Medically Assisted Reproduction and Risk of Cancer Among Offspring.

Importance: Cancer is a leading cause of death among children worldwide. Treatments used for medically assisted reproduction (MAR) are suspected risk factors because of their potential for epigenetic disturbance and associated congenital malformations. Objective: To assess the risk of cancer, overall and by cancer type, among children born after MAR compared with children conceived naturally. Design, Setting, and Participants: For this cohort study, the French National Mother-Child Register (EPI-MERES) was searched for all live births that occurred in France between January 1, 2010, and December 31, 2021 (and followed up until June 30, 2022). The EPI-MERES was built from comprehensive data of the French National Health Data System. Data analysis was performed from December 1, 2021, to June 30, 2023. Exposure: Use of assisted reproduction technologies (ART), such as fresh embryo transfer (ET) or frozen ET (FET), and artificial insemination (AI). Main Outcomes and Measures: The risk of cancer was compared, overall and by cancer type, among children born after fresh ET, FET, or AI and children conceived naturally, using Cox proportional hazards regression models adjusted for maternal and child characteristics at birth. Results: This study included 8 526 306 children with a mean (SD) age of 6.4 (3.4) years; 51.2% were boys, 96.4% were singletons, 12.1% were small for gestational age at birth, and 3.1% had a congenital malformation. There were 260 236 children (3.1%) born after MAR, including 133 965 (1.6%) after fresh ET, 66 165 (0.8%) after FET, and 60 106 (0.7%) after AI. A total of 9256 case patients with cancer were identified over a median follow-up of 6.7 (IQR, 3.7-9.6) years; 165, 57, and 70 were born after fresh ET, FET, and AI, respectively. The overall risk of cancer did not differ between children conceived naturally and those born after fresh ET (hazard ratio [HR], 1.12 [95% CI, 0.96 to 1.31]), FET (HR, 1.02 [95% CI, 0.78 to 1.32]), or AI (HR, 1.09 [95% CI, 0.86 to 1.38]). However, the risk of acute lymphoblastic leukemia was higher among children born after FET (20 case patients; HR 1.61 [95% CI, 1.04 to 2.50]; risk difference [RD], 23.2 [95% CI, 1.5 to 57.0] per million person-years) compared with children conceived naturally. Moreover, among children born between 2010 and 2015, the risk of leukemia was higher among children born after fresh ET (45 case patients; HR, 1.42 [95% CI, 1.06 to 1.92]; adjusted RD, 19.7 [95% CI, 2.8 to 43.2] per million person-years). Conclusions and Relevance: The findings of this cohort study suggest that children born after FET or fresh ET had an increased risk of leukemia compared with children conceived naturally. This risk, although resulting in a limited number of cases, needs to be monitored in view of the continuous increase in the use of ART.

Risk of gastrointestinal perforation in patients with rheumatic diseases exposed to janus kinase inhibitors versus adalimumab: nationwide cohort study.

OBJECTIVE: To compare the risk of gastrointestinal perforation (GIP), a rare but serious adverse event, in patients initiating a Janus kinase inhibitor (JAKi; tofacitinib, baricitinib, upadacitinib or filgotinib) versus adalimumab (tumor necrosis factor inhibitor) among a comprehensive real-world population of patients with rheumatic diseases. METHODS: We conducted a nationwide population-based cohort study of the French national health data system, the exposed group initiating a JAKi and the comparison group adalimumab. We included all individuals with a rheumatic disease who had their first dispensation of these treatments from July 2017 to December 2021. The primary endpoint was the occurrence of GIP (end of follow-up May 2022). Weighted hazard ratios (wHRs) were estimated with the inverse probability of treatment weighting method to account for confounding factors. Concomitant administration of systemic corticosteroids, non-steroidal anti-inflammatory drugs and proton pump inhibitors were time-varying variables. RESULTS: The cohort included 39,758 patients: 12,335 and 27,423 in the JAKi and adalimumab groups (mean age 58.2 and 47.3 years; female 76% and 58%; rheumatoid arthritis 85.3% and 27.3%, and psoriatic arthritis/axial spondyloarthritis 14.7% and 72.7%). During follow-up, 38 and 42 GIPs occurred in the JAKi and adalimumab groups, incidence rates were 2.1 (95% CI 1.5-2.8) and 1.1 (0.8-1.5) per 1000 person-years respectively. Rates of GIP did not differ between JAKi and adalimumab groups : wHR 1.1 (95% CI 0.7-1.9) (p=0.65). Despite lack of power in some subgroup analyses, results were consistent whatever the JAKi or rheumatic disease subgroup. CONCLUSION: In this nationwide cohort study, the rates of GIP did not differ between groups of patients initiating JAKi and adalimumab treatment. These results need to be confirmed in other observational studies.

Use of progestogens and the risk of intracranial meningioma: national case-control study.

OBJECTIVE: To assess the risk of intracranial meningioma associated with the use of selected progestogens. DESIGN: National case-control study. SETTING: French National Health Data System (ie, Système National des Données de Santé). PARTICIPANTS: Of 108 366 women overall, 18 061 women living in France who had intracranial surgery for meningioma between 1 January 2009 and 31 December 2018 (restricted inclusion periods for intrauterine systems) were deemed to be in the case group. Each case was matched to five controls for year of birth and area of residence (90 305 controls). MAIN OUTCOME MEASURES: Selected progestogens were used: progesterone, hydroxyprogesterone, dydrogesterone, medrogestone, medroxyprogesterone acetate, promegestone, dienogest, and intrauterine levonorgestrel. For each progestogen, use was defined by at least one dispensation within the year before the index date (within three years for 13.5 mg levonorgestrel intrauterine systems and five years for 52 mg). Conditional logistic regression was used to calculate odds ratio for each progestogen meningioma association. RESULTS: Mean age was 57.6 years (standard deviation 12.8). Analyses showed excess risk of meningioma with use of medrogestone (42 exposed cases/18 061 cases (0.2%) v 79 exposed controls/90 305 controls (0.1%), odds ratio 3.49 (95% confidence interval 2.38 to 5.10)), medroxyprogesterone acetate (injectable, 9/18 061 (0.05%) v 11/90 305 (0.01%), 5.55 (2.27 to 13.56)), and promegestone (83/18 061 (0.5%) v 225/90 305 (0.2 %), 2.39 (1.85 to 3.09)). This excess risk was driven by prolonged use (≥one year). Results showed no excess risk of intracranial meningioma for progesterone, dydrogesterone, or levonorgestrel intrauterine systems. No conclusions could be drawn concerning dienogest or hydroxyprogesterone because of the small number of individuals who received these drugs. A highly increased risk of meningioma was observed for cyproterone acetate (891/18 061 (4.9%) v 256/90 305 (0.3%), odds ratio 19.21 (95% confidence interval 16.61 to 22.22)), nomegestrol acetate (925/18 061 (5.1%) v 1121/90 305 (1.2%), 4.93 (4.50 to 5.41)), and chlormadinone acetate (628/18 061 (3.5%) v 946/90 305 (1.0%), 3.87 (3.48 to 4.30)), which were used as positive controls for use. CONCLUSIONS: Prolonged use of medrogestone, medroxyprogesterone acetate, and promegestone was found to increase the risk of intracranial meningioma. The increased risk associated with the use of injectable medroxyprogesterone acetate, a widely used contraceptive, and the safety of levonorgestrel intrauterine systems are important new findings.

Nonaneurysmal perimesencephalic subarachnoid hemorrhage on noncontrast head CT: An accuracy, inter-rater, and intra-rater reliability study.

BACKGROUND AND PURPOSE: To evaluate the reliability and accuracy of nonaneurysmal perimesencephalic subarachnoid hemorrhage (NAPSAH) on Noncontrast Head CT (NCCT) between numerous raters. MATERIALS AND METHODS: 45 NCCT of adult patients with SAH who also had a catheter angiography (CA) were independently evaluated by 48 diverse raters; 45 raters performed a second assessment one month later. For each case, raters were asked: 1) whether they judged the bleeding pattern to be perimesencephalic; 2) whether there was blood anterior to brainstem; 3) complete filling of the anterior interhemispheric fissure (AIF); 4) extension to the lateral part of the sylvian fissure (LSF); 5) frank intraventricular hemorrhage; 6) whether in the hypothetical presence of a negative CT angiogram they would still recommend CA. An automatic NAPSAH diagnosis was also generated by combining responses to questions 2-5. Reliability was estimated using Gwet's AC1 (κG), and the relationship between the NCCT diagnosis of NAPSAH and the recommendation to perform CA using Cramer's V test. Multi-rater accuracy of NCCT in predicting negative CA was explored. RESULTS: Inter-rater reliability for the presence of NAPSAH was moderate (κG = 0.58; 95%CI: 0.47, 0.69), but improved to substantial when automatically generated (κG = 0.70; 95%CI: 0.59, 0.81). The most reliable criteria were the absence of AIF filling (κG = 0.79) and extension to LSF (κG = 0.79). Mean intra-rater reliability was substantial (κG = 0.65). NAPSAH weakly correlated with CA decision (V = 0.50). Mean sensitivity and specificity were 58% (95%CI: 44%, 71%) and 83 % (95%CI: 72 %, 94%), respectively. CONCLUSION: NAPSAH remains a diagnosis of exclusion. The NCCT diagnosis was moderately reliable and its impact on clinical decisions modest.

Endovascular Parent Vessel Occlusion Versus Flow Diversion in the Treatment of Large and Giant Aneurysms: A Randomized Comparison.

OBJECTIVE: Parent vessel occlusion (PVO) is a time-honored treatment for unclippable or uncoilable intracranial aneurysms. Flow diversion (FD) is a recent endovascular alternative that can occlude the aneurysm and spare the parent blood vessel. Our aim was to compare outcomes of FD with endovascular PVO. METHODS: This is a prespecified treatment subgroup analysis of the Flow diversion in Intracranial Aneurysms trial (FIAT). FIAT was an investigator-led parallel-group all-inclusive pragmatic randomized trial. For each patient, clinicians had to prespecify an alternative management option to FD before stratified randomization. We report all patients for whom PVO was selected as the best alternative treatment to FD. The primary outcome was a composite of core-lab determined angiographic occlusion or near-occlusion at 3-12 months combined with an independent clinical outcome (mRS<3). Primary analyses were intent-to-treat. There was no blinding. RESULTS: There were 45 patients (16.2% of the 278 FIAT patients randomized between 2011 and 2020 in 3 centers): 22 were randomly allocated to FD and 23 to PVO. Aneurysms were mainly large or giant (mean 22 mm) anterior circulation (mainly carotid) aneurysms. A poor primary outcome was reached in 11/22 FD (50.0%) compared to 9/23 PVO patients (39.1%) (RR: 1.28, 95% CI [0.66-2.47]; P = 0.466). Morbidity (mRS >2) at 1 year occurred in 4/22 FD and 6/23 PVO patients. Angiographic results and serious adverse events were similar. CONCLUSIONS: The comparison between PVO and FD was inconclusive. More randomized trials are needed to better determine the role of FD in large aneurysms eligible for PVO.

Safety of Vedolizumab and Ustekinumab Compared With Anti-TNF in Pregnant Women With Inflammatory Bowel Disease.

BACKGROUND & AIMS: Limited data are available on the consequences of prenatal exposure to vedolizumab and ustekinumab. We aimed to compare the safety of vedolizumab and ustekinumab with that of anti-tumor necrosis factor (TNF) in pregnant women with inflammatory bowel diseases (IBD). METHODS: Using nationwide, comprehensive data of the EPI-MERES registry, we identified pregnancies in women with IBD in France, exposed to anti-TNF, vedolizumab, and ustekinumab between 2014 and 2021. We compared pregnancy outcomes and complications in the offspring according to treatment exposure during pregnancy. We applied a propensity score matching for maternal, IBD, and pregnancy characteristics. RESULTS: Three hundred ninety-eight pregnancies exposed to vedolizumab were compared with 1592 pregnancies exposed to anti-TNF; 464 pregnancies exposed to ustekinumab were compared with 1856 pregnancies exposed to anti-TNF. Overall, compared with anti-TNF, neither vedolizumab nor ustekinumab was associated with increased risks of abortion, caesarean section, stillbirth, preterm birth, serious infections, malignancies, or congenital abnormality in children. Women exposed to ustekinumab had an increased risk of small for gestational age births. CONCLUSIONS: Overall, the safety of vedolizumab and ustekinumab compared with anti-TNF use during pregnancy is reassuring. Further studies are needed to confirm these findings.

Cross-sectional study examining factors impacting on uptake of postpartum type 2 diabetes screening among women diagnosed with hyperglycaemia in pregnancy.

AIMS: Early postpartum glucose screening of women with hyperglycaemia in pregnancy (HIP) can identify women who have the highest risk of developing impaired glucose tolerance and T2DM. This study examines the association between demographics, events during pregnancy, socioeconomic status and postpartum T2DM screening. METHODS: Using the French National Health Data System, this cross-sectional study included all deliveries where the mother had HIP in France in 2015, (n = 76,862). The odds ratio (OR) for attending postpartum screening was calculated via multi-level logistic regression. RESULTS: T2DM screening uptake at six months postpartum was 42·9% [95 % Confidence Interval: 42·6-43·3]. Several characteristics were associated with lower uptake: living in the most deprived area(OR = 0·78[0·74-0·83]); being < 25 years-old (reference age group 25-29;≤17: 0.53 [0·31-0·90];18-24: 0.73[0·69-0·78]); smoking (0·65[0·62-0·68]); obesity (0·93[0·89-0·97]); caesarean delivery (0·95[0·92-0·99]). Factors associated with higher uptake included primiparity (1·30[1·26-1·34]); having followed the French recommendations for HIP screening (1·24[1·20-1·28]); insulin prescription (1·75[1·69-1·81]) and pre-eclampsia (1·30[1·19-1·42]). p < 0.01 is justified due to sample size. CONCLUSION: Improving identification of factors affecting postpartum T2DM screening uptake, such as demographics, socioeconomic context and events during pregnancy, may lead to development of target interventions to aide adherence to screening regime and thereby diagnosis of women with prediabetes or diabetes, for whom secondary and tertiary prevention is crucial.

Pregnancy outcomes in women with rheumatoid arthritis: an 11-year French nationwide study.

BACKGROUND: Rheumatoid arthritis (RA) can affect women of childbearing age. The management of patients with RA during pregnancy has evolved over the past decades, especially with the availability of new therapeutic molecules. OBJECTIVES: To describe pregnancy in women with RA, to compare pregnancy outcomes with those of women in the general population and to compare pregnancy outcomes in women with active and inactive RA. METHODS: Using the French National Health Data System, we identified all pregnancies ending between 2010 and 2020 in patients with and without RA. Characteristics were described. Active RA was defined by conventional synthetic/biological/targeted synthetic disease-modifying antirheumatic drug initiation, systemic or intra-articular corticosteroid administration and/or RA-related hospitalisation. Pregnancy outcomes were compared computing multivariable logistic marginal regression model using generalised estimating equation (GEE). RESULTS: We included 11 792 RA and 10 413 681 non-RA pregnancies. Among RA pregnancies, 74.5% ended in live births and 0.4% in stillbirths. RA pregnancies resulted more frequently in preterm births (adjusted OR (ORa) 1.84; 95% CI 1.69 to 2.00) and very preterm births (ORa 1.43; 95% CI 1.20 to 1.71), low birth weight (ORa 1.65; 95% CI: 1.52 to 1.90), caesarean section (ORa 1.46; 95% CI 1.38 to 1.55) and pregnancy-related hospitalisation (ORa 1.30; 95% CI 1.22 to 1.39). Disease activity decreased during pregnancy. Active RA had higher rates of prematurity (ORa 2.02; 95% CI 1.71 to 2.38), small for gestational age (ORa 1.53; 95% CI 1.28 to 1.83) and caesarean section (ORa 1.25; 95% CI 1.11 to 1.40) than non-active RA. CONCLUSION: Pregnancies in women with RA were associated with more adverse outcomes, especially if the disease was active. These findings should encourage physicians to closely monitor RA during this crucial period.

Maternal and neonatal outcomes according to the timing of diagnosis of hyperglycaemia in pregnancy: a nationwide cross-sectional study of 695,912 deliveries in France in 2018.

AIMS/HYPOTHESIS: We aimed to assess maternal-fetal outcomes according to various subtypes of hyperglycaemia in pregnancy. METHODS: We used data from the French National Health Data System (Système National des Données de Santé), which links individual data from the hospital discharge database and the French National Health Insurance information system. We included all deliveries after 22 gestational weeks (GW) in women without pre-existing diabetes recorded in 2018. Women with hyperglycaemia were classified as having overt diabetes in pregnancy or gestational diabetes mellitus (GDM), then categorised into three subgroups according to their gestational age at the time of GDM diagnosis: before 22 GW (GDM<22); between 22 and 30 GW (GDM22-30); and after 30 GW (GDM>30). Adjusted prevalence ratios (95% CI) for the outcomes were estimated after adjusting for maternal age, gestational age and socioeconomic status. Due to the multiple tests, we considered an association to be statistically significant according to the Holm-Bonferroni procedure. To take into account the potential immortal time bias, we performed analyses on deliveries at ≥31 GW and deliveries at ≥37 GW. RESULTS: The study population of 695,912 women who gave birth in 2018 included 84,705 women (12.2%) with hyperglycaemia in pregnancy: overt diabetes in pregnancy, 0.4%; GDM<22, 36.8%; GDM22-30, 52.4%; and GDM>30, 10.4%. The following outcomes were statistically significant after Holm-Bonferroni adjustment for deliveries at ≥31 GW using GDM22-30 as the reference. Caesarean sections (1.54 [1.39, 1.72]), large-for-gestational-age (LGA) infants (2.00 [1.72, 2.32]), Erb's palsy or clavicle fracture (6.38 [2.42, 16.8]), preterm birth (1.84 [1.41, 2.40]) and neonatal hypoglycaemia (1.98 [1.39, 2.83]) were more frequent in women with overt diabetes. Similarly, LGA infants (1.10 [1.06, 1.14]) and Erb's palsy or clavicle fracture (1.55 [1.22, 1.99]) were more frequent in GDM<22. LGA infants (1.44 [1.37, 1.52]) were more frequent in GDM>30. Finally, women without hyperglycaemia in pregnancy were less likely to have preeclampsia or eclampsia (0.74 [0.69, 0.79]), Caesarean section (0.80 [0.79, 0.82]), pregnancy and postpartum haemorrhage (0.93 [0.89, 0.96]), LGA neonate (0.67 [0.65, 0.69]), premature neonate (0.80 [0.77, 0.83]) and neonate with neonatal hypoglycaemia (0.73 [0.66, 0.82]). Overall, the results were similar for deliveries at ≥37 GW. Although the estimation of the adjusted prevalence ratio of perinatal death was five times higher (5.06 [1.87, 13.7]) for women with overt diabetes, this result was non-significant after Holm-Bonferroni adjustment. CONCLUSIONS/INTERPRETATION: Compared with GDM22-30, overt diabetes, GDM<22 and, to a lesser extent, GDM>30 were associated with poorer maternal-fetal outcomes.

COVID-19 Hospitalization in Solid Organ Transplant Recipients on Immunosuppressive Therapy.

Importance: Solid organ transplant recipients are at high risk of severe infection with SARS-CoV-2 compared with the general population. However, factors associated with COVID-19-related severity in this population are still insufficiently explored in the literature. Objective: To examine which health conditions and immunosuppressive drugs for preventing graft rejection are associated with the risk of COVID-19-related hospitalization in solid organ transplant recipients. Design, Setting, and Participants: Using the French National Health Data System, this cohort study assessed patients of any age who received transplants between their date of birth and entry into the cohort on February 15, 2020. The cohort was followed up between February 15, 2020, and July 31, 2022. Exposures: Immunosuppressive drugs, including steroids, and health conditions (age, sex, and comorbidities). Main Outcomes and Measures: The main outcome was hospitalization for COVID-19, defined by main diagnostic International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes. Factors associated with the outcome were identified with a nonconditional logistic regression. Confounding by indication was controlled using a multivariable model with adjustment for individual confounders. Each transplanted organ was examined separately. Results: Overall, 60 456 participants (median [IQR] age, 59 [47-67] years; 63.7% male) were included in the study, of whom 41 463 (68.6%) had kidney transplants, 14 464 (23.9%) had liver transplants, 5327 (8.8%) had heart transplants, and 2823 (4.6%) had lung transplants. Among them, 12.7% of kidney transplant recipients, 6.4% of liver transplant recipients, 12.9% of heart transplant recipients, and 18.0% of lung transplant recipients were hospitalized for COVID-19. In kidney transplant recipients, steroids (adjusted odds ratio [AOR], 1.60; 95% CI, 1.49-1.73) and mycophenolic acid (AOR, 1.37; 95% CI, 1.25-1.51) were associated with a high risk of hospitalization. In liver transplant recipients, tacrolimus (AOR, 0.77; 95% CI, 0.61-0.98) was associated with a decreased risk, and steroids (AOR, 1.60; 95% CI, 1.38-1.86) and mycophenolic acid (AOR, 1.61; 95% CI, 1.37-1.90) were associated with an increased risk of hospitalizations. In heart transplant recipients, cyclosporine (AOR, 0.67; 95% CI, 0.47-0.94) was associated with a decreased risk, and steroids (AOR, 1.42; 95% CI, 1.11-1.82), mycophenolic acid (AOR, 1.29; 95% CI, 1.02-1.64), sirolimus (AOR, 2.71; 95% CI, 1.20-6.09), and everolimus (AOR, 1.24; 95% CI, 1.01-1.51) were associated with an increased risk of hospitalization. Only steroids (AOR, 1.72; 95% CI, 1.19-2.48) were associated with a high risk of COVID-19 hospitalization in lung transplant recipients. Conclusions and Relevance: This study suggests that mycophenolic acid, sirolimus, and steroids are associated with an increased risk of COVID-19-related hospitalization in solid organ transplant recipients. These results should be considered by clinicians treating transplant recipients and may help inform epidemic-related decisions for this population in the future.

Risk of Guillain-Barré Syndrome Following COVID-19 Vaccines: A Nationwide Self-Controlled Case Series Study.

BACKGROUND AND OBJECTIVES: Guillain-Barré syndrome (GBS) has been inconsistently associated with some coronavirus disease 2019 (COVID-19) vaccines. We aimed to quantify the risk of GBS according to the type of COVID-19 vaccine in a large population. METHODS: Using the French National Health Data System linked to the COVID-19 vaccine database, we analyzed all individuals aged 12 years or older admitted for GBS from December 27, 2020, to May 20, 2022. We estimated the relative incidence (RI) of GBS within 1-42 days after vaccination up to the first booster dose compared with baseline periods using a self-controlled case series design. We then derived the number of cases attributable to the vaccination. Analyses were adjusted for the period and stratified by age group, sex, and for the presence of severe acute respiratory syndrome coronavirus 2 or common acute infections. RESULTS: Of 58,530,770 people aged 12 years or older, 88.8% received at least 1 COVID-19 vaccine dose and 2,229 were hospitalized for GBS during the study period. Patients had a median age of 57 years, and 60% were male patients. The RI of GBS between 1-42 days was 2.5 (95% CI 1.8-3.6) for the first dose of ChAdOx1-S and 2.4 (95% CI 1.2-5.0) for the unique dose of Ad26.COV2.S vaccine. We estimated 6.5 attributable GBS cases per million persons having received a first dose of ChAdOx1-S and 5.7 cases per million for the Ad26.COV2.S vaccine. Except for the age group of 12-49 years after the second dose of the messenger RNA (mRNA)-1273 vaccine (RI 2.6, 95% CI 1.2-5.5), none of the RI estimates were found significantly increased for the mRNA vaccines. DISCUSSION: In summary, we found increased risks of GBS after the first administration of ChAdOx1-S and Ad26.COV2.S vaccines. In this comprehensive assessment at the French population level, there was no statistically significant increase in the risk of GBS after the administration of mRNA vaccines. This is reassuring in the context of the ongoing and future use of mRNA-based booster vaccination.

Protection of COVID-19 Vaccination Against Hospitalization During the Era of Omicron BA.4 and BA.5 Predominance: A Nationwide Case-Control Study Based on the French National Health Data System.

Background: Knowing the duration of effectiveness of coronavirus disease 2019 (COVID-19) booster doses is essential to providing decision-makers with scientific arguments about the frequency of subsequent injections. We estimated the level of protection against COVID-19-related hospitalizations (Omicron BA.4-BA.5) over time after vaccination, accounting for breakthrough infections. Methods: In this nationwide case-control study, all cases of hospitalizations for COVID-19 identified in the comprehensive French National Health Data System between June 1, 2022, and October 15, 2022, were matched with up to 10 controls by year of birth, sex, department, and an individual COVID-19 hospitalization risk score. Conditional logistic regressions were used to estimate the level of protection against COVID-19-related hospitalizations conferred by primary and booster vaccination, accounting for history of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Results: A total of 38 839 cases were matched to 377 653 controls; 19.2% and 9.9% were unvaccinated, respectively, while 68.2% and 77.7% had received ≥1 booster dose. Protection provided by primary vaccination reached 45% (95% CI, 42%-47%). The incremental effectiveness of booster doses ranged from 69% (95% CI, 67%-71%; ≤2 months) to 22% (95% CI, 19%-25%; ≥6 months). Specifically, the second booster provided an additional protection compared with the first ranging from 61% (95% CI, 59%-64%; ≤2 months) to 7% (95% CI, 2%-13%; ≥4 months). Previous SARS-CoV-2 infection conferred a strong, long-lasting protection (51% ≥20 months). There was no incremental effectiveness of a second booster among individuals infected since the first booster. Conclusions: In the era of Omicron BA.4 and BA.5 predominance, primary vaccination still conferred protection against COVID-19 hospitalization, while booster doses provided an additional time-limited protection. The second booster had no additional protection in case of infection since the first booster.

Prevalence and associated factors of antibiotic exposure during pregnancy in a large French population-based study during the 2010-19 period.

BACKGROUND: Although bacterial infections are frequent during pregnancy, the prescription of antibiotics to pregnant women represents a challenge for physicians, driven by the benefit-risk balance. OBJECTIVES: To assess the extent of prenatal antibiotic exposure and its associated factors. METHODS: This study included pregnancies in the National Mother-Child EPI-MERES Register 2010-19 (built from the French Healthcare Data System) regardless of outcome. Antibiotic exposure was defined as having at least one antibiotic prescription filled during pregnancy. The prevalence of pregnancies exposed to antibiotics was estimated. Univariable Poisson regression with generalized estimating equations was used to compare the number of antibiotic prescriptions filled during pregnancy and the period after pregnancy with the period 1 year before pregnancy. Multivariable Poisson regression was used to investigate factors associated with antibiotic exposure during pregnancy. RESULTS: Among 9 769 764 pregnancies, 3 501 294 (35.8%) were exposed to antibiotics and amoxicillin was the most common. Compared with a similar period 1 year before pregnancy, the number of filled antibiotic prescriptions was lower during pregnancy [incidence rate ratio (IRR) 0.903 (95% CI 0.902-0.905)] and during the period 1 year after pregnancy [IRR 0.880 (95% CI 0.879-0.881)]. Region of residence, deprivation index, smoking-related conditions and chronic diseases (especially chronic respiratory diseases) were associated with antibiotic exposure during pregnancy. CONCLUSIONS: Antibiotic prescriptions are filled less frequently during pregnancy than during the preceding year. This may be due to a more relevant benefit-risk assessment. Pregnant women living with social deprivation, those with smoking-related conditions and those with chronic diseases are more likely to fill antibiotic prescriptions.

Persistence of second-line biologics in psoriasis after first-line biologic failure: a nationwide cohort study from the French health insurance database (SNDS).

BACKGROUND: Many biologics are available for psoriasis and have been compared in real-life studies based on their persistence (i.e. time between initiation and discontinuation). However, after first-line biologic failure, data are lacking on the choice of second-line biologic among the four available classes [tumour necrosis factor inhibitors (TNFi); interleukin (IL)-12/IL-23 inhibitor (IL-12/IL-23i); IL-17 inhibitors (IL-17i); and IL-23 inhibitors (IL-23i)]. OBJECTIVES: To compare the long-term persistence of available second-line biologics in psoriasis according to prior exposure. METHODS: This nationwide cohort study involved the administrative healthcare database of the French health insurance scheme linked to a hospital discharge database. Participants were adults with psoriasis, defined as having at least two prescriptions of a topical vitamin D derivative within a 2-year period, with initiation of a second-line biologic between 1 January 2015 and 31 December 2021. We included patients who initiated a second-line biologic directly after first-line discontinuation (i.e. without a 'washout' period). The end of follow-up was 30 June 2022. Discontinuation was defined as > 90 days without filling a prescription for the same treatment after the period covered by the previous prescription. Comparison of persistence by biologic class involved using propensity score-weighted Cox models (inverse probability treatment weighting) and adjustment of specific systemic nonbiologics (time-dependent variables). RESULTS: We included 8693 patients [mean (SD) age 50 (14) years; 50.5% male]; 2824 (32.5%) started TNFi, 1561 (18.0%) IL-12/IL-23i, 2707 (31.1%) IL-17i and 1601 (18.4%) IL-23i. Overall, 1- and 3-year persistence rates were 60% and 30%, respectively. After weighting and adjustment, persistence was longer with IL-12/IL-23i [weighted hazard ratio (HRw) 0.68, 95% confidence interval (CI) 0.62-0.76)], IL-17i (HRw 0.70, 95% CI 0.64-0.78) and IL-23i (HRw 0.36, 95% CI 0.31-0.42) than TNFi, except after first-line IL-17i treatment, with no difference between IL-12/IL-23i, IL-17i and TNFi second-line persistence. Persistence was longer with IL-23i as a second-line treatment than IL-12/IL-23i (HRw 0.53, 95% CI 0.44-0.63) and IL-17i (HRw 0.51, 95% CI 0.44-0.60), regardless of first-line treatment, with no difference seen between IL-12/IL-23i and IL-17i (HRw 0.97, 95% CI 0.87-1.09). CONCLUSIONS: This real-life study suggests the longer persistence of IL-23i than TNFi, IL-17i and IL-12/IL-23i as second-line treatment for psoriasis. Persistence rates for all biologics remained low at 3 years.

Severe SARS-CoV-2 infection as a marker of undiagnosed cancer: a population-based study.

No study has yet investigated if a severe SARS-CoV-2 infection represents a marker of an undiagnosed cancer. This population-based study, using the SNDS database, identified from 02/15/2020 to 08/31/2021, 41,302 individuals hospitalized in intensive care unit due to SARS-CoV-2 (ICU-gr) and 713,670 control individuals not hospitalized for SARS-CoV-2 (C-gr). Individuals were matched according to year of birth, sex and French department. The cancer incidence was compared in the two groups during the follow-up period (index date-12/31/2021), using Cox proportional hazards models adjusted on matching variables, socioeconomic characteristics and comorbidities. In the ICU-gr, 2.2% (n = 897) was diagnosed with a cancer in the following months, compared to 1.5% (n = 10,944) in the C-gr. The ICU-gr had a 1.31 higher risk of being diagnosed with a cancer following hospital discharge compared to the C-gr (aHR 1.31, 95% CI 1.22-1.41). A global similar trend was found when competing risk of death was taken into account (aHR 1.25, 95% CI 1.16-1.34). A significant higher risk was found concerning renal (aHR 3.16, 95% CI 2.33-4.27), hematological (aHR 2.54, 95% CI 2.07-3.12), colon (aHR 1.72, 95% CI 1.34-2.21), and lung (aHR 1.70, 95% CI 1.39-2.08) cancers. This suggests that a severe SARS-CoV-2 infection may represent a marker of an undiagnosed cancer.

Endovascular treatment of brain arteriovenous malformations: clinical outcomes of patients included in the registry of a pragmatic randomized trial.

OBJECTIVE: The role of endovascular treatment in the management of patients with brain arteriovenous malformations (AVMs) remains uncertain. AVM embolization can be offered as stand-alone curative therapy or prior to surgery or stereotactic radiosurgery (SRS) (pre-embolization). The Treatment of Brain AVMs Study (TOBAS) is an all-inclusive pragmatic study that comprises two randomized trials and multiple registries. METHODS: Results from the TOBAS curative and pre-embolization registries are reported. The primary outcome for this report is death or dependency (modified Rankin Scale [mRS] score > 2) at last follow-up. Secondary outcomes include angiographic results, perioperative serious adverse events (SAEs), and permanent treatment-related complications leading to an mRS score > 2. RESULTS: From June 2014 to May 2021, 1010 patients were recruited in TOBAS. Embolization was chosen as the primary curative treatment for 116 patients and pre-embolization prior to surgery or SRS for 92 patients. Clinical and angiographic outcomes were available in 106 (91%) of 116 and 77 (84%) of 92 patients, respectively. In the curative embolization registry, 70% of AVMs were ruptured, and 62% were low-grade AVMs (Spetzler-Martin grade I or II), while the pre-embolization registry had 70% ruptured AVMs and 58% low-grade AVMs. The primary outcome of death or disability (mRS score > 2) occurred in 15 (14%, 95% CI 8%-22%) of the 106 patients in the curative embolization registry (4 [12%, 95% CI 5%-28%] of 32 unruptured AVMs and 11 [15%, 95% CI 8%-25%] of 74 ruptured AVMs) and 9 (12%, 95% CI 6%-21%) of the 77 patients in the pre-embolization registry (4 [17%, 95% CI 7%-37%] of 23 unruptured AVMs and 5 [9%, 95% CI 4%-20%] of 54 ruptured AVMs) at 2 years. Embolization alone was confirmed to occlude the AVM in 32 (30%, 95% CI 21%-40%) of the 106 curative attempts and in 9 (12%, 95% CI 6%-21%) of 77 patients in the pre-embolization registry. SAEs occurred in 28 of the 106 attempted curative patients (26%, 95% CI 18%-35%, including 21 new symptomatic hemorrhages [20%, 95% CI 13%-29%]). Five of the new hemorrhages were in previously unruptured AVMs (n = 32; 16%, 95% CI 5%-33%). Of the 77 pre-embolization patients, 18 had SAEs (23%, 95% CI 15%-34%), including 12 new symptomatic hemorrhages [16%, 95% CI 9%-26%]). Three of the hemorrhages were in previously unruptured AVMs (3/23; 13%, 95% CI 3%-34%). CONCLUSIONS: Embolization as a curative treatment for brain AVMs was often incomplete. Hemorrhagic complications were frequent, even when the specified intent was pre-embolization before surgery or SRS. Because the role of endovascular treatment remains uncertain, it should preferably, when possible, be offered in the context of a randomized trial.

Suicidal risk associated with finasteride versus dutasteride among men treated for benign prostatic hyperplasia: nationwide cohort study.

Finasteride, a 5α-reductase inhibitor used in benign prostatic hyperplasia and androgenetic alopecia, has been associated with an increased suicidal risk, whereas it is unclear whether such risk is similar to that for another 5α-reductase inhibitor, dutasteride. We aimed to assess the risk of suicidal behaviours with finasteride relative to dutasteride. A nationwide cohort study was conducted using the French National Health Data System (SNDS). Men aged 50 years or older initiating finasteride 5 mg or dutasteride 0.5 mg in France between 01-01-2012 and 30-06-2016 were included and followed until outcome (suicide death identified from death certificate or self-harm hospitalisation), treatment discontinuation or switch, death, or 31-12-2016. Self-harm by violent means or resulting in admission to an intensive care unit were also examined. Cox proportional hazards models controlled for age and psychiatric and non-psychiatric conditions by inverse probability of treatment weighting (IPTW). Analyses were stratified according to psychiatric history. The study compared 69,786 finasteride new users to 217,577 dutasteride new users (median age: 72.0 years [Q1-Q3 = 64.5-80.2] vs. 71.1 [Q1-Q3 = 65.0-79.2]). During follow-up, 18 suicide deaths (0.57/1000 person-years) and 34 self-harm hospitalisations (1.08/1000) occurred among finasteride users versus 47 deaths (0.43/1000) and 87 hospitalisations (0.79/1000) among dutasteride users. Overall, finasteride was not associated with an increased risk of any suicidal outcome (IPTW-adjusted Hazard Ratio = 1.21 [95% Confidence Interval .87-1.67]), suicide death or self-harm hospitalisation. However, among individuals with a history of mood disorders, finasteride was associated with an increased risk of any suicidal outcome (25 versus 46 events; HR = 1.64 [95% CI 1.00-2.68]), suicide death (8 versus 10 events; HR = 2.71 [95% CI 1.07-6.91]), self-harm by violent means (6 versus 6 events; HR = 3.11 [95% CI 1.01-9.61]), and self-harm with admission to an intensive care unit (7 versus 5 events; HR = 3.97 [95% CI 1.26-12.5]). None of these risks was significantly increased among individuals without a psychiatric history. These findings do not support an increased risk of suicide with finasteride used in the treatment of benign prostatic hyperplasia. However, an increased risk cannot be excluded among men with a history of mood disorder, but this result based on a limited number of events should be interpreted with caution.

Opposed evolution of the osseous and soft parts of progestin-associated osteomeningioma after progestin intake discontinuation.

OBJECTIVE: Numerous studies have confirmed a strong association between progestins and meningiomas and the regression and/or stabilization of meningiomas after discontinuation of treatment. Osteomeningiomas represent a small subgroup of meningiomas that appear to be more common among progestin-related meningiomas. However, the specificity of the behavior of this subset of meningiomas after discontinuation of progestin has not yet been assessed. METHODS: Thirty-six patients (mean age 49.5 years) who presented with at least one progestin-related osteomeningioma (48 tumors total) were identified from a prospectively collected database of patients and had been referred to our department for meningioma and had documented use of cyproterone acetate, nomegestrol acetate, and/or chlormadinone acetate. Hormonal treatment was stopped at the time of diagnosis for all the patients, and the clinical and radiological evolution of this subgroup of tumors was evaluated. RESULTS: For half of the 36 patients, treatment was prescribed for signs of hyperandrogenism, such as hirsutism, alopecia, or acne. Most lesions were spheno-orbital (35.4%) or frontal (31.2%). Although the tissular part of the meningioma shrank in 77.1% of cases, the osseous part exhibited discordant behavior with 81.3% showing volume progression. The combination of estrogens, as well as the prolonged duration of progestin treatment, seems to increase the risk of progression of the osseous part after treatment discontinuation (p = 0.02 and p = 0.028, respectively). No patient required surgical treatment at diagnosis or during the study. CONCLUSIONS: These results show that while the soft intracranial part of progestin-related osteomeningioma tumor is the most likely to regress after treatment discontinuation, the bony part is more likely to increase in volume. These findings suggest the need for careful follow-up of these patients, especially those with tumors near the optical apparatus.

Patient Selection in a Pragmatic Study on the Management of Patients with Brain Arteriovenous Malformations.

BACKGROUND: The Treatment of Brain Arteriovenous Malformations Study (TOBAS) is an all-inclusive pragmatic study comprising 2 randomized clinical trials (RCTs). Patients excluded from the RCTs are followed in parallel treatment and observation registries, allowing a comparison between RCT and registry patients. METHODS: The first randomized clinical trial (RCT-1) offers 1:1 randomized allocation of intervention versus conservative management for patients with arteriovenous malformation (AVM). The second randomized clinical trial (RCT-2) allocates 1:1 pre-embolization or no pre-embolization to surgery or radiosurgery patients judged treatable with or without embolization. Characteristics of RCT patients are reported and compared to registry patients. RESULTS: From June 2014 to May 2021, 1010 patients with AVM were recruited; 498 patients were observed and 373 were included in the treatment registries. Randomized allocation in RCT-1 was applied to 139 (26%) of the 512 patients (including 127 of 222 [57%] with unruptured AVMs) considered for curative treatment. RCT-1 AVM patients differed (in rupture status, Spetzler-Martin grade and baseline modified Rankin Score) from those in the observation or treatment registries (P < 0.001). Most patients had small (<3 cm; 71%) low-grade (Spetzler-Martin I-II; 64%) unruptured (91%) AVMs. The allocated management was conservative (n = 71) or curative (n = 68), using surgery (n = 39), embolization (n = 16), or stereotactic radiosurgery (n = 13). Pre-embolization was considered for 179/309 (58%) patients allocated/assigned to surgery or stereotactic radiosurgery; 87/179 (49%) were included in RCT-2. RCT-2 patient AVMs differed in size, eloquence and grade from patients of the pre-embolization registry (P < 0.01). Most had small (<3 cm in 82%) low-grade (83%) AVMs in non-eloquent brain (64%). CONCLUSIONS: Patients included in the RCTs differ significantly from registry patients. Meaningful results can be obtained if multiple centers actively participate in the TOBAS RCTs.