Regulation of Gut Microbiota through Breast Milk Feeding Benefits Language and Cognitive Development of Preterm Toddlers.

Feeding practice is essential to growth and development of preterm toddlers. However, the relationship of feeding mode with gut microbiota and neurodevelopment outcomes of preterm toddlers has not been characterized fully. We conducted this cohort study to assess neurodevelopment outcomes and gut microbiota community structures of preterm toddlers who received either breast milk, formula or mixed feeding. Fifty-five preterm toddlers born <37 weeks and 24 term toddlers were recruited in the study. Bayley III mental and physical index scores were measured among preterm toddlers at 12 ± 2 and 18 ± 2 months corrected age (CA). Gut microbiome composition was analyzed by 16S rRNA gene sequencing in fecal samples collected from all participants at 12 months, 16 months and 20 months after birth. We found exclusive breast milk feeding for over three months in the first six months after birth was associated with significant increase in language composite score at 12 months CA (86 (79,97) vs. 77 (71.75,79), p = 0.008) and both language (106.05 ± 14.68 vs. 90.58 ± 12.25, p = 0.000) and cognitive composite score at 18 months CA (107.17 ± 10.85 vs. 99.00 ± 9.24, p = 0.007). The alpha diversity, beta diversity and composition of gut microbiota from those breastfed preterm toddlers not only resembled healthy term toddlers but also followed similar structure of preterm toddlers with enhanced language and cognitive performance. Our results suggest exclusive breast milk feeding for over three months in preterm toddlers leads to optimal cognitive and language development and well-balanced microbiota.

Evaluation of developmental profiles of children with hydrocephalus / Evaluación de perfiles de desarrollo de niños con hidrocefalia

Objective The objective of this study was to compare the developmental characteristics of children with hydrocephalus with those of healthy children. Material and methods A total of 109 children aged between 2 and 46 months were included in the study, 54 patients diagnosed with hydrocephalus and 55 healthy children were evaluated with demographic data forms and Denver Developmental Screening Test II. Results The mean personal–social (p<0.001), fine motor-adaptive (p<0.001), language (p<0.001), and gross motor subscale scores were significantly lower in children with hydrocephalus than in the control group. Personal–social (p=0.002) and gross motor (p=0.029) subscale scores were significantly lower in children with obstructive hydrocephalus than communicating hydrocephalus. There was a significant negative correlation between language scores and ages of the children with hydrocephalus (r=−0.350, p=0.009). It was found that children with obstructive hydrocephalus carry a 6.7 folds higher risk of experiencing problems in terms of personal–social development compared to those with communicating hydrocephalus (p=0.011). Conclusion We found that patients with hydrocephalus were developmentally retarded compared to the healthy control subjects. Retardation was the most prominent in the obstructive group. Our results showed that neurodevelopmental follow-up should be carried-out regularly in pediatric patients with hydrocephalus, and early intervention should be started in necessary cases. (AU)

Objetivo El objetivo de este estudio fue comparar las características del desarrollo de niños con hidrocefalia con las de los niños sanos. Materiales y métodos Se incluyeron en este estudio un total de 109 niños con edades entre dos y 46 meses. Del total, 54 pacientes diagnosticados con hidrocefalia y 55 niños sanos fueron evaluados con formularios de datos geográficos y test screening de desarrollo Denver II. Resultados El promedio de los puntajes de las subescalas: desarrollo personal y social (p<0,001), motricidad fina-adaptativa (p=0,001), lengua (p=0,001) y motricidad gruesa fueron significativamente menores en niños con hidrocefalia que en el grupo control. Los puntajes de las subescalas desarrollo personal y social (p=0,002) y motricidad gruesa (p=0,029) resultaron significativamente menor en niños con hidrocefalia obstructiva que en hidrocefalia comunicante. Hubo una correlación negativa significativa entre los puntajes de lengua y las edades de los niños con hidrocefalia. (r=−0,350, p=0,009). Se encontró que los niños con hidrocefalia obstructiva portaban 6,7 veces un mayor riesgo de experimentar problemas en términos de desarrollo personal-social comparado con aquellos con hidrocefalia comunicante (p=0,011). Conclusión Encontramos que pacientes con hidrocefalia presentaron un retraso madurativo en comparación con los sujetos de control sanos. El retraso madurativo fue lo más prominente en el grupo obstructivo. Nuestros resultados mostraron que debería realizarse un seguimiento de neurodesarrollo regularmente en pacientes pediátricos con hidrocefalia y una intervención temprana debería comenzar en los casos que lo requieran. (AU)

Evaluation of developmental profiles of children with hydrocephalus.

OBJECTIVE: The objective of this study was to compare the developmental characteristics of children with hydrocephalus with those of healthy children. MATERIAL AND METHODS: A total of 109 children aged between 2 and 46 months were included in the study, 54 patients diagnosed with hydrocephalus and 55 healthy children were evaluated with demographic data forms and Denver Developmental Screening Test II. RESULTS: The mean personal-social (p<0.001), fine motor-adaptive (p<0.001), language (p<0.001), and gross motor subscale scores were significantly lower in children with hydrocephalus than in the control group. Personal-social (p=0.002) and gross motor (p=0.029) subscale scores were significantly lower in children with obstructive hydrocephalus than communicating hydrocephalus. There was a significant negative correlation between language scores and ages of the children with hydrocephalus (r=-0.350, p=0.009). It was found that children with obstructive hydrocephalus carry a 6.7 folds higher risk of experiencing problems in terms of personal-social development compared to those with communicating hydrocephalus (p=0.011). CONCLUSION: We found that patients with hydrocephalus were developmentally retarded compared to the healthy control subjects. Retardation was the most prominent in the obstructive group. Our results showed that neurodevelopmental follow-up should be carried-out regularly in pediatric patients with hydrocephalus, and early intervention should be started in necessary cases.

Screening for Neurodevelopmental Delay for Preterm Very Low Birth Weight Infants at Tertiary Care Center in Saudi Arabia.

Background Preterm infants are more susceptible to death, short-term complications, and long-term complications such as neurodevelopmental impairments. However, definitive assessment tools are not available in a resource-limited setting. Hence a screening tool is needed the Arabic-speaking population. Method Infants born at a gestational age of <32 weeks or a very low birth weight (VLBW) of less than 1500 g were recruited into a cross-sectional study. We identified infants (n = 61) admitted to the neonatal ICU at King Abdulaziz Medical City and reached 18 up to 24 months of corrected gestational age (CGA). The developmental assessment was done at 18, 20, 22, and 24 CGAs using the Ages and Stages Questionnaire third edition - Arabic version (ASQ3-A). The primary outcomes are early detection rate of neurodevelopmental delay (NDD), defined as a delay in one or more of the following: communication, gross motor, fine motor, problem-solving, and personal-social skills as per ASQ3-A. Results Sixty-one out of 92 eligible infants (36 excluded) completed the sufficient assessment. Twenty-six infants (42.6%) had at least one NDD in one of the following domains: communication skills: (11.5%), gross motor: (11.5%), fine motor: (19.7%), problem-solving skills: twelve infants (19.7%), and personal-social skills: twenty infants (23%). Perinatal events and periventricular leukomalacia (PVL) were significant independent predictors for the NDD. Conclusion This single-center study in Saudi Arabia screened preterm, VLBW infants based on ASQ3-A, twenty infants (42.6%) had an abnormal NDD at a corrected age of 18-24 months. Perinatal events and PVL were independent predictors of NDD. We recommend that all preterm VLBW infants in Saudi Arabia be evaluated by a neurodevelopmental screening tool, ASQ3-A, especially in resource-limited settings to start early intervention. Also, more extensive multicenter studies are to be carried out with definitive diagnostic tools to have a national benchmark for the long-term neurodevelopmental impairment.

The "Fortilat" Randomized Clinical Trial Follow-Up: Neurodevelopmental Outcome at 18 Months of Age.

Adequate nutrition is fundamental to neonatal survival and short-term outcomes, but it also has long-term consequences on quality of life and neurologic development of preterm infants. Donkey milk has been suggested as a valid alternative for children allergic to cows' milk proteins, due to its biochemical similarity to human milk; we, hence, hypothesized that donkey milk could be a suitable basis for developing an innovative human milk fortifier for feeding preterm infants. The aim of the current study was to extend the findings and to evaluate the neurodevelopmental outcomes at 18 months of corrected age of the infants enrolled in the clinical trial named "Fortilat". Infants born ≤1500 g and <32 weeks of gestational age were randomized to receive either a combination of bovine milk-based multicomponent fortifier and protein supplement or a combination of a novel multicomponent fortifier and protein supplement derived from donkey milk. The followed fortification protocol was the same for the two groups and the two diets were designed to be isoproteic and isocaloric. All infants enrolled were included in a developmental assessment program. The neurodevelopmental assessment was performed at 18 ± 6 months of corrected age. Minor and major neurodevelopmental impairment and General Quotient (GQ) at the Griffiths-II Mental Development Scale were considered. The GQ was considered both in continuous and as two classes: lower than and higher than (or equal to) a defined cutoff (GQcl). The difference in GQ and GQcl between the two arms was estimated using Mann-Whitney-Wilcoxon test or Fischer exact test, respectively, on the assumption of casual loss at follow-up. A further analysis was performed using generalized linear models. There were 103 children (bovine milk-derived fortifier arm = 54, donkey milk-derived fortifier arm = 49) included for the neurodevelopmental follow-up. All observations were included in the interval of 18 ± 6 months of corrected age. No significant difference was observed between the two arms in the incidence of neurologic sequelae and the GQs were similar in the two arms. Our results demonstrated no difference for the donkey milk-derived fortifier compared to standard bovine-derived fortifier regarding long-term neurodevelopmental outcomes.

Study on serum Tau protein level and neurodevelopmental outcome of placental abruption with neonatal hypoxic-ischemic encephalopathy.

Objective: The aim of this study was to explore differences in serum Tau protein levels and neurodevelopmental prognoses of placental abruption or umbilical cord around neck with hypoxic-ischemic encephalopathy (HIE).Methods: Forty neonates with moderate/severe HIE divided into placental abruption with HIE group (placental abruption with hypoxic-ischemic encephalopathy (PA-HIE) group) (n = 18) and umbilical cord around the neck with HIE group (umbilical cord around the neck with hypoxic-ischemic encephalopathy (UCAN-HIE) group) (n = 22). Healthy term newborns comprised the control group (n = 35). Serum Tau protein levels were measured using an enzyme-linked immunosorbent assay 24 hours (3.50 hours [1.00-24.00]) after birth. Neurodevelopment outcomes were assessed based on the Gesell Developmental Scale at 9 months of age.Results: Serum Tau protein levels were significantly higher in 40 cases (1013 pg/ml [538.04-1190.42]) than in the control group (106.41 pg/ml [64.55-154.71], p = .0001). Serum Tau protein levels in the PA-HIE group (1024.46 pg/ml [657.88-1190.42]) were significantly higher than those in the UCAN-HIE group (892.78 pg/ml [538.04-1179.50], p = .0149). The development quotient score in the PA-HIE group (67.0 [47.0-90.0]) was significantly lower than that in the UCAN-HIE group (81.5 [52.6-100.0]) (p = .0028). The component ratio of neurodevelopmental retardation in the PA-HIE group (44.45%) was significantly higher than that in the UCAN-HIE group (22.73%) (X2 = 13.3138, p = .0013).Conclusions: Compared with the UCAN-HIE group, the serum Tau protein level and the component ratio of neurodevelopmental retardation were significantly higher in the PA-HIE group.

Inflammatory biomarkers in children with cerebral palsy: A systematic review.

BACKGROUND: An exacerbated systemic inflammatory response has been associated with the occurrence of central nervous system injuries that may determine, in long term, motor, sensorial and cognitive disabilities. Persistence of this exacerbated inflammatory response seems to be involved in the pathophysiology of cerebral palsy (CP). METHODS: A systematic search was conducted in Bireme, Embase, PubMed and Scopus including studies that were published until August 2019. The key words used were "cerebral palsy", "brain injury", "inflammation", "oxidative stress", "cytokines", "chemokines", "neuropsychomotor development", "neurodevelopment outcomes" and "child". The quality of the eligible studies was determined according to the criteria suggested by the Newcastle-Ottawa Scale (NOS). RESULTS: Fourteen eligible studies aimed to investigate the association between peripheral inflammatory molecules and neurodevelopment in infants. The studies differed regarding CP-related risk factors and its classification. Inflammatory proteins were measured in blood, plasma, serum, cerebrospinal fluid or urine. In ten studies, higher circulating levels of cytokines, including IL-1ß, IL-6, TNF and CXCL8/IL-8, were associated with abnormal neurological findings. CONCLUSION: The investigation of the potential association between inflammatory molecules and neurological development in children with CP requires further original studies in order to clarify the influence of prenatal and perinatal inflammation on neurological outcomes.

The diagnostic value of cerebrospinal fluid protein in the assessment of neurological outcome in preterm infants with sepsis / 中国小儿急救医学

Objective To investigate the diagnostic value of cerebrospinal fluid protein in the assess-ment of neurological outcome in preterm infants with sepsis. Methods A total of 80 preterm infants with sepsis were enrolled in the department of neonatology of Shanghai Children's Hospital from June 2014 to June 2016. The lumbar puncture was completed within 24 hours after diagnosis of sepsis,and the results of ce-rebrospinal fluid protein were obtained. The prognosis of neurological development was assessed according to Gesell Developmental Quotient ( DQ) at 6 months of adjusted gestational age. DQ> 85 was used as an indi-cator of good prognosis group. DQ≤85 was assigned to the poor prognosis group. The differences in protein content of cerebrospinal fluid between these two groups were retrospectively analyzed. The receiver operating characteristic ( ROC) curve was used to evaluate the diagnostic value of cerebrospinal fluid in evaluating the prognosis of preterm infants with sepsis. Results Cerebrospinal fluid protein content of poor prognosis group was higher than those in good prognosis group[(2005. 56 ± 582. 85)mg/L vs. (1367. 92 ± 362. 29)mg/L, t= -6. 019,P<0. 01]. The area under the ROC curve was 0. 819(95％CI 0. 711 -0. 927,P<0. 05). The optimal threshold of cerebrospinal fluid protein was 1560 mg/L with specificity of 75. 5％ and sensitivity of 81. 5％. Conclusion Cerebrospinal fluid protein content has certain diagnostic value on the assessment of sepsis premature neurological prognosis.

Impact of preterm birth on parental separation: a French population-based longitudinal study.

OBJECTIVE: The objective of this study was to investigate both the effects of low gestational age and infant's neurodevelopmental outcome at 2 years of age on the risk of parental separation within 7 years of giving birth. DESIGN: Prospective. SETTING: 24 maternity clinics in the Pays-de-la-Loire region. PARTICIPANTS: This study included 5732 infants delivered at <35 weeks of gestation born between 2005 and 2013 who were enrolled in the population-based Loire Infant Follow-up Team cohort and who had a neurodevelopmental evaluation at 2 years. This neurodevelopmental evaluation was based on a physical examination, a psychomotor evaluation and a parent-completed questionnaire. OUTCOME MEASURE: Risk of parental separation (parents living together or parents living separately). RESULTS: Ten percent (572/5732) of the parents reported having undergone separation during the follow-up period. A mediation analysis showed that low gestational age had no direct effect on the risk of parental separation. Moreover, a non-optimal neurodevelopment at 2 years was associated with an increased risk of parental separation corresponding to a HR=1.49(1.23 to 1.80). Finally, the increased risk of parental separation was aggravated by low socioeconomic conditions. CONCLUSIONS: The effect of low gestational age on the risk of parental separation was mediated by the infant's neurodevelopment.

Cord Blood IL-16 Is Associated with 3-Year Neurodevelopmental Outcomes in Perinatal Asphyxia and Hypoxic-Ischaemic Encephalopathy.

Activation of the inflammatory pathway is increasingly recognized as an important mechanism of injury following neonatal asphyxia and encephalopathy. This process may contribute to the poor prognosis seen in some cases, despite therapeutic hypothermia. Our group has previously identified raised interleukin (IL)-6 and IL-16, measured in umbilical cord blood at birth, to be predictive of grade of hypoxic-ischaemic encephalopathy (HIE). Our aim in this study was to examine the ability of these cytokines to predict the 3-year neurodevelopmental outcome in the same cohort. As part of a prospective, longitudinal cohort study set in a single tertiary maternity unit, term infants with biochemical and clinical evidence of perinatal asphyxia were recruited at birth. Umbilical cord blood was collected and analyzed for IL-6 and IL-16 using a Luminex assay. The neurodevelopmental outcome of these infants was assessed at 3 years using the Bayley Scales of Infant and Toddler Development (Edition 3). Early cord blood measurement of IL-6 and IL-16 and long-term outcome were available in 33/69 infants. Median (IQR) IL-16 differentiated infants with a severely abnormal outcome (n = 6) compared to all others (n = 27), (646 [466-1,085] vs. 383.5 [284-494] pg/mL; p = 0.012). IL-16 levels were able to predict a severe outcome with an area under the receiver-operating characteristic (ROC) curve of 0.827 (95% CI 0.628-1.000; p = 0.014). Levels ≥514 pg/mL predicted a severe outcome with a sensitivity of 83% and a specificity of 81%. IL-16 also outperformed other routine biochemical markers available at birth for the prediction of severe outcome. APGAR scores at 1 and 10 min were also predictive of a severe outcome (p = 0.022 and p = 0.036, respectively). A combination of IL-16 with these clinical markers did not improve predictive value, but IL-16 combined with electroencephalogram grading increased the area under the ROC curve. IL-6 did not show any association with 3-year outcome. This is the first report studying the association of IL-16 measured at birth with long-term outcome in a cohort of neonates with perinatal asphyxia. IL-16 may be an early biomarker of severe injury and aid in the long-term prognostication in infants with HIE.

Neurofunctional assessment at term equivalent age can predict 3-year neurodevelopmental outcomes in very low birth weight infants.

AIM: Preterm infants are at high risk of developing motor delay, learning difficulties and behavioural problems and the availability of valid neurodevelopmental assessments is a major clinical issue. This study evaluated the relationship between preterm infants' neurofunctional assessment at term equivalent age and neurodevelopment outcome at three years of chronological age. METHODS: Neurofunctional assessment was performed in 70 very low birth weight infants at term equivalent age and neurodevelopmental outcome was assessed at three years of chronological age with the Griffiths Mental Development Scale - Extended Revised. RESULTS: At term equivalent age, 81% of the children had normal neurofunctional scores and 82.5% of those showed normal neurodevelopmental outcome at three years. Of the 19% who had impaired development at term equivalent age, 38.5% had neurodevelopmental delay at three years. Impaired neurofunctional status was associated with an increased risk of developmental delay in the global quotient (odds ratio 12.1) and locomotor sub-quotient (odds ratio 18.35) compared with normal neurofunctional status. Infants with sepsis or necrotising enterocolitis also faced a higher risk of neurodevelopmental delay. CONCLUSION: Neurofunctional assessment performed at term equivalent age appeared to provide early identification of preterm infants at risk of neurodevelopmental delay at three years of chronological age.