Maternal influenza and birth outcomes: systematic review of comparative studies.

BACKGROUND: Although pregnant women are considered at high risk for severe influenza disease, comparative studies of maternal influenza and birth outcomes have not been comprehensively summarised. OBJECTIVE: To review comparative studies evaluating maternal influenza disease and birth outcomes. SEARCH STRATEGY: We searched bibliographic databases from inception to December 2014. SELECTION CRITERIA: Studies of preterm birth, small-for-gestational-age (SGA) birth or fetal death, comparing women with and without clinical influenza illness or laboratory-confirmed influenza infection during pregnancy. DATA COLLECTION AND ANALYSIS: Two reviewers independently abstracted data and assessed study quality. MAIN RESULTS: Heterogeneity across 16 studies reporting preterm birth precluded meta-analysis. In a subgroup of the highest-quality studies, two reported significantly increased preterm birth (risk ratios (RR) from 2.4 to 4.0) following severe 2009 pandemic H1N1 (pH1N1) influenza illness, whereas those assessing mild-to-moderate pH1N1 or seasonal influenza found no association. Five studies of SGA birth showed no discernible patterns with respect to influenza disease severity (pooled odds ratio 1.24; 95% CI 0.96-1.59). Two fetal death studies were of sufficient quality and size to permit meaningful interpretation. Both reported an increased risk of fetal death following maternal pH1N1 disease (RR 1.9 for mild-to-moderate disease and 4.2 for severe disease). CONCLUSIONS: Comparative studies of preterm birth, SGA birth and fetal death following maternal influenza disease are limited in number and quality. An association between severe pH1N1 disease and preterm birth and fetal death was reported by several studies; however, these limited data do not permit firm conclusions on the magnitude of any association. TWEETABLE ABSTRACT: Comparative studies are limited in quality but suggest severe pandemic H1N1 influenza increases preterm birth.

Influenza and congenital anomalies: a systematic review and meta-analysis.

STUDY QUESTION: Does first trimester maternal influenza infection increase the risk of non-chromosomal congenital anomalies (CA)? SUMMARY ANSWER: First trimester maternal influenza exposure is associated with raised risk of a number of non-chromosomal CA, including neural tube defects, hydrocephaly, congenital heart defects, cleft lip, digestive system defects and limb reduction defects. WHAT IS KNOWN ALREADY: Hyperthermia is a well-established risk factor for neural tube defects. Previous studies suggest influenza may be a risk factor not only for neural tube defects, but also other CA. No systematic review has previously been undertaken. STUDY DESIGN, SIZE, DURATION: Systematic review and meta-analysis. A search of EMBASE and PUBMED was performed for English and Dutch studies published up to July 2013. A total of 33 studies (15 case-control, 10 cohort and 8 ecological) were included in the systematic review of which 22 studies were included in the meta-analysis. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: A total of 29 542 babies with congenital anomaly (1112 exposed) from case-control studies and 1608 exposed pregnancies resulting in 56 babies with congenital anomaly from cohort studies were included in the meta-analysis. Maternal influenza exposure was defined as any reported influenza, influenza-like illness or fever with flu, with or without serological or clinical confirmation during the first trimester of pregnancy. Data for 24 (sub)groups with congenital anomaly available from ≥3 studies were analysed using the DerSimonian-Laird random effects model. The hypothesis of publication bias was assessed using funnel plots and risk of bias of included studies was assessed using a slightly modified version of the Newcastle-Ottawa scale. MAIN RESULTS AND THE ROLE OF CHANCE: First trimester maternal influenza exposure was associated with an increased risk of any congenital anomaly [adjusted odds ratio (AOR) 2.00, 95% CI: 1.62-2.48], neural tube defects [odds ratio (OR) 3.33, 2.05-5.40], hydrocephaly (5.74, 1.10-30.00), congenital heart defects (1.56, 1.13-2.14), aortic valve atresia/stenosis (AOR 2.59, 1.21-5.54), ventricular septal defect (AOR 1.59, 1.24-2.14), cleft lip (3.12, 2.20-4.42), digestive system (1.72, 1.09-2.68) and limb reduction defects (2.03, 1.27-3.27). An increased risk for cleft lip (but not for cleft palate) was also reported by ecological studies not included in the meta-analysis. Study outcomes reported for 27 subgroups of congenital anomaly could not be included in the meta-analysis. Visual inspection of funnel plots did not suggest evidence for publication bias. LIMITATIONS, REASONS FOR CAUTION: This study enrolled observational studies that can be subject to limitations such as confounding, retrospective maternal exposure reports and non-response of intended participants. Influenza exposed pregnancies can also have been exposed to influenza related medication. WIDER IMPLICATIONS OF THE FINDINGS: Prevention of influenza in pregnant women may reduce congenital anomaly risk, and would be relevant to more than just neural tube defects. More research is needed to determine whether influenza and/or its related medication is teratogenic, to determine the role of hyperthermia in teratogenicity and the role of other environmental factors such as nutritional status in determining susceptibility.

State of the art in benefit-risk analysis: medicines.

Benefit-risk assessment in medicine has been a valuable tool in the regulation of medicines since the 1960s. Benefit-risk assessment takes place in multiple stages during a medicine's life-cycle and can be conducted in a variety of ways, using methods ranging from qualitative to quantitative. Each benefit-risk assessment method is subject to its own specific strengths and limitations. Despite its widespread and long-time use, benefit-risk assessment in medicine is subject to debate and suffers from a number of limitations and is currently still under development. This state of the art review paper will discuss the various aspects and approaches to benefit-risk assessment in medicine in a chronological pathway. The review will discuss all types of benefit-risk assessment a medicinal product will undergo during its lifecycle, from Phase I clinical trials to post-marketing surveillance and health technology assessment for inclusion in public formularies. The benefit-risk profile of a drug is dynamic and differs for different indications and patient groups. In the end of this review we conclude benefit-risk analysis in medicine is a developed practice that is subject to continuous improvement and modernisation. Improvement not only in methodology, but also in cooperation between organizations can improve benefit-risk assessment.

State of the art in benefit-risk analysis: consumer perception.

Benefit and risk perception with respect to food consumption, have been a part of human daily life from beginning of time. In today's society the food chain is long with many different types of actors and low degree of transparency. Making informed food choices where knowledge of benefits and risks is part of the decision making process are therefore complicated for consumers. Thus, to understand how consumers perceive benefits and risks of foods, their importance in relation to quality evaluations are aspects that need to be addressed. The objective of this paper is to discuss state of the art in understanding consumer perceptions of benefits and risks of foods in order to improve understanding of consumer behaviour in the food domain. Risks may be associated with both acute and long term consequences, some of which may have serious effects. Perceived risks are connected to morbidity and mortality along two dimensions relating to unknown risk, and to which extent the risk is dreaded by the consumer. Unfamiliar, uncertain, unknown, uncontrollable, and severe consequences are some factors associated with risk perception. Novel food processing techniques, for instance, score high on several of these parameters and are consequently regarded with suspicion and perceived as risky by consumers. On a daily basis, benefits of foods and food consumption are more important in most consumers' minds than risks. Benefits are often associated with food's ability to assuage hunger, and to provide pleasure through eating and socialising. In addition, two main categories of benefits that are important for acceptance of product innovations are health and environmental benefits. Benefit and risk perception of foods seem to be inversely correlated, so when something is perceived as being highly beneficial, it is correspondingly perceived as having low risk. However, slightly different paths are used in the formation of these perceptions; benefit perception is based on heuristics and experience, while risk perception is to a larger extent the result of cognitive information processing. Consumers are particularly conservative when it comes to perception and acceptance of foods compared to other products. Benefit-risk evaluations tend to be skewed towards acceptance of all that is traditional and well-known (benefits), and rejection or suspicion towards anything that is novel or highly processed (risks) regardless of actual risk. Knowledge of how consumers perceive benefits and risks of foods, may contribute to understanding benefit-risk perception in other areas related to personal, societal or environmental perspectives.

State of the art in benefit-risk analysis: economics and marketing-finance.

All market participants (e.g., investors, producers, consumers) accept a certain level of risk as necessary to achieve certain benefits. There are many types of risk including price, production, financial, institutional, and individual human risks. All these risks should be effectively managed in order to derive the utmost of benefits and avoid disruption and/or catastrophic economic consequences for the food industry. The identification, analysis, determination, and understanding of the benefit-risk trade-offs of market participants in the food markets may help policy makers, financial analysts and marketers to make well-informed and effective corporate investment strategies in order to deal with highly uncertain and risky situations. In this paper, we discuss the role that benefits and risks play in the formation of the decision-making process of market-participants, who are engaged in the upstream and downstream stages of the food supply chain. In addition, we review the most common approaches (expected utility model and psychometrics) for measuring benefit-risk trade-offs in the economics and marketing-finance literature, and different factors that may affect the economic behaviour in the light of benefit-risk analyses. Building on the findings of our review, we introduce a conceptual framework to study the benefit-risk behaviour of market participants. Specifically, we suggest the decoupling of benefits and risks into the separate components of utilitarian benefits, hedonic benefits, and risk attitude and risk perception, respectively. Predicting and explaining how market participants in the food industry form their overall attitude in light of benefit-risk trade-offs may be critical for policy-makers and managers who need to understand the drivers of the economic behaviour of market participants with respect to production, marketing and consumption of food products.

State of the art in benefit-risk analysis: introduction.

Risk-taking is normal in everyday life if there are associated (perceived) benefits. Benefit-Risk Analysis (BRA) compares the risk of a situation to its related benefits and addresses the acceptability of the risk. Over the past years BRA in relation to food and food ingredients has gained attention. Food, and even the same food ingredient, may confer both beneficial and adverse effects. Measures directed at food safety may lead to suboptimal or insufficient levels of ingredients from a benefit perspective. In BRA, benefits and risks of food (ingredients) are assessed in one go and may conditionally be expressed into one currency. This allows the comparison of adverse and beneficial effects to be qualitative and quantitative. A BRA should help policy-makers to make more informed and balanced benefit-risk management decisions. Not allowing food benefits to occur in order to guarantee food safety is a risk management decision much the same as accepting some risk in order to achieve more benefits. BRA in food and nutrition is making progress, but difficulties remain. The field may benefit from looking across its borders to learn from other research areas. The BEPRARIBEAN project (Best Practices for Risk-Benefit Analysis: experience from out of food into food; http://en.opasnet.org/w/Bepraribean) aims to do so, by working together with Medicines, Food Microbiology, Environmental Health, Economics & Marketing-Finance and Consumer Perception. All perspectives are reviewed and subsequently integrated to identify opportunities for further development of BRA for food and food ingredients. Interesting issues that emerge are the varying degrees of risk that are deemed acceptable within the areas and the trend towards more open and participatory BRA processes. A set of 6 'state of the art' papers covering the above areas and a paper integrating the separate (re)views are published in this volume.

State of the art in benefit-risk analysis: food microbiology.

Over the past years benefit-risk analysis (BRA) in relation to foods and food ingredients has gained much attention; in Europe and worldwide. BRA relating to food microbiology is however a relatively new field of research. Microbiological risk assessment is well defined but assessment of microbial benefits and the weighing of benefits and risk has not been systematically addressed. In this paper the state of the art in benefit-risk analysis in food microbiology is presented, with a brief overview of microbiological food safety practices. The quality and safety of foods is commonly best preserved by delaying the growth of spoilage bacteria and contamination by bacterial pathogens. However, microorganisms in food can be both harmful and beneficial. Many microorganisms are integral to various food production processes e.g. the production of beer, wine and various dairy products. Moreover, the use of some microorganisms in the production of fermented foods are often claimed to have beneficial effects on food nutrition and consumer health. Furthermore, food safety interventions leading to reduced public exposure to foodborne pathogens can be regarded as benefits. The BRA approach integrates an independent assessment of both risks and benefits and weighs the two using a common currency. Recently, a number of initiatives have been launched in the field of food and nutrition to address the formulation of the benefit-risk assessment approach. BRA has recently been advocated by EFSA for the public health management of food and food ingredients; as beneficial and adverse chemicals can often be found within the same foods and even the same ingredients. These recent developments in the scoping of BRA could be very relevant for food microbiological issues. BRA could become a valuable methodology to support evaluations and decision making regarding microbiological food safety and public health, supplementing other presently available policy making and administrative tools for microbiological food safety management.

State of the art in benefit-risk analysis: food and nutrition.

Benefit-risk assessment in food and nutrition is relatively new. It weighs the beneficial and adverse effects that a food (component) may have, in order to facilitate more informed management decisions regarding public health issues. It is rooted in the recognition that good food and nutrition can improve health and that some risk may be acceptable if benefit is expected to outweigh it. This paper presents an overview of current concepts and practices in benefit-risk analysis for food and nutrition. It aims to facilitate scientists and policy makers in performing, interpreting and evaluating benefit-risk assessments. Historically, the assessments of risks and benefits have been separate processes. Risk assessment is mainly addressed by toxicology, as demanded by regulation. It traditionally assumes that a maximum safe dose can be determined from experimental studies (usually in animals) and that applying appropriate uncertainty factors then defines the 'safe' intake for human populations. There is a minor role for other research traditions in risk assessment, such as epidemiology, which quantifies associations between determinants and health effects in humans. These effects can be both adverse and beneficial. Benefit assessment is newly developing in regulatory terms, but has been the subject of research for a long time within nutrition and epidemiology. The exact scope is yet to be defined. Reductions in risk can be termed benefits, but also states rising above 'the average health' are explored as benefits. In nutrition, current interest is in 'optimal' intake; from a population perspective, but also from a more individualised perspective. In current approaches to combine benefit and risk assessment, benefit assessment mirrors the traditional risk assessment paradigm of hazard identification, hazard characterization, exposure assessment and risk characterization. Benefit-risk comparison can be qualitative and quantitative. In a quantitative comparison, benefits and risks are expressed in a common currency, for which the input may be deterministic or (increasingly more) probabilistic. A tiered approach is advocated, as this allows for transparency, an early stop in the analysis and interim interaction with the decision-maker. A general problem in the disciplines underlying benefit-risk assessment is that good dose-response data, i.e. at relevant intake levels and suitable for the target population, are scarce. It is concluded that, provided it is clearly explained, benefit-risk assessment is a valuable approach to systematically show current knowledge and its gaps and to transparently provide the best possible science-based answer to complicated questions with a large potential impact on public health.

State of the art in benefit-risk analysis: environmental health.

Environmental health assessment covers a broad area: virtually all systematic analysis to support decision making on issues relevant to environment and health. Consequently, various different approaches have been developed and applied for different needs within the broad field. In this paper we explore the plurality of approaches and attempt to reveal the state-of-the-art in environmental health assessment by characterizing and explicating the similarities and differences between them. A diverse, yet concise, set of approaches to environmental health assessment is analyzed in terms of nine attributes: purpose, problem owner, question, answer, process, use, interaction, performance and establishment. The conclusions of the analysis underline the multitude and complexity of issues in environmental health assessment as well as the variety of perspectives taken to address them. In response to the challenges, a tendency towards developing and applying more inclusive, pragmatic and integrative approaches can be identified. The most interesting aspects of environmental health assessment are found among these emerging approaches: (a) increasing engagement between assessment and management as well as stakeholders, (b) strive for framing assessments according to specific practical policy needs, (c) integration of multiple benefits and risks, as well as (d) explicit incorporation of both scientific facts and value statements in assessment. However, such approaches are yet to become established, and many contemporary mainstream environmental health assessment practices can still be characterized as relatively traditional risk assessment.

Looking beyond borders: integrating best practices in benefit-risk analysis into the field of food and nutrition.

An integrated benefit-risk analysis aims to give guidance in decision situations where benefits do not clearly prevail over risks, and explicit weighing of benefits and risks is thus indicated. The BEPRARIBEAN project aims to advance benefit-risk analysis in the area of food and nutrition by learning from other fields. This paper constitutes the final stage of the project, in which commonalities and differences in benefit-risk analysis are identified between the Food and Nutrition field and other fields, namely Medicines, Food Microbiology, Environmental Health, Economics and Marketing-Finance, and Consumer Perception. From this, ways forward are characterized for benefit-risk analysis in Food and Nutrition. Integrated benefit-risk analysis in Food and Nutrition may advance in the following ways: Increased engagement and communication between assessors, managers, and stakeholders; more pragmatic problem-oriented framing of assessment; accepting some risk; pre- and post-market analysis; explicit communication of the assessment purpose, input and output; more human (dose-response) data and more efficient use of human data; segmenting populations based on physiology; explicit consideration of value judgments in assessment; integration of multiple benefits and risks from multiple domains; explicit recognition of the impact of consumer beliefs, opinions, views, perceptions, and attitudes on behaviour; and segmenting populations based on behaviour; the opportunities proposed here do not provide ultimate solutions; rather, they define a collection of issues to be taken account of in developing methods, tools, practices and policies, as well as refining the regulatory context, for benefit-risk analysis in Food and Nutrition and other fields. Thus, these opportunities will now need to be explored further and incorporated into benefit-risk practice and policy. If accepted, incorporation of these opportunities will also involve a paradigm shift in Food and Nutrition benefit-risk analysis towards conceiving the analysis as a process of creating shared knowledge among all stakeholders.

Diagnostic accuracy of culture-based and PCR-based detection tests for methicillin-resistant Staphylococcus aureus: a meta-analysis.

A systematic review and meta-analysis were performed to determine and compare the sensitivity and specificity of PCR-based and culture-based diagnostic tests for methicillin-resistant Staphylococcus aureus (MRSA). Our analysis included 74 accuracy measurements from 29 publications. Nine tests were evaluated: the PCR-based Genotype MRSA Direct and IDI-MRSA, the chromogenic media CHROMagar, Chromogenic MRSA Medium, MRSA ID, MRSA Select and ORSAB, and the nonchromogenic culture media MSA-Cefoxitin and MSA-Oxacillin. For four chromogenic media, incubation periods of 18-24 and 48 h were evaluated. Considerable heterogeneity was detected in most analyses. A significantly higher sensitivity was found for the overall PCR pooled estimate (92.5; 95% CI 87.4-95.9) and the chromogenic media after 48 h of incubation (87.6; 95% CI 82.1-91.6) compared to the overall sensitivity of chromogenic media after 18-24 h (78.3; 95% CI 71.0-84.1). The specificity of chromogenic media after 18-24 h (98.6; 95% CI 97.7-99.1) was higher than the specificity of PCR (97.0; 95% CI 94.5-98.4) but declined after 48 h of incubation (94.7; 95% CI 91.6-96.8).The most sensitive chromogenic medium after 18-24 h of incubation was Chromogenic MRSA Medium (sensitivity: 89.3; 95% CI 72.8-96.3), whereas the most specific chromogenic medium after 18-24 h of incubation was MRSA Select (specificity: 99.4; 95% CI 98.6-99.7). After 48 h of incubation, MRSA Select had the highest sensitivity (93.2; 95% CI 83.5-97.0), whereas CHROMagar had the highest specificity (96.4; 95% CI 91.3-98.5). This meta-analysis showed statistically significant differences in diagnostic accuracy between several of the tests and the test methods evaluated. A reduction of the incubation time of chromogenic media (from 48 to 18-24 h) increases specificity but reduces sensitivity.