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.

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.

[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.

[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.

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.

Analysis of the Wilms' tumor suppressor gene (WT1) in patients 46,XY disorders of sex development.

CONTEXT: The Wilms' tumor suppressor gene (WT1) is one of the major regulators of early gonadal and kidney development. WT1 mutations have been identified in 46,XY disorders of sex development (DSD) with associated kidney disease and in few isolated forms of 46,XY DSD. OBJECTIVE: The objective of the study was the evaluation of WT1 mutations in different phenotypes of isolated 46,XY DSD and clinical consequences. DESIGN: The design of the study was: 1) sequencing of the WT1 gene in 210 patients with 46,XY DSD from the German DSD network, consisting of 150 males with severe hypospadias (70 without cryptorchidism, 80 with at least one cryptorchid testis), 10 males with vanishing testes syndrome, and 50 raised females with partial to complete 46,XY gonadal dysgenesis; and 2) genotype-phenotype correlation of our and all published patients with 46,XY DSD and WT1 mutations. RESULTS: We have detected WT1 mutations in six of 80 patients with severe hypospadias (7.5%) and at least one cryptorchid testis and in one of 10 patients with vanishing testes syndrome (10%). All patients except one developed Wilms' tumor and/or nephropathy in childhood or adolescence. CONCLUSION: WT1 analysis should be performed in newborns with complex hypospadias with at least one cryptorchid testis and in isolated 46,XY partial to complete gonadal dysgenesis. Kidney disease might not develop until later life in these cases. WT1 analysis is mandatory in all 46,XY DSD with associated kidney disease. WT1 analysis is not indicated in newborns with isolated hypospadias without cryptorchidism. Patients with WT1 mutations should be followed up closely because the risk of developing a Wilms' tumor, nephropathy, and/or gonadal tumor is very high.

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.

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.

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.

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.

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.

Rates of very preterm birth in Europe and neonatal mortality rates.

OBJECTIVE: To estimate the influence of variation in the rate of very preterm delivery on the reported rate of neonatal death in 10 European regions. DESIGN: Comparison of 10 separate geographically defined European populations, from nine European countries, over a 1-year period (7 months in one region). PARTICIPANTS: All births that occurred between 22(+0) and 31(+6) weeks of gestation in 2003. MAIN OUTCOME MEASURE: Neonatal death rate adjusted for rate of delivery at this gestation. RESULTS: Rate of delivery of all births at 22(+0)-31(+6) weeks of gestation and live births only were calculated for each region. Two regions had significantly higher rates of very preterm delivery per 1000 births: Trent UK (16.8, 95% CI 15.7 to 17.9) and Northern UK (17.1, 95% CI 15.6 to 18.6); group mean 13.2 (95% CI 12.9 to 13.5). Four regions had rates significantly below the group average: Portugal North (10.7, 95% CI 9.6 to 11.8), Eastern and Central Netherlands (10.6, 95% CI 9.7 to 11.6), Eastern Denmark (11.2, 95% CI 10.1 to 12.4) and Lazio in Italy (11.0, 95% CI 10.1 to 11.9). Similar trends were seen in live birth data. Published rates of neonatal death for each region were then adjusted by applying (a) a standardised rate of very preterm delivery and (b) the existing death rate for babies born at this gestation in the individual region. This produced much greater homogeneity in terms of neonatal mortality. CONCLUSIONS: Variation in the rate of very preterm delivery has a major influence on reported neonatal death rates.

[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.

Increased rate of prematurity associated with antenatal antiretroviral therapy in a German/Austrian cohort of HIV-1-infected women.

OBJECTIVE: The aim of the study was to assess the risk of adverse pregnancy outcomes after antenatal antiretroviral therapy in a well-defined prospective cohort of nontransmitting HIV-infected women. METHODS: Prospective monitoring of 183 mother-child pairs from 13 centres in Germany and Austria, delivering between 1995 and 2001, was carried out. Following German-Austrian guidelines recommending an elective Caesarean section (CS) at 36 weeks, prematurity was defined as <36 weeks' gestation for these analyses. RESULTS: Of 183 mother-child pairs, 42% were exposed to antenatal monotherapy and 17% to dual therapy. Of the 75 women exposed to highly active antiretroviral therapy (HAART), 21 (28%) received protease inhibitor (PI)-based HAART and the remaining 54 received nonnucleoside reverse transcriptase inhibitor-based HAART. In multivariable analysis (176 pregnancies), PI-based HAART exposure during pregnancy was associated with an increased risk of premature delivery [adjusted odds ratio 3.40; 95% confidence interval (CI) 1.13-10.2; P=0.029, compared with monotherapy]. Congenital abnormalities affected 3.3% infants. Perinatally, 18.9% of children (34 of 179) had respiratory problems requiring interventions, which were associated with prematurity but not with type of treatment exposure. From adjusted regression analysis, the mean birth weight z-score for children exposed to HAART with PI (+0.46; 95% CI 0.01-0.92; P=0.047) or dual therapy (+0.43; 95% CI 0.03-0.82; P=0.034) was slightly but significantly higher than that for those exposed to monotherapy; head circumference was appropriate for gestational age and there were no significant differences between treatment groups. CONCLUSIONS: Use of antenatal PI-based HAART initiated before or during pregnancy was associated with a significantly increased risk of premature delivery at <36 weeks' gestation. The overall crude prematurity rate was 34% (63 of 183; 95% CI 28-42).

[Anesthesiological management of the EXIT procedure. Case report and literature review]. / Die EXIT-Prozedur als anästhesiologische Herausforderung. Fallbericht und Literaturübersicht.

The ex-utero intra-partum (EXIT) procedure enables the surgeon to perform invasive procedures in an infant during cesarean section before clamping the umbilical cord. Specific anesthesiological concepts are necessary for ensuring sufficient umbilical perfusion. We report the case of a 33-year-old female undergoing cesarean section in the 36th week of pregnancy because of a large fetal cervical tumor. The EXIT procedure was performed in order to secure the infant's airway during delivery. The anesthesiological management and interdisciplinary tasks are discussed in the literature review.

[Differential diagnosis of a polyhydramnion in hyperprostaglandin E syndrome: a case report]. / Differenzialdiagnose des Polyhydramnions beim Hyperprostaglandin-E-Syndrom: Case-Report.

INTRODUCTION: A polyhydramnion is diagnosed in 0.4 to 3.3 % of all pregnancies. The most common causes of increased amniotic fluid include maternal diabetes mellitus, fetal malformations and chromosomal aberrations, twin-to-twin transfusion syndrome, rhesus incompatibility syndrome, and congenital infections. After exclusion of other etiologies for polyhydramnion, the very rare, autosomal-recessive transferred hyperprostaglandin E syndrome (HPS) has to be considered. PATIENTS AND METHODS: We report on a 31-year-old women who visited our obstetrical outpatient clinics at 22 + 4 weeks of gestation for prenatal ultrasound scanning and amniocentesis. This, the patient's third pregnancy had been without complications so far. She had delivered two children before, one of them bearing the HPS. The women herself suffered from epilepsy. At 26 + 0 weeks of gestation the pregnancy was complicated by a polyhydramnion requiring serial amniocentesis for reducing amniotic fluid load. Among others, her amniotic fluid was analyzed for chloride concentration and for genetic aberrations regarding HPS. Serological investigations and an oral glucose tolerance test (oGTT) were performed. RESULTS: Amniocentesis revealed a normal chromosomal pattern. The oGTT demonstrated values in the normal range. Serological investigations regarding TORCH infections were without pathological findings. The chloride concentration was highly increased in the amniotic fluid, which is suspicious for HPS. Finally, molecular analysis proved an NKCC2-mutation responsible for HPS. A cesarean section was performed at 33 + 3 weeks of gestation. CONCLUSION: If HPS is suspected to be the cause of polyhydramnions, the chloride concentrations in the amniotic fluid and molecular analysis for HPS should be performed. Interdisciplinary care, diagnostics and therapy in an experienced perinatal center are essential for an optimal outcome of the pregnancy and the newborn infant.

Neonate with spinal hypoplasia on T12 and a localized vertebral malformation on L4.

We report a case of a neonate with sectional narrowing of the spinal cord on the level of T12 to L2 and a deformed vertebral body on a different level, L4. In previously described cases of sectional spinal dysgenesis, the vertebral and spinal cord malformations are usually found on the same level. Our case may represent a new variant of spinal dysgenesis.