Protein intakes and their nutritional sources during the first 2 years of life: secondary data evaluation from the European Childhood Obesity Project.

BACKGROUND/OBJECTIVES: High protein intake in infancy affects future obesity risk and other health outcomes. We aim to describe total protein intake and its sources in a birth cohort in five European countries over the first 2 years of life. SUBJECTS/METHODS: A total of 746 formula-fed infants were included. Three-day weighed dietary records at 6, 7, 8, 9, 12, 18 and 24 months of age were used. Kruskal-Wallis, ANOVA and Friedman's tests were used to assess possible differences in nutritional intake among countries and over time. RESULTS: Dairy products were the main components of the infants' diets. Cow's milk was rarely introduced before 12 months of age, whereas infants' formula was the main contributor of protein intake. Food choices and protein intake differed among countries (P<0.001). Protein intake often exceeded European recommendations from 9 months onwards, partly because of the substitution of dairy protein (mainly infant formula) by meat protein. Two nutritional patterns were identified that were characterised by differences in energy, fat, protein and animal protein intake. Finally, food consumption was not always in line with protein intakes, and thus infants from some countries showed high consumption of specific food groups but relatively low protein intakes. CONCLUSIONS: During weaning, over-limited substitution of dairy products with other sources (especially meat) resulted in relatively high protein intakes in formula-fed infants. Differences in preferences of specific protein sources from complementary foods existed among European countries. Great opportunities in improving early nutrition were revealed, although cultural and geographical differences should always be considered.

Possible effects of repeated exposure to ibuprofen and acetaminophen on the intestinal immune response in young infants.

There has been an exponential increase in the frequency of immune deviations in young children. Consequently, research investigating environmental causes for this increase has become a Public Health priority. We have summarized the experimental observations and epidemiological data that could link repeated acetaminophen and ibuprofen exposure in early infancy to this increase. Recent observations on the maturational immunity of the intestinal sub-mucosal lamina propria underscore indeed the importance of prostaglandins (PGE2s). PGE2 appearing at this sub-mucosal level is a product of arachidonic acid metabolism mediated by type-2 cyclooxygenase (COX-2) situated on the membrane of many immune cells. Moreover, it seems that acetaminophen - like ibuprofen - also carries a non-selective inhibitory action on peripheral COXs, besides its central action. This inhibitory action of acetaminophen on COX2 only relates to physiological, low arachidonic acid concentrations. This explains the difference in anti-inflammatory effects. The impact of repeated inhibition of mucosal PGE2 synthesis due to COX-inhibitor exposure on maturational immunity has been demonstrated in animal experiments. Repeatedly exposed young animals do not develop tolerance to food antigens and exhibit autoimmune deviations. Several recent epidemiological studies have also reported on the magnitude of acetaminophen and ibuprofen exposure in children and the increase in immune deviations, it is important to better understand the potential negative impact of repeated inhibitions of prostaglandin synthesis by COX2s during infancy. Since acetaminophen and ibuprofen are commonly administered analgesics and antipyretics, a well-designed prospective strategy for pharmacovigilance and -epidemiology of COX-inhibitor exposure in infancy is urgently needed.

[Paracetamol (acetaminophen) use in neonatology: a (re)appreciation of an old drug]. / Utilisation du paracétamol (acétaminophène) en néonatologie : (re)découverte d'un ancien principe actif.

In neonates, paracetamol is mainly used for its analgesic action. This drug is actually preferred by neonatologists because of its broad therapeutic index. Recently, it has been demonstrated that paracetamol is also an anti-cyclooxygenase (COX) medication through its inhibitory action on the peroxidase arm of central and peripheral COX (Boutaud et al., 2002; Toussaint et al., 2010; Graham et al., 2013; Hinz et al., 2008; Hinz and Brune, 2011). As such, this drug interferes with the synthesis of prostaglandins. This inhibition of peroxidase is, however, limited to a low concentration of arachidonic acid (AA) (around 2µM, in vitro) when the plasmatic concentration of paracetamol is experimentally 10µM, actually within the same range as compared to the therapeutic concentrations in vivo. This may partly explain its low anti-inflammatory effect as compared to ibuprofen and indomethacin, which exert their inhibition on COX whatever the AA concentrations are. This new well-demonstrated action of paracetamol on peripheral COX-2 of intact cells could explain recent observations making this drug a potential alternative in treating patent ductus arteriosus. However, the higher dosages that have been claimed by some authors in this indication still remain to be validated. This inhibition that paracetamol shows on the physiological synthesis of prostaglandins E2 (PGE2) could also explain some long-term immune deviations because the physiological concentration of PGE2 is a well-known actor in the genesis of immune homeostasis in the submucosal area. Indeed, recent epidemiology studies have pointed out immune deviations in children repeatedly exposed to paracetamol earlier in life. Consequently, this is actually the new discovery of an old drug. From these new data on paracetamol, a more focused pharmacovigilance on the long-term effects of paracetamol repeatedly given in the early stage should be urgently initiated.

[Prostaglandins and the immune response at the intestinal submucosal level. A potential site for interference with the repeated use of paracetamol and ibuprofen at a young age?]. / Les prostaglandines et l'immunité du chorion sous-muqueux intestinal. Questions à propos de l'usage répété du paracétamol et de l'ibuprofène en bas âge.

Immune deviations have been shown to exponentially increase in young children. As a consequence, research investigating possible environmental reasons for this increase is considered a public health priority. An improved understanding of the immunity of the intestinal submucosal lamina propria has demonstrated the importance of prostaglandins (PGE2s) on its local development with general immune consequences further on. PGE2s appear at this intestinal submucosal level from the metabolism of arachidonic acid mediated by type-2 cyclooxygenases (COX2s) situated in the membranes of many immune cells. The potential risk of repeated inhibition of PGE2 synthesis at a young age has been demonstrated in experiments with animals systemically exposed to a non-steroidal anti-inflammatory drug (NSAID). The repeatedly exposed animal cannot develop tolerance to food antigens and exhibits autoimmune deviations. Acetaminophen (paracetamol) and ibuprofen are analgesic and antipyretic medications given to children either alone or in combination, most often without medical prescription. Recently, it has been demonstrated that paracetamol, like ibuprofen, also carries, besides its central action, a non-selective inhibitory action on peripheral COXs. However, this inhibitory action only relates to physiological concentrations of arachidonic acid and explains the difference in their respective anti-inflammatory effects. Since recently published data have repeatedly reported an increase of immune deviations associated with paracetamol exposure at a young age, it appears important to better understand the possible negative impact of excessive and repetitive inhibitions of the physiological synthesis of prostaglandins by COX2s in childhood during which all immune mechanisms are built up at the intestinal submucosal level. Therefore, a well-designed prospective strategy for pharmacovigilance of these COX inhibitors repeatedly given during childhood is urgently needed.

[Use of therapeutic hypothermia in sudden unexpected postnatal collapse]. / Malaise grave inopiné du nouveau-né à terme : une place possible pour l'hypothermie thérapeutique.

Sudden postnatal collapse of a full-term newborn is uncommon but may result in severe consequences: these include death; epilepsy; and motor, cognitive, or sensory impairment. Most authors suggest applying a therapeutic hypothermia approach when a previously healthy newborn develops moderate or severe encephalopathy after a sudden postnatal collapse occurring within the first hours or days after birth. However, this technique has still not been validated by randomized trials. Only a few cases have been reported in the literature. This article describes five apparently healthy newborns, born between 2007 and 2012, who suffered moderate to severe encephalopathy following a postnatal collapse on their first day of life. It describes their clinical history as well as their treatment and follow-up. The article focuses on the implementation of hypothermia in this indication and its limitations. Two newborns underwent classic therapeutic hypothermia, two others underwent temperature regulation (one at 34.5 °C, the other one for only 15 h because she quickly improved). One newborn, with severe pulmonary arterial hypertension, did not receive therapeutic hypothermia. Two newborns died (one had classic hypothermia and the other hypothermia at 34.5 °C), the outcome of the three survivors at three years, 18 months, and 15 months is good with only transient postural anomalies. Follow-up must be continued to assess their cognitive development and particularly their memorization processes. Additional research and centralization of the cases is required to evaluate the feasibility, safety, and benefits of therapeutic hypothermia in this situation.

Management of the neonate at risk for early-onset Group B streptococcal disease (GBS EOD): new paediatric guidelines in Belgium.

Despite group B streptococcal (GBS) screening in late pregnancy and intrapartum antimicrobial prophylaxis, early-onset sepsis in neonates remains a common source of neonatal morbidity and mortality especially in preterm neonates. The identification of neonates with early-onset sepsis is usually based on perinatal risk factors. Clinical signs are aspecific and laboratory tests are not sensitive. Therefore, many clinicians will overtreat at-risk infants. Inappropriate treatment with antibiotics increases the risk for late-onset sepsis, necrotizing enterocolitis, mortality, and prolongs hospitalisation and costs. In 2003, the Belgian Health Council published guidelines for the prevention of perinatal GBS infections. This report presents the Belgian paediatric management guidelines, which have been endorsed by the Belgian and Flemish societies of neonatology and paediatrics. The most imported changes in the 2014 guidelines are the following: recommendations for a lumbar puncture; clarification of normal spinal fluid parameters and blood neutrophil indices corrected for gestation age; specific timing for diagnostic testing after birth; no indication for diagnostic testing in asymptomatic newborns unless additional risk factors; a revised algorithm for management of neonates according to maternal and neonatal risk factors; and premature infants described as those below 35 weeks instead of 37 weeks. The guidelines were made on the basis of the best evidence and on expert opinion when inadequate evidence exists.

[Implementation of the intestinal micro flora in the early stage and adequate immunity later on]. / Etablissement du microbiote intestinal en bas âge et qualité de l'immunité ultérieure.

The pre and postnatal development of human immunity are remarkably continuous. The feto-placental unit builds up to promote a climate of immune tolerance specifically driven in this way by the maternal immunity. The process of birth triggers the development of the infant's postnatal immunity, in first place through the bacterial colonisation of a sterile intestinal mucosa. The progressive immune response stabilisation at the sub-mucosa level during the first year of life will arise from the interface between the host and its microflora. It will take place progressively and will occur thanks to a variety of successive and complementary very complex immune mechanisms, under the influence of a rich and diversified intestinal microbiotia. Solid scientific arguments allow hypothesising that immune deviances later in life could be the consequence of an inadequate bacterial pressure on the intestinal mucosa at the early stage. A variety of epigenetic modifications taking place in this early stage could account for the deviant programming of later immunity. Each health care provider should acknowledge that some therapeutic and nutritional interventions during the first year of life may interfere with this complex immune development, giving rise to a risk of increasing immune deviancies later on.

[Dietary antigen tolerance in the early stage]. / La tolérance alimentaire chez le nourrisson: nouvelles données immunologiques et implications pratiques.

The first months of life have to be seen as a crucial period in term of implementation of the postnatal immunity. This immunological induction will be made possible through an optimization of the interface between innate and adaptive immunities in the submucosal area. A better understanding of those complex mechanisms should allow finding the best way to introduce the dietary antigen in the early stage. Maybe, it should favour a optimal tolerance to the dietary antigen and reduce the now observed increase of immune deviances later on.

[Early bacterial colonisation of the intestine: why it matters?]. / Colonisation bactérienne de l'intestin dans l'enfance: pourquoi y accorder autant d'importance?

The birth process allows the progressive formation of complex intestinal microflora composed of myriad bacteria, leading to this recently identified host-bacterial mutualism in the human intestine. This kind of cross-talk originating from birth is opportunistically used by the young host to initiate its own immune system. Recent epidemiogical data support the hypothesis that some increasing immune deviances observed in the last 2 decades could have originated from a modification of the bacterial environment in young populations. Our modern approach to perinatal care may, to some extent, have modified inadequately the overall quality of this bacterial-host interface. The international medical community has to be made aware of the increasing importance that initial colonising intestinal microflora could have on the health and well-being of the host later in life. It is of great concern to decrease these possible negative influences and to discover in the near future the possible means of helping to manipulate positively the gut microbiotia of infants.

Effects of co-administration of ibuprofen-lysine on the pharmacokinetics of amikacin in preterm infants during the first days of life.

The aim of this study was to assess the effects of intravenous co-administration of ibuprofen-lysine on the pharmacokinetics of amikacin during the first days of life in preterm infants. The pharmacokinetics of amikacin were retrospectively calculated in a cohort of 73 neonates (gestational age <31 weeks) who received either ibuprofen-lysine or placebo following inclusion in the multicentre ibuprofen prophylaxis study. Assuming a one-compartment model with instantaneous input and first-order output, there was no significant difference in the median distribution volume (0.63 vs. 0.59 liters/kg), but the median serum half-life (16.4 vs. 12.4 h) of amikacin was significantly longer (p <0.02), and the clearance (0.36 vs. 0.6 ml/kg/min; p <0.005) of amikacin was significantly lower in infants who received ibuprofen-lysine. We conclude that the time interval between consecutive amikacin administrations should be prolonged, if ibuprofen-lysine is co-administered.

[Human milk: a perpetual (re)appreciation]. / A la perpétuelle (re)découverte du lait maternel.

Based upon recent studies, it appears more and more evident that exclusive breast-feeding can be said as the best functional food, the last being defined as: "a food that has components or ingredients bringing a specific medical or physiological benefit to the host, other than purely nutritional effects". In particular, human breast milk does favour optimal bacterial intestinal colonization with bifidobacteria and lactic acid bacteria in the neonates and contains a large number of components with antimicrobial activity.

Maternal tobacco smoking and lung epithelium-specific proteins in amniotic fluid.

The bronchiolar 16 kD Clara cell secretory protein (CC16) and the alveolar surfactant-associated protein A (SP-A) are secreted in the amniotic fluid (AF), where they reflect the growth and the maturity of the fetal lung. To evaluate the possible effects of in utero tobacco smoke exposure upon infant bronchoalveolar epithelium function and maturity, CC16 and SP-A levels were determined in AF obtained at term (36-41 wk) from 28 nonsmoking, 18 smoke-exposed, and 28 smoking mothers with uncomplicated pregnancies. Tobacco smoke exposure was assessed by questionnaire and the assay in AF and maternal urine of cotinine, a stable nicotine metabolite. The specificity of the changes of CC16 and SP-A concentrations in AF was assessed by comparison with nonpulmonary proteins of high- (albumin and transferrin) or low-molecular weight (beta2-microglobulin, retinol binding protein, cystatin-C). Pulmonary and nonpulmonary AF proteins were also compared by two-dimensional gel electrophoresis between smoking and nonsmoking mothers. The levels of CC16 and SP-A as well as low- and high-molecular-weight proteins were not significantly different between the three smoking categories. The protein pattern of AF, established by two-dimensional gel electrophoresis, did not reveal any quantitative or qualitative difference between nonsmoking (n = 10), smoke-exposed (n = 5), and smoking mothers (n = 5). By multiple regression analysis of possible determinants, tobacco smoke did not emerge as a significant predictor of CC16 and SP-A concentrations in AF. SP-A level was dependent only on gestational age at birth (r2 = 0.1, p = 0.001), whereas CC16 correlated only with the levels of low-molecular weight proteins (r2 = 0.2, p = 0.0001). The latter correlation suggests that CC16 enters AF not only as a result of its secretion at the surface of the respiratory tract but also partly following its elimination by the fetal kidney. This study suggests that maternal smoking during pregnancy is not associated with alterations of the secretory functions of the epithelium of the distal airways and the alveoli at term.

[Diagnosis and follow-up of a large intrahepatic portocaval fistula in a newborn]. / Diagnostic et suivi d'une large fistule porto-cave intrahépatique chez un nouveau-né.

Portocaval fistulas are rare and only exceptionally discovered in newborns. We report the case of a large portocaval fistula associated with portal hypoperfusion detected at Doppler US imaging in an otherwise asymptomatic 5 week old infant. The patient remained asymptomatic over the following two years. At that time, preoperative angiogram showed a normal portal venous system and the fistula was surgically closed. Postoperative US showed a normal and patent portal system, without evidence of portal hypertension.

[Antibiotics in pregnancy: importance of rational utilization]. / Antibiothérapie en maternité: importance d'une utilisation rationnelle.

It is now clear that antibiotic treatment in the antenatal period significantly does prolong pregnancy during conservative management of preterm premature rupture of membranes and reduces neonatal infectious diseases as well as neonatal-related morbidities. In the same way, prophylactic intrapartum antibiotherapy reduces the incidence of early-onset group B Streptococcus-induced sepsis. Nevertheless, on the other hand, antibiotics in the perinatal period are associated with an increase of neonatal sepsis by organisms resistant to maternally administered antibiotics. In addition, antibiotic treatment in this period of time is emerging as one of the possible sources of the dramatic increase in atopic disorders in infants and children owing to the interference with the normal process of intestinal microbial colonization. So, guidelines for using antibiotics in the perinatal period can be said as one of the major priority in public health. Antibiotics have therefore to be rightly choosen and must be used in a rational manner. Local microbial epidemiology, period of infection onset, clinical evaluation, all together allow the physician to use antibiotics, always in association, according to the "well-thought-out wager". In addition, the pharmacodynamic/pharmacokinetic relationship of each drug has to be known, in order to increase efficacy, decrease toxicity and reduce microbial resistance. It is especially mandatory in neonatology where the differences in drug distribution and drug elimination are of great concern, as compared to children and adults. The aim of this paper is to point out such very important aspects using antibiotics in the perinatal period.

A comparison of ibuprofen and indomethacin for closure of patent ductus arteriosus.

BACKGROUND: Indomethacin is the conventional treatment for hemodynamically important patent ductus arteriosus in preterm infants. However, its use is associated with various side effects. In a prospective study, we compared ibuprofen and indomethacin with regard to efficacy and safety for the early treatment of patent ductus arteriosus in preterm infants. METHODS: We studied 148 infants (gestational age, 24 to 32 weeks) who had the respiratory distress syndrome and an echocardiographically confirmed, hemodynamically important patent ductus arteriosus. The infants were randomly assigned at five neonatal intensive care centers to receive three intravenous doses of either indomethacin (0.2 mg per kilogram of body weight, given at 12-hour intervals) or ibuprofen (a first dose of 10 mg per kilogram, followed at 24-hour intervals by two doses of 5 mq per kilogram each), starting on the third day of life. The rate of ductal closure, the need for additional treatment, side effects, complications, and the infants' clinical course were recorded. RESULTS: The rate of ductal closure was similar with the two treatments: ductal closure occurred in 49 of 74 infants given indomethacin (66 percent), and in 52 of 74 given ibuprofen (70 percent) (relative risk, 0.94; 95 percent confidence interval, 0.76 to 1.17; P=0.41). The numbers of infants who needed a second pharmacologic treatment or surgical ductal ligation did not differ significantly between the two groups. Oliguria occurred in 5 infants treated with ibuprofen and in 14 treated with indomethacin (P=0.03). There were no significant differences with respect to other side effects or complications. CONCLUSIONS: Ibuprofen therapy on the third day of life is as efficacious as indomethacin for the treatment of patent ductus arteriosus in preterm infants with the respiratory distress syndrome and is significantly less likely to induce oliguria.

[Perinatal thrombocytopenia of maternal origin]. / Les thrombopénies périnatales d'origine maternelle.

Maternal causes of perinatal thrombocytopenia include neonatal alloimmune thrombocytopenia, autoimmune disorders, intrauterine infections and hypertensive diseases. The diagnosis of these pathologies is difficult because they can occur in sick neonates, but also in healthy babies without a history suggesting illness. The treatment has to be quickly established in order to decrease eventual hemorrhagic complications. These latter can be amplified by several clinical circumstances and especially by the platelet immaturity of this time of life. The risk of recurrence for the next pregnancies has to be determined and can lead to diagnostic or therapeutic measures during the antenatal period.