IMPORTANCE: Despite apparent progress in perinatal care, children born extremely or very preterm (EP/VP) remain at high risk for cognitive deficits. Insight into factors contributing to cognitive ...outcome is key to improve outcomes after EP/VP birth. OBJECTIVE: To examine the cognitive abilities of children of EP/VP birth (EP/VP children) and the role of perinatal and demographic risk factors. DATA SOURCES: PubMed, Web of Science, and PsycINFO were searched without language restriction (last search March 2, 2017). Key search terms included preterm, low birth weight, and intelligence. STUDY SELECTION: Peer-reviewed studies reporting intelligence scores of EP/VP children (<32 weeks of gestation) and full-term controls at age 5 years or older, born in the antenatal corticosteroids and surfactant era, were included. A total of 268 studies met selection criteria, of which 71 covered unique cohorts. DATA EXTRACTION AND SYNTHESIS: MOOSE guidelines were followed. Data were independently extracted by 2 researchers. Standardized mean differences in intelligence per study were pooled using random-effects meta-analysis. Heterogeneity in effect size across studies was studied using multivariate, random-effects meta-regression analysis. MAIN OUTCOMES AND MEASURES: Primary outcome was intelligence. Covariates included gestational age, birth weight, birth year, age at assessment, sex, race/ethnicity, socioeconomic status, small for gestational age, intraventricular hemorrhage, periventricular leukomalacia, bronchopulmonary dysplasia (BPD), necrotizing enterocolitis, sepsis, and postnatal corticosteroid use. RESULTS: The 71 included studies comprised 7752 EP/VP children and 5155 controls. Median gestational age was 28.5 weeks (interquartile range IQR, 2.4 weeks) and the mean age at assessment ranged from 5.0 to 20.1 years. The median proportion of males was 50.0% (IQR, 8.7%). Preterm children had a 0.86-SD lower IQ compared with controls (95% CI, −0.94 to −0.78, P < .001). Results were heterogeneous across studies (I2 = 74.13; P < .001). This heterogeneity could not be explained by birth year of the cohort. Multivariate meta-regression analysis with backward elimination revealed that BPD explained 65% of the variance in intelligence across studies, with each percent increase in BPD rate across studies associated with a 0.01-SD decrease in IQ (0.15 IQ points) (P < .001). CONCLUSIONS AND RELEVANCE: Extremely or very preterm children born in the antenatal corticosteroids and surfactant era show large deficits in intelligence. No improvement in cognitive outcome was observed between 1990 and 2008. These findings emphasize that improving outcomes after EP/VP birth remains a major challenge. Bronchopulmonary dysplasia was found to be a crucial factor for cognitive outcome. Lowering the high incidence of BPD may be key to improving long-term outcomes after EP/VP birth.
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.
Mother's own milk (MOM) is protective against gut microbiota alterations associated with necrotizing enterocolitis (NEC) and feeding intolerance among preterm infants. It is unclear whether this ...benefit is preserved with donor milk (DM) feeding.
We aimed to compare microbiota development, growth, and feeding tolerance in very-low-birth-weight (VLBW) infants fed an exclusively human milk diet of primarily MOM or DM.
One hundred and twenty-five VLBW infants born at Texas Children's Hospital were enrolled and grouped into cohorts based on percentage of MOM and DM in enteral feeds. Feeds were fortified with DM-derived fortifier per unit protocol. Weekly stool samples were collected for 6 wk for microbiota analysis 16S ribosomal RNA (rRNA) sequencing. A research nurse obtained weekly anthropometrics. Clinical outcomes were compared via Wilcoxon's rank-sum test and Fisher's exact test, as well as multivariate analysis.
The DM cohort (n = 43) received on average 14% mothers’ milk compared with 91% for the MOM cohort (n = 74). Diversity of gut microbiota across all time points (n = 546) combined was increased in MOM infants (P < 0.001). By 4 and 6 wk of life, microbiota in MOM infants contained increased abundance of Bifidobacterium (P = 0.02) and Bacteroides (P = 0.04), whereas DM-fed infants had increased abundance of Staphylococcus (P = 0.02). MOM-fed infants experienced a 60% reduction in feeding intolerance (P = 0.03 by multivariate analysis) compared with DM-fed infants. MOM-fed infants had greater weight gain than DM-fed infants.
Compared with DM-fed infants, MOM-fed infants have increased gut microbial community diversity at the phylum and genus levels by 4 and 6 wk of life, as well as better feeding tolerance. MOM-fed infants had superior growth. The incidence of NEC and other gastrointestinal morbidity is low among VLBW infants fed an exclusively human milk diet including DM-derived fortifier. This trial was registered at clinicaltrials.gov as NCT02573779.
Sequelae of academic underachievement, behavioral problems, and poor executive function (EF) have been extensively reported for very preterm (<or=33 weeks' gestation) and/or very low birth weight ...(VLBW) (<or=1500 g) children. Great variability in the published results, however, hinders the field in studying underlying dysfunctions and developing intervention strategies. We conducted a quantitative meta-analysis of studies published between 1998 and 2008 on academic achievement, behavioral functioning, and EF with the aim of providing aggregated measures of effect size for these outcome domains.
Suitable for inclusion were 14 studies on academic achievement, 9 studies on behavioral problems, and 12 studies on EF, which compared a total of 4125 very preterm and/or VLBW children with 3197 term-born controls. Combined effect sizes for the 3 outcome domains were calculated in terms of Cohen's d. Q-test statistics were performed to test homogeneity among the obtained effect sizes. Pearson's correlation coefficients were calculated to examine the impact of mean birth weight and mean gestational age, as well as the influence of mean age at assessment on the effect sizes for academic achievement, behavioral problems, and EF.
Combined effect sizes show that very preterm and/or VLBW children score 0.60 SD lower on mathematics tests, 0.48 SD on reading tests, and 0.76 SD on spelling tests than term-born peers. Of all behavioral problems stacked, attention problems were most pronounced in very preterm and/or VLBW children, with teacher and parent ratings being 0.43 to 0.59 SD higher than for controls, respectively. Combined effect sizes for parent and teacher ratings of internalizing behavior problems were small (<0.28) and for externalizing behavior problems negligible (<0.09) and not significant. Combined effect sizes for EF revealed a decrement of 0.57 SD for verbal fluency, 0.36 SD for working memory, and 0.49 SD for cognitive flexibility in comparison to controls. Mean age at assessment was not correlated with the strength of the effect sizes. Mathematics and reading performance, parent ratings of internalizing problems, teacher ratings of externalizing behavior, and attention problems, showed strong and positive correlations with mean birth weight and mean gestational age (all r values > 0.51).
Very preterm and/or VLBW children have moderate-to-severe deficits in academic achievement, attention problems, and internalizing behavioral problems and poor EF, which are adverse outcomes that were strongly correlated to their immaturity at birth. During transition to young adulthood these children continue to lag behind term-born peers.
We performed an updated meta‐analysis incorporating the results of recent randomised controlled trials (RCTs) to measure the effectiveness of probiotic supplementation in preventing necrotising ...enterocolitis (NEC) and death in very low‐birth‐weight (VLBW) infants, and to investigate any differences in efficacy by probiotic agent. Using meta‐regression analysis, we assessed the contribution of other measured variables on the overall effect size and between‐study variability. Conclusion: Overall, probiotics lead to significant reductions in NEC incidence and mortality in VLBW infants. Differences in probiotic agents and the influence of prenatal steroids and feeding regimens may explain the differences in outcomes between studies.
This report presents data from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network on care of and morbidity and mortality rates for very low ...birth weight infants, according to gestational age (GA).
Perinatal/neonatal data were collected for 9575 infants of extremely low GA (22-28 weeks) and very low birth weight (401-1500 g) who were born at network centers between January 1, 2003, and December 31, 2007.
Rates of survival to discharge increased with increasing GA (6% at 22 weeks and 92% at 28 weeks); 1060 infants died at <or=12 hours, with most early deaths occurring at 22 and 23 weeks (85% and 43%, respectively). Rates of prenatal steroid use (13% and 53%, respectively), cesarean section (7% and 24%, respectively), and delivery room intubation (19% and 68%, respectively) increased markedly between 22 and 23 weeks. Infants at the lowest GAs were at greatest risk for morbidities. Overall, 93% had respiratory distress syndrome, 46% patent ductus arteriosus, 16% severe intraventricular hemorrhage, 11% necrotizing enterocolitis, and 36% late-onset sepsis. The new severity-based definition of bronchopulmonary dysplasia classified more infants as having bronchopulmonary dysplasia than did the traditional definition of supplemental oxygen use at 36 weeks (68%, compared with 42%). More than one-half of infants with extremely low GAs had undetermined retinopathy status at the time of discharge. Center differences in management and outcomes were identified.
Although the majority of infants with GAs of >or=24 weeks survive, high rates of morbidity among survivors continue to be observed.
Human milk-based fortifiers (HMBFs) are being adopted in neonatal care to enrich the nutrients in human milk for very low birth weight (VLBW) infants despite being costly and there being limited ...efficacy data. No randomized clinical trial has evaluated the use of HMBF compared with bovine milk–based fortifiers (BMBFs) in the absence of formula feeding.
To determine if HMBF compared with BMBF for routine nutrient enrichment of human milk improves feeding tolerance, reduces morbidity, reduces fecal calprotectin (a measure of gut inflammation), and supports the growth of infants <1250 g.
In this blinded randomized clinical trial, infants born weighing <1250 g were recruited from neonatal units in Ontario, Canada between August 2014 and November 2015. The infants were fed mother's milk and donor milk as required. Fortification commenced at 100 mL/kg per day of HMBF (0.81 kcal/mL) or BMBF (0.72 kcal/mL) and advanced at 140 mL/kg per day to 0.88 and 0.78 kcal/mL, respectively. The primary outcome was percentage of infants with a feeding interruption for ≥12 h or a >50% reduction in feeding volume. Secondary outcomes included a dichotomous mortality and morbidity index (i.e., affirmative for any one of death, late-onset sepsis, necrotizing enterocolitis, chronic lung disease, or severe retinopathy of prematurity), fecal calprotectin, and growth.
Of 232 eligible infants, 127 (54.7%) were randomized (n = 64 HMBF, n = 63 BMBF). Mean ± SD birth weight and gestational age of infants were 888 ± 201 g and 27.7 ± 2.5 wk, respectively. No statistically significant differences were identified in feeding interruptions 17/64 HMBF, 20/61 BMBF; unadjusted risk difference: −6.2% (95% CI: −22.2%, 9.8%). There was no statistically significant difference in the mortality and morbidity index (35.9% HMBF, 49.2% BMBF, adjusted P = 0.07), changes in fecal calprotectin, or growth z scores.
Among infants born weighing <1250 g and exclusively fed human milk, the use of HMBF did not improve feeding tolerance or reduce mortality and morbidity compared with BMBF. This trial was registered at clinicaltrials.gov as NCT02137473.
•Preterm birth or Low Birth Weight LBW is a risk factor for developmental delays.•Motor and cognitive delays often co-occur in preterm/LBW children.•Reviewed studies provide evidence for a ...longitudinal link in these children.•Motor development in the first year of life predicts later cognitive skills.•Further work is needed to examine underlying mechanisms and possible confounds.
The current review focuses on evidence for a link between early motor development and later cognitive skills in children born preterm or with Low Birth Weight (LBW). Studies with term born children consistently show such a link. Motor and cognitive impairments or delays are often seen in children born preterm or with LBW throughout childhood and studies have established a cross-sectional association between the two. However, it is not yet clear if, and if so, how, motor and cognitive skills are longitudinally interrelated in these children. Longitudinal studies with this population including measures of motor development during the first year of life and cognitive measures at later measurement points were included. The 17 studies included usually show a link between level and/or quality of motor development during the first year of life and later cognitive skills in children born preterm and/or with LBW. However, given the small number of studies, and a possible effect of early interaction between motor and cognitive skills affecting this relation, more work is clearly needed.
To identify changes in mortality and neonatal morbidities for infants with birth weight 501 to 1500 g born from 2000 to 2009.
There were 355806 infants weighing 501 to 1500 g who were born in ...2000-2009. Mortality during initial hospitalization and major neonatal morbidity in survivors (early and late infection, chronic lung disease, necrotizing enterocolitis, severe retinopathy of prematurity, severe intraventricular hemorrhage, and periventricular leukomalacia) were assessed by using data from 669 North American hospitals in the Vermont Oxford Network.
From 2000 to 2009, mortality for infants weighing 501 to 1500 g decreased from 14.3% to 12.4% (difference, -1.9%; 95% confidence interval, -2.3% to -1.5%). Major morbidity in survivors decreased from 46.4% to 41.4% (difference, -4.9%; 95% confidence interval, -5.6% to -4.2%). In 2009, mortality ranged from 36.6% for infants 501 to 750 g to 3.5% for infants 1251 to 1500 g, whereas major morbidity in survivors ranged from 82.7% to 18.7%. In 2009, 49.2% of all very low birth weight infants and 89.2% of infants 501 to 750 g either died or survived with a major neonatal morbidity.
Mortality and major neonatal morbidity in survivors decreased for infants with birth weight 501 to 1500 g between 2000 and 2009. However, at the end of the decade, a high proportion of these infants still either died or survived after experiencing ≥ 1 major neonatal morbidity known to be associated with both short- and long-term adverse consequences.
The aim of this study was to determine the effect of human milk feeding during NICU hospitalization on neurodevelopment at 24 months of corrected age in very low birth weight infants. A cohort of 316 ...very low birth weight newborns (weight ≤ 1500 g) was prospectively enrolled in a follow-up program on admission to the Neonatal Intensive Care Unit of S. Orsola Hospital, Bologna, Italy, from January 2005 to June 2011. Neurodevelopment was evaluated at 24 months corrected age using the Griffiths Mental Development Scale. The effect of human milk nutrition on neurodevelopment was first investigated using a multiple linear regression model, to adjust for the effects of gestational age, small for gestational age, complications at birth and during hospitalization, growth restriction at discharge and socio-economic status. Path analysis was then used to refine the multiple regression model, taking into account the relationships among predictors and their temporal sequence. Human milk feeding during NICU hospitalization and higher socio-economic status were associated with better neurodevelopment at 24 months in both models. In the path analysis model intraventricular hemorrhage-periventricular leukomalacia and growth restriction at discharge proved to be directly and independently associated with poorer neurodevelopment. Gestational age and growth restriction at birth had indirect significant effects on neurodevelopment, which were mediated by complications that occurred at birth and during hospitalization, growth restriction at discharge and type of feeding. In conclusion, our findings suggest that mother's human milk feeding during hospitalization can be encouraged because it may improve neurodevelopment at 24 months corrected age.
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