Keywords
perinatal depression
placental permeability
fetal toxicity
selective serotonin reuptake inhibitors
pregnancy-induced hypertension
pharmacogenetics
Abstract
Depressive disorders in the perinatal period represent a critical challenge in modern psychopharmacology, requiring a differentiated approach when prescribing antidepressants to minimize the risks of fetotoxicity. Timely therapy is essential to prevent the negative impact of maternal depression on fetal development; however drug selection must be based on a profound understanding of placental pharmacokinetics. The aim of the study is to systematize current pharmaco-epidemiological and toxicological data regarding the safety of antidepressant use in the perinatal period to minimize toxic effects on the fetus and ensure a stable therapeutic effect for the mother. A comprehensive analysis of scientific literature was conducted using international electronic databases of evidence-based medicine: PubMed and Cochrane Library. The results of large clinical cohort observations, latest ex vivo human placental dual perfusion experimental models, longitudinal metabolomic profiling data, and pharmacogenetic evaluations of the maternal genotype's influence on drug concentration stability were analyzed. Evidence-based medicine data analysis for 2021–2025 established that the transplacental transfer of antidepressants is a molecule-specific process. The level of fetal exposure critically depends on molecular lipophilicity, the degree of plasma protein binding, and the functioning of efflux transporters, particularly P-glycoprotein, which actively pumps certain antidepressants from the fetal circulation back to the maternal side. Results from the latest ex vivo studies have, for the first time, clearly differentiated fetal transfer rates for the most commonly used selective serotonin reuptake inhibitors (SSRIs). Sertraline demonstrated the lowest rate (33.2%), while for paroxetine and escitalopram, these values were significantly higher – 43.4% and 48.2%, respectively. It was established that the risks of congenital malformations (specifically cardiovascular anomalies) associated with modern SSRI use remain low and often correlate with maternal concomitant somatic factors rather than the direct action of the drugs. Particular attention was paid to pharmacogenetic variability: it was proven that CYP2C19 cytochrome phenotypes significantly affect the stability of pharmacotherapy. Specifically, women with intermediate metabolism face a high risk of subtherapeutic escitalopram/citalopram concentrations during pregnancy, which may lead to depressive relapse, as well as the development of toxic effects in the early postpartum period. Metabolomic profiling revealed that the use of serotonin-norepinephrine reuptake inhibitors is associated with a dose-dependent increase in the risk of gestational hypertension, necessitating careful monitoring of vascular tone and placental perfusion to prevent fetal hypoxia. As the conclusion, an effective safety strategy in the perinatal period must be based on the principles of personalized medicine. Clinical priority is recommended for molecules with proven lowest placental flux (specifically sertraline), allowing for the limitation of systemic exposure to the fetus. It is necessary to consider the patient's individual pharmacogenetic profile (CYP2C19 phenotype) when selecting the dosage. Such a comprehensive approach will minimize the toxic impact on the fetus and ensure a favorable prognosis for the mother and the harmonious development of the child.
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