The PREGVAXGRIP study: a cohort study to assess foetal and neonatal consequences of in utero exposure to vaccination against A(H1N1)v2009 influenza.

BACKGROUND: In October 2009, in the context of an A(H1N1)v2009 influenza pandemic, a vaccination campaign was launched in France, in which one of the priority groups was pregnant women, on account of the high risk of developing complications following infection by this virus. OBJECTIVE: The aim of this multicentric, prospective, observational study was to assess safety and pregnancy outcomes in a cohort of pregnant women when receiving the A(H1N1)v2009 influenza pandemic vaccine. METHODS: This was a prospective study that followed up pregnant women recruited mainly in vaccination centres and maternity departments. Following the expected delivery date, follow-up data were collected concerning the delivery, the infant, and, if appropriate, the reasons why the pregnancy did not reach its term. RESULTS: Between 1 November 2009 and 31 March 2010, 2,415 pregnant women were included at the time of vaccination; 97.6 % of women received a vaccine without adjuvant and 2.4 % received an adjuvanted vaccine. Ninety-two (3.9 %) women were vaccinated during the first trimester of pregnancy, 1,090 (46.5 %) during the second trimester, and 1,162 (49.6 %) during the third trimester. One hundred and thirty-three adverse events (5.5 % of women) were reported, of which 12 were unexpected or serious. There were 2,246 (93.0 %) known pregnancy outcomes with 12 spontaneous abortions (0.5 %), 6 stillbirths (0.3 %), and 4 therapeutic abortions (0.2 %). There were 65 neonates with congenital anomalies, among which 31 were major. But only one congenital malformation (1.4 %) was reported for the 92 women vaccinated in their first trimester. Of the women, 93.3 % were delivered full term and 6.7 % preterm. For 96 (4.2 %) neonates, a disorder was reported in the neonatal period and 130 (5.6 %) were transferred to the neonatology department. CONCLUSIONS: This study suggests that exposure to the A(H1N1)v2009 pandemic influenza vaccine during pregnancy does not increase the risk of adverse pregnancy outcomes. However, because of the relatively small number of women exposed during the first trimester, other studies are needed to exclude an increased risk of malformation.

Comparative analysis of adverse drug reactions to tetracyclines: results of a French national survey and review of the literature.

BACKGROUND: The question of quantitative and qualitative differences between adverse drug reactions (ADRs) to tetracyclines was raised many years ago, especially for minocycline and doxycycline. OBJECTIVES: To assess and compare ADRs related to tetracyclines according to sales figures in France through a national survey. METHODS: ADR data were collected from the French Pharmacovigilance Database (FPD), marketing authorization holders (MAH) and the literature. Sales analyses were based on MAH data provided annually to the French Drugs Agency. RESULTS: Among the tetracyclines available in France, doxycycline and minocycline are the most frequently used. However, their sales decreased between 1995 and 2007, more sharply for minocycline than doxycycline. According to the FPD, based on MAH data and published reports, minocycline-associated ADRs were more serious and were reported more frequently than for the other tetracyclines. Minocycline and doxycycline ADR patterns differed: gastrointestinal disorders (especially oesophageal lesions) predominated with doxycycline, while intracranial hypertension and hepatic disorders were primarily reported with minocycline. Autoimmune disorders, drug reaction with eosinophilia and systemic symptoms (DRESS) and other hypersensitivity reactions were also more frequent with minocycline. ADRs reported with lymecycline and metacycline were essentially cutaneous and gastrointestinal disorders. CONCLUSIONS: In the absence of markedly better efficacy against the various indications for tetracyclines, the minocycline benefit/risk ratio was clearly lower than that of doxycycline, and possibly those of lymecycline and metacycline. In light of these findings, minocycline should no longer be considered first-line therapy for inflammatory skin disorders, especially acne.

[Second wave of the French drug harmonisation programme to prevent medication errors: overall appreciation of healthcare professionals]. / Évaluation de l'impact auprès des professionnels de la mise en œuvre de la seconde vague du plan d'harmonisation de l'étiquetage des injectables.

BACKGROUND: Medication errors are a significant cause of severe healthcare-associated complications. In December 2006, the French Health Products Agency (Afssaps) has issued a protocol to harmonise labeling of injectable drugs vials. In 2007, a first change was launched for four drugs and was followed in 2008-2009 by a second wave concerning 42 active drugs. METHODS: The present study describes how healthcare professionals have perceived this change and their overall appreciation of the drug harmonisation programme. A survey using an electronic questionnaire was distributed to medical and non-medical professionals in anaesthesia and intensive care and pharmacists in a representative sample of 200 French hospitals. RESULTS: The harmonisation procedure was felt as being overall satisfactory by 53% of professionals who had responded but it was recognised that the new procedure is associated with improved readability and understanding of drug dosage. The use of colour coding was also well accepted by the personnel of clinical units. Respondents expressed significant criticisms regarding both the communication plan and the way the plan was implemented locally in hospitals. Old and new labeling coexisted in 66% of responding hospitals and many respondents described being aware of errors or near-misses that were considered related to the transition. For many important topics, pharmacists had views that were significantly different from clinicians. CONCLUSION: This national survey describing the perception of healthcare professionals regarding the new harmonisation procedure for injectable drugs highlighted some progress but also a number of deficiencies, notably regarding communication and implementation of the change in clinical units. This survey will be used by the French Health Products Agency to improve future steps of the long-lasting campaign against medication errors.

Benzodiazepine-like hypnotics and the associated risk of road traffic accidents.

The aim of the study was to investigate the association between the use of benzodiazepine or benzodiazepine-like hypnotics and the risk of road traffic accidents. Data from three French national databases were matched: the health-care insurance database, police reports, and the police database of injury-related traffic accidents. A total of 72,685 drivers involved in injury-related road traffic accidents in France, from 2005 to 2008, were included in the study. The risk of being responsible for a traffic accident was higher in users of benzodiazepine hypnotics (odds ratio (OR) = 1.39 (1.08-1.79)) and in the 155 drivers to whom a dosage of more than one pill of zolpidem a day had been dispensed during the 5 months before the collision (OR = 2.46 (1.70-3.56)). No association was found between the use of zopiclone and risk of traffic accidents. Although this study did not find any association between the use of zolpidem as recommended and causation of traffic accidents, the potential risk related to possible abuse of the drug and risky driving behaviors should be further investigated. The results related to benzodiazepine hypnotics are consistent with those of previous studies.

[The use of postnatal corticosteroid therapy in premature infants to prevent or treat bronchopulmonary dysplasia: current situation and recommendations]. / Utilisation de la corticothérapie postnatale chez le nouveau-né prématuré dans la prévention et le traitement de la dysplasie bronchopulmonaire : état des lieux et conduite à tenir.

In the last few years, several studies related to the benefit/risk balance of postnatal corticosteroids administered to premature neonates for prevention or treatment of bronchopulmonary dysplasia (BPD) have been published. These data encourage caution, given the risk of long-term adverse neurodevelopmental outcomes. In the meantime, the clinical profile of BPD has been altered based on the progress made in the pre- and postnatal care of premature infants. In 2006, a survey conducted in France in neonatal centers showed that corticosteroids were still frequently used (57% of the centers) following various protocols in very preterm-born infants for respiratory impairment. To promote safer practices and rational use of corticosteroids in the prevention and treatment of BPD in preterm-born neonates, we reviewed the available data in order to establish recommendations. Systemic administration of corticosteroids for prevention or treatment of BPD: (i) should not be used during the first 4 days of life; (ii) is not indicated in the first 3 weeks of life nor (iii) in extubated infants (nasal ventilation or oxygen therapy). The systemic administration of steroids can only be considered after the first 3 weeks of life in very preterm-born ventilator-dependent infants to facilitate extubation (or prevent reintubation related to the severity of BPD). Postnatal dexamethasone administration studied in several randomized clinical trials was shown to have an unfavorable benefit/risk profile, mainly because of the long-term adverse neurocognitive outcomes. Very few studies have been conducted with betamethasone in the postnatal period. According to sparse data, this drug might be as efficacious as dexamethasone, but its long-term risk profile is unknown. It should be noted that following prenatal administration, the benefit/risk profile of betamethasone is better than that of dexamethasone, especially with regard to neurocognitive development. Intravenous hydrocortisone administered at an early stage for the prevention of BPD is being evaluated and should not be administered in this indication, except within clinical trials approved by the ethics committee. No other corticosteroids have been evaluated in the postnatal period in respiratory indications. In conclusion, in the situations described above for which systemic corticosteroids could be justified, the use of betamethasone (or hydrocortisone) appears to be better. As usual, the lowest possible dose of corticosteroids should be administered for the shortest possible duration. The betamethasone-equivalent dose of 0.125 mg/kg/day for 3 days is deemed adequate. If inhaled, corticosteroid therapy may facilitate extubation. Neither its efficacy in respiratory diseases nor its long-term risk profile has been so far established.

Life-threatening eosinophilic pleuropericardial effusion related to vitamins B5 and H.

OBJECTIVE: To report a case of eosinophilic pleuropericarditis resulting from concomitant use of vitamins B5 and H. CASE SUMMARY: A 76-year-old white woman was admitted to the hospital because of chest pain and dyspnea related to pleurisy and a pericardial tamponade. This patient had no history of allergy and had been taking vitamins B5 and H for two months. Blood tests performed showed an inflammatory syndrome and a high eosinophil concentration (1200-1500 cells/mm3). Pleurocentesis and pericardiotomy yielded a sterile exudative fluid with an eosinophilic infiltrate. There were no nuclear antibodies and no rheumatic factor; screenings for viruses, parasites, bacteria, and malignant tumor were negative. A myelogram, biopsy of the iliac crest bone, and concentration of immunoglobulin E were also normal. After withdrawal of the vitamins, the patient recovered and the eosinophilia disappeared. DISCUSSION: Prolonged hypereosinophilia has marked predilection to damage specific organs, including the heart, but pleuropericardial effusion is uncommon. Drug-related pleuropericarditis usually occurs without an increased eosinophil count. Other drugs responsible for eosinophilic pleuropericarditis are cephalosporins, dantrolene, propylthiouracil, and nitrofurantoin. To our knowledge, this is the first case report of pleuropericarditis related to vitamins B5 and H. CONCLUSIONS: This case suggests that vitamins B5 and H may cause symptomatic, life-threatening, eosinophilic pleuropericarditis. Physicians prescribing these commonly used vitamins should be aware of this potential adverse reaction.

[The European pharmacovigilance: regulatory aspects]. / La pharmacovigilance européenne: aspects réglementaires.

ESTABLISHMENT: The European pharmacovigilance system has been operating since 1995 when the European Agency for the Evaluation of Medicinal Products as well as two new European registration procedures were established. STRUCTURE: This system is very similar to the French organization and is based on a decentralized collection and validation of safety data by member states and a centralized evaluation and decision making process at the European Agency for the Evaluation of Medicinal Products performed by the Committee for Proprietary Medicinal Products (CPMP) and its Pharmacovigilance Working Party. A EUROPEAN SYSTEM: In light of the experience gained, the European pharmacovigilance system moved to an interactive system which relies on a close cooperation between member states ensuring the common evaluation and management of safety concerns.

[French system of drug surveillance]. / Le système francais de pharmacovigilance.

The French drug surveillance system is characterized by: a network of thirty one regional drug surveillance centres, located to provide convenient proximity to health care professionals; a causality assessment method, compulsory for all persons involved in drug surveillance, to assess the causal relationship between an adverse effect and one or more drugs; if necessary, an additional evaluation of the causal relationship will be performed using pharmaco-epidemiology methods; a Technical committee and a National Commission of Drug Surveillance which centralize and assess all the data in order to provide a consensual advice to the relevant authorities on necessary measures, to prevent, or reduce a drug related adverse effect; in the case of an inquiry, the drug surveillance department of the pharmaceutical company and the network of regional drug surveillance centers will pool their data with the aim to exchange information and ideas.

[Pharmacovigilance off the beaten track: herbal surveillance or pharmacovigilance of medicinal plants]. / Une pharmacovigilance hors des sentiers battus: la phytovigilance où la pharmacovigilance des plantes médicinales.

For several years, herbal medicines have been increasingly consumed by patients without prescription. They are traditionally innocuous but as medicinal products they require drug surveillance in order to identify their risks. However, the first concern is to give them a legal status, to evaluate their efficacy and to control their safety. Published data show that the risk is due either to a contaminant or to an added drug or falsification. Since 1985, the Regional Pharmacovigilance Centres have received about 341 reports of undesirable effects due to herbal medicines: among them 30 cases of hepatitis were reported associated with germander which has been now withdrawn from the French market. This example well illustrates the role of the national system and its responsibility for collecting and evaluating ADRs due to herbal medicines.

[Acute methotrexate poisoning: apropos of 16 cases reported to the Paris Poison Control Center and review of the literature]. / L'intoxication aiguë au méthotrexate: a propos de 16 cas rapportés au Centre Anti-Poisons de Paris et revue de la littérature.

16 cases of acute methotrexate (MTX) poisoning were reported to the Paris Poison Control Centre and 62 others were published between 1974 and 1995. Until 1992, MTX was mainly prescribed for neoplastic diseases. Clinical features involve acute renal failure, pancytopenia, and cutaneous or mucous injury. These cases emphasise major risk factors responsible for misuse and overdosage. Since 1992, MTX has been increasingly used in rheumatological or pulmonary diseases (rheumatoid arthritis, steroid-dependent asthma). Most of the overdosages were due to a medical misuse (in the dosage regimen or a misunderstanding of the prescription by nurse, pharmacist or patient). All patients had a bone marrow suppression. The treatment is based especially on early administration of folinic acid rescue.

[Hypersensitivity to glucocorticoids: reflections on a published case report sample]. / Hypersensibilités aux glucocorticoïdes: réflexions à partir d'un échantillon de cas rapportés dans la littérature.

Hypersensitivity reactions associated with glucocorticoid treatment are rare but well known; the purpose of this study was to identify the responsible constituent (the excipient or the glucocorticoid). 32 cases published from 1970 have been analysed. In 75 per cent of cases, the patients received the glucocorticoid (hydrocortisone and methylprednisolone principally) by the intravenous route. Clinical manifestations reported were respiratory or cutaneous, with a short interval to onset. Skin tests were performed in 20 patients, but cutaneous challenge identified an agent responsible for hypersensitivity in only three cases. The heterogeneity of the test results in these 32 cases makes it difficult to identify a unifying explanation for the reactions, or propose a therapeutic schedule.

[Evaluation of unexpected and toxic effects of omeprazole (Mopral) reported to the regional centers of pharmacovigilance during the first 22 postmarketing months]. / Bilan des effets inattendus et toxiques de l'oméprazole (Mopral) rapportés aux centres régionaux de pharmacovigilance, au cours des 22 premiers mois de commercialisation.

Omeprazole has been marketed in France since 1989, for the healing of peptic ulcers, erosive reflux esophagitis and the Zollinger Ellison syndrome. It is a proton pump inhibitor which inhibits the acid secretion in the stomach. In the majority of the clinical trials, omeprazole has been found to be well tolerated: headache, dizziness, skin rash, constipation have just been noted. Since September 1989, 143 adverse reactions have been reported to pharmacovigilance centres and Astra France: 37 neurological and psychiatric side effects, especially confusion in patients with hepatic diseases and/or advanced age; 35 cutaneous reactions, generally rash and urticaria; 22 hematological effects: leucopenia and agranulocytosis have been reported but the relation with omeprazole is very uncertain; 10 gastrointestinal effects, generally diarrhoea, nausea, vomiting and abdominal pain; 8 hepatic disorders, especially moderate elevation of aminotransferases. This study confirms the safety of this drug, during short treatment; the frequency of notified adverse effects is about 1/12 200 treatments of 4 weeks. The ministry of health, has decided, in november 1991, to inform the prescribers of this potential toxicity of omeprazole, particularly, of the risk of confusion, hepatotoxicity and leucopenia.