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International audience; BackgroundAntenatal betamethasone is recommended before preterm delivery to accelerate fetal lung maturation. However, reports of growth and neurodevelopmental dose-related side-effects suggest that the current dose (12 mg plus 12 mg, 24 h apart) might be too high. We therefore investigated whether a half dose would be non-inferior to the current full dose for preventing respiratory distress syndrome.MethodsWe designed a randomised, multicentre, double-blind, placebo-controlled, non-inferiority trial in 37 level 3 referral perinatal centres in France. Eligible participants were pregnant women aged 18 years or older with a singleton fetus at risk of preterm delivery and already treated with the first injection of antenatal betamethasone (11·4 mg) before 32 weeks’ gestation. We used a computer-generated code producing permuted blocks of varying sizes to randomly assign (1:1) women to receive either a placebo (half-dose group) or a second 11·4 mg betamethasone injection (full-dose group) 24 h later. Randomisation was stratified by gestational age (before or after 28 weeks). Participants, clinicians, and study staff were masked to the treatment allocation. The primary outcome was the need for exogenous intratracheal surfactant within 48 h after birth. Non-inferiority would be shown if the higher limit of the 95% CI for the between-group difference between the half-dose and full-dose groups in the primary endpoint was less than 4 percentage points (corresponding to a maximum relative risk of 1·20). Four interim analyses monitoring the primary and the secondary safety outcomes were done during the study period, using a sequential data analysis method that provided futility and non-inferiority stopping rules and checked for type I and II errors. Interim analyses were done in the intention-to-treat population. This trial was registered with ClinicalTrials.gov, NCT02897076.FindingsBetween Jan 2, 2017, and Oct 9, 2019, 3244 women were randomly assigned to the half-dose (n=1620 [49·9%]) or the full-dose group (n=1624 [50·1%]); 48 women withdrew consent, 30 fetuses were stillborn, 16 neonates were lost to follow-up, and 9 neonates died before evaluation, so that 3141 neonates remained for analysis. In the intention-to-treat analysis, the primary outcome occurred in 313 (20·0%) of 1567 neonates in the half-dose group and 276 (17·5%) of 1574 neonates in the full-dose group (risk difference 2·4%, 95% CI –0·3 to 5·2); thus non-inferiority was not shown. The per-protocol analysis also did not show non-inferiority (risk difference 2·2%, 95% CI –0·6 to 5·1). No between-group differences appeared in the rates of neonatal death, grade 3–4 intraventricular haemorrhage, stage ≥2 necrotising enterocolitis, severe retinopathy of prematurity, or bronchopulmonary dysplasia.InterpretationBecause non-inferiority of the half-dose compared with the full-dose regimen was not shown, our results do not support practice changes towards antenatal betamethasone dose reduction.

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.

Low weight in early infancy is a known risk factor for cardio-metabolic syndrome in adult life. However, little is known either about developmental programming in subjects of normal birthweight or about events between the ages which separate early programming and the occurrence of disease at late adulthood. We tested the hypothesis that circulating concentrations of leptin, adiponectin and insulin in young, healthy adults, born with a birth size within the normal range, are influenced by early life growth patterns. In an observational study of 188 healthy volunteers aged 18–25 years (97 males, 91 females) we investigated the association of metabolic function with their birth size, their growth during childhood and their body composition. High plasma leptin in early adulthood, a risk factor for cardio-metabolic syndrome, was associated with low weight at age 2 years (correlation coefficient controlled for adult weight = −0.21, P P

BackgroundVitamin D (VitD) is involved in lung development but its influence on respiratory distress syndrome of extremely preterm (EPT) infants have been little investigated. In this study, we examined the influence of low vitamin D status at birth on early respiratory outcomes of this vulnerable infant population.MethodsCord blood 25(OH)D levels ≤ 75 nmol/L were considered as Low vitamin D levels. Stepwise logistic regression and classification regression-tree analyses were used and the primary outcome was the combined outcome of death or mechanical ventilation need by the end of the first week (death or MV DoL7) as a marker od RDS severity.ResultsThe mean (SD) GA and birth weight were 26 (1.4) weeks and 801 (212) gr, respectively; 81/109 (74%) infants had low 25(OH)D levels. Infants with low VitD levels had 25% higher initial FiO2 levels (p < 0.05) and were more likely to be mechanically ventilated on DoL7 (36 vs. 7%, p < 0.05). Adjusted for gestational age, they had 10-fold higher odds of death or MV DoL7 (p < 0.01). By regression tree analysis, the rate of death or MV DoL7 increased from 18 to 71% in infants with GA < 26 weeks and with cord blood 25(OH)D levels higher and lower than 74 nmol/L, respectively (p < 0.05).ConclusionLow vitamin D levels at birth are associated with early adverse respiratory outcomes in infants with GA less 29 weeks. Further largest studies are needed to confirm this association.

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&ndash, 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 &minus, 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 &lt, 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&ndash, 0.82, p &lt, 0.001) and 0.54 (0.44&ndash, 0.67, 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.

International audience; ObjectiveTo determine whether neighbourhood socioeconomic status (SES) was associated with large for gestational age (LGA) while considering key sociodemographic and clinical confounding factors.Setting and patientAll singleton infants whose parents were living in the city of Marseilles, France, between 2013 and 2016.MethodPopulation-based study based on new-born hospital birth admission charts from the French National Uniform Hospital Discharge Data Set Database. LGA infants were compared to appropriate-for-gestational-age (AGA) infants. Multiple generalized logistic model analysis was used to examine factors associated with LGA.ResultsA total of 43,309 singleton infants were included, and 4,747 (11%) were born LGA. LGA infants were more likely to have metabolic and respiratory diseases and to be admitted to the neonatal intensive care unit. Multiparity, advanced maternal age, obesity and diabetes were associated with an increased risk of LGA. Lower neighbourhood SES was associated with LGA (aOR = 1.24, 95% CI: 1.14; 1.36; p 35 years old.ConclusionNeighbourhood SES could be considered an important factor for clinicians to better identify mothers at risk of having LGA births in addition to well-known risk factors such as maternal diabetes, obesity and age. The intensification of the association between SES and LGA with increasing maternal age suggests that neighbourhood disadvantage may act on LGA cumulatively over time.

Background: Cardiovascular and chronic kidney diseases are a part of non-communicable chronic diseases, the leading causes of premature death worldwide. They are recognized as having early origins through altered developmental programming, due to adverse environmental conditions during development. Preterm birth is such an adverse factor. Rates of preterm birth increased in the last decades, however, with the improvement in perinatal and neonatal care, a growing number of preterm born subjects has now entered adulthood. Clinical and experimental evidence suggests that preterm birth is associated with impaired or arrested structural or functional development of key or-gans/systems making preterm infants vulnerable to cardiovascular and chronic renal diseases at adult-hood. This review analyzes the evidence of such cardiovascular and renal changes, the role of perina-tal and neonatal factors such as antenatal steroids and potential pathogenic mechanisms, including de-velopmental programming and epigenetic alterations. Conclusion: Preterm born subjects are exposed to a significantly increased risk for altered cardio-vascular and renal functions at young adulthood. Adequate, specific follow-up measures remain to be determined. While antenatal steroids have considerably improved preterm birth outcomes, repeated therapy should be considered with caution, as antenatal steroids induce long-term cardio-vascular and metabolic alterations in animals’ models and their involvement in the accelerated cellular senescence observed in human studies cannot be excluded.

International audience; 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

Resume Introduction Les progres de la medecine perinatale ont permis la survie de nouveau-nes de plus en plus immatures. Cependant, l’extreme prematurite est a haut risque d’anomalies du developpement. Nous avons etudie le devenir neurocognitif a 3 ans d’une cohorte d’enfants nes avant 26 semaines d’amenorrhee (SA). Methode Il s’est agi d’une etude observationnelle descriptive d’une cohorte d’enfants nes entre 23 + 0 SA et 25 + 6 SA, dans la region Provence-Alpes-Cote-d’Azur (PACA) Ouest–Corse du Sud, entre 2007 et 2011. Les donnees du suivi du reseau d’aval « Naitre et devenir » ont permis de classer les enfants en trois groupes : absence de deficience, deficience intermediaire et deficience severe. A l’aide d’une regression logistique, nous avons recherche les facteurs perinatals predictifs d’un devenir favorable a 3 ans. Resultats Cent soixante-deux enfants avaient ete admis en neonatologie. Parmi les 101 survivants (62 %), 66 avaient effectue leur visite a 3 ans. Le taux de survie augmentait avec l’âge gestationnel : 33 % a 23 SA, 57 % a 24 SA et 68 % a 25 SA. Les caracteristiques perinatales des perdus de vue etaient comparables a celles des enfants suivis. Aucune deficience n’a ete depistee chez 56 % et une deficience severe etait presente chez 6 %. Une paralysie cerebrale etait presente chez 13 % des enfants. La faible duree de ventilation mecanique (odd ratio [OR] = 0,96 [0,93–0,99] ; p = 0,03) et la presence d’une corticotherapie antenatale complete (OR = 4,7 [1–7,7–17] ; p = 0,02) etaient associees a l’absence de deficience a 3 ans. Conclusion Ameliorer la prise en charge perinatale de ces nouveau-nes reste un enjeu majeur des equipes soignantes. L’evaluation neurocognitive doit se poursuivre jusqu’a la petite enfance afin de depister les troubles des apprentissages.

The consequences of early postpartum discharge (EPPD, within 2 days after birth) on newborn health remain debated. Early discharge has been associated with increased neonatal morbidity. However, neonatal re-hospitalization can be prevented by careful follow-up during the 1st week after birth. We compared the early neonatal hospitalization of term newborns over 2 years in two hospitals: Karolinska University Hospital in Stockholm (n=7300 births), which allowed early discharge from 6h after birth with specific neonatal follow-up, and Marseille University Hospital (AP-HM) (n=4385) where postpartum discharge was more conventional after 72 h. During the study period, the EPPD rate was 41% vs. 2% in Stockholm and Marseille, respectively (P

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.

The survival of preterm babies has increased over the last few decades. However, disorders associated with preterm birth, known as oxygen radical diseases of neonatology, such as retinopathy, bronchopulmonary dysplasia, periventricular leukomalacia, and necrotizing enterocolitis are severe complications related to oxidative stress, which can be defined by an imbalance between oxidative reactive species production and antioxidant defenses. Oxidative stress causes lipid, protein, and DNA damage. Preterm infants have decreased antioxidant defenses in response to oxidative challenges, because the physiologic increase of antioxidant capacity occurs at the end of gestation in preparation for the transition to extrauterine life. Therefore, preterm infants are more sensitive to neonatal oxidative stress, notably when supplemental oxygen is being delivered. Furthermore, despite recent advances in the management of neonatal respiratory distress syndrome, controversies persist concerning the oxygenation saturation targets that should be used in caring for preterm babies. Identification of adequate biomarkers of oxidative stress in preterm infants such as 8-iso-prostaglandin F2α, and adduction of malondialdehyde to hemoglobin is important to promote specific therapeutic approaches. At present, no therapeutic strategy has been validated as prevention or treatment against oxidative stress. Breastfeeding should be considered as the main measure to improve the antioxidant status of preterm infants. In the last few years, melatonin has emerged as a protective molecule against oxidative stress, with antioxidant and free-radical scavenger roles, in experimental and preliminary human studies, giving hope that it can be used in preterm infants in the near future.

International audience; 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.

International audience; Neonatal hypoxic-ischemic encephalopathy (NHIE) is a dramatic perinatal complication, associated with poor neurological prognosis despite neuroprotection by therapeutic hypothermia, in the absence of an available curative therapy. We evaluated and compared ready-to-use human umbilical cord blood cells (HUCBC) and bankable but allogeneic endothelial progenitors (ECFC) as cell therapy candidate for NHIE. We compared benefits of HUCBC and ECFC transplantation 48 hours after injury in male rat NHIE model, based on the Rice-Vannucci approach. Based on behavioral tests, immune-histological assessment and metabolic imaging of brain perfusion using single pho-ton emission computed tomography (SPECT), HUCBC, or ECFC administration provided equally early and sustained functional benefits, up to 8 weeks after injury. These results were associated with total normalization of injured hemisphere cerebral blood flow assessed by SPECT/CT imaging. In conclusion, even if ECFC represent an efficient candidate, HUCBC autologous criteria and easier availability make them the ideal candidate for hypoxic-ischemic cell therapy. STEM CELLS TRANSLATIONAL Neonatal hypoxic ischemic encephalopathy is a dramatic perinatal complication. Neurological and neurosensory sequelae are frequent in survivors, including motor or learning disabilities, cerebral palsy, or epilepsy. Facing the absence of effective curative therapy, many hopes have been credited in cell therapy strategies. Based on behavioral tests, immune-histological assessment and metabolic imaging of brain perfusion using single photon emission computed tomog-raphy, we report in this work that cell transplantation of both human umbilical cord blood cells and endothelial progenitors provided equally early and sustained functional benefits, up to adulthood.

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 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.

International audience; Objective: Preterm birth is associated with altered angiogenesis and with increased risk of cardiovascular dysfunction and hypertension at adulthood. We previously demonstrated that in preterm newborns circulating cord blood endothelial progenitor cells (ECFC), responsible for angio/vasculogenesis, are reduced in number and display altered angiogenic properties. Altered angiogenic function was associated with a decreased expression of pro-angiogenic genes, among which the AMOT gene which is a strong positive regulator of angiogenesis. Such dysregulation may be related to epigenetic factors. In this study we analyse the methylation profiling of the AMOT gene during development, through a comparative analysis of the cord blood ECFC of preterm newborns and their term counterpart.Methods: We used both cloning-sequencing and pyrosequencing experiments to perform a comparative analysis of the DNA methylation profile of the promoter CpG island of AMOT gene in the cord blood ECFC of 16 preterm newborns (28–35 weeks gestational age-GA) and 15 term newborns (>37 weeks GA).Results: Twenty nine clones (obtained from 2 term newborns) and forty clones (obtained from 3 preterm newborns) were sequenced. The AMOT gene methylation rate was significantly higher in preterm compared to term newborns (4.5% versus 2.5% respectively: χ2 = 3.84; P = 1.8 10−02). Bisulfite pyrosequencing identified four CpG dinucleotides with significantly higher methylation levels in preterm newborns. This CpG-targeted methylation significantly decreased with increasing gestational age.Conclusions: These findings highlight importance of pro-angiogenic AMOT gene methylation in ECFC, suggesting that epigenetic mechanisms may control the regulation of angiogenesis during development. Therefore they pave the way to specific short term and long term complications of preterm birth by altered angiogenesis.

The structural and functional development of the kidney is responsible for a significant impact on postnatal adaptation to extrauterine life. Prenatal or neonatal impairment of nephrogenesis may carry long term, lifelong consequences in terms of reduced nephron endowment, chronic kidney disease, and cardiovascular risks at adulthood. Intrauterine growth restriction, preterm birth, congenital renal, and urinary tract anomalies are for long widely incriminated. Neonatal administration of nephrotoxic drugs has been associated with short-term acute kidney injury and longer chronic kidney disease. This review attempts at offering a comprehensive understanding of the renal development, the neonatal renal transition to extrauterine life and subsequent maturation phase during early infancy. It also focuses on developmental and maturational changes that impact lifelong renal function and adult health.

The kidney is a major organ for drug elimination. The function of the neonatal kidney is markedly immature with a reduction of renal blood flow, of glomerular filtration and of active tubular secretion, even in healthy, term infants. Maturation of renal function in particular of glomerular filtration rate is gestational age and postnatal age-dependant. Moreover, many neonatal pathological conditions such as preterm birth, sepsis or perinatal asphyxia can also affect renal function. These developmental changes have a major impact on drug metabolism and elimination. Alterations in renal clearance can influence significantly both drugs efficacy and toxicity. Moreover, nephrogenesis is a still ongoing process in a number of premature infants before 36 wks postconceptional age. Drugs and toxic factors that may alter the constitution of the congenital nephron number endowment during this period may have long term consequences on arterial pressure and renal function at adulthood.

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.

The patency of the ductus arteriosus has ever been considered as a pathological situation in preterm infants and one likely cause of mortality and morbidity, including broncho-pulmonary dysplasia, necrotizing enterocolitis, intraventricular haemorrhage, retinopathy of prematurity. The incidence of patent ductus arteriosus is inversely proportional to gestational age and infants with the lowest gestational ages are the most exposed to the complications of prematurity. So, associations between patent ductus arteriosus and the other morbidities may not be causative and patent ductus arteriosus could be more a sign of immaturity and severity of disease than the cause of these problems. Non-steroidal anti-inflammatory agents, such as indomethacin or ibuprofen, have been shown to be effective in closing or preventing patent ductus arteriosus, with differences in side effects. However nearly all randomized controlled trials have been designed with the closure of the ductus arteriosus, not mortality or morbidity, as the main endpoint. Thus, evidence is still lacking on the eventual benefits for the patient of pharmacological or surgical intervention on PDA. Moreover, both ibuprofen and indomethacin efficacy seems markedly reduced in extremely low gestational age infants, who are the most likely to benefit from such intervention. The explanation of the reduced pharmacodymanic effect in such population is unclear; so far, studies using increased dosing of ibuprofen have failed to show a clear benefit. Prophylaxis with indomethacin or ibuprofen has failed to show sustained benefits on neurodevelopment at 2 years of age in low gestational age infants. New curative trials may aim at investigating the effects of early curative administration of ibuprofen, which has reduced side effects compared to indomethacin, on immature kidney function, on mortality and morbidity in very low gestational age infants, ideally with a combined endpoint such as survival in the absence of severe neurodevelopmental alteration at 2 years age. Despite an understandable reluctance given the historical background of systematic, therapeutic closure of ductus arteriosus in preterm infants, there are no definite ethical obstacles to a placebo-controlled design.

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 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

RESUME Les deux dernieres decennies nous ont montre que les maladies cardio-vasculaires et le diabete de type 2, mais aussi d’autres causes majeures de mortalite a l’âge adulte dans les pays industrialises, prennent leur origine au cours du developpement et de la croissance perinatals. La periode de la vie qui s’etend de la conception a la premiere enfance s’est revelee ainsi une periode unique de sensibilite, au cours de laquelle l’environnement cree une empreinte durable et contribue a programmer les principales fonctions physiologiques, le risque des principales maladies a l’âge adulte, et en fait la sante de chaque individu, la vie durant. L’exemple le plus souvent cite est l’association entre le faible poids de naissance, et le risque de deces par insuffisance coronarienne a l’âge adulte. Mais de nombreuses conditions nutritionnelles, pathologiques ou environnementales sont desormais reconnues comme influencant le risque de maladies aussi diverses que l’obesite, certaines formes de cancer, comme certains troubles psychiques. A travers le modele de la programmation precoce de l’hypertension arterielle, cette revue examinera les caracteristiques, remarqua-blement communes, des mecanismes physiologiques (en particulier renaux et vasculaires) et moleculaires mis en jeu ; le continuum de programmation entre le normal et le pathologique ; le role des facteurs nutritionnels precoces et secondaires ; les marqueurs precoces de risque auquel il peut etre fait appel. L’impact de ces constations en termes de sante publique est considerable a l’echelle globale, a un moment ou nombre de pays emergents sur le plan economique connaissent une forte croissance economique et ou un nombre important d’individus dans le monde connait une transition brutale d’environnement nutritionnel. Cependant, d’interessantes possibilites de prevention precoce, en agissant durant la periode peri-conceptionnelle, durant la grossesse, et sur la nutrition et les comportements des la premiere enfance se font jour.

Clinical trials are essential in neonates to evaluate scientifically the efficacy and safety of drugs. However, major specificities condition clinical research in human neonates. To review specific constraints to be taken into account in neonatal research studies. A review of the literature and contribution of authors’ opinions was carried out. 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.

Patency of the ductus arteriosus (PDA), a common complication of preterm birth, has been associated to increased risk for intraventricular cerebral hemorrhage, necrotizing enterocolitis, bronchopulmonary dysplasia and death. Consequently, prophylactic or curative treatment has been advocated before the critical left-to-right shunting occurs. A host of studies has shown that both pharmacological agents and surgical closure are effective in closing the ductus arteriosus in premature infants. Indomethacin has long been the drug of choice. However, renal and cerebral haemodynamic side effects have been frequently reported. Strategies to minimise adverse effects of indomethacin, such as the association with frusemide, dopamine or the use of low-dose prolonged treatment with indomethacin have failed or shown partial benefit. Other NSAIDs have been investigated. But either the profile of adverse effects was unfavourable, as in the case of mefenamic acid, or their efficacy was less than that of indomethacin for PDA closure. More recently, ibuprofen has been proposed for the treatment of PDA as it was shown to induce less adverse effects on cerebral blood flow, intestinal and renal hemodynamics, while retaining similar efficacy to indomethacin. However, since renal perfusion, GFR and diuresis in early neonatal life strongly depend on the vasodilator effects of PGs on the afferent glomerular arterioles, ibuprofen, as other COX-inhibitors may not be exempt of some renal undesirable effects. While numerous studies have shown that PDA is a risk factor associated with immaturity and with increased incidence of complications of preterm birth, including broncho-pulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis and death, there is little evidence that such association is causative. Moreover, still little evidence exists from even recent randomized controlled trials that the pharmacological closure of PDA benefits to premature infants in terms of clinically significant short-term or medium-term outcomes, beyond a positive effect on DA patency. The use of COX-inhibitors for the prophylaxis or closure of PDA during the first hours or days of life should thus be cautious and based on an individual evaluation of benefit and risk. There is need of a randomized, placebo-controlled trials designed to assess the benefits in terms of mortality and morbidity outcomes of an early, or even very early pharmacological closure of PDA in extremely low gestational age infants.

Various antenatal events impair nephrogenesis in humans as well as in several animal models. The consecutive low nephron endowment may contribute to an increased risk for cardiovascular and renal diseases in adulthood. However, little knowledge is available on the influence of the postnatal environment, especially nutrition, on nephrogenesis. Moreover, the consequences of early postnatal nutrition in late adulthood are not clear. We used a model of early postnatal overfeeding (OF) induced by reduction of litter size (3 pups/litter) in rats. Systolic blood pressure (SBP; plethysmography), glomerular filtration rate (clearance of creatinine), glomerular number and volume, and glomerulosclerosis were evaluated in 22-mo-old aging offspring. Early postnatal OF was associated with increased weight gain during the suckling period (+40%, P < 0.01) and a 20% increase in glomerular number ( P < 0.05). However, an increase in SBP at 12 mo by an average of 18 mmHg and an increase in proteinuria (2.6-fold) and glomerulosclerosis at 22 mo of age were observed in OF male offspring compared with controls. In conclusion, early postnatal OF in the rat enhances postnatal nephrogenesis, but elevated blood pressure and glomerulosclerosis are still observed in male adults. Factors other than glomerular number reduction are likely to contribute to the arterial hypertension induced by early postnatal OF.

In this study, low birth weight was induced in rats by feeding the dams with a low-protein diet during pregnancy. Kidneys from the fetuses at the end of gestation were collected and showed a reduction in overall and relative weight, in parallel with other tissues (heart and liver). This reduction was associated with a reduction in nephrons number. To better understand the molecular basis of this observation, a transcriptome analysis contrasting kidneys from control and protein-deprived rats was performed, using a platform based upon long isothermic oligonucleotides, strengthening the robustness of the results. We could identify over 1800 transcripts modified more than twice (772 induced and 1040 repressed). Genes of either category were automatically classified according to functional criteria, making it possible to bring to light a large cluster of genes involved in coagulation and complement cascades. The promoters of the most induced and most repressed genes were contrasted for their composition in putative transcription factor binding sites, suggesting an overrepresentation of the AP1R binding site, together with the transcription induction of factors actually binding to this site in the set of induced genes. The induction of coagulation cascades in the kidney of low-birth-weight rats provides a putative rationale for explaining thrombo-endothelial disorders also observed in intrauterine growth-restricted human newborns. These alterations in the kidneys have been reported as a probable cause for cardiovascular diseases in the adult.

International audience; 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.

The number of pregnant women and women of childbearing age who are receiving drugs is increasing. A variety of drugs are prescribed for either complications of pregnancy or maternal diseases that existed prior to the pregnancy. Such drugs cross the placental barrier, enter the fetal circulation and potentially alter fetal development, particularly the development of the kidneys. Increased incidences of intrauterine growth retardation and adverse renal effects have been reported. The fetus and the newborn infant may thus experience renal failure, varying from transient oligohydramnios to severe neonatal renal insufficiency leading to death. Such adverse effects may particularly occur when fetuses are exposed to NSAIDs, ACE inhibitors and specific angiotensin II receptor type 1 antagonists. In addition to functional adverse effects, in utero exposure to drugs may affect renal structure itself and produce renal congenital abnormalities, including cystic dysplasia, tubular dysgenesis, ischaemic damage and a reduced nephron number. Experimental studies raise the question of potential long-term adverse effects, including renal dysfunction and arterial hypertension in adulthood. Although neonatal data for many drugs are reassuring, such findings stress the importance of long-term follow-up of infants exposed in utero to certain drugs that have been administered to the mother.

Sartans are selective type 1 angiotensin II receptor-antagonists that are used in the treatment of arterial hypertension. Few reports are available concerning the use of sartans during pregnancy. We report two cases of adverse fetal outcome in hypertensive pregnancies exposed to sartans. In the first case, anamnios and fetal renal failure due to severe tubular dysgenesia led to termination of pregnancy in the 27th week. The second patient presented with hypocalvaria and developed fetal renal failure. The use of sartans during the two last trimesters of pregnancy should be strictly avoided.

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.

In the 1980s, David Barker and Colleagues proposed that the major causes of cardiovascular and metabolic diseases have their roots in early development. There is now robust evidence that an hyperglycemic intrauterine environment is responsible not only for significant short-term morbidity in the fetus and the neonate but also for an increased risk of developing diabetes as well as other chronic, noncommunicable diseases at adulthood. The risk is higher in pregestational diabetes, but unrecognized and/or poorly managed gestational diabetes (GDM) may have similar consequences. Although a relatively clear picture of the pathogenesis of the fetal and neonatal complications of maternal diabetes and of their interrelationship is available today, the intimate molecular mechanisms involved in the long term are far from being understood. While the rate of GDM is sharply increasing in association with the pandemic of obesity and of type 2 diabetes over the world, we review here the current understanding of short- and long-term outcomes of fetuses exposed to a diabetic environment.

Cardiovascular diseases are one of the leading causes of mortality. Hypertension (HT) is one of the principal risk factors associated with death. Chronic kidney disease (CKD), which is probably underestimated, increases the risk and the severity of adverse cardiovascular events. It is now recognized that low birth weight is a risk factor for these diseases, and this relationship is amplified by a rapid catch-up growth or overfeeding during infancy or childhood. The pathophysiological and molecular mechanisms involved in the “early programming” of CKD are multiple and partially understood. It has been proposed that the developmental programming of arterial hypertension and chronic kidney disease is related to a reduced nephron endowment. However, this mechanism is still discussed. This review discusses the complex relationship between birth weight and nephron endowment and how early growth and nutrition influence long term HT and CKD. We hypothesize that fetal environment reduces moderately the nephron number which appears insufficient by itself to induce long term diseases. Reduced nephron number constitutes a “factor of vulnerability” when additional factors, in particular a rapid postnatal growth or overfeeding, promote the early onset of diseases through a complex combination of various pathophysiological pathways.

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.

The definitive kidney, the methanephros, is formed by two processes, nephrogenesis (the formation of glomerulus and tubules) and branching morphogenesis (the formation of collecting ducts, calyces, pelvis and ureters). The metanephric kidney takes place after the formation and involution of two embryonic kidneys, the pronephros (non functional organ) and the mesonephros (first functional kidney), that in turn evolves into the ureteric bud (UB). The metanephros appears during the fifth gestational week, and develops from the specific interaction between the epithelial ureteric bud and the undifferentiated metanephric mesenchyme (MM). This interaction is crucial for the differentiation of the mesenchyme and the induction of UB branching division (Fig. 124.1). The UB arises in response to signals elaborated by the mesenchyme and then undergoes branching morphogenesis following the invasion of the MM by the UB. This process gives a 15 branch generation. At 20–22 weeks of gestation, branching morphogenesis is completed and results in the collecting system. Mesenchymal cells that are in close contact with the invading UB undergo an epithelial transformation. The induced metanephric mesenchyme (MM) gives the nephrons, through the consecutive stages of condensation, renal vesicule, vascular cleft, and S-shaped body. The glomerular capillary tuft is formed via recruitment and proliferation of endothelial and mesangial cells precursors. The nephrons develop in successive stages from the inner to the outer area of the fetal kidney in parallel with the vascular system. In the human, the primitive glomerulus appears at approximately 9–10 weeks of gestation. The nephrogenesis is completed by 34–36th weeks of gestation [1]. About 60% of the nephrons develop during the third trimester of gestation, while nephrogenesis may continue ex-utero in preterm infants [2]. Once nephrogenesis is complete, stroma cells differentiate into fibroblasts, pericytes and lymphocytes-like cells. At birth the final nephron number varies from 800,000 and 1 million per kidney. Such variation in nephron number is due to genetic factors and to the fetal environment [3]. Several genes and molecular pathways control the formation of the renal collecting system and nephrogenesis, such as transcriptional factors (PAX-2, WT1), growth factors (IGF, EGF, TGF), oncogenes, the extracellular matrix, and vascular factors (Table 124.1) [4]. These factors act at a specific time of kidney development especially when the UB interacts with the adjacent MM. Blockade of vascular endothelial growth factor receptor (VEGF-R), inhibition of the renin angiotensin system (RAS) and knock-out for cyclooxigenase (COX)-2 gene expression are associated with impaired nephrogenesis including glomerular cysts, dysplasic tubules and tubular dysgenesis [5, 6, 7].