In recent years, many scholars have conducted data mining research based on large pharmacovigilance databases[8]. The accessibility of open databases in public health, pharmacy, and clinical fields has significantly facilitated and advanced such research endeavors. The aim of this study was to scrutinize AE reports of drug-induced congenital abnormalities in newborns within the FAERS database and to explore the relationship between specific drugs and congenital abnormalities.
Our analysis of the FAERS database unveiled a heightened incidence of reported psychotropic drugs. Among the top ten psychotropic drugs by the number of reports were Venlafaxine, Quetiapine, Olanzapine, Sertraline, Citalopram, Mirtazapine, Duloxetine, Paroxetine, Aripiprazole and Fluoxetine. Subsequent analyses employing four signal detection methods confirmed an association between all ten drugs and congenital abnormalities. These medications, classified as AA, SSRI, SNRI and NaSSA based on their pharmacological effects. Notably, venlafaxine (27), quetiapine (27), olanzapine (26), sertraline (25), and citalopram (23) exhibited the highest number of signals. It is crucial to clarify that this finding does not insinuate that a particular drug poses a higher risk compared to others. Instead, it indicates that these drugs demonstrate the most significant association with congenital abnormalities.
4.1 Atypical Antipsychotics (Quetiapine, Olanzapine, Aripiprazole)
Our study observed cases where Quetiapine, Olanzapine, and Aripiprazole, these three types of AAs, were associated with congenital abnormalities, suggesting that pregnant women using these medications may face a higher risk of giving birth to babies with congenital abnormalities. AAs, also known as second-generation antipsychotic drugs, act as antagonists of serotonin and dopamine and are commonly used to treat acute mental illnesses such as schizophrenia, bipolar disorder, and severe depression[9]. Existing data indicate that antipsychotic drugs exhibit different adverse drug reactions (ADR) across different age groups, including children and pregnant women[10, 11]. Our research found that Quetiapine primarily manifested as signals related to heart disease, while Olanzapine had the most signals associated with the nervous system and musculoskeletal tissue, and Aripiprazole had the most signals related to the respiratory system.
Upon analysis, we found that Quetiapine exhibited the highest and strongest signals related to heart organ diseases, primarily presenting as tachycardia and cardiac malformations, which is consistent with existing studies[12]. Additionally, the musculoskeletal muscle abnormal signal results of Olanzapine are consistent with existing research conclusions[13]. However, the results regarding the relationship between Olanzapine and neurological abnormalities in newborns are uncertain. A study evaluating whether the risk of neurodevelopmental disorders (NDD) increases in children exposed to antipsychotic drugs during pregnancy suggested that the risk of NDD in children born to women who took antipsychotic drugs during pregnancy increased. However, this result seems to be explainable by maternal characteristics and not related to prenatal exposure to antipsychotic drugs[14]. Moreover, there is limited research on the association between Aripiprazole and newborn abnormalities. Our study found that this drug may be closely associated with conditions such as pneumococcal septicemia, meconium aspiration syndrome, and pulmonary hypertension.
4.2 Selective Serotonin Reuptake Inhibitors (Sertraline, Citalopram, Paroxetine, Fluoxetine)
Sertraline, Citalopram, and Paroxetine in our study exhibited signals linked to cardiac abnormalities. Fluoxetine exhibited the fewest signals, with none particularly prominent. SSRIs, commonly prescribed antidepressants, are primarily utilized for treating depression, anxiety, and other mental disorders[15]. SSRIs are believed to treat mental disorders effectively by enhancing the synaptic availability of serotonin (5-HT), which readily crosses the placenta during embryonic development and can influence specific cells and tissues, potentially resulting in congenital malformations, particularly cardiac ones[16–19]. Moreover, our study noted associations between Escitalopram and the renal/urinary system and nervous system, Sertraline and the respiratory system, and Paroxetine and mental disorders. Research on Fluoxetine is currently limited. Our study identified signals related to meconium staining and neonatal seizures.
Furthermore, Escitalopram and Paroxetine exhibited strong signals associated with attention deficit hyperactivity disorder (ADHD), congenital scoliosis, congenital aortic valve insufficiency, and Arnold-Chiari malformation. Arnold-Chiari malformation, a condition characterized by the downward displacement of the brainstem and cerebellar tonsils protruding through the foramen magnum, is poorly understood[20, 21]. With no satisfactory treatment methods currently available, vigilance regarding the potential risks posed by SSRIs is warranted.
4.3 Serotonin-Norepinephrine Reuptake Inhibitors (Venlafaxine, Duloxetine)
Our research identified signals of neonatal adverse respiratory events linked to venlafaxine. Extensive literature supports the notion that venlafaxine induces neonatal withdrawal syndrome[22–24], marked by symptoms such as tachycardia, rapid breathing, respiratory distress, dystonia, and others[25]. These findings are consistent with the signals identified in our study. Additionally, strong associations were noted between venlafaxine and pyelonephritis, congenital vesicoureteric reflux, poor neonatal weight gain, and temperature regulation disorder.
Despite the non-significant distribution of duloxetine in SOC signals. Our study reveals a robust association between duloxetine and congenital telangiectasia, gastroschisis, neonatal thrombocytopenia, liver disorder, and neonatal hyponatremia. Most existing studies have investigated whether duloxetine increases the risk of preterm birth or infants being small for gestational age, without evidence of congenital malformation risk[26–28]. One study suggests that duloxetine is unlikely to pose a significant teratogenic risk but may be linked to an elevated risk of postpartum hemorrhage and a slight increase in cardiac malformations[26]. Our findings are not fully consistent with the conclusions drawn in these studies.
4.4 Norepinephrine Reuptake Inhibitor (Mirtazapine)
Our research shows that Mirtazapine is associated with an increased risk of birth defects, specifically affecting bone development, including adactyly, syndactyly, and plagiocephaly. Mirtazapine possesses a distinctive pharmacological profile, which implies differences in both its efficacy and adverse effects compared to other antidepressants[17]. Nevertheless, there is a scarcity of studies regarding the exposure to mirtazapine in pregnant women and newborns. Current studies indicate that mirtazapine exposure during pregnancy is not linked to severe congenital malformations, contradicting our findings[29–31]. Furthermore, we found that mirtazapine was strongly linked to neonatal hyponatremia, neonatal seizures, and congenital inguinal hernia.