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Purpose: The primary objective was to evaluate the impact of necrotising enterocolitis (NEC) and spontaneous intestinal perforation (SIP) on mortality and neurodevelopmental outcomes at 2 years' corrected age (CA) in infants born before 32 weeks' gestation (WG)., Methods: We studied neurodevelopment at 2 years' CA of infants with NEC or SIP who were born before 32 WG from the EPIPAGE-2 cohort study. The primary outcome was death or the presence of moderate-to-severe motor or sensory disability defined by moderate-to-severe cerebral palsy or hearing or visual disability. The secondary outcome was developmental delay defined by a score < 2 SDs below the mean for any of the five domains of the Ages and Stages Questionnaire., Results: At 2 years' CA, 46% of infants with SIP, 34% of infants with NEC, and 14% of control infants died or had a moderate-to-severe sensorimotor disability (p < 0.01). This difference was mainly due to an increase in in-hospital mortality in the infants with SIP or NEC. Developmental delay at 2 years' CA was more frequent for infants with SIP than controls (70.8% vs 44.0%, p = 0.02) but was similar for infants with NEC and controls (49.3% vs 44.0%, p = 0.5). On multivariate analysis, the likelihood of developmental delay was associated with SIP (adjusted odds ratio = 3.0, 95% CI 1.0-9.1) but not NEC as compared with controls., Conclusion: NEC and SIP significantly increased the risk of death or sensorimotor disability at 2 years' CA. SIP was also associated with risk of developmental delay at 2 years' CA., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aim: The aim of this paper was to review the role that donor human milk plays in caring for very low birth weight (VLBW) infants., Methods: This review focussed on academic papers and background information published in English and French up to 8 August 2021., Results: Donor human milk provides a useful bridge to successful breastfeeding in hospitalised neonates and does not have a negative impact on the use of mother's own milk and breastfeeding rates at discharge. It helps to prevent key complications of prematurity, particularly necrotising enterocolitis up to 36 weeks of postmenstrual age, which is more common in infants fed formulas based on cows' milk. When it is carefully fortified, it supports the postnatal growth of the majority of very preterm infants. Well-organised, accessible human milk banks are required to cover the needs of hospitalised infants, and donor human milk must be prioritised for patients who derive the greatest health benefit from it. These include very preterm infants and those born at term, or near term, with surgical digestive malformations or congenital heart disease., Conclusion: Safe, high-quality donor human milk, which is distributed by well-organised human milk banks, is essential for the most vulnerable hospitalised neonates., (© 2022 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Importance: An international expert committee recently revised its recommendations on amino acid intake for very preterm infants, suggesting that more than 3.50 g/kg/d should be administered only to preterm infants in clinical trials. However, the optimal amino acid intake during the first week after birth in these infants is unknown., Objective: To evaluate the association between early amino acid intake and cognitive outcomes at age 5 years., Design, Setting, and Participants: Using the EPIPAGE-2 (Epidemiologic Study on Small-for-Gestational-Age Children-Follow-up at Five and a Half Years) cohort, a nationwide prospective population-based cohort study conducted at 63 neonatal intensive care units in France, a propensity score-matched analysis was performed comparing infants born at less than 30 weeks' gestation who had high amino acid intake (3.51-4.50 g/kg/d) at 7 days after birth with infants who did not. Participants were recruited between April 1 and December 31, 2011, and followed up from September 1, 2016, to December 31, 2017. Full-scale IQ (FSIQ) was assessed at age 5 years. A confirmatory analysis used neonatal intensive care unit preference for high early amino acid intake as an instrumental variable to account for unmeasured confounding. Statistical analysis was performed from January 15 to May 15, 2021., Exposures: Amino acid intake at 7 days after birth., Main Outcomes and Measures: The primary outcome was an FSIQ score greater than -1 SD (ie, ≥93 points) at age 5 years. A complementary analysis was performed to explore the association between amino acid intake at day 7 as a continuous variable and FSIQ score at age 5 years. Data from cerebral magnetic resonance imaging at term were available for a subgroup of preterm infants who participated in the EPIRMEX (Cerebral Abnormalities Detected by MRI, Realized at the Age of Term and the Emergence of Executive Functions) ancillary study., Results: Among 1789 preterm infants (929 boys [51.9%]; mean [SD] gestational age, 27.17 [1.50] weeks) with data available to determine exposure to amino acid intake of 3.51 to 4.50 g/kg/d at 7 days after birth, 938 infants were exposed, and 851 infants were not; 717 infants from each group could be paired. The primary outcome was known in 396 of 646 exposed infants and 379 of 644 nonexposed infants who were alive at age 5 years and was observed more frequently among exposed vs nonexposed infants (243 infants [61.4%] vs 206 infants [54.4%], respectively; odds ratio [OR], 1.33 [95% CI, 1.00-1.71]; absolute risk increase in events [ie, the likelihood of having an FSIQ score >-1 SD at age 5 years] per 100 infants, 7.01 [95% CI, 0.06-13.87]; P = .048). In the matched cohort, correlation was found between amino acid intake per 1.00 g/kg/d at day 7 and FSIQ score at age 5 years (n = 775; β = 2.43 per 1-point increase in FSIQ; 95% CI, 0.27-4.59; P = .03), white matter area (n = 134; β = 144 per mm2; 95% CI, 3-285 per mm2; P = .045), anisotropy of the corpus callosum (n = 50; β = 0.018; 95% CI, 0.016-0.021; P < .001), left superior longitudinal fasciculus (n = 42; β = 0.018; 95% CI, 0.010-0.025; P < .001), and right superior longitudinal fasciculus (n = 42; β = 0.014 [95% CI, 0.005-0.024; P = .003) based on magnetic resonance imaging at term. Confirmatory and sensitivity analyses confirmed these results. For example, the adjusted OR for the association between the exposure and the primary outcome was 1.30 (95% CI, 1.16-1.46) using the instrumental variable approach among 978 participants in the overall cohort, and the adjusted OR was 1.35 (95% CI, 1.05-1.75) using multiple imputations among 1290 participants in the matched cohort., Conclusions and Relevance: In this cohort study, high amino acid intake at 7 days after birth was associated with an increased likelihood of an FSIQ score greater than -1 SD at age 5 years. Well-designed randomized studies with long-term follow-up are needed to confirm the benefit of this nutritional approach.

Necrotizing enterocolitis (NEC) is among the most relevant gastrointestinal diseases affecting mostly prematurely born infants with low birth weight. While intestinal dysbiosis has been proposed as one of the possible factors involved in NEC pathogenesis, the role of the gut microbiota remains poorly understood. In this study, the gut microbiota of preterm infants was explored to highlight differences in the composition between infants affected by NEC and infants prior to NEC development. A large-scale gut microbiome analysis was performed, including 47 shotgun sequencing data sets generated in the framework of this study, along with 124 retrieved from publicly available repositories. Meta-analysis led to the identification of preterm community state types (PT-CSTs), which recur in healthy controls and NEC infants. Such analyses revealed an overgrowth of a range of opportunistic microbial species accompanying the loss of gut microbial biodiversity in NEC subjects. Moreover, longitudinal insights into preterm infants prior to NEC development indicated Clostridium neonatale and Clostridium perfringens species as potential biomarkers for predictive early diagnosis of this disease. Furthermore, functional investigation of the enzymatic reaction profiles associated with pre-NEC condition suggested DL-lactate as a putative metabolic biomarker for early detection of NEC onset. IMPORTANCE Necrotizing enterocolitis (NEC) is a severe gastrointestinal disease occurring predominantly in premature infants whose etiology is still not fully understood. In this study, the analysis of infant fecal samples through shotgun metagenomics approaches revealed a marked reduction of the intestinal (bio)diversity and an overgrowth of (opportunistic) pathogens associated with the NEC development. In particular, dissection of the infant's gut microbiome before NEC diagnosis highlighted the potential involvement of Clostridium genus members in the progression of NEC. Remarkably, our analyses highlighted a gastrointestinal DL-lactate accumulation among NEC patients that might represent a novel potential functional biomarker for the early diagnosis of NEC.

Lactoferrin is one of the most represented and important bioactive proteins in human and mammal milk. In humans, lactoferrin is responsible for several actions targeting anti-infective, immunological, and gastrointestinal domains in neonates, infants, and young children. Evidence-based data vouch for the ability of supplemented lactoferrin to prevent sepsis and necrotizing enterocolitis in preterm infants and to reduce the burden of morbidity related to gastrointestinal and respiratory pathogens in young children. However, several issues remain pending regarding answers and clarification related to quality control, correct intakes, optimal schedules and schemes of supplementations, interactions with probiotics, and different types of milk and formulas. This review summarizes the current evidence regarding lactoferrin and discusses the areas in need of further guidance prior to the adoption of strategies that include a routine use of lactoferrin in neonates and young children., Competing Interests: None., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Importance: Up-to-date estimates of the health outcomes of preterm children are needed for assessing perinatal care, informing parents, making decisions about care, and providing evidence for clinical guidelines., Objectives: To determine survival and neonatal morbidity of infants born from 22 through 34 completed weeks' gestation in France in 2011 and compare these outcomes with a comparable cohort in 1997., Design, Setting, and Participants: The EPIPAGE-2 study is a national, prospective, population-based cohort study conducted in all maternity and neonatal units in France in 2011. A total of 2205 births (stillbirths and live births) and terminations of pregnancy at 22 through 26 weeks' gestation, 3257 at 27 through 31 weeks, and 1234 at 32 through 34 weeks were studied. Cohort data were collected from January 1 through December 31, 1997, and from March 28 through December 31, 2011. Analyses for 1997 were run for the entire year and then separately for April to December; the rates for survival and morbidities did not differ. Data are therefore presented for the whole year in 1997 and the 8-month and 6-month periods in 2011., Main Outcomes and Measures: Survival to discharge and survival without any of the following adverse outcomes: grade III or IV intraventricular hemorrhage, cystic periventricular leukomalacia, severe bronchopulmonary dysplasia, retinopathy of prematurity (stage 3 or higher), or necrotizing enterocolitis (stages 2-3)., Results: A total of 0.7% of infants born before 24 weeks' gestation survived to discharge: 31.2% of those born at 24 weeks, 59.1% at 25 weeks, and 75.3% at 26 weeks. Survival rates were 93.6% at 27 through 31 weeks and 98.9% at 32 through 34 weeks. Infants discharged home without severe neonatal morbidity represented 0% at 23 weeks, 11.6% at 24 weeks, 30.0% at 25 weeks, 47.5% at 26 weeks, 81.3% at 27 through 31 weeks, and 96.8% at 32 through 34 weeks. Compared with 1997, the proportion of infants surviving without severe morbidity in 2011 increased by 14.4% (P < .001) at 25 through 29 weeks and 6% (P < .001) at 30 through 31 weeks but did not change appreciably for those born at less than 25 weeks. The rates of antenatal corticosteroid use, induced preterm deliveries, cesarean deliveries, and surfactant use increased significantly in all gestational-age groups, except at 22 through 23 weeks., Conclusions and Relevance: The substantial improvement in survival in France for newborns born at 25 through 31 weeks' gestation was accompanied by an important reduction in severe morbidity, but survival remained rare before 25 weeks. Although improvement in survival at extremely low gestational age may be possible, its effect on long-term outcomes requires further studies. The long-term results of the EPIPAGE-2 study will be informative in this regard.

Background: Mild rectal bleeding (MRB) is a particular clinical entity different from necrotizing enterocolitis, which significantly influences neonatal care in preterm infants. We aimed to determine the risk factors and to evaluate prospectively the clinical course of MRB., Methods: We consecutively included in a case-control study all infants with birth weight ≤ 1500 g or gestational age ≤ 32 weeks admitted to our unit, and presenting MRB, defined as either isolated or associated with mild clinical or radiological signs. We matched each Case with two Controls. Clinical data before, after and at time of MRB were collected, together with stool cultures at time of MRB (or at similar postnatal age in Controls). Multiple logistic regression analysis was performed to determine independent risk factors for the development of MRB., Results: During 4 years, among 823 very low birth weight (VLBW) infants admitted to our unit, 72 (8.8%) had MRB. The median duration of rectal bleeding was 1.1 [1-2] days and the fasting period lasted 2.9 [2-10] days. A relapse occurred in 24% of cases. In multivariate analysis, only hypertension during pregnancy (p = 0.019), growth restriction at onset of bleeding (p = 0.026), and exposure to ibuprofen (p = 0.003) were independent risk factors for MRB. In Cases there were more infants with Clostridium Difficile in stools than in Controls (p = 0.017)., Conclusion: Hypertension during pregnancy, even without intrauterine growth restriction, appeared to carry the same risk for MRB as exposure to ibuprofen and extrauterine growth restriction.

Aim: To evaluate the impact of an improved nutritional policy for extremely low birthweight (ELBW) infants on nutritional deficits and postnatal growth., Method: We compared two groups of 37 ELBW infants, born before and after the introduction of an improved nutritional policy in April 2006. Group A (born 2005 to early 2006) and group B (born 2009) stayed in a French neonatal intensive care unit (NICU) for at least 7 weeks. Optimal energy and protein intakes were 120 and 3.5 g/kg/day, respectively, and used to calculate cumulative deficits. Delta z-scores for weight, length and head circumference were calculated between birth and 36 weeks of postmenstrual age (PMA). The improved nutritional policy focused on earlier and higher parenteral intake of lipids and proteins, earlier and higher human milk fortification and earlier transition to preterm formula., Results: The two groups did not differ in gestational age and birthweight. However, protein and energy deficits were significantly reduced in group B. Between birth and 36 weeks of PMA, delta z-scores were significantly reduced for length (p = 0.012) but not for weight (p = 0.09) or head circumference (p = 0.83)., Conclusion: Higher parenteral intake and close attention to enteral feeding reduced nutritional deficits and linear growth restriction in infants admitted to a French NICU., (©2012 The Author(s)/Acta Paediatrica ©2012 Foundation Acta Paediatrica.)

Aim: To assess cerebral lesions and other medical as well as social characteristics as predictors of risk of mild and severe cognitive deficiencies in very preterm infants., Methods: As part of the EPIPAGE population-based prospective cohort study, perinatal data and cognitive outcome at 5 years of age were recorded for 1503 infants born before 33 weeks of gestation in nine regions of France in 1997. Mild cognitive deficiency was defined as a Mental Processing Composite score on the Kaufman Assessment Battery for Children test of between 70 and 84, and severe cognitive deficiency as a score of <70., Results: After controlling for cerebral lesions and other medical as well as social factors, low parental socio-economic status and lack of breastfeeding were significant predictors of mild and severe cognitive deficiencies, whereas presence of cerebral lesions, being small for gestational age and having a large number of siblings were predictors of severe cognitive deficiency., Conclusion: Predictors of poor cognitive outcome in very preterm infants are low social status, lack of breastfeeding, presence of cerebral lesions on ultrasound scan, being born small for gestational age and having a high number of siblings. Social factors predicted both mild and severe cognitive deficiencies, whereas medical factors predicted mostly severe cognitive deficiencies., (© 2011 The Author(s)/Acta Paediatrica © 2011 Foundation Acta Paediatrica.)

Objectives: We compared the frequency of behavioral problems in very preterm and term children at 5 years of age. We hypothesized that behavioral problems would be associated with cognitive impairment and environmental factors and that differences between the 2 groups would be reduced but persist after adjusting for cognitive performance and environmental factors., Patients and Methods: The Etude Epidémiologique sur les Petits Ages Gestationnels (EPIPAGE) study was a prospective population-based cohort study that included all births occurring between 22 and 32 weeks' gestation and a control group of infants born at 39 to 40 weeks' gestation in 1997 in 9 French regions. Neonatal and obstetrics data were collected at birth. At 5 years of age, sociodemographic status and neurodevelopmental and cognitive development of the children, as well as maternal mental well-being, were assessed. The behavioral problems of 1102 very preterm and 375 term singletons without major impairments were studied by using the parent-completed Strengths and Difficulties Questionnaire., Results: Parents of very preterm children reported significantly more behavioral problems, with a twofold higher prevalence compared with term children for hyperactivity/inattention, emotional symptoms, and peer problems. Behavioral problems were associated with low cognitive performance, developmental delay, hospitalizations of the child, young maternal age, and poor maternal mental well-being. Very preterm children were still at higher risk of behavioral problems compared with term children after adjustment for cognitive performance and all others factors., Conclusions: Behavioral problems were strongly related to cognitive impairment, but very preterm children were still at higher risk even after adjusting for cognitive performance. Early screening for behavioral problems should be encouraged for all very preterm children, and maternal well-being should also be the focus of special attention.

Premature newborns are particularly vulnerable to iatrogenic hypothyroidism due to iodine exposure, usually through skin absorption of iodine-containing disinfectants or intravenous administration of iodinated contrast agents. We report here a case of severe iatrogenic hypothyroidism with goiter and cholestasis, discovered six weeks after a contrast enema using sodium ioxitalamate, an iodinated contrast agent. Prematurity, intrauterine growth retardation, and enteral feeding intolerance could explain why this complication occurred after contrast enema. Our observations suggest that indications of contrast enema in neonates need to be carefully considered, and when necessary, thyroid function should be monitored, especially in very premature infants.

In a retrospective epidemiologic study conducted from January 1996 to December 2002, 2555 low-birth-weight infants (less than 2500 g) were admitted to the neonatal intensive care unit of E Herriot Hospital in Lyon, France. Very low birth weight (795 infants) was defined as a birth weight below 1500 g. The total mortality rate among these latter infants was 8%. The mortality rate was less than 25% among infants with a gestational age of at least 25 weeks. Neonatal morbidity mainly consisted of respiratory distress syndrome and cerebral hemorrhage. Sequelae at age 2 years (corrected) affected less than 10% of surviving in very-low-birth-weight infants. Gestational age is thus an important predictor of survival and functional outcome in very-low-birth-weight infants.