infants with BPD were included of whom 28.3% received postnatal corticosteroids. Infants receiving corticosteroids were less mature (GA 25.0 vs. 26.3 weeks) and of lower birthweight (0.70 vs. 0.84 kg) than those not receiving treatment. There were no significant differences between those who did and did not receive corticosteroids in weight gain (p=0.61) or head circumference growth (p=0.33) from birth to discharge. Single vs. multiple courses of postnatal corticosteroids did not result in significant differences in weight (p=0.62) or head circumference (p=0.13) growth. CONCLUSIONS: Postnatal corticosteroid treatment did not affect the longer term growth of preterm infants with BPD.

Risks of nonchromosomal birth defects, small-for-gestational age birthweight, and prematurity with in vitro fertilization: effect of number of embryos transferred and plurality at conception versus at birth.

PURPOSE: Excess embryos transferred (ET) (> plurality at birth) and fetal heartbeats (FHB) at 6 weeks' gestation are associated with reductions in birthweight and gestation, but prior studies have been limited by small sample sizes and limited IVF data. This analysis evaluated associations between excess ET, excess FHB, and adverse perinatal outcomes, including the risk of nonchromosomal birth defects. METHODS: Live births conceived via IVF from Massachusetts, New York, North Carolina, and Texas included 138,435 children born 2004-2013 (Texas), 2004-2016 (Massachusetts and North Carolina), and 2004-2017 (New York) were classified by ET and FHB. Major birth defects were reported by statewide registries within the first year of life. Logistic regression was used to estimate adjusted odds ratios (AORs) and 95% CIs of the risks of a major nonchromosomal birth defect, small-for-gestational age birthweight (SGA), low birthweight (LBW), and preterm birth (≤36 weeks), by excess ET, and excess ET + excess FHB, by plurality at birth (singletons and twins). RESULTS: In singletons with [2 ET, FHB =1] and [≥3 ET, FHB=1], risks [AOR (95% CI)] were increased, respectively, for major nonchromosomal birth defects [1.13 (1.00-1.27) and 1.18 (1.00-1.38)], SGA [1.10 (1.03-1.17) and 1.15 (1.05-1.26)], LBW [1.09 (1.02-1.13) and 1.17 (1.07-1.27)], and preterm birth [1.06 (1.00-1.12) and 1.14 (1.06-1.23)]. With excess ET + excess FHB, risks of all adverse outcomes except major nonchromosomal birth defects increased further for both singletons and twins. CONCLUSION: Excess embryos transferred are associated with increased risks for nonchromosomal birth defects, reduced birthweight, and prematurity in IVF-conceived births.

Music enhances structural maturation of emotional processing neural pathways in very preterm infants.

Prematurity disrupts brain maturation by exposing the developing brain to different noxious stimuli present in the neonatal intensive care unit (NICU) and depriving it from meaningful sensory inputs during a critical period of brain development, leading to later neurodevelopmental impairments. Musicotherapy in the NICU environment has been proposed to promote sensory stimulation, relevant for activity-dependent brain plasticity, but its impact on brain structural maturation is unknown. Neuroimaging studies have demonstrated that music listening triggers neural substrates implied in socio-emotional processing and, thus, it might influence networks formed early in development and known to be affected by prematurity. Using multi-modal MRI, we aimed to evaluate the impact of a specially composed music intervention during NICU stay on preterm infant's brain structure maturation. 30 preterm newborns (out of which 15 were exposed to music during NICU stay and 15 without music intervention) and 15 full-term newborns underwent an MRI examination at term-equivalent age, comprising diffusion tensor imaging (DTI), used to evaluate white matter maturation using both region-of-interest and seed-based tractography approaches, as well as a T2-weighted image, used to perform amygdala volumetric analysis. Overall, WM microstructural maturity measured through DTI metrics was reduced in preterm infants receiving the standard-of-care in comparison to full-term newborns, whereas preterm infants exposed to the music intervention demonstrated significantly improved white matter maturation in acoustic radiations, external capsule/claustrum/extreme capsule and uncinate fasciculus, as well as larger amygdala volumes, in comparison to preterm infants with standard-of-care. These results suggest a structural maturational effect of the proposed music intervention on premature infants' auditory and emotional processing neural pathways during a key period of brain development.

Relationships between Early Nutrition, Illness, and Later Outcomes among Infants Born Preterm with Hyperglycemia.

OBJECTIVE: To evaluate the effects of hyperglycemia on body composition and neurodevelopment, and how early nutrition and illness modify these relationships in infants born preterm. STUDY DESIGN: Prospective data were collected from infants born <32 weeks of gestational age (N = 97), including inpatient days of hyperglycemia (blood glucose >150 mg/dL) and nutrient intake. Body composition was measured at discharge and 4 months' postmenstrual age (PMA). Bayley Scales of Infant Development III (BSID-III) were administered at 12 months' PMA. Linear regression analysis was performed, adjusting for birth gestational age. Associations between hyperglycemia, body composition, and BSID-III were analyzed in models accounting for first-week nutrition and early illness severity via Score for Neonatal Acute Physiology-II. RESULTS: Mean birth gestational age was 27.8 (SD 2.4) weeks. Hyperglycemia occurred in 48.5% of infants. Hyperglycemia for ≥5 days was negatively associated with fat mass and fat free mass z scores at discharge, and fat free mass z score at 4 months' PMA (P < .05 all). Hyperglycemia for ≥5 days was negatively associated with cognition, language, and motor scores on the BSDI at 12 months (P ≤ .01 all). Associations with body composition and BSID-III were diminished when models included first week nutrition yet remained unchanged when illness severity was included. CONCLUSIONS: In infants <32 weeks, ≥5 days of hyperglycemia is associated with decreased lean mass at 4 months' PMA and poorer neurodevelopmental outcome at 12 months' PMA. These associations may be mediated by decreased first week nutrition, potentially related to reduced glucose infusion rate for management of hyperglycemia.

Higher- or Usual-Volume Feedings in Infants Born Very Preterm: A Randomized Clinical Trial.

OBJECTIVE: To determine whether higher-volume feedings improve postnatal growth among infants born very preterm. STUDY DESIGN: Randomized clinical trial with 1:1 parallel allocation conducted from January 2015 to June 2018 in a single academic medical center in the US. In total, 224 infants with a birth weight 1001-2500 g born at <32 weeks of gestation were randomized to higher-volume (180-200 mL/kg/d) or usual-volume (140-160 mL/kg/d) feedings after establishing full enteral feedings (≥120 mL/kg/d). The primary outcome was growth velocity (g/kg/d) from randomization to study completion at 36 weeks of postmenstrual age or hospital discharge if earlier. RESULTS: Growth velocity increased among infants in the higher-volume group compared with the usual-volume group (mean [SD], 20.5 [4.5] vs 17.9 [4.5] g/kg/d; P < .001). At study completion, all measurements were higher among infants in the higher-volume group compared with the usual-volume group: weight (2365 [324] g, z score -0.60 [0.73] vs 2200 [308] g, z score -0.94 [0.71]; P < .001); head circumference (31.9 [1.3] cm, z score -0.30 [0.91] vs 31.4 [1.3] cm, z score -0.53 [0.84]; P = .01); length (44.9 [2.1] cm, z score -0.68 [0.88] vs 44.4 [2.0], z score -0.83 [0.84]; P = .04); and mid-arm circumference (8.8 [0.8] cm vs 8.4 [0.8] cm; P = .002). Bronchopulmonary dysplasia, patent ductus arteriosus, necrotizing enterocolitis, or other adverse outcomes did not differ between groups. CONCLUSIONS: In infants born very preterm weighing 1001-2500 g at birth, higher-volume feedings increased growth velocity, weight, head circumference, length, and mid-arm circumference compared with usual-volume feedings without adverse effects. TRIAL REGISTRATION: ClinicalTrials.gov; NCT02377050.

Human milk fortification: the clinician and parent perspectives.

This study reports on the human milk fortification session at the 2019 NEC Society Symposium, which included clinicians and parents discussing the evidence comparing fortification options such as efficacy, safety, cost effectiveness, and the need for parents to be informed about fortifier choice. With the current literature available and the varying standard of care practices for human milk fortification, further studies are needed to determine the most complete diet for preterm infants. The optimal diet would not only provide key nutrients and energy for growth and development, but also improve short- and long-term outcomes. Parents, as advocates and providers for their infant, should be informed, educated, and included in the discussion and decisions regarding fortification of human milk for their infant.

Serial assessment of fat and fat-free mass accretion in very preterm infants: a randomized trial.

BACKGROUND: Clinicians could modify dietary interventions during early infancy by monitoring fat and fat-free mass accretion in very preterm infants. METHODS: Preterm infants were randomly assigned to either having reports on infant body composition available to the clinicians caring for them (intervention group) or not having reports available (control group). All infants underwent serial assessments of body composition by air-displacement plethysmography before 32 weeks of postmenstrual age (PMA) and at 36 weeks PMA. The primary outcome was percent body fat (%BF) at 3 months of corrected age (CA). RESULTS: Fifty infants were randomized (median gestational age: 30 weeks; mean ± SD birth weight: 1387 ± 283 g). The mean %BF increased from 7 ± 4 before 32 weeks PMA to 20 ± 5 at 3 months CA. The differences in mean %BF between the intervention group and the control group were not statistically significant at 36 weeks PMA (14.5 vs. 13.6) or 3 months CA (20.8 vs. 19.4). Feeding practices and anthropometric measurements during hospitalization did not differ between groups. CONCLUSIONS: Serial assessments of body composition in both intervention and control groups showed consistent increments in %BF. However, providing this information to clinicians did not influence nutritional practices or growth. IMPACT: Serial assessments of body composition in preterm infants at 32 and 36 weeks postmenstrual age show consistent increments in % body fat up to 3 months of corrected age. However, providing this information to the clinician did not influence nutritional practices or growth.

Nutritional interventions to reduce rates of infection, necrotizing enterocolitis and mortality in very preterm infants.

Observational studies demonstrating reduced rates of infections, necrotizing enterocolitis (NEC), and mortality in preterm infants fed their own mother's milk, as opposed to formula, have prompted endeavors to achieve similar effects with the right choice of food and food additives. In a systematic review of meta-analyses and randomized controlled trials (RCTs), we considered nutritional interventions aimed at reducing the rates of infections, NEC, or mortality in very preterm infants. The overall effects of particular interventions were presented as risk ratios with 95% confidence intervals. In RCTs, pasteurized human donor milk, as opposed to formula, reduced NEC but not infections or mortality. No differences emerged between infants receiving human or bovine milk-based fortifiers. Pooled data of small trials and a recent large RCT suggested that bovine lactoferrin reduced rates of fungal sepsis without impact on other infections, NEC, or mortality. Pooled data of RCTs assessing the use of prebiotic oligosaccharides found reduced infection but not mortality. Enteral L-glutamine (six RCTs) lowered infection rates, and enteral L-arginine (three RCTs) reduced NEC. A meta-analysis sensitivity approach found multiple-strain (but not single-strain) probiotics to be highly effective in reducing NEC and mortality. Thus, selected food components may help to improve outcomes in preterm infants.

Basal ganglia and thalamic tract connectivity in very preterm and full-term children; associations with 7-year neurodevelopment.

BACKGROUND: Altered basal ganglia and thalamic connectivity may be critical for cognitive, motor and behavioural impairments common to very preterm (<32 weeks' gestational age) children. This study aims to (1) compare corticostriatal and thalamocortical tract connectivity between very preterm and term-born children at 7 years of age; (2) explore tract connectivity associations with 7-year neurodevelopmental outcomes, and whether these relationships differed between groups. METHODS: Eighty-three very preterm and 19 term-born (≥37 weeks' gestational age) children underwent structural and diffusion magnetic resonance imaging and had a neuropsychological assessment at 7 years. Corticostriatal and thalamocortical tracts were reconstructed and white matter connectivity was estimated with apparent fibre density. RESULTS: Compared with term-born controls, very preterm children had decreased connectivity in tracts linking the caudate to right motor areas (-10%, p = 0.03) and the thalamus with left motor areas (-5.7%, p = 0.03). Reduced connectivity in corticostriatal and thalamocortical tracts was associated with adverse motor functioning in both groups (p = 0.06). Decreased connectivity of the left caudate and putamen with the lateral prefrontal cortex was associated with lower reading performance for controls (p = 0.06). CONCLUSION: Corticostriatal and thalamocortical tracts are vulnerable to very preterm birth. Poorer connectivity in these tracts may underlie the motor impairments observed in very preterm children.

Early fortification of human milk versus late fortification to promote growth in preterm infants.

BACKGROUND: Uncertainty exists about the optimal point at which multi-component fortifier should be added to human milk for promoting growth in preterm infants. The most common practice is to start fortification when the infant's daily enteral feed volume reaches 100 mL/kg body weight. Another approach is to commence fortification earlier, in some cases as early as the first enteral feed. Early fortification of human milk could increase nutrient intake and growth rates but may increase the risk of feed intolerance and necrotising enterocolitis (NEC). OBJECTIVES: To assess effects on growth and safety of early fortification of human milk versus late fortification in preterm infants To assess whether effects vary based upon gestational age (≤ 27 weeks; 28 to 31 weeks; ≥ 32 weeks), birth weight (< 1000 g; 1000 to 1499 g; ≥ 1500 g), small or appropriate for gestational age, or type of fortifier (bovine milk-based human milk fortifier (HMF); human milk-based HMF; formula powder) SEARCH METHODS: We used the standard strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 8); OVID MEDLINE (R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Daily and Versions (R) (1946 to 15 August 2019); MEDLINE via PubMed (1 August 2018 to 15 August 2019) for the previous year; and the Cumulative Index to Nursing and Allied Health Literatue (CINAHL) (1981 to 15 August 2019). We searched clinical trials databases and reference lists of included studies. SELECTION CRITERIA: We included randomised controlled trials that compared early versus late fortification of human milk in preterm infants. We defined early fortification as fortification started at < 100 mL/kg/d enteral feed volume or < 7 days postnatal age, and late fortification as fortification started at ≥ 100 mL/kg/d feeds or ≥ 7 days postnatal age. DATA COLLECTION AND ANALYSIS: Both review authors assessed trial eligibility and risk of bias and independently extracted data. We analysed treatment effects in individual trials, and we reported risk ratio (RR) for dichotomous data and mean difference (MD) for continuous data, with respective 95% confidence intervals (CIs). We used the GRADE approach to assess the certainty of evidence. MAIN RESULTS: We included two trials with a total of 237 infants. All participants were very low birth weight infants (birth weight < 1500 g). Early fortification was started at 20 mL/kg/d enteral feeds in one study and 40 mL/kg/d in the other study. Late fortification was started at 100 mL/kg/d feeds in both studies. One study used bovine milk-based fortifier, and the other used human milk-based fortifier. Meta-analysis showed that early fortification may have little or no effect on growth outcomes including time to regain birth weight (MD -0.06 days, 95% CI -1.32 to 1.20 days), linear growth (MD 0.10 cm/week, 95% CI -0.03 to 0.22 cm/week), or head growth (MD -0.01 cm/week, 95% CI -0.07 to 0.06 cm/week) during the initial hospitalisation period. Early fortification may have little or no effect on the risk of NEC (MD -0.01, 95% CI -0.07 to 0.06). The certainty of evidence was low for these outcomes due to risk of bias (lack of blinding) and imprecision (small sample size). Early fortification may have little or no effect on incidence of surgical NEC, time to reach full enteral feeds, extrauterine growth restriction at discharge, proportion of infants with feed interruption episodes, duration of total parenteral nutrition (TPN), duration of central venous line usage, or incidence of invasive infection, all-cause mortality, and duration of hospital stay. The certainty of evidence was low for these outcomes due to risk of bias (lack of blinding) and imprecision (small sample size). We did not have data for other outcomes such as subsequent weight gain after birth weight is regained, parenteral nutrition-associated liver disease, postdischarge growth, and neurodevelopmental outcomes. AUTHORS' CONCLUSIONS: Available evidence is insufficient to support or refute early fortification of human milk in preterm infants. Further large trials would be needed to provide data of sufficient quality and precision to inform policy and practice.