First trimester pregnancy exposure to fosfomycin and risk of major congenital anomaly: a comparative study in the EFEMERIS database.

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%; ORa = 0.80 [0.44-1.47]), or to pregnancies unexposed to fosfomycin and nitrofurantoin (2.0% versus 2.1%; ORa = 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.

Longitudinal Methods for Modeling Exposures in Pharmacoepidemiologic Studies in Pregnancy.

In many perinatal pharmacoepidemiologic studies, exposure to a medication is classified as "ever exposed" versus "never exposed" within each trimester or even over the entire pregnancy. This approach is often far from real-world exposure patterns, may lead to exposure misclassification, and does not to incorporate important aspects such as dosage, timing of exposure, and treatment duration. Alternative exposure modeling methods can better summarize complex, individual-level medication use trajectories or time-varying exposures from information on medication dosage, gestational timing of use, and frequency of use. We provide an overview of commonly used methods for more refined definitions of real-world exposure to medication use during pregnancy, focusing on the major strengths and limitations of the techniques, including the potential for method-specific biases. Unsupervised clustering methods, including k-means clustering, group-based trajectory models, and hierarchical cluster analysis, are of interest because they enable visual examination of medication use trajectories over time in pregnancy and complex individual-level exposures, as well as providing insight into comedication and drug-switching patterns. Analytical techniques for time-varying exposure methods, such as extended Cox models and Robins' generalized methods, are useful tools when medication exposure is not static during pregnancy. We propose that where appropriate, combining unsupervised clustering techniques with causal modeling approaches may be a powerful approach to understanding medication safety in pregnancy, and this framework can also be applied in other areas of epidemiology.

Topical sertaconazole during pregnancy and risk of adverse pregnancy outcome and major congenital anomalies: Comparative study in the EFEMERIS database.

INTRODUCTION: Topical sertaconazole is indicated in the treatment of vaginal or mucocutaneous fungal infections due to Candida and dermatophytosis. To our knowledge, there is no data available in the literature on the potential effects of sertaconazole during pregnancy. The aim of this study was to evaluate the potential risks of topical sertaconazole use during pregnancy for the foetus and pregnancy. MATERIALS AND METHODS: The EFEMERIS database was used, which contained medications prescribed and dispensed to pregnant women in the Haute-Garonne region whose pregnancy ended between July 2004 and December 2018. We compared pregnant women exposed to sertaconazole at least once during pregnancy to unexposed. Crude and adjusted odds ratios (OR) of major congenital anomalies and small gestational age at birth were estimated using logistic regression models. For other outcomes, hazard ratios (HR) were estimated by Cox regression models. RESULTS: The study included 16,222 pregnant women (15.0%) who were given sertaconazole and 91,976 who were not. Exposure to sertaconazole during pregnancy was not associated with increased risks of any of the investigated outcomes, including natural pregnancy termination (HRa  = 0.92 [0.78-1.08]), preterm birth (HRa  = 1.06 [0.95-1.17]) and small for gestational age at birth (ORa  = 0.78 [0.66-0.92]). No association between risk of major congenital anomalies overall and maternal exposure to sertaconazole during the first trimester was observed (ORa  = 1.01 [0.84-1.21]). DISCUSSION: This is the first study involving a large number of pregnant women to assess the potential risks of sertaconazole during pregnancy. This study does not indicate an increased risk of adverse pregnancy outcome and major congenital anomalies from exposure to topical sertaconazole.

Impact of pregnancy on antidepressant treatment course: a population-based comparative cohort study in France.

The prevention of relapses and the treatment of depression during pregnancy are difficult challenges. The maintenance of antidepressants in pregnancy with its concomitant risks to mother and child needs to be weighed against those associated with not treating the disease. This study aimed at quantifying the impact of the occurrence of pregnancy on the course of antidepressant treatment among newly treated women (< 6 months). We performed a comparative observational cohort study using the nationwide French reimbursement healthcare system database. Women who conceived in 2014 and initiated an antidepressant at any time in the 6 months before pregnancy were compared with nonpregnant women newly exposed to antidepressants with matching on age, antidepressant exposure, history of psychiatric disorders, and area of residence. The primary outcome was a composite of antidepressant discontinuation, switch to another antidepressant, and concomitant use of antidepressants. The secondary outcome was the resumption of antidepressant during follow-up. We used Cox marginal proportional hazards models to compare time to outcomes between pregnant and nonpregnant women. The pregnant cohort included 6593 women, and the comparison cohort 29,347 nonpregnant women. In the period following the first month of treatment, pregnant women were more likely to experience treatment modification, and especially to stop receiving it, compared with nonpregnant women (adjusted hazard ratio (aHR) 1.58; 95%CI, 1.51-1.62). Pregnant women who discontinued treatment had a 41% decreased incidence of antidepressant resumption compared with nonpregnant women (aHR 0.59; 95%CI, 0.56-0.62). Pregnancy was a determinant of antidepressant treatment modification, and especially of discontinuation.

Antidepressants during pregnancy: a French drug utilisation study in EFEMERIS cohort.

BACKGROUND: Previous studies have suggested that exposure to some antidepressants (AD) during pregnancy could be associated with an increased risk of congenital malformations and neurodevelopment disorders for the child. We conducted a study to describe the use of AD during pregnancy in France. METHODS: We performed a drug utilisation study in EFEMERIS, a French cohort of pregnant women. At the time of the present study, 89,170 pregnant women, who were pregnant from 2005 to 2014 in Haute-Garonne were included. Prevalence and incidence of AD prescriptions during pregnancy, characteristics of AD users, and trends in AD use over the 10-year period were studied. RESULTS: During the 10-year study period, 1620 women registered in EFEMERIS (1.8%) received at least one prescription and dispensation for AD during pregnancy: 1363 during the first (1.5%), 591 during the second (0.7%), and 412 during the third (0.5%) trimester. A total of 2874 women (3.2%) got a prescription for an AD during the 3 months before and/or during pregnancy; 2187 of them (76.1%) stopped AD before pregnancy or during the first trimester. Selective serotonin reuptake inhibitors represented the most prescribed class during pregnancy (1.3%). A very slight decrease in the prevalence of AD prescriptions in pregnant women over time (1.7% in 2014 vs 2% in 2005) and some variations within classes were observed. CONCLUSIONS: Nearly, 2% of women received antidepressant drugs during pregnancy. This assessment encourages following research on these drugs including the potential risk of neurodevelopmental disorders in children after an exposure to antidepressants during pregnancy.

Prescription of antiepileptic medicines including valproate in pregnant women: A study in three European countries.

PURPOSE: To study patterns of antiepileptic drugs (AED) prescribing, particularly valproate, during pregnancy over a 10-year period in the UK, Italy, and France. METHODS: Data on pregnancies conceived after 1 January 2007 with outcomes before 31 December 2016 were extracted from four European electronic health care databases (380 499 in the United Kingdom (UK), 66 681 in France, and 649 918 in Italy [355 767 in Emilia Romagna and 294 151 in Tuscany]). Prevalence of AEDs with an ATC code starting N03A and clobazam (N05BA09) were stratified by country and calendar year. RESULTS: AED prescribing during pregnancy varied from 3.0 (2.8-3.1) per 1000 pregnancies in Emilia Romagna to 7.8 (7.5-8.0) in the UK, 5.9 (5.6-6.1) in Tuscany, and 6.3 (5.7-6.9) in France. Lamotrigine was commonly prescribed in all regions with a third of women exposed to an AED during pregnancy taking lamotrigine in the UK and France. Valproate was prescribed to 28.6% of AED exposed pregnant women in Tuscany, 21.6% in France, 16.7% in Emilia Romagna, and 11.9% in the UK. Over the study period, the prevalence of AED prescribing increased in the UK mainly due to increases in pregabalin and gabapentin, declined in France mainly related to decreases in clonazepam, and remained constant in Italy. Valproate prescriptions declined to a prevalence <1 per 1000 pregnancies in 2015 to 2016 in the UK, France, and Emilia Romagna. CONCLUSIONS: Variations in AED prescribing during pregnancy indicate the potential for further reductions, particularly of valproate. Increases in pregabalin/gabapentin prescribing, for which risks are not well known, are a cause for concern.

Did advice on the prescription of sodium valproate reduce prescriptions to women? An observational study in three European countries between 2007 and 2016.

OBJECTIVES: In November 2014, the CMDh (a regulatory body representing EU Member States) advised doctors not to prescribe sodium valproate for epilepsy or bipolar disorder in preg nant women, in women who can become pregnant, or in girls unless other treatments are ineffective or not tolerated. This study aimed to determine if this warning led to changes in prescription patterns. DESIGN AND SETTING: Cohort of 5.4 million women aged between 10 and 50 years identified in electronic health care data from United Kingdom, France, and Italy (2007-2016). MAIN OUTCOME MEASURES: Anti-epileptic drug (AED) prescriptions. RESULTS: The prevalence of women receiving AED prescriptions in 2016 varied from 12.2 per 1000 to 29 per 1000 in the four regions. The incidence of prescribing any AED (excluding clonazepam, gabapentin, and pregabalin) fell each year on average by 7.5% (95% CI, 7.0%-8.0%; Emilia Romagna), 9.6% (8.3%-11.0%; France), 7.1% (6.7%-7.6%; Tuscany), and 0.4% (0.2%-1.0%; United Kingdom). The relative odds of prescribing sodium valproate rather than any other AED decreased more after 2014 compared with before the end of 2014 in France (OR = 0.77; 95% CI, 0.60-0.98), Tuscany (0.81; 0.76-0.86), Emilia Romagna (0.83; 0.76-0.90), and the United Kingdom (0.92; 0.80-1.06; not statistically significant). CONCLUSIONS: There is evidence that the CMDh warning did lead to changes in prescription patterns of sodium valproate in women of childbearing age. There were considerable differences in prescribing practice amongst regions of Europe.

Patterns of antidepressant use during pregnancy: a nationwide population-based cohort study.

AIMS: We explored the patterns of antidepressant use during pregnancy. METHODS: A cohort of women who started a pregnancy in 2014 was identified using data from the French reimbursement healthcare system (covering approximately 99% of the population). Antidepressant usage (initiated before or during pregnancy) was assessed. Explored changes in antidepressant treatment were: associations, switches, discontinuation and resumption of antidepressants during pregnancy. RESULTS: The cohort included 766 508 pregnancies (755 519 women). Antidepressant use during pregnancy was 25.7 per 1000 [95% CI: 25.3-26.0]. New use concerned 3.9 per 1000 [95% CI: 3.7-4.0]; the most initiated class during pregnancy was selective serotonin reuptake inhibitors (SSRIs), while the most prescribed individual drug in second and third trimesters was amitriptyline, a tricyclic. Most changes were observed before pregnancy and during the first trimester: 63% of ongoing treatments in the year before pregnancy were discontinued before conception; 68% of treatments maintained after conception were discontinued during the first trimester; switches or antidepressant associations mostly occurred during the periconceptional period or during the first trimester. Regardless of initial antidepressant, switches to sertraline were the most frequent. Associations mainly consisted of a prescription of tri-/tetracyclic or mirtazapine/mianserin in addition to an SSRI. Discontinuation during pregnancy led to treatment resumption in 22% of pregnancies. CONCLUSIONS: These results suggest that pregnancy was planned or the treatment especially adapted in accordance with existing recommendations in a large proportion of women under antidepressants or in whom such treatments have been initiated after starting a pregnancy.

Prescription of asthma medications before and during pregnancy in France: An observational drug study using the EFEMERIS database.

OBJECTIVE: Asthma affects between 3% to 8% of pregnant women. Previous studies have suggested that women's prescriptions for asthma medications change during pregnancy. The aim was to describe the prescription of asthma medications before and during pregnancy in France. METHODS: Women from the EFEMERIS, a French database assessing the drugs prescribed, dispensed and reimbursed during pregnancy, delivering between July 2004 and December 2012, were included. Women, who were dispensed asthma medications on at least two dates from 3 months prior to pregnancy through delivery, were considered. RESULTS: 2,977 women out of 69,205 (4%) were selected. They were prescribed 2.4 ± 1.2 different anti-asthmatic drugs with 3.5 ± 2.7 different dispensing dates. Almost 62% of the women were dispensed at least one prescription for short-acting ß2-agonist (SABA), 63% at least one inhaled corticosteroid (IC), 42% a fixed-combination of an IC and a long-acting ß2-agonist (LABA) and 8% a LABA. An increase in SABA and IC prescriptions and a decrease in fixed-combination prescriptions were observed during pregnancy compared to pre-pregnancy period. A rapid drop in prescriptions for montelukast was observed. Among the 1,507 women who were prescribed asthma medication before pregnancy, one third had a drop in dispensed asthma medications from the beginning of pregnancy. CONCLUSIONS: The prevalence of dispensed asthma medications varies during pregnancy. There is a decrease in the prescriptions of fixed-combinations during pregnancy and an increase in the prescriptions of ICs. It appears important to study the potential impact of such changes on fetuses and newborns.

Interest of the trajectory method for the evaluation of outcomes after in utero drug exposure: example of anxiolytics and hypnotics.

PURPOSE: The aim of this study was to examine the potential benefit to take into account duration and intensity of drug exposure using the recently published method based on individual drug trajectories. This approach was used to define profiles of exposure to anxiolytics/hypnotics during pregnancy and to evaluate the potential effect on newborn health. METHODS: The study was performed in EFEMERIS database (54 918 mother-children pairs). An estimation of adaptation to extrauterine life was assessed using several criteria especially cardio-respiratory symptoms. A proxy variable called "neonatal pathology" was created. The occurrence of this event was studied using two approaches: The Standard Method comparing exposed and unexposed newborns, The Trajectory Method comparing the different profiles of exposure. RESULTS: Around 5% of newborns (n = 2768) were identified to be exposed to anxiolytics or hypnotics during pregnancy. Using the Standard Method, 6.2% of exposed newborns developed a "neonatal pathology" against 4.8% of unexposed newborns (odds ratios [OR] = 0.9[0.8-1.2], p = 0.7). With the Trajectory Method taking into account evolution of exposure during pregnancy and treatment intensity, four profiles of pregnant women were identified. A significant difference in the rates of "neonatal pathologies" was observed between profiles (p = 0.0002). Newborns of the two profiles exposed in utero to high constant level of anxiolytics or hypnotics were more at risk of developing "neonatal pathology" than unexposed newborns (OR1  = 2.0 [1.0-3.9] and OR2  = 7.6 [2.8-20.5]). CONCLUSIONS: The present study demonstrates the interest of this method based on individual drug trajectories for the evaluation of outcomes in pharmaco-epidemiological studies and more specifically during pregnancy. Copyright © 2017 John Wiley & Sons, Ltd.

Risk of infections during the first year of life after in utero exposure to drugs acting on immunity: A population-based cohort study.

The aim of the study was to evaluate the association between in utero exposure to drugs that potentially exhibit immunosuppressive activity and occurrence of infections during the first year of life. We conducted a cohort study on the prescription data of pregnant women and their children registered in EFEMERIS cohort (France), during a one-year period. We classified in utero child exposure according to the number of reimbursements for immunosuppressive drugs during pregnancy. The number of infectious episodes during the first year of life was estimated through the number of anti-infective drugs dispensed. The association was estimated by a quasi-Poisson regression with adjustment for confounders. The study population consisted of 9614 children, 3141 of whom had been exposed to immunosuppressive drugs during pregnancy. The most frequently immunosuppressive drugs prescribed were corticosteroids. The mean number of infectious episodes during the first year after birth gradually increased with the number of immunosuppressive drugs dispensed during pregnancy (from 2.38 in controls to 3.88 in the most exposed group). After adjustment for potential confounders, in utero exposure to immunosuppressive drugs was significantly associated with the number of infectious episodes during the first year of life (RR 3ormoreexposuresVS0=1.35, 95% CI 1.24-1.46). Intrauterine exposure to potentially immunosuppressive drugs could be associated with an increased susceptibility to infections in early childhood.

Atropinic burden of drugs during pregnancy and psychological development of children: a cohort study in the EFEMERIS database.

AIM: The aim of this study was to evaluate the potential effect of in utero exposure to drugs with atropinic properties on infant psychological development using atropinic burden (AB) scales. METHODS: Women from the EFEMERIS cohort, a French database including prescribed and dispensed reimbursed drugs during pregnancy and pregnancy outcomes, delivering between 2004 and 2010 were included (n = 43 740). Each drug was classified as having no (score = 0), few (score = 1) or strong (score = 3) atropinic properties. AB per woman was calculated by adding the atropinic scores of drugs prescribed during pregnancy. AB was categorized as exposure or no exposure. Secondary analyses were performed by dividing the exposure into four scores = [0], [1-8], [9-17] and [≥18]. Data for psychological development were extracted from children's medical certificates completed at 9 and 24 months. RESULTS: Thirty-four% (n = 14 925) of women received at least one atropinic drug during pregnancy. Women with AB ≥1 were older and received more drugs during pregnancy than unexposed women. At 24 months, more infants of mothers with AB ≥1 had difficulties to 'name a picture' (ORa , 1.18, 95% CI 1.03, 1.36) and to 'understand instructions' (ORa , 1.61, 95% CI 1.13, , 2.30]) compared with infants of unexposed women. Analyses of four groups of exposure and analyses excluding women receiving psychotropics led to similar results. CONCLUSIONS: The study showed significant association between in utero exposure to drugs with atropinic properties and fewer infant cognitive acquisitions at 24 months. Further exploring the potential effect of simultaneous use of drugs with atropinic effects among pregnant women will bring into consideration whether such prescriptions could be inappropriate for the child.

How to take into account exposure to drugs over time in pharmacoepidemiology studies of pregnant women?

PURPOSE: The aim of this study was to develop a new pharmacoepidemiological method to take into account intensity and evolution of drug exposure, applied to pregnant women. METHODS: Pregnant women were classified according to their drug exposure, in three steps: Conversion of prescription data into exposure variables (using ATC-DDD) Construction of individual trajectories of exposure Clustering of individual trajectories of exposure (using the R package Kml) We applied this method to psychotropic drugs prescribed during pregnancy. The present study involved women, included in the EFEMERIS database, who gave birth in Haute-Garonne (France) between 2004 and 2010 (N = 54 918). RESULTS: Exposure to psychotropic drugs of 3708 pregnant women was studied (6.7%). The pregnant women could be classified into four groups with homogeneous trajectories of exposure: low constant exposure during pregnancy (Cluster A: 70.8% of women); decreasing exposure during the first trimester of pregnancy and low constant exposure thereafter (Cluster B: 19.6%); moderate constant exposure (Cluster C: 8.2%); and high albeit decreasing exposure (Cluster D: 1.4%). CONCLUSIONS: The proposed new method enabled us to describe more precisely women's exposure to drugs during pregnancy, and to distinguish different profiles of exposure. This method could be used to investigate specific outcomes related to duration and intensity of drug exposure during pregnancy, and also to study adverse drug reactions throughout life. Copyright © 2016 John Wiley & Sons, Ltd.

Healthcare databases in Europe for studying medicine use and safety during pregnancy.

PURPOSE: The aim of this study was to describe a number of electronic healthcare databases in Europe in terms of the population covered, the source of the data captured and the availability of data on key variables required for evaluating medicine use and medicine safety during pregnancy. METHODS: A sample of electronic healthcare databases that captured pregnancies and prescription data was selected on the basis of contacts within the EUROCAT network. For each participating database, a database inventory was completed. RESULTS: Eight databases were included, and the total population covered was 25 million. All databases recorded live births, seven captured stillbirths and five had full data available on spontaneous pregnancy losses and induced terminations. In six databases, data were usually available to determine the date of the woman's last menstrual period, whereas in the remainder, algorithms were needed to establish a best estimate for at least some pregnancies. In seven databases, it was possible to use data recorded in the databases to identify pregnancies where the offspring had a congenital anomaly. Information on confounding variables was more commonly available in databases capturing data recorded by primary-care practitioners. All databases captured maternal co-prescribing and a measure of socioeconomic status. CONCLUSION: This study suggests that within Europe, electronic healthcare databases may be valuable sources of data for evaluating medicine use and safety during pregnancy. The suitability of a particular database, however, will depend on the research question, the type of medicine to be evaluated, the prevalence of its use and any adverse outcomes of interest. © 2014 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons, Ltd.

Pregnancy outcome in women exposed to dopamine agonists during pregnancy: a pharmacoepidemiology study in EFEMERIS database.

PURPOSE: The objective of this exposed-unexposed study was to evaluate potential effects of dopamine agonists during pregnancy. METHODS: Data from EFEMERIS, a cohort of 57,408 pregnant women living in South West France, were used to compare exposed and unexposed women. The exposed group included 183 women (0.3 %) who received at least one prescription for one dopamine agonist during pregnancy. These women were individually matched with two unexposed women from the cohort for age and the month-and-year of the start of pregnancy. Pregnancy losses, birth defects, preterm births, low birth weight and psychomotor development were studied. RESULTS: Bromocriptine was the most frequently prescribed dopamine agonist, followed by cabergoline and quinagolide. Most (75 %) of the dopamine agonists were prescribed at the beginning of pregnancy (first trimester). There was no difference between the two groups concerning pregnancy history and demographic data. After adjustment for potential confounders, prescription and dispensation of dopamine agonists was associated with an increased risk of pregnancy loss [PORa = 3.7; 95 % confidence interval (CI) 1.8-7.4] and preterm birth (PORa = 3.6; 95 % CI 1.5-8.3). The prevalence of birth defects and low birth weight was not significantly different between the two groups. No difference in psychomotor development at either 9 or 24 months was observed between the two groups. CONCLUSION: This study suggests that prenatal exposure to dopamine agonists may be associated with an increased risk of pregnancy loss and preterm birth.

[Drug in pregnancy: studies in the French database EFEMERIS]. / Évaluation des médicaments chez la femme enceinte : à propos de la base de données française EFEMERIS.

The present article describes the first French database of drugs prescribed and dispensed during pregnancy and the outcome of these pregnancies, named EFEMERIS (Évaluation chez la Femme Enceinte des MÉdicaments et de leurs RISques). At the present time, EFEMERIS contains anonymous data concerning around 78,000 pregnant women who gave birth to a baby between 1 July 2004 to 31 December 2012 in Haute-Garonne (South West France) and who are registered in the French health insurance service. Data sources include 1- the French health insurance database (drugs prescribed during pregnancy), 2- the mother and child protection centre database (newborn health) 3- the antenatal diagnostic centre database (medical pregnancy interruptions) and 4- medical data from the hospital (PMSI). EFEMERIS provides exact data on period of exposure to drugs, pregnancy terminations, and follow up of the babies 9 months and 2 years after birth. It is incremented each year with around 10 000 new pregnancies. Analysis of data until December 2011 shows a prevalence rate of congenital anomalies of 2.4%. Pregnant women were prescribed around 10 different reimbursed drugs during their pregnancy, the potential risk of a lot of these medications having not been evaluated during pregnancy. EFEMERIS can be used to monitor the prescription of reimbursed drugs to French pregnant women as well as to identify adverse pregnancy outcomes such as congenital malformation or effects on psychomotor development of the child. Examples of some studies already performed are given.

The EFEMEREYE Study: prenatal medication exposure and ocular anomaly occurrence in EFEMERIS health database.

PURPOSE: To describe ocular anomalies (OAs) in children and fetuses in a French general population, to estimate their prevalence, and to investigate a possible association between prenatal medication exposure and the occurrence of OA in utero or in early childhood. METHODS: We conducted a case-control study using the EFEMERIS cohort, a database containing pregnancies registered in Haute-Garonne and their outcomes. We collected OA descriptions of fetuses at the time of pregnancy termination or of children at birth and the results of eye examinations of children at 9 months and 2 years of age. RESULTS: The prevalence of overall OAs was 2.13%, of which 0.04% were congenital ocular malformations (COMs). A total of 2,968 cases and 136,619 controls were selected for analysis. There was a significant difference between the two groups with regard to prenatal exposure to medications for the digestive tract and metabolism, the cardiovascular system, and the respiratory system. Multivariable analysis revealed an increased risk of OA in children of mothers exposed to magnesium during and 1 month before pregnancy (OR = 1.24; 95% CI, 1.11-1.38). CONCLUSIONS: This first pharmaco-epidemiological study on OA in France suggests that OA may be associated with exposure to commonly used medications. Given the rarity of COM, larger, international studies are warranted.

Bleeding adverse drug reactions (ADRs) in patients exposed to antiplatelet plus serotonin reuptake inhibitor drugs: analysis of the French Spontaneous Reporting Database for a controversial ADR.

AIM: The aim of the present study was to investigate bleeding adverse drug reactions (ADRs) in patients exposed to serotonin reuptake inhibitors (SRI) plus antiplatelet agents using the French Pharmacovigilance Database (FPVDB) regarding the controversial data in the literature. METHODS: The case/non-case method was used to measure the association between bleedings and exposure to SRIs plus antiplatelet agents versus antiplatelet drugs alone. RESULTS: Over 3 years, a total of 1,977 spontaneous reports of ADRs were collected with antiplatelet drugs, and antiplatelet agents plus SRIs in patients aged over 50 years, of which 1,331 (67.3 %) concerned bleeding. Multivariate logistic regression analysis failed to show any significant association [adjusted ROR = 0.8 (0.5-1.2)]. CONCLUSION: The data did not demonstrate any significant association between bleeding ADRs and exposure to SRI + antiplatelet agents versus antiplatelets alone. Considering other conflicting results, this risk should be kept in mind by physicians when treating patients with several risk factors.

[Analysis of prescriptions associated to hormone replacement therapy in Midi-Pyrénées region]. / Analyse des prescriptions associées au traitement hormonal de la ménopause en Midi-Pyrénées.

The aim of the present study was 1- to describe hormone replacement therapy (HRT) prescription in Midi-Pyrénées region (South West France) and 2- to compare the prescriptions of associated drugs to those of women who took HRT with prescriptions to women who did not take HRT. From 2004 to 2008, HRT prescription decreased for women aged 50 to 59 years in Midi-Pyrénées: 13.95% to 10.33% estradiol/progestin association consumers. During the first 6 months of 2008, 20,161 women took the association estradiol/progestin. Transdermal/percutaneous forms of estradiol (71.21%) and natural progesterone were mainly prescribed. The number of different dispensed drugs was significantly higher in the HRT group: 5.18 versus 2.82 in the control group (p < 0.0001). All classes were concerned except antineoplastic drugs and immunomodulators, drugs for diabetes and raloxifene which were more prescribed to controls. In the period of the study, 7,035 patients took estrogen alone (25.87% of HRT consumers). The same phenomena were observed in this group. Women exposed to HRT in Midi-Pyrénées, great consumers of drugs, represent a population who require particular medical supervision, because of the risks of HRT and pathologies and/or numerous associated drugs.

Prenatal Drug Exposure in Children With a History of Neuropsychiatric Care: A Nested Case-Control Study.

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.