Gerhard Jorch

The Effect of Epoetin-beta (recombinant-human-erythropoietin) On the Need for Transfusion in Very-low-birth-weight Infants

BACKGROUND Anemia of prematurity is characterized by low reticulocyte counts and inadequate erythropoietin response, for which many very-low-birth-weight infants receive multiple blood transfusions. We investigated whether early treatment of such infants with recombinant human erythropoietin would reduce their need for transfusions. METHODS We performed a controlled, blinded trial in 241 infants with very low birth weights at 12 centers in six European countries. When three days old, the infants were randomly assigned either to the epoetin group or to the control group. Those in the epoetin group received 250 IU of epoetin beta per kilogram of body weight subcutaneously three times a week from day 3 to day 42 (for a total of 17 doses); those in the control group did not receive this drug. Infants in both groups received oral iron (2 mg per day) from day 14 onward. RESULTS The control infants needed a mean of 1.25 transfusions each, as compared with 0.87 transfusion for epoetin-treated infants (P = 0.013). The median cumulative volume of blood transfused per kilogram per day was 0.41 ml in the control group (first quartile, 0 ml; third quartile, 0.8 ml) and 0.09 ml in the epoetin group (first quartile, 0 ml; third quartile, 0.8 ml) (P = 0.044). The rate of success, defined as an absence of need for transfusions and a hematocrit that never fell below 32 percent, was 4.1 percent in the control group and 27.5 percent in the epoetin group (P = 0.008). Epoetin was most beneficial in boys with birth weights of 1200 g or more and a base-line hematocrit of 48 percent or more. No toxic effects were observed in the epoetin group; as compared with the control group, the epoetin group had an increased incidence of septicemia (14 vs. 7 episodes, P not significant) and reduced weight gain (520 vs. 571 g, P = 0.02). CONCLUSIONS Infants with very low birth weights have less need of transfusions if given epoetin beta during the first six weeks of life (250 IU per kilogram three times a week). We recommend early epoetin treatment for all such infants, but further studies of nutrition and iron supplementation during treatment are needed.

Modifiable risk factors for SIDS in Germany: Results of GeSID

BACKGROUND The incidence of sudden infant death syndrome (SIDS) has been falling in Germany over the last decade. However, little is known about the prevalence and the importance of well-known risk factors in Germany since a local prevention campaign in 1992. DESIGN A 3-y, population-based, case-control study was conducted in half of Germany, consisting of 333 cases. All sudden and unexpected deaths in infancy, if they fitted the inclusion criteria, were included in the study. Parental interview was carried out soon after the death, and three living control infants, matched for age, gender, region and sleep time, were recruited. RESULTS The prevalence of placing infants prone to sleep was only 4% in the control group, but this was associated with a markedly increased risk of SIDS (adjusted odds ration, aOR=6.08). Other modifiable risk factors for SIDS were: maternal smoking during pregnancy, breastfeeding for less than 2 wk (aOR=1.71) and co-sleeping (aOR=2.71), while using a pacifier during the last sleep reduced the risk (aOR=0.39). CONCLUSIONS Previously recognized risk factors for SIDS also occur in Germany. Despite knowledge about the major modifiable risk factors for SIDS, these factors are still present in Germany. To reduce the incidence of SIDS in Germany, a continued effort is needed to inform all parents about preventable risk factors for SIDS.

Neonatal outcome in small for gestational age infants: do they really better?

Abstract Background: There still is a controversy as to the neonatal outcome of small for gestational age (SGA) infants compared to a appropriate for gestational age (AGA) preterm infants. As a part of a randomized multicenter trial on timing of bovine surfactant therapy, we aimed at investigating short-term outcome variables in SGA-infants compared with AGA-infants. Methods: SGA-infants were classified weighing below the 10th percentile at birth and were compared to AGA-infants in terms of prenatal and neonatal characteristics and neonatal outcome. Results: A total of 317 infants were enrolled, 59 SGA-and 258 AGA-infants. Both groups did not differ in gestational age, however, SGA-infants had a lower birth weight. Preterm premature rupture of fetal membranes was observed more frequently in AGA-, preeclampsia in SGA-infants. The rate of intubation, severity of RDS, rate of surfactant administration, pulmonary airleaks and days on the ventilator did not differ between both groups. However prolonged nasal CPAP, supplemental oxygen therapy and chronic lung disease at 28 days and 36 weeks was diagnosed more often in SGA-infants. Furthermore mortality was significantly higher in SGA-infants as well as total NICU and total hospital days. Conclusion: As SGA-infants have an increased mortality rate and an increased risk for developing chronic lung disease, further studies should focus on prevention of intrauterine growth restriction and its complications.

Risk factors for intraventricular hemorrhage in a birth cohort of 3721 premature infants.

Abstract Aims: In our study we determined possible risk factors for intraventricular hemorrhage grade III to IV (IVH) based on a regional German neonatal data base and tried to build a logistic-regression model to predict the risk of IVH according to gestational age. Materials: We identified 3721 premature infants, 22 to 36 completed weeks of gestational age, born from 1994 through 1997. 136 (3.7%) IVH were diagnosed sonographically. 60 (44%) infants with IVH died. We examined the following variables as risk factors for IVH: gestational age, sex, blood pH of 7.2 or less, body temperature of 35°C or less, multiple birth, small-for-gestational age, intubation after birth, transport to another hospital. Results: In the full logistic regression model sex, blood pH of 7.2 or less, multiple birth, and small-for-gestational age were not associated with a significant risk of IVH. Body temperature of 35°C or less was associated with an increased risk of IVH (adjusted odds ratio, 1.92; 95% confidence interval, 1.09 to 3.40). Intubation after birth increased the risk of IVH in neonates under 28 weeks of gestational age (OR, 3.72; 95% CI, 1,65 to 8.38) only to a moderate extent, but significantly in neonates 32 to 36 weeks of gestational age (OR, 16.51; 95% CI: 7.35 to 36.18). The risk of IVH was mainly related to gestational age. Neonates delivered before 28 weeks of gestation (OR, 75.72; 95% CI, 46.14 to 124.30) faced the highest risk of IVH. Transport to another hospital was connected with an increased risk of IVH regardless of gestational age (adjusted OR, 1.95; 95% CI, 1.07 to 2.56). Conclusion: The frequency of IVH could be reduced significantly, if extremely premature infants, the vast majority of patients suffering from IVH, did not have to be transferred postnatally to another hospital.

Impact on blood pressure and intestinal perfusion of dobutamine or dopamine in hypotensive preterm infants

In a prospective study hemodynamic effects of dobutamine or dopamine (10 micrograms/kg/min) were investigated in 20 preterm infants who had protracted arterial hypotension refractory to volume therapy. Doppler ultrasonography of the superior mesenteric artery (SMA) was applied to verify intestinal perfusion and blood pressure was recorded in parallel. Mean arterial pressure (MAP) raised significantly in both groups (from 31.0 +/- 6.8 to 37.7 +/- 9.8 mm Hg during dobutamine and from 27.7 +/- 3.6 to 36.0 +/- 9.3 mm Hg during dopamine). Mean blood flow velocity increased from 25.8 +/- 13.5 to 31.5 +/- 16 cm/s with dobutamine and from 16.3 +/- 5.0 to 19.0 +/- 6.0 cm/s with dopamine (significant for dobutamine). Vascular resistance of SMA (indicated by resistance index; RI) decreased from 0.81 +/- 0.07 to 0.74 +/- 0.11 for dobutamine and from 0.89 +/- 0.06 to 0.79 +/- 0.07 for dopamine (significant for both groups). These data indicate that in the dose tested here both catecholamines are equally effective in raising MAP and lead to a significant increase of intestinal perfusion. Thus, a negative impact on mesenteric blood supply, predisposing to necrotizing enterocolitis, is not probable.

German study on sudden infant death (GeSID): design, epidemiological and pathological profile

The German study on sudden infant death (GeSID) is a multi-centre case-control study aiming at the assessment of etiological factors and risk factors of SIDS. This report describes the study design and the methods applied and presents some general findings. Between 1998 and 2001, 455 cases of sudden and unexpected death of infants aged between 8 and 365 days were recruited into the study. The study comprised at least 11 out of the 16 German states with 18 centres involved. In 1999 and 2000, 75% of all SIDS cases registered with the Federal Office of Statistics (ICD 10/R95, n=384) in the study area were recruited into the study (n=286). A standardised autopsy including extended histology, microbiology, virology, toxicology and neuropathology investigations was carried out. Of the parents 82% (n=373) agreed to fill in an extensive questionnaire containing 120 questions reflecting all important aspects of the infant’s development. For each SIDS case, the parents of three living control infants were interviewed. These controls were matched for age, gender and region (n=1,118). The response rate of the controls was 58.7%. Data were linked with medical records obtained from obstetrics departments, the children’s hospitals, and general practitioners. Death scene investigation was performed in 4 study areas (cases: n=64, controls: n=191). All cases were classified into one of 4 categories using defined criteria: 7.3% of the children were assigned to category 1 (no pathological findings: SIDS), 61.1% to category 2 (minor findings: SIDS+), 20.4% to category 3 (severe findings: SIDS+) and 11.2% to category 4 (findings which explained the death: non-SIDS). In case conferences the previous history and circumstantial factors were included and an extended category (E-cat.) was defined. The consideration of these factors for the final classification is of great importance in the causal explanation of some cases. An analysis of 18 main variables in cases of categories 1–3 (SIDS) compared to the cases of category 4 (non-SIDS) showed significant differences for the sleeping position, coughing the day before death and breast-feeding indicating that the cases of both groups should be separated for further analyses.

Do risk factors differ between explained sudden unexpected death in infancy and sudden infant death syndrome

Background: In Germany, 2910 infants died in 2004; for many infants the reason was clear, especially prematurity or congenital abnormalities. However, 394 babies die every year suddenly and unexpectedly. The cause may be immediately clear, but is often not obvious. Aims: (1) To describe the causes of explained sudden unexpected death in infancy (SUDI) and (2) to compare risk factors for sudden infant death syndrome (SIDS) and explained SUDI. Methods: A 3-year population-based case–control study in Germany, 1998–2001. Results: 455 deaths, of which 51 (11.2%) were explained. Most of these deaths were due to respiratory or generalised infections. The risk factors for SIDS and explained SUDI were remarkably similar except for sleep position and breast feeding. Prone sleeping position is a major risk factor for SIDS (adjusted odds ratio (OR) 7.16, 95% confidence interval (CI) 3.85 to 13.31) but not for explained SUDI (adjusted OR 1.71, 95% CI 0.25 to 11.57). Not being breast fed in the first 2 weeks of life is a risk factor for SIDS (adjusted OR 2.37, 95% CI 1.46 to 3.84) but not for explained SUDI (adjusted OR 0.39, 95% CI 0.08 to 1.83). Conclusions: Prone sleeping position is a unique risk factor for SIDS. Socioeconomic disadvantage and maternal smoking are risk factors for both SIDS and explained SUDI, and provide an opportunity for targeted intervention.

Reproducibility of Cerebral Near Infrared Spectroscopy in Neonates

Near infrared spectroscopy (NIRS) allows to study cerebral hemodynamics and oxygenation in neonates, which may be useful for early detection of cerebral hypoxemia. So far this method is not reliable enough to be used clinically. Reproducibility is one of the prerequisites for reliable quantitative monitoring. The aim of this study was to assess the reproducibility of the NIRS parameters HbO2 and HbD (oxygenated and deoxygenated hemoglobin concentration) and the derived NIRS parameters HbT (tissue hemoglobin concentration, HbT = HbO2 + HbD) and rSO2 (regional cerebral oxygen saturation, rSO2 = HbO2/HbT). Two observers repeated a total number of 500 measurements in 25 neonates. Additionally, a baseline measurement was done to assess the physiological variation in every neonate. For all NIRS parameters, the inter-patient variance contributed most to the total variance, while the interobserver variance was the smallest variance component. The cerebral oxygen saturation parameter rSO2 showed a good reproducibility, with an inter-measurement variance slightly but not significantly higher than the physiological baseline variation. The NIRS concentration parameters HbO2, HbD, and HbT were less reproducible, with significant variation due to repeated sensor replacement. However, for cerebral oximetry rSO2 is likely to be more important than the other NIRS parameters, so that NIRS has the potential to become a quantitative cerebral monitoring method.

Epidemiological features of sudden infant death after a German intervention campaign in 1992.

Abstract After national intervention campaigns, considerable declines in incidence for both sudden infant death (SID) and prone position have been observed worldwide. In the following investigation, German data on postinterventional risk factor patterns are presented for the first time. We analysed data from a 2-year population-based case-control study on SID carried out in two German districts between 1993 and 1994. We confirmed Complete covering of the baby (OR = 44.9, 95%-CI 95, 291), prone sleeping position (OR = 11.7; 5.3, 26.2), heavy maternal smoking during pregnancy (OR = 8.5; 3.2, 33.2 for > ten cigarettes per day), non-breastfeeding (OR = 7.7; 2.7, 22.3) and missing maternal professional training (OR = 7.6; 3.6, 16.2) as risk factors for cot death. After adjustment for other major risk factors in a logistic regression model, sleeping on cushions lost statistical significance, whereas all other major risk factors remained relevant. Conclusions Despite intervention campaigns, complete covering of the baby, prone position and heavy maternal smoking are still major risk factors for cot death. Except for sleeping on cushions, all major epidemiological risk factors for cot death act independantly. Despite encouraging success in the reduction of risk factors for cot death, there is still substantial need for future endeavours towards a further reduction of modifiable risk factors for SID.

Neuroblastoma triggers an immunoevasive program involving galectin-1-dependent modulation of T cell and dendritic cell compartments

The immunosuppressive strategies devised by neuroblastoma (NB), the most common solid extracranial childhood cancer, are poorly understood. Here, we identified an immunoevasive program triggered by NB through secretion of galectin‐1 (Gal‐1), a multifunctional glycan‐binding protein. Human and mouse NB cells express and secrete Gal‐1, which negatively regulates T cell and dendritic cell function. When injected subcutaneously in syngeneic A/J mice, knockdown transfectants expressing low amounts of Gal‐1 (NXS2/L) showed reduction of primary tumor growth by 83–90% and prevented spontaneous liver metastases in contrast to NXS2 cell variants (NXS2/H, NXS2 wildtype) expressing high amounts of Gal‐1. Splenocytes from mice receiving Gal‐1 knockdown NXS2/L cells secreted higher amounts of IFN‐γ and displayed enhanced cytotoxic T‐cell function compared to NXS2/H or NXS2 controls. Immunohistochemical analysis revealed a six‐ to tenfold increase in the frequency of CD4+ and CD8+ T cells infiltrating tumors from mice receiving knockdown transfectants. This effect was confirmed by in vitro migration assays. Finally, supernatants of NXS2/H or NXS2 cells suppressed dendritic cell (DC) maturation and induce T cell apoptosis, whereas these effects were only marginal on DCs and T cells exposed to supernatants from NXS2/L cells. These results demonstrate a novel immunoinhibitory role of the Gal‐1‐glycan axis in NB, highlighting an alternative target for novel immunotherapeutic modalities.