[The new version of the french teratology information service « CRAT ¼ website]. / La nouvelle version du site internet du Centre de Référence sur les Agents Tératogènes et ses fonctionnalités optimisées.

The Centre de Référence sur les Agents Tératogènes (CRAT) is a unique french national reference center involved in the risk assessment of exogenous agents (mainly drugs, but also medical imaging and addictions) on pregnancy, breastfeeding and fertility. To help improve patient care, CRAT makes its expertise available to healthcare professionals via its website (www.lecrat.fr), a free, independent and public online resource regularly updated by its multidisciplinary team. In December 2023, a new version was launched, based on the evolutions desired by the CRAT team and on a satisfaction survey of website's users. A predictive search bar integrated into the home page now enables users to find the specific information they are looking for more quickly. To optimize the access via smartphones, a mobile version is now available.

Post-Conceptional Exposure to Clomiphene Citrate and Congenital Malformations: A Cohort Study.

BACKGROUND: Clomiphene citrate is an ovulation inductor for which inadvertent post-conceptional exposures may occur in early pregnancy. In preclinical studies, post-conceptional exposures showed a teratogenic effect in different species. In humans, to date, little is known about the outcomes of inadvertently post-conceptionally exposed pregnancies. OBJECTIVES: The objectives of our study were to assess the association between post-conceptional exposures to clomiphene citrate and major and minor congenital malformations in the offspring. METHODS: A retrospective cohort study of prospectively ascertained cases was undertaken, based on clinical data from the Centre de Référence sur les Agents Tératogènes (CRAT), Paris, France. Women with post-conceptional exposure to clomiphene citrate (n = 309), and unexposed pregnant women (n = 1236, 1:4 ratio) with prospectively collected data, known pregnancy outcome and delivery date prior to 01/02/2022, were matched by calendar year. An adjudication committee classified major and minor congenital malformations according to the EUROCAT (European Registration of Congenital Anomalies and Twins) classification. RESULTS: Among post-conceptional exposed women, no increased risk of major malformation was found (crude relative risk = 0.64, 95% confidence interval 0.19-2.15) as compared to unexposed women. Three major and ten minor congenital malformations were reported in the exposed group. An increased risk of minor malformations was found (crude relative risk = 4.05, 95% confidence interval 1.70-9.64) although there was no specific clinical pattern. CONCLUSIONS: Post-conceptional exposure to clomiphene citrate was not associated with an increased risk of major congenital malformations. Given potential confounding and information biases, the results about minor malformations should be interpreted with caution as no specific clinical pattern was identified.

[Use of anti-IL-1 drugs during pregnancy]. / État des lieux sur les anti-IL-1 chez la femme enceinte.

Anti-Interleukin-1 (Anti-IL-1) drugs are used to treat some chronic rheumatic diseases that can affect young people, including women of childbearing age. Two anti-IL-1 drugs are available in France: anakinra and canakinumab. Data on their use during pregnancy are still limited. Based on the published literature, we carried out a review of the use of these anti-IL-1 therapies during pregnancy: therapeutic indications, pharmacological profiles and assessment of embryonic, fetal and neonatal risks. Based on this analysis, and given the absence of any reported concern, it is possible to consider the use of these two treatments during pregnancy if the clinical situation so requires and under certain conditions. Based on the data available to date, anakinra should be preferred to canakinumab whenever possible.

[Evaluation of the satisfaction of healthcare professionals using the CRAT website, and launch of a new version]. / Évaluation de la satisfaction des professionnels de santé utilisateurs du site internet du CRAT et lancement d'une nouvelle version.

In preparation for a new version of the CRAT (Centre de référence sur les agents tératogènes) website, an evaluation of user satisfaction was carried out. An invitation to complete an online questionnaire covering the various dimensions of the website (appearance, content, interactivity, ease of use, technical performance) was sent in April 2022 to healthcare professionals who referred to CRAT for clinical expertise over the previous two years. After sending out 3224 individual e-mail invitations, 758 evaluators completed the questionnaire in full (response rate: 23.5%). The evaluation revealed a high-level of overall satisfaction among site users (98.0% very satisfied or satisfied). Satisfaction with the site's appearance was also high, although comments were made about the site's lack of a modern web design. Health professionals recognized in their responses the reliable, relevant and up-to-date nature of the content of this free, public online resource, independent of the pharmaceutical industry. On the basis of these highly favorable assessments, with content that has been widely acclaimed and areas for improvement that have caught the attention of site users (evolution of its appearance, of the search tool, implementation of a mobile site), a new version of www.lecrat.fr was launched in the fall of 2023.

[Varicella vaccination, pregnancy and breastfeeding: The current situation]. / Vaccination contre la varicelle, grossesse et allaitement : un état des lieux.

The varicella vaccine is recommended for women with no history of varicella who are planning to become pregnant, as well as for post-pregnancy women, to prevent the occurrence of this illness and its severe complications, especially an embryopathy, when it occurs in a pregnant woman (congenital varicella syndrome). This live attenuated vaccine should not be administered during pregnancy, nor in the month preceding it. However, when this occurs inadvertently, the data collected on the outcomes of exposed pregnancies, although few in women seronegative at the time of vaccination, allow to reassure the patients to date, as no congenital varicella syndrome has been reported to date following accidental vaccination in early pregnancy. On the other hand, during breastfeeding, a woman may be vaccinated if there is an expected short- or medium-term benefit (varicella exposure, planned pregnancy…).

[Clinical monitoring of children with in utero exposure to angiotensin-converting-enzyme inhibitors and angiotensin II receptor blockers]. / Toxicité fœtale et néonatale des inhibiteurs de l'enzyme de conversion et des sartans : quelle surveillance pour les enfants exposés in utero ?

Angiotensin-converting-enzyme inhibitors and angiotensin II receptor blockers are widely used to reduce high blood pressure or in other conditions such as congestive heart failure and prevention of diabetic nephropathy. To date, no teratogenic effect has been attributed to them, but in the 2nd and 3rd trimesters of pregnancy, their foetotoxicity is broadly documented: transient oligohydramnios or anamnios, associated to possible neonatal anuria and permanent renal damage, which can lead to intrauterine or neonatal death. Long-term effects among children with in utero exposure are poorly known, but the regression of an oligohydramnios might not always be associated with normal renal function after birth or later in life. This justifies seeking the advice of a pediatric nephrologistto consider the most appropriate monitoring for the child at birth and in the following weeks, and possibly beyond, even in case of normal prenatal ultrasound.

Spatio-temporal clustering of amyotrophic lateral sclerosis in France: A population-based study.

OBJECTIVE: To assess spatial aggregates of amyotrophic lateral sclerosis (ALS) incident cases, using a solid geo-epidemiological statistical method, in France. METHODS: This population-based study (2003-2011) investigated 47.1 million person-years of follow-up (PYFU). Case ascertainment of incident ALS cases was based on multiple sources (ALS referral centers, hospital centres and health insurance data). Neurologists confirmed all ALS diagnoses. Exhaustiveness was estimated through capture-recapture. Aggregates were investigated in four steps: (a) geographical modelling (standardized incidence ratio (SIR) calculation), (b) analysis of the spatial distribution of incidence (Phothoff-Winttinghill's test, Global Moran's Index, Kulldorf's spatial scan statistic, Local Moran's Index), (c) classification of the level of certainty of spatial aggregates (i.e. definite cluster; probable over-incidence area; possible over-incidence area) and (d) evaluation of the robustness of the results. RESULTS: The standardized incidence of ALS was 2.46/100,000 PYFU (95% CI 2.31-2.63, European population as reference) based on 1199 incident cases. We identified 13 areas of spatial aggregates: one cluster (stable in robustness analysis), five probable over-incidence areas (2 stable in robustness analysis) and seven possible over-incidence areas (including 4 stable areas in robustness analysis). A cluster was identified in the Rhône-Alpes region: 100 observed vs 54.07 expected cases for 2,411,514 PYFU, SIR: 1.85 (95% CI 1.50-2.25). CONCLUSION: We report here one of the largest investigations of incidence and spatial aggregation of ALS ever performed in a western country. Using a solid methodology framework for case ascertainment and cluster analysis, we identified 13 areas that warrant further investigation.

Corrigendum to Impact of plate shape on the conservation of food praxis in institutionalised elderly adults with severe Alzheimer's disease or mixed dementia: Praxalim an observational before-after non-randomized study.

[This corrects the article DOI: 10.1016/j.ijnsa.2020.100005.].

Time-trend evolution and determinants of sex ratio in Amyotrophic Lateral Sclerosis: a dose-response meta-analysis.

BACKGROUND: A noticeable change of the male-to-female sex ratio (SR) has been observed in Amyotrophic Lateral Sclerosis (ALS) leading to an apparent regression of SR with time (SR close to 1:1). OBJECTIVE: To provide a global SR estimate and investigate its relation with respect to population age. METHODS: A systematic review and meta-analysis was conducted including only population-based studies with a high-quality methodology in European ancestral origin population. Male-to-female SR was estimated by three different measures: SR number, SR crude incidence and SR standardized incidence. Standard and dose-response meta-analyses were performed to assess the pooled SR measures (irrespective of population age) and the evolution of the SR measures with respect to population age, respectively. Potential sources of heterogeneity were investigated via meta-regression. RESULTS: Overall, 3254 articles were retrieved in the literature search. Thirty-nine studies stratified by time periods were included. The overall pooled male-to-female ratio was 1.28 (95% CI 1.23-1.32) for SR number, 1.33 (95% CI 1.29-1.38) for SR crude incidence and 1.35 (95% CI 1.31-1.40) for SR standardized incidence. The SR number with respect to population age reveals a progressive reduction of SR at increasing age, while the SR crude incidence in relation to age displays a U-shaped curve. CONCLUSIONS: The number and the incidence of ALS cases were consistently higher in males than females. Dose-response meta-analysis showed that SR measures change with respect to population age. Further original research is needed to clarify if our findings are reproducible in other populations.

Hypermetabolism is a reality in amyotrophic lateral sclerosis compared to healthy subjects.

RATIONALE: Hypermetabolism (HM) in Amyotrophic lateral sclerosis (ALS) is the reflection of a high energy metabolic level, but this alteration seems controversial. The main objective of the study was to confirm the existence of HM during ALS compared to healthy subjects. METHODS: A cohort of ALS patients was compared to a control group without metabolic disorder. The assessment included anthropometric criteria measurements, body composition by bioelectric impedance analysis and resting energy expenditure (REE) by indirect calorimetry. HM was defined as a variation > +10% between measured and calculated REE. Statistical analysis used Mann-Withney and Chi2 tests. Multivariate analysis included logistic regression. RESULTS: 287 patients and 75 controls were included. The metabolic level was higher in ALS patients (1500 kcal/24 h [1290-1693] vs. 1230 kcal/24 h [1000-1455], p < 0.0001) as well as the REE/fat free mass ratio (33.5 kcal/kg/24 h [30.4-37.8] vs. 28.3 kcal/kg/24 h [26.1-33.6], p < 0.0001). 55.0% of ALS patients had HM vs. 13.3% of controls (p < 0.0001). HM was strongly and positively associated with ALS (OR = 9.50 [4.49-20.10], p < 0.0001). CONCLUSIONS: HM in ALS is a reality, which affects more than half of the patients and is associated with ALS. This work confirms a very frequent metabolic deterioration during ALS. The identification of HM can allow a better adaptation of the patients' nutritional intake.

Comorbidities of epilepsy in low and middle-income countries: systematic review and meta-analysis.

Epilepsy is a major public health concern in low and middle-income countries (LMICs) and comorbidities aggravate the burden associated with the disease. The epidemiology of these comorbidities has not been well described, although, identifying the main comorbidities of epilepsy, and their relative importance, is crucial for improving the quality of care. Comorbidities were defined as disorders coexisting with or preceding epilepsy, or else compounded or directly attributed to epilepsy or to its treatment. A meta-analysis of the proportion of main comorbidities by subcontinent as well as overall was also conducted. Out of the 2,300 papers identified, 109 from 39 countries were included in this systematic review. Four groups of comorbidities were identified: parasitic and infectious diseases (44% of comorbid conditions), somatic comorbidities (37%), psychosocial (11%), as well as psychiatric comorbidities (8%). Heterogeneity was statistically significant for most variables then random effect models were used. The most frequently studied comorbidities were: neurocysticercosis (comorbid proportion: 23%, 95% CI: 18-29), head trauma (comorbid proportion: 9%, 95% CI: 5-15) malnutrition (comorbid proportion: 16%, 95% CI: 28-40), stroke (comorbid proportion: 1.3%, 95% CI: 0.2-7.0), and discrimination for education (comorbid proportion: 34%, 95% CI: 28-40). Many comorbidities of epilepsy were identified in LMICs, most of them being infectious.

Increased resting energy expenditure compared with predictive theoretical equations in amyotrophic lateral sclerosis.

OBJECTIVES: Approximately 50% to 60% of amyotrophic lateral sclerosis (ALS) is characterized by an increase in metabolic rate. The Harris and Benedict (HB) 1919 formula is the equation mainly used to calculate resting energy expenditure (cREE) compared with measured REE (mREE) by indirect calorimetry (IC), but other formulas are also applied in current practice. The present study aimed to assess mREE in patients with ALS compared with 12 cREE formulas and study the relevant threshold of REE variation to screen patients with a higher evolving risk. METHODS: Nutritional assessments and body composition (by bioimpedance analysis) were performed in patients with ALS. mREE was measured by IC, and cREE was calculated using the HB 1919, HB 1984, World Schofield, De Lorenzo, Johnstone, Mifflin, World Health Organization/Food and Agriculture Organization, Owen, Fleisch, Wang, Rosenbaum, and Nelson formulas. Functional and respiratory evolution and survival by log-rank test according to two thresholds of REE variation (10% and 20%) were studied. RESULTS: A total of 315 patients with ALS were included in the study. The median mREE was 1503 kcal/24 h (range, 1290-1698 kcal/24 h), which was higher than all predictive equations (P < 0.0001). Depending on the predictive equation, REE variation >10% and 20% was found in 35.2% to 76.3% and 14.6% to 53.3% of patients with ALS, respectively. Patients with an REE variation >20% with HB 1919 and HB 1984 had a lower survival. Moreover, with this same threshold and the Mifflin formula, patients had higher functional and respiratory evolutions and lower survival. CONCLUSIONS: The increase in metabolic rate is present according to the different cREE formulas used compared with IC. In clinical practice, REE formulas (e.g., HB 1919, HB 1984, or Mifflin) can be used as a reference value compared with IC to screen patients with ALS with an REE variation >20% and a higher evolving risk.

Validity of death certificates in the identification of cases of amyotrophic lateral sclerosis (ALS) in the Limousin region, France. A population-based study.

Objectives: Mortality data have been used as a proxy for amyotrophic lateral sclerosis (ALS) incidence. However, the accuracy of death certificates (DCs) needs to be validated. This study aims to assess the accuracy of DCs in the identification of ALS cases. Methods: This is a retrospective population-based validation study. DC information, provided by the "Centre d'épidémiologie sur les causes médicales de décès", including ICD10 codes for specific cause of death for patients recorded in the French register of ALS cases in the Limousin region (FRALim) and deceased between 2000 and 2011, was assessed. The FRALim register was used as gold standard. Results: In the study period, DCs were available for 197 patients diagnosed with ALS, of whom 185 (93.9%) were correctly identified with an ICD10 code (G12.2) corresponding to ALS. The overall sensitivity was 93.9% (95% CI 89.6-96.8) and the positive predictive value (PPV) was 64.9 (59.1-70.4), with higher values in the period 2004-2011 (75.0-78.9). Stratification for sex, age, and year at death did not show difference in accuracy, except a lower PPV during the first years of observation. Conclusions: DCs identifying subjects with a diagnosis of ALS in the Limousin region, France showed an overall good sensitivity and moderate PPV. The absence of ALS diagnosis as the main and underlying cause of death on DCs highlights the need to use DC in combination with other administrative data to create algorithms with higher accuracy performances.

Predictive formulas for estimation of height in sub-Saharan African older people: A new formula (EPIDEMCA study).

OBJECTIVES: Chumlea's formulas are a way of predicting height from knee height (KHt), including among individuals >60 y of age who cannot stand upright. However, the formulas were developed with white and African American people and have not yet been validated in native Africans >60 y of age. The aims of the study were to assess Chumlea's formulas in older people in central Africa and to propose a new validated formula for the same population. METHODS: Height (MHt) and KHt were measured in a population of individuals >65 y of age from the Republic of Congo and the central African Republic. Predicted height (PHt) was calculated using Chumlea's formulas for the American black population (CBP) and for whites (CC). The percentages of accurate predictions (±5 cm) were compared between MHt and PHt. A new formula was estimated after randomization in a derivation sample (n = 877) and assessed for accuracy in a validation sample (n = 877). RESULTS: The study included 1754 individuals. Prediction was accurate (±5 cm) in 66.8% and 63.2% of CBP and CC, respectively. Overestimation was as high as 24.1% and 29%, respectively. Because an overestimation is unacceptable in clinical practice and population surveys, a new formula was proposed: height (cm) = 72.75 + (1.86 × KHt [cm]) - (0.13 × age [y]) + 3.41 × sex (0: women; 1: men). This new formula significantly increases accuracy (71.3%) and decreases overestimation (14.7%). The nutritional status based on body mass index did not differ with the MHt and the PHt by the new formula. CONCLUSION: Chumlea's formulas provided a poor estimate of height in this population sample. The proposed formula more accurately estimates height in older native Africans. This formula should be tested in other sub-Saharan African countries to extend its use in clinical practice and in future studies.

Predictive factors for gastrostomy at time of diagnosis and impact on survival in patients with amyotrophic lateral sclerosis.

BACKGROUND: Gastrostomy is recommended in patients with Amyotrophic Lateral Sclerosis (ALS) in the presence of weight loss over 10% as compared to usual weight, repeated aspirations or meal time duration longer than 45 min. Currently, the impact of gastrostomy on survival of ALS patients is not clear. AIMS: i) to describe diagnosis factors associated with the indication for gastrostomy ii) to evaluate survival of ALS patients with gastrostomy indication according to their acceptance of feeding tube placement. METHODS: Patients with ALS were included and followed in the ALS referral centre of Limoges's teaching hospital between 2006 and 2017. Neurological, nutritional and respiratory status was assessed prospectively from diagnosis to death. Statistical analysis was performed using Mann-Whitney test, Chi2 tests, Cox model and multivariate logistic regression. RESULTS: Two hundred and eighty-five patients were included. Among the 182 for whom gastrostomy was indicated, 63.7% accepted the placement. The median time was 7.3 months [IQR: 3.2-15.0] and 2.7 months [IQR: 0.9-5.8] respectively from diagnosis to indication and from indication to placement. Weight loss >5% significantly increased the risk of death by 17% (p < 0.0001). At time of diagnosis, bulbar onset, a loss of one point in the body mass index or on the bulbar functional scale were all positively associated with indication for gastrostomy (aOR = 10.0 [95%CI: 1.96-25.0]; p = 0.002, aOR = 1.17 [95%CI: 1.02-1.36]; p = 0.025 and aOR = 1.19 [95%CI: 1.06-1.32]; p = 0.002, respectively). However, gastrostomy placement did not have any impact on survival (aHR = 1.25 [95%CI: 0.88-1.79]; p = 0.22). CONCLUSION: Both neurological and nutritional criteria were associated with an indication for gastrostomy at diagnosis. Gastrostomy placement had no impact on survival. The study of earlier gastrostomy placement might be of interest in further prospective studies.

Cytomegalovirus (CMV) Shedding in French Day-Care Centers: A Nationwide Study of Epidemiology, Risk Factors, Centers' Practices, and Parents' Awareness of CMV.

BACKGROUND: Congenital cytomegalovirus (CMV) remains an important healthcare burden, resulting from primary or secondary infection in pregnant women. Exposure to young children's saliva is a major risk factor, as prevalence of CMV shedding can reach 34%. METHODS: This cross-sectional, multicenter, nationwide study was conducted in randomly selected day care centers (DCCs), and complemented with a survey among parents and DCCs. All children aged >3 months were eligible. The study measured the CMV shedding prevalence in children's saliva and described CMV genotypes epidemiology. The risk factors for CMV shedding and high viral load were evaluated using multivariable models. RESULTS: A total of 93 DCCs participated. Among the 1770 enrolled children with evaluable samples, the CMV shedding prevalence was 40% (713/1770, 95% confidence interval, 34.6-46.1), independently associated with children aged between 12 and 18 months, history of CMV infection in ≥1 parents, a mid-level income. Prevalence increased with DCC staff workload and attending children number. Viral load was ≥5 log-copies CMV/mL in 48% (342/713). Risk factors for higher viral load included children aged between 12 and 18 months, and still being breastfed. The most frequent genotype combinations were gB1-gN4c-gH2 (6.9%), gB1-gN2-gH2 (6.3%), gB4a-gN3a-gH1 (6.3%), and gB1-gN3b-gH2 (5,7%). CMV awareness was low in parents: their serological status was unknown by 72% of mothers and 82% of fathers. Only 41% knew something about CMV. CONCLUSIONS: CMV shedding was independently associated with risk factors related to the children, family and DCC. Some of these risk factors may influence prevention strategies, including through an improved information provided to parents. CLINICAL TRIALS REGISTRATION: NCT01704222.