The use of anorexic drugs was associated with the development of primary pulmonary hypertension. Active surveillance for this disease should be considered, particularly since their use is expected to increase in the near future.

The VEINES-QOL/Sym is a practical and scientifically sound, patient-reported measure of outcomes in CVDL that has been developed with rigorous methods. As the only fully validated measure of quality of life and symptoms that is appropriate for use across the full spectrum of CVDL-related conditions, that is quick and easy to administer, and that is available in four languages, the VEINES-QOL/Sym provides a rigorous tool for improving the evaluation of outcomes in clinical trials, epidemiologic studies, and audit.

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Results indicate that impairment in physical QOL in patients with VV is associated with concomitant venous disease, rather than the presence of VV per se. Findings concerning QOL in patients with VV can only be reliably interpreted when concomitant venous disease is taken into account. In patients with VV alone, the objectives of cosmetic improvement and the improvement of QOL should be considered separately.

Information derived from routinely collected real‐world data has for a long time been used to support regulatory decision making on the safety of drugs and has more recently been used to support marketing authorization submissions to regulators. There is a lack of detailed information on the use and types of this real‐world evidence (RWE) as submitted to regulators. We used resources held by the European Medicines Agency (EMA) to describe the characteristics of RWE included in new marketing authorization applications (MAAs) and extensions of indication (EOIs) for already authorized products submitted to the EMA in 2018 and 2019. For MAAs, 63 of 158 products (39.9%) contained RWE with a total of 117 studies. For 31.7% of these products, the RWE submitted was derived from data collected before the planned authorization. The most common data sources were registries (60.3%) followed by hospital data (31.7%). RWE was mainly included to support safety (87.3%) and efficacy (49.2%) with cohort studies being the most frequently used study design (88.9%). For EOIs, 28 of 153 products (18.3%) contained RWE with a total of 36 studies. For 57.1% of these products, studies were conducted prior to the EOIs. RWE sources were mainly registries (35.6%) and hospital data (27.0%). RWE was typically used to support safety (82.1%) and efficacy (53.6%). Cohort studies were the most commonly used study design (87.6%). We conclude that there is widespread use of RWE to support evaluation of MAAs and EOIs submitted to the EMA and identify areas where further research is required.

Physician-evaluated clinical category, based on the CEAP classification, predicts patient-reported QOL and symptom severity in CVD.

BackgroundAntidepressant exposure during pregnancy has been associated with an increased risk of autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) in several observational studies. We performed a systematic review of these studies to highlight the effect that important methodological limitations have on such analyses and to consider approaches to the conduct, reporting and interpretation of future studies.MethodsA review of MEDLINE and EMBASE identified case–control, cohort and sibling studies assessing the risk of ASD and ADHD with antidepressant use during pregnancy. Approaches to confounding adjustment were described. Crude and adjusted effect estimates for comparisons between antidepressant exposure during pregnancy vs. all unexposed women were first meta-analysed using a generic inverse variance method of analysis, followed by effect estimates for alternative pre-selected comparison groups.ResultsA total of 15 studies measuring ASD as an outcome (involving 3,585,686 children and 40,585 cases) and seven studies measuring ADHD as an outcome (involving 2,765,723 patients and 52,313 cases) were identified. Variation in confounding adjustment existed between studies. Updated effect estimates for the association between maternal antidepressant exposure during pregnancy vs. all unexposed women remained statistically significant for ASD (adjusted random-effects risk ratio [RaRR] 1.53, 95% confidence interval [CI] 1.31–1.78). Similar significant associations were observed using pre-pregnancy maternal antidepressant exposure (RaRR 1.48, 95% CI 1.29–1.71) and paternal antidepressant exposure during pregnancy (1.29, 95% CI 1.08–1.53), but analyses restricted to using women with a history of affective disorder (1.18, 95% CI 0.91–1.52) and sibling studies (0.96, 95% CI 0.65–1.42) were not statistically significant. Corresponding associations for risk of ADHD with exposure were: RaRR 1.38, 95% CI 1.13–1.69 (during pregnancy), RaRR 1.38, 95% CI 1.14–1.69 (during pre-pregnancy), RaRR 1.71, 95% CI 1.31–2.23 (paternal exposure), RaRR 0.98, 95% CI 0.77–1.24 (women with a history of affective disorder) and RaRR 0.88, 95% CI 0.70–1.11 (sibling studies).ConclusionsExisting observational studies measuring the risk of ASD and ADHD with antidepressant exposure are heterogeneous in their design. Classical comparisons between exposed and unexposed women during pregnancy are at high risk of residual confounding. Alternative comparisons and sibling designs may aid the interpretation of causality and their utility requires further evaluation, including understanding potential limitations of undertaking meta-analyses with such data.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-017-0993-3) contains supplementary material, which is available to authorized users.

AimsEvaluating the public health impact of regulatory interventions is important but there is currently no common methodological approach to guide this evaluation. This systematic review provides a descriptive overview of the analytical methods for impact research.MethodsWe searched MEDLINE and EMBASE for articles with an empirical analysis evaluating the impact of European Union or non‐European Union regulatory actions to safeguard public health published until March 2017. References from systematic reviews and articles from other known sources were added. Regulatory interventions, data sources, outcomes of interest, methodology and key findings were extracted.ResultsFrom 1246 screened articles, 229 were eligible for full‐text review and 153 articles in English language were included in the descriptive analysis. Over a third of articles studied analgesics and antidepressants. Interventions most frequently evaluated are regulatory safety communications (28.8%), black box warnings (23.5%) and direct healthcare professional communications (10.5%); 55% of studies measured changes in drug utilization patterns, 27% evaluated health outcomes, and 18% targeted knowledge, behaviour or changes in clinical practice. Unintended consequences like switching therapies or spill‐over effects were rarely evaluated. Two‐thirds used before–after time series and 15.7% before–after cross‐sectional study designs. Various analytical approaches were applied including interrupted time series regression (31.4%), simple descriptive analysis (28.8%) and descriptive analysis with significance tests (23.5%).ConclusionWhilst impact evaluation of pharmacovigilance and product‐specific regulatory interventions is increasing, the marked heterogeneity in study conduct and reporting highlights the need for scientific guidance to ensure robust methodologies are applied and systematic dissemination of results occurs.