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The author describes the personality of Alessandro Liberati - an Italian doctor and researcher - ten years after his death: a competent, kind person with a good sense of humor. The take-home message is that it is worth engaging in the institutions in which we work throughout our lives and that the improvement of individual health conditions and public health go through daily work capable of combining values and the best scientific evidence available.

The 2020 National Report "Medicines use in Italy", produced by the National Observatory on the Use of Medicines (OsMed) of the Italian Medicines Agency (AIFA), describes the Italian pharmaceutical assistance through different available information flows that allow to recompose pharmaceutical territorial and hospital assistance, concerning both the national health service and private citizens. In the Report the results of numerous analyzes, both general and focused on specific therapeutic categories and classes, relating to pharmaceutical expenditure and consumption, are reported, but it is also present an in-depth analysis about monitoring registries and conditional reimbursement agreements, and a comparison between the most relevant Italian data and those of nine other European countries.

Research is lacking on the reversibility of antimicrobial resistance (AMR). Thus, we aimed to determine the influence of previous antibiotic use on the development and decay over time of third generation cephalosporin (3GC)-resistance of E. coli. Using the database of hospital laboratories of the Autonomous Province of Bolzano/Bozen (Italy), anonymously linked to the database of outpatient pharmaceutical prescriptions and the hospital discharge record database, this matched case-control study was conducted including as cases all those who have had a positive culture from any site for 3GC resistant E. coli (3GCREC) during a 2016 hospital stay. Data were analyzed by conditional logistic regression. 244 cases were matched to 1553 controls by the date of the first isolate. Male sex (OR 1.49, 95% CI 1.10–2.01), older age (OR 1.11, 95% CI 1.02–1.21), the number of different antibiotics taken in the previous five years (OR 1.20, 95% CI 1.08–1.33), at least one antibiotic prescription in the previous year (OR 1.92, 95% CI 1.36–2.71), and the diagnosis of diabetes (OR 1.57, 95% CI 1.08–2.30) were independent risk factors for 3GCREC colonization/infection. Patients who last received an antibiotic prescription two years or three to five years before hospitalization showed non-significant differences with controls (OR 0.97, 95% CI 0.68–1.38 and OR 0.85, 95% CI 0.59–1.24), compared to an OR of 1.92 (95% CI 1.36–2.71) in those receiving antibiotics in the year preceding hospitalization. The effect of previous antibiotic use on 3GC-resistance of E. coli is highest after greater cumulative exposure to any antibiotic as well as to 3GCs and in the first 12 months after antibiotics are taken and then decreases progressively.

Comparable clinical efficacy and safety of the reference rituximab (MABTHERA) and its biosimilars has been established in randomized trials. However, safety concerns are often raised when switching from reference to biosimilar products and between different biosimilars. In this prospective observational study we aimed at evaluating the safety of switching between reference and biosimilar rituximab (TRUXIMA and RIXATHON) at Trento General Hospital (Italy). All patients (n = 83) with Non Hodgkin’s Lymphoma (NHL, n = 72) and Chronic Lymphocytic Leukemia (CLL, n = 11) who received rituximab between March 2018 and March 2019 were asked to take part in the study. In 2017 and 2018 two tenders were carried out and two different biosimilars became available in the hospital, these were used sequentially. Thus, patients with or without previous treatments with the originator rituximab either received a biosimilar or were switched between different biosimilars. The incidence of adverse events in these groups of patients is described. The study population received 465 rituximab infusions and all received biosimilars. Fifty patients (60%) experienced at least one switch between different biosimilars or between rituximab originator and biosimilar, whereas 33 (40%) received one of the two biosimilars and one patient received reference rituximab. Adverse events (n = 146) were reported in 71 patients (84.5%). Treatment-related grade 3–4 events were reported in 5 patients (5.9%), whereas grade 1 rituximab related infusion events were observed in 6 patients (7.1%). No safety signal emerged in association with the use of a specific biosimilar nor with the practice of switching. Adverse events were similar, in terms of seriousness and frequency, to those described in the literature, providing further support to the clinical safety of rituximab biosimilars.

In February 2020, Italy was the first European country to detect coronavirus disease 2019 (COVID-19) in individuals and rapidly turned into one of the most-affected regions of the world. The National Health Service (NHS), which provides universal coverage to citizens, was challenged as never before in the history of the institution. Because no approved drug was available, patients received potentially effective drugs, participated in clinical trials, accessed compassionate drug use programs, or self-medicated.1 The aim of this study was to evaluate changes in drug demand during the early phase of the COVID-19 outbreak in Italy compared with the period before the outbreak.

Background Antibiotic resistance is now a global emergency. An increasing number of infections are becoming difficult to treat and lead to longer hospitalizations, higher medical costs and increased mortality. The aim of this study is to assess, in a population at low prevalence of use of antibiotics, whether a previous use of these drugs is associated with the occurrence of clinically relevant resistance of E.coli to fluoroquinolones (FQs), one of the most widespread and critical bacteria resistance in Italy. Methods Through a data linkage of databases of the health information systems of the Province of Bolzano (Italy) a case-control study was carried out using 2016 data. All subjects for which the resistance of E. coli to FQs was tested by the regional microbiology reference laboratory were included in the study. Those with a positive FQs-resistant E.coli isolate were defined as cases (n = 409), while the others were considered controls (n = 933). For each subject the total number of prescriptions of any antibiotics and the total number of prescriptions of FQs in the previous year were detected through a record linkage with the drug prescription database. Information on potential confounding factors (age, gender, number of hospital admissions, days of hospitalization, number of surgeries, diagnosis of chronic diseases) were obtained from the database of hospital admissions. Multivariate logistic regression analysis was used to study the association between previous use of antibiotics (any and FQs only) and development of E.coli resistance to FQs. Results It was observed that for each unit increase in the number of prescriptions of any antibiotic, the probability for E.coli to develop FQs resistance significantly rises by 16%. This probability is much higher (45%) if the prescribed antibiotic is a FQ. Conclusions This study confirms the association between previous consumption of antibiotics and the onset of resistance even in an area with a low prevalence of use. Key messages The results of this study reiterate the need to prescribe and dispense antibiotics only when they are really needed. Health information systems allows to study the role of antibiotic use in the development of bacterial resistance, providing useful information for audit interventions among healthcare professionals.

Purpose Erythropoiesis-stimulating agents (ESAs), are used for treating chronic kidney disease (CKD)-related anemia, contributing to CKD costs. The study was aimed at investigating direct healthcare costs of CKD patients treated with ESAs and the potential savings achievable by increasing the use of biosimilars and preventing inappropriate ESA use. Methods A multi-center, cohort study was conducted using claims databases of five large Italian geographic areas. Yearly mean direct healthcare costs per patient were estimated, stratifying by CKD stage. The total yearly cost and potential savings related to ESA use were estimated: (a) considering 25/50/75% of originator ESA substitution with biosimilars; (b) eliminating inappropriate ESA dispensing. Results During the study period, the ESA-related yearly mean cost represented 17% of total yearly costs in stage I-III, decreasing to 13% in stage IV-V and 6% in dialysis. Among originator users, assuming a 25% of biosimilar uptake, the annual cost-savings of ESA treatment would represent 10.5% of total ESA costs in CKD stage I-V and 7.7% in dialysis. Among incident ESA users for which hemoglobin levels were available, 9% started inappropriately ESA treatment, increasing to 62.0% during the first year of maintenance therapy. Hypothesizing prevention of the first inappropriate ESA dispensing, the total yearly cost-savings would amount to €35 772, increasing to €167 641 eliminating the inappropriate dispensing during maintenance therapy. Conclusions Higher use of lowest cost ESA, prevention of inappropriate ESA use as well as other strategies aimed at slowing down the progressive renal impairment are essential for minimizing clinical and economic burden of CKD.

The effectiveness of the tiotropium Respimat® formulation in routine clinical practice is still an open issue due to concern about the generalizability of the Tiotropium Safety and Performance in Respimat® (TIOSPIR) trial findings. Our aim was to compare the incidence of acute respiratory events between new users of tiotropium Respimat® and HandiHaler®. The study population comprised patients aged ≥45 years resident in two Italian regions who received a first tiotropium prescription (HandiHaler® or Respimat®) between 1 July 2011 and 30 November 2013. The cohort was identified within the database of drug prescriptions reimbursed by the Italian National Health Service. Clinical outcomes were obtained from hospital records. The primary outcome was the first hospitalization for respiratory events, including chronic obstructive pulmonary disease (COPD) exacerbation, respiratory failure, hypoxemia/hyperventilation and pneumonia, during the exposure period. The hazard ratios were estimated for the propensity score matched groups with Cox regression. After matching, 31,334 patients with incident tiotropium prescriptions were included. Similar incidence rates of the primary outcome between the Respimat® and HandiHaler® users were identified (adjusted hazard ratio 0.95, 95% CI 0.84–1.07). No differences emerged in the subgroup analyses conducted according to the baseline characteristics of the tiotropium users. This study confirms the findings observed in the TIOSPIR trial in a more heterogeneous population that included patient subgroups with severe respiratory disease and unstable COPD.

Granulocyte colony-stimulating factors (G-CSFs) are biological products for which the main indication of use is chemotherapy-induced neutropenia. Biosimilars of G-CSFs have been available in Europe since 2007. The objective of this study was to investigate the prescribing pattern of G-CSFs in five Italian centres using different healthcare policy interventions to promote the use of biosimilars in routine care. This retrospective, population-based drug utilization study was conducted during the years 2009–2014 using the administrative databases of the Caserta, Treviso and Palermo Local Health Units (LHUs) and the Tuscany and Umbria regions. G-CSF users were characterized and the prevalence of use, proportion of biosimilar users and switching pattern of different G-CSFs were evaluated over time and across centres. Overall, 30,247 patients were treated with G-CSFs in the years 2009–2014, of which 29,083 (96.2 %) were naive users. The overall prevalence of G-CSF use increased from 0.8 per 1000 inhabitants in 2009 to 1.1 per 1000 in 2014. An increase in the proportion of the use of the biosimilar filgrastim by the total G-CSF users was observed in all centres: from 0.2 % (2009) to 66.2 % (2014). However, heterogeneity across different centres was reported, with the largest increase in Treviso LHU (from 0 to 89.1 % from 2009 to 2014). During the first year of treatment, switching between different G-CSFs was frequent (20.3 %). Heterogeneity in the use of G-CSF and, in particular, biosimilar filgrastim across different Italian centres was observed, probably due to different regional healthcare policy interventions. During the first year of treatment, switching between different G-CSFs was frequent. Considering the impact of biological drugs on pharmaceutical expenses, it is necessary to harmonize healthcare policies promoting the use of biological drugs with the lowest cost.

The clinical development of drugs is based on a consolidated model that adopts, as a reference, the conduct of consecutive dose-finding and activity studies (the phases), up to the classical randomized controlled trials (RCTs), which are strictly regulated by a study protocol. This model is likely to be too rigid, since it cannot incorporate the information that gradually becomes available. To overcome, at least partly, this limited flexibility, so-called adaptive designs have been proposed: in these designs, it is possible to introduce changes and also to modify relevant aspects of a single design on the basis of results/information obtained in the study itself. This article presents the main characteristics of these designs and discusses the precautions to be taken into account in the application in clinical studies.

Background Population-based registries implement the comprehensive collection of all disease events that occur in a well-characterized population within a certain time period and represent the preferred tools for disease monitoring at a population level. Main characteristics of a Population-based registry are to provide answers to defined research questions, also related to clinical and health policy purposes, assuring completeness of event identification, and implementing a process of case adjudication (validation) according to standardised diagnostic criteria. Methods The application of a standard methodology results in the availability of reliable and comparable data and facilitates the transferability of health information for research and evidence-based health policies. Although registries are extremely useful, they require considerable resources to be implemented and maintained, high cost and efforts, to produce stable and reliable indicators. Results Thanks to available health information and information technology, current administrative databases on hospital admissions and discharges, medication use, in-patient care utilization, surgical operations, drug dispensations, ticket exemption and invasive procedures are increasingly available. They represent basic sources of information for implementing Population-based registries. Main strengths and limitations of Population-based registries are described taking into consideration the example of cardiovascular diseases, as well as future challenges and opportunities for implementing Population-based registries at European level. Conclusions The integration of population-based registries and current administrative health databases may help to complete the picture of the disease rebuilding the evolution of the disease as a continuum from the onset to the possible consequent complications.

The new call on independent research on drugs issued in October 2016 by the Italian Medicines Agency (AIFA) explicitly reported that proposals based on systematic reviews were not admissible, and no justification or explanation for this choice was given. Prompted by this policy decision, here, we briefly discuss the potential usefulness of systematic reviews in responding to regulatory needs. First, systematic reviews, by collecting, analysing and critically appraising all relevant studies on a specific topic, may be used by different stakeholders as a basis for making clinical and policy recommendations, including regulatory recommendations. Second, systematic reviews may advance knowledge as primary clinical research does. Third, systematic reviews may be particularly useful to detect signals of unknown adverse effects. Fourth, systematic reviews may be used to identify knowledge gaps. Systematic reviews may simultaneously produce new findings and summarize existing knowledge, with the potential of informing regulatory decisions more pragmatically and more rapidly than other research designs. We suggest that national and international calls on independent research on drugs should not put primary clinical research against systematic reviews, as it implies a focus on the methods instead of on the questions being asked. As most calls only broadly define the research areas and the topics to be covered, we argue that it should be up to the applicant to make a proposal on which design provides the most valid and useful answer, and up to the assessors to carefully check the validity, feasibility and relevance of such a proposal.

The cardiovascular safety of tiotropium Respimat formulation in the routine clinical practice is still an open issue. Our aim was to compare the risk of acute myocardial infarction and heart rhythm disorders in incident users of either tiotropium Respimat or HandiHaler. The study population comprises patients aged ≥45 years, resident in two Italian regions with a first prescription of tiotropium (HandiHaler or Respimat) between 01/07/2011-30/11/2013. The cohort was identified through the database of prescriptions reimbursed by the Italian National Health Service. Comorbidities and clinical outcomes were obtained from hospital records. The primary outcome was the first hospitalization for acute myocardial infarction and/or for heart rhythm disorders during the exposure period. Hazard ratios were estimated in the propensity score-matched groups through Cox regression. After matching, 31,334 patients with incident prescription of tiotropium were included. The two groups were balanced with regard to baseline characteristics. Similar incidence rates of the primary outcome between Respimat and HandiHaler users were identified (adjusted hazard ratio 1.02, 95% CI 0.82-1.28). No risk difference between Respimat and HandiHaler emerged when considering clinical events separately. This large cohort study showed a comparable acute cardiovascular safety profile of the two tiotropium formulations.

Introduction In this drug utilization study, we aimed at assessing the pattern of triptan use in Italy by means of the drug prescription databases of two local health authorities, accounting for approximately 1 million citizens. Methods The study population included all residents aged 18 to 84 years in the Vercelli province (about 175,000 inhabitants) and in the Umbria region (about 885,000 inhabitants), who had at least one dispensation for triptans in 2012. A frequent user, who might be at risk of medication-overuse headache (MOH), was defined as a patient being dispensed at least 10 defined daily doses (DDD) of triptans every month for at least three consecutive months. Results Triptans were used by 0.7%–1% of the population. While most patients were dispensed fewer than 60 DDDs per year, about 10% of all triptan users were classified as frequent users. In both areas, patients below the age of 29 were less likely to be frequent users while the 40- to 49-year-old population was the most affected, with no sex difference. About two-thirds of frequent users persisted in this behavior for an additional three-month period in the following six months. Conclusions Our data indicate that approximately 10% of all triptan users in the Italian population are potentially at risk for MOH. An approach based on drug prescription databases could be useful to identify patients at risk for MOH.

Background Systematic reviews (SR) of clinical evidence are rightfully considered the basis for developing recommendations to support decisions in current practice. To avoid bias, SRs are expected to be systematic in their research strategy and are exhaustive. The drawback of the latter criteria relies in the substantial work needed to conduct and keep SRs updated. The objective of this paper is to compare a research strategy based on the review of a selected number of core journals, which we consider a ‘pragmatic review’ (PR), with that derived by an SR in estimating the efficacy of treatments. Methods Five clinical areas were considered for the comparison between the two strategies: chronic obstructive pulmonary disease, dermatology, heart failure, renal diseases and stroke. We extracted a systematic sample from all the Cochrane SRs pertaining to each area and were published before April 2010. Two groups of journals were considered in the PR: six general journals that commonly published research for the five clinical areas, and five specialist journals with the highest impact factor in each area. To assess the agreement in the findings of SRs and PRs, we considered both the direction of the estimates and P-values. Results A sample of 27 SRs included 171 overall analyses and 259 subgroup analyses related to primary outcomes. The PR captured one or more clinical trials in 24 of the 27 SRs (89%), and 118 of the 171 overall analyses (69%) were replicated. The PR supported the recommendations to use (or not) the study treatment in 11 of the 13 SRs (85%), which ended with a clinical recommendation. Conclusions We verified in a sample of SRs that the conclusion of a research strategy based on a pre-defined set of general and specialist medical journals is able to replicate almost all the clinical recommendations of a formal SR.

Background In 2005 the Italian Medicines Agency (AIFA) started a program on independent research on drugs, with the aim to promote clinical research in areas of limited commercial interest. For 3 years (2005–2007) an area of the program was reserved to studies in the field of rare diseases. There is a concern that public funding of research may be wasted. We investigated the outcome of the program. Methods We conducted a cohort study on the projects that were funded by the AIFA in the area of rare diseases. The outcomes were the proportion of published studies, time to publication, impact factor of the publishing journals and relevance for clinical practice. We retrieved published articles through a literature search in peer reviewed biomedical journals indexed by Pubmed. We used the Kaplan–Meier method to estimate the cumulative probability of publication by time from project starting to publication. Results During the period 2005–2007, 62 projects were funded in the area of rare diseases. Most of the studies (n 39; 63 %) had a randomized design and in 22 (35 %) the control group received an active treatment. For 39 studies (63 %) we retrieved a publication in a peer reviewed journal. The median time to publication was 74 months and, at the maximum period of follow up (109 months), the cumulative probability of publication reached 77 %. The median impact factor was 5.4 (range 1.4–52.4). Considering the clinical relevance, more than 30 % of the published articles presented conclusive findings; an additional 10 % of the studies reached potential breakthrough findings. Conclusions Even though it takes time to set up and conduct a funding program for independent research on drugs, the results are highly rewarding. Independent funding is crucial in supporting studies aimed at answering questions that are relevant for clinical practice despite the lack of sufficient commercial interest. Electronic supplementary material The online version of this article (doi:10.1186/s13023-016-0420-4) contains supplementary material, which is available to authorized users.

Background The acceptability of switching between reference drugs and their biosimilars is often disputed. It is unclear whether this concern is specific to the use of biosimilars or is relevant to the practice of switching between any biological drugs. Objective The objective of this study was to quantify the occurrence of switching between different erythropoiesis-stimulating agents. Methods A retrospective drug utilization study was conducted in the Umbria region (Italy). The study population included all residents who received their first epoetin prescription between 1 July 2011 and 31 December 2014. The Umbria drug prescription database and the regional archive of residents were used to gather information. Switching was defined as any transition between different epoetins (different substances and/or different products of the same substance) in a series of two prescriptions. The probability of switching was described in relationship to the duration of treatment in a survival analysis. Results Overall, 3258 subjects received prescriptions of epoetins. Among the 2896 patients with at least two prescriptions, 354 (12.2 %) experienced one or more switches. The probability of switching depended on the duration of treatment: approximately 15 % of users switched within 12 months of observation and 25 % switched within 2 years. Switching was not limited to reference and biosimilar epoetins and it affected patent and off-patent epoetins equally. Conclusions Switching between different epoetins was related to the duration of use and most episodes of switching involved epoetins that have never been contrasted in a comparability exercise. The present level of switching may provide reassurance to physicians when taken together with other sources of comparative evidence. Electronic supplementary material The online version of this article (doi:10.1007/s40259-015-0155-0) contains supplementary material, which is available to authorized users.

Purpose In some cases of drug therapy, the available evidence might be sufficient to extend the indications to children without further clinical studies. Methods We reviewed the available evidence for one of the categories of drugs most frequently used off-label in children: proton pump inhibitors (PPIs) used for the treatment of gastroesophageal reflux disease (GERD). A classification of the appropriateness of off-label use of PPIs in children with GERD was also performed. Results Of the five PPIs evaluated, only omeprazole has a paediatric indication in Europe. Overall, 19 clinical trials were retrieved and evaluated on the basis of pharmacokinetics, efficacy and safety data. The off-label use of omeprazole, esomeprazole and lansoprazole in children was evaluated as appropriate given the consistent available evidence retrieved in literature. Conclusion This study demonstrates the existence of a large body of clinical evidence on the use of PPIs in children. Regulatory agencies and ethical committees should cope with this issue for ethical reasons to avoid unnecessary trial replication.

This article presents a summary of the discussion which took place during the works of PRIER II in the session dedicated to the methodology of registries. Following a thorough analysis of the possible methods and the limits which deal with the collection of clinical data through the registries, the different points of view were compared, perhaps the most relevant, related to this activity. All this has been done by taking advantage by the possibility to observe aspects from different points of view. In particular, the exercise considered those who have to deal with the methodological aspects of the registries as an operator of public health or as a private operator who creates services for companies. The final goal, again, was to line up a few essential points accompanied by reasoning and comments useful to anyone who wants to address the issue of registries from the methodological point of view.

The article collects the summary of the discussion occurred in the setting of PRIER II, in the session dedicated to the taxonomy of registries. Shown below, some specific contributions by health professionals working at the regional departments, which deal with registries, as well as the contribution on the same subject by specialists working at some pharmaceutical companies. In particular, after the presentation summarized in the article by prof. Giuseppe Costa1, the contributions, respectively by a representative of the Emilia-Romagna Region, of a health and hospital service and by the PRIER II workgroup, are following. Finally, a collective work with all participants to the working group took place to focus on all the issues considered to be crucial in defining clinical registries. At the same discussion table, institutional representatives of the regulatory national and regional branch were also invited to take into consideration the points of view of all public and private registry users, in particular in their benefits, limits and purposes. Going through the discussion on a specific check list and deepening a number of statements identified by the working group, a list of key points, essential to characterize each clinical registry, was produced.

Objectives The study aims at investigating the influence of several factors on the probability of receiving one of the two tiotropium formulations (Respimat or Handihaler). Design Drug utilisation study. Setting All residents in the Region Umbria, Italy, aged ≥45 years, who received prescriptions of tiotropium during 2011–2012. Participants Two groups of patients were studied: (1) incident users of the two tiotropium formulations (ie, without tiotropium prescriptions in the previous 6 months); (2) switchers from Handihaler to Respimat. Users of the two formulations were compared with regard to baseline characteristics and medical history. The adjusted OR of receiving Respimat was estimated for several factors. Results Incident users of the two formulations (4390 participants) had similar characteristics. They were older and with more comorbidities than patients included in randomised control trials (RCTs). Among prevalent users of Handihaler, the probability of switching to Respimat was greater in patients with severe respiratory disease (users of ≥4 respiratory drugs: adjusted OR=4.62; 95% CI 2.46 to 8.69) and among β-blocker users (adjusted OR=1.76; 95% CI 1.13 to 2.75). Age above 75 years and lipid-lowering drug use reduced the probability of switching. A positive association was also found between neurological conditions and the use of Respimat. Conclusions When starting tiotropium treatment, the choice between the two formulations is weakly affected by comorbidities and chronic obstructive pulmonary disease severity. Instead, these characteristics influence the likelihood of switching from Handihaler to Respimat. Since tiotropium users in clinical practice are more severe than those included in RCTs, further aetiological studies are needed to compare the safety profile of the two formulations in routine care.

Objective To assess the risk of maternal, fetal, and neonatal outcomes associated with the administration of an MF59 adjuvanted A/H1N1 vaccine during pregnancy. Design Historical cohort study. Setting Singleton pregnancies of the resident population of the Lombardy region of Italy. Participants All deliveries between 1 October 2009 and 30 September 2010. Data on exposure to A/H1N1 pandemic vaccine, pregnancy, and birth outcomes were retrieved from regional databases. Vaccinated and non-vaccinated women were compared in a propensity score matched analysis to estimate risks of adverse outcomes. Main outcome measures Main maternal outcomes included type of delivery, admission to intensive care unit, eclampsia, and gestational diabetes; fetal and neonatal outcomes included perinatal deaths, small for gestational age births, and congenital malformations. Results Among the 86 171 eligible pregnancies, 6246 women were vaccinated (3615 (57.9%) in the third trimester and 2557 (40.9%) in the second trimester). No difference was observed in terms of spontaneous deliveries (adjusted odds ratio 1.02, 95% confidence interval 0.96 to 1.08) or admissions to intensive care units (0.95, 0.47 to 1.88), whereas a limited increase in the prevalence of gestational diabetes (1.26, 1.04 to 1.53) and eclampsia (1.19, 1.04 to 1.39) was seen in vaccinated women. Rates of fetal and neonatal outcomes were similar in vaccinated and non-vaccinated women. A slight increase in congenital malformations, although not statistically significant, was present in the exposed cohort (1.14, 0.99 to 1.31). Conclusions Our findings add relevant information about the safety of the MF59 adjuvanted A/H1N1 vaccine in pregnancy. Residual confounding may partly explain the increased risk of some maternal outcomes. Meta-analysis of published studies should be conducted to further clarify the risk of infrequent outcomes, such as specific congenital malformations.

Supported by a specific act of the Italian Parliament.The committees and members of the Italian StudyGroup for the Di Bella Multitherapy Trials are asfollows. Research Coordinating Center: D. Greco,R. Raschetti, B. Caffari, F. Chiarotti, R. Da Cas, B.De Mei, G. Di Giovambattista, M. Maggini, F. Men-niti-Ippolito, S. Modigliani, P. Popoli, P. Ruggeri, S.Spila-Alegiani, C. Tomino, G. Traversa, P. Bruzzi, T.Gamucci. Steering Committee: G. Benagiano, D.Amadori, P. Bruzzi, E. Buiatti, E. Ciranni, F. Cog-netti, G. Colucci, P.F. Conte, G. Di Bella*, D. Greco,S. Iacobelli, F. Mandelli, E. Marubini, M. Massotti,S. Monfardini, F. Oleari, R. Raschetti, G. L. San-nazzari, L. Tomatis, U. Veronesi. (*Dr. G. Di Bella,the son of Dr. L. Di Bella, only participated in thefirst two meetings of the Steering Committee. Onmany occasions, he strongly disagreed with theperformance and results of the trials. No part ofthe current article has been discussed with orendorsed by Dr. G. Di Bella.) International ReviewBoard: P. Calabresi (Rhode Island), F. Cavalli (Bell-inzona, Switzerland), P. Kleihues (Lyon Cedex,France), J.G. Mc Vie (London, UK), H. Pinedo (Am-sterdam, The Netherlands), K. Sikora (Lyon Cedex,France), T. Tursz (Villejuif Cedex, France). Indepen-dent Endpoint Evaluation Committee: A. R. Bianco,R. Labianca, P. L. Rossi Ferrini, G. Simonetti, A.Sobrero. Investigators: Ancona—R. Cellerino, S.Antognoli, R. Berardi, R. Bracci, P. Lippe, F. Pulita;Aosta—F. Di Vito, D. Martinod, M. Musi; Avi-ano—A. Veronesi, R. Lazzarini; Bari—G. Colucci(Principal Investigator [PI]), V. Attolico, F. Giotta, M.Longo, E. Maiello; Bologna—S. Tura, F. Gherlin-zoni, M. Tani; Bolzano—H. Amor, P. Borona, F.Girardi, C. Graiff; Cagliari—G. Broccia, M. G. Co-rona, A. Desogus, V. Mascia, S. Pasqualucci; Ca-tania—G. Failla, M. R. Aiello, S. Cordio, P. Finoc-chiaro. Chieti—S. Iacobelli (PI), E. Melena, M. DeTursi, M. T. Scognamiglio, N. Tinari; Forli`—D.Amadori (PI), M. Maltoni, O. Nanni, F. Scardovi, P.Serra; Genoa—R. Rosso, F. Boccardo, A. Barp, T.Coli, M. Grimaldi; Milan—N. Cascinelli, L. Ascani,E. Bajetta, P. Bidoli, A. Cassata, D. De Candis, W.Giannessi, G. Procopio; Milan—S. Di Donato, A.Boiardi, D. Cerri, M. Eoli, A. Silvani; Milan—U.Veronesi (PI), M. Colleoni, N. Rotmensz; Na-ples—S. Monfardini (PI), G. Comella, A. De Mat-teis, A. Gravina, C. Gridelli, F. Perrone, M. R.Salzano, C. Sandomenico; Naples—C. Battista, G.Iodice, R. Fico, A. Nicchia; Padua—M. Lise, G. L.De Salvo, E. Di Lenardo, G. Iadicicco; Palermo—B.Agostara, I. Cafarelli; Perugia—M. Tonato, F.Radicchi, S. Sorbolini, O. Taschini; Pisa—P. F.Conte (PI), A. Carmignani, L. Del Mastro, A. Gen-nari, C. Orlandini; Potenza—L. Manzione, A. Di-nota, G. Lombardi; Reggio Calabria—G. Gasparini,M. G. Arena, M. Fanelli, F. Modafferi, A. Morabito;Rome—F. Mandelli (PI), P. Fazi, F. Mauro, M.Martelli, C. Ricci, M. Vignetti; Rome—F. Cognetti(PI), A. D’Alessio, S. De Marco, V. Ferraresi, T.Gamucci, D. Giannarelli, E. Magnani, P. Rellecati,E. M. Ruggeri, M. Zeuli; Turin—G. L. Sannazzari(PI), M. Borgognone, R. Chio`, A. Gasco, R. Ragona,M. Sacco, R. Soffietti, R. Verna, M. Tessa;Turin—A. Pileri; Trento—E. Galligioni, A. Lucenti,F. Moltrer, F. Paolazzi.The authors thank the Stabilimento ChimicoFarmaceutico Militare, Florence, Italy (Colonel G.Muzzi, Director), for the production of the melato-nin tablets and retinoid solution and the Group forthe supervision and control of custom-made drugsof the Istituto Superiore di Sanita`, Roma (E. Cir-anni, Director; R. Alimenti, S. Alimonti, G. Cavaz-zutti, L. Gagliardi, B. Gallinella, G. Incarnato, F. LaTorre, A. Mosca, G. Multari, L. Turchetto, L. Valvo).Address for reprints: Giuseppe Traversa, M.D., De-partment of Epidemiology and Biostatistics, IstitutoSuperiore di Sanita`, Viale Regina Elena 299, 00161Rome, Italy.Received April 26, 1999; revision received July 22,1999; accepted July 29, 1999.

To compare the risk of hospitalization for gastroduodenal ulcer associated with the use of ketorolac and other non-steroidal anti-inflammatory drugs (NSAIDs).A cohort and a nested case-control study were carried out. All residents in the region of Umbria (Italy), aged 35-84 years, who had been given at least one NSAID prescription in 1993 and 1994 were identified. Exposure to drugs was ascertained through a drug prescription database. We estimated rate ratios of hospitalization for gastroduodenal ulcer with or without complications in the current, recent or past period according to exposure to different NSAIDs.Rate ratio estimates, adjusted for age and sex, were 2.8 for any current NSAID and 1.4 for any recent NSAID. The highest rate ratios of lesions of any severity for current NSAID use were observed for piroxicam (RR: 4.6) and ketorolac (RR: 3.4). For gastrointestinal haemorrhage or perforation the highest rate ratios were those for ketorolac (RR: 5.9) and piroxicam (RR: 4.8). Rate ratio estimates did not change after adjustment for concomitant use of gastrotoxic drugs, use of gastroprotective agents not associated with NSAIDs and prior use of NSAIDs.Our study demonstrates the need to adhere to the restrictions relating to the indications and duration of use of ketorolac. At present piroxicam represents a greater public health concern since it is confirmed to be among the most gastrotoxic NSAIDs and is one of the most commonly prescribed NSAIDs in Italy.