Effects of erythropoietin on erythrocyte deformability in non-transfused preterm infants

AIM: Suppression of erythropoiesis due to low plasma erythropoietin levels is an important factor in the development of anaemia of prematurity. Premature infants may therefore be treated with recombinant human erythropoietin (rhEPO). This prospective, randomised and controlled study was designed to find out whether rhEPO treatment improves erythrocyte deformability in preterm infants. METHODS: Sixteen infants were treated with rhEPO (250 IU/kg three times weekly) a total of 15 times beginning on day of life 5 whereas fifteen infants served as controls. Haemoglobin concentration, haematocrit, reticulocyte count, ferritin level and erythrocyte deformability were measured on days 5, 14, 28, 42 and 63. Erythrocyte elongation was determined as an indicator of erythrocyte deformability using a shear stress diffractometer (Rheodyn SSD) at shear forces of 0.3 to 60 Pa. RESULTS: Haemoglobin concentration was significantly higher on days 28 and 42 and reticulocyte percentage on day 28 in the rhEPO group compared to the controls. Serum ferritin was lower in the rhEPO group on day 28. Erythrocyte deformability was significantly increased on days 28 and 42 in the infants receiving rhEPO. We found a strong relationship between erythrocyte elongation and reticulocyte count. CONCLUSION: RhEPO markedly increases the erythropoiesis in preterm infants in the critical first weeks of life and the anaemia of prematurity is obviously reduced. The erythrocyte deformability improved under rhEPO treatment. Erythrocyte deformability was significantly related to the reticulocyte count indicating that the improvement of erythrocyte deformability was due to the formation of well-deformable young erythrocytes.

Lung volume, breathing pattern and ventilation inhomogeneity in preterm and term infants

BACKGROUND: Morphological changes in preterm infants with bronchopulmonary dysplasia (BPD) have functional consequences on lung volume, ventilation inhomogeneity and respiratory mechanics. Although some studies have shown lower lung volumes and increased ventilation inhomogeneity in BPD infants, conflicting results exist possibly due to differences in sedation and measurement techniques. METHODOLOGY/PRINCIPAL FINDINGS: We studied 127 infants with BPD, 58 preterm infants without BPD and 239 healthy term-born infants, at a matched post-conceptional age of 44 weeks during quiet natural sleep according to ATS/ERS standards. Lung function parameters measured were functional residual capacity (FRC) and ventilation inhomogeneity by multiple breath washout as well as tidal breathing parameters. Preterm infants with BPD had only marginally lower FRC (21.4 mL/kg) than preterm infants without BPD (23.4 mL/kg) and term-born infants (22.6 mL/kg), though there was no trend with disease severity. They also showed higher respiratory rates and lower ratios of time to peak expiratory flow and expiratory time (t(PTEF)/t(E)) than healthy preterm and term controls. These changes were related to disease severity. No differences were found for ventilation inhomogeneity. CONCLUSIONS: Our results suggest that preterm infants with BPD have a high capacity to maintain functional lung volume during natural sleep. The alterations in breathing pattern with disease severity may reflect presence of adaptive mechanisms to cope with the disease process.

Regional and overall ventilation inhomogeneities in preterm and term-born infants

OBJECTIVES: We compared ventilation inhomogeneity assessed by electrical impedance tomography (EIT) and multiple breath washout (MBW) in preterm and term-born infants. We hypothesised that EIT measurements in spontaneously breathing infants are repeatable and that differences in regional ventilation distribution measured by EIT can distinguish between preterm and term-born infants. DESIGN: Cross-sectional group comparison study. SETTING: Lung function laboratory at a University Children's Hospital. PARTICIPANTS: Seventeen healthy term-born and 15 preterm infants at a matched postmenstrual age of 44 weeks. MEASUREMENTS AND RESULTS: We concurrently measured ventilation inhomogeneity by EIT, ventilation inhomogeneity (LCI) and functional residual capacity (FRC) by MBW and tidal breathing variables during unsedated quiet sleep. EIT measurements were highly repeatable (coefficient of variation 3.6%). Preterm infants showed significantly more ventilation of the independent parts of the lungs compared to healthy term-born infants assessed by EIT (mean difference 5.0, 95 CI 1.3-8%). Whereas the two groups showed no differences in lung volumes or ventilation inhomogeneities assessed by MBW, EIT discriminated better between term and preterm infants. (FRC/kg: mean difference 1.1 mL, 95% CI -1.4-3.8 mL; LCI: mean difference 0.03, 95% CI -0.32-0.25). CONCLUSIONS: EIT shows distinct differences in ventilation distribution between preterm and term-born infants, which cannot be detected by MBW. Although preterm infants are capable of dynamically maintaining overall functional residual volume and ventilation distribution, they show some spatial differences from fullterm infants.

Variability in pain response to a non-pharmacological intervention across repeated routine pain exposure in preterm infants: a feasibility study

AIM: To explore the variability in pain response in preterm infants across time who received sucrose during routine heel stick. METHOD: Single group, exploratory repeated measures design. SETTING: Two tertiary level neonatal intensive care units (NICU) in Switzerland. SUBJECTS: Nine preterm infants born between 28 2/7 and 31 4/7 weeks of gestation during their first 14 days of life. MEASUREMENTS: Pain was assessed by the Bernese Pain Scale for Neonates (BPSN), the Premature Infant Pain Profile (PIPP) and the Visual Analogue Scale (VAS). Salivary cortisol was analysed. RESULTS: 72-94% of the variability was within-subject variability, indicating inconsistency of pain responses across the 5 heel sticks. Interrater agreement was highest during heel sticks 1-3 and decreased during heel stick 4 and 5, indicating a possible alteration of pain patterns. No significant differences in the amount of cortisol could be detected before and after the heel sticks (p = 0.55), indicating no stress-induced peak after the painful intervention. However, a general gradual decrease of cortisol levels across time could be detected. CONCLUSION: A high variability in pain response among preterm neonates across time could be described. Consistency of cortisol levels before and after the heel sticks could indicate the effectiveness of sucrose across time.

Lung mechanics and gas exchange in ventilated preterm infants during treatment of hyaline membrane disease with multiple doses of artificial surfactant (Exosurf)

Eight premature infants ventilated for hyaline membrane disease and enrolled in the OSIRIS surfactant trial were studied. Lung mechanics, gas exchange [PaCO2, arterial/alveolar PO2 ratio (a/A ratio)], and ventilator settings were determined 20 minutes before and 20 minutes after the end of Exosurf instillation, and subsequently at 12-24 hour intervals. Respiratory system compliance (Crs) and resistance (Rrs) were measured by means of the single breath occlusion method. After surfactant instillation there were no significant immediate changes in PaCO2 (36 vs. 37 mmHg), a/A ratio (0.23 vs. 0.20), Crs (0.32 vs. 0.31 mL/cm H2O/kg), and Rrs (0.11 vs. 0.16 cmH2O/mL/s) (pooled data of 18 measurement pairs). During the clinical course, mean a/A ratio improved significantly each time from 0.17 (time 0) to 0.29 (time 12-13 hours), to 0.39 (time 24-36 hours) and to 0.60 (time 48-61 hours), although mean airway pressure was reduced substantially. Mean Crs increased significantly from 0.28 mL/cmH2O/kg (time 0) to 0.38 (time 12-13 hours), to 0.37 (time 24-38 hours), and to 0.52 (time 48-61 hours), whereas mean Rrs increased from 0.10 cm H2O/mL/s (time 0) to 0.11 (time 12-13 hours), to 0.13 (time 24-36 hours) and to (time 48-61 hours) with no overall significance. A highly significant correlation was found between Crs and a/A ratio (r = 0.698, P less than 0.001). We conclude that Exosurf does not induce immediate changes in oxygenation as does the instillation of (modified) natural surfactant preparations. However, after 12 and 24 hours of treatment oxygenation and Crs improve significantly.(ABSTRACT TRUNCATED AT 250 WORDS)

Neonatal procedural pain exposure and pain management in ventilated preterm infants during the first 14 days of life

OBJECTIVES: Ventilated preterm infants are at high risk for procedural pain exposure. In Switzerland there is a lack of knowledge about the pain management in this highly vulnerable patient population. The aims of this study were to describe the type and frequency of procedures and to determine the amount of analgesia given to this patient group in two Swiss neonatal intensive care units. METHOD: A retrospective cohort study was performed examining procedural exposure and pain management of a convenience sample of 120 ventilated preterm infants (mean age = 29.7 weeks of gestation) during the first 14 days of life after delivery and born between May 1st 2004 and March 31st 2006. RESULTS: The total number of procedures all the infants underwent was 38,626 indicating a mean of 22.9 general procedures performed per child and day. Overall, 75.6% of these procedures are considered to be painful. The most frequently performed procedure is manipulation on the CPAP prongs. Pain measurements were performed four to seven times per day. In all, 99.2% of the infants received either non-pharmacological and/or pharmacological agents and 70.8% received orally administered glucose as pre-emptive analgesia. Morphine was the most commonly used pharmacological agent. DISCUSSION: The number of procedures ventilated preterm infants are exposed to is disconcerting. Iatrogenic pain is a serious problem, particularly in preterm infants of low gestational age. The fact that nurses assessed pain on average four to seven times daily per infant indicates a commitment to exploring a painful state in a highly vulnerable patient population. In general, pharmacological pain management and the administration of oral glucose as a non-pharmacological pain relieving intervention appear to be adequate, but there may be deficiencies, particularly for extremely low birth weight infants born <28 weeks of gestation.

Catch-up alveolarization in ex-preterm children: evidence from (3)He magnetic resonance

RATIONALE Histologic data from fatal cases suggest that extreme prematurity results in persisting alveolar damage. However, there is new evidence that human alveolarization might continue throughout childhood and could contribute to alveolar repair. OBJECTIVES To examine whether alveolar damage in extreme-preterm survivors persists into late childhood, we compared alveolar dimensions between schoolchildren born term and preterm, using hyperpolarized helium-3 magnetic resonance. METHODS We recruited schoolchildren aged 10-14 years stratified by gestational age at birth (weeks) to four groups: (1) term-born (37-42 wk; n = 61); (2) mild preterm (32-36 wk; n = 21); (3) extreme preterm (<32 wk, not oxygen dependent at 4 wk; n = 19); and (4) extreme preterm with chronic lung disease (<32 wk and oxygen dependent beyond 4 wk; n = 18). We measured lung function using spirometry and plethysmography. Apparent diffusion coefficient, a surrogate for average alveolar dimensions, was measured by helium-3 magnetic resonance. MEASUREMENTS AND MAIN RESULTS The two extreme preterm groups had a lower FEV1 (P = 0.017) compared with term-born and mild preterm children. Apparent diffusion coefficient was 0.092 cm(2)/second (95% confidence interval, 0.089-0.095) in the term group. Corresponding values were 0.096 (0.091-0.101), 0.090 (0085-0.095), and 0.089 (0.083-0.094) in the mild preterm and two extreme preterm groups, respectively, implying comparable alveolar dimensions across all groups. Results did not change after controlling for anthropometric variables and potential confounders. CONCLUSIONS Alveolar size at school age was similar in survivors of extreme prematurity and term-born children. Because extreme preterm birth is associated with deranged alveolar structure in infancy, the most likely explanation for our finding is catch-up alveolarization.

Preterm birth, infant weight gain, and childhood asthma risk: A meta-analysis of 147,000 European children

BACKGROUND Preterm birth, low birth weight, and infant catch-up growth seem associated with an increased risk of respiratory diseases in later life, but individual studies showed conflicting results. OBJECTIVES We performed an individual participant data meta-analysis for 147,252 children of 31 birth cohort studies to determine the associations of birth and infant growth characteristics with the risks of preschool wheezing (1-4 years) and school-age asthma (5-10 years). METHODS First, we performed an adjusted 1-stage random-effect meta-analysis to assess the combined associations of gestational age, birth weight, and infant weight gain with childhood asthma. Second, we performed an adjusted 2-stage random-effect meta-analysis to assess the associations of preterm birth (gestational age <37 weeks) and low birth weight (<2500 g) with childhood asthma outcomes. RESULTS Younger gestational age at birth and higher infant weight gain were independently associated with higher risks of preschool wheezing and school-age asthma (P < .05). The inverse associations of birth weight with childhood asthma were explained by gestational age at birth. Compared with term-born children with normal infant weight gain, we observed the highest risks of school-age asthma in children born preterm with high infant weight gain (odds ratio [OR], 4.47; 95% CI, 2.58-7.76). Preterm birth was positively associated with an increased risk of preschool wheezing (pooled odds ratio [pOR], 1.34; 95% CI, 1.25-1.43) and school-age asthma (pOR, 1.40; 95% CI, 1.18-1.67) independent of birth weight. Weaker effect estimates were observed for the associations of low birth weight adjusted for gestational age at birth with preschool wheezing (pOR, 1.10; 95% CI, 1.00-1.21) and school-age asthma (pOR, 1.13; 95% CI, 1.01-1.27). CONCLUSION Younger gestational age at birth and higher infant weight gain were associated with childhood asthma outcomes. The associations of lower birth weight with childhood asthma were largely explained by gestational age at birth.

Monitoring of Urinary Calcium and Phosphorus Excretion in Preterm Infants - Comparison of two Methods

OBJECTIVES: Premature babies require supplementation with calcium and phosphorus to prevent metabolic bone disease of prematurity. To guide mineral supplementation, two methods of monitoring urinary excretion of calcium and phosphorus are used: urinary calcium or phosphorus concentration and calcium/creatinine or phosphorus/creatinine ratios. We compare these two methods in regards to their agreement on the need for mineral supplementation. METHODS: Retrospective chart review of 230 premature babies with birthweight <1500 g, undergoing screening of urinary spot samples from day 21 of life and fortnightly thereafter. Hypothetical cut-off values for urine calcium or phosphorus concentration (1 mmol/l) and urine calcium/creatinine ratio (0.5 mol/mol) or phosphorus/creatinine ratio (4 mol/mol) were applied to the sample results. The agreement on whether or not to supplement the respective minerals based on the results with the two methods was compared. Multivariate general linear models sought to identify patient characteristic to predict disagreeing results. RESULTS: 24.8% of cases disagreed on the indication for calcium supplementation, 8.8% for phosphorus. Total daily calcium intake was the only patient characteristic associated with discordant results. CONCLUSIONS: With the intention to supplement the respective mineral, comparison of urinary mineral concentration with mineral/creatinine ratio is moderate for Calcium and good for Phosphorus. The results do not allow to identify superiority of either method on the decision which babies require calcium and/or phosphorus supplements.

Influence of Gestational Age and Parental Education on Executive Functions of Children Born Very Preterm

Background: Children born very preterm (<32 weeks’ gestational age; VPT) and/or very low birth weight (<1500 g; VLBW) are at high risk of deficits in executive functions, namely inhibition, working memory, and shifting. Both, gestational age and socioeconomic factors, such as parental education, are known to influence executive functions, with children born at lower gestational age and with lower educated parents displaying worse executive skills. This study aimed to investigate if maternal and paternal education moderated the relationship between gestational age and executive functions in VPT/VLBW children aged 8-12 years. It was hypothesised that the disadvantageous effect of low gestational age could be buffered more easily in families with higher educational background. Methods: Sixty VPT/VLBW children born in the cohort of 1998-2003 were recruited. All children completed executive function tasks (inhibition, working memory, and shifting). Results: There was a significant dose-response-relationship between gestational age and inhibition, with children being born at earlier gestational age showing worse inhibition. However, neither maternal nor paternal education moderated the relationship between gestational age and executive functions significantly. Conclusion: children than parental education. The disadvantageous effect of low gestational age was equal in children with higher and lower educated parents. However, the impact of gestational age and parental education on executive functions may differ depending on the socioeconomic spectrum of the study sample.

Maturation of oral feeding skills in preterm infants.

AIM: Safe and successful oral feeding requires proper maturation of sucking, swallowing and respiration. We hypothesized that oral feeding difficulties result from different temporal development of the musculatures implicated in these functions. METHODS: Sixteen medically stable preterm infants (26 to 29 weeks gestation, GA) were recruited. Specific feeding skills were monitored as indirect markers for the maturational process of oral feeding musculatures: rate of milk intake (mL/min); percent milk leakage (lip seal); sucking stage, rate (#/s) and suction/expression ratio; suction amplitude (mmHg), rate and slope (mmHg/s); sucking/swallowing ratio; percent occurrence of swallows at specific phases of respiration. Coefficients of variation (COV) were used as indices of functional stability. Infants, born at 26/27- and 28/29-week GA, were at similar postmenstrual ages (PMA) when taking 1-2 and 6-8 oral feedings per day. RESULTS: Over time, feeding efficiency and several skills improved, some decreased and others remained unchanged. Differences in COVs between the two GA groups demonstrated that, despite similar oral feeding outcomes, maturation levels of certain skills differed. CONCLUSIONS: Components of sucking, swallowing, respiration and their coordinated activity matured at different times and rates. Differences in functional stability of particular outcomes confirm that maturation levels depend on infants' gestational rather than PMA.

Congenital diaphragmatic hernia in the preterm infant.

BACKGROUND: Congenital diaphragmatic hernia (CDH) remains a significant cause of death in newborns. With advances in neonatal critical care and ventilation strategies, survival in the term infant now exceeds 80% in some centers. Although prematurity is a significant risk factor for morbidity and mortality in most neonatal diseases, its associated risk with infants with CDH has been described poorly. We sought to determine the impact of prematurity on survival using data from the Congenital Diaphragmatic Hernia Registry (CDHR). METHODS: Prospectively collected data from live-born infants with CDH were analyzed from the CDHR from January 1995 to July 2009. Preterm infants were defined as <37 weeks estimated gestational age at birth. Univariate and multivariate logistic regression analysis were>performed. RESULTS: During the study period, 5,069 infants with CDH were entered in the registry. Of the 5,022 infants with gestational age data, there were 3,895 term infants (77.6%) and 1,127 preterm infants (22.4%). Overall survival was 68.7%. A higher percentage of term infants were treated with extracorporeal membrane oxygenation (ECMO) (33% term vs 25.6% preterm). Preterm infants had a greater percentage of chromosomal abnormalities (4% term vs 8.1% preterm) and major cardiac anomalies (6.1% term vs 11.8% preterm). Also, a significantly higher percentage of term infants had repair of the hernia (86.3% term vs 69.4% preterm). Survival for infants that underwent repair was high in both groups (84.6% term vs 77.2% preterm). Survival decreased with decreasing gestational age (73.1% term vs 53.5% preterm). The odds ratio (OR) for death among preterm infants adjusted for patch repair, ECMO, chromosomal abnormalities, and major cardiac anomalies was OR 1.68 (95% confidence interval [CI], 1.34-2.11). CONCLUSION: Although outcomes for preterm infants are clearly worse than in the term infant, more than 50% of preterm infants still survived. Preterm infants with CDH remain a high-risk group. Although ECMO may be of limited value in the extremely premature infant with CDH, most preterm infants that live to undergo repair will survive. Prematurity should not be an independent factor in the treatment strategies of infants with CDH.

Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network.

OBJECTIVE: This report presents data from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network on care of and morbidity and mortality rates for very low birth weight infants, according to gestational age (GA). METHODS: Perinatal/neonatal data were collected for 9575 infants of extremely low GA (22-28 weeks) and very low birth weight (401-1500 g) who were born at network centers between January 1, 2003, and December 31, 2007. RESULTS: Rates of survival to discharge increased with increasing GA (6% at 22 weeks and 92% at 28 weeks); 1060 infants died at CONCLUSION: Although the majority of infants with GAs of >or=24 weeks survive, high rates of morbidity among survivors continue to be observed.

Content of prenatal care and spontaneous preterm birth: Findings from the 1988 National Maternal and Infant Health Survey

The purposes of this study were to examine (1) the relationship between selected components of the content of prenatal care and spontaneous preterm birth; and (2) the degree of comparability between maternal and caregivers' responses regarding the number of prenatal care visits, selected components of the content of prenatal care, and gestational age, based on analyses of the 1988 National Maternal and Infant Health Survey conducted by the National Centers for Health Statistics. Spontaneous preterm birth was subcategorized into very preterm and moderately preterm births, with term birth as the controls. The study population was limited to non-Hispanic Anglo- and African-American mothers. The racial differences in terms of birth outcomes were also compared.^ This study concluded that: (1) there was not a high degree of comparability (less than 80%) between maternal and prenatal care provider's responses regarding the number of prenatal care visits and the content of prenatal care; (2) there was a low degree of comparability (less than 50%) between maternal and infant's hospital of delivery responses regarding gestational age at birth; (3) there were differences in selected components of the content of prenatal care between the cases and controls, overall and stratified by ethnicity (i.e., hemoglobin/hematocrit test, weight measurement, and breast-feeding counseling), but they were confounded with missing values and associated preterm delivery bias; (4) there were differences in selected components of the content of prenatal care between Anglo- and African-American cases (i.e., vitamin/mineral supplement advice, weight measurement, smoking cessation and drug abuse counseling), but they, too, were difficult to interpret definitively due to item nonresponse and preterm delivery biases; (5) no significant predictive association between selected components of the content of prenatal care and spontaneous preterm birth was found; and (6) inadequate/intermediate prenatal care and birth out of wedlock were found to be associated with moderately preterm birth.^ Future research is needed to examine the validity of maternal and prenatal care providers' responses and identify the sources of disagreement between their responses. In addition, further studies are needed to examine the relationship between the quality of prenatal care and preterm birth. Finally, the completeness and quality of patient and provider data on the utilization and content of prenatal care needs to be strengthened in subsequent studies. ^