Nadja Haiden

A Randomized, Controlled Trial of the Effects of Adding Vitamin B12 and Folate to Erythropoietin for the Treatment of Anemia of Prematurity

BACKGROUND. Premature infants, especially those with birth weights of <1500 g, often suffer from anemia of prematurity and associated problems. Erythropoietin therapy is a safe effective way to prevent and to treat anemia of prematurity. We hypothesized that combined administration of vitamin B12 and folate with erythropoietin and iron would enhance erythropoietin-induced erythropoiesis. METHODS. In a randomized, controlled trial, 64 premature infants (birth weight: 801–1300 g) receiving erythropoietin and iron supplementation were assigned randomly to receive either vitamin B12 (3 μg/kg per day) and folate (100 μg/kg per day) (treatment group) or a lower dose of folate (60 μg/kg per day) (control group). RESULTS. During the 4-week observation period, vitamin B12 and folate enhanced erythropoietin-induced erythropoiesis significantly, as indicated by a 10% increase in red blood cell counts, compared with folate alone. Hemoglobin and hematocrit levels remained stable in the treatment group, whereas they decreased in the control group. Vitamin B12 levels in the treatment group increased over baseline and control values, whereas red blood cell folate levels were comparable between the groups. Subsequent analysis showed slight nonsignificant differences in baseline red blood cell count, hemoglobin level, hematocrit level, and mean corpuscular volume values, which must be addressed as a limitation. CONCLUSIONS. With the limitation of a slight imbalance in baseline data between the study groups, combined therapy with vitamin B12, folate, erythropoietin, and orally and intravenously administered iron seemed more effective in stimulating erythropoiesis among premature infants, compared with erythropoietin, iron, and low-dose folate alone. Additional trials are necessary to confirm these data.

Effects of a Combined Therapy of Erythropoietin, Iron, Folate, and Vitamin B12 on the Transfusion Requirements of Extremely Low Birth Weight Infants

OBJECTIVES. Erythropoietin is frequently administered to premature infants to stimulate erythropoiesis. The primary goal of erythropoietin therapy is to reduce transfusions, but the efficacy of erythropoietin has not been convincingly demonstrated in this regard. The aim of this trial was to investigate whether combined administration of vitamin B12, folic acid, iron, and erythropoietin could decrease transfusion requirements in extremely low birth weight infants. PATIENTS AND METHODS. In a randomized, controlled trial, extremely low birth weight infants with a birth weight ≤800g and a gestational age ≤32 weeks were randomly assigned to a group receiving combination treatment or a control arm. RESULTS. The treatment increased levels of folate in red blood cells, vitamin B12, ferritin, transferrin receptor levels in plasma, and reticulocyte counts. The proportion of infants requiring no transfusions was lower in the treatment group (38%) as compared with controls (5%). The treatment group and the need for mechanical ventilation were independent predictors of the number of transfusions in multiple regression analysis. Cox regression analysis indicated that combined therapy resulted in a 79% risk reduction for any transfusion. CONCLUSION. Combined treatment with erythropoietin, intravenous iron, folate, and vitamin B12 during the first weeks reduces the need for transfusion in extremely low birth weight infants.

Probiotics ( Lactobacillus acidophilus and Bifidobacterium bifidum ) prevent NEC in VLBW infants fed breast milk but not formula

Background:Specific probiotics prevent necrotizing enterocolitis (NEC). A mixture of lactobacilli and bifidobacteria (Infloran) was highly effective in Asian very-low-birth-weight (VLBW) infants. We analyzed the effect of Infloran on NEC, NEC severity, and the influence of enteral feedings (breast milk vs. formula) on NEC prevention in a cohort of European VLBW infants.Methods:Infloran was implemented for routine use at our department. VLBW infants receiving probiotics were prospectively followed (2010–2012) and compared with historic controls (2008–2009). Data on NEC, neonatal morbidity, feeding tolerance, and descriptive parameters on NEC cases were analyzed.Results:Infloran had no statistically significant impact on NEC (controls: 24/233 (10.3%); probiotics: 16/230 (7%); P = 0.2). However, NEC was significantly reduced in infants of the probiotics group who were fed any breast milk (20/179 (11.2%) vs. 10/183 (5.5%); P = 0.027), whereas it was ineffective in infants exclusively fed formula (4/54 (7.4%) vs. 6/44 (13.6%); P = 0.345). Occurrence of severe NEC (IIIb), time until full feeds, and gastric residuals were similar.Conclusion:Infloran was of lower efficacy in a European VLBW cohort and showed a reduction of NEC only in infants fed breast milk. Future studies should investigate the influence of feeding formula or breast milk on the effect of probiotics.

Changes in thrombopoiesis and platelet reactivity in extremely low birth weight infants undergoing erythropoietin therapy for treatment of anaemia of prematurity.

Erythropoietin (Epo) is frequently administered to premature infants to stimulate erythropoiesis. There is evidence from studies in animals and healthy adults that Epo also interacts with thrombopoiesis and platelet function. This study investigates the effect of Epo therapy on platelet reactivity, peripheral platelet counts and thiazole orange-positive (TO+) platelets in extremely low birth weight (ELBW) infants. In a randomised-controlled trial, ELBW infants with a birth weight < or =800 g and a gestational age < or =32 weeks were either randomised to a group receiving Epo during the first weeks of life or to a control group. Our results show that thrombin receptor-activating peptide (TRAP-6) -induced expression of P-selectin increased significantly during the first two weeks of Epo treatment. With the exception of week five, the number of TO+ platelets was significantly higher during the first eight weeks in Epo-treated infants compared to controls. The increase of TO+ platelets was not paralleled by an increase in total platelet count. We can conclude that Epo therapy has a short-lasting effect on platelet reactivity toTRAP-6 in ELBW infants during the first two weeks of life. Furthermore, Epo therapy is associated with an increase in the number of TO+ platelets compared to controls.

Small volume enemas do not accelerate meconium evacuation in very low birth weight infants

We hypothesized that small volume enemas accelerate meconium evacuation in very low birth weight (VLBW) infants. In a randomized controlled trial, VLBW infants (n = 81) received either repeated daily small volume enemas if complete spontaneous meconium passage failed within 24 h or no intervention. Small volume enemas did not accelerate complete meconium evacuation, which occurred after 6.0 to 9.6 (95% CI) d in the intervention group and after 7.7 to 11.0 (95% CI) d in the control group. No adverse events were observed. Daily administration of small volume enemas had no effect on total meconium evacuation defined by the time of last meconium passage.

Effect of fortifiers and additional protein on the osmolarity of human milk: is it still safe for the premature infant?

Objectives: The present guidelines of the American Academy of Pediatrics recommend that osmolarity not exceed 450 mOsm/kg (or approximately an osmolarity of 400 mOsm/L) for breast milk or infant formulae, to minimize the risk factors for necrotizing enterocolitis. A commercial protein supplement has been developed to meet special protein requirements (4.0–4.5 g · kg−1 · day−1) of infants with a birth weight <1000 g. Because its effect on osmolarity has not been systematically studied, we characterized the effects of fortification on the osmolarity of human milk (HM). Methods: Osmolarity of fresh and processed HM was measured at baseline, after fortification with a commercial HM fortifier and after further supplementation with additional protein increasing in 0.5-g steps up to 4.0 g. Measurements were performed immediately after adding fortifier and/or protein and after 24 hours. In addition, changes in osmolarity were determined after adding therapeutic additives such as iron, multivitamin supplement, and calcium-phosphorus capsules. Results: Native HM samples (n = 84) had 297 mOsm/L, (median; 95% confidence interval 295–299 mOsm/L). Adding HM fortifier increased osmolarity up to 436 mOsm/L (95% confidence interval 431–441 mOsm/L). Additional protein supplementation increased osmolarity by 23.5 mOsm/L per 0.5-g step, up to a maximum of 605 mOsm/L. Pasteurization decreased osmolarity by 20–30 mOsm/L (P < 0.001), and storage for 24 hours slightly increased osmolarity (by 11.5 mOsm/L P = 0.0002). Therapeutic additives increased osmolarity up to 868 mOsm/L. Conclusions: Adding HM fortifier and additional protein to HM increased osmolarity to >400 mOsm/L and therefore above the recommended threshold. Because of the excessive increase in osmolarity combinations of HM + fortifier and additional protein should not be applied together with multivitamins or other additives.

Microbial invasion of the amniotic cavity at birth is associated with adverse short-term outcome of preterm infants.

Abstract Aims: To determine the frequency and clinical significance of microbial invasion of the amniotic cavity at the time of delivery in preterm infants. Methods: Prospective cohort study during June 2001 and January 2002. Preterm infants < 33+6 weeks of gestation who had amniotic fluid and placental tissue sampled for culture during cesarean section were included. Results: Of a total of 80 neonates, 42 had negative culture results, 22 had growth of Ureaplasma urealyticum, and 16 had growth of other pathogens. Isolation of Ureaplasma urealyticum was associated with a decreased risk of developing hyaline membrane disease after birth but a more than 20 times increased risk of developing chronic lung disease. Patients with growth of other pathogens had a significantly higher mortality than patients with negative culture results. Conclusions: Isolation of microorganisms from the amniotic cavity at birth is associated with an adverse outcome of the preterm infant. In the light of extremely small numbers of positive blood cultures in preterm infants after birth, we consider it reasonable to recommend routine culturing of amniotic cavity tissues/fluid obtained during cesarean section in order to increase the identification rate of pathogens potentially involved in the pathogenesis of perinatal infections.

Pain and stress management in the Neonatal Intensive Care Unit — A national survey in Austria

ZusammenfassungNeugeborene sind — entgegen langjähriger Meinung — zur Schmerzwahrnehmung fähig und zeigen eine Vulnerabilität für schmerzreaktive Kurzzeit-und Langzeitkonsequenzen.Die Ursache eines inadäquaten analgetischen Managements ist zum einen begründet im mangelnden Bewusstsein, dass Neugeborene, besonders Frühgeborene Schmerzen empfinden können, viel mehr jedoch im Respekt vor potentiellen Nebenwirkungen von zentral wirksamen Medikamenten. Ziel der Studie ist die Erfassung gegenwärtigen Vorgehens zur Schmerzprävention, Analgesie und Sedierung in der Neonatologie.Die Arbeit umfasst die Ergebnisse einer Österreich weit durchgeführten Erhebung an neonatologischen Intensivstationen.Alle Befragten bestätigen, dass Neu- und Frühgeborene Schmerzen sowohl wahrnehmen als auch ausdrücken können, und nahezu alle meinten, Schmerz und die Reaktion darauf beeinflusse die neonatale Morbidität. Validerte Schmerzerfassungs-Scores werden an 11% aller befragten neonatologischen Intensivstationen (NICUs) angewandt, an 75% existieren standardisierte Analgesieprotokolle und an allen Abteilungen (100%) werden auch nicht pharmakologische Behandlungsstrategien angewandt. Die Anwendung präventiver Maßnahmen im Rahmen routinemäßig durchgeführter, schmerzhafter Prozeduren erfolgt in 8% bis 95%. In 8% findet Schmerzprävention vor Nabelgefäßkatheter Implantation statt, in 29% und 46% vor subcutanen Injektionen bzw. Fersenstich. Nahezu alle verabreichen Analgetika vor Lumbalpunktionen und Thoraxdrainagen und 100% im Falle einer elektiven Intubation.SchlussfolgerungDas Bewusstsein der Wertigkeit und Auswirkungen von Stress bei Neugeborenen, verursacht durch Schmerzen, ist unter Neonatologen sehr groß. Dennoch wird die Notwendigkeit einer suffizienten Analgesie bei dieser sensitiven Patientenpopulation nach wie vor unterschätzt. Kontinuierliche Fortbildung und Information über die sichere Anwendung analgetischer Medikation in der Neonatologie sind unumgänglich.SummaryNeonates are sensitive to pain and vulnerable to both its short-term and long-term effects. Management of analgesia is thought to be hampered by lack of awareness that newborns are capable of experiencing pain and by fears about adverse effects associated with analgesics. The purpose of this study was to assess current medical practice in preventive analgesia and sedation in the neonate throughout Austria.This report details the results of a survey in 28 neonatal intensive care units (NICUs) in Austria. Data collection took place from October to December 2001.All NICUs reported the capability of newborns to experience and express pain and nearly all stated the possibility of pain affecting morbidity. Validated scores for pain assessment were used by 11% of NICUs, standardized protocols for analgesia existed in 75%, and 100% practiced non-pharmacological treatment strategies. The use of preventive measures in routinely performed painful procedures ranged from 8% to 96%. For example, only 8% of NICUs prevent distress and pain prior to umbilical vessel catheterization, 29% prior to subcutaneous injections and 46% prior to heel lancing. Nearly all NICUs apply analgesia before lumbar puncture and thoracicdrain placement, and all use analgesic and/or sedative medication in elective intubation.ConclusionThere is widespread awareness among neonatologists of the importance and effects of distress caused by pain in newborns. However, the necessity of providing sufficient analgesia is underestimated. Further information on the safety of analgesic drugs in neonatology is imperative.

The Effect of an Osmotic Contrast Agent on Complete Meconium Evacuation in Preterm Infants

OBJECTIVE: To determine whether enteral application of the osmotic contrast agent Gastrografin accelerates complete meconium excretion and improves feeding tolerance in very low birth weight infants. METHODS: This study was a stratified, randomized, placebo-controlled trial in premature infants with a birth weight <1500 g and a gestational age <32 weeks who received 3 mL/kg Gastrografin diluted 1:3 with water within their first 24 hours of life, or placebo. RESULTS: Passage of last meconium occurred after a median of 7 days (95% confidence interval: 6–9 days, n = 39) in the intervention group and after 8 days (95% confidence interval: 7–10 days, n = 39) in the control group (P = .61); however, Gastrografin application was associated with a 7.5-day shorter time to full enteral feedings, a 24-day shorter stay in the NICU, and a 17-day reduction in the overall hospital stay in the intervention group compared with the control group. A numerically higher incidence of necrotizing enterocolitis (21%) was observed in the intervention group, however. CONCLUSIONS: Gastrografin application did not accelerate meconium evacuation, but the higher stool frequency during the first week of life had a beneficial effect on the time to full enteral feedings and later hospital stay; however, it may increase the necrotizing enterocolitis risk. Further investigations are needed with modified protocols, and the prophylactic use of Gastrografin cannot currently be recommended without further clinical trials.

Characterization and Differentiation of Iron Status in Anemic Very Low Birth Weight Infants Using a Diagnostic Nomogram

Background: In the early weeks of life, very low birth weight (VLBW) infants experience intense laboratory blood sampling leading to clinically significant anemia and the need for red blood cell transfusion. Although controversial, treatment with recombinant human erythropoietin (EPO) and iron has been recommended to stimulate erythropoiesis; optimal dosing of EPO and iron is still uncertain. Objectives: To assess the validity of a four-quadrant diagnostic plot of iron availability (ferritin index) versus iron demand for erythropoiesis (reticulocyte hemoglobin content, CHr) for differentiating iron status in anemic VLBW infants. Methods: Study subjects were enrolled in a previously reported randomized controlled trial of clinically stable VLBW infants <31 weeks’ gestation and <1,300 g at birth to receive 18 days of treatment with: group 1: oral iron; group 2: EPO + oral iron, and group 3: EPO + intravenous + oral iron. Results: At the end of treatment the ferritin index was significantly higher in both EPO groups compared to the control group. By day 18, CHr of the control group declined into the quadrant of the diagnostic plot characteristic of functional iron deficiency and anemia of chronic disease. Both EPO groups ended in the quadrants that are characteristic for latent iron deficiency and iron deficiency anemia, respectively. Conclusions: The diagnostic plot for differentiating anemia in VLBW infants may be an informative, clinically useful tool for iron status assessment under different physiologic and therapeutic erythropoietic states. Larger additional studies in difficult patient populations are needed before the clinical utility of this diagnostic procedure can be unequivocally confirmed.