Paternal Valproate Treatment and Risk of Childhood Neurodevelopmental Disorders: Precautionary Regulatory Measures Are Insufficiently Substantiated.

On January 12, 2024 the safety committee of the European Medicines Agency (EMA) recommended precautionary measures over a potential risk of neurodevelopmental disorders in children born to men treated with valproate. These new measures recommend patient supervision by a specialist in the management of epilepsy, bipolar disorder, or migraine. In the United Kingdom, the Medicines and Healthcare products Regulatory Agency (MHRA) issued a far more stringent precaution, warning against prescribing valproate to anyone under 55 years of age. We, members of the European Network of Teratology Information Services (ENTIS) and the Organization of Teratology Information Specialists (OTIS), believe that the EMA and MHRA warnings were premature. We are of the opinion that the underlying scientific data do not convincingly substantiate the inference of a paternally mediated risk from valproate to children, much less to an extent that justifies these far-reaching recommendations.

Use of methylphenidate and reporting of valvular heart disease: Global pharmacovigilance analysis in children and adults.

INTRODUCTION: Methylphenidate (MPH) is a common treatment of attention-deficit/hyperactivity disorder (ADHD). Concern has been raised regarding its cardiovascular safety, partly in relation with its micromolar affinity for the 5-HT2B receptor, whose activation may result in valvular heart disease (VHD). METHODS: To explore the association between the use of MPH and VHD reporting, we performed a disproportionality analysis within the WHO global safety database (VigiBase) using data, since inception until March 6th 2024, from: (i) the full database and (ii) different age groups (children/adolescents 6-17 years; adults 18-64 years). To avoid competition bias, safety reports with amphetamine-like appetite suppressants were excluded. Disproportionality was expressed using reporting odds-ratio (ROR) and its 95% confidence interval (CI). RESULTS: Of 29 129 spontaneous reports with MPH, 23 VHD cases (7.9 per 10 000 reports) were identified, including 13 adults and 10 children. Most cases concerned injury on the mitral valve. A disproportionate reporting was observed overall (ROR 1.6, 95% CI 1.1-2.4). Analysis according to age group found that disproportionality in VHD reporting was found in adults only (ROR 2.7, 95% CI 1.6-4.7) but not in children/adolescents (ROR 1.7, 95% CI 0.9-3.2). Furthermore, amongst MPH users only, VHD reporting was higher in adults compared to children (ROR 2.7, 95% CI 1.2-6.3). CONCLUSION: VHD reporting appears rare with MPH compared to other adverse events and is increased in adults only. Our findings support a potential safety signal of VHD in adults exposed to MPH. A risk in that population cannot be excluded and requires further assessment.

Polypharmacy, drug-drug interactions, and adverse drug reactions among systemic sclerosis patients: A cross-sectional risk factor study.

OBJECTIVES: Polypharmacy, drug-drug interactions (DDI) and related adverse drug reaction (ADR) are understudied in SSc. The aim of this work was to determine the prevalence and determinants of DDI and ADR in a real-life prospective cohort of SSc patients. METHODS: We performed a retrospective analysis of the drug prescriptions of SSc patients admitted to the daily scleroderma clinic between January 2020 and April 2022. DDI were identified using 2 prescription analysis applications, and adjudicated related ADRs occurring during a one-year follow-up were reported. Risk factors for DDI and ADR were identified using multivariate analysis. RESULTS: One hundred and eight SSc patients were included. The median number of medications per patient was 6 [4-9]. Seventy-one (65.7 %) patients had 5 or more medications, and 23 (21.3 %) had 10 or more. Seventy-two (66.7 %) patients had DDIs on their prescriptions at inclusion. Patients with DDIs had more medications than patients without DDIs (7 [5-10] versus 3 [2-5], p < 0.0001). Six (8.3) patients experienced ADRs during the one-year follow-up. Patients with ADRs had more medications (14 [10-18] versus 7 [5-10] p < 0.001) and more DDIs (12 [7-32] versus 3 [1-6]; p < 0.001) than patients without ADRs. Multivariate analysis confirmed that the number of prescribed medications was independently positively associated with DDIs (OR: 2.25 [1.52-3.32], p < 0.0001) as well as with ADRs (OR: 1.68 [1.17-2.40], p < 0.01). CONCLUSIONS: SSc patients are significantly exposed to polypharmacy, DDIs and related ADRs, particularly in cases of severe illness, and especially if 5 or more medications are prescribed.

In Utero Exposure to Antibiotics and Risk of Serious Infections in the First Year of Life.

INTRODUCTION AND OBJECTIVE: Given the high prevalence of antibiotic prescription during pregnancy in France and previous studies suggesting an increased risk of infection in offspring with such exposures, our study aimed to investigate the association between prenatal exposure to systemic antibiotics and serious infections in full-term infants during their first year of life. METHODS: We conducted a retrospective population-based cohort study on singleton, full-term liveborn non-immunocompromised infants, using the French National Health Data System (SNDS) between 2012 and 2021. Systemic antibiotic dispensing in ambulatory care settings during pregnancy defined the exposure. Outcomes concerned serious infections (i.e., infections requiring hospitalization) in offspring identified between 3 and 12 months of life, hence excluding infections of maternal origin. Adjusted odds ratios (aORs) were estimated using logistic regression with multivariate models to control for potential confounders. RESULTS: Of 2,836,630 infants included, 39.6% were prenatally exposed to systemic antibiotics. Infants prenatally exposed to antibiotics had a higher incidence of serious infections compared with unexposed infants {aOR 1.12 [95% confidence interval (95% CI) 1.11-1.13]}. Similar associations were observed according to the timing of exposure during pregnancy, antibiotic class, and site of infections. The strongest association was observed when infants were prenatally exposed to three or more antibiotic courses during pregnancy [aOR 1.21 (95% CI 1.19-1.24)]. Limitations include residual confounders, such as genetic susceptibility to infections and the role of the underlying pathogen agent. CONCLUSION: Prenatal exposure to systemic antibiotics is very common and is associated with a weak yet significant associations with subsequent serious infectious events during the first year of life. While our study revealed associations, it is important to note that causation cannot be established, given the acknowledged limitations, including potential confounding by indication.

Trends in harmful drug exposure during pregnancy in France between 2013 and 2019: A nationwide cohort study.

OBJECTIVE: Describe the trends of exposure to harmful drugs during pregnancy over recent years in France. DESIGN: Nationwide cohort study. SETTING: The French National administrative health Data System (SNDS). POPULATION: Pregnancies starting between 2013 and 2019 and outcomes corresponding to live births, medical terminations of pregnancy, and stillbirths. METHODS: Each pregnancy was divided into a preconceptional period of 90 days before conception and three trimesters from conception to birth. Harmful drugs were defined according to their risks to the fetus: teratogenicity or fetotoxicity. Exposure was defined using the critical period during pregnancy for each type of harmful drug: preconceptional period or first trimester for teratogenic drugs and second or third trimesters for fetotoxic drugs. MAIN OUTCOME MEASURES: Prevalence of pregnancies exposed to at least one harmful drug. RESULTS: Among 5,253,284 pregnancies, 204,402 (389 per 10,000) pregnancies were exposed to at least one harmful drug during the critical periods: 48,326 (92 per 10,000) pregnancies were exposed to teratogenic drugs during the preconceptional period or the first trimester, and 155,514 (299 per 10,000) pregnancies were exposed to fetotoxic drugs during the second or third trimesters. Teratogenic drugs were mainly retinoids for topical use (44 per 10,000 pregnancies), antiepileptics (13 per 10,000 pregnancies) and statins (13 per 10,000 pregnancies). Fetotoxic drugs were mainly non-steroidal anti-inflammatory drugs (NSAIDs), for systemic (128 per 10,000 pregnancies) and topical use (122 per 10,000 pregnancies). Exposure to teratogenic drugs decreased from the preconceptional period to the first trimester. Exposure to fetotoxic drugs decreased from the second to the third trimester. Between 2013 and 2019, we found a decrease in harmful drug exposure overall, mainly for topical and systemic NSAIDs and for topical retinoids. CONCLUSIONS: In this nationwide study, about one in 25 pregnancies was exposed to at least one harmful drug, mainly NSAIDs and topical retinoids. Although the prevalence of harmful drug exposure decreased over the study period, NSAID exposure in the second and third trimester remains of concern.

Risk of Hypertensive Disorders and Preterm Birth in Pregnant Women With Systemic Vasculitides: A Nationwide Population-Based Cohort Study.

OBJECTIVE: Even though systemic vasculitides (SVs) affect primarily patients over 50 years of age, they can occur among women of childbearing age. Preterm birth (PTB) and hypertensive disorders are frequent complications of pregnancy in SVs. This study aims to evaluate the risk of hypertensive disorders and PTB among pregnant women with SVs, and to identify associated risk factors. METHOD: Using the French health insurance data warehouse, we conducted a nationwide cohort study including all pregnancies between 2013 and 2018 in women with SVs. Theses pregnancies were matched to pregnancies among women without SVs. We estimated risk of hypertensive disorders and PTB risk during pregnancy among women with SVs and investigated associated risk factors using a nested case-control design. RESULTS: Among 3,155,723 pregnancies, we identified 646 pregnancies in women with SVs, matched to 3,230 controls. SVs were significantly associated with hypertensive disorders (odds ratio [OR] 1.7, 95% confidence interval [95% CI] 1.3-2.2) and PTB (OR 1.8, 95% CI 1.4-2.3). Chronic renal failure before pregnancy, history of or treated arterial hypertension, the occurrence of vasculitides flare during pregnancy, and the subgroup of SVs were independently associated with the occurrence of hypertensive disorders. Maternal age at delivery, chronic renal failure before conception, and the occurrence of vasculitides flare during pregnancy were independently associated with the occurrence of PTB. CONCLUSION: About one of seven pregnancies in women with SVs is associated with hypertensive disorders or preterm birth. The occurrence of vasculitides flare was associated with these complications. Our findings support the importance of prepregnancy counseling to ensure disease stability.

Drug-induced fetal and offspring disorders, beyond birth defects.

Studies on drug utilization in western countries disclosed that about nine over ten women use at least one or more drugs during pregnancy. Determining whether a drug is safe or not in pregnant women is a challenge of all times. As a developing organism, the fetus is particularly vulnerable to effects of drugs used by the mother. Historically, research has predominantly focused on birth defects, which represent the most studied adverse pregnancy outcomes. However, drugs can also alter the ongoing process of pregnancy and impede the general growth of the fetus. Finally, adverse drug reactions can theoretically damage all developing systems, organs or tissues, such as the central nervous system or the immune system. This extensive review focuses on different aspects of drug-induced damages affecting the fetus or the newborn/infant, beyond birth defects, which are not addressed here.

Effects of maternal modafinil treatment on fetal development and neonatal growth parameters - a multicenter case series of the European Network of Teratology Information Services (ENTIS).

OBJECTIVE: In recent years, safety concerns about modafinil exposure during pregnancy have emerged. In particular, increased risks for major congenital anomalies (MCA) and impaired fetal growth were reported, although study results were conflicting. Our investigation aims to examine previously reported safety signals. METHOD: Multicenter case series based on data from 18 Teratology Information Services from 12 countries. Modafinil exposed pregnancies with an estimated date of birth before August 2019 were included in this study. For prospectively ascertained pregnancies, cumulative incidences of pregnancy outcomes, rate of nonchromosomal MCA in first trimester exposed pregnancies and percentiles of neonatal/infant weight and head circumference (HC) were calculated. Potential dose-dependent effects on fetal growth were explored by linear regression models. Retrospectively ascertained cases were screened for pattern of MCA and other adverse events. RESULTS: One hundred and seventy-five prospectively ascertained cases were included, of which 173 were exposed at least during the first trimester. Cumulative incidences for live birth, spontaneous abortion and elective termination of pregnancy were 76.9% (95% CI, 68.0%-84.8%), 9.3% (95% CI, 5.0%-16.9%), and 13.9% (95% CI, 8.1%-23.1%), respectively. Nonchromosomal MCA was present in 3/150 live births, corresponding to an MCA rate of 2.0% (95%CI, 0.6%-6.1%), none were reported in pregnancy losses. Compared to reference standards, birth weight (BW) tended to be lower and neonatal HC to be smaller in exposed newborns (data available for 144 and 73 of 153 live births, respectively). In nonadjusted linear regression models, each 100 mg increase of average dosage per pregnancy day was associated with a decrease in standard deviation score (SDS) of -0.28 SDS (95% CI, -0.45 to -0.10) for BW and of -0.28 SDS (95% CI, -0.56 to 0.01) for HC. Screening of 22 retrospectively reported cases did not reveal any specific pattern of MCA or other adverse outcomes. CONCLUSION: The results do not indicate an increased risk of MCA after in utero exposure to modafinil, but a tendency toward lower BW and reduced neonatal HC. However, these findings should be regarded as preliminary. Until further studies allow for a definite conclusion, modafinil should not be used during pregnancy.

Will the future of pharmacovigilance be more automated?

INTRODUCTION: Artificial intelligence (AI) based tools offer new opportunities for pharmacovigilance (PV) activities. Nevertheless, their contribution to PV needs to be tailored to preserve and strengthen medical and pharmacological expertise in drug safety. AREAS COVERED: This work aims to describe PV tasks in which the contribution of AI and intelligent automation (IA) tools is required, in the context of a continuous increase of spontaneous reporting cases and regulatory tasks. A narrative review with expert selection of pertinent references was performed through Medline. Two areas were covered, management of spontaneous reporting cases and signal detection. PERSPECTIVE: The use of AI and IA tools will assist a large spectrum of PV activities, both in public and private PV systems, in particular for tasks of low added value (e.g. initial quality check, verification of essential regulatory information, search for duplicates). Testing, validating, and integrating these tools in the PV routine are the actual challenges for modern PV systems, to guarantee high-quality standards in terms of case management and signal detection.

Association of depression and suicidal behaviour reporting with HIV integrase inhibitors: a global pharmacovigilance study.

OBJECTIVES: Concerns have been raised regarding neuropsychiatric adverse drug reactions of integrase inhibitors (INSTIs) in patients living with HIV. The aim of this study was to assess the risk of depression and suicidality reporting with INSTIs based on a global pharmacovigilance database. METHODS: Depression and suicidality cases in patients treated with INSTIs were identified within the WHO global database of individual case safety reports, VigiBase. Risk of depression and suicidality reporting with INSTIs compared with other ART was assessed using disproportionality analyses (case/non-case statistical approach). RESULTS: Of 19 991 410 reports over the study period, 124 184 reports concerned patients exposed to ART, including 22 661 patients exposed to an INSTI. Among patients treated with an INSTI, 547 cases of depression and 357 cases of suicidality were identified. Disproportionality analyses showed that depression [reporting OR (ROR) 3.6; 95% CI: 3.2-4.0] and suicidality (ROR 4.7; 95% CI: 4.1-5.4) were more reported with the use of INSTIs compared with other ART. Amongst INSTIs, depression reporting was significantly greater for bictegravir and dolutegravir, whereas suicidality reporting was significantly greater for dolutegravir only. CONCLUSIONS: Our findings suggest that depression and suicidality are adverse drug reactions of all INSTI agents, especially dolutegravir, which may occur within the first months of therapy.

Local anesthetics systemic toxicity in children: analysis of the French pharmacovigilance database.

PURPOSE: To characterize clinical profile of pediatric local anesthetic (LA) systemic toxicity (LAST) and to identify determinants of life-threatening outcomes. METHODS: Spontaneous reports notified to the French Pharmacovigilance Network were retrieved and followed by a case-by-case review, according to the following criteria: LA as suspected drug, age < 18 years, adverse drug reactions related to nervous system, cardiac, respiratory, psychiatric or general disorders. Multivariate logistic regression analysis was performed to identify factors leading to life-threatening reaction (i.e. continuous seizures or cardiorespiratory arrest). RESULTS: Among 512 cases retrieved, 64 LAST cases were included (neonates 11%, infants 30%, children 36%, adolescents 23%) mainly involving lidocaine (47%), lidocaine + prilocaine (22%) and ropivacaine (14%). Toxicity profiles were neurological (58%), cardiac (11%) or mixed (20%) and 7 patients (11%) developed methemoglobinemia. LAST was life-threatening for 23 patients (36%) and 2 patients died. Doses were above recommendations in 26 patients (41%) and were not different between life-threatening and non-life-threatening cases. The context of use (general and orthopedic surgery, p = 0.006) and the type of LA agent (lidocaine, p = 0.016) were independently associated with a life-threatening outcome. CONCLUSION: In this national retrospective analysis, LAST in children appear to be a rare event. Neurological and cardiac signs were the most frequently reported reactions. LAST in children can be life-threatening, even at therapeutic doses. Although a fatal outcome may anecdotally occur, the vast majority of patients recovered after appropriate medical care.

Management of Gastro-Intestinal Toxicity of the Pi3 Kinase Inhibitor: Optimizing Future Dosing Strategies.

The phosphatidylinositol 3-kinase (PI3K) pathway plays a key role in cancer progression and in host immunity. Idelalisib was the first of this class to be approved with the second-generation Pi3 kinase inhibitors copanlisib, duvelisib and umbralisib, subsequently being approved in the United States. Real-world data are lacking, however, in relation to the incidence and toxicity of Pi3 kinase inhibitor-induced colitis. We here review, in the first instance, the general landscape of the Pi3K inhibitors in the context of hematological malignancies, with a focus on the adverse gastrointestinal side effects reported by various clinical trials. We further review the available worldwide pharmacovigilance data in relation to these drugs. Finally, we describe our own real-world experience with idelalisib-induced colitis management in our center and in a national setting.

Azathioprine-induced vanishing bile duct syndrome: The value of early thiopurine metabolism assessment.

About 15% to 28% of patients treated with thiopurines experienced adverse drug reactions, such as haematological and hepatic toxicities. Some of these related to the polymorphic activity of the thiopurine S-methyltransferase (TPMT), the key detoxifying enzyme of thiopurine metabolism. We report here a case of thiopurine-induced ductopenia with a comprehensive pharmacological analysis on thiopurine metabolism. A 34-year-old woman, with a medical history of severe systemic lupus erythematosus with recent introduction of azathioprine therapy, presented with mild fluctuating transaminase blood levels consistent with a hepatocellular pattern, which evolved to a cholestatic pattern over the next weeks. A blood thiopurine metabolite assay revealed low 6-thioguanine nucleotides (6-TGN) level and a dramatically increased 6-methylmercaptopurine ribonucleotides (6-MMPN) level, together with an unfavourable [6-MMPN:6-TGN] metabolite ratio and a high TPMT activity. After a total of about 6 months of thiopurine therapy, a transjugular liver biopsy revealed a ductopenia, and azathioprine discontinuation led to further clinical improvement. In line with previous reports from the literature, our case supports the fact that ductopenia is a rare adverse drug reaction of azathioprine. The mechanism of reaction is unknown but may involve high 6-MMPN blood level, due to unusual thiopurine metabolism (switched metabolism). Early therapeutic drug monitoring with measurement of 6-TGN and 6-MMPN blood levels may help physicians to identify patients at risk of similar duct injury.

Assessing the risk of adverse pregnancy outcomes and birth defects reporting in women exposed to ganciclovir or valganciclovir during pregnancy: a pharmacovigilance study.

OBJECTIVES: Cytomegalovirus (CMV) is the leading cause of congenital infection worldwide. Reference anti-CMV treatment is valganciclovir/ganciclovir, which is contraindicated in pregnancy given questions about teratogenicity. METHODS: We analysed reports from VigiBase, the world's largest safety database, and performed a disproportionality analysis of adverse pregnancy outcomes associated with (val)ganciclovir compared with any other drugs or with (val)aciclovir as comparators. RESULTS: Among 3 104 984 reports related to childbearing-age women or to pregnancy topics, 6186 were exposed to (val)ganciclovir or (val)aciclovir including 251 adverse pregnancy outcomes with (val)ganciclovir (n = 34) or (val)aciclovir (n = 217). We did not evidence any increased reporting of any adverse pregnancy outcome [miscarriage, stillbirth, small weight for gestational age, preterm birth (<37 weeks of gestation)] or birth defects with (val)ganciclovir compared with the use of (val)aciclovir during pregnancy. Four cases of oesophageal and anorectal atresia were identified with (val)ganciclovir, which may be related to concomitant drugs/medical conditions and require further analyses. CONCLUSIONS: These preliminary results require confirmation but suggest the possibility for trial evaluation of val(ganciclovir) in severe maternal or fetal CMV infections.

[Performing pharmacoepidemiological studies using the French health insurance data warehouse (SNDS): How to translate guidelines into practice]. / Réalisation d'études pharmacoépidémiologiques à partir du système national des données de santé (SNDS) : application des recommandations dans la pratique.

The French health insurance data warehouse named SNDS is one of the largest medico-administrative in the world allowing for powerful pharmacoepidemiological studies, based on real-life data collected prospectively. In addition to the absolute necessity of a strong pharmacological rationale, recommendations have been thought to improve the quality of pharmacoepidemiological studies. These guidelines emphasize the importance of an accurate definition of the study population, outcome and exposure, especially for studies performed on medico-administrative databases. Compliance with certain guidelines, particularly those concerning the identification of a specific population or an outcome and the definition of risk periods or exposure periods, may be difficult when performing studies on the SNDS because of its structure and the nature of the data recorded. The objective of this article is to provide advice for the conduct of pharmacoepidemiological studies according to the recommendationswhen using the SNDS, given its specificities. The performing of reliable studies from this rich but complex data warehouse requires the expertise of researchers with deep knowledge both in the SNDS and in pharmacological reasoning.