Language outcomes at 36 months in prematurely born children is associated with the quality of developmental care in NICUs.

OBJECTIVE: The aim of this study was to examine the relationship between the quality levels of NICU developmental care (DC) and language skills at 36 months in very preterm (VPT) children. STUDY DESIGN: Language skills of 78 VPT children from 19 NICUs and 90 full-term controls was assessed using a standardized language test. We compared children' language task performance by splitting NICUs into units with high- and low-quality of DC according to two main factors: (1) infant centered care (ICC), and (2) infant pain management (IPM). RESULTS: VPT children from low-care units with respect to ICC obtained lower scores in sentence comprehension, compared to children from high-care units. No differences were found between preterm children from high-quality ICC NICUs and full-term children. CONCLUSIONS: Findings suggest that higher quality of DC related to infant centered care can mitigate delays in language skills at 36 months in children born VPT.

Neonatal developmental care in infant pain management and internalizing behaviours at 18 months in prematurely born children.

BACKGROUND: Very preterm infants are exposed to adverse stressful experiences, which may result in long-term behavioural outcomes. The developmental care practices, including pain management and environmental support, can minimize the effects of stress exposure. However, developmental care quality levels may vary among Neonatal Intensive Care Units (NICUs) and little is known about how differences in developmental care quality affect long-term behavioural outcomes. The aim of this study was to examine the relation between quality levels NICUs developmental care and behaviour problems at 18 months corrected age in preterm children. METHODS: The behaviour of 134 preterm children from 22 NICUs and 123 full-term controls was examined using the questionnaire Child Behaviour Checklist 1½-5. We compared the behavioural profile of children by splitting NICUs into units with high- and low quality of developmental care according to two main care factors: (1) infant centered care (ICC) index, and (2) infant pain management (IPM) index. RESULTS: Preterm children from low-care units in IPM group reported higher scores in Internalizing Problems, compared to children from high-care units. No differences were found between preterm children from high-care in IPM and full-term children. No significant IPM effect was found for externalizing problems. No significant ICC effect emerged both for internalizing and externalizing problems. CONCLUSIONS: Findings suggest that higher quality of developmental care related to infant pain management can mitigate behavioural problems at 18 months in children born preterm, to such an extent that preterm children exhibit a behavioural profile similar to that displayed by full-term children.

Coronary microvascular dysfunction correlates with the new onset of cardiac allograft vasculopathy in heart transplant patients with normal coronary angiography.

Coronary microvascular dysfunction is emerging as a strong predictor of outcome in heart transplantation (HT). We assessed the validity of microvascular dysfunction, defined by means of a reduced coronary flow reserve (CFR), as a factor associated with new onset epicardial cardiac allograft vasculopathy (CAV) or death. We studied 105 patients at 4 ± 1 years post-HT with a normal coronary angiography (CA). New onset CAV was assessed by CA. CFR was assessed in the left anterior descending (LAD) coronary artery by transthoracic Doppler echocardiography and calculated as the ratio of hyperaemic to basal blood flow velocity. A CFR ≤ 2.5 was considered abnormal. Epicardial CAV onset or death was assessed during a follow-up of 10 years. New onset CAV was diagnosed in 30 patients (28.6%) (Group A), and the CA was normal in the remaining 75 patients (71.4%) (Group B). Group A had reduced CFR compared with group B (2.4 ± 0.6 vs. 3.2 ± 0.7, p < 0.0001). A CFR ≤ 2.5 was independently associated with a higher probability of new onset CAV (p < 0.0001) and a higher probability of death, regardless of CAV onset (p < 0.01). Microvascular dysfunction is independently associated with the onset of epicardial CAV, and associated with a higher risk of death, regardless of CAV onset.

Everolimus prevents coronary microvasculopathy in heart transplant recipients with normal coronary angiograms: an anatomo-functional study.

BACKGROUND: Coronary allograft vasculopathy (CAV) involves both epicardial vessels and coronary microcirculation. Little is known about the effect of everolimus on coronary microvasculopathy in heart transplantation (HT). The aim of our study was to assess the pathological substrate of coronary flow reserve (CFR) impairment in HT patients and the effect of everolimus on microvascular remodeling and CFR. METHODS: We studied 28 HT patients with normal coronary angiograms (25 male, age at HT 54±10 years). Immunosuppressive regimen consisted of cyclosporine and everolimus (10 patients) or mycophenolate mophetil (18 patients). They were evaluated with digital microscopy for morphometric analysis of fibrosis and microvascular remodeling. Coronary flow velocity in the left anterior descending coronary artery was detected using transthoracic Doppler echocardiography at rest and during adenosine infusion. CFR was the ratio of hyperaemic diastolic flow velocity (DFV) to resting DFV. A CFR≤2.5 was considered abnormal and sign of coronary microvascular dysfunction. RESULTS: In patients with CFR≤2.5 the thickness of the tunica media of intramyocardial arterioles was greater than in patients with CFR>2.5 (39±2 vs 17±3 µm; P=.02). Microvascular remodeling was significantly higher in patients with CFR≤2.5 (72.7±2.4 vs 50.4±8.4%; P<.007). Capillary density and fibrosis were comparable between groups (157.2±42.4 vs 175.7±42.4 capillaries/mm2; P=.3; and 6.8±5 vs 8.3±4.9%; P=.4, respectively). The thickness of the tunica media of intramyocardial arterioles was lower in patients whose therapy included everolimus (15±2 vs 32±4 µm, P=.03) and CFR was higher (3.2±0.5 vs 2.8±0.9; P=.03). CONCLUSION: The pathological substrate of reduced CFR in HT patients seems to be a hypertrophic remodeling of coronary arterioles. Everolimus appears to prevent such microvascular remodeling and preserve coronary flow reserve.

Opioids for neonates receiving mechanical ventilation: a systematic review and meta-analysis.

OBJECTIVE: To evaluate the effect of opioid analgesics, compared to placebo, no drug, or other non-opioid analgesics or sedatives, on pain, duration of mechanical ventilation, mortality, growth and neurodevelopmental outcomes in newborn infants on mechanical ventilation. METHODS: This was a systematic review and meta-analysis of randomised controlled trials (RCTs). Data sources used were Cochrane, MEDLINE, EMBASE and CINAHL databases, and references from review articles. RCTs or quasi-RCTs comparing opioids to a control, or to other analgesics or sedatives in newborn infants on mechanical ventilation were reviewed. RESULTS: A total of 13 studies on 1505 infants were included. Infants given opioids showed reduced Premature Infant Pain Profile (PIPP) scores compared to the control group (weighted mean difference (WMD) -1.71, 95% CI -3.18 to -0.24). Heterogeneity was significantly high in all analyses of pain. Meta-analyses of mortality, duration of mechanical ventilation and long-term and short-term neurodevelopmental outcomes showed no statistically significant differences. Very preterm infants given morphine took significantly longer to reach full enteral feeding than those in control groups (WMD 2.10 days, 95% CI 0.35 to 3.85). One study that compared morphine with midazolam showed similar pain scores, but fewer adverse effects with morphine. CONCLUSIONS: There is insufficient evidence to recommend routine use of opioids in mechanically ventilated newborns. Opioids should be used selectively, when indicated by clinical judgment and evaluation of pain indicators. If sedation is required, morphine is safer than midazolam.

Opioids for neonates receiving mechanical ventilation.

BACKGROUND: Mechanical ventilation is a potentially painful and discomforting intervention widely used in neonatal intensive care units. Newborn babies (neonates) demonstrate increased sensitivity to pain, which may affect clinical and neurodevelopmental outcomes. The use of drugs that reduce pain might be important in improving survival and neurodevelopmental outcomes. OBJECTIVES: To determine the effect of opioid analgesics (pain-killing drugs derived from opium e.g. morphine), compared to placebo, no drug, or other non-opioid analgesics or sedatives, on pain, duration of mechanical ventilation, mortality, growth and neurodevelopmental outcomes in newborn infants on mechanical ventilation. SEARCH STRATEGY: Electronic searches included: the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2007); MEDLINE (1966 to June 2007); EMBASE (1974 to June 2007); and CINAHL (1982 to 2007). Previous reviews and lists of relevant articles were cross-referenced. SELECTION CRITERIA: Randomised controlled trials or quasi-randomised controlled trials comparing opioids to a control, or to other analgesics or sedatives in newborn infants on mechanical ventilation. DATA COLLECTION AND ANALYSIS: Data were extracted independently by two review authors. Categorical outcomes were analysed using relative risk and risk difference; and continuous outcomes with weighted mean difference or standardised mean difference. A fixed effect model was used for meta-analysis except where heterogeneity existed, in which case a random effects model was used. MAIN RESULTS: Thirteen studies on 1505 infants were included. Infants given opioids showed reduced premature infant pain profile (PIPP) scores compared to the control group (weighted mean difference -1.71; 95% confidence interval -3.18 to -0.24). Differences in execution and reporting of trials mean that this meta-analysis should be interpreted with caution. Heterogeneity was significantly high in all analyses of pain, even when lower quality studies were excluded and analysis limited to very preterm newborns. Meta-analyses of mortality, duration of mechanical ventilation, and long and short-term neurodevelopmental outcomes showed no statistically significant differences. Very preterm infants given morphine took significantly longer to reach full enteral feeding than those in control groups (weighted mean difference 2.10 days; 95% confidence interval 0.35 to 3.85). One study compared morphine with a sedative: the treatments showed similar pain scores, but morphine had fewer adverse effects. AUTHORS' CONCLUSIONS: There is insufficient evidence to recommend routine use of opioids in mechanically ventilated newborns. Opioids should be used selectively, when indicated by clinical judgment and evaluation of pain indicators. If sedation is required, morphine is safer than midazolam. Further research is needed.

Opioids for neonates receiving mechanical ventilation.

BACKGROUND: Mechanical ventilation is a potentially painful intervention widely used in neonatal intensive care units. Since newborn babies (neonates) demonstrate increased sensitivity to pain, which may affect clinical and neurodevelopmental outcomes, the use of drugs which reduce pain might be very important. OBJECTIVES: To determine the effect of opioid analgesics (pain-killing drugs derived from opium e.g. morphine), compared to placebo, no drug, or other non-opioid analgesics or sedatives, on pain, duration of mechanical ventilation, mortality, growth and neurodevelopmental outcomes in newborn infants on mechanical ventilation. SEARCH STRATEGY: Electronic searches included: the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 3, 2004); MEDLINE (1966 to June 2004); EMBASE (1974 to June 2004); and CINAHL (1982 to 2003). Previous reviews and lists of relevant articles were cross-referenced. SELECTION CRITERIA: Randomised controlled trials or quasi-randomised controlled trials comparing opioids to a control, or to other analgesics or sedatives in newborn infants on mechanical ventilation. DATA COLLECTION AND ANALYSIS: Data were extracted by two reviewers independently. Categorical outcomes were analysed using relative risk and risk difference; and continuous outcomes with weighted mean difference or standardised mean difference. A fixed effect model was used for meta-analysis except where heterogeneity existed, when a random effects model was used. MAIN RESULTS: Thirteen studies on 1505 infants were included. Infants given opioids showed reduced premature infant pain profile (PIPP) scores compared to the control group (weighted mean difference -1.71; 95% confidence interval -3.18 to -0.24). Differences in execution and reporting of trials mean that this meta-analysis should be interpreted with caution. Heterogeneity was significantly high in all analyses of pain, even when lower quality studies were excluded and analysis limited to very preterm newborns. Meta-analyses of mortality, duration of mechanical ventilation, and long and short term neurodevelopmental outcomes showed no statistically significant differences. Very preterm infants given morphine took significantly longer to reach full enteral feeding than those in control groups (weighted mean difference 2.10 days; 95% confidence interval 0.35 to 3.85). One study compared morphine with a sedative: the treatments showed similar pain scores, but morphine had fewer adverse effects. AUTHORS' CONCLUSIONS: There is insufficient evidence to recommend routine use of opioids in mechanically ventilated newborns. Opioids should be used selectively, when indicated by clinical judgment and evaluation of pain indicators. If sedation is required, morphine is safer than midazolam. Further research is needed.

Assessing mortality risk in very low birthweight infants: a comparison of CRIB, CRIB-II, and SNAPPE-II.

BACKGROUND: Illness severity scores are increasingly used for risk adjustment in clinical research and quality assessment. Recently, a simplified version of the score for neonatal acute physiology (SNAPPE-II) and a revised clinical risk index for babies (CRIB-II) score have been published. AIM: To compare the discriminatory ability and goodness of fit of CRIB, CRIB-II, and SNAPPE-II in a cohort of neonates < 1500 g birth weight (VLBWI). METHODS: Data from 720 VLBWI, admitted to 12 neonatal units in Lombardy (Northern Italy) participating in a regional network, were analysed. The discriminatory ability of the scores was assessed measuring the area under the receiver operating characteristic curve (AUC). Outcome measure was in-hospital death. RESULTS: CRIB and CRIB-II showed greater discrimination than SNAPPE-II (AUC 0.90 and 0.91 v 0.84, p < 0.0004), partly because of the poor quality of some of the data required for the SNAPPE-II calculation-for example, urine output-but also because of the relative weight given to some items. In addition to each score, several variables significantly influenced survival in logistic regression models. Antenatal steroid prophylaxis, singleton birth, absence of congenital anomalies, and gestational age were independent predictors of survival for all scores, in addition to caesarean section and not being small for gestation (for SNAPPE-II) and a five minute Apgar score of > or = 7 (for SNAPPE-II and CRIB). CONCLUSIONS: CRIB and CRIB-II had greater discriminatory ability than SNAPPE-II. Risk adjustment using all scores is imperfect, and other perinatal factors significantly influence VLBWI survival. CRIB-II seems to be less confounded by these factors.

Determination of oxidative status in breast and formula milk.

AIM: To investigate to what extent formula milk and stored breast milk, commonly used in hospitals, could be pro-oxidant sources for newborn babies. METHODS: We determined total antioxidant capacity and lipid peroxidation products, such as lipid peroxides, TBARS and conjugated dienes, in fresh and stored (at -20 degrees C) samples of breast milk and in different brands of formula milk. RESULTS: There were notable differences in the oxidation parameters in several brands of formula milk, particularly concerning the levels of lipid peroxides and total antioxidant capacity. No difference was found in the mean total antioxidant capacity between formula and breast milk, even if the vitamin content is much higher in formula milk than in breast milk. On the contrary, all the considered lipid peroxidation products were higher in human milk (HM) than formula milk (FM), and lipid peroxides were much higher in HM stored at -20 degrees C. Many differences were found between different formula milks. CONCLUSION: There was a conspicuous formation of lipid peroxides in HM stored at -20 degrees C, which was probably caused by an increased presence of free fatty acids due to lipoprotein lipase activity during storage. Unexpectedly, even fresh HM had a higher concentration of lipid peroxidation products when compared to FM. This could be ascribed to the higher susceptibility of HM to degradation during analysis because of manipulation and light exposure. However, it is also interesting that the high content of lipid peroxides did not correspond to a low total antioxidant capacity in either breast or formula milk. This could signify that such levels of lipid peroxidation products might be present naturally in milk and HM after expression is subject to a strong peroxidation either at room temperature or at -20 degrees C.

Developmental quotient at 24 months and fatty acid composition of diet in early infancy: a follow up study.

AIM: A follow up study of developmental quotient (DQ) at 24 months of toddlers whose diets in early infancy differed in fatty acid composition, and in whom an association between diet and DQ was observed at 4 months. METHODS: 81 toddlers were distributed among three groups according to early type of diets standard infant formula (SFo, n = 30); long chain polyunsaturated fatty acid (LC-PUFA) enriched formula (LCPFo, n = 26); human milk (HM, n = 25). DQ at 24 months was assessed by Brunet-Léxine's psychomotor developmental test. A subgroup (n = 20; SFo 8; LCPFo 6; HM 6) was tested for erythrocyte phosphatidyicholine and phosphatidylethanolamine. RESULTS: No DQ differences were found by analysis of variance. Neither DQ nor erythrocyte docosahexaenoic acid at 4 months were predictors of DQ scores at 24 months. Phosphatidylcholine arachidonic and docosahexaenoic acid correlated positively, and phosphatidylcholine linoleic acid and phosphatidylethanolamine eicosapentaenoic acid negatively, with DQ. Multiple regression analysis including these variables explained 52% of inter-individual DQ variance. A strong association was found between the erythrocyte phosphatidylcholine arachidonic/ linoleic acid ratio and DQ (r = 0.75; p = 0.0001). CONCLUSIONS: The diet/DQ association found at 4 months was not predictive of DQ scores at 24 months. Irrespective of dietary or genetic factors, there appears to be a strong correlation between the LC-PUFA composition of the red cell membrane and higher neurodevelopmental performance.

Neurodevelopmental quotient of healthy term infants at 4 months and feeding practice: the role of long-chain polyunsaturated fatty acids.

A direct influence of dietary long-chain polyunsaturated fatty acids (LC-PUFA) on the developmental quotient (DQ) of the healthy term infant remains unexplored. To test this hypothesis, we designed a prospective study of three types of diet. Twenty-nine infants received a LC-PUFA-supplemented formula, 31 received a standard infant formula, and 30 infants were breast-fed exclusively. Neurodevelopmental response was measured by the Brunet-Lézine psychomotor development test at 4 mo. The fatty acid status was also assessed among three diet subgroups (59 subjects) at 4 mo. Formula-fed infants who received LC-PUFA supplementation scored significantly higher (p < 0.01) on the Brunet-Lézine scale than infants who received the standard formula. Breast-fed infants also performed better than those fed the standard formula. Arachidonic acid and docosahexaenoic acid levels in circulating lipids and erythrocyte phospholipids were higher among breast-fed infants and among the group fed the arachidonic- and docosahexaenoic acid-supplemented formula. These findings are suggestive that formula supplementation with one or both of these fatty acids can benefit term infants in neurodevelopmental performance.

Calcium intakes in a sample of 35,000 Italian schoolchildren.

The calcium intakes of 35,072 Italian schoolchildren aged 7-10 years were investigated as part of a nation-wide survey of nutritional patterns. The Friuli, Piedmont, Latium and Sicily regions of Italy were selected as representative of the nation's north-south and east-west socio-economic divisions. A food-frequency questionnaire was used to assess the nutritional intakes of the whole sample. The validity of the food-frequency questionnaire method was assessed in a sub-sample of children by traditional methods: 24-h dietary recall and a weighted food diary. The data indicate that the mean calcium intakes of girls were below the recommended daily intake of 800 mg in all of the regions except Sicily, and that the calcium intakes of boys were above the recommended daily intake in all of the regions except Friuli. These results suggest that there may be deficiencies in the calcium intakes of this age-group in the wider population, particularly in girls. Food-frequency questionnaires are potentially valuable as part of a multi-method approach in large-scale nutritional monitoring.

Determination of intra- and inter-individual variability and its effect on the number of days required to assess the usual intake of a 1-year-old infant population.

Diet variability influences the accuracy of the assessment of the relationship between nutrient intake and disease. The present study investigates intra- and inter-individual variability in an infant population at 12 months. The mothers of 79 infants completed a 7-day weighted food record. No significant difference in nutrient intake was observed between males and females. For some nutrients an intra-/inter-individual variability ratio > 1 was found. Adjustment for total calorie intake slightly altered the intra-/inter-individual variability ratio of many nutrients. An error margin of 10% or less for calories can be expected within an 18-day study. Most nutrients however would need to be studied for over 30 days to give an error margin < or = 10%. For dietary cholesterol, vitamins A, B6, C, and E, bracketing the error within the 10% margin would require an unrealistic time frame. Adjustments for calorie intake reduced the number of days in the dietary record for some nutrients. A lower intra/inter-individual variability ratio was seen when data for adults and older infants were compared.

Effects of diet on the lipid and fatty acid status of full-term infants at 4 months.

OBJECTIVE: To compare the effects of the exogenous supply of long-chain polyunsaturated fatty acids (LCP) and cholesterol on the lipid and fatty acid status in full-term, 4-month old infants. METHODS: Twenty-three infants received a standard infant formula while twenty-one were given a formula enriched with LCP and cholesterol in a prospective, randomized study. The composition of the two formulas differed only in fat quality. A group of fifteen breastfed infants fed was used as reference. No one was complemented with solid foods before blood sampling at 4 months of life. RESULTS: Differences in total-cholesterol and low-density lipoprotein-cholesterol (LDL-C) levels between feeding groups were mainly gender-related. Dietary cholesterol tended to increase LDL-C plasma levels. The breastfed and the enriched formula-fed groups had higher levels of circulating LCP than the group that received the standard formula. In the erythrocytes of infants fed the standard formula, C22:6 n-3 levels were less than 50% those of the breastfed and the enriched formula-fed ones. Higher C20:4 n-6 levels were found in the erythrocytes of the enriched formula-fed group. CONCLUSIONS: Formula-fed, full-term infants maintain a lipid and fatty acid status close to that of breastfed infants when supplied with dietary LCP and cholesterol.

Relationships between the fatty acid status and insulinemic indexes in obese children.

The relationship between the fatty acid (FA) status and indices of insulin secretion in young obese subjects at risk of developing insulin resistance and its complications was investigated. In 12 subjects (8-14 years) at first diagnosis of obesity the FA composition of total plasma and circulating and erythrocyte phospholipids was related to basal and peak insulinemia and the insulinemic area resulting from a standard oral glucose tolerance test. Negative correlations were shown between both delta-6-desaturation products and 20:5 n-3 levels and insulinemic values. On the contrary, circulating total saturated and monounsaturated FA and erythrocyte phospholipid products of delta-5- and delta-4-desaturation positively correlate with insulinemic indices. The observed relationships could be markers of developing insulin resistance and suggest the possibility of a dietary intervention.

Antigen-reduced infant formulas versus human milk: growth and metabolic parameters in the first 6 months of life.

OBJECTIVE: To compare growth and metabolic parameters of infants fed special formulas for atopy prevention to breast-fed infants. METHODS: Eighty-two infants with family history of IgE-mediated diseases completed a 6-month nutritional follow-up within a clinical trial to assess the effectiveness of the dietary intervention in preventing atopy. Infants were subdivided according to the type of milk feeding from the end of the first month of life up to sixth month: human milk (HM) group (29 infants); soy formula (SF) group (15 infants); whey-based low-degree hydrolysate (WHy) group (15 infants); casein-based high-degree hydrolysate (CHy) group (13 infants); soy plus collagen-based high-degree hydrolysate group (10 infants). Anthropometric indices were determined at 0, 3 and 6 months of life and a fasting blood sample for hematochemical parameters was obtained at 5 months of life before beginning the introduction of solid foods. RESULTS: Lower values of body mass index and higher blood urea nitrogen were displayed by the CHy group at 3 months. Plasma aminoacidograms showed higher essential amino acids (AA)/total AA in SF, WHy and CHy groups but lower branched chain AA/essential AA in all formula-fed infants in comparison with the HM group. CONCLUSIONS: Special formulas (in particular high-degree protein hydrolysates) should be carefully evaluated when used for prolonged periods of time in healthy infants at familial risk of atopy.