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Introduction Valproic acid (VPA) is rarely used in neonatal period. In children under 2 years old, serious adverse effects are appear to be more frequent. Aim The aim of our study is to report the adverse effects observed in a population of full-term newborns treated with VPA. Method Full-term newborns, hospitalized at the Toulouse CHU, who presented with neonatal seizures and who received long-term treatment with VPA between 2004 and 2014 were included. Results For 5 of the 123 newborns treated with VPA, treatment had to be discontinued due to adverse effects. Three patients presented with disturbances in consciousness within 48 hours of treatment initiation, one case with a moderate overdose and two with hyperammoniemia (157 and 327 μmol/L) without any drug overdose or underlying liver or metabolic disease (VPA-induced hyperammonemic encephalopathy). Two patients presented with secondary hematological alterations. No patient presented with liver toxicity or exacerbation of an underlying metabolic disease. Conclusion While the serious adverse effects of VPA notedwere all reversiblewith the discontinuation of the treatment, the occurrence of encephalopathies with hyperammoniemia is a serious complication that is potentially lethal and calls for close clinicalmonitoring of newborns treated with valproate.We provide precautions for the implementation and follow-up of VPA in newborns. [ABSTRACT FROM AUTHOR]

Introduction: Respiratory tract disorders are common in children. However, there is no available data on the prescription of respiratory medications for children in France. This study aimed to provide an overview of medications for obstructive airway diseases prescriptions for children during the initial ten years of their lives within POMME, a French population-based cohort of children., Material and Methods: This longitudinal, population-based study used data from the French POMME birth cohort, comprising children born in Haute Garonne between July 2010 and June 2011. Anonymous medical information, including medication reimbursement data, was collected between ages 0 and 10 years. Exposure was defined as at least one prescription for respiratory medications (ATC code R03*), focusing on specific subclasses. Data were analyzed by age, season, and prescribing physicians' specialties., Results: Out of 5956 children, 4951 (83.1 %) received respiratory medication prescriptions. Inhaled corticosteroids (ICSs) were the most prescribed (95.3 %), followed by short-acting β2-agonists (68.8 %). The number of prescriptions increased with age, except for ICSs alone, which peaked between 6 months and 2 years. The average number of prescriptions per child was relatively low., Discussion: This study highlighted high prescription rates of respiratory medications in children under 10 years, with ICSs being the most prevalent. While these medications are primarily intended for asthma management, the findings suggested a significant proportion of off-label prescriptions, especially in young children. Further research and clinical guidance are warranted to ensure appropriate medication use in the pediatric population., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Considering data from the literature in favor of active educational intervention to teach pharmacovigilance, we describe an innovative model of distance learning clinical reasoning sessions (CRS) of pharmacovigilance with 3rd year medical French students., Methods: The three main objectives were to identify the elements necessary for the diagnosis of an adverse drug reaction, report an adverse drug reaction and perform drug causality assessment. The training was organized in 3 stages. First, students practiced clinical reasoning (CRS) by conducting fictive pharmacovigilance telehealth consultations. Second, students wrote a medical letter summarizing the telehealth consultation and analyzing the drug causality assessment. This letter was sent to the teacher for a graded evaluation. In the third stage was a debriefing course with all the students., Results: Of the 293 third-year medical students enrolled in this course, 274 participated in the distance learning CRS. The evaluation received feedback from 195 students, with an average score of 8.85 out of 10. The qualitative evaluation had only positive feedback. The students appreciated the different format of the teaching, with the possibility to be active., Conclusion: Through distance CRS of pharmacovigilance, medical students' competences to identify and report adverse drug reactions were tested. The students experienced the pharmacovigilance skills necessary to detect adverse drug reactions in a manner directly relevant to patient care. The overall evaluation of the students is in favor of this type of method., (Copyright © 2024 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Background: Among antidepressants, serotonin-norepinephrine reuptake inhibitors (SNRIs) are particularly expected to increase the risk of hypertensive disorders of pregnancy (HDP) with regard to their biological mechanism. We aimed to evaluate the association between prenatal exposure to SNRI and HDP., Methods: In EFEMERIS, a French database including pregnant women covered by the French Health Insurance System of Haute-Garonne (2004-2019), we compared the incidence of HDP among women exposed to SNRI monotherapy during the first trimester of pregnancy to the incidence among 2 control groups: (1) women exposed to selective serotonin reuptake inhibitor (SSRI) monotherapy during the first trimester and (2) women not exposed to antidepressants during pregnancy. We conducted crude and also multivariate logistic regressions., Results: Of the 156,133 pregnancies, 143,391 were included in the study population, including 210 (0.1%) in the SNRI group, 1,316 (0.9%) in the SSRI group, and 141,865 (98.9%) in the unexposed group. After adjustment for depression severity and other mental conditions, the risk of HDP was significantly higher among women exposed to SNRIs (n = 20; 9.5%) compared to women exposed to SSRIs (n = 72; 5.5%; adjusted odds ratio [aOR] [95% CI] = 2.32 [1.28-4.20]) and to unexposed women (n = 6,224; 4.4%; aOR [95% CI] = 1.89 [1.13-3.18])., Conclusion: This study indicated an increased risk of HDP in women treated with SNRIs versus women treated with SSRIs., (© Copyright 2023 Physicians Postgraduate Press, Inc.)

Pharmacoepidemiological research in pregnant women has focused on adverse drug reactions for the course of pregnancy or for the unborn child, but little is known on the risks for the mother. We reported the results of a study that compared adverse drug reactions in pregnant women with non-pregnant women of childbearing age, and investigated whether which types of adverse reactions were more often reported in pregnant women and which drugs were more often involved. This study was carried out in the French pharmacovigilance database (BNPV). We compared adverse drug reactions reported between 1 January 2010 and 31 December 2019 in pregnant women with those reported in of non-pregnant women of childbearing age. We cross-matched each pregnant woman with three non-pregnant women of childbearing age according to geographic area, age and year the adverse reaction was reported. Data analysis revealed that serious adverse reactions were more frequently reported in pregnant women, including anaphylactic reactions. Other adverse reactions including tachycardia, hypotension and hepatic injury were also more frequent in pregnant women than in non-pregnant women of the same age. This could be explained by physiological changes in pregnancy that lead to greater sensitivity to certain adverse reactions. Some drugs, such as phloroglucinol, metoclopramide, iron, atosiban and nifedipine, were more frequently involved in adverse reactions in pregnant women. These drugs are specifically used during pregnancy, which may explain why they are over-represented in adverse reactions. This is the first comparative descriptive study on drug adverse reactions in pregnant women. Specific epidemiological and pharmacokinetic studies are necessary to confirm these results and better understand the differences observed to improve the monitoring of pregnant women exposed to certain drugs., (Copyright © 2022 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Purpose: Fosfomycin trometamol has been recommended as first-line bactericidal antibiotic for urinary tract infections in pregnant women since 2015 in France. However, studies assessing fosfomycin safety in pregnancy are sparse. This study aimed to assess the risk of major Congenital Anomaly (CA) after fosfomycin exposure during the first trimester of pregnancy., Methods: We performed a comparative study in EFEMERIS, the French database including expecting mothers covered by the French Health Insurance System of Haute-Garonne from July 1st, 2004 to December 31th, 2018. EFEMERIS contains prescribed and dispensed reimbursed medications during pregnancy and pregnancy outcomes. Logistic regressions have been conducted to compare three groups: (1) pregnancies exposed at least once to fosfomycin; (2) pregnancies exposed at least once to nitrofurantoin; and (3) pregnancies exposed neither to fosfomycin nor to nitrofurantoin, another antibiotic prescribed for urinary infections, before and during pregnancy., Results: A total of 2724 (2.0%) pregnant women received at least one fosfomycin prescription during the first trimester, 650 (0.5%) received nitrofurantoin during the first trimester, and 133,502 (97.5%) pregnant women were not exposed to fosfomycin nor to nitrofurantoin. First trimester pregnancy exposure to fosfomycin was not associated with an increased risk of major CA, compared to first trimester exposure to nitrofurantoin (2.0% versus 2.5%; OR a  = 0.80 [0.44-1.47]), or to pregnancies unexposed to fosfomycin and nitrofurantoin (2.0% versus 2.1%; OR a  = 0.97 [0.73-1.30])., Conclusion: This is the first large comparative study assessing fosfomycin safety in pregnancy. It does not exhibit an increased risk of major CA after fosfomycin exposure during the first trimester of pregnancy., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: About 1.3 million pregnant women lived with HIV and were eligible to receive antiretroviral therapy (ART) worldwide in 2021. The World Health Organization recommends protease inhibitors (PI)-based regimen as second or third-line during pregnancy. With remaining pregnant women exposed to PIs, there is still an interest to assess whether this treatment affects perinatal outcomes. Adverse perinatal outcomes after prenatal exposure to PI-based ART remain conflicting: some studies report an increased risk of preterm birth (PTB) and low-birth-weight (LBW), while others do not find these results. We assessed adverse perinatal outcomes associated with prenatal exposure to PI-based compared with non-nucleoside reverse transcriptase (NNRTI)-based ART., Methods: We performed a systematic review searching PubMed, Reprotox, Clinical Trial Registry (clinicaltrials.gov) and abstracts of HIV conferences between 01/01/2002 and 29/10/2021. We used Oxford and Newcastle-Ottawa scales to assess the methodological quality. Studied perinatal outcomes were spontaneous abortion, stillbirth, congenital abnormalities, PTB (< 37 weeks of gestation), very preterm birth (VPTB, < 32 weeks of gestation), LBW (< 2500 grs), very low-birth-weight (VLBW, < 1500 g), small for gestational age (SGA) and very small for gestational age (VSGA). The association between prenatal exposure to PI-based compared to NNRTI-based ART was measured for each adverse perinatal outcome using random-effect meta-analysis to estimate pooled relative risks (RR) and their corresponding 95% confidence intervals (CI). Pre-specified analyses were stratified according to country income and study quality assessment, and summarized when homogeneous., Results: Out of the 49,171 citations identified, our systematic review included 32 published studies, assessing 45,427 pregnant women. There was no significant association between prenatal exposure to PIs compared to NNRTIs for VPTB, LBW, SGA, stillbirth, and congenital abnormalities. However, it was inconclusive for PTB, and PI-based ART is significantly associated with an increased risk of VSGA (sRR 1.41 [1.08-1.84]; I 2  = 0%) compared to NNRTIs., Conclusions: We did not report any significant association between prenatal exposure to PIs vs NNRTIs-based regimens for most of the adverse perinatal outcomes, except for VSGA significantly increased (+ 41%). The evaluation of antiretroviral exposure on pregnancy outcomes remains crucial to fully assess the benefice-risk balance, when prescribing ART in women of reproductive potential with HIV., Prospero Number: CRD42022306896., (© 2023. The Author(s).)

Background and Objectives: Neuropsychiatric disorders in childhood after prenatal drug exposure raises concerns. Most of the published studies focused on psychotropic medications. This study investigated which prenatal medication exposure was associated with neuropsychiatric disorders in childhood., Methods: A case-control study, nested in the French POMME cohort, was conducted to compare prenatal medication exposure between children with a history of neuropsychiatric care (ages 0-8 years) and children in a control group. POMME included children born in Haute-Garonne to women covered by the general Health Insurance System, between 2010 and 2011 ( N = 8,372). Cases were identified through: (1) reimbursement for neuropsychiatric care; (2) psychomotor development abnormalities specified on health certificates; and (3) reimbursement for methylphenidate or neuroleptics. Controls had none of these criteria. Prenatal exposure to each of the major "Anatomical Therapeutic Chemical" classes was compared between the groups. Class(es) for which there was a statistically significant difference (after Bonferroni adjustment, i.e., p < 0.0033 ) was(were) compared using logistic regression., Results: A total of 723 (8.6%) cases and 4,924 (58.8%) controls were identified. This study showed a statistically significant difference in prenatal exposure to nervous system drugs (excluding analgesics) between the groups [ORa: 2.12 (1.55; 2.90)]. Differences (not statistically significant at the 0.0033 threshold) were also observed for the ATC classes: Musculoskeletal, Genito-urinary System and Sex Hormones, Alimentary Tract and Anti-infectives., Conclusion: Through identification of children with neuropsychiatric disorders and of their prenatal medication exposure, this study provides guidance for the assessment of long-term neuropsychiatric effects after prenatal medication exposure, without focusing on psychotropic medications., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Benevent, Hurault-Delarue, Araujo, Revet, Sommet, Lacroix and Damase-Michel.)

Background: In France, few data are available on the prescription patterns of antiemetic medications in pregnant women., Objectives: The purpose of this study was to describe antiemetic medication prescriptions and trends over time. Can we observe significant changes in pregnant woman prescriptions in recent years?, Methods: We conducted a drug utilization study among pregnant women using data from the EFEMERIS database, including 135 574 pregnant women who had a pregnancy outcome between 2004 and 2017 in Haute-Garonne (France)., Results: During the study period, 40 028 women (29.5%) received at least one antiemetic prescription during pregnancy. Metoclopramide (56.6%), domperidone (34.9%), and metopimazine (28.5%) were the most commonly prescribed antiemetics, whatever the trimester of pregnancy. Prescriptions of ondansetron only concerned 53 women (0.1%). The prevalence of women who received at least one prescription for an antiemetic decreased from 32.5% in 2010 to 21.6% in 2017. This decline mainly concerned domperidone prescriptions (from 13.1% in 2010 to 1.2% in 2017). Metoclopramide prescriptions also decreased slightly (18.3% in 2010 and 14.0% in 2017). Metopimazine prescriptions increased lowly (8.0% in 2010 and 9.0% in 2017)., Conclusion: This study showed a decrease of antiemetic prescriptions between 2010 and 2017, linked to the sharp decrease in domperidone use from 2011, probably related to warnings about the risk of cardiovascular adverse effects following exposure to domperidone. We could not observe real switches to other antiemetic medications. No switches to ondansetron could be noted either, with only rare exposure during pregnancy, contrary to other countries, like the United States., (© 2021 Société Française de Pharmacologie et de Thérapeutique.)

Introduction: Domperidone is widely used during pregnancy, although the risks associated with pregnant women have not been adequately evaluated., Objective: The objective of this study was to compare the rate of pregnancy outcomes and congenital anomalies between pregnant women exposed and unexposed to domperidone during pregnancy., Methods: We conducted a retrospective cohort study comparing pregnant women exposed and unexposed to domperidone during pregnancy. We used the EFEMERIS database containing the prescriptions and dispensing of drugs to pregnant women in Haute-Garonne, who had a pregnancy outcome between July 2004 and December 2017. We compared pregnant women who were exposed to domperidone at least once during pregnancy to unexposed pregnant women. Logistic regression and Cox proportional risk models were applied., Results: Overall, 13,964 pregnancies (10.3% of pregnancies) were given domperidone. A reduction in the number of pregnant women exposed to domperidone (2004: 17.1% to 2017: 1.2%) was noted. More than 75% of pregnancies were exposed to domperidone in the first trimester of pregnancy. The rate of natural pregnancy termination in pregnant women exposed to domperidone was lower than that in unexposed pregnant women (adjusted hazard ratio = 0.78 [0.71-0.87]). The malformation rate in fetuses/newborns exposed in utero (first trimester) to domperidone is comparable to that of unexposed fetuses/newborns (adjusted odd ratio = 0.89 [0.77-1.03])., Conclusions: This is the first comparative study to enrol a large number of pregnant women exposed to domperidone. Data regarding the malformation rate following exposure to domperidone during the first trimester of pregnancy are reassuring. Women exposed to domperidone during pregnancy have a decreased risk for natural pregnancy termination, probably owing to an indication bias.

Purpose: To describe drug prescriptions in pregnant women in France and to identify teratogenic and fetotoxic drug prescriptions., Methods: This study was carried out using data from Échantillon Généraliste des Bénéficiaires (EGB), a French national health database which includes 1/97 th of the French population. Our study population included all pregnant women, aged 10 to 60, who were registered in the EGB and had a pregnancy outcome between 2015 and 2016. Drugs prescribed and dispensed to women during pregnancy and the 3 months before, were collected and described for each year and according to pregnancy trimesters. Prescriptions of major teratogen or fetotoxic drugs were described., Results: We identified 18,279 pregnancies. Among them, 93% received drug prescriptions and dispensations during pregnancy with an average of 7.4±5.5 different drugs. "Alimentary tract and metabolism (75.4%)", "nervous system (64.0%)" and "blood and blood forming organs (58.7%)" classes were the most frequently prescribed to pregnant women. The 5 most frequently prescribed drugs were paracetamol (60.6%), iron (49.2%), folic acid (45.6%), phloroglucinol (44.0%) and colecalciferol (41.4%). The most commonly prescribed drugs included some that have not yet been well evaluated in pregnancy. Prescriptions and dispensations of teratogenic or fetotoxic drugs, as Non-Steroidal Anti-Inflammatory Drugs and retinoids were observed. Valproic acid prescriptions to pregnant women have become extremely rare., Conclusion: This descriptive study demonstrates that numerous drugs are prescribed and dispensed to pregnant women in France. These include drugs with a proven teratogenic or fetotoxic effect and many drugs that have not yet been well evaluated in pregnancy., (Copyright © 2020 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used drugs. On June 2008 and February 2009, Dear Doctor Letters (DDLs) were sent by the French Health Authorities (AFSSAPS) to remind practitioners of risks with NSAIDs after the fifth month of pregnancy. The aim of this study was to evaluate the impact of these letters on NSAID prescriptions during late pregnancy. EFEMERIS is a French database that registers drugs prescribed and reimbursed during pregnancy and outcomes between 2004 and 2015. We performed a descriptive study and a 'before-and-after' comparison of NSAID prescriptions between 3 June 2006 and 3 June 2008 ('before group'), and between 1 March 2010 and 1 March 2012 ('after group'). We carried out a Cochran Armitage trend test to check whether the rate of women exposed to NSAIDs varies linearly over time. We identified 948 (4.38%) pregnant women in the 'before group' and 678 (2.73%) in the 'after group' receiving at least one NSAID prescription in late pregnancy (P < 0.0001). Between 2006 and 2012, mainly prescriptions for morniflumate/niflumic acid (1.7% vs. 0.9%; P < 0.0001), ibuprofen (0.8% vs. 0.6%; P = 0.01) and ketoprofen (0.7% vs. 0.3%; P < 0.0001) fell significantly after DDLs. The Cochran Armitage trend test shows that the percentage of women exposed to NSAIDs in late pregnancy decreased significantly during the study period (P < 0.0001). This study highlighted a significant decrease in the percentage of women receiving NSAID prescriptions during late pregnancy after DDLs. This decrease is not linked to a specific women's profile or prescriber's medical discipline., (© 2019 Société Française de Pharmacologie et de Thérapeutique.)

Childhood digestive disorders are a common occurrence and are sometimes unexplained. Maternal medication during the development of the foetus' digestive system may contribute to the increase in childhood digestive disorders, especially with drugs acting on the cholinergic system. This study investigated the association between prenatal exposure to drugs with atropinic properties and the use of digestive disorder medications in childhood (0-3 years). Children from POMME (PrescriptiOn Médicaments Mères Enfants), a French database of reimbursed drugs for pregnant women and their children, were included (N = 8 372). Each drug prescribed during antenatal life was assigned an atropinic score (0 = null, 1 = low, 3 = strong). The prenatal atropinic burden was calculated as the sum of atropinic scores of drugs prescribed. More than 30% (N = 2 652) of the children were prenatally exposed to atropinic drugs. They used significantly more digestive disorder medications than unexposed children (RRa = 1.11 [1.06; 1.16]). The strength of the association increased with the prenatal atropinic burden. Our results suggest long-term digestive effects after prenatal exposure to atropinic drugs., (© 2018 Société Française de Pharmacologie et de Thérapeutique.)

Clinical evaluation of drugs before approval is based on the experimental design of clinical trial with randomization of drug exposure. Unfortunately, conclusions of clinical trials are necessarily limited to patients included into the trials. It is thus necessary to compare these experimental data coming from clinical trials with the real use of drugs in clinical practice. Pharmacoepidemiology is the study of interactions between drugs and human populations, investigating, in real conditions of life, benefits, risks and use of drugs. Pharmacoepidemiology applies to drugs the methods and/or reasoning of both pharmacology and epidemiology. The development of pharmacoepidemiology should improve the "rational drug use"., (Copyright © 2018 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Taking a medication is usually a challenge for a pregnant woman as the beneficial drug effect on the mother has to be considered regarding its potential adverse effects, not only for her but also for her unborn child. As medication use is common in pregnant women, by chance or necessity, it gives the opportunity to evaluate the consequences of prenatal drug exposure in real life through pharmacoepidemiological studies. This paper provides an overview of data sources, study designs and data analysis methods that can be used for pregnancy medication safety studies. In the future, the implementation of responsive international networks may be the keystones of drug evaluation in pregnancy., (Copyright © 2019 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

In contrast to statins, the risk of diabetes with fibrates was not clearly studied. This study investigates a putative signal of diabetes associated with the use of fibrates using the World Health Organization (WHO) global individual case safety reports database, VigiBase ® . We included all reports registered until the 31st December 2017 in VigiBase ® to measure the risk of reporting 'hyperglycemia or new onset of diabetes' (SMQ term) compared with all other reports [as a reporting odds ratio (ROR 95% CI)] for fibrates, statins, and the combination fibrates + statins. The likelihood that diabetes resulted from statin-fibrate interaction was also estimated. According to the interaction additive model, a ROR value for coexposure exceeding the sum of the RORs estimated for each individual class of drug supports a potential drug-drug interaction (DDI). To assess the stability of our results, we performed several sensitivity analyses, according to outcome definition and after exclusion of putative competitive (hyperglycemic) drugs. We included 19 149 patients exposed to fibrates (without statins), 177 323 to statins (without fibrates) and 3 247 to statins plus fibrates. In contrast to statins (ROR = 1.75, 95% CI 1.72-1.78), no association was found for fibrates (ROR = 0.76, 95% CI 0.71-0.82). The ROR value was lower for the combination statins plus fibrates (ROR = 1.46, 95% CI 1.28-1.67). Similar trends were found in sensitivity analyses. This study, performed in the real conditions of use, failed to find a signal of diabetes with fibrates. It strengths the association previously described with statin without any evidence for a statin-fibrate DDI., (© 2018 Société Française de Pharmacologie et de Thérapeutique.)

Introduction: The POMME (PrescriptiOn Médicaments Mères Enfants) cohort has been implemented for the evaluation of the long-term consequences of medicine prenatal exposure. It holds anonymous medical information as well as information on medicine and healthcare reimbursement to the children, from the first day of intra-uterine life until childhood., Objective: This article provides a description of the cohort regarding its structure and content and presents an outlook of the studies that could be performed with this new data source., Methods: Data sources include (1) the French Health Insurance Database (medicines and medical care prescriptions and reimbursements to children and mothers during pregnancy) and (2) the Mother and Child Protection Centre Database (child health certificates at birth, 9 months of age and 24 months of age). Children born in Haute-Garonne (south-west France), over a period of 1 year (from 1 July to 30 June), are registered in POMME every 5 years. The cohort began on 1 July, 2010., Results: To date, 8372 children have been recorded in POMME. They have reached 7 years of age now. Among them, 4249 (50.8%) are boys, 286 (3.4%) were from multiple pregnancies and 519 (6.2%) were born prematurely. They were prenatally exposed to 9.8 ± 6.1 medications. After birth, drug exposure was greatest in children aged 0-2 years. Children were mostly exposed to paracetamol, anti-infective agents and respiratory system drugs; 908 (10.8%) children presented with at least two signs of psychomotor development disorders., Conclusions: POMME provides an observatory study on drug exposure and medical care use in children. This innovative cohort would make it possible to assess the risk of the long-term consequences of prenatal medicine exposure.

Purpose: There is little data on the effects of cancer chemotherapy in pregnant women. The objective of this study was to describe pregnancy outcomes of women exposed to cancer chemotherapy, recorded in the French Terappel database., Methods: We performed a descriptive, prospective study of the pregnancies of women exposed to cancer chemotherapy recorded in Terappel between June 1984 and December 2016. Terappel is a French database that has recorded questions of health professionals and/or individuals at the Regional Pharmacovigilance Centres about drugs and pregnancy. For each question, pregnancies are monitored and the outcome is recorded in the database., Results: In total, 75 questions about "anti-cancer drugs and pregnancy" received by 16 Regional Pharmacovigilance Centres between 1997 and 2016 were recorded in Terappel. Breast cancer accounted for 62.7% of the cases, followed by leukaemia (13.3%) and lymphoma (9.3%). Cyclophosphamide is the leading anti-cancer drug with 40.0% of exposed pregnant women, followed by 5-fluorouracil (34.7%), epirubicin (32.0%), tamoxifen (26.7%), and doxorubicin (16.0%). Among the 75 pregnancies, we observed 55 births with 57 children (73.3%) (two cases of twins), nine medical terminations of pregnancy (12.0%), six voluntary terminations of pregnancy (8.0%), three intrauterine foetal deaths (4.0%), and two miscarriages (2.7%). We found a malformation rate of 7.8%. Sixteen of 57 (28.1%) newborns developed one or more neonatal pathologies., Conclusion: Pregnancy of women taking anti-cancer drugs resulted in birth in 73% of cases. Nevertheless, pregnant women exposed to cancer chemotherapy remains at risk of malformations and neonatal conditions related to prematurity and drugs., (© 2018 John Wiley & Sons, Ltd.)

Competing Interests: B Duly-Bouhanick déclare des liens ponctuels avec Astra Zeneca, Lilly, MSD, NovoNordisk, Sanofi et Servier. J. Doucet déclare des liens ponctuels avec Novo Nordisk, Lilly, Merck Serono et Heath Care. A.-P. Trouvin déclare des liens ponctuels avec Pfizer, Astellas et Menarini. M. Lambert déclare des liens avec Bayer, Pfizer-BMS, LEO pharma, Roche, Novartis et Acteliown. A.-A. Zulfiqar, R. Arcani, A. Daumas, P. Villani, S. Perrot, J.-L. Montastruc et C. Yelnik déclarent n’avoir aucun lien d’intérêts. J. Benevent, D. Orlikowski et S. Puigrenier n'ont pas fourni de déclaration de liens d'intérêt.

Introduction: As the ear development extends from the 4th to the 30th week of pregnancy, in utero exposure to ototoxic drugs might lead to hearing impairment in the fetus. The main study objective was to assess the association between in utero drug exposure and the occurrence of hearing impairment in 2-year-old children., Methods and Materials: A case-control study was carried out using the EFEMERIS database, recording medications dispensed during pregnancy and the compulsory health certificates for child at 8 days, 9 and 24 months. Cases were defined as children with an abnormal hearing examination recorded on the 24-month certificate and controls as children with a normal hearing examination. Exposure was defined as at least one prescription and dispensation to the mother of drugs grouped at the 3rd level of the Anatomical Therapeutic and Chemical Classification level, compared to no exposure. Univariate logistic regressions were carried out. If the 95% confidence interval (95% CI) of the odds ratio (OR) was significant, a multivariable logistic regression was performed, adjusted on confounders., Results: A total of 1,245 cases with abnormal hearing evaluation and 28,046 controls were selected for analysis. Case and control mothers were comparable in terms of age, education and congenital infection. Cases and controls were comparable in terms of prematurity, asphyxia and weight at birth. However, among cases (versus controls), there were more ear deformities (0.6% vs 0.0% p≤0.001), and more recurring otitis (11.3% vs 5.3% p≤0.0001). When adjusted on confounders, the following drugs remained significant versus no exposure: acetylsalicylic acid at low dosage (OR 95% CI 1.61 [1.09-2.37]), valproic acid or valpromide (OR 95% CI 5.20 [1.93-14.00]), systemic corticosteroids (OR 95% CI 0.75 [0.61-0.93]. In a sensitivity analysis which excluded children with recurrent otitis at 24 months, these three results remained significant., Conclusions: This is the first study evaluating the risk of hearing disorders due to in utero exposure to drugs. Hearing loss was associated with valproic acid and low-dose acetylsalicylic acid exposure during pregnancy. Conversely, children with normal hearing were more likely to have been exposed in utero to corticosteroids than children with hearing loss., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Three studies have suggested a potential positive association between the use of tamoxifen in breast cancer and Parkinsonism, mainly after long-term exposure., Objectives: To explore this potential signal, we performed a case/non-case study using the World Health Organization Global Individual Case Safety Reports (ICSRs) database, VigiBase® between 1979 and 2018., Methods: Among women ≥ 55 years, we measured the risk of reporting "Parkinsonism" compared with all other adverse drug reactions [as a reporting odds ratio (ROR 95% CI)] for tamoxifen compared to all other drugs or aromatase inhibitors., Results: During the study period, 356 ICSRs of Parkinsonism reported with tamoxifen were identified. We failed to find a positive association between tamoxifen exposure and Parkinsonism in comparison with exposure to other drugs (ROR = 0.79; 95% CI 0.71-0.88) or aromatase inhibitors (ROR = 0.39; 95% CI 0.33-0.46)., Conclusion: This study did not find evidence for Parkinsonism associated with tamoxifen.

Antipsychotic drugs possess side atropinic (anticholinergic) properties that may induce several adverse drug reactions (ADRs), such as memory loss or cognitive impairment. The aim of this study was to investigate anticholinergic burden in patients treated with antipsychotic drugs. All ADR reports including at least one antipsychotic and registered between 2000 and 2015 in the Midi-Pyrénées PharmacoVigilance Database were extracted and analyzed using the Anticholinergic Duran's list. The primary objective of this cross-sectional study was to calculate anticholinergic burden in antipsychotic-treated patients; the secondary one was to investigate associated factors. Among the 1948 reports, the average number of atropinic drugs per report was 2.4 ± 1.4. At least one atropinic drug was found in 59.4% of reports (1158), in addition to antipsychotic drugs. The mean anticholinergic burden per report was 3.9 ± 2.9. A value ≥3 was found in 61.7% of the reports. A significant association between anticholinergic burden, age, and male gender of patients was found. The mean value of anticholinergic burden remained stable during the study period. This study showed high values of anticholinergic burden in patients receiving antipsychotics. Thus, considering the potential noxious clinical impact of atropinic properties on cognitive functions, an appropriate approach should be used to reduce prescription of antipsychotics with a high anticholinergic burden but also coprescription of other frequently associated atropinic drugs, such as antiparkinsonians, H1 antihistamines, or imipraminic antidepressants in these patients., (© 2017 Société Française de Pharmacologie et de Thérapeutique.)

Background: QT interval prolongations were described with citalopram and escitalopram. However, the effects of the other serotonin reuptake inhibitors (SRIs) remained discussed. In order to identify a putative signal with other SRIs, the present study investigates the reports of QT interval prolongation with SRIs in two pharmacovigilance databases (PVDB)., Methods: Two kinds of investigations were performed: (1) a comparative study in VigiBase®, the WHO PVDB, where notifications of QT prolongation with six SRIs (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) were selected. Cases with overdose or pregnancy were excluded. The relationship between the "suspected" SRI and occurrence of QT prolongation was assessed by calculating reporting odds ratio (ROR) in a case/non-case design. (2) A descriptive study of QT prolongation reports with citalopram and escitalopram in the French FPVD., Results: In VigiBase®, 855 notifications were identified (mean age 56.2 years, mainly women 73%). Among them, 172 (20.1%) were associated to escitalopram; 299 (35.0%), to citalopram; 186 (21.8%), to fluoxetine; 94 (11.0%), to sertraline; 66 (7.7%), to paroxetine; and 38 (4.4%) to fluvoxamine. A significant ROR value (higher than 1) was only found for citalopram (3.35 CI95% [2.90-3.87]) or escitalopram (2.50 [2.11-2.95]). In the FPVD, eight reports of QT prolongation were found with citalopram and 27 with escitalopram, mainly in women (77.1%) with a mean age of 73.2 years. In 23 cases (66%), SRIs were associated with other suspected drugs, mainly cardiotropic or psychotropic ones. Hypokalemia was associated in six patients., Conclusion: This study, performed in real conditions of life, shows a clear signal of QT prolongation with only two SRIs, citalopram and escitalopram, indicating that QT prolongation is not a SRI class effect.

Introduction: Prescription of medications to pregnant women is usually a challenge as the drug benefit has to be considered regarding its potential adverse effects. As medication use is common in pregnant women, by chance or necessity, it gives the opportunity to evaluate the consequences of prenatal drug exposure in real life through pharmacoepidemiologic studies. Area covered: Data sources are numerous. Some of them have been created for the particular purpose of assessing medications during pregnancy. Augmented databases enable the study of delayed effects in late childhood and provide information on potential confounders. Each data source exhibits strengths and weaknesses. Several designs can be used to assess the safety of medications during pregnancy. Innovative designs have been developed in order to bypass major limits of classical methods. Expert opinion: An efficient system could follow up each pregnant woman, who had taken a medication, and consider her as a precious information for the knowledge of drug potential adverse actions against the child, who must be followed up to identify long term-effects. The diversity of data sources and approaches of pharmacoepidemiologic studies, the implementation of international networks as well as the improvement of adverse signal detection are the keystones of such an evaluation.

The potential favorizing role of drugs in sleep apnea syndrome (SAS) is unknown. This study investigates drugs associated with SAS in a pharmacovigilance database. SAS recorded as adverse drug reactions (ADRs) in VigiBase ® , the WHO pharmacovigilance database (more than 11 million reports), from 1978 to 2015 was selected. The risk of SAS reports was estimated using the case-noncase method, with cases being SAS and noncases all other recorded ADRs. During this 37-year period, 3325 ADRs including the word SAS were registered (0.05% of the database). Mean age was 51.2 ± 16.9 years with 52% men. ADRs were 'serious' in around 82% of cases. The case-noncase study found an association between SAS and exposition with sodium oxybate, rofecoxib, quetiapine, and clozapine for individual drugs and coxibs, antipsychotics, benzodiazepines, and opium alkaloids for drug classes. The potential role of other drugs is discussed. This study suggests that SAS can be associated with some drugs (mainly psychotropics) that are able to reveal or aggravate such a disease. Physicians should take into account the role of drugs in the etiological appraisal and management of SAS., (© 2016 Société Française de Pharmacologie et de Thérapeutique.)

Objective: To assess the value of the prenasal thickness to nasal bone length ratio (PT/NBL) for detecting trisomy 21 (T21) after the first trimester., Method: Two examiners blinded to fetal T21 status retrospectively measured prenasal thickness (PT) and nasal bone length (NBL) of T21 and control fetuses at 15-36 weeks' gestational age on two-dimensional images from all T21-screening ultrasounds from November 2010 to April 2013. ROC curve analysis and its diagnostic values determined the best cut-off value for the ratio. Interobserver reproducibility was assessed., Results: Good quality ultrasound profile images were available for 26 fetuses with T21 compared to 91 normal fetuses. The median PT/NBL ratio was 1.28 for T21 and 0.73 for control fetuses (p<0.0001). The PT/NBL ratio performed significantly better (AUC 0.99; 95%CI 0.97-1) than either PT (0.82; 0.73-0.91) or NBL (0.91; 0.85-0.98). The optimal PT/NBL ratio cut-off was 0.98, with a sensitivity of 88.5% [76.2-100%] and a specificity of 100%. Interobserver variability was low., Conclusion: The PT/NBL ratio is a strong marker for detecting T21 in the second and third trimesters, significantly more effective than either indicator alone., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

We present a study of 31 cases of pathologic cervical smear with an inconclusive colposcopy. The aim of this study was to compare the results of the cervical smear, colposcopy, cervical biopsy, endocervical curettage and conization. The endocervical curettage is a valuable complement to the colposcopy, especially in the case of an inconclusive colposcopy.

The effects of the use of biological glue in the crater that is left after CO2 laser conisation was studied in a series of 32 cases and compared with a previous study carried out using the same technical methods by the same surgeons. The use of biological glue has as its aim to improve capillary haemostasis after conisation; and so increasing the security of leaving these conisation craters in order to improve the chance of normal morphology later. Biological glue has furthermore never given a febrile reaction, nor has it ever increased the likelihood of scar stenosis. Biological glue however is just an extra method of helping normal morphological healing with a good transformation zone and retaining fertility. When conisation is carried most extensively (in particular as far as depth is concerned) and with the use of powerful laser beams, the application of biological glue seem to guarantee most forms of postoperative haemostasis and good healing.