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.

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.

From Inception to ConcePTION: Genesis of a Network to Support Better Monitoring and Communication of Medication Safety During Pregnancy and Breastfeeding.

In 2019, the Innovative Medicines Initiative (IMI) funded the ConcePTION project-Building an ecosystem for better monitoring and communicating safety of medicines use in pregnancy and breastfeeding: validated and regulatory endorsed workflows for fast, optimised evidence generation-with the vision that there is a societal obligation to rapidly reduce uncertainty about the safety of medication use in pregnancy and breastfeeding. The present paper introduces the set of concepts used to describe the European data sources involved in the ConcePTION project and illustrates the ConcePTION Common Data Model (CDM), which serves as the keystone of the federated ConcePTION network. Based on data availability and content analysis of 21 European data sources, the ConcePTION CDM has been structured with six tables designed to capture data from routine healthcare, three tables for data from public health surveillance activities, three curated tables for derived data on population (e.g., observation time and mother-child linkage), plus four metadata tables. By its first anniversary, the ConcePTION CDM has enabled 13 data sources to run common scripts to contribute to major European projects, demonstrating its capacity to facilitate effective and transparent deployment of distributed analytics, and its potential to address questions about utilization, effectiveness, and safety of medicines in special populations, including during pregnancy and breastfeeding, and, more broadly, in the general population.

Breast cancer screening and overdiagnosis.

Overdiagnosis is a harmful consequence of screening which is particularly challenging to estimate. An unbiased setting to measure overdiagnosis in breast cancer screening requires comparative data from a screened and an unscreened cohort for at least 30 years. Such randomised data will not become available, leaving us with observational data over shorter time periods and outcomes of modelling. This collaborative effort of the International Cancer Screening Network quantified the variation in estimated breast cancer overdiagnosis in organised programmes with evaluation of both observed and simulated data, and presented examples of how modelling can provide additional insights. Reliable observational data, analysed with study design accounting for methodological pitfalls, and modelling studies with different approaches, indicate that overdiagnosis accounts for less than 10% of invasive breast cancer cases in a screening target population of women aged 50 to 69. Estimates above this level are likely to derive from inaccuracies in study design. The widely discrepant estimates of overdiagnosis reported from observational data could substantially be reduced by use of a cohort study design with at least 10 years of follow-up after screening stops. In contexts where concomitant opportunistic screening or gradual implementation of screening occurs, and data on valid comparison groups are not readily available, modelling of screening intervention becomes an advantageous option to obtain reliable estimates of breast cancer overdiagnosis.

Cervical cancer survivors and health care use: A Danish population-based register study.

OBJECTIVE: To evaluate the impact of a cervical cancer (CC) diagnosis on use of health care and prescription drugs. METHODS: This population-based register-study included Danish women aged 23-59 years and diagnosed with CC in 2001-2005. Women with a cervical screening outcome were used as comparison group. We obtained number of contacts to general practitioners (GPs), hospitals, psychologists/psychiatrists and defined daily doses (DDD) of analgesic/psychotropic prescription drugs. A difference-in-differences-design was used to estimate effect of a CC diagnosis on health-care use from five-year periods before and after the diagnosis/screening outcome. RESULTS: In total, 926 women with CC and 1,004,759 women without cancer were included. In five years following the date of CC diagnosis, CC patients had increased their use of GPs with 8.6 (95% CI 4.8-12.4) contacts more than women in the comparison group, and with 4.12 (95% CI 3.99-4.25) more hospital contacts. In contrast, use of psychologists/psychiatrists was low and largely unaffected by the CC diagnosis. For use of prescription drugs, analgesics increased with 80 (95% CI 60-100) DDD more in CC patients than in comparison women, and for psychotropics with 304 (95% CI 261-347) DDD more. CONCLUSIONS: A CC diagnosis was followed by an increase in use of GPs, hospitals, and analgesic/psychotropic prescription drugs, while use of psychologist/psychiatrist was largely unaffected. This pattern may indicate that pain/mental health concerns after CC either persisted or were alleviated by other means only.

Breast cancer mortality and overdiagnosis after implementation of population-based screening in Denmark.

INTRODUCTION: Service breast cancer screening is difficult to evaluate because there is no unscreened control group. Due to a natural experiment, where 20% of women were offered screening in two regions up to 17 years before other women, Denmark is in a unique position. We utilized this opportunity to assess outcome of service screening. MATERIALS AND METHODS: Screening was offered in Copenhagen from 1991 and Funen from 1993 to women aged 50-69 years. We used difference-in-differences methodology with a study group offered screening; a historical control group; a regional control group; and a regional-historical control group, comparing breast cancer mortality and incidence, including ductal carcinoma in situ, between study and historical control group adjusted for changes in other regions, and calculating ratios of rate ratios (RRR) with 95% confidence intervals (CI). Data came from Central Population Register; mammography screening databases; Cause of Death Register; and Danish Cancer Register. RESULTS: For breast cancer mortality, the study group accumulated 1,551,465 person-years and 911 deaths. Long-term breast cancer mortality in Copenhagen was 20% below expected in absence of screening; RRR 0.80 (95% CI 0.71-0.90), and in Funen 22% below; RRR 0.78 (95% CI 0.68-0.89). Combined, cumulative breast cancer incidence in women followed 8+ years post-screening was 2.3% above expected in absence of screening; RRR 1.023 (95% CI 0.97-1.08). DISCUSSION: Benefit-to-harm ratio of the two Danish screening programs was 2.6 saved breast cancer deaths per overdiagnosed case. Screening can affect only breast cancers diagnosed in screening age. Due to high breast cancer incidence after age 70, only one-third of breast cancer deaths after age 50 could potentially be affected by screening. Increasing upper age limit could be considered, but might affect benefit-to-harm ratio negatively.

Impact of chronic diseases on effect of breast cancer screening.

BACKGROUND: Although breast cancer screening reduces breast cancer mortality at the population level, subgroups of women may benefit differently. We investigated the impact of health status on the effect of breast cancer screening. METHODS: The study included 181 299 women invited in two population-based screening programs in Denmark and 1 526 446 control subjects, followed from April 1981 to December 2014. Poisson regressions were used to compare the observed breast cancer mortality rate in women invited to screening with the expected rate in the absence of screening among women with and without chronic diseases. Chronic diseases were defined as any diagnosis in the Charlson Comorbidity Index during 4 years before the first invitation to screening. RESULTS: Almost 10% of women had chronic diseases before first invitation to screening. Whereas we observed a reduction in breast cancer mortality following invitation to screening of 28% (95% CI, 20% to 35%) among women without chronic diseases, only a 7% (95% CI, -39% to 37%) reduction was seen for women with chronic diseases (P-value for interaction = .22). For participants, the reduction, corrected for selection bias, was 35% (95% CI 16% to 49%) for women without, and 4% (95% CI -146% to 62%) for women with chronic diseases (P-value for interaction = .43). CONCLUSION: Our data indicate a marginal effect of mammography screening on breast cancer mortality in women with chronic diseases. If our results are confirmed in other populations, the presence of chronic diseases will be an important factor to take into consideration in personalized screening.

Limitations in the Effect of Screening on Breast Cancer Mortality.

PURPOSE: Randomized, controlled trials showed that screening reduces breast cancer mortality rates, but some recent observational studies have concluded that programmatic screening has had minor effect on breast cancer mortality rates. This apparent contradiction might be explained by the use of aggregated data in observational studies. We assessed the long-term effect of screening using individual-level data. MATERIALS AND METHODS: Using data from mammography screening in the Copenhagen and Danish national registers, we compared the observed breast cancer mortality rate in women invited to screening with the expected rate in absence of screening. The effect was examined using the "naïve model," which included all breast cancer deaths; the "follow-up model," which counted only breast cancer deaths in women diagnosed after their first invitation to screening; and the "evaluation model," which is similar to the follow-up model during screening age, but after screening age, which counted only breast cancer deaths and person-years in women diagnosed during screening age. RESULTS: We included 18,781,292 person-years, 976,743 of which were from women invited to screening. The naïve and follow-up models showed, respectively, 10% and 11% reduction in breast cancer mortality after invitation to screening. However, many breast cancer deaths occurred in women whose cancer was diagnosed when they were no longer eligible for screening. Accounting for this dilution, the evaluation model showed a 20% (95% CI, 10% to 29%) reduction in breast cancer mortality after invitation to screening. CONCLUSION: Screening had a clear long-term beneficial effect with a 20% reduction in breast cancer-associated mortality in the invited population. However, this effect was, by nature, restricted to breast cancer deaths in women who could potentially benefit from screening. Our study highlights the complexity in evaluating the long-term effect of breast cancer screening from observational data.

Overdiagnosis in breast cancer screening: The impact of study design and calculations.

Overdiagnosis in breast cancer screening is an important issue. A recent study from Denmark concluded that one in three breast cancers diagnosed in screening areas in women aged 50-69 years were overdiagnosed. The purpose of this short communication was to disentangle the study's methodology in order to evaluate the soundness of this conclusion. We found that both the use of absolute differences as opposed to ratios; the sole focus on non-advanced tumours and the crude allocation of tumours and person-years by screening history for women aged 70-84 years, all contributed to the very high estimate of overdiagnosis. Screening affects cohorts of screened women. Danish registers allow very accurate mapping of the fate of every woman. We should be past the phase where studies of overdiagnosis are based on the fixed age groups from routine statistics.

Benefit-to-harm ratio of the Danish breast cancer screening programme.

The primary aim of breast cancer screening is to reduce breast cancer mortality, but screening also has negative side-effects as overdiagnosis. To evaluate a screening programme, both benefits and harms should be considered. Published estimates of the benefit-to-harm ratio, the number of breast cancer deaths prevented divided by the number of overdiagnosed breast cancer cases, varied considerably. The objective of the study was to estimate the benefit-to-harm ratio of breast cancer screening in Denmark. The numbers of breast cancer deaths prevented and overdiagnosed cases [invasive and ductal carcinoma in situ (DCIS)] were estimated per 1,000 women aged 50-79, using national published estimates for breast cancer mortality and overdiagnosis, and national incidence and mortality rates. Estimations were made for both invited and screened women. Among 1,000 women invited to screening from age 50 to age 69 and followed until age 79, we estimated that 5.4 breast cancer deaths would be prevented and 2.1 cases overdiagnosed, under the observed scenario in Denmark of a breast cancer mortality reduction of 23.4% and 2.3% of the breast cancer cases being overdiagnosed. The estimated benefit-to-harm ratio was 2.6 for invited women and 2.5 for screened women. Hence, 2-3 women would be prevented from dying from breast cancer for every woman overdiagnosed with invasive breast cancer or DCIS. The difference between the previous published ratios and 2.6 for Denmark is probably more a reflection of the accuracy of the underlying estimates than of the actual screening programmes. Therefore, benefit-to-harm ratios should be used cautiously.

Neuraminidase inhibitors during pregnancy and risk of adverse neonatal outcomes and congenital malformations: population based European register study.

Objective To evaluate the possible effects of exposure to neuraminidase inhibitors during embryo-fetal life with respect to adverse neonatal outcomes and congenital malformations.Design Population based multinational observational cohort study and meta-analysis.Setting National registers covering information on maternal healthcare, births, and prescriptions in Denmark, Norway, and Sweden and the EFEMERIS database from the Haute-Garonne district in France.Participants All women together with their singleton infants born between 1 January 2008 and 31 December 2010. Only infants born at 154 days of gestation or later were included. Infants were defined as exposed if the women filled a prescription during pregnancy for either of the two neuraminidase inhibitors oseltamivir or zanamivir.Main outcomes Low birth weight, low Apgar score, preterm birth, small for gestational age birth, stillbirth, neonatal mortality, neonatal morbidity, and congenital malformations. Crude and adjusted hazard ratios of preterm birth were estimated using Cox regression models. Crude and adjusted odds ratios for other outcomes were estimated by logistic regression models.Results The study included 5824 (0.8%) exposed women and their infants and 692 232 who were not exposed. Exposure to neuraminidase inhibitors in utero was not associated with increased risks of any of the investigated neonatal outcomes, including low birth weight (adjusted odds ratio 0.77, 95% confidence interval 0.65 to 0.91), low Apgar score (adjusted odds ratio 0.87, 0.67 to 1.14), preterm birth (adjusted hazard ratio 0.97, 0.86 to 1.10), small for gestational age birth (adjusted odds ratio 0.72, 0.59 to 0.87), stillbirth (adjusted odds ratio 0.81, 0.51 to 1.30), neonatal mortality (adjusted odds ratio 1.13, 0.56 to 2.28), and neonatal morbidity (adjusted odds ratio 0.92, 0.86 to 1.00). No increased risk of congenital malformations overall associated with maternal exposure was observed during the first trimester (adjusted odds ratio 1.06, 0.77 to 1.48). Similarly, no significantly increased risks of any of the outcomes were observed in an analysis restricted to oseltamivir alone.Conclusions This large multinational register study found no increased risks of adverse neonatal outcomes or congenital malformations associated with exposure to neuraminidase inhibitors during embryo-fetal life. The results support previously reported findings that the use of neuraminidase inhibitors is not associated with increased risks of adverse fetal or neonatal outcomes.

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.

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.

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.

First epidemiological data for venotonics in pregnancy from the EFEMERIS database.

OBJECTIVE: There are few published data about possible effects of veinotonics in pregnant women. The present study investigates potential adverse drug reactions of veinotonics in pregnancy. METHOD: EFEMERIS is a database including prescribed and dispensed reimbursed drugs during pregnancy (data from Caisse Primaire d'Assurance Maladie) and outcomes (data from Maternal and Infant Protection Service and Antenatal diagnostic Centre). Women who delivered from 1 July 2004 to December 2007 in Haute-Garonne and were registered in the French Health Insurance Service have been included in the EFEMERIS database. We compared pregnancy outcomes and newborn health between women exposed to veinotonics during pregnancy and unexposed women. RESULTS: We found that 8998 women (24%) had received at least one prescription for venotonic agents during their pregnancy, corresponding to the period of organogenesis in 1200 cases. We compared data for these women with those for the 27,963 women for whom these drugs were not prescribed during pregnancy. The most widely used veinotonics were hesperidin, diosmin and troxerutin. Pregnancies led to 98.4% versus 93.6% of live births, 0.2% versus 0.2% of postnatal deaths and 1.6% versus 6.4% of pregnancy termination (miscarriage, ectopic pregnancy, medical termination, intrauterine death) in exposed and non-exposed groups, respectively. The risks of pregnancy termination (HR = 0.71 (0.60-0.84)) and prematurity (HR = 0.82 (0.73-0.93)) remained significantly lower in the women exposed to venotonics than in unexposed women. In the group of newborns whose mother had a prescription of veinotonics during organogenesis, 39 out of 1200 (3.4%) had a malformation versus 789 (3.0%) in the control group (ORa = 1.134 (0.873-1.472)). The risk of neonatal diseases was not increased by exposure to venotonic agents in the third trimester (4.9% versus 6.1% for the controls, ORa = 1.07 (0.95-1.20)). CONCLUSION: We found no increased risk of adverse pregnancy outcome among women exposed to veinotonics compared with unexposed pregnant women.

[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.

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.