The influence of nutrition on white matter development in preterm infants: a scoping review.

White matter (WM) injury is the most common type of brain injury in preterm infants and is associated with impaired neurodevelopmental outcome (NDO). Currently, there are no treatments for WM injury, but optimal nutrition during early preterm life may support WM development. The main aim of this scoping review was to assess the influence of early postnatal nutrition on WM development in preterm infants. Searches were performed in PubMed, EMBASE, and COCHRANE on September 2022. Inclusion criteria were assessment of preterm infants, nutritional intake before 1 month corrected age, and WM outcome. Methods were congruent with the PRISMA-ScR checklist. Thirty-two articles were included. Negative associations were found between longer parenteral feeding duration and WM development, although likely confounded by illness. Positive associations between macronutrient, energy, and human milk intake and WM development were common, especially when fed enterally. Results on fatty acid and glutamine supplementation remained inconclusive. Significant associations were most often detected at the microstructural level using diffusion magnetic resonance imaging. Optimizing postnatal nutrition can positively influence WM development and subsequent NDO in preterm infants, but more controlled intervention studies using quantitative neuroimaging are needed. IMPACT: White matter brain injury is common in preterm infants and associated with impaired neurodevelopmental outcome. Optimizing postnatal nutrition can positively influence white matter development and subsequent neurodevelopmental outcome in preterm infants. More studies are needed, using quantitative neuroimaging techniques and interventional designs controlling for confounders, to define optimal nutritional intakes in preterm infants.

Preterm Birth is Associated with Lower Academic Attainment at Age 12 Years: A Matched Cohort Study by Linkage of Population-Based Datasets.

OBJECTIVE: To compare academic attainment at age 12 years in preterm children born below 30 weeks of gestation with matched term-born peers, using standardized, nationwide and well-validated school tests. STUDY DESIGN: This population-based, national cohort study was performed by linking perinatal data from the nationwide Netherlands Perinatal Registry with educational outcome data from Statistics Netherlands and included 4677 surviving preterm children born at 250/7-296/7 weeks of gestational age and 366 561 controls born at 40 weeks of gestational age in 2000-2007. First, special education participation rate was calculated. Subsequently, all preterm children with academic attainment test data derived at age 12 years were matched to term-born children using year and month of birth, sex, parity, socioeconomic status, and maternal age. Total, language, and mathematics test scores and secondary school level advice were compared between these 2 groups. RESULTS: Children below 30 weeks of gestation had a higher special education participation rate (10.2% vs 2.7%, P < .001) than term-born peers. Preterm children had lower total (-0.37 SD; 95% CI -0.42 to -0.31), language (-0.21 SD; 95% CI -0.27 to -0.15), and mathematics (-0.45 SD; 95%CI -0.51 to -0.38) z scores, and more often a prevocational secondary school level advice (62% vs 46%, P < .001). CONCLUSIONS: A substantial proportion of children born before 30 weeks of gestation need special education at the end of elementary schooling. These children have significant deficits on all measures of academic attainment at age 12 years, especially mathematics, compared with matched term-born peers.

Increase in Brain Volumes after Implementation of a Nutrition Regimen in Infants Born Extremely Preterm.

OBJECTIVE: To assess the effect of early life nutrition on structural brain development in 2 cohorts of extremely preterm infants, before and after the implementation of a nutrition regimen containing more protein and lipid. STUDY DESIGN: We included 178 infants retrospectively (median gestational age, 26.6 weeks; IQR, 25.9-27.3), of whom 99 received the old nutrition regimen (cohort A, 2011-2013) and 79 the new nutrition regimen (cohort B, 2013-2015). Intake of protein, lipids, and calories was calculated for the first 28 postnatal days. Brain magnetic resonance imaging (MRI) was performed at 30 weeks postmenstrual age (IQR, 30.3-31.4) and term-equivalent age (IQR, 40.9-41.4). Volumes of 42 (left + right) brain structures were calculated. RESULTS: Mean protein and caloric intake in cohort B (3.4 g/kg per day [P < .001] and 109 kcal/kg per day [P = .038]) was higher than in cohort A (2.7 g/kg per day; 104 kcal/kg per day). At 30 weeks, 22 regions were significantly larger in cohort B compared with cohort A, whereas at term-equivalent age, only the caudate nucleus was significantly larger in cohort B compared with cohort A. CONCLUSIONS: An optimized nutrition protocol in the first 28 days of life is associated with temporarily improved early life brain volumes.

Neurodevelopmental outcome at 5.5 years in Dutch preterm infants born at 24-26 weeks' gestational age: the EPI-DAF study.

OBJECTIVE: After lowering the Dutch threshold for active treatment from 25 to 24 completed weeks' gestation, survival to discharge increased by 10% in extremely preterm live born infants. Now that this guideline has been implemented, an accurate description of neurodevelopmental outcome at school age is needed. DESIGN: Population-based cohort study. SETTING: All neonatal intensive care units in the Netherlands. PATIENTS: All infants born between 240/7 and 266/7 weeks' gestation who were 5.5 years' corrected age (CA) in 2018-2020 were included. MAIN OUTCOME MEASURES: Main outcome measure was neurodevelopmental outcome at 5.5 years. Neurodevelopmental outcome was a composite outcome defined as none, mild or moderate-to-severe impairment (further defined as neurodevelopmental impairment (NDI)), using corrected cognitive score (Wechsler Preschool and Primary Scale of Intelligence Scale-III-NL), neurological examination and neurosensory function. Additionally, motor score (Movement Assessment Battery for Children-2-NL) was assessed. All assessments were done as part of the nationwide, standardised follow-up programme. RESULTS: In the 3-year period, a total of 632 infants survived to 5.5 years' CA. Data were available for 484 infants (77%). At 5.5 years' CA, most cognitive and motor (sub)scales were significantly lower compared with the normative mean. Overall, 46% had no impairment, 36% had mild impairment and 18% had NDI. NDI-free survival was 30%, 49% and 67% in live born children at 24, 25 and 26 weeks' gestation, respectively (p<0.001). CONCLUSIONS: After lowering the threshold for supporting active treatment from 25 to 24 completed weeks' gestation, a considerable proportion of the surviving extremely preterm children did not have any impairment at 5.5 years' CA.

Opportunities and Challenges of Prognostic Models for Extremely Preterm Infants.

Predicting the short- and long-term outcomes of extremely preterm infants remains a challenge. Multivariable prognostic models might be valuable tools for clinicians, parents, and policymakers for providing accurate outcome estimates. In this perspective, we discuss the opportunities and challenges of using prognostic models in extremely preterm infants at population and individual levels. At a population level, these models could support the development of guidelines for decisions about treatment limits and may support policy processes such as benchmarking and resource allocation. At an individual level, these models may enhance prenatal counselling conversations by considering multiple variables and improving transparency about expected outcomes. Furthermore, they may improve consistency in projections shared with parents. For the development of prognostic models, we discuss important considerations such as predictor and outcome measure selection, clinical impact assessment, and generalizability. Lastly, future recommendations for developing and using prognostic models are suggested. Importantly, the purpose of a prognostic model should be clearly defined, and integrating these models into prenatal counselling requires thoughtful consideration.

Toddler motor performance and intelligence at school age in preterm born children: A longitudinal cohort study.

BACKGROUND: Current knowledge regarding differences in verbal intelligence scores (VIQ) and performance intelligence scores (PIQ) in preterm born children is limited. As early motor performance may be essential for developing later visual-perceptual and visual-motor skills, early motor performance may be associated with PIQ. AIMS: To evaluate whether in preterm born children motor performance at two years was associated with PIQ at eight years. METHODS: Single-centre cohort study including 88 children born <30 weeks' gestation between 2007 and 2011, who completed the Bayley Scales of Infant and Toddler Development-III (BSID-III) at two years and the Wechsler Intelligence Scale for Children-III-NL (WISC-III-NL) at eight years. Outcome measurements (mean (SD)) were gross and fine motor performance based on the BSID-III, and PIQ and VIQ based on the WISC-III-NL. Linear regression analysis was performed to evaluate the association between motor performance at two years and PIQ at eight years. RESULTS: At two years, mean BSID-III gross motor scaled score was 9.0 (SD 3.0) and fine motor score was 11.5 (SD 2.3). At eight years, mean PIQ was 94.9 (SD 13.5) and mean VIQ 101.8 (SD 13.7). A one-point increase in fine motor scaled score was associated with 1.7 points (95% CI 0.5-2.8) increase in PIQ. Gross motor scaled score was not associated with PIQ. CONCLUSIONS: Fine motor performance in toddlerhood was related to PIQ at school age, with lower scores indicating a lower PIQ. Early assessment of fine motor performance may be beneficial in identifying children at risk for lower performance intelligence.

Two-year neurodevelopmental outcome in children born extremely preterm: the EPI-DAF study.

OBJECTIVE: In 2010, the Dutch practice regarding initiation of active treatment in extremely preterm infants was lowered from 25 completed weeks' to 24 completed weeks' gestation. The nationwide Extremely Preterm Infants - Dutch Analysis on Follow-up Study was set up to provide up-to-date data on neurodevelopmental outcome at 2 years' corrected age (CA) after this guideline change. Design: National cohort study. PATIENTS: All live born infants between 240/7 weeks' and 266/7 weeks' gestational age who were 2 years' CA in 2018-2020. MAIN OUTCOME MEASURE: Impairment at 2 years' CA, based on cognitive score (Bayley-III-NL), neurological examination and neurosensory function. RESULTS: 651 of 991 live born infants (66%) survived to 2 years' CA, with data available for 554 (85%). Overall, 62% had no impairment, 29% mild impairment and 9% moderate-to-severe impairment (further defined as neurodevelopmental impairment, NDI). The percentage of survivors with NDI was comparable for infants born at 24 weeks', 25 weeks' and 26 weeks' gestation. After multivariable analysis, severe brain injury and low maternal education were associated with higher odds on NDI. NDI-free survival was 48%, 67% and 75% in neonatal intensive care unit (NICU)-admitted infants at 24, 25 and 26 weeks' gestation, respectively. CONCLUSIONS: Lowering the threshold has not been accompanied by a large increase in moderate-to-severely impaired infants. Among live-born and NICU-admitted infants, an increase in NDI-free survival was observed from 24 weeks' to 26 weeks' gestation. This description of a national cohort with high follow-up rates gives an accurate description of the range of outcomes that may occur after extremely preterm birth.

Prognostic Models Predicting Mortality in Preterm Infants: Systematic Review and Meta-analysis.

CONTEXT: Prediction models can be a valuable tool in performing risk assessment of mortality in preterm infants. OBJECTIVE: Summarizing prognostic models for predicting mortality in very preterm infants and assessing their quality. DATA SOURCES: Medline was searched for all articles (up to June 2020). STUDY SELECTION: All developed or externally validated prognostic models for mortality prediction in liveborn infants born <32 weeks' gestation and/or <1500 g birth weight were included. DATA EXTRACTION: Data were extracted by 2 independent authors. Risk of bias (ROB) and applicability assessment was performed by 2 independent authors using Prediction model Risk of Bias Assessment Tool. RESULTS: One hundred forty-two models from 35 studies reporting on model development and 112 models from 33 studies reporting on external validation were included. ROB assessment revealed high ROB in the majority of the models, most often because of inadequate (reporting of) analysis. Internal and external validation was lacking in 41% and 96% of these models. Meta-analyses revealed an average C-statistic of 0.88 (95% confidence interval [CI]: 0.83-0.91) for the Clinical Risk Index for Babies score, 0.87 (95% CI: 0.81-0.92) for the Clinical Risk Index for Babies II score, and 0.86 (95% CI: 0.78-0.92) for the Score for Neonatal Acute Physiology Perinatal Extension II score. LIMITATIONS: Occasionally, an external validation study was included, but not the development study, because studies developed in the presurfactant era or general NICU population were excluded. CONCLUSIONS: Instead of developing additional mortality prediction models for preterm infants, the emphasis should be shifted toward external validation and consecutive adaption of the existing prediction models.

[Developmental problems in prematures]. / Ontwikkelingsproblemen bij vroeggeborenen.

The French EPIPAGE-2 study evaluated a large group of premature born children (24-34 weeks' gestational age (GA))) at age 5.5 years. Outcome information of the whole cohort was presented after careful imputation including/using the variable socio-economic-status (SES), because participation rate improved with increasing SES. Survival improved with increasing GA. Survival without moderate or severe impairment was 20% in children born at 24-26 weeks' GA, but among the survivors 75% had no or mild impairment. Mild cognitive impairment rates were comparable and common among all GA groups (25-28%) and thus frequent in prematures. School problems were also common. In addition to prematurity, SES is an important risk factor for developmental impairment. Follow-up programs for premature infants beyond 30 weeks' GA are less common and may need extra attention in low SES families. Future studies should focus on both prevention of prematurity and programs to improve outcome.

Developmental Trajectories in Very Preterm Born Children Up to 8 Years: A Longitudinal Cohort Study.

Aim: Long-term outcome data in preterm children is often limited to cross-sectional measurement of neurodevelopmental impairment (NDI) at the corrected age of 24-36 months. However, impairments may only become overt during childhood or resolve with time, and individual trajectories in outcome over time may vary. The primary aim of this study was to describe NDI in very preterm born children at three subsequent ages of 2, 5, and 8 years of age. As a secondary aim, a longitudinal analysis was performed on the individual longitudinal trajectories in NDI from 2 to 8 years of age. Methods: Single-center prospective cohort study including children born between 1990 and 2011 below 30 weeks' gestation and followed into 2019. The outcome measurement was NDI assessed at 2, 5, and 8 years of age. NDI is a composite score that includes cognitive, neurological, visual, and auditory functions, in which problems were categorized as none, mild, moderate, or severe. Cognitive function measured as total DQ/IQ score was assessed by standardized psychometric tests. Neurological, visual, and auditory functions were assessed by the neonatologist. Results: In total, 921 children were eligible for follow-up, of whom 726 (79%) children were assessed. No NDI was seen in 54, 54, and 62%, mild NDI was seen in 31, 36, and 30%, and moderate-to-severe NDI was seen in 15, 9.2, and 8.6% of the children at 2, 5, and 8 years, respectively. From 2 to 8 years, 63% of the children remained in the same NDI category, 20% of the children improved to a better NDI category, and 17% deteriorated toward a worse NDI category. No differences were found in baseline characteristics of infants that improved or deteriorated. Extreme prematurity, male gender and low parental education were associated with worse NDI status at all time points. Although we observed considerable individual variation over time in NDI status, the course of the trajectories in NDI were not associated with gestation, gender, and parental education. Conclusions: Continued follow-up until school life is essential in order to provide optimal and individually focused referrals and care when needed.

The Need for Special Education Among ELBW and SGA Preterm Children: A Cohort Study.

Background: Preterm infants with pre- or postnatal growth restriction may have an additional risk of adverse neurodevelopmental outcome. Whereas reduced cognitive ability and behavioral problems have consistently been associated with prematurity, a more comprehensive evaluation is necessary to identify those preterm infants who are at increased risk for difficulties in school performance. This study evaluated the association between extremely low birth weight (ELBW) and the need for special education and determined if there is an additional risk for the need for special education among small for gestational age (SGA) children. Methods: This is a single-center cohort study including singleton children born below 30 weeks' gestation between 1990 and 2011 and followed into 2019. ELBW + was defined as a birth weight below 1,000 g, which was compared to ELBW-. Within all ELBW+ children, SGA+ was defined as a birth weight <10th percentile according to Fenton, which was compared to SGA-. The dichotomous outcome measurement was the need for special education at 8 years of age or not, reflecting if the children required a special educational setting designed to accommodate educational, behavioral, and/or medical needs. Results: In total, 609 children were eligible for follow-up, of whom 390 (64%) children were assessed at 8 years. Of these, 56 (14%) children needed special education, most often determined by cognitive deficiency (43%), behavioral problems (29%), or both (16%). Among the 191 ELBW+ children, 35 (18%) attended special education, compared to 21 (11%) among ELBW- children (p-value 0.041). A decreasing risk for the need for special education was found from 25% in ELBW+/SGA+ children to 16% in ELBW+/SGA- children and 11% in ELBW-/SGA- children (p-value 0.025). Multivariable logistic regression showed an odds ratio of 2.88 (95% CI 1.20-6.78) for ELBW+/SGA+ children vs. ELBW-/SGA- children for the need for special education. Conclusions: This study showed that ELBW children are at increased risk for the need for special education compared to non-ELBW children. In addition, children that are both ELBW and SGA do have the highest risk for the need for special education. Classifying children as ELBW and SGA can be useful in follow-up for identifying preterm children with an additional risk for adverse long-term outcome.

Nutritional Intake, White Matter Integrity, and Neurodevelopment in Extremely Preterm Born Infants.

BACKGROUND: Determining optimal nutritional regimens in extremely preterm infants remains challenging. This study aimed to evaluate the effect of a new nutritional regimen and individual macronutrient intake on white matter integrity and neurodevelopmental outcome. METHODS: Two retrospective cohorts of extremely preterm infants (gestational age < 28 weeks) were included. Cohort B (n = 79) received a new nutritional regimen, with more rapidly increased, higher protein intake compared to cohort A (n = 99). Individual protein, lipid, and caloric intakes were calculated for the first 28 postnatal days. Diffusion tensor imaging was performed at term-equivalent age, and cognitive and motor development were evaluated at 2 years corrected age (CA) (Bayley-III-NL) and 5.9 years chronological age (WPPSI-III-NL, MABC-2-NL). RESULTS: Compared to cohort A, infants in cohort B had significantly higher protein intake (3.4 g/kg/day vs. 2.7 g/kg/day) and higher fractional anisotropy (FA) in several white matter tracts but lower motor scores at 2 years CA (mean (SD) 103 (12) vs. 109 (12)). Higher protein intake was associated with higher FA and lower motor scores at 2 years CA (B = -6.7, p = 0.001). However, motor scores at 2 years CA were still within the normal range and differences were not sustained at 5.9 years. There were no significant associations with lipid or caloric intake. CONCLUSION: In extremely preterm born infants, postnatal protein intake seems important for white matter development but does not necessarily improve long-term cognitive and motor development.

Survival and causes of death in extremely preterm infants in the Netherlands.

OBJECTIVE: In the Netherlands, the threshold for offering active treatment for spontaneous birth was lowered from 25+0 to 24+0 weeks' gestation in 2010. This study aimed to evaluate the impact of guideline implementation on survival and causes and timing of death in the years following implementation. DESIGN: National cohort study, using data from the Netherlands Perinatal Registry. PATIENTS: The study population included all 3312 stillborn and live born infants with a gestational age (GA) between 240/7 and 266/7 weeks born between January 2011 and December 2017. Infants with the same GA born between January 2007 and December 2009 (N=1400) were used as the reference group. MAIN OUTCOME MEASURES: Survival to discharge, as well as cause and timing of death. RESULTS: After guideline implementation, there was a significant increase in neonatal intensive care unit (NICU) admission rate for live born infants born at 24 weeks' GA (27%-69%, p<0.001), resulting in increased survival to discharge in 24-week live born infants (13%-34%, p<0.001). Top three causes of in-hospital mortality were necrotising enterocolitis (28%), respiratory distress syndrome (19%) and intraventricular haemorrhage (17%). A significant decrease in cause of death either complicated or caused by respiratory insufficiency was seen over time (34% in 2011-2014 to 23% in 2015-2017, p=0.006). CONCLUSIONS: Implementation of the 2010 guideline resulted as expected in increased NICU admissions rate and postnatal survival of infants born at 24 weeks' GA. In the years after implementation, a shift in cause of death was seen from respiratory insufficiency towards necrotising enterocolitis and sepsis.