Early postnatal nutrition and renal consequences in preterm infants.

Perinatal nutritional factors may lead to decreased nephron endowment, decreased kidney function, and long-term development of chronic kidney disease and non-communicable diseases. At the same time, optimal postnatal nutrition and catch-up growth are associated with better neurodevelopmental outcomes in preterm infants. Therefore, nutritional management of preterm infants is a major challenge for neonatologists. In this context, the Section of Nutrition, Gastroenterology and Metabolism reviewed the current knowledge on nutritional issues related to kidney function. This narrative review discusses the clinical impact of early postnatal nutrition on long-term kidney function. In preterm infants, data are largely lacking to determine the extent to which early nutrition contributes to nephrogenesis and nephron endowment. However, some nutritional principles may help clinicians better protect the developing kidney in preterm infants. IMPACT: Clinical data show that preterm infants are an emerging population at high risk for chronic kidney disease. Both undernutrition and overnutrition can alter long-term kidney function. In preterm infants, data are largely lacking to determine the extent to which early postnatal nutrition contributes to nephrogenesis, nephron endowment and increased risk for chronic kidney disease. Some nutritional principles may help clinicians better protect the developing kidney in preterm infants: avoiding extrauterine growth restriction; providing adequate protein and caloric intakes; limiting exposure to high and prolonged hyperglycaemia; avoiding micronutrient deficiencies and maintaining acid-base and electrolyte balance.

Relationship between large and small for gestational age and hospital readmission after postpartum discharge: a population-based, data-linkage study.

This study aims to determine the association of small for gestational age (SGA) and large for gestational age (LGA) at birth with hospital readmission after postpartum discharge for up to 28 days of delivery. This is a population-based, data-linkage study using the French National Uniform Hospital Discharge Database. "Healthy" singleton term infants born between January 1st, 2017, and November 30th, 2018, in the French South region were included. SGA and LGA were defined as birth weight < 10th and > 90th percentiles, respectively, according to sex and gestational age. A multivariable regression analysis was performed. Among 67,359 included infants, 2441 (3.6%) were readmitted, and 61% of them were hospitalized within 14 days postpartum. Hospitalized infants were more likely to be LGA at birth (10.3% vs. 8.6% in non-hospitalized infants, p < 0.01); the proportion of SGA infants did not differ between both groups. Compared to appropriate birth weight for GA (AGA) infants, LGA infants were more often hospitalized for infectious diseases (57.7% vs. 51.3%, p = 0.05). After regression analysis, LGA infants had a 20% higher odds of being hospitalized than those born AGA (aOR (95%CI) = 1.21 (1.06-1.39)), while aOR (95%CI) for SGA was 1.11 (0.96-1.28). CONCLUSION:  In contrast to SGA, LGA was associated with hospital readmission during the first month of life. Follow-up protocols that include LGA should be evaluated. WHAT IS KNOWN: • Newborns are at high risk of hospital readmission during the postpartum period. • However, the influence of appropriateness for gestational age at birth, i.e. being born small for gestational age (SGA) or large for gestational age (LGA), has been little evaluated. WHAT IS NEW: • In contrast to SGA born infants, we found that infants born LGA were at high risk of hospital admission and the main cause was infectious diseases. • This population should be considered at risk of early adverse outcomes and should require attentive medical follow-up after postpartum discharge.

Neighborhood Disadvantage and Early Respiratory Outcomes in Very Preterm Infants with Bronchopulmonary Dysplasia.

OBJECTIVE: To investigate the impact of neighborhood conditions on respiratory-related hospital admissions in the first year after discharge from the neonatal unit in a population of infants born very preterm with bronchopulmonary dysplasia (BPD). STUDY DESIGN: Very preterm infants (gestational age <33 weeks) who had BPD at 36 weeks postconceptional age and who received follow-up in a French regional medical network were included. Socioeconomic context was estimated using a neighborhood-based Socioeconomic Deprivation Index. Poisson regression analysis was used to identify risk factors associated with rehospitalization. RESULTS: The study included 423 infants with a mean gestational age of 27 ± 2 weeks and mean birth weight of 941 ± 277 g; 51% of the population lived in a disadvantaged area. The hospital admission rate was increased by 8.8% for infants living in affluent areas and by 24% for those living in disadvantaged areas (P <.01) and reached 30% in extremely preterm infants from disadvantaged areas. After adjusting for perinatal characteristics, home oxygen therapy, and season of birth, the respiratory-related hospitalization rate was almost 3-fold higher in infants living in disadvantaged areas, with an adjusted incidence rate ratio of 2.79 (95% CI, 1.29-6.09; P <.01). CONCLUSIONS: Disadvantaged neighborhoods adversely impact early respiratory outcomes in infants born very preterm with BPD. The social context should be considered in routine follow-up care of children born preterm. Further studies investigating the underlying mechanisms are warranted for implementing preventive strategies.

Arginase upregulation and eNOS uncoupling contribute to impaired endothelium-dependent vasodilation in a rat model of intrauterine growth restriction.

Individuals born after intrauterine growth restriction (IUGR) are at increased risk of developing cardiovascular diseases in adulthood, notably hypertension (HTN). Alterations in the vascular system, particularly impaired endothelium-dependent vasodilation, may play an important role in long-term effects of IUGR. Whether such vascular dysfunction precedes HTN has not been fully established in individuals born after IUGR. Moreover, the intimate mechanisms of altered endothelium-dependent vasodilation remain incompletely elucidated. We therefore investigated, using a rat model of IUGR, whether impaired endothelium-dependent relaxation precedes the development of HTN and whether key components of the l-arginine-nitric oxide (NO) pathway are involved in its pathogenesis. Pregnant rats were fed with a control (CTRL, 23% casein) or low-protein diet (LPD, 9% casein) to induce IUGR. Systolic blood pressure (SBP) was measured by tail-cuff plethysmography in 5- and 8-wk-old male offspring. Aortic rings were isolated to investigate relaxation to acetylcholine, NO production, endothelial NO synthase (eNOS) protein content, arginase activity, and superoxide anion production. SBP was not different at 5 wk but significantly increased in 8-wk-old offspring of maternal LPD (LP) versus CTRL offspring. In 5-wk-old LP versus CTRL males, endothelium-dependent vasorelaxation was significantly impaired but restored by preincubation with l-arginine or the arginase inhibitor S-(2-boronoethyl)-l-cysteine; NO production was significantly reduced but restored by l-arginine pretreatment; total eNOS protein, dimer-to-monomer ratio, and arginase activity were significantly increased; superoxide anion production was significantly enhanced but normalized by pretreatment with the NO synthase inhibitor Nω-nitro-l-arginine. In this model, IUGR leads to early-impaired endothelium-dependent vasorelaxation, resulting from arginase upregulation and eNOS uncoupling, which precedes the development of HTN.

Influence of Socioeconomic Context on the Rehospitalization Rates of Infants Born Preterm.

OBJECTIVE: To investigate the impact of social inequalities on the risk of rehospitalization in the first year after discharge from the neonatal unit in a population of preterm-born children. STUDY DESIGN: Preterm infants were included if they were born between 2006 and 2013 at ≤32 + 6 weeks of gestation and who received follow-up in a French regional medical network with a high level of healthcare. Socioeconomic context was estimated using a neighborhood-based socioeconomic deprivation index. Univariate and logistic regression analyses were used to identify risk factors associated with rehospitalization. RESULTS: For the 2325 children, the mean gestational age was 29 ± 2 weeks and the mean birth weight was 1315 ± 395 g. In the first year, 22% were rehospitalized (n = 589); respiratory diseases were the primary cause (44%). The multiple rehospitalization rate was 18%. Multivariable analysis showed that living in the most deprived neighborhoods (socioeconomic deprivation index of 5) was associated with overall rehospitalization (OR, 2.2; 95% CI, 1.5-3.6; P <.001), and multiple rehospitalizations (OR, 2.5; 95% CI, 1.2-4.9; P <.01); with socioeconomic deprivation index of 1 (least deprived) as reference. Deprivation was associated with all causes of hospitalization. Female sex (P <.001) and living in an urban area (P = .001) were protective factors. CONCLUSIONS: Despite regional routine follow-up for all children, rehospitalization after very preterm birth was higher for children living in deprived neighborhoods. Families' social circumstances need to be considered when evaluating the health consequences of very preterm birth.

A Quality Improvement Initiative to Reduce the Need for Mechanical Ventilation in Extremely Low Gestational Age Neonates.

Objective Limiting early intubation and mechanical ventilation in extremely low gestational age neonates (ELGAN) may decrease neonatal morbidity and mortality. The aim of our study was to demonstrate the feasibility, efficacy, and tolerability of a delivery room respiratory management protocol, including delayed umbilical cord clamping (DUCC) in combination with optimized nCPAP with high PEEP levels and less invasive surfactant administration (LISA). Study Design This cohort quality improvement study analyzed the respiratory and neonatal outcomes of all consecutive infants born between 24+0 and 26+6 weeks' gestation before (period 1, n = 40) and after (period 2, n = 52) implementing the new protocol. Results Compared with the period 1 infants, the period 2 infants had a lower rate of intubation in the delivery room (31 vs. 90%, p = 0.001) and were less likely to need mechanical ventilation on day 3 (28 vs. 62%, p = 0.002) and during the hospital stay (75 vs. 92.5%, p < 0.05). The two groups did not differ in terms of mortality or neonatal morbidity. Conclusion A delivery room respiratory management protocol based on DUCC, optimized nCPAP with high PEEP levels, and LISA procedure is both feasible and safe, and improved ELGAN respiratory outcomes.

The magnitude of nephron number reduction mediates intrauterine growth-restriction-induced long term chronic renal disease in the rat. A comparative study in two experimental models.

BACKGROUND: Intrauterine growth restriction (IUGR) is a risk factor for hypertension (HT) and chronic renal disease (CRD). A reduction in the nephron number is proposed to be the underlying mechanism; however, the mechanism is debated. The aim of this study was to demonstrate that IUGR-induced HT and CRD are linked to the magnitude of nephron number reduction, independently on its cause. METHODS: Systolic blood pressure (SBP), glomerular filtration rate (GFR), proteinuria, nephron number, and glomerular sclerosis were compared between IUGR offspring prenatally exposed to a maternal low-protein diet (9% casein; LPD offspring) or maternal administration of betamethasone (from E17 to E19; BET offspring) and offspring with a normal birth weight (NBW offspring). RESULTS: Both prenatal interventions led to IUGR and a similar reduction in birth weight. In comparison to NBW offspring, BET offspring had a severe nephron deficit (-50% in males and -40% in females, p < 0.01), an impaired GFR (-33%, p < 0.05), and HT (SBP+ 17 mmHg, p < 0.05). Glomerular sclerosis was more than twofold higher in BET offspring than in NBW offspring (p < 0.05). Long-term SBP, GFR, and glomerular sclerosis were unchanged in LPD offspring while the nephron number was moderately reduced only in males (-28% vs. NBW offspring, p < 0.05). CONCLUSION: In this study, the magnitude of nephron number reduction influences long term renal disease in IUGR offspring: a moderate nephron number is an insufficient factor. Extremely long-term follow-up of adults prenatally exposed to glucocorticoids are required.

High protein intake in neonatal period induces glomerular hypertrophy and sclerosis in adulthood in rats born with IUGR.

BACKGROUND: Intrauterine growth restriction (IUGR) and postnatal nutrition are risk factors for cardiovascular and renal diseases in both humans and animals. The long-term renal effects of protein intake early in life remain unknown. The objective was to evaluate the effects of a neonatal feeding with high protein (HP) milk on renal functions and structure in IUGR male rats. METHODS: Maternal gestational low protein diet was used to produce IUGR. At day 5, IUGR pups were gastrostomized in the "pup-in-the cup" model and received either normal protein (NP) milk or HP (+50% protein content) milk until day 21. After weaning, the animals were fed the same standard diet. Renal functions and structure were assessed at postnatal day 18 (D18) and in adult offspring. RESULTS: During the preweaning period, the postnatal weight gain between the two groups was unaffected. On D18, kidneys from HP offspring were heavier with significant glomerular hypertrophy (+40%, P < 0.05). HP diet was associated with significant proteinuria and glomerulosclerosis (+49%, P < 0.05). Glomerular number was unaltered. CONCLUSION: Neonatal HP feeding following IUGR affects renal functions and structure at adulthood. These alterations may result from a single nephron glomerular hyperfiltration.

Biological Impact of Recent Guidelines on Parenteral Nutrition in Preterm Infants.

OBJECTIVES: Recent guidelines for preterm neonates recommend early initiation of parenteral nutrition (PN) with high protein and relatively high caloric intake. This review considers whether these changes could influence homeostasis in very preterm infants during the first few postnatal weeks. METHODS: This systematic review of relevant literature from searches of PubMed and recent guidelines was reviewed by investigators from several perinatal centers in France. RESULTS: New recommendations for PN could be associated with metabolic acidosis via the increase in the amino acid ion gap, hyperchloremic acidosis, and ammonia acidosis. The introduction of high-intake amino acids soon after birth could induce hypophosphatemia and hypercalcemia, simulating a "repeat feeding-like syndrome" and could be prevented by the early intake of phosphorus, especially in preterm infants born after fetal growth restriction. Early high-dose amino acid infusions are relatively well tolerated in the preterm infant with regard to renal function. Additional studies, however, are warranted to determine markers of protein intolerance and to specify the optimal composition and amount of amino acid solutions. CONCLUSIONS: Optimal PN following new guidelines in very preterm infants, despite their demonstrated benefits on growth, may induce adverse effects on ionic homeostasis. Clinicians should implement appropriate monitoring to prevent and/or correct them.

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.

Association of Maternal Gestational Vitamin D Supplementation with Respiratory Health of Young Children.

This study aimed to evaluate the association between maternal gestational Vitamin D3 supplementation and early respiratory health in offspring. This was a population-based record-linkage study which used data from the French National Health Database System. Maternal Vitamin D3 supplementation consisted of a single high oral dose of cholecalciferol, (100,000 IU) from the seventh month of pregnancy, according to national guidelines. In total, 125,756 term-born singleton children were included, of which 37% had respiratory illness defined as hospital admission due to respiratory causes or inhalation treatment up to 24 months of age. Infants prenatally exposed to maternal Vitamin D3 supplementation (n = 54,596) were more likely to have a longer gestational age (GA) at birth (GA 36-38 weeks, 22% vs. 20%, p < 0.001 in exposed vs. non-exposed infants, respectively). After adjusting for the main risk factors (maternal age, socioeconomic level, mode of delivery, obstetrical and neonatal pathology, birth weight appropriateness, sex, and birth season), the risk of RD was found to be 3% lower than their counterparts (aOR [IC 95%], 0.97 [0.95-0.99], p = 0.01). In conclusion, this study provides evidence for the association between maternal gestational Vitamin D3 supplementation and improved early respiratory outcomes in young children.

Impact of cardiac surgical timing on the neurodevelopmental outcomes of newborns with Complex congenital heart disease (CHD).

Background: More than half of infants with complex congenital heart disease (CHD) will have a neurodevelopmental disorder of multifactorial causes. The preoperative period represents a time-window during which neonates with complex CHD are in a state of hypoxia and hemodynamic instability, which fosters the emergence of brain injuries and, thus, affects early brain networks and neurodevelopmental outcomes. Currently, there is no consensus regarding the optimal age for cardiac surgery in terms of neurodevelopmental outcomes, and its definition is a real challenge. Our aim is to determine the relationship between cardiac surgical timing and long-term neurodevelopmental outcomes for various types of complex CHD. Methods: We hypothesize that earlier surgical timing could represent a neuroprotective strategy that reduces perioperative white matter injuries (WMIs) and postoperative morbidity, leading to improved neurodevelopmental outcomes in infants with complex CHD. Firstly, our prospective study will allow us to determine the correlation between age at the time of surgery (days of life) and neurodevelopmental outcomes at 24 months. We will then analyze the correlation between age at surgery and (i) the incidence of WMIs (through pre- and postoperative MRIs), (ii) postoperative morbidity, and (iii) the duration of the hospital stay. Implications and Dissemination: This research protocol was registered in the Clinical Trial Registry (National Clinical Trial: NCT04733378). This project aims to help launch the first Neurocardiac Investigation Clinic in Marseille - AP-HM - to propose an overall personalized monitoring and treatment program for patients operated on for complex CHD.

Echocardiography as a guide for patent ductus arteriosus ibuprofen treatment and efficacy prediction.

OBJECTIVE: To evaluate echocardiography criteria in predicting the response to ibuprofen treatment. DESIGN: A prospective cohort study of preterm infants untreated or treated with ibuprofen for patent ductus arteriosus. SETTING: Three academic neonatal intensive care units. PATIENTS: Two hundred fifty-two preterm infants of 27-31 wks gestation. INTERVENTIONS: Ibuprofen treatment within the first 5 days of life was indicated when at least two out of four conventional echocardiography criteria were observed: ductal diameter >2 mm, left-right ductal shunt maximum velocity <2 m/sec, mean flow velocity in left pulmonary artery >0.4 m/sec, and end-diastolic flow velocity in left pulmonary artery >0.2 m/sec. MEASUREMENTS AND MAIN RESULTS: Of the infants analyzed, 135 had a closed ductus at an average age of 1.9 ± 0.9 days, and 43 had an open ductus but <2 predefined criteria. Seventy-four infants (29%) received ibuprofen on day 2.2 ± 1.1. Sixteen infants failed ibuprofen and nine had to undergo surgical ligation. The left-right ductal shunt maximum velocity criterion had the best negative predictive value for treatment response, while the ductal diameter criterion had the best positive predictive value. CONCLUSIONS: Echocardiography may be a useful tool to help patent ductus arteriosus management. A combined use of ductal diameter and left-right ductal shunt maximum velocity criteria allows a more accurate prediction of the response of infants with patent ductus arteriosus to ibuprofen treatment.

Clinical research in newborn infants: difficulties and specificity.

BACKGROUND: Clinical trials are essential in neonates to evaluate scientifically the efficacy and safety of drugs. However, major specificities condition clinical research in human neonates. OBJECTIVE: To review specific constraints to be taken into account in neonatal research studies. METHODS: A review of the literature and contribution of authors' opinions was carried out. RESULTS AND CONCLUSION: Neonatal specificities that induce obstacles in neonatal studies and proposals are detailed. This review also looks at recommendations recently developed by the European Commission to promote safe and ethical research in neonatology.

Adverse consequences of accelerated neonatal growth: cardiovascular and renal issues.

Epidemiological and experimental studies show that the risk of cardiovascular and metabolic diseases at adulthood is inversely related to the weight at birth. Although with less evidence, low birth weight has been suggested to increase the risk of chronic kidney disease (CKD). It is well established that the developmental programming of arterial hypertension and of renal disease involves in particular renal factors, especially nephron endowment, which is reduced in low birth weight and maternal diabetes situations. Experimental studies, especially in rodents, have demonstrated the long-term influence of postnatal nutrition and/or postnatal growth on cardiovascular, metabolic and renal functions, while human data are scarce on this issue. Vascular and renal diseases appear to have a "multihits" origin, with reduced nephron number the initial hit and rapid postnatal growth the second hit. This review addresses the current understanding of the role of the kidney, both as a mechanism and as a target, in the developmental origins of adult disease theory, with a particular focus on the long-term effects of postnatal growth and nutrition.

[Early origins of arterial hypertension and cardiovascular diseases]. / Les origines précoces de l'hypertension artérielle et des maladies cardio-vasculaires.

Research has shown that most of the principal causes of mortality in industrialized countries have their roots in early development. Thus, the period from conception through pregnancy to early infancy is uniquely sensitive to long-lasting effects of environmental insults, potentially leading to physiological malprogramming and lifelong disease. Beyond the classical association between low birth weight and increased coronary mortality in adulthood, peri-conceptional and perinatal insults can set the scene for later obesity, cancer and behavioral disorders. Taking the developmental programming of hypertension as an example, this review addresses the remarkably similar mechanisms of early programming, particularly those involving the kidney and vasculature ; the continuum between normality and disease ; the role of early and later nutrition ; and early biomarkers and epigenetic mechanisms of later cardiovascular and metabolic disorders. The developmental origins of adult health and disease represent a global research challenge as emerging countries undergo major nutritional and environmental upheavals. Much research is focused on the benefits of early nutritional and lifestyle interventions, in both animal models and human studies.

Case Report: Clostridium neonatale Bacteremia in a Preterm Neonate With Necrotizing Enterocolitis.

Necrotizing enterocolitis is a life-threatening acquired gastrointestinal disorder among preterm neonates and is associated with a high mortality rate and long-term neurodevelopmental morbidity. No etiologic agent has been definitively established; nonetheless, the most implicated bacteria include members of the Clostridium genus. We reported here on a case of Clostridium neonatale bacteremia in a preterm neonate with necrotizing enterocolitis, providing more information regarding the potential role of this bacterium in pathogenesis of necrotizing enterocolitis. We emphasized the sporulating form of C. neonatale that confers resistance to disinfectants usually applied for the hospital environmental cleaning. Further works are needed to establish the causal relationship between the occurrence of NEC and the isolation of C. neonatale, with promising perspectives in terms of diagnostic and therapeutic management.

Association of First-Week Nutrient Intake and Extrauterine Growth Restriction in Moderately Preterm Infants: A Regional Population-Based Study.

The purpose of this study was to determine the influence of first-week nutrition intake on neonatal growth in moderate preterm (MP) infants. Data on neonatal morbidity and nutrition intake on day of life 7 (DoL7) were prospectively collected from 735 MP infants (320/7-346/7 weeks gestational age (GA)). Multivariable regression was used to assess the factors associated with extrauterine growth restriction (EUGR) defined as a decrease of more than 1 standard deviation (SD) in the weight z-score during hospitalization. Mean (SD) gestational age and birth weight were 33.2 (0.8) weeks and 2005 (369) g. The mean change in the weight z-score during hospitalization was -0.64 SD. A total of 138 infants (18.8%) had EUGR. Compared to adequate growth infants, EUGR infants received 15% and 35% lower total energy and protein intake respectively (p < 0.001) at DoL7. At DoL7, each increase of 10 kcal/kg/d and 1 g/kg/d of protein was associated with reduced odds of EUGR with an odds ratio of 0.73 (95% CI, 0.66-0.82; p < 0.001) and 0.54 (0.44-0.67; p < 0.001), respectively. Insufficient energy and protein intakes on DoL7 negatively affected neonatal growth of MP infants. Nutritional support should be optimized from birth onwards to improve neonatal weight growth.