[Hydroxychloroquine during pregnancy: a review of retinal toxicity in the newborns]. / Toxicité rétinienne de l'hydroxychloroquine chez le nouveau-né exposé in utero.

OBJECTIVE: The objective of this study is to review the published data on ocular toxicity in newborns after in utero exposure to hydroxychloroquine. METHODS: All publications related ophthalmologic follow-up of newborns or infants who were exposed to hydroxychloroquine during pregnancy were selected. RESULTS: Nine studies were analyzed, concerning 246 infants for which an ophthalmological examination was available. None of the infants had signs of ocular toxicity at the clinical stage. Among the 31 infants having electrophysiologics explorations, 4 had suggestive signs of retinal toxicity at the preclinical stage. This could probably be explained by a low cumulative dose, the immaturity of the fetal retina and the low light stimulation in utero. However, without a remote monitoring of infants, it is difficult to conclude to the absence of functional impairment. CONCLUSION: Data are not for a major risk of retinal toxicity associated with exposure in utero to hydroxychloroquine.

[Neonatal risks of drugs exposure at the end of pregnancy]. / Risque néonatal des médicaments pris à la fin de la grossesse.

Foetal drugs exposure consequences depend according to the drug involved and to the length of the exposure which in the sum of length of treatment and of drug elimination (5 half life). Decisions are based upon risk evaluation and are a compromise between a risk banalisation and an excess of carefully. We described risks management for drugs used for a disease due to the pregnancy (glucocorticoïdes, antibiotics) then for drugs used for a chronic disease often preceding the pregnancy (non steroidal anti-inflammatory, serotonin recapture inhibitors, benzodiazepines, antiepileptics, conversion enzyme inhibitors/renine angiotensine antagonists, betabloquants). We also present the elements to take in account for the best drug choice at the end of pregnancy and/or for an adapted advice if the drug has been already taken: the drug itself (pharmacological effects, kinetics in neonate, toxicity marker, risk detection tool), drug amount possibly received by the neonate and literature data about neonatal manifestations due to the drug.

Drug exposure during the periconceptional period: a study of 1793 women.

BACKGROUND: Many studies have described the prescribing of drugs to pregnant women, but only very few have data concerning the periconceptional period specifically. AIM: The aim of the study was to evaluate the incidence of exposure to teratogenic drugs during early pregnancy and to determine whether a safer drug exists. METHODS: In a French health insurances database, we analyzed drugs prescribed during the period starting 1 month before and ending 2 months after the beginning of pregnancy between 1 January 2006 and 31 December 2007. Based on the Summary of Product Characteristics (SPC), drugs we considered were those 'contraindicated', 'not recommended', 'to be avoided', and 'possible' for use during the first trimester of pregnancy. For drugs 'contraindicated', we established if there were alternatives with similar efficacy for the mother and lower risk for the fetus. RESULTS: Over a period of 2.25 years, 8754 drugs were prescribed to 1793 women starting 1 month prior to and ending 2 months after conception. Among these drugs, 20 (0.2%) were 'contraindicated', 195 (2.2%) were 'not recommended', and 1209 (13.8%) were 'to be avoided' during the first trimester of pregnancy. Twenty (1.1%) women received at least one drug that was 'contraindicated' during the first trimester, 171 (9.5%) received a drug that was 'not recommended' and 768 (42.8%) received a drug that was 'to be avoided'. At least one possible alternative was available for all except one 'contraindicated' drug. CONCLUSIONS: During the highest teratogenic risk period, 1.1% of women received a contraindicated drug, despite existence of a safer alternative drug. This may be partly accounted for by physicians not being aware of the pregnancy at the time the drug was administered and could be reduced by adding a section entitled 'women of child-bearing potential' to the SPC.

Isotretinoin exposure during pregnancy: assessment of spontaneous reports in France.

BACKGROUND: In three previous studies, we have shown that pregnant women were still being exposed to isotretinoin and that compliance with recommendations was incomplete. The relaxation of these recommendations (summary of product characteristics 2004), combined with the release of generic brands, encouraged us to carry out a fourth study. OBJECTIVE: To assess isotretinoin exposure during pregnancy following the application of less stringent recommendations and the marketing of generic isotretinoin brands. METHODS: All cases of isotretinoin exposure during pregnancy, between 1 January 2003 and 31 December 2006, spontaneously reported to pharmacovigilance centres, the Teratogenic Agent Information Centre, and pharmaceutical companies in France were assessed. Cases were classified for analysis into the following groups: 'conception <1 month after isotretinoin discontinuation', 'conception during isotretinoin treatment' and 'patient already pregnant when isotretinoin was started'. The rate of spontaneously reported isotretinoin exposure during pregnancy was estimated by dividing the number of isotretinoin-exposed pregnancies by the number of women of childbearing age treated with isotretinoin. RESULTS: Over 4 years, 147 cases of isotretinoin exposure during the teratogenic risk period were spontaneously reported, i.e. 'conception <1 month after isotretinoin discontinuation' (23%), 'conception during isotretinoin treatment' (61%), and 'patient already pregnant when isotretinoin was started' (16%). Nineteen percent of the patients did not use any form of contraception. In 23% of the patients, the method of contraception used did not comply with recommendations, while in 86% of the cases, isotretinoin was prescribed by a dermatologist. Among the 44 pregnancies with available data on fetuses or neonates, there were two (4.5%) malformations compatible with the time of exposure and with isotretinoin embryopathy. The rate of spontaneously reported isotretinoin exposure during pregnancy has increased by approximately 30%, from 0.32 (95% CI 0.26, 0.38) to 0.41 (95% CI 0.34, 0.49) per 1000 women of childbearing age treated since 1999-2002. CONCLUSIONS: We suggest that recommendations be tightened, with specific information regarding the most effective contraceptive method combined with compulsory monthly pregnancy testing during treatment. The French Drug Agency has informed the European Medicines Agency of the need for measures aimed at improving compliance.

Drug dependence associated with triptans and ergot derivatives: a case/non-case study.

INTRODUCTION: The aim of this case/non-case study was to assess and compare the risk of drug dependence associated with different migraine-specific drugs, i.e., ergot derivatives and triptans, using the French pharmacovigilance database. METHODS: Reports on drug side effects recorded in this database between January 1985 and June 2007 were analyzed, and triptans (almotriptan, eletriptan, naratriptan, sumatriptan, and zolmitriptan) as well as ergot derivatives used in acute migraine were examined. For all reports, cases were defined as those reports corresponding to "drug abuse," "physical or mental drug dependence," and "pharmacodependence," whereas "non-cases" were defined as all the remaining SED reports. The method's reliability was assessed by calculating the risk associated with a negative (amoxicillin) and a positive (benzodiazepines) control. The risk of dependence associated with each drug and control was evaluated by calculating the odds ratio (OR) with a confidence interval of 95%. RESULTS: Among the 309,178 reports recorded in the database, drug dependence accounted for 0.8% (2,489) of the reports, with 10.9% (449) involving a triptan, and 9.33% (332) an ergot derivative. The risk of dependence was similar for triptans and ergot derivatives and did not differ from that of benzodiazepines. In the triptan group, the risk (odds ratio [95% CI]) ranged from 10.3 [4.8-22.3] for sumatriptan to 21.5 for eletriptan [10.1-45.6], while in the ergot derivative group, it ranged from 12 [8-17.9] for ergotamine to 20.6 [8-53] for dihydroergotamine. CONCLUSIONS: These findings confirm the hypothesis that triptans and ergot derivatives are associated with an increased risk of drug dependence.

Avoidability of adverse drug reactions spontaneously reported to a French regional drug monitoring centre.

BACKGROUND: Adverse drug reactions (ADRs) are now recognized as a major category of iatrogenic illness in terms of morbidity and mortality. OBJECTIVE: To describe the type and frequency of avoidable ADRs spontaneously reported to a regional drug monitoring centre following inappropriate prescribing, as a basis for preventive actions. METHODS: A prospective, observational study of ADRs reported to the Regional Drug Monitoring Centre of Tours, France, between 26 November 2002 and 28 November 2003. The outcome measure was ADRs secondary to inappropriate prescribing that were defined as entirely or partly avoidable, i.e. at least one of the recommendations in various sections of the summary of product characteristics (SPC; indication, route of administration, dose, duration of treatment, dose adaptation, precautions for use, monitoring of treatment, absolute contraindications and contraindicated interactions) had not been respected. The link between the lack of conformity of the drug prescription with the SPC and occurrence of the ADR was evaluated by a working group using two criteria: (i) is nonconformity of the prescription of this drug a known and validated risk factor for this ADR?; and (ii) are there other aetiologies or other risk factors for this ADR? RESULTS: Three hundred and sixty ADRs in 294 adults and 66 children were analysed. The prescription was considered inappropriate for 213 of the 659 (32%) drugs implicated in ADRs, corresponding to 161 patients (45%). The ADR was adjudged entirely avoidable for 32 (9%) patients, partly avoidable for 28 (8%) patients and unavoidable for 300 (83%) patients. Not taking into account a history of allergy or altered renal function and not respecting the recommended dose were the most frequent causes of entirely avoidable ADRs. Allopurinol and lamotrigine were the drugs most frequently involved in serious avoidable ADRs. CONCLUSIONS: Preventive actions should focus on more systematic allergy checks when prescribing drugs and on dose adaptation in cases of altered renal function.