Exposure to anti-seizure medication during pregnancy and the risk of autism and ADHD in offspring: a systematic review and meta-analysis.

Background: Evidence of an association between maternal use of anti-seizure medication (ASM) during pregnancy and the risk of autism spectrum disorder (ASD) or attention-deficit/hyperactivity disorder (ADHD) in children is conflicting. This systematic review and meta-analysis aimed to summarize the relationship between fetal exposure to ASM and the development of ASD or ADHD in offspring. Methods: A comprehensive literature search was conducted in PubMed and other databases to identify relevant epidemiological studies published from inception until 1 March 2024. Results: Seven cohort studies were included in the meta-analysis. The results showed that maternal exposure to ASMs during pregnancy was associated with an increased risk of ASD [odds ratio (OR): 2.1, 95% confidence interval (CI): 1.63-2.71; p < 0.001] in the general population. This association became weaker (ASD: OR: 1.38, 95% CI: 1.11-1.73; p = 0.004) when the reference group was mothers with a psychiatric disorder or epilepsy not treated during pregnancy. Furthermore, an increased risk of ADHD was observed when the study data adjusted for drug indications were pooled (OR: 1.43, 95% CI: 1.07-1.92; p = 0.015). In subgroup analyses based on individual ASM use, only exposure to valproate preconception was significantly associated with an increased risk of ASD or ADHD. Conclusion: The significant association between maternal ASM use during pregnancy and ASD or ADHD in offspring may be partially explained by the drug indication or driven by valproate.

[The regulatory mechanism of Raf/MEK/ERK pathway on the rat cardiac hypertrophy induced by transverse aortic constriction].

OBJECTIVE: To investigate the mRNA, protein expression levels and the phosphorylation levels of key factors in rapidly accelerated fibrosarcoma/mitogen-activated protein kinase kinase/extracellular regulated protein kinases (Raf/MEK/ERK) pathway, and to clarify the regulatory function of Raf/MEK/ERK pathway in myocardial hypertrophy. METHODS: Twenty SD rats were divided into sham-operated group and model group. The myocardial hypertrophy model was established by transverse aortic constriction (TAC). At 12 weeks after TAC, blood samples were collected from the submandibular vein, and the serum was separated to detect the content of N terminal pro B type natriuretic peptide (NT-proBNP). After that, the rats were subjected to echocardiography and hemodynamic measurement. Then the pathological changes of myocardial tissue were observed. And the levels of mRNA, protein expression and the phosphorylation of key factors in Raf/MEK/ERK pathway were detected in myocardial tissue. RESULTS: Compared with sham-operated group, left ventricular end-diastolic interventricular septal thickness (IVSd), left ventricular end-systolic interventricular septal thickness (IVSs), left ventricular end-diastolic posterior wall thickness (LVPWd) and left vebtricular end-systolic posterior wall thickness (LVPWs) in TAC model group were increased significantly (P＜0.05,P＜0.01), left ventricular end-systolic diameter (LVIDs) was decreased significantly (P＜0.01), LV Mass and LW(LV Mass/Weight)were increased significantly (P＜0.05, P＜0.01). The levels of heart rate (HR), left ventricular pressure maximal rate of rise (+dp/dtmax), left ventricular pressure maximal rate of fall (-dp/dtmax) were decreased significantly (P＜0.01). The serum level of NT-proBNP in TAC rat was increased significantly (P＜0.01). The myocardial cells in TAC model group were arranged disorderly, myocardial cell hypertrophy, cytoplasm were increased significantly, and inflammatory cells infiltrated. A large amount of collagen fibers were deposited and large area of myocardial cells were stained blue in TAC rat. The expression levels of phospho-c-Raf (Ser259) and phospho-c-Raf (Ser338) in myocardial tissue were significantly increased (P＜0.01), meanwhile the expression levels of phospho- MEK1/2(Ser217/Ser221) and phospho-ERK1/2 (Thr202/Tyr204) were also significantly increased (P＜0.01). CONCLUSION: The regulatory role of Raf / MEK / ERK pathway in cardiac hypertrophy may be through the activation of phosphorylation of c-raf, MEK1, Mek2, ERK1 and ERK2 at specific sites.