Neurodevelopmental outcomes after prenatal exposure to lamotrigine monotherapy in women with epilepsy: a systematic review and meta-analysis.

BACKGROUND: Lamotrigine has become one of the most commonly prescribed antiseizure medications (ASM) in epileptic women during pregnancy and therefore requires regular updates regarding its safety. The aim of this study was to estimate the association between in utero exposure to lamotrigine monotherapy and the occurrence of neurodevelopmental outcomes. METHODS: All comparative studies assessing the occurrence of neurodevelopmental outcomes after epilepsy-indicated lamotrigine monotherapy exposure during pregnancy were searched. First, references were identified through a snowballing approach, then, through electronic databases (Medline and Embase) from 2015 to June 2022. One investigator evaluated study eligibility and extracted data and a second independent investigator reviewed the meta-analysis (MA). A systematic review and random-effects model approach were performed using a collaborative WEB-based meta-analysis platform (metaPreg.org) with a registered protocol (osf.io/u4gva). RESULTS: Overall, 18 studies were included. For outcomes reported by at least 4 studies, the pooled odds ratios and 95% confidence interval obtained with the number of exposed (N1) and unexposed children (N0) included were: neurodevelopmental disorders as a whole 0.84 [0.66;1.06] (N1 = 5,271; N0 = 22,230); language disorders or delay 1.16 [0.67;2.00] (N1 = 313; N0 = 506); diagnosis or risk of ASD 0.97 [0.61;1.53] (N1 = at least 5,262; N0 = 33,313); diagnosis or risk of ADHD 1.14 [0.75;1.72] (N1 = at least 113; N0 = 11,530) and psychomotor developmental disorders or delay 2.68 [1.29-5.56] (N1 = 163; N0 = 220). The MA of cognitive outcomes included less than 4 studies and retrieved a significant association for infants exposed to lamotrigine younger than 3 years old but not in the older age groups. CONCLUSION: Prenatal exposure to lamotrigine monotherapy is not found to be statistically associated with neurodevelopmental disorders as a whole, language disorders or delay, diagnosis or risk of ASD and diagnosis or risk of ADHD. However, the MA found an increased risk of psychomotor developmental disorders or delay and cognitive developmental delay in less than 3 years old children. Nevertheless, these findings were based exclusively on observational studies presenting biases and on a limited number of included children. More studies should assess neurodevelopmental outcomes in children prenatally exposed to lamotrigine.

Use of proton pump inhibitors during pregnancy: A systematic review and meta-analysis of congenital malformations.

Use of proton pump inhibitors (PPI) are common among pregnant women to relieve gastrointestinal symptoms. The number of exposed pregnancies is therefore considerable, and a recent meta-analysis (MA) from 2020 raised concern about their teratogenicity. The aim of the study was to provide a MA of the risk of major congenital malformations (MCM) after PPI exposure during the first trimester of pregnancy. A systematic review and random-effects model approach were performed using a collaborative WEB-based meta-analysis platform (metaPreg.org) with a registered protocol (osf.io/u4gva). The primary outcome was the incidence of overall MCM. The secondary outcomes of interest were specific MCM reported by at least three studies. All comparative studies assessing these outcomes in PPI exposed pregnancies were searched from inception to April 2022. From the 211 initially identified studies, 11 were included in the MA. The pooled odds ratio (OR) for the primary outcome showed no significant results based on 5 618 exposed pregnancies (OR 1.10, 95% CI [0.95;1.26]; I²=0%). Similarly, no result was significant for the secondary outcomes. The total exposed sample size ranged from 3 161-5 085; OR ranged between 0.60 and 1.92; heterogeneity was between 0% and 23%. Based on the results of the present MA, first trimester PPI exposure was not associated with a significantly increased risk of overall or specific MCM. However, this MA included only observational studies which are prone to bias and there were insufficient data to evaluate PPI at a substance level. Future studies are needed to address this concern.

Risk of drug use during pregnancy: master protocol for living systematic reviews and meta-analyses performed in the metaPreg project.

BACKGROUND: Knowledge about the risks of drugs during pregnancy is continuously evolving due to the frequent publication of a large number of epidemiological studies. Systematic reviews and meta-analyses therefore need to be regularly updated to reflect these advances. To improve dissemination of this updated information, we developed an initiative of real-time full-scale living meta-analyses relying on an open online dissemination platform ( www.metapreg.org ). METHOD: All living meta-analyses performed in this project will be conducted in accordance with this master protocol after adaptation of the search strategy. A systematic literature search of PubMed and Embase will be performed. All analytical studies (e.g., cohort, case-control, randomized studies) reporting original empirical findings on the association between in utero exposure to drugs and adverse pregnancy outcomes will be included. Study screening and data extraction will be performed in a semi-automation way supervised by a biocurator. A risk of bias will be assessed using the ROBINS-I tools. All clinically relevant pregnancy adverse outcomes (malformations, stillbirths, neuro-developmental disorders, pre-eclampsia, etc.) available in the included studies will be pooled through random-effects meta-analysis. Heterogeneity will be evaluated by I2 statistics. DISCUSSION: Our living systematic reviews and subsequent updates will inform the medical, regulatory, and health policy communities as the news results evolve to guide decisions on the proper use of drugs during the pregnancy. SYSTEMATIC REVIEW REGISTRATION: Open Science Framework (OSF) registries.

Feasibility study and evaluation of expert opinion on the semi-automated meta-analysis and the conventional meta-analysis.

PURPOSE: To assess the feasibility and acceptance of the semi-automated meta-analysis (SAMA). The objectives are twofold, namely (1) to compare expert opinion on the quality of protocols, methods, and results of one conventional meta-analysis (CMA) and one SAMA and (2) to compare the time to execute the CMA and the SAMA. METHODS: Experts evaluated the protocols and manuscripts/reports of the CMA and SAMA conducted independently on the safety of metronidazole in pregnancy. Expert opinion was collected using AMSTAR 2 checklist. Time spent was recorded using case report forms. RESULTS: The overall scores of the opinion of all experts for protocols, methods, and results for SAMA (6.75) and CMA (6.87) were not statistically different (p = 0.88). The experts' confidence in the results of each MA was 7.89 ± 1.17 and 8.11 ± 0.92, respectively. The time to completion was 14 working days for SAMA and 24.7 for CMA. MA tasks such as calculation of effect estimates, subgroup/sensitivity analysis, and publication bias investigation required no investment in time for SAMA. CONCLUSION: In conclusion, our study demonstrated the feasibility of SAMA and suggests acceptance for risk assessment by an expert committee. Our results suggest that SAMA reduces the time required for a MA without altering expert confidence in the methodological and scientific rigor. As our study was limited to one example, the generalization of our results requires confirmation by other studies.

Risk of malformation after ondansetron in pregnancy: An updated systematic review and meta-analysis.

Ondansetron is increasingly used off label to treat nausea and vomiting during pregnancy. The main objective of this study was to evaluate the risk of major congenital malformations (MCM), cardiac defects and orofacial clefts associated with first trimester exposure to ondansetron using a meta-analytic approach. MEDLINE, ClinicalTrials.gov and Scopus were searched until November 2019. All comparative cohort and case-control studies on MCM, cardiac or orofacial defects and use of ondansetron during pregnancy were included. A team of paired reviewers independently extracted data using a proprietary collaborative WEB-based meta-analysis platform (metaPreg.org). Pooled odd ratios with corresponding 95% CIs were calculated using random effects models. From 214 records initially retrieved, 12 studies were included. Using all available information to date, first trimester exposure to ondansetron was found to be associated with an increased risk of (a) ventricular septal defects (VSD) (OR 1.11, 95% CI 1.00-1.23; p < .05; n = 6 studies; I2 = 0%) and (b) oral clefts (OR 1.22, 95% CI 1.00-1.49; p < .05; n = 4 studies; I2 = 0%). No significant association was observed for the risk of cleft palate but, when excluding the study that contributed to the study heterogeneity, we found an OR of 1.48 (95% CI 1.19-1.84; p < .01; n = 5 studies; I2 = 0%). No statistically significant association was found for MCM, overall cardiac malformations, atrial septal defects and cleft lip with or without cleft palate. Exploratory investigations of other malformations showed an increased risk of diaphragmatic hernia, hypoplastic left heart and "respiratory system anomalies."

Self-poisoning with baclofen in alcohol-dependent patients: national reports to French Poison Control Centers, 2008-2013.

BACKGROUND: Alcohol use disorders are frequently associated with self-intoxication in attempted suicide. In France since 2008, the off-label use of baclofen for treatment of alcohol dependence has greatly increased, leading to temporary regulation of use of the drug. At the request of the national authorities, the French Poison Control Centers carried out a retrospective survey to give an overview of baclofen exposure in this population. METHODS: A retrospective study was carried out from January 2008 to December 2013, focusing on baclofen exposures in alcohol-dependent patients managed by the nine national French Poison Control Centers. RESULTS: 294 observations of baclofen exposures in alcohol-dependent patients were identified in our database. Of these, 220 were suicide attempts by self-poisoning and 74 were unintentional. The mean age of patients was 41.7 years, with a sex-ratio of 1.6. Patients attempting suicide with baclofen were younger than those with unintentional exposures, and 43.6% of them were women (vs 22.9%, p < 0.01). The mean supposed ingested dose was higher (480.7 mg) in patients who attempted suicide (vs 192.5 mg, p < 0.0001). 21.8% of intentional exposures involved baclofen alone. Psychiatric comorbidity (50.4%) was more frequent in the group of self-poisoning (p < 0.001). 132 patients were coded as severely exposed (60.0%). Nine victims died, but the causal link between self-poisoning with baclofen and fatal outcome should be interpreted with particular caution. CONCLUSIONS: Baclofen self-poisoning by alcohol-dependent patients is a serious concern for the French health authorities. Our results are similar to those previously published, suggesting that most patients with baclofen overdose should be admitted to an intermediate or intensive care unit as the clinical course requires close monitoring. Because suicidal ideation and suicide attempts are more prevalent in people with substance use disorders than in the general population, and because of the lack of recommendations governing baclofen prescription in such a situation, its use needs to be better controlled.

Child poisonings with methadone in France: A 6-year prospective national survey since the availability of capsules in 2008.

BACKGROUND: Methadone for opiate substitution was available only in syrup formulation prior to 2008. In 2007, the French Health Authorities made solid forms available. A national survey was performed in order to evaluate the modification of child poisonings induced by such a new pharmaceutical formulation. METHODS: A prospective study was set up (April 15, 2008 to April 15, 2014) with the analysis of cases of unintentional ingestion of methadone by patients under 18 years old and managed by the 10 French poison control centers at the national level. As soon as a new pediatric exposure was recorded in the informatics data bank of the Poison Centers, a telephone survey was performed by the Marseilles' Poison Center to obtain the evolution and all the necessary details. RESULTS: 87 cases of child poisonings with the 2 forms were reviewed (syrup, 56 patients; capsules, 31 patients). Comparison shows that patients were similar for both formulations (no significant difference concerning age [median 2 years], sex ratio [M/F 0.85], previous history, and ingested quantities of methadone). There was a similar severity profile with both formulations proving that methadone can lead to lethal child intoxications (1 death with capsules and 4 with syrup). The relative risk of pediatric accidents is also the same with 2 formulations, leading the health authorities, in collaboration with laboratories, to design and distribute flyers. The aim was to inform patients who are also parents about the high danger risk of their treatment for children, whatever the formulation of methadone present in the house. DISCUSSION: The results of this survey were similar to those of another national study by the French Poison Centers concerning adult suicide attempts with methadone. Both prospective studies led to the conclusion that methadone must be considered as a dangerous molecule for patients and their families. The recent availability of a solid formulation in France did not change the profile of poisonings with this opiate substitute treatment.

Reproductive disorders in hairdressers and cosmetologists: a meta-analytical approach.

OBJECTIVES: The aim of this study was to perform a systematic review and to use a meta-analytical approach to assess quantitatively the risk of adverse pregnancy outcomes in hairdressers and cosmetologists. METHODS: A systematic literature search up to 1 February 2012 was carried out using major bibliographic databases, grey literature, contacts with research teams working on the subject, review papers and reference lists of selected articles. Observational studies reporting measures of effects in relation with body care (hairdressers, cosmetologists, etc.) and reproductive disorders were included. Study quality was assessed by three reviewers. The estimated risk ratios (RR) from all studies reporting on identical outcomes were combined using an average of logarithm transformation of estimated RR weighted by their inverted variance. Statistical heterogeneity across studies was assessed using Cochran's Q test. To explore the sources of heterogeneity, several sensitivity analyses and subgroup analyses were conducted based on study quality, country, study period, alcohol consumption, smoking habit, jobs and control populations. RESULTS: Nineteen studies were selected and reviewed in-depth. The combined risk ratios (RRcs) of five reproductive outcomes were calculated and found to be significantly increased for four outcomes: time to pregnancy, which had an RRc of 1.11 (95% CI: 1.03-1.19); premature birth, which had an RRc of 1.05 (95% CI: 0.99-1.11); small for gestational age, which had an RRc of 1.24 (95 CI%: 1.10-1.41); low birth weight, which had an RRc of 1.21 (95% CI: 1.06-1.39); and embryonic and fetal losses, which had an RRc of 1.19 (95% CI: 1.03-1.38). CONCLUSIONS: This work confirms a weak increase in risk of some reproductive disorders in female hairdressers/cosmetologists. However, the evidence level is rather weak, and a causal association between job and reproductive outcomes cannot be asserted.

Probabilistic dietary exposure to phycotoxins in a recreational shellfish harvester subpopulation (France).

Phycotoxins, secondary phytoplankton metabolites, are considered as an important food safety issue because their accumulation by shellfish may render them unfit for human consumption. However, the likely intakes of phycotoxins via shellfish consumption are almost unknown because both contamination and consumption data are very scarce. Thus, two 1-year surveys were conducted (through the same population: recreational shellfish harvesters and from the same geographical area) to assess: shellfish consumption and contamination by major toxins (domoic acid (DA) group, okadaic acid (OA) group and spirolides (SPXs)). Recreational shellfish harvesters had been targeted as an at-risk subpopulation because they consume more shellfish than general population and because they eat not only commercial shellfish species controlled by official authorities but also their own harvests of shellfish species may be in non-controlled areas and more over shellfish species non-considered in the official control species. Then, these two kinds of data were combined with deterministic and probabilistic approaches for both acute and chronic exposures, on considering the impact of shellfish species and cooking on phycotoxin levels. For acute risk, monitoring programs seem to be adequate for DAs, whereas OAs could be a matter of concern for high consumers (their acute intakes were up to ninefold the acute reference dose (ARfD)). About chronic risk, OAs are a matter of concern. The daily OAs intakes were close to the ARfD, which is, by definition, greater than the tolerable daily intake. Moreover, SPX contamination is low but regular, no (sub)chronic SPX toxicity data exist; but in case of (sub)chronic toxicity, SPX exposure should be considered.

Relevant shellfish consumption data for dietary exposure assessment among high shellfish consumers, Western Brittany, France.

Shellfish consumption can be a major pathway of exposure to pollutants for humans. It is fundamental to know if people eat enough shellfish to cause health problems, firstly in high consumers as recreational shellfish harvesters. The objectives of this study were to investigate the types of shellfish eaten, number of meals, portion size, sources of shellfish and shellfish consumption rates among French recreational shellfish harvesters; to determine factors affecting consumption patterns and to examine the reliability of the two methods used: a Food Frequency Questionnaire and a one-month food diary. The mean consumption rates were 11.63 and 26.21 g/person/day for shellfish derived from a self-harvested source only and from all sources, respectively. Harvester consumption rates were between 6- and 15-fold higher than the general French population. The comparison between the FFQ and the food diary showed that results were reliable. Thereby, our results are relevant to assess risk due to shellfish consumption.