Rare diseases (RD) patient registries are powerful instruments that help develop clinical research, facilitate the planning of appropriate clinical trials, improve patient care, and support healthcare management. They constitute a key information system that supports the activities of European Reference Networks (ERNs) on rare diseases. A rapid proliferation of RD registries has occurred during the last years and there is a need to develop guidance for the minimum requirements, recommendations and standards necessary to maintain a high-quality registry. In response to these heterogeneities, in the framework of RD-Connect, a European platform connecting databases, registries, biobanks and clinical bioinformatics for rare disease research, we report on a list of recommendations, developed by a group of experts, including members of patient organizations, to be used as a framework for improving the quality of RD registries. This list includes aspects of governance, Findable, Accessible, Interoperable and Reusable (FAIR) data and information, infrastructure, documentation, training, and quality audit. The list is intended to be used by established as well as new RD registries. Further work includes the development of a toolkit to enable continuous assessment and improvement of their organizational and data quality.

Waste is part of the agenda of the European Environment and Health Process and included among the topics of the Sixth Ministerial Conference on Environment and Health. Disposal and management of hazardous waste are worldwide challenges. We performed a systematic review to evaluate the evidence of the health impact of hazardous waste exposure, applying transparent and a priori defined methods. The following five steps, based on pre-defined systematic criteria, were applied. 1. Specify the research question, in terms of “Population-Exposure-Comparators-Outcomes” (PECO). Population: people living near hazardous waste sites; Exposure: exposure to hazardous waste; Comparators: all comparators; Outcomes: all diseases/health disorders. 2. Carry out the literature search, in Medline and EMBASE. 3. Select studies for inclusion: original epidemiological studies, published between 1999 and 2015, on populations residentially exposed to hazardous waste. 4. Assess the quality of selected studies, taking into account study design, exposure and outcome assessment, confounding control. 5. Rate the confidence in the body of evidence for each outcome taking into account the reliability of each study, the strength of the association and concordance of results. Fifty-seven papers of epidemiological investigations on the health status of populations living near hazardous waste sites were selected for the evidence evaluation. The association between 95 health outcomes (diseases and disorders) and residential exposure to hazardous waste sites was evaluated. Health effects of residential hazardous waste exposure, previously partially unrecognized, were highlighted. Sufficient evidence was found of association between exposure to oil industry waste that releases high concentrations of hydrogen sulphide and acute symptoms. The evidence of causal relationship with hazardous waste was defined as limited for: liver, bladder, breast and testis cancers, non-Hodgkin lymphoma, asthma, congenital anomalies overall and anomalies of the neural tube, urogenital, connective and musculoskeletal systems, low birth weight and pre-term birth; evidence was defined as inadequate for the other health outcomes. The results, although not conclusive, provide indications that more effective public health policies on hazardous waste management are urgently needed. International, national and local authorities should oppose and eliminate poor, outdated and illegal practices of waste disposal, including illegal transboundary trade, and increase support regulation and its enforcement.

Following a reduction in global child mortality due to communicable diseases, the relative contribution of congenital anomalies to child mortality is increasing. Although infant survival of children born with congenital anomalies has improved for many anomaly types in recent decades, there is less evidence on survival beyond infancy. We aimed to systematically review, summarise, and quantify the existing population-based data on long-term survival of individuals born with specific major congenital anomalies and examine the factors associated with survival. Seven electronic databases (Medline, Embase, Scopus, PsycINFO, CINAHL, ProQuest Natural, and Biological Science Collections), reference lists, and citations of the included articles for studies published 1 January 1995 to 30 April 2020 were searched. Screening for eligibility, data extraction, and quality appraisal were performed in duplicate. We included original population-based studies that reported long-term survival (beyond 1 year of life) of children born with a major congenital anomaly with the follow-up starting from birth that were published in the English language as peer-reviewed papers. Studies on congenital heart defects (CHDs) were excluded because of a recent systematic review of population-based studies of CHD survival. Meta-analysis was performed to pool survival estimates, accounting for trends over time. Of 10,888 identified articles, 55 (n = 367,801 live births) met the inclusion criteria and were summarised narratively, 41 studies (n = 54,676) investigating eight congenital anomaly types (spina bifida [n = 7,422], encephalocele [n = 1,562], oesophageal atresia [n = 6,303], biliary atresia [n = 3,877], diaphragmatic hernia [n = 6,176], gastroschisis [n = 4,845], Down syndrome by presence of CHD [n = 22,317], and trisomy 18 [n = 2,174]) were included in the meta-analysis. These studies covered birth years from 1970 to 2015. Survival for children with spina bifida, oesophageal atresia, biliary atresia, diaphragmatic hernia, gastroschisis, and Down syndrome with an associated CHD has significantly improved over time, with the pooled odds ratios (ORs) of surviving per 10-year increase in birth year being OR = 1.34 (95% confidence interval [95% CI] 1.24–1.46), OR = 1.50 (95% CI 1.38–1.62), OR = 1.62 (95% CI 1.28–2.05), OR = 1.57 (95% CI 1.37–1.81), OR = 1.24 (95% CI 1.02–1.5), and OR = 1.99 (95% CI 1.67–2.37), respectively (p < 0.001 for all, except for gastroschisis [p = 0.029]). There was no observed improvement for children with encephalocele (OR = 0.98, 95% CI 0.95–1.01, p = 0.19) and children with biliary atresia surviving with native liver (OR = 0.96, 95% CI 0.88–1.03, p = 0.26). The presence of additional structural anomalies, low birth weight, and earlier year of birth were the most commonly reported predictors of reduced survival for any congenital anomaly type. The main limitation of the meta-analysis was the small number of studies and the small size of the cohorts, which limited the predictive capabilities of the models resulting in wide confidence intervals. This systematic review and meta-analysis summarises estimates of long-term survival associated with major congenital anomalies. We report a significant improvement in survival of children with specific congenital anomalies over the last few decades and predict survival estimates up to 20 years of age for those born in 2020. This information is important for the planning and delivery of specialised medical, social, and education services and for counselling affected families. This trial was registered on the PROSPERO database (CRD42017074675).

INTRODUCTION Congenital anomalies (CAs) represent one of the main cause of foetal death, infant mortality and morbidity, and long-term disability. CAs have been object of systematic registration activity for a long-time in many geographical areas in Europe and worldwide. CAs are often associated with disabilities of different types and severity, including the developed Countries worldwide. According to the World Health Organization (WHO), each year approximately 3,2 million of children worldwide are born with a CA and approximately 300,000 newborns with a diagnosis of birth defect die within the first 28 days of life. In Europe, CAs are the leading cause of perinatal mortality: the European Surveillance of Congenital Anomalies (EUROCAT) network estimated a perinatal mortality associated with CAs of 9.2 per 10,000 births in 2008-2012. In Italy, the Ministry of Health estimates that, on the average of 500,000 births each year, about 25,000 present at least one CA. Moreover, approximately 25% of infant mortality is due to CAs and about 50% of infant mortality is attributable to perinatal morbidity, almost always of prenatal origin. Regarding long-term survival, a recent population study conducted between 1985 and 2003 in the UK estimated a 20.5-year survival of 85.5% of children born with at least one CA. According to the Centre for Disease Control and Prevention, approximately 3.3% of live births in the United States have a severe birth defect. Since CAs represent a significant public health issue, an effective primary prevention strategy should be a priority for public policies and healthcare system. Regarding aetiology, although in many cases the cause is still unknown, it has been hypothesized that CAs may be developed during the first trimester of pregnancy as a result of hereditary polygenic defects or of a gene-environment interaction. The aetiology is predominantly multifactorial, caused by complex interactions between genes and environment, which modify the normal embryo-foetal development, especially during the organogenesis phase. In particular, environmental factors (e.g., chemical toxicants, infection agents, maternal disease, and exogenous factors) can have preconceptional mutagenic action, postconceptional teratogenic effects, periconceptional endocrine disruption or epigenetic action. Regarding genetic causes, there are genetic-chromosomal aberrations or dysgeneses. Furthermore, socioeconomic factors affect reproductive health by differentiating the exposure to the other risk factors as well as the access to prevention measures. In recent years, the importance of the environment as a major factor of reproductive risk has been highlighted. An individual may be exposed to pollutants present in the workplace and the population may be exposed to multiple sources of environmental contamination of water, soil, and air matrices. Pregnant women and the developing foetus are particularly sensitive to the effects of environmental exposure. OBJECTIVE The aim of the present working paper is to produce an updated review of the epidemiological evidence on the risk of CAs associated with environmental exposures, socioeconomic, and main individual risk factors, such as cigarette smoking and alcohol consumption, according to the approach proposed by Pirastu et al. 2010 in the framework of the SENTIERI Project (the Italian Epidemiological Study of Residents in National Priority Contaminated Sites). DESIGN AND METHODS Literature search was carried out in PubMed, following the SENTIERI project criteria to evaluate evidence, by selecting articles in English or Italian language published from 2011 to 2016 regarding human studies. For this review, descriptive and analytical epidemiological studies (cohort, case-control, cross-sectional, and ecological), systematic reviews, and metanalyses reporting association estimates between the outcome and at least one of the risk factors were selected. As in Pirastu et al., the sources of environmental exposure have been classified into four macrocategories: industries, mines, landfills, and incinerators. The sources of individual exposure considered were: active and passive cigarette smoking, alcohol consumption, socioeconomic status (SES), occupational and environmental exposures related to air pollutants from vehicular traffic only. The obtained results were assessed according to the evaluation criteria on the epidemiological evidence related to the association between the outcome and exposures predefined and published by the SENTIERI working group (WG). For the evidence assessment, the SENTIERI WG criteria favoured firstly primary sources and quantitative metanalyses, secondly, consistency among sources. The evaluation of the epidemiological evidence for the association between outcome and the exposure has been classified into three categories: sufficient (S), limited (L), inadequate (I). RESULTS Industries: during the period under review, six single studies evaluating the association between industrial sites exposure and the risk of CAs were found. The epidemiological evidence of association between outcome and exposure has been considered limited. Mines: from the bibliographic research, three single studies investigating possible cause-effect relationship between maternal residential proximity to mines and the risk of CAs have been collected providing inadequate epidemiological evidence. Landfills: during the period under review, one systematic review and one literature review evaluating the causal associations between maternal residential proximity to landfills and CAs were identified. The epidemiological evidence is limited and concerns almost exclusively sites containing industrial or hazardous waste. Incinerators: a systematic review has been selected; it concludes that the evidence for the association between maternal residential proximity to incinerators and CAs are inadequate. Cigarette smoking: the literature search identified eight...