Changes in management policies for extremely preterm births and neonatal outcomes from 2003 to 2012: two population-based studies in ten European regions.

OBJECTIVE: To investigate changes in maternity and neonatal unit policies towards extremely preterm infants (EPTIs) between 2003 and 2012, and concurrent trends in their mortality and morbidity in ten European regions. DESIGN: Population-based cohort studies in 2003 (MOSAIC study) and 2011/2012 (EPICE study) and questionnaires from hospitals. SETTING: 70 hospitals in ten European regions. POPULATION: Infants born at <27 weeks of gestational age (GA) in hospitals participating in both the MOSAIC and EPICE studies (1240 in 2003, 1293 in 2011/2012). METHODS: We used McNemar's Chi2 test, paired t-tests and conditional logistic regression for comparisons over time. MAIN OUTCOMES MEASURES: Reported policies, mortality and morbidity of EPTIs. RESULTS: The lowest GA at which maternity units reported performing a caesarean section for acute distress of a singleton non-malformed fetus decreased from an average of 24.7 to 24.1 weeks (P < 0.01) when parents were in favour of active management, and 26.1 to 25.2 weeks (P = 0.01) when parents were against. Units reported that neonatologists were called more often for spontaneous deliveries starting at 22 weeks GA in 2012 and more often made decisions about active resuscitation alone, rather than in multidisciplinary teams. In-hospital mortality after live birth for EPTIs decreased from 50% to 42% (P < 0.01). Units reporting more active management in 2012 than 2003 had higher mortality in 2003 (55% versus 43%; P < 0.01) and experienced larger declines (55 to 44%; P < 0.001) than units where policies stayed the same (43 to 37%; P = 0.1). CONCLUSIONS: European hospitals reporting changes in management policies experienced larger survival gains for EPTIs. TWEETABLE ABSTRACT: Changes in reported policies for management of extremely preterm births were related to mortality declines.

[Treatment of neonatal asphyxia with a special focus on therapeutic hypothermia]. / Behandlung der neonatalen Asphyxie unter besonderer Berücksichtigung der therapeutischen Hypothermie.

In recent years the treatment of newborns for neonatal asphyxia has experienced a lot of new developments. A major milestone were the positive results of various trials for prophylactic treatment of hypoxic-ischemic encephalopathy by moderate cooling of the child or of his head. With this paper we attempt to provide a consented guideline to aid in the treatment decision for affected newborns and thus achieve a more homogeneous treatment strategy throughout Germany.

[Planning delivery in cases of congenital malformations from the neonatologist's point of view]. / Geburtsplanung bei fetalen Fehlbildungen aus neonatologischer Sicht.

Nowadays, most major congenital malformations are detected by prenatal ultrasound long before birth. This offers the opportunity to plan and organise the birth of such a baby in the most favourable setting. This paper gives an overview about how to decide on place, timing, and mode of delivery in some typical congenital malformations from the neonatologist's point of view. As, in most cases scientific evidence is lacking, there is an urgent need for prospective clinical trials. The question concerning the best place of birth is answered in a national guideline, which has been consented by several scientific societies. In this guideline, the transfer of the pregnant woman to a high level perinatal centre is recommended in the case of a known foetal malformation. Delivery outside a perinatal centre has been shown to increase mortality in infants with congenital diaphragmatic hernia and complications in infants born with gastroschisis. With respect to the timing of the delivery, the risks of an iatrogenic preterm birth must be considered in relation to the potential benefit for the newborn baby. There seems to be some advantage of a birth before the regular date only in few malformations. In most cases of congenital malformation, only a Caesarean section has a remarkable advantage with respect to the organisation of the delivery room management, but has no medical necessity for the baby. In summary, the delivery of a baby with a congenital malformation should be planned and organised by an interdisciplinary team of prenatal and postnatal specialists in close contact and consent with the parents.

Do clown visits improve psychological and sense of physical well-being of hospitalized pediatric patients? A randomized-controlled trial.

The study tested whether clown visits would be associated with an increase in psychological and perceived physical well-being of pediatric patients. Patients (6-14 years old) were randomized to a clown visit (n=50) or no-visit control (n=50). Patients and parents were administered a modified version of the KINDL-R questionnaire at pretest, immediately after the clown visit (posttest), and at a 4-h follow-up. The experimental group showed an increase in self-reported and parent-reported psychological well-being at posttest. However, these effects were not maintained at follow-up. There was no effect of the clown visit on perceived physical well-being. It is concluded that clown visits appear to improve psychological well-being of pediatric patients, but the effects may only be short lived.

Plasmapheresis prior to omalizumab administration in a 15-year-old boy with severe asthma and very high IgE levels: sustained effect over 2 years.

BACKGROUND: Anti-IgE therapy with omalizumab is an innovative therapy option in patients with severe allergic asthma. However, many patients are excluded from this treatment due to very high serum IgE levels which lie above the weight-dependent cut-off for a reasonable omalizumab administration (700 kU/l). OBJECTIVE: We sought to evaluate whether a preceding plasma exchange is suitable to establish the starting basis for a subsequent anti-IgE therapy in a 15 year-old boy with steroid-resistant unstable allergic asthma whose pretreatment serum IgE levels ranged between 3 000 and 8 000 kU/l. METHODS: Our aim was to create a period with relatively low IgE serum concentrations, which could be overridden by a high dose of omalizumab. 3 sessions of plasmapheresis were performed and 3×3 000 ml plasma were exchanged against albumin solution. RESULTS: We removed an absolute amount of 8 650 kU total IgE. During plasmapheresis, serum IgE levels markedly declined and fell below 500 kU/l. Immediately after the third plasma exchange, we started omalizumab therapy. As expected, total IgE levels began to rise again upon cessation of plasmapheresis, and after 2 months the pre-treatment values were reached. In contrast, serum concentrations of free IgE remained stable on a level of about 80 kU/l during the whole observation period. During this period, the boy displayed a considerable improvement of asthma control and an increase in quality of life. In addition, his previously poor lung function normalized. CONCLUSIONS: Plasmapheresis prior to omalizumab administration is suitable to temporarily reduce grossly elevated serum IgE levels and might facilitate anti-IgE therapy in selected patients previously considered not suitable for this therapy.

Composition of the immunoglobulin classic antigen-binding site regulates allergic airway inflammation in a murine model of experimental asthma.

BACKGROUND: When bound to mast cell FcepsilonRI, IgE serves as antigen receptor for allergic reactions, permitting specific identification of the allergen. Although the core of the classic antigen-binding site is heavy chain complementarity determining region 3 (CDR-H3), recent studies suggest that allergens might also bind IgE in a superantigen-like fashion outside the classic antigen-binding site. OBJECTIVE: We sought to evaluate the contribution of the classic CDR-H3-centric antigen-binding site to the development of an allergic phenotype. METHODS: Using a murine model of experimental asthma, we characterized a gene-targeted mouse strain expressing an altered range of CDR-H3s (DeltaD-iD mice) in response to the hydrophobic allergen ovalbumin (OVA). Mutant and wild-type (wt) mice were sensitized intraperitoneally with OVA; non-sensitized mice served as controls. RESULTS: We found the composition of the classic CDR-H3-centric antigen-binding site to be critical for the development of characteristic aspects of allergic asthma. (i) Compared with wt animals, DeltaD-iD mice showed a significantly less pronounced OVA-induced rise in allergen-specific IgE levels and hence in total serum IgE levels. (ii) In addition, DeltaD-iD mice demonstrated a significant reduction in eosinophilic airway inflammation, as well as in interleukin-4 (IL-4), IL-5 and IL-13 levels in BAL fluids. CONCLUSION: Allergic sensitization and airway inflammation depend on the composition of the predominant CDR-H3 repertoire, suggesting that the classic CDR-H3-centric antigen-binding site plays a crucial role in creating the immunological interface between allergen and IgE. Our results further emphasize a central role of IgE, not only in mediating but also in regulating the allergic immune response.

Organisation of obstetric services for very preterm births in Europe: results from the MOSAIC project.

OBJECTIVE: To study the impact of the organisation of obstetric services on the regionalisation of care for very preterm births. DESIGN: Cohort study. SETTING: Ten European regions covering 490 000 live births. POPULATION: All children born in 2003 between 24 and 31 weeks of gestation. METHOD: The rate of specialised maternity units per 10 000 total births, the proportion of total births in specialised units and the proportion of very preterm births by referral status in specialised units were compared. MAIN OUTCOME MEASURE: Birth in a specialised maternity unit (level III unit or unit with a large neonatal unit (at least 50 annual very preterm admissions). RESULTS: The organisation of obstetric care varied in these regions with respect to the supply of level III units (from 2.3 per 10 000 births in the Portuguese region to 0.2 in the Polish region), their characteristics (annual number of deliveries, 24 hour presence of a trained obstetrician) and the proportion of all births (term and preterm) that occur in these units. The proportion of very preterm births in level III units ranged from 93 to 63% in the regions. Different approaches were used to obtain a high level of regionalisation: high proportions of total deliveries in specialised units, high proportions of in utero transfers or high proportions of high-risk women who were referred to a specialised unit during pregnancy. CONCLUSION: Consensus does not exist on the optimal characteristics of specialised units but regionalisation may be achieved in different models of organisation of obstetric services.

Obstetric interventions for babies born before 28 weeks of gestation in Europe: results of the MOSAIC study.

OBJECTIVE: To describe obstetric intervention for extremely preterm births in ten European regions and assess its impact on mortality and short term morbidity. DESIGN: Prospective observational cohort study. SETTING: Ten regions from nine countries participating in the 'Models of Organising Access to Intensive Care for Very Preterm Babies in Europe' (MOSAIC) project. POPULATION: All births from 22 to 29 weeks of gestation (n = 4146) in 2003, excluding terminations of pregnancy. METHODS: Comparison of three obstetric interventions (antenatal corticosteroids, antenatal transfer and caesarean section for fetal indication) rates at 22-23, 24-25 and 26-27 weeks to that at 28-29 weeks and the association of the level of intervention with pregnancy outcome. MAIN OUTCOME MEASURES: Use of antenatal corticosteroids, antenatal transfer and caesarean section by two-week gestational age groups as well as a composite score of these three interventions. Outcomes included stillbirth, in-hospital mortality and intraventricular haemorrhage (IVH) grades III and IV and/or periventricular leucomalacia (PVL) and bronchopulmonary dysplasia (BPD). RESULTS: There were large differences between regions in interventions for births at 22-23 and 24-25 weeks. Differences were most pronounced at 24-25 weeks; in some regions these babies received the same care as babies of 28-29 weeks, whereas elsewhere levels of intervention were distinctly lower. Before 26 weeks and especially at 24-25 weeks, there was an association between the composite intervention score and mortality. No association was observed at 26-27 weeks. For survivors at 24-25 weeks, the intervention score was associated with higher rates of BPD, but not with IVH or PVL. CONCLUSIONS: There are large differences between European regions in obstetric practices at the lower limit of viability and these are related to outcome, especially at 24-25 weeks.

Hyperferritinemia as the diagnostic clue in life-threatening hemophagocytic lymphohistiocytosis.

We report on a seventeen year old girl with persistent fever of unknown origin. An initial episode of abdominal pain led to laparotomy and appendectomy, which did not reveal any pathological findings. In the course of the next 3 weeks, the girl's general condition progressively deteriorated. Despite extensive diagnostics, no explanation was found. In summary, the girl was cared for by five different departments in two hospitals before she was admitted to our Children's Hospital. We too were initially misguided by the clinical picture of an infectious disease and treated the girl unsuccessfully with antibiotics. The clue in this case was the finding of a markedly elevated level of serum ferritin. While a normal upper value of less than 400 microg/l is reported, our patient displayed levels above 60,000 microg/l. Such extreme elevations of serum ferritin have been almost exclusively reported for hemophagocytic syndromes, as hemophagocytic lymphohistiocytosis (HLH). In HLH, impaired cytolytic function of T cells and natural killer cells leads to a state of hyperinflammation. We treated our patient with immunoglobulins and corticosteroids. Simultaneously, we started immunomodulatory therapy with oral cyclosporine A. The clinical response to this treatment was remarkable. The child's general condition stabilized quickly and the fever vanished. Additionally, the recovery was accompanied by a normalization of laboratory findings. In conclusion, HLH is a potentially life-threatening disease, which has to be considered in cases with fever of unknown origin. In our case, the diagnostic clue was an extreme elevation of ferritin.

[Risk factors and prevention of retinopathy of prematurity]. / Risikofaktoren und Prävention der Retinopathia praematurorum.

The history of retinopathy of prematurity (ROP) gives a prime example of how dangerous the uncontrolled introduction of a new medical treatment--particularly in the field of neonatology--may be. The most important risk factors for the development of ROP are the immaturity of premature infants as well as uncontrolled and/or inadequate treatment with oxygen. In comparison to the fetus, the premature infant is exposed to a nonphysiologically high oxygen concentration. This hyperoxia leads to formation of aggressive oxygen radicals on the one hand and, on the other hand, to temporarily reduced production of growth factors such as vascular endothelial growth factor and erythropoietin, which both play an important role in the pathogenesis of ROP. The most important measure to prevent ROP is restrictive and carefully monitored oxygen treatment. Medical treatment to prevent ROP includes injection of D-penicillamine and retinol, but the available data are still limited, particularly with regard to the long-term effects of this treatment. A higher oxygenation in prethreshold ROP does not lead to recovery of ocular findings, but it increases the incidence of pulmonary complications. A reduction of light intensity in neonatal intensive care units proved not to be efficient for preventing ROP. To avoid blindness, standardized screening of the risk group is needed.

Effects of standardized acoustic stimulation in premature infants: a randomized controlled trial.

OBJECTIVE: The objective of this study was to investigate the effects of recorded lullabies and taped maternal voice in premature infants. STUDY DESIGN: Sixty-two preterm infants in a stable condition with 30<37 weeks of gestation and <10 days of postnatal age were randomly assigned to hear (A) recorded lullabies or (B) taped maternal voice for 30 min each evening during 14 consecutive days or (C) receive no standardized acoustic stimulation (control group). Heart rate and respiratory rate were recorded daily before, during and after the intervention (A and B) or a comparable period with no intervention (C), whereas activity was measured on days 1, 7 and 14 of the intervention using accelerometers. RESULTS: Both interventions led to a significant decrease in heart rate and respiratory rate during and after the stimulation when compared with the control group. The changes were more pronounced in infants with higher gestational ages (P=0.001). Lower activity was measured during the intervention when compared with the control group (P<0.01). CONCLUSIONS: Standardized acoustic stimulation with recorded lullabies and taped maternal voice led to a decrease in heart rate and respiratory rate, and was associated with lower activity. Whether this indicates a reduced stress reaction needs to be investigated in further studies.

An effective and safe protocol involving zidovudine and caesarean section to reduce vertical transmission of HIV-1 infection.

OBJECTIVE: To investigate zidovudine prophylaxis with caesarean section to reduce mother-to-infant HIV transmission. INTERVENTIONS: Elective caesarean section before labour, usually at 36-38 weeks of gestation, plus a short oral course of zidovudine, normally starting at week 32, intravenous zidovudine before caesarean section and for 10 days for the neonate (the reduced Berlin regimen). RESULTS: Of 179 mother-infant pairs 104 received no antiretroviral prophylaxis or therapy (control group), 48 received the reduced Berlin prophylaxis regimen, 18 received combination therapy and nine received only part of the prophylaxis regimen. Of the antiretroviral group, 68 were delivered by elective caesarean section. The HIV transmission rate was zero in the antiretroviral group [95% confidence interval (CI) 0-4.7] and 12.6% (6.4-19.0) in the control group. The reduction in vertical transmission was 90% for the Berlin regimen, with an 80 and 70% reduction in risk associated with antiretroviral treatment and caesarean section, respectively. Maternal CD4 cell count but not viral load had some confounding effect on the reduction in risk attributed to caesarean section and the prophylactic regimen. Neonatal haematological abnormalities associated with antiretroviral intervention lasted for up to 7 weeks. Weight and length, although significantly lower at birth, were normal by 6-8 weeks. CONCLUSION: A much reduced three-arm regimen of zidovudine prophylaxis in combination with caesarean section before labour is highly effective in reducing the risk of vertical HIV transmission and is safe for the infant.

Autosomal-recessive neural crest syndrome with albinism, black lock, cell migration disorder of the neurocytes of the gut, and deafness: ABCD syndrome.

We report on a macrosomic newborn girl with albinism, a black lock at the right temporo-occipital region, and retinal depigmentation. Bilateral deafness was confirmed by brainstem auditory-evoked potentials. In addition, the infant had a severe defect of intestinal innervation. Biopsy showed aganglionosis of the large intestine, and total absence of neurocytes and nerve fibers in the small intestine, indicating a total lack of sympathetic and parasympathetic innervation. The infant died of intestinal dysfunction at 5 weeks. She was the 14th child of consanguineous Kurdish parents. Four sibs of our patient had the same syndrome and died a few days after birth. The other 9 sibs are well, with an unremarkable phenotype. A syndrome of albinism, black lock, deafness, and a total lack of intestinal neural innervation has not yet been reported. It represents a new neural crest syndrome with autosomal-recessive inheritance.

Cord blood erythropoietin in relation to different markers of fetal hypoxia.

OBJECTIVE: To investigate the relationship between erythropoietin concentration in umbilical venous blood and clinical signs of fetal hypoxia. METHODS: We measured erythropoietin concentrations in umbilical venous blood from 200 consecutively born neonates using an enzyme-linked immunosorbent assay (ELISA) with two monoclonal antibodies. Results were available within 6 hours. Inter-assay variation was 8.5% and the mean intra-assay variation was 14.2%. RESULTS: Using a multiple regression analysis, we found that the erythropoietin concentration correlated significantly (P < .01) with fetal growth retardation and umbilical acidosis but not with gestational age, meconium-stained amniotic fluid (AF), abnormal fetal heart rate (FHR) pattern, or Apgar score at 5 minutes. Median erythropoietin concentrations were 25.1 mU/mL in infants with no risk factors or complications during pregnancy and delivery (n = 19), 25.8 mU/mL after complicated pregnancy (n = 95), 50.6 mU/mL with meconium-stained AF (n = 12), 44.7 mU/mL with abnormal FHR pattern (n = 40), 47.8 mU/mL with both stained AF and abnormal FHR pattern (n = 10), and 72.6 mU/mL with umbilical acidosis (n = 24). The median erythropoietin concentration increased significantly with decreasing pH and with increasing base deficit in umbilical arterial blood. The erythropoietin concentration in umbilical venous blood (cutoff value 50 mU/mL) discriminated between infants with no clinical signs of fetal hypoxia and those with umbilical acidosis with a sensitivity of 75% and a specificity of 90%. CONCLUSIONS: Elevated erythropoietin concentrations in umbilical venous blood indicate prolonged fetal hypoxia. The ELISA technique might be a useful tool for determining the exact time course of erythropoietin concentrations in fetal hypoxia.

Acute and chronic fetal hypoxia in monochorionic and dichorionic twins.

OBJECTIVE: To assess the risk for acute and chronic fetal hypoxia in twin pregnancies. METHODS: We investigated 50 sets of twins (24-38 weeks' gestation, 660-3200 g birth weight) admitted consecutively to our neonatal intensive care unit. Seventy-six infants were appropriate for gestational age (AGA; tenth to 90th percentile), 20 were small for gestational age (SGA; below the tenth percentile), and four were large for gestational age (above the 90th percentile). Twenty-six singleton AGA term newborns served as controls. Umbilical arterial pH was used as a marker for acute and umbilical venous erythropoietin concentration for chronic fetal hypoxia. The results are given as median followed by quartiles. RESULTS: We identified 40 sets of diamniotic-dichorionic twins and ten sets of diamniotic-monochorionic twins with transplacental vascular shunts. In the second-born twin, umbilical arterial pH was lower (7.29, 7.23-7.33) than in the firstborn (7.31, 7.25-7.34) (P = .03), and the incidence of a low pH (less than 7.20) was higher (19 versus 11%). Two second-born twins and none of the firstborn twins had an umbilical arterial pH less than 7.05. In SGA twins, the erythropoietin concentration was elevated (34.8, 22.8-325 mU/mL) compared with that in AGA twins (16.2, 8.2-26.6 mU/mL) (P < .01). In AGA twins, erythropoietin concentration did not differ from that in AGA singleton newborns (19.6, 14.7-31.6 mU/mL). In 12 of 17 twin sets with weight discordancy greater than 15% and in all five twin sets with weight difference greater than 25%, erythropoietin concentration was higher in the smaller twin. The proportion of infants and of complete sets with elevated erythropoietin levels was higher (P < .01) in monochorionic than in dichorionic pregnancies. CONCLUSION: The second-born twin is at increased risk for acute birth asphyxia. Fetal growth restriction in twin pregnancies is associated with chronic fetal hypoxia. Monochorionic twins are at higher risk for chronic fetal hypoxia than are dichorionic twins.

Umbilical venous erythropoietin and umbilical arterial pH in relation to morphologic placental abnormalities.

OBJECTIVE: To investigate the relation between the biochemical markers of umbilical venous erythropoietin and umbilical arterial pH and morphologic placental abnormalities in fetal hypoxia. METHODS: Placentas from 300 high-risk newborn infants (gestational age 24-42 weeks) were examined macroscopically and microscopically following standardized criteria. The morphologic findings were correlated with the erythropoietin concentration in umbilical venous blood and with umbilical arterial pH at birth. Venous hematocrit and circulating nucleated red blood cells were measured in 112 of these infants during the first 6 hours of life. RESULTS: The umbilical venous erythropoietin concentration correlated significantly (r = 0.74) with the number of circulating nucleated red blood cells. In 26 placentas without morphologic abnormalities, the median (and 25th and 75th percentiles) erythropoietin concentration was 35.2 mU/mL (19.2-48.7) and umbilical arterial pH was 7.30 (7.20-7.33). The erythropoietin concentration was elevated significantly when placental examination showed evidence of acute villous circulatory disturbance (61.3 mU/mL; 24.2-125.1), fetal vasculopathy (85.6 mU/mL; 23.7-119.7), or chorioamnionitis with fetal reaction (51.3 mU/mL; 27.7-118.7). The erythropoietin concentration varied significantly with the stage of placental meconium phagocytosis; it was 62.7 mU/mL (16.3-125.9) if meconium phagocytosis was classified as recent, 128.2 mU/mL (44.4-1483.2) if it was classified as a few hours old, and 66.2 mU/mL (46.3-140.1) if it was classified as a few days old. Umbilical arterial pH was not altered significantly with different morphologic placental abnormalities. CONCLUSIONS: Fetal erythropoietin production is stimulated by hypoxia after a few hours' delay and leads to increased erythropoiesis. Placental examination combined with measurement of umbilical venous erythropoietin and umbilical arterial pH provides information about earlier fetal hypoxia.

Comparison of mortality risk: a score for very low birthweight infants.

AIM: To develop and evaluate a score which quantifies mortality risk in very low birthweight (VLBW) infants (birthweight below 1500 g) at admission to the neonatal intensive care unit. METHODS: Five hundred and seventy two VLBW infants admitted from 1978 to 1987 were randomly assigned to a cohort (n = 396) for score development and a cohort (n = 176) for score validation. Two hundred and ninety four VLBW infants admitted from 1988 to 1991 were used to compare risk adjusted mortality between the two eras. RESULTS: Using multiple regression analysis, birthweight, Apgar score at 5 minutes, base excess at admission, severity of respiratory distress syndrome, and artificial ventilation were predictive of death in the development cohort. According to regression coefficients, a score ranging from 3 to 40 was developed. At a cutoff of 21, it predicted death in the validation cohort with a sensitivity of 0.85, a specificity of 0.73, and a correct classification rate of 0.76. The area under the receiver operating characteristic curve was 0.86. There was no significant difference in risk severity and in risk adjusted mortality between the eras 1978-87 and 1988-91. CONCLUSION: The present score is robust, easily obtainable at admission, and permits early randomisation based on mortality risk.

HFE gene mutation and transferrin saturation in very low birthweight infants.

AIM: To determine if there is an association between high transferrin saturation and the C282Y HFE gene mutation in very low birthweight (VLBW) infants. METHODS: One hundred and forty three VLBW infants receiving recombinant erythropoietin and 3 to 9 mg/kg/day of enteral iron were studied. Genomic DNA was extracted from filter paper cards. The C282Y mutation was determined by restriction fragment length polymorphism analysis. RESULTS: Six infants were heterozygous for the mutation; none was homozygous. Ten infants had a transferrin saturation above 80% at least once. No infant was positive for both transferrin saturation above 80% and the mutation. CONCLUSIONS: The data strongly suggest that there is no association between high transferrin saturation and the HFE gene mutation in VLBW infants during the first weeks of life.

Factors related to transfusion in very low birthweight infants treated with erythropoietin.

The need for red cell transfusions is reduced but not eliminated by recombinant human erythropoietin (rhEPO) in very low birthweight (VLBW) infants. To detect factors associated with the decision to transfuse VLBW infants during rhEPO treatment and to explain rhEPO 'non-responders', the subgroup of those 120 VLBW infants who were treated with rhEPO 750 IU/kg per week in the second European Multicentre rhEPO Trial was evaluated. Sixty (50%) infants received at least one transfusion during erythropoietin treatment. Transfusion was frequent in infants with extremely low birthweight (79% for 750-999 g), low gestational age (70% for < or = 28 weeks), low initial haematocrit or low initial reticulocyte count (61% for haematocrit < or = 0.48 and reticulocytes < or = 9%, respectively). Considerable differences among centres were found for sampling blood loss, iron supply, and transfusion rate, which ranged from 13% to 73% and was related to the volume of diagnostic blood loss (19% vs 80% for blood loss < 1 vs > or = 1 ml/kg per day). The prognostic variables birthweight, initial haematocrit, and gestational age were found to be most predictive for transfusion. To improve rhEPO response in VLBW infants, there is a need to minimise diagnostic blood loss, to prevent iron deficiency, and to develop rational criteria for transfusion in preterm infants.