H. N. Lafeber

Development of the Hypothalamic-Pituitary-Adrenal Axis in the Fetus and Preterm Infant

The development of the hypothalamic-pituitary-adrenal (HPA) axis in the human fetus is a complex process. The feto-placental unit may be responsible for important maturational processes in vital organ systems in the fetus. A late gestational cortisol surge may be important in fetal maturation, particularly maturation of the lungs. Several striking differences exist between the function of the HPA axis in the fetus and in adults, such as a relative deficiency of 3beta-hydroxysteroid dehydrogenase in the fetal adrenal cortex. With the transition from intrauterine to extra-uterine life several changes occur in the function of the HPA axis. In infants born before term, the function of the HPA axis may still be immature at both the central and adrenal level. This immaturity of the HPA axis may be important in the development of neonatal morbidity. The present review describes the development of the HPA axis in the fetus and in preterm infants and discusses the possible role of HPA immaturity in the development of neonatal morbidity.

Neuromotor Function and School Performance in 7 year old children born as high-risk preterm infants

Neuromotor behavior was studied in 63 children at a mean age of 7 years. They were born at a gestational age less than 32 weeks and/or birthweight under 1500 g and were categorized according to their medical history in conformance with the Neonatal Medical Index (from category I to V, from few to serious complications). We included only children considered at high risk as categorized in III to V. The neuromotor behavior study focuses on different subcategories, such as hand function, quality of walking, posture, passive muscle tone, coordination, and diadochokinesia. Hand preference and/or lateralization, the presence of associated movements, and/or asymmetry were noted, as was school performance. Then gender, gestational age, birthweight, and dysmaturity were investigated as confounding factors. The outcome at 7 years was correlated with the Neonatal Medical Index and the neonatal brain ultrasonography classification. None of the children scored 100% on the combined subcategories. Nineteen children (30%) had an overall score between 75 and 99%. Significant relationships between all different subcategories were found. Lack of hand preference, poor lateralization, and male gender were related to poor overall outcome. Poor motor control was correlated to special schooling and education below age level. The Neonatal Medical Index proved to have a significant influence on total outcome and the subcategories at the age of 7 years, with the worst outcome in children formerly classified in category V. Neuromotor behavior at 7 years of age was not related to birthweight, gestational age, dysmaturity, and neonatal brain ultrasonography classification only. (J Child Neurol 2002;17:325-332).

Pharmacokinetics of meropenem in preterm neonates

The objective of this study was to evaluate and compare the pharmacokinetics of meropenem in premature neonates, both after the first dose and during steady state at day 5, after a 1-minute intravenous administration to evaluate the possibility of twice-daily administration. Seven premature neonates received 15 mg/kg meropenem twice daily on clinical grounds as a 1-minute infusion. After the first dose and during steady state at day 5, serum levels of meropenem were measured for 12 hours after intravenous administration. Meropenem pharmacokinetics at the first dose were studied in seven children (mean birth weight 925 g, mean postnatal age 21 days). Serum concentration–time curves could be described with a one-compartment model. Mean total body clearance was 0.157 L/kg per hour, volume of distribution was 0.74 L/kg, and half-life was 3.4 hours. At day 5 at steady state, pharmacokinetic properties did not differ significantly. No side effects were noted. A 1-minute intravenous administration is feasible. Pharmacokinetic properties are comparable at day 5 compared with the first dose, and half-life is such that twice-daily administration of 15 mg/kg produces adequate serum concentrations.

Predictive value of EEG in neonates with periventricular leukomalacia

The aim of this study was to evaluate whether EEG (i.e. positive Rolandic sharp waves) can be used to predict neurodevelopment in newborn infants with periventricular leukomalacia and compare the predictive value with that of MRI. A sequential cohort of neonates (n=45; 33 males, 12 females; mean gestational age 31.2 weeks, SD 2.7, range 27 to 37.8 weeks; mean birthweight 1592g, SD 601g) with periventricular hyperechogenicities on cranial ultrasound was recruited for this study. EEGs were analyzed for positive Rolandic sharp waves. Neurodevelopment was evaluated at the ages of 12 and 18 months. In the whole group the probability of a poor outcome was 24% and the probability of any impairment was 33%. If the number of positive Rolandic sharp waves was no more than 0.1 per minute, the probability of a poor outcome was reduced to 9% (95% confidence interval [95% CI] 2 to 27%) and the probability of any impairment was reduced to 13% (95% CI 4 to 32%). In all infants with more than 0.1 positive Rolandic sharp waves per minute the probability of a poor outcome was 41% (95% CI 23 to 61%) and of any impairment was 55% (95% CI 34 to 73%). In these infants MRI identified infants with a poor outcome with a sensitivity of 1.00 (95% CI 0.70 to 1.00) and a specificity of 0.92 (95% CI 0.67 to 0.99), and infants with any impairment with a sensitivity of 0.83 (95% CI 0.55 to 0.95) and a specificity of 1.00 (95% CI 0.72 to 1.00). Results suggest that if an EEG of an infant with periventricular leukomalacia contains no more than 0.1 positive Rolandic sharp waves per minute the probability of a normal or mildly delayed development is high (0.91, 95% CI 0.73 to 0.98). MRI enhances the accuracy of the outcome prediction slightly; however, owing to a wide confidence interval, this advantage is negligible. However, if the frequency of the positive Rolandic sharp waves exceeds 0.1 per minute, MRI can significantly enhance the precision of the prediction of outcome.

Growth in Preterm Infants Until Six Months Postterm: The Role of Insulin and IGF-I

Background/Aims: Since insulin-like growth factor type I (IGF-I) and insulin regulate growth in term infants, they were studied in relation to nutrient intake and growth until 6 months corrected age (CA) in preterm infants. Methods: In 138 preterm infants (51% male, gestational age (expressed as median (IQR)) 30.6 (1.9) weeks, birth weight 1,368 (389) g) weight SDS, length SDS, IGF-I, and insulin were measured at term age, 3 and 6 months CA. Results: IGF-I and insulin at term age were associated with weight SDS and length SDS at term age and 3 months CA. IGF-I and insulin at 3 months CA were associated with weight SDS and length SDS at 3 and 6 months CA. IGF-I and insulin at term age were negatively associated with gain in weight SDS and gain in length SDS between term age and 6 months CA (IGF-I: β = -1.03, 95% CI -1.65;-0.41, p = 0.001 and β = -0.78, 95% CI -1.32;-0.23, p = 0.005; insulin: β = -0.19, 95% CI -0.37;-0.01, p = 0.044 and β = -0.18, 95% CI -0.35;-0.01, p = 0.035). Nutrient intake was not associated with IGF-I or insulin. Conclusions: The present study suggests that IGF-I and insulin are important growth regulators in preterm infants until 6 months CA, independent of nutrient intake.

The corticotrophin‐releasing hormone test in preterm infants

The developing hypothalamic–pituitary–adrenal axis (HPAA) may be immature and not yet fully functional in preterm infants. This may result in an inappropriate adrenal response to stress. Little is known about the pituitary–adrenal response to corticotrophin‐releasing hormone (CRH) stimulation during the early neonatal period in preterm infants born before 32 weeks of gestation. Therefore, in a first study we investigated the pituitary–adrenal response to 1 µg/kg CRH i.v. in 13 preterm infants born ≤ 32 weeks of gestation. In addition, in a randomized placebo‐controlled study we compared the pituitary–adrenal response of 1 µg/kg CRH to placebo and stimulation with 2 µg/kg CRH.

Lean mass and fat mass accretion between term age and 6 months post-term in growth-restricted preterm infants

Early growth restriction followed by nutritional intakes that permit accelerated growth may result in adiposity and metabolic disease in later life. This study compared growth, body composition and nutritional intake between term age and 6 months post-term in 83 appropriate-for-gestational-age preterm infants with growth restriction at term age (AGA GR+), 15 AGA without growth restriction at term age (AGA GR−) and 33 small-for-gestational-age (SGA) preterm infants. AGA GR+ and SGA preterm infants had higher protein intake, higher energy intake and higher gain in weight SDS between term age and 6 months post-term, with similar lean mass (LM) and lower fat mass (FM) at 6 months post-term compared with AGA GR− preterm infants. In conclusion, despite higher energy and protein intake compared with AGA GR− preterm infants during the first 6 months post-term, AGA GR+ and SGA preterm infants restore their LM without excessive FM.

Gentamicin pharmacokinetics in preterm infants with a patent and a closed ductus arteriosus.

AbstractBackground and aim: A patent ductus arteriosus (PDA) may influence renal and hepatic blood flow and hence pharmacokinetics of drugs in neonates compared to neonates with a closed ductus arteriosus (CDA). A 10‐percent difference of gentamicin pharmacokinetic parameters between PDA and CDA has been reported, but its implications are unclear. The relevance of this difference relative to the variability within the neonatal population was investigated. Methods: Twenty‐four neonates (12 with a PDA and 12 with a CDA) treated with gentamicin were retrospectively included. Before closing treatment of the PDA, serum levels were drawn and analysed for regular therapeutic drug monitoring of gentamicin. Data were analysed using the standard two‐stage approach (STS) and an iterative 2‐stage Bayesian population analysis approach (It2B). Results: Both types of analysis showed no significant differences between both populations for gentamicin total body clearance per kg bodyweight (CL/kg). Volume of distribution per kg bodyweight (Vd/kg) tended to be larger and elimination rate (Kel) tended to be smaller in neonates with PDA. Multiple regression analysis showed for both populations highly significant correlations between total body clearance and body weight (p<0.0001) or gestational age (p<0.0001), and between volume of distribution and body weight (p<0.0001) or gestational age (p<0.0001). Conclusion: Although neonates with a PDA may have small differences in gentamicin pharmacokinetics compared to neonates with a CDA, this is not relevant for clinical practice taking the variability within that population into account.

35 Postnatal Serum Insulin-Like Growth Factor I Deficiency Is Associated with Chronic Lung Disease of Prematurity

Objective: Insulin-like growth factor I (IGF-I) is necessary for normal growth and development in infants. Recent research suggested that deficiency of IGF-I is associated with the development of oxygen-induced retinopathy of prematurity (1). We hypothesized that low IGF-I levels in might be a risk factor for oxygen-induced pulmonary damage in preterm infants, which causes chronic lung disease (CLD) of prematurity.Methods: We measured growth hormone (GH) secretory patterns and levels of IFG-I and IFG binding protein 3 (IGFBP-3) in 34 preterm infants (gestational ages: 25–32 weeks, weights 526-1985 grams) at risk of developing chronic lung disease. Measurements were performed in clinically stable infants, requiring respiratory support. Between the 4th and 12th day of life, 6 h (with hourly intervals) and 24 h (with 6 h intervals) growth hormone samples were taken. In addition, IGF-I and IGFBP-3 levels were measured in the first blood sample. Results were adjusted for gestational age and birth weight SD score.Results: No significant differences in GH concentration were found between the different time points studied in the 6 h or the 24 h profiles or in infants who developed CLD vs no CLD (mean GH respectively 77±11 vs 79±8 mg/l, p=0.86, adjusted p= 0.56). IGF-I levels were significantly lower in CLD vs no CLD even adjusted for gestational age and birth weight SD score (respectively 1.3±0.1 vs 1.9±0.2 nmol/l, p=0.02, adjusted p=0.04). IGFBP-3 levels were not significantly different between both groups (CLD 0.60±0.04 mg/l vs no CLD 0.71±0.05 mg/l, p=0.11, adjusted p=0.94).Conclusion: Our results support the hypothesis that IGF-1 deficiency may increase the risk of development of CLD. Since GH levels did not differ between infants who did developed CLD and those who did, differences in IGF-I levels may be explained by relative growth hormone resistance. Alternatively, levels may be lower by a decreased production of IGF-I in preterm infants. Our findings are comparable to those find by others with respect to the relationship between IGF-I and the development of retinopathy of prematurity. IGF-I may play an important role in the development of serious squelae associated with prematurity, which requires further investigation.

Cortisol and Growth Hormone (Gh) Secretion in Chronic Lung Disease (Cld) in the Preterm Human Newborn 248

Background: Cortisol and GH secretion were studied in preterm newborns to assess the relation between the secretion of these hormones and the development of CLD.