Association of Standardized Parenteral Nutrition with Early Neonatal Growth of Moderately Preterm Infants: A Population-Based Cohort Study.

In preterm infants, early nutrient intake during the first week of life often depends on parenteral nutrition. This study aimed to evaluate the influence of standardized parenteral nutrition using three-in-one double-chamber solutions (3-in-1 STD-PN) on early neonatal growth in a cohort of moderately preterm (MP) infants. This population-based, observational cohort study included preterm infants admitted to neonatal centers in the southeast regional perinatal network in France. During the study period, 315 MP infants with gestational ages between 320/7 and 346/7 weeks who required parenteral nutrition from birth until day-of-life 3 (DoL3) were included; 178 received 3-in-1 STD-PN solution (56.5%). Multivariate regression was used to assess the factors associated with the relative body-weight difference between days 1 and 7 (RBWD DoL1-7). Infants receiving 3-in-1 STD-PN lost 36% less body weight during the first week of life, with median RBWD DoL1-7 of -2.5% vs. -3.9% in infants receiving other PN solutions (p < 0.05). They also received higher parenteral energy and protein intakes during the overall first week, with 85% (p < 0.0001) and 27% (p < 0.0001) more energy and protein on DoL 3. After adjusting for confounding factors, RBWD DoL1-7 was significantly lower in the 3-in-1 STD-NP group than in their counterparts, with beta (standard deviation) = 2.08 (0.91), p = 0.02. The use of 3-in-1 STD-PN provided better energy and protein intake and limited early weight loss in MP infants.

Effect of Massage with Oil Balanced in Essential Fatty Acids on Development and Lipid Parameters in Very Premature Neonates: A Randomized, Controlled Study.

Background: Oil massage versus only massage can increase preterm newborn development, especially weight gain, via a supposed percutaneous absorption of oil lipids, but data are contradictory. Aims: Investigating whether massage with a vegetable oil balanced in essential fatty acids improves neonatal weight gain, and digestive autonomy as proxy for neuro-development outcomes. Methods: A prospective monocentric randomized study was conducted in very premature newborns who received massage with oil (isio4 10 mL/kg/day, n = 18) versus with no oil (n = 18) for five consecutive days (10-min session twice daily) at a corrected gestational age of 34−35 weeks. Anthropometrics and clinical characteristics were recorded. Plasma triglyceride and total cholesterol concentrations were analyzed with an enzymatic kit. The fatty acid composition (weight%, mg/mL) of total plasma lipids and of red blood cell (RBC) membrane was analyzed by gas chromatography. Results: Weight gain velocity at the end of massage period was 12.3 ± 1.4 g/kg/day with oil vs. 9.8 ± 1.4 g/kg/day with no oil (p = 0.1). Digestive autonomy, plasma lipid parameters, polyunsaturated fatty acids in plasma total lipids or in RBC were comparable. The no oil group displayed a higher RBC level in nervonic acid at discharge (4.3 ± 0.2 vs. 3.4 ± 0.2%; p = 0.025) and in C18:1n-9 plasmalogen species at the end of the massage period and at discharge (0.73 ± 0.06 vs. 0.48 ± 0.06; 0.92 ± 0.06 vs. 0.69 ± 0.06%; p < 0.01), two molecules that are involved in neurodevelopment. Conclusions: The use of isio4 oil did not provide additional benefits for the development of very premature newborns, neither changed lipid metabolism nor polyunsaturated fatty acid biological status, which did not corroborate the existence of a percutaneous route for oil lipid absorption. The reason for different levels of nervonic acid and plasmalogen in RBC remains to be explored.

Long Term Neurodevelopmental Outcomes after Sevoflurane Neonatal Exposure of Extremely Preterm Children: A Cross-Sectional Observationnal Study.

Sevoflurane, a volatile anesthetic, is used when extremely preterm neonates (EPT) undergo painful procedures. Currently, no existing studies analyze sevoflurane's long-term effects during the EPT's immediate neonatal period. Our primary objective was to compare the EPT's neurocognitive development regardless of any sevoflurane exposure prior to 45 weeks corrected gestational age (GA). We analyzed those live discharges, less than 28 weeks GA, who were either exposed, unexposed, and/or multiply exposed to sevoflurane before 45 weeks GA. All data were obtained from a cross-sectional multicenter study (GPQoL study, NCT01675726). Children, both exposed and non-exposed to sevoflurane, were sampled using a propensity-guided approach. Neurological examinations (Touwen), cognitive and executive functions (WISC IV, NEPSY, Rey figure), and assessments when the children were between 7 and 10 years old, were correlated to their neonatal sevoflurane exposure. There were 139 children in the study. The mean gestational age was 26.2 weeks (±0.8) GA and the mean birth weight was 898 g (±173). The mean age of their evaluation was 8.47 years old (±0.70). Exposure to sevoflurane to the mean corrected age 27.10 (3.37) weeks GA had a significant correlation with cerebral palsy (adjusted odds ratio (aOR): 6.70 (CI 95%: 1.84-32.11)) and other major disorders (cerebral palsy and/or severe cognitive retardation) (aOR: 2.81 [95% CI: 1.13-7.35]). Our results demonstrate the possibility of long-term effects on EPT infants who had a sevoflurane exposure before 45 weeks corrected GA. However, these results will require further confirmation by randomized controlled trials.

Predictive value of brain MRI at term-equivalent age in extremely preterm children on neurodevelopmental outcome at school-age.

This study's objective was to correlate the abnormalities in brain MRIs performed at corrected-term age for minor or moderate neurocognitive disorders in children school-age born extremely premature (EPT) and without serious sequelae such as autism, cerebral palsy, mental impairment. Data were issued from a cross-sectional multicenter study (GP-Qol study, number NCT01675726). Clinical examination and psychometric assessments were performed when the children were between 7 and 10 years old during a day-long evaluation. Term-equivalent age brain MRIs on EPT were analyzed with a standardized scoring system. There were 114 children included in the study. The mean age at the time of evaluation, was 8.47 years old (± 0.70). 59% of children with at least one cognitive impairment and 53% who had a dysexecutive disorder. Only ten EPT (8.7%) presented moderate to severe white and grey matter abnormalities. These moderate to severe grey matter abnormalities were associated with at least two abnormal executive functions [OR 3.08 (95% CI 1.04-8.79), p = 0.04] and language delay [OR 3.25 (95% CI 1.03-9.80), p = 0.04]. These results remained significant in the multivariate analysis. Moderate to severe ventricular dilatation abnormalities (15%, n = 17) were associated with ideomotor dyspraxia [OR 7.49 (95% CI 1.48-35.95), p = 0.02] and remained significant in multivariate analysis [OR 11.2 (95% CI 1.45-131.4), p = 0.02]. Biparietal corrected diameters were moderate abnormal in 20% of cases (n = 23) and were associated to visuo spatial integration delay [OR 4.13 (95% CI 1.23-13.63), p = 0.02]. Cerebral MRI at term-equivalent age with scoring system analysis can provide information on long-term neuropsychological outcomes at school-age in EPTs children having no severe disability.

Cardio-Respiratory Events and Food Autonomy Responses to Early Uni-Modal Orofacial Stimulation in Very Premature Babies: A Randomized, Controlled Study.

Uni-modal orofacial stimulation (OFS) for preventing very preterm infants' oral disorders is highly controversial. Our study sought to demonstrate that OFS reduced cardio-respiratory events and improved food autonomy in a population of very preterm infants. Our study was randomized, controlled, prospective, and unicentric. The preterm included were born between 26-29 weeks gestational age (GA) with a corrected postnatal age <33 weeks GA. They were randomized into two groups: the experimental group underwent OFS, according to a protocol established, over 10 consecutive days, and the control group underwent no OFS. The primary outcome was the number of cardiorespiratory events: apnea-bradycardia (with or without desaturations) or number of isolated desaturations, which were evaluated at four separate times. Measurements occurred during the first, fourth and eighth independent feedings. Seventeen patients were included in the experimental group and 18 in the control group. The number of cardiorespiratory events for all independent feeding times was significantly reduced in the OFS group (p = 0.003) with univariate analysis, but not with multivariable analysis. The quantity of milk ingested during the first autonomous feeding was higher in the experimental group. The acquisition of food autonomy and the duration of hospitalization were similar in the two groups. While our study does not affirm that an early unimodal OFS improves premature infants' cardiorespiratory evolution and/or the acquisition of food autonomy, it does indicate an improved food efficiency during their first autonomous feedings.

The Neurobehavioral Phenotype of School-Aged, Very Prematurely Born Children with No Serious Neurological Sequelae: A Quality of Life Predictor.

School-aged extremely preterm (EPT) children have multiple specific neurocognitive/behavioral disorders that are often associated with other disorders; this manifests a true neurobehavioral "phenotype" of prematurity. To determine a profile of cognitive/behavioral impairments in a population of school-aged EPT children (7-10 years-old) without major disabilities, a cross-sectional study was conducted in five medical centers. An algorithm distributed the study population according to four WISC-IV subtests, five NEPSY-2 subtests, and two variables of figure of Rey. The behavior (SDQ), anxiety (Spielberg STAI-C), and generic QoL (Kidscreen 10 and VSP-A) were also evaluated. The study included 231 school-aged EPT children. Three neurobehavioral "phenotypes" were defined according to their severity: 1 = moderately, 2 = minor, and 3 = unimpaired. In all the profiles, the working memory, perceptual reasoning, as well as mental flexibility, were close to or below average, and their emotional behavior was always troubled. Self-esteem and school-work were the most impacted QoL areas. The unimpaired neurobehavior exhibited emotional behavioral impairment and executive dysfunction. The profile analysis defined distinct outcome groups and provided an informative means of identifying factors related to developmental outcomes. The QoL deterioration is determined by the severity of the three neurobehavioral "phenotypes", which is defined as well as by dysexecutive and/or behavioral disorders.

Specific cognitive correlates of the quality of life of extremely preterm school-aged children without major neurodevelopmental disability.

BACKGROUND: We examined how specific cognitive behavioral impairments impacted quality of life (QoL) within a large multicenter cohort of 7-10 year olds surviving extremely preterm (EPT) without major neurodevelopmental disability. METHODS: Between 7 and 10 years of age, two generic, self-proxy, and parental evaluations were obtained. QoL measurement questionnaires (Kidscreen-10/VSPA (Vécu et Santé Perçue de l'Enfant et de l'Adolescent)) were used and compared to a reference population. The general and specific cognitive functions, such as executive functions, behavior and anxiety, and clinical neurologic examination, were also assessed. RESULTS: We analyzed 211 school-aged EPT children. The mean gestational age was 26.2 (±0.8) weeks, birth weight was 879 g (±181) and the mean age was 8.4 years (±0.87). Children with a Full-Scale Index Quotient ≥89, who were considered as normal, had a lower QoL. Specific cognitive impairments: comprehensive language delay, visuo-spatial integration defect, and dysexecutive disorders) were the QoL correlates in the domains of school performance and body image. CONCLUSIONS: School and health care professionals need to increase their focus on EPT children's lower so as to recognize the preterm behavioral/cognitive phenotype and their potential need for supportive measures. Research on preventive interventions is warranted to investigate if these long-term effects of an EPT birth can be attenuated in neonatal period and after.

Quality of life of extremely preterm school-age children without major handicap: a cross-sectional observational study.

OBJECTIVE: To determine the quality of life (QoL) of school-aged children who were born <28+0 weeks of gestation and who have no resultant major disabilities. DESIGN, SETTING AND PATIENTS: A cross-sectional multicentre study of extremely preterm (EPT) infants born <28+0 weeks, discharged alive and free from severe impairments (cerebral palsy, autism, major cognitive disabilities). Two generic, self-evaluation and hetero-evaluation (by parent) QoL measurement questionnaires (Kidscreen 10/VSP-A) were used and then compared with French population reference. MAIN OUTCOME MEASURES: Clinical examination, an assessment of cognitive functions and QoL between 7 and 10 years of age. RESULTS: 40 (7.5%) severely disabled children were excluded. Among those 471 eligible, the lost to follow-up group (169 (36%)) paralleled those 302 (64%) included in the study. The mean gestational age was 26.2 (±0.8), birth weight was 879 (±181) g and the mean age was 8.4 (±0.87) years. 48% of participants had minor or moderate cognitive disabilities based on their Full-Scale Index Quotient. Working memory, attention and mental flexibility scored as low-average. Except for family relationships, the EPT QoL VSP-A and Kidscreen 10 assessment were significantly lower based on the children's and parent's perspectives. Children reported the most significant QoL decline as (1) friends' relationships, (2) self-esteem and (3) leisure, while parents indicated (1) psychological well-being, (2) schoolwork and (3) vitality. CONCLUSION: The QoL of a school-age EPT child without severe impairment was lower relative to a reference population from both the parents' and child's points of view. This evaluation should help to better understand the long-term outcomes and to provide better support for them and their families. TRIAL REGISTRATION NUMBER: NCT01675726, pre-results.

Analgesic Effect of Maternal Human Milk Odor on Premature Neonates: A Randomized Controlled Trial.

BACKGROUND: Two studies have demonstrated an analgesic effect of maternal milk odor in preterm neonates, without specifying the method of olfactory stimulation. Research aim: This study aimed to assess the analgesic effect of maternal milk odor in preterm neonates by using a standardized method of olfactory stimulation. METHODS: This trial was prospective, randomized, controlled, double blinded, and centrally administered. The inclusion criteria for breastfed infants included being born between 30 and 36 weeks + 6 days gestational age and being less than 10 days postnatal age. There were two groups: (a) A maternal milk odor group underwent a venipuncture with a diffuser emitting their own mother's milk odor and (2) a control group underwent a venipuncture with an odorless diffuser. The primary outcome was the Premature Infant Pain Profile (PIPP) score, with secondary outcomes being the French scale of neonatal pain-Douleur Aiguë du Nouveau-né (DAN) scale-and crying duration. All neonates were given a dummy. RESULTS: Our study included 16 neonates in the maternal milk odor group and 17 in the control group. Neonates exposed to their own mother's milk odor had a significantly lower median PIPP score during venipuncture compared with the control group (6.3 [interquartile range (IQR) = 5-10] versus 12.0 [IQR = 7-13], p = .03). There was no significant difference between the DAN scores in the two groups ( p = .06). Maternal milk odor significantly reduced crying duration after venipuncture (0 [IQR = 0-0] versus 0 [IQR = 0-18], p = .04). CONCLUSION: Maternal milk odor has an analgesic effect on preterm neonates.

A case of Norman-Roberts syndrome identified from postnatal diagnosis of microlissencephaly.

Lissencephaly is a rare brain malformation. What differentiates microlissencephaly from classical lissencephaly and other variants is the presence of severe microcephaly. Very few postnatal cases of Norman-Roberts syndrome are described in the literature. We report a case of microlissencephaly with a polymalformative syndrome that prompted postnatal diagnosis of Norman-Roberts syndrome.

Prognostic value of abdominal sonography in necrotizing enterocolitis of premature infants born before 33 weeks gestational age.

OBJECTIVE: The purpose of this study was to assess the prognostic value of abdominal sonography in necrotizing enterocolitis (NEC) in preterm infants with a gestational age less than 33 weeks of gestation, using surgery and/or death as the primary outcome and stenosis as the secondary outcome. METHODS: A retrospective study of 95 premature infants (mean gestational age: 28.6 weeks), presenting with NEC between January 2009 and November 2011 and who underwent plain abdominal radiography and sonography, was performed. In uni- and multivariate analyses, radiographic and sonographic findings were correlated with complications ('surgery and/or death' and 'stenosis'). RESULTS: Sonographic findings of free intraperitoneal air (odd ratio [OR]=8.0; IC, 1.4-44.2), free abdominal fluid (OR 3.5; IC 1.3-9.4), portal venous gas (OR 3.9; IC, 1.2-12.9), and bowel wall thickening (OR 2.8; IC,1.1-7.2) were significantly associated with surgery and/or death. Intramural gas was significantly correlated (OR=11.8; IC, 1.5-95.8) with intestinal stenosis following NEC. None of the radiographic findings were associated with complications. CONCLUSION: Abdominal sonography is a reliable tool for the prognostic assessment of NEC in preterm infants.

Pharmacokinetics and absolute bioavailability of phenobarbital in neonates and young infants, a population pharmacokinetic modelling approach.

Phenobarbital is widely used for treatment of neonatal seizures. Its optimal use in neonates and young infants requires information regarding pharmacokinetics. The objective of this study is to characterize the absolute bioavailability of phenobarbital in neonates and young infants, a pharmacokinetic parameter which has not yet been investigated. Routine clinical pharmacokinetic data were retrospectively collected from 48 neonates and infants (weight: 0.7-10 kg; patient's postnatal age: 0-206 days; GA: 27-42 weeks) treated with phenobarbital, who were administered as intravenous or suspension by oral routes and hospitalized in a paediatric intensive care unit. Total mean dose of 4.6 mg/kg (3.1-10.6 mg/kg) per day was administered by 30-min infusion or by oral route. Pharmacokinetic analysis was performed using a nonlinear mixed-effect population model software). Data were modelled with an allometric pharmacokinetic model, using three-fourths scaling exponent for clearance (CL). The population typical mean [per cent relative standard error (%RSE)] values for CL, apparent volume of distribution (Vd ) and bioavailability (F) were 0.0054 L/H/kg (7%), 0.64 L/kg (15%) and 48.9% (22%), respectively. The interindividual variability of CL, Vd , F (%RSE) and residual variability (%RSE) was 17% (31%), 50% (27%), 39% (27%) and 7.2 mg/L (29%), respectively. The absolute bioavailability of phenobarbital in neonates and infants was estimated. The dose should be increased when switching from intravenous to oral administration.

Comparison of ultrasound and X-ray in determining the position of umbilical venous catheters.

OBJECTIVE: Thoraco-abdominal X-ray (TAX) is the most frequent used method to determine the route and tip position (TP) of umbilical venous catheters (UVCs). The aim of this study was to compare ability of TAX and ultrasonography (US) to determine UVC route and TP. PATIENTS AND METHODS: All neonates requiring UVC or admitted to our Paediatric and Neonatal Intensive Care with UVC were included in this prospective study. Catheter position was controlled by TAX and interpreted by the physician in charge of the patient. US examinations were performed by a paediatric radiologist blinded to TAX result. The UVC route (central or not central) and TP determined by each method were compared to the "actual UVC route and TP", as determined by senior paediatric radiologist and neonatologist referents joint interpretation of TAX and US results. RESULTS: Sixty-one UVCs were assessed in 60 neonates of mean gestational age of 34.7±4.2 weeks. To determine catheter route, sensitivity and specificity were respectively 96.4% and 93.9% for US and 92.8% and 78.8% for TAX. To determine catheter tip position, sensitivity and specificity were respectively 93.3% and 95.6% for US and 66.7% and 63.0% for TAX (p<0.001). Failure of TAX to define UVC tip position increased with birth weight (p<0.005). CONCLUSION: TAX and US are reliable in determining UVC route (central or not) but US examination is superior to TAX in determining UVC TP.

Comparative analysis of perinatal and postnatal factors, and general movement in extremely preterm infants.

STUDY AIM: To describe general movement in extremely premature infants and examine correlations with risk factors for antenatal, perinatal, and postnatal morbidity. STUDY TYPE: Prospective, single-center study. Nineteen patients were followed up. METHODOLOGY: The infants' general movement was analyzed using video recordings. Qualitative and quantitative assessments were performed during the writhing movement (WM) period and fidgety movement (FM) period. The quality of the general movements (GMs) and the scores achieved were then correlated with antenatal, perinatal, and postnatal factors. RESULTS: Infants' motor activity fluctuated during the WM period, especially in extremely premature infants where poor repertoire is often observed. No correlations were found between WMs and obstetric factors. Gestational age correlated with WMs' quality (p=0.023). WMs correlated with factors of postnatal morbidity such as chronic lung disease (CLD) (p=0.034) and nosocomial infections (p=0.05). At 3 months corrected age, the spontaneous movement quality are correlated with neurological explorations such as US brain (p=0.032), MRI (p=0.039), EEG (p=0.036), and neurological follow-up assessments (p=0.015). CONCLUSION: Prudence must be used when performing the analysis of general movement in extremely preterm infants. WMs may be influenced by perinatal morbidity, and possibly by the severe brain immaturity of these infants. WMs correlate with CLD and nosocomial infections. Analysis of general movement in infants of 3 months corrected age is a valuable means to detect neurological disorders.

Longitudinal follow-up of a cohort of 350 singleton infants born at less than 32 weeks of amenorrhea: neurocognitive screening, academic outcome, and perinatal factors.

OBJECTIVE: To analyse the incidence of neurodevelopmental disorders at the age 6-10 years, in children born at less than 32 weeks of amenorrhea, and to identify the perinatal and neonatal factors associated with adverse neurodevelopmental outcomes at this age. STUDY DESIGN: Longitudinal prospective trial in a French university and tertiary perinatal care centre. A total of 350 preterm singletons born in hospital at less than 32 weeks of amenorrhea between 1997 and 2001 were included. Children were invited for examination to screen for neurocognitive disorders between 4 and 8 years of age and re-contacted when they were between 6 and 10 years of age to evaluate school results. Three profiles of neurocognitive outcome were defined (normal, minor disorder, or major disorder) and correlated with maternal, antenatal, perinatal, and neonatal factors. RESULTS: The survival rate of our cohort was 80.8% (283/350) and the proportion of survivors followed-up was 71.4% (202/283). There were 137 children (68%) with normal profiles, 29 (14%) with minor disorders, and 36 (18%) with major disorders. For those born at less than 28 weeks of amenorrhea, the survival rate was 62.7% (64/102) and the proportion of survivors followed-up was 78.1% (50/64). Among these children, 24 (48.0%) had normal outcomes, 8 (16.0%) suffered from minor disorders, and 18 (36.0%) had major disorders. The three principal independent risk factors for major or minor disorders at school age were gestational age less than 28 weeks of amenorrhea (adjusted odds ratio: 1.28 [95% confidence interval: 1.06-1.56]), chronic lung disease at birth (adjusted odds ratio: 2.92 [95% confidence interval: 1.15-7.42]), and an abnormal electroencephalogram before discharge (adjusted odds ratio: 2.61 [95% confidence interval: 1.10-6.18]). Moreover, abnormal brain ultrasonography was identified as an independent risk factor for occurrence of major disorders (adjusted odds ratio: 2.98 [95% confidence interval: 1.31-6.71]). CONCLUSION: Very preterm infants remain at high risk for long-term neurodevelopmental disorders. Several neonatal factors, particularly chronic lung disease, seem to be important determinants of long-term outcome.

Evaluation of a tool to screen at preschool age for minor cognitive disorders liable to affect schooling among children born premature.

PURPOSE: To evaluate a detection tool designed to help paediatricians identify, at preschool age, minor neurocognitive disorders that interfere with normal schooling. METHODS: One hundred-and-fourteen preterm singletons born between 1997 and 2001 at less than 32 weeks of amenorrhoea, in a tertiary perinatal care center, were invited to visit us for a medical examination and a rapid neurocognitive assessment (BREV) when they were aged between 4 and 8 years and were re-contacted at 6-10 years of age to evaluate their current schooling situation. Results of BREV and schooling parameters were compared. RESULTS: Mean gestational age was 29 weeks and mean birth weight was 1,164 g. Fifteen children (13.2%) showed abnormal results on BREV testing and had unusual schooling histories. Among the 68 children with normal BREV, 65 (95.6%) had achieved normal schooling. The sensitivity of the BREV test in this population for detection of minor disorders interfering with schooling was thus 83.3% (95% CI = 57.7-95.6) and the predictive value of a negative test was 95.6% (95% CI = 86.8-98.9). For the 57 children (50%) assessed before the age of 5 years, the sensitivity and the predictive value of a negative test were both 100%. CONCLUSION: Our survey shows that the BREV test can, in a population of preschool children who were born premature, screen for minor neurocognitive disorders that impact schooling parameters. BREV assessment, used in the setting of follow-up of premature infants, would identify children in need of early remedial education before schooling under-attainment or failure developed.