Safety of metamizole: a systematic review of the literature.

WHAT IS KNOWN AND OBJECTIVE: Metamizole was withdrawn from the market in the United States and several European countries following reports of fatal agranulocytosis among users, but is still available in many countries in Europe, South America and Asia. Over the past several decades, a number of epidemiologic studies have been conducted to quantify the risk of agranulocytosis and other adverse effects associated with metamizole and other non-narcotic analgesics. The objective of this study was to perform a systematic review of the safety of metamizole. METHODS: Epidemiologic studies published between 1 January 1980 and 15 December 2014 were identified through systematic searches of PubMed and Google Scholar; the reference sections of selected articles were also reviewed to identify potentially relevant studies. Studies included in this review focused on the safety of metamizole, that is on outcomes such as haematologic abnormalities, gastrointestinal bleeding, anaphylaxis and hepatotoxicity. Two study investigators independently reviewed the abstracts and articles to determine relevant studies according to prespecified criteria. RESULTS AND DISCUSSION: A total of 22 articles met the criteria for evaluation. The majority of studies that evaluated agranulocytosis indicated an increased risk associated with metamizole, with relative risk (RR) estimates ranging from 1·5 (95% CI, 0·8-2·7) to 40·2 (95% CI, 14·7-113·3). Findings of three case-control studies do not suggest an association between metamizole and aplastic anaemia. Of the five case-control studies that evaluated the risk of upper gastrointestinal bleeding, four found a statistically significant increased risk associated with metamizole (RR estimates ranging from 1·4 to 2·7). There is insufficient evidence to determine whether metamizole increases the risk of other outcomes (e.g. hepatic effects, anaphylaxis, congenital anomalies). Few studies evaluated the effects of dose, route of administration or duration of therapy. WHAT IS NEW AND CONCLUSION: Published studies reported differences in the magnitude of risk of adverse outcomes associated with metamizole use and often had small sample sizes and a number of other limitations that may have biased the results. Further research is needed to better quantify the potential risks associated with metamizole compared to other non-narcotic analgesics.

Transparency and Reproducibility of Observational Cohort Studies Using Large Healthcare Databases.

The scientific community and decision-makers are increasingly concerned about transparency and reproducibility of epidemiologic studies using longitudinal healthcare databases. We explored the extent to which published pharmacoepidemiologic studies using commercially available databases could be reproduced by other investigators. We identified a nonsystematic sample of 38 descriptive or comparative safety/effectiveness cohort studies. Seven studies were excluded from reproduction, five because of violation of fundamental design principles, and two because of grossly inadequate reporting. In the remaining studies, >1,000 patient characteristics and measures of association were reproduced with a high degree of accuracy (median differences between original and reproduction <2% and <0.1). An essential component of transparent and reproducible research with healthcare databases is more complete reporting of study implementation. Once reproducibility is achieved, the conversation can be elevated to assess whether suboptimal design choices led to avoidable bias and whether findings are replicable in other data sources.

[Methodological challenges concerning the selection of diseases for a standardized multimorbidity index]. / Methodische Herausforderungen bei der Auswahl von Erkrankungen für einen standardisierten Multimorbiditätsindex.

Multimorbidity is defined as the coexistence of two or more chronic diseases. However, this complex health status, which primarily affects elderly, is still insufficiently understood. One reason is the underrepresentation of older, multimorbid people in studies. Another reason is that there is no agreement on the number and type of diseases, which have to be considered in the assessment of multimorbidity. Therefore, this article provides an overview on the status quo of research on multimorbidity indices and describes in detail, what kind of methodological challenges have to be faced regarding the development of a standardized index. Finally, recommendations are made for criteria, which can be used for the selection of diseases relevant for multimorbidity.

[Federal admission criteria for levels of perinatal care: definition, interpretation and first conclusions]. / Aufnahmekriterien nach dem G-BA-Beschluss: definition, interpretation und erste schlussfolgerungen.

BACKGROUND: The outcome of high risk pregnancies is better in tertiary hospitals. The German government introduced levels of perinatal care only in 2006. The aim of this study was to investigate how many children are to be expected for each level, taking the possible width of interpretation of the admission criteria into account. MATERIALS AND METHODS: Perinatal quality assurance data from four German states (2005) were available. Based on the admission criteria used for level definitions, children were categorised into four different levels of care. To illustrate the possible width of interpretation of these admission criteria three analytical strategies were used. In addition, the distribution of children on different types of hospitals prior to the introduction of levels of care was analysed. RESULTS: Most deliveries (86-93 %) correspond to the lowest level, and only 1-5 % to the highest. Up to 15 % of children who should have been cared for in the highest level were born in hospitals with less than 500 annual deliveries. Among the neonates with risk profiles corresponding to the admission criteria for the two highest levels, up to 30 % were born in delivery units without NICUs. The majority (83 %) of attached NICUs had low caseloads (< 50 neonates < 1500 g / year). CONCLUSION: Most children fulfil the admission criteria for the lowest level of care whereas the need for specialised centres is rather low. Optimising the place of birth appropriately remains a challenge. Definition of levels of care based on admission criteria are difficult to implement due to a broad variety of interpretations.

Interleukin-10 high producer allele and ultrasound-defined periventricular white matter abnormalities in preterm infants: a preliminary study.

OBJECTIVES: Inflammation plays a role in prematurity, in neonatal disorders of the brain, lung, eye, bowel, and in developmental disability among preterm infants. We initiated a pilot study in preterm children to determine the prevalence of single nucleotide polymorphisms (SNPs) in the infection/inflammation-associated genes for interleukin (IL)-10 (- 1082 G/A), IL-1beta (+ 3953 C/T), tumor necrosis factor (TNF)-alpha (- 308 G/A) and toll-like receptor 4 (TLR-4) (Asp299Gly) and whether these SNPs affect the risk for neonatal disorders. STUDY DESIGN: We genotyped 73 children >/= 2 years of age whose gestational age at birth was < 32 weeks, and explored the associations between genotypes and neonatal disorders and developmental status at age 2 + years. RESULTS: Infants homozygous for the high IL-10 producer - 1082 G-allele (n = 15) were significantly less likely to develop ultrasound-defined periventricular echodensities. A non-significant, but prominent, risk reduction for bronchopulmonary dysplasia, high-grade retinopathy, cerebral palsy, and developmental delay at age 2 + years was present. Polymorphisms in the IL-1beta, TNF-alpha, and TLR-4 genes were too infrequent in our pilot sample to allow for reasonable analysis. CONCLUSION: Infants homozygous for the IL-10 high producer - 1082 G allele might be at reduced risk for prematurity-associated disorders.

[Can data from quality assurance programs such as peri-/neonatal compilations be used for secondary epidemiological studies?]. / Können Daten aus Qualitätssicherungsprogrammen wie der Peri-/Neonatalerhebung für sekundärepidemiologische Untersuchungen genutzt werden?

BACKGROUND: The aim of this study was to explore whether population-based data from a regional quality control program can be utilized to compare the neonatal outcome of small for gestational age (SGA) and appropriate size for gestational age (AGA) new-borns. METHODS: The Center for Quality Management in Health Care maintains perinatal data for almost all births in Lower Saxony (Germany). Neonatal data are collected for all infants admitted to hospital within 10 postnatal days. We evaluated linked perinatal and neonatal datasets of 4126 very low birthweight infants (VLBW; < 1500 g), born in 1991 - 1996. After checking for completeness, representativeness, and validity, exclusion criteria were defined to minimize bias and to yield similar proportions of SGA- and AGA-neonates. Since inclusion of all multiple births would lead to an overestimation of maternal risk factors, one sibling was randomly selected from each set of multiples. Bias arising from not well defined study populations should be shown based on univariable mortality analyses (Kaplan-Meier survival curves). RESULTS: Application of exclusion criteria resulted in a final study population of 1623 independent (disjunctive) new-borns from 25 - 29 weeks gestation, 173 of whom were SGA, 1450 AGA. Kaplan-Meier curves from the initial study population and the well defined study base differed significantly. Trend analysis revealed a significant (p < 0.05) increase in proportions of both VLBW (from 0.95 % in 1991 to 1.11 % in 1996; + 17 %) and SGA infants (from 22.7 % to 27.4 %; + 21 %) within the observational period. A well defined data selection process is necessary if data collected for other purposes are to be used for epidemiological studies. Neglecting this labour-intensive work may be one reason for the varying results on the outcome of SGA and AGA infants.

Population based study on the outcome of small for gestational age newborns.

OBJECTIVE: To explore whether and how population based data from a regional quality control programme can be used to investigate the hypothesis that small for gestational age (SGA) very low birthweight infants (VLBW, <1500 g) are at increased risk of death, severe intraventricular haemorrhage (IVH), and periventricular leucomalacia (PVL), but at decreased risk of respiratory distress syndrome (RDS). METHODS: Analyses of population based perinatal/neonatal data (1991-96) from a quality control programme in Lower Saxony, Germany. After assessment of data validity and representativeness, exclusion criteria were defined: birth weight >90th centile, severe malformations, siblings of multiple births, and gestational age (GA) <25 or >29 weeks. Outcomes of interest were death, severe IVH, PVL, and RDS. Multivariable analyses were performed by Cox proportional hazard and logistic regression models. RESULTS: Within the data validation procedure, an increase in proportions of both VLBW (from 0.95% in 1991 to 1.11% in 1996; +17%) and SGA (from 22.7% to 27.4%; +21%) infants became apparent (p<0.05). The study population consisted of 1623 infants (173 SGA). Mortality was 12.1% (n = 196), with an adjusted hazard ratio for SGA infants of 2.54, 95% confidence interval (CI) 1.70 to 3.79. Both groups were at similar risk of severe IVH (adjusted odds ratio 0.93, 95% CI 0.5 to 1.65) and PVL (1.54, 95% CI 0.78 to 2.87), but SGA infants had less RDS (0.57, 95% CI 0.35 to 0.93). Male sex, multiple birth, hypothermia (<35.5 degrees C), and sepsis were associated with IVH and RDS. Infants admitted to hospitals with <36 VLBW admissions/year had increased mortality (adjusted hazard ratio 1.56, 95% CI 1.12 to 2.18). CONCLUSIONS: SGA VLBW infants are at increased risk of death, but not of IVH and PVL, and at decreased risk of RDS. That mortality is higher in smaller hospitals needs further investigation.

[Patient volume and facilities measurements as quality indicators of peri- and neonatal care: a review of data from the last 4 years]. / Volumen- und Ausstattungsmerkmale als peri- und neonatale Qualitätsindikatoren: Eine Ubersicht über Daten der letzten 4 Jahre.

AIM: This article reviews recent studies on the relationship between patient volume, level of care, and peri- or neonatal outcome for term and preterm infants. METHODS: A PubMed search was performed using various combinations of keywords related to neonates, patient volume and outcome published since 2000. RESULTS: Two studies on term infants showed that perinatal mortality in Norway and Germany was 2 - 3 times higher for term infants born in institutions with less than 500, and 40 - 80 % higher in those with < 1000 births/year compared to larger hospitals. For preterm infants, the mortality risk for those born in hospitals without a level III neonatal intensive care unit (NICU) was almost twice as high as for those born in hospitals with such an NICU. With regard to patient volume, studies from both the USA and Germany showed a significantly, up to 56 % higher mortality risk for infants admitted to units with less than 36 or 50 very low birth weight (VLBW) admissions per year compared to larger NICUs. CONCLUSIONS: Although patient volume or level of care are poor predictors of neonatal outcome, the above data provide arguments for a more rigorous perinatal centralisation, aiming to restrict term deliveries to hospitals with at least 1000 births per year and VLBW deliveries to perinatal centres with 24 h on-site availability of a neonatologist and at least 36 - 50 VLBW admissions per year. This may result in a significant reduction in perinatal mortality in Germany. In the interest of the families at risk of loosing their child, we must strive further to achieve this goal.