Prevalence, demographic and spatial distribution of treated epilepsy in France in 2020: a study based on the French national health data system.

BACKGROUND: Although still incomplete, the epidemiology of epilepsy shows substantial variations in the burden of the condition according to demographic, social and territorial characteristics. This study aimed to estimate the prevalence of treated epilepsy and to investigate its demographic and spatial distribution in 2020 in France, a country where the nationwide epidemiological situation of the condition remains largely unknown. METHODS: We used the French national health data system, which covers nearly the entire population residing in France (over 67 million of inhabitants in metropolitan and overseas departments). Prevalent cases were identified using long-term disease status, hospitalisation for epilepsy (ICD-10 codes G40 or G41), and reimbursements for antiseizure medications and electroencephalograms. RESULTS: In 2020, we identified 685,122 epilepsy cases, corresponding to an overall prevalence of 10.2 per 1000 inhabitants [95% confidence interval 10.1-10.2], with similar rates in men and women. Estimates were found to increase with age, with an accelerated rise in the second half of the life, which occurred earlier in men than in women. We observed a monotonic gradient of variation with socio-economic deprivation (in non-military metropolitan subjects aged 18-54 years) as well as territorial heterogeneity, with the mountainous centre of France as well as some French overseas departments having the highest prevalence. CONCLUSIONS: Our results revise upwards the estimation of epilepsy prevalence in France, showing that it now ranks among the highest in developed countries. Our study also confirms the important socio-territorial heterogeneity of the condition that reflects health inequalities in this country.

Medical child abuse: Medical history and red flags in French adolescents.

BACKGROUND: Medical child abuse (MCA; or Munchausen syndrome by proxy) is a severe form of adult and medical maltreatment of children. Currently, few data on MCA in adolescents exist. OBJECTIVE: To describe the clinical characteristics and medical history of children and adolescents aged 10 to 18 years with suspected or confirmed MCA in the pediatric hospital setting. METHODS: We included patients aged 10 to 18 years who were seen in five tertiary care hospitals in the Paris area and identified by physician recall such as suspected MCA between 2015 and 2021. RESULTS: We included 29 adolescents; the mean (SD) age was 12.9 (10.8-15.0) years at suspected diagnosis. Medical wandering was common, with a mean of 23 (12.8-33.2) alleged symptoms and 33 (9.2-56.8) specialized consultations in a mean of six different hospitals. The mean number of emergency visits was 11.8 (0-25.9) and radiologic exams 24.3 (5-43.6). Overall, 62 % (18/29) of the adolescents had an underlying organic pathology. The impact of MCA on quality of life was major, with a high rate of school dropout (96 %). The mean delay to the suspected diagnosis was 5.8 (2.6-9) years, and even when recognized, it was rarely the subject of a social or judiciary report (only 42 % of adolescents). In total, 50 % of the adolescents subsequently exhibited Munchausen syndrome. CONCLUSION: Adolescent MCA is poorly known among the medical profession. Increasing awareness, education and knowledge of risk factors could contribute to better care.

[Child maltreatment and Covid-19: A crisis within a crisis]. / Maltraitance envers les enfants et Covid-19 - Une crise dans la crise.

The fight against the SARS-CoV-2 pandemic was carried out through strong restrictive measures, including general population lockdown, which allowed the convergence of risk factors for child abuse. During this period, the French national hotline for children in danger recorded a 56% increase in calls. Calls followed by an alert to departmental child protection services increased by 30%. Through an algorithm created by our team, we showed a 50% increase in the relative frequency of hospitalizations for physical abuse in children aged 0-5 years during the lockdown. This has fueled thinking about subsequent health measures to protect the youngest children. Our goal is now to use this algorithm for epidemiological purposes as a barometer of abuse or in daily practice to help the diagnosis of physical abuse in young children.

Title: Maltraitance envers les enfants et Covid-19 - Une crise dans la crise. Abstract: En France, au début de l'année 2020, environ 690 000 vies ont pu être épargnées grâce au confinement général de la population et aux mesures restrictives de lutte contre la Covid-19. Conséquence inattendue, ces mesures ont eu un impact sur une autre frange vulnérable de la population : celle des jeunes enfants, pour lesquels il a été démontré une augmentation des maltraitances subies à cette période. À partir de données de la littérature et de l'apport de nos travaux de recherche dans le domaine, nous proposons une documentation de cette crise des violences intra-familiales, intriquée dans la crise sanitaire de la Covid-19.

Do children with mathematical learning disabilities use the inversion principle to solve three-term arithmetic problems?: The impact of presentation mode.

Numerical inversion is the ability to understand that addition is the opposite of subtraction and vice versa. Three-term arithmetic problems can be solved without calculation using this conceptual shortcut. To verify that this principle is used, inverse problems (a + b - b) can be compared with standard problems (a + b - c). If this principle is used, performance on inverse problems will be higher than performance on standard problems because no calculation is required. To our knowledge, this principle has not been previously studied in children with mathematical learning disabilities (MLD). Our objectives were (a) to study whether 10-year-olds with MLD are able to use this conceptual principle in three-term arithmetic problems and (b) to evaluate the impact of the presentation mode. A total of 64 children with or without MLD solved three-term arithmetic problems (inverse and standard) in two presentation modes (symbolic and picture). The results showed that even though children with MLD have difficulties in performing arithmetic problems, they can do so when the inverse problem is presented with pictures. The picture presentation mode allowed children with MLD to efficiently identify and use the conceptual inversion shortcut and thus to achieve a similar performance to that of typically developing children. These results provide interesting perspectives for the care of children with MLD.

Effects of the 2020 health crisis on acute alcohol intoxication: A nationwide retrospective observational study.

BACKGROUND: Recent data suggest that the COVID-19 pandemic and associated restrictions may have influenced alcohol use and promoted addictive behavior. We aimed to investigate the impact of the pandemic on acute alcohol intoxication (AAI) in France. METHODS: We identified all hospital stays related to alcohol abuse in 2018-2020. Differences in number of hospitalizations between 2019 and 2020 were tested using Poisson regressions. Differences between observed and expected deliveries of drugs used in alcohol dependence in 2020 were also studied. RESULTS: There was a decrease in the number of hospitalizations for AAI between 2019 and 2020 (-9677[-11·4%],RR:0·89[0·88-0·89]). This decrease was observed among men and women of all age groups, except women ≥ 85 years. We observed an increase in in-hospital mortality during 2020 and more hospitalizations for AAI with certain medical complications, especially during the first 2020 lockdown. There was a drop in observed deliveries of drugs used in alcohol dependence during the first 2020 lockdown. CONCLUSIONS: The decrease in the number of hospitalizations for AAI in 2020 could be explained by several factors: fewer available hospital beds due to COVID-19, individuals with AAI delaying or avoiding medical care due to COVID-19 fears, and decreases driven by younger age groups returning to live with parents and socializing less. While alcohol consumption patterns have changed with the implementation of social distancing measures and lockdowns, the increase in mortality and the share of hospitalizations with complications suggest that these measures had an impact on event severity in a context of strained access to healthcare.

Hospitalization for self-harm during the early months of the COVID-19 pandemic in France: A nationwide retrospective observational cohort study.

BACKGROUND: Little is known to date about the impact of COVID-19 pandemic on self-harm. METHODS: The number of hospitalizations for self-harm (ICD-10 codes X60-X84) in France from 1st January to 31st August 2020 (including a two-month confinement) was compared to the same periods in 2017-2019. Statistical methods comprised Poisson regression, Cox regression and Student's t-test, plus Spearman's correlation test relating to spatial analysis of hospitalizations. OUTCOMES: There were 53,583 self-harm hospitalizations in France during January to August 2020. Compared to the same period in 2019, this represents an overall 8·5% decrease (Relative Risk [95% Confidence Interval] = 0·91 [0·90-0·93]).This decrease started in the first week of confinement and persisted until the end of August. Similarly, decrease was found in both women (RR=0·90 [0·88-0·92]) and men (RR=0·94 [0·91-0·95]), and in all age groups, except 65 years and older. Regarding self-harm hospitalizations by means category, increases were found for firearm (RR=1·20 [1·03-1·40]) and for jumping from heights (RR=1·10 [1·01-1·21]). There was a trend for more hospitalizations in intensive care (RR=1·03 [0·99-1·07]). The number of deaths at discharge from hospital also increased (Hazard Ratio = 1·19 [1·09-1·31]). Self-harm hospitalizations were weakly correlated with the rates of hospitalization for COVID-19 across administrative departments (Spearman's rho =-0·21; p = 0·03), but not with overall hospitalizations. INTERPRETATION: The COVID-19 pandemic had varied effects on self-harm hospitalizations during the early months in France. Active suicide prevention strategies should be maintained. FUNDING: French National Research Agency.

Physical abuse of young children during the COVID-19 pandemic: Alarming increase in the relative frequency of hospitalizations during the lockdown period.

BACKGROUND: In France, the COVID-19 pandemic led to a general lockdown from mid-March to mid-May 2020, forcing families to remain confined. We hypothesized that children may have been victims of more physical abuse during the lockdown, involving an increase in the relative frequency of hospitalization. METHODS: Using the national administrative database on all admissions to public and private hospitals (PMSI), we selected all children aged 0-5 years hospitalized and identified physically abused children based on ICD-10 codes. We included 844,227 children hospitalized in March-April 2017-2020, of whom 476 (0.056%) were admitted for physical abuse. Relative frequency of hospitalization for physical abuse observed in March to April 2020 were compared with those from the same months in the three previous years (2017-2019). FINDINGS: Even if absolute number of children exposed to physical abuse did not fluctuate significantly, we found a significant increase in the relative frequency of young children hospitalized for physical abuse from 2017 (0.053%) to 2020 (0.073%). Compared with the 2017-2019 period, and considering the observed decrease in the number of overall hospital admissions during the first lockdown, the number of children exposed to physical violence was 40% superior to what would be expected. INTERPRETATION: The sharp increase in the relative frequency of hospitalizations for physical abuse in children aged 0-5 years in France is alarming. As only the most severe cases were brought to the hospital for treatment during the lockdown, our figures probably only represent the tip of the iceberg of a general increase of violence against young children.

Risk of early neurodevelopmental disorders associated with in utero exposure to valproate and other antiepileptic drugs: a nationwide cohort study in France.

Information available on the risks of neurodevelopmental disorders (NDs) associated with in utero exposure to valproate (VPA) and to other antiepileptic drugs (AEDs) is limited. A nationwide population-based cohort study was conducted based on comprehensive data of the French National Health Data System (SNDS). Liveborn infants without brain malformation, born between January 2011 and December 2014, were followed from birth up to December 2016. NDs were identified based on diagnoses of mental or behavioural disorders and utilization of speech therapy, orthoptic or psychiatric services. The risk of NDs was compared between children exposed in utero to AED monotherapy and unexposed children, using Cox proportional hazard models adjusted for maternal and neonatal characteristics. The cohort included 1,721,990 children, 8848 of whom were exposed in utero to AED monotherapy. During a mean follow-up of 3.6 years, 15,458 children had a diagnosis of mental or behavioural disorder. In utero exposure to VPA was associated with an increased risk of NDs overall (aHR: 3.7; 95% CI 2.8-4.9) and among children born to a mother without mental illness (aHR 5.1; 95% CI 3.6-7.3). A dose-response relationship was demonstrated and the risk of NDs was more particularly increased for an exposure to VPA during the second or third trimesters of pregnancy. Among the other AEDs, only pregabalin was consistently associated with an increased risk of NDs (aHR: 1.5; 95% CI 1.0-2.1). This study confirms a four to fivefold increased risk of early NDs associated with exposure to VPA during pregnancy. The risk associated with other AEDs appears much lower.

Risk of early neurodevelopmental outcomes associated with prenatal exposure to the antiepileptic drugs most commonly used during pregnancy: a French nationwide population-based cohort study.

OBJECTIVES: To assess the association between prenatal exposure to monotherapy with the antiepileptic drugs (AEDs) most commonly used during pregnancy and the risk of various neurodevelopmental outcomes compared with lamotrigine. DESIGN: Nationwide population-based cohort study. SETTING: French national healthcare databases. PARTICIPANTS: Children born alive between 2011 and 2014 and prenatally exposed to AED monotherapy. PRIMARY AND SECONDARY OUTCOME MEASURES: Outcomes included neurodevelopmental disorders (NDD), defined by International Classification of Diseases, 10th Revision codes F70-F98-pervasive developmental disorders (PDD, F84) and mental retardation (MR, F70-F79) were studied separately-and visits to speech therapists. The reference group comprised children prenatally exposed to lamotrigine. Children were followed until outcome, loss to follow-up, death or 31 December 2016. We performed inverse probability of treatment weighting analyses using the propensity score, which included maternal and infant characteristics. Hazard ratios (HRs) were calculated using Cox models. RESULTS: The cohort comprised 9034 children, 2916 of which were exposed to lamotrigine, 1627 to pregabalin, 1246 to clonazepam, 991 to valproic acid (VPA), 621 to levetiracetam, 502 to carbamazepine, 477 to topiramate, 378 to gabapentin and 143 to oxcarbazepine. None of these AEDs, except VPA, was associated with an increased risk of any of the four neurodevelopmental outcomes investigated. Exposure to VPA was associated with increased risks of NDDs (HR=2.7, 95% CI (1.8 to 4.0)), PDD (HR=4.4 (2.1 to 9.3)), MR (HR=3.1 (1.5 to 6.2)) and visits to speech therapists (HR=1.5 (1.1 to 1.9)), with a dose-response relationship. CONCLUSIONS: No increased risk of any of the neurodevelopmental outcomes investigated in this study was observed with prenatal exposure to levetiracetam, pregabalin, oxcarbazepine, topiramate, gabapentin, clonazepam or carbamazepine, compared with lamotrigine. However, this study corroborates the well-known association between maternal use of VPA during pregnancy and the risk of neurodevelopmental disorders in the offspring. Longer follow-up is necessary to confirm these findings.

Seasonal influenza vaccine and Guillain-Barré syndrome: A self-controlled case series study.

OBJECTIVE: To evaluate the risk of Guillain-Barré syndrome (GBS) following seasonal influenza vaccination based on French nationwide data. METHODS: All cases of GBS occurring in metropolitan France between September 1 and March 31 from 2010 to 2014 were identified from the French national health data system. Data were analyzed according to the self-controlled case series method. The risk period started 1 day after the patient received vaccine (D1) until 42 days after vaccination (D42). The incidence of GBS during this risk period was compared to that of the control period (D43-March 31). The incidence rate ratio (IRR) was estimated after adjusting for seasonality and presence or not of acute infections. RESULTS: Between September and March, of the 2010/2011 to 2013/2014 influenza vaccination seasons, 3,523 cases of GBS occurred in metropolitan France and were included in the study. Among them, 15% (527 patients) had received influenza vaccination. A total of 140 patients developed GBS during the 42 days following influenza vaccination. The crude risk of developing GBS was not significantly increased during the 42 days following influenza vaccination (IRR, 1.02; 95% confidence interval [CI], 0.83-1.25; p = 0.85). This result remained nonsignificant after adjustment for calendar months and the incidence of acute gastrointestinal and respiratory tract infections (IRR, 1.10; 95% CI, 0.89-1.37; p = 0.38). In contrast, the risk of GBS was fourfold higher after acute respiratory tract infection (IRR, 3.89; 95% CI, 3.52-4.30; p < 0.0001) or gastrointestinal infection (IRR, 3.64; 95% CI, 3.01-4.40; p < 0.0001). CONCLUSIONS: No association between seasonal influenza vaccination and GBS was shown during the 42 days following vaccination.

Surgery and risk of Guillain-Barré syndrome: A French nationwide epidemiologic study.

OBJECTIVE: To assess the association between Guillain-Barré syndrome (GBS) and recent surgery based on French nationwide data. METHODS: Data were extracted from the French health administrative databases (SNIIRAM/PMSI). All patients hospitalized for GBS between 2009 and 2014 were identified by ICD-10 code G61.0 as main diagnosis. Patients previously hospitalized for GBS in 2006, 2007, and 2008 were excluded. Surgical procedures were identified from the hospital database. Hospitalizations for surgery with no infection diagnosis code entered during the hospital stay were also identified. The association between GBS and a recent surgical procedure was estimated using a case-crossover design. Case and referent windows were defined as 1-60 days and 366-425 days before GBS hospitalization, respectively. Analyses were adjusted for previous episodes of gastroenteritis and respiratory tract infection, identified by drug dispensing data. RESULTS: Of the 8,364 GBS cases included, 175 and 257 patients had undergone a surgical procedure in the referent and case windows, respectively (adjusted odds ratio [OR] = 1.53, 95% confidence interval [CI]: 1.25-1.88). A slightly weaker association was observed for surgical procedures with no identified infection during the hospitalization (OR = 1.40, 95% CI: 1.12-1.73). Regarding the type of surgery, only surgical procedures on bones and digestive organs were significantly associated with GBS (OR and 95% CI = 2.78 [1.68-4.60] and 2.36 [1.32-4.21], respectively). CONCLUSION: In this large nationwide epidemiologic study, GBS was moderately associated with any type of recent surgery and was more strongly associated with bone and digestive organ surgery.

Guillain-Barré syndrome in France: a nationwide epidemiological analysis based on hospital discharge data (2008-2013).

Guillain-Barré syndrome (GBS) is potentially life threatening and typically occurs after an infection. No detailed information is available concerning the epidemiological characteristics of GBS in France. We estimated age- and sex-specific incidence rates (IRs) based on a French nationwide hospital discharge database. All patients hospitalized for GBS between 2008 and 2013 were identified by International Classification of Diseases-10 code G61.0 as principal diagnosis. Patients previously hospitalized for GBS in 2006 and 2007 were excluded. Sensitivity analyses were performed by considering alternative case definitions, based on more restrictive sets of codes. A total of 9,391 patients were identified, leading to an overall crude IR of 2.42 per 100,000 person-years (world standardized IR = 2.00). IRs increased with age, reaching a peak in the 70-79-year age group. IR was 46% higher in men than in women, and 44% higher in winter than in summer. In children, the highest IR was observed at the age of 2 years. These patterns were not modified by the use of alternative case definitions. This French nationwide study showed similar GBS epidemiological patterns in adults to those reported in other countries. We also report a childhood incidence peak around the age of 2 years, as previously observed in Latin American and Chinese populations.

Time knowledge acquisition in children aged 6 to 11 years and its relationship with numerical skills.

Acquisition of time knowledge (TK; the correct representation and use of time units) is linked to the development of numerical abilities, but this relationship has not been investigated in children. The current study examined the acquisition of TK and its association with numerical skills. A total of 105 children aged 6 to 11 years were interviewed with our Time Knowledge Questionnaire (TKQ), developed for purposes of this study, and the Zareki-R, a battery for the evaluation of number processing and mental calculation. The TKQ assessed conventional time knowledge (temporal orientation, temporal sequences, relationships between time units, and telling the time on a clock), estimation of longer durations related to birthday and life span, and estimation of the duration of the interview. Time knowledge increased with age, especially from 6 to 8 years, and was strongly linked to numerical skills. Regression analyses showed that four numerical components were implicated in TK: academic knowledge of numbers and number facts (e.g., reading Arabic numerals, mental calculation), number line estimation (e.g., correspondence between a number and a distance), contextual estimation (e.g., many/few leaves on a tree, children in a family), and numerical tasks involving verbal working memory (e.g., comparison of numbers presented orally). Numerical correlations with TK varied according to children's age; subtests based on academic knowledge of numbers, working memory, and number line estimation were linked with TK in the younger children, but only contextual estimation was associated with TK in the older children.

Multiple sclerosis in children: an update on clinical diagnosis, therapeutic strategies, and research.

The clinical features, diagnostic challenges, neuroimaging appearance, therapeutic options, and pathobiological research progress in childhood-and adolescent-onset multiple sclerosis have been informed by many new insights in the past 7 years. National programmes in several countries, collaborative research efforts, and an established international paediatric multiple sclerosis study group have contributed to revised clinical diagnostic definitions, identified clinical features of multiple sclerosis that differ by age of onset, and made recommendations regarding the treatment of paediatric multiple sclerosis. The relative risks conveyed by genetic and environmental factors to paediatric multiple sclerosis have been the subject of several large cohort studies. MRI features have been characterised in terms of qualitative descriptions of lesion distribution and applicability of MRI aspects to multiple sclerosis diagnostic criteria, and quantitative studies have assessed total lesion burden and the effect of the disease on global and regional brain volume. Humoral-based and cell-based assays have identified antibodies against myelin, potassium-channel proteins, and T-cell profiles that support an adult-like T-cell repertoire and cellular reactivity against myelin in paediatric patients with multiple sclerosis. Finally, the safety and efficacy of standard first-line therapies in paediatric multiple sclerosis populations are now appreciated in more detail, and consensus views on the future conduct and feasibility of phase 3 trials for new drugs have been proposed.

Risk of herpes zoster in patients prescribed inhaled corticosteroids: a cohort study.

BACKGROUND: Little is known concerning risk factors for herpes zoster in the general population. We hypothesised that inhaled corticosteroids (ICS) are a risk factor for herpes zoster especially among users of inhibitors of cytochrome P450 enzymes involved in their metabolism. METHODS: We identified a cohort of adult users of respiratory medications in the General Practice Research Database and carried out a nested case control analysis of inhaled corticosteroid use among 8900 new cases of herpes zoster and 88032 controls matching on age and calendar time. RESULTS: The adjusted odds ratio for the relationship between current use of ICS and the occurrence of herpes zoster was 1.00 (95% confidence interval (CI), 0.94-1.07). There was no increase in risk of herpes zoster even at higher ICS doses; odds ratio 1.05 (95% CI, 0.96-1.14). Among subjects with concomitant prescriptions for an ICS and an inhibitor of cytochrome P450 3A4, the point estimate for the association between herpes zoster and the use of higher doses of inhaled corticosteroids was 1.23 (95% CI, 0.81-1.88). CONCLUSIONS: The use of inhaled corticosteroids, even at high doses and in conjunction with inhibitors of their metabolism, was not a significant risk factor for the occurrence of herpes zoster in adults.

Incidence and natural history of mucopolysaccharidosis type III in France and comparison with United Kingdom and Greece.

Sanfilippo syndrome, or mucopolysaccharidosis type III (MPSIII) is a lysosomal storage disease with predominant neurological manifestations in affected children. It is considered heterogeneous with respect to prevalence, clinical presentation, biochemistry (four biochemical forms of the disease referred to as MPSIIIA, B, C, and D are known), and causative mutations. The perspective of therapeutic options emphasizes the need for better knowledge of MPSIII incidence and natural history. We performed parallel retrospective epidemiological studies of patients diagnosed with MSPIII in France (n = 128), UK (n = 126), and Greece (n = 20) from 1990 to 2006. Incidences ranged from 0.68 per 100,000 live-births in France to 1.21 per 100,000 live-births in UK. MPSIIIA, which predominates in France and UK, was absent in Greece, where most patients have MPSIIIB. The study confirmed the large allelic heterogeneity of MPSIIIA and MPSIIIB and detected several yet undescribed mutations. Analysis of clinical manifestations at diagnosis and over a 6-7 years follow-up indicated that almost all patients, whatever the disease subtype, expressed neurological manifestations before the age of 5 years, including language acquisition delay, cognitive delay, and/or abnormal behavior. In contrast to relatively homogeneous early onset manifestations, disease progression showed significant variation depending on subtype and age at diagnosis. Different severities of disease progressions and different allele distribution between France and UK suggested that mutations are not equally deleterious, although genotype-phenotype correlation could not be established. Notwithstanding the rapidity of further clinical deterioration, all MPSIII patients suffer early onset devastating neurological manifestations that deserve early treatment when available.

School performance in a cohort of children with CNS inflammatory demyelination.

BACKGROUND: Acute CNS inflammatory demyelination in childhood may induce permanent cognitive impairment. However, there has been no epidemiological assessment of prognostic factors for school performance in a cohort of children with such a disease. METHODS: The cohort consisted of 344 children from the French "KIDSEP" neuropediatric cohort with at least one clinically defined attack of CNS inflammatory demyelination occurring before the age of 16 years, and with at least two years of follow-up (inclusion from 1990 to 2003, follow-up until June 2007). We used multivariate survival analysis (Cox model) to evaluate the prognostic value for grade retention between the start of elementary school ( approximately 6 years of age) and the end of high school ( approximately 17-18 years of age), of variables related to both the socioeconomic status of the parents and the characteristics of the disease at onset. RESULTS: The cohort was monitored for a mean of 8.0+/-3.4 years. Grade retention after disease onset was recorded for 151 patients (43.9%). The risk of grade retention was significantly higher for boys, children from families with lower social status and poorer housing conditions, children over the age of 11 years at disease onset and children suffering optic neuritis or brainstem dysfunction at the first attack or irreversible disability, even if only moderate, following the first attack. CONCLUSIONS: The risk factors for poor school performance are related to low socioeconomic status and to factors predictive of a relapsing severe course of the disease, leading to the diagnosis of multiple sclerosis.

Combined oral contraceptive use and the risk of systemic lupus erythematosus.

OBJECTIVE: To assess whether the risk of incident systemic lupus erythematosus (SLE) is associated with the use of combined oral contraceptives (COCs), because studies of the link between exogenous hormonal exposure and the risk of SLE have produced conflicting results. METHODS: We conducted a population-based nested case-control study among women ages 18-45 years, using the UK's General Practice Research Database. All incident cases of SLE from 1994-2004 (n = 786) were identified in the database and matched with up to 10 controls (n = 7,817) among women without SLE at the time of the case's diagnosis. RESULTS: The adjusted rate ratio (RR) of incident SLE associated with any use of COC was 1.19 (95% confidence interval [95% CI] 0.98-1.45), whereas with current use it was 1.54 (95% CI 1.15-2.07). The rate was particularly increased in current users who had only recently started COC use (RR 2.52, 95% CI 1.14-5.57) compared with longer-term current users (RR 1.45, 95% CI 1.06-1.99). The risk appeared to be particularly elevated with current exposure to first- or second-generation contraceptives (RR 1.65, 95% CI 1.20-2.26), and increasing with the dose of ethinyl estradiol (RR 1.42, 1.63, and 2.92 for < or =30 microg, 31-49 microg, and 50 microg, respectively). CONCLUSION: The use of COCs is associated with an increased risk of SLE. This risk is particularly elevated in women who recently started contraceptive use, suggesting an acute effect in a small subgroup of susceptible women.