Risk of Congenital Anomalies Associated with Psychotropic Medications: A Review of Neonatal Reports in the FDA Adverse Event Reporting System (FAERS)

Risk of Congenital Anomalies Associated with Psychotropic Medications: A Review of Neonatal Reports in the FDA Adverse Event Reporting System (FAERS) | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Risk of Congenital Anomalies Associated with Psychotropic Medications: A Review of Neonatal Reports in the FDA Adverse Event Reporting System (FAERS) Jingping Zheng, Lin Ma, Yankun Liang, Zhenpo Zhang, Qimin Wu, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4333094/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose The objective of this article is to explore commonly prescribed psychotropic medications, such as atypical antipsychotics (AAs), selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), regarding their potential association with congenital anomalies in newborns. This analysis will be based on data obtained from the Food and Drug Administration Adverse Event Reporting System (FAERS). Methods Spontaneously reported cases involving congenital anomalies in newborns (under 28 days old) were extracted and reviewed from the FAERS database covering the period from January 2004 to June 2023. We employed four methods (ROR, PRR, BCPMM, MGPS) to identify signals associated with neonatal deformities caused by specific drugs in newborns. Results The FAERS database encompassed 21,605 reported cases involving newborns, of which 6,208 reported congenital abnormalities. Among these cases, 6,164 (99.29%) explicitly attributed the adverse event to the drug. Following calculations utilizing four signal detection methods, the top ten psychiatric drugs associated with congenital abnormalities in newborns were Venlafaxine, Quetiapine, Olanzapine, Sertraline, Citalopram, Mirtazapine, Duloxetine, Paroxetine, Aripiprazole, and Fluoxetine. These drugs demonstrated heightened signal frequencies concerning heart disease, neurological disorders, respiratory-chest-mediastinal conditions, and musculoskeletal-connective tissue disorders. Conclusions The use of psychotropic medications during pregnancy has been observed to correlate with the potential risk of specific congenital abnormalities. Pregnant women with psychiatric disorders are advised to use psychotropic drugs with caution. Healthcare professionals should actively understand the potential risks of specific psychotropic medications in causing particular congenital abnormalities, enabling them to provide informed counseling and explore more suitable treatment options for patients. Biological sciences/Drug discovery/Drug regulation Biological sciences/Drug discovery/Drug safety Antipsychotics pregnancy newborn adverse event pharmacovigilance Figures Figure 1 Figure 2 1 INTRODUCTION Pregnancy leads to substantial biological and psychosocial changes in women, frequently causing increased anxiety and stress[ 1 ]. Pregnant women experienced a notably higher prevalence of depression, anxiety, and other mood disorders during the COVID-19 pandemic[ 2 ], leading to a greater reliance on psychotropic medications. Common psychotropic medications comprise antidepressants, anxiolytics, and antipsychotics[ 3 ]. The safety of psychotropic medications in pregnancy has garnered significant attention. Currently, divergent perspectives exist regarding the association between prenatal exposure to psychotropic drugs and congenital abnormalities in newborns. For example, a cohort study that included 1,341,715 pregnant women reported that antipsychotic use in early pregnancy generally did not significantly increase the overall risk of congenital malformations[ 4 ]. Conversely, a separate cohort study involving 28,122 pregnant women with early exposure to antipsychotics suggests that the observed increased risk of cleft lip associated with olanzapine, gastroschisis, and specific brain abnormalities caused by other atypical antipsychotics[ 5 ]. Hence, comprehensive comprehension of the safety and potential risks associated with these medications during pregnancy is imperative, necessitating proactive identification and mitigation of any adverse effects on both maternal and fetal health. Our study aimed to achieve three primary objectives: (1) Identify safety signals for individual psychotropic medications and their potential correlation with congenital anomalies in the FAERS database. (2) Discover new or robust adverse event (AE) signals potentially linked with a specific drug or drug class. (3) Perform a comparative analysis of AE risks among different medications. 2 METHODS We conducted a retrospective pharmacovigilance study to explore whether there is an association between congenital abnormalities in newborns and psychotropic drugs. Specifically, we reviewed cases in the FAERS database from the first quarter of 2004 to the second quarter of 2023. We screened cases of infants under 28 days of age resulting from “congenital abnormalities”. We used four different signal detection methods, such as Reporting Odds Ratio (ROR), Medicines and Healthcare products Regulatory Agency (MHRA), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinker (MGPS) to calculate all signals associated with congenital abnormalities for psychoactive drugs[ 6 ]. The combination of these four methods can not only effectively detect signals but also reduce the interference of false positive signals. Only when a signal meets the criteria of all four methods simultaneously, will it be judged as a positive signal. Finally, we utilized MedDRA to define preferred terms (PT) and System Organ Class (SOC) to classify and discuss the signals. We focused on signals with high rankings or unknown signal. 3 RESULTS 3.1 Annual data analysis As illustrated in Fig. 1 , from January 2004 to June 2023, the FAERS database documented 21,605 cases related to newborns, of which 6,208 cases indicated “congenital anomaly” as the outcome. Among these cases, 53.58% were male offspring, 36.50% were female offspring, and 9.92% had an undisclosed gender. Typically, the annual count of reports for males exceeded that of females. Generally, the annual report count showed a rapid increase followed by fluctuations. Reports of congenital anomalies experienced a significant rise between 2013 and 2014, increasing from 427 cases in 2013 to 809 cases in 2014, subsequently followed by a decrease. 3.2 Psychotropic medications and congenital Anomalies As presented in Table 1 , out of 6,208 reports concerning congenital anomalies submitted to the FDA, 6,164 (99.29%) clearly attributed adverse events (AE) to medications. After performing calculations using four signal detection methods, the top ten psychiatric drugs associated with congenital abnormalities in newborns were Venlafaxine, Quetiapine, Olanzapine, Sertraline, Citalopram, Mirtazapine, Duloxetine, Paroxetine, Aripiprazole, and Fluoxetine. Among these drugs, Venlafaxine and Quetiapine exhibited the highest number of signals, both at 27, followed by Olanzapine (26) and Sertraline (25). Conversely, Paroxetine had the highest incidence of congenital Anomalies, with Citalopram and Sertraline following suit. It is essential to stress that these cases were relatively infrequent in the complete dataset. These medications were classified into Atypical Antipsychotics (AAs), Selective Serotonin Reuptake Inhibitors (SSRIs), Serotonin Norepinephrine Reuptake Inhibitors (SNRIs), and Non-Selective Serotonin and Norepinephrine Reuptake Inhibitors (NaSSA) based on their pharmacological properties. These ten medications consist of four SSRIs, three AAs, two SNRIs, and one NaSSA. Table 1 Psychotropic Medications Related Congenital Anomaly Reports in FAERS Database from 2004Q1-2023Q2. Drug Name Signals Adverse Event Reports (%) (n = 6164) Class# Venlafaxine 27 266 (4.32%) SNRIs Quetiapine 27 245 (3.97%) AAs Olanzapine 26 90 (1.46%) AAs Sertraline 25 285 (4.62%) SSRIs Citalopram 23 339 (5.50%) SSRIs Mirtazapine 17 74 (1.20%) NaSSA Duloxetine 16 71 (1.15%) SNRIs Paroxetine 14 360 (5.84%) SSRIs Aripiprazole 8 141 (2.29%) AAs Fluoxetine 2 246 (3.99%) SSRIs # Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs), Atypical Antipsychotics (AAs), Selective Serotonin Reuptake Inhibitors (SSRIs),Non-Selective Serotonin and Norepinephrine Reuptake Inhibitor (NaSSA) 3.3 Signals distributed across System Organ Classes Overall, the signals of psychotropic drugs were concentrated in the SOC categories of heart disease, musculoskeletal-connective tissue disease, neurological disease, and respiratory-thoracic-mediastinal disease, as illustrated in Fig. 2 . Specifically, upon comparing the signals of three Atypical Antipsychotics (AAs) within SOCs, quetiapine predominantly displayed signals linked to cardiovascular issues, olanzapine demonstrated the highest number of signals related to the nervous and musculoskeletal systems, and aripiprazole exhibited the most signals associated with respiratory conditions. When comparing four Selective Serotonin Reuptake Inhibitors (SSRIs), with the exception of fluoxetine, the signals identified by the other three SSRIs (Sertraline, Citalopram, Paroxetine) displayed notable associations with cardiac organs. Of the two Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs), venlafaxine signaling was predominantly linked to respiratory-thoracic-mediastinal diseases, whereas duloxetine did not exhibit notable prominence across various SOCs. As a Noradrenergic and Specific Serotonergic Antidepressant (NaSSA), mirtazapine signals primarily concentrate in musculoskeletal tissues and various neurological systems. 3.4 The top5 signals of ten psychotropic drugs Given ROR's superior sensitivity among the four signal detection methods[ 7 ], we focus on analyzing the top five signals for ten psychotropic drugs using the lower bound of the 95% confidence interval (95% CI lower ROR), As presented in Table 2 . Among all signals, the most notable intensity was observed in “Blood creatine phosphokinase MB increased” (95% CI lower ROR = 35.41) and “Myoglobin blood increased” (95% CI lower ROR = 35.41) associated with Olanzapine. Additionally, Duloxetine demonstrated its most prominent signal with “Telangiectasia congenital” (95% CI lower ROR = 33.15). Mirtazapine exhibited its most prominent signal with “Neonatal hyponatremia” (95% CI lower ROR = 22.98), whereas Quetiapine's most significant signal related to “Junctional ectopic tachycardia” (95% CI lower ROR = 18.01). Venlafaxine displayed the strongest signal associated with “Pyelonephritis” 95% CI lower ROR = 17.91). Citalopram and Paroxetine exhibited their most notable signal intensity concerning “Attention deficit/Hyperactivity disorder” (95% CI lower ROR = 11.28). Aripiprazole's most notable signal pertained to “Enterococcal sepsis” (95% CI lower ROR = 9.73), while Sertraline's most notable signal intensity was associated with “Coordination abnormal” (95% CI lower ROR = 9.18). Fluoxetine exhibited only two signals, with the strongest signal being “Meconium in amniotic fluid” (95% CI lower ROR = 4.58). Table 2 The top5 signals of ten psychotropic drugs Class# Drug PT a 95%CI lower ROR PRR IC-2SD 95%CI lower EGBM AA Olanzapine Blood creatine phosphokinase MB increased 8 35.41 173.72 0.04 8.89 Myoglobin blood increased 8 35.41 173.72 0.04 8.89 Fever neonatal 12 35.34 115.81 0.69 11.78 Blood lactate dehydrogenase increased 9 29.24 115.81 0.28 9.79 Oesophageal stenosis 10 24.74 86.86 0.44 9.94 Quetiapine Junctional ectopic tachycardia 9 18.01 86.23 0.07 4.14 Mitral valve atresia 11 17.53 65.7 0.4 4.94 Aortic valve atresia 13 12.97 39.42 0.67 5.15 Enterococcal sepsis 10 10.47 36.96 0.32 4.33 Right ventricular false tendon 10 10.47 36.96 0.32 4.33 Aripiprazole Enterococcal sepsis 4 9.73 34.35 0.19 5.91 Right ventricular false tendon 4 9.73 34.35 0.19 5.91 Breech presentation 6 5.3 12.88 0.83 4.28 Pulmonary arterial hypertension 4 4.86 14.72 0.32 3.83 Meconium aspiration syndrome 4 3.7 10.85 0.29 3.1 SNRI Duloxetine Telangiectasia congenital 5 33.15 33.15 0.31 14.64 Gastroschisis 7 16.93 16.93 1.24 11.84 Thrombocytopenia neonatal 5 9.25 9.25 0.80 7.35 Liver disorder 3 8.85 8.85 0.03 6.64 Neonatal hyponatraemia 3 8.10 8.10 0.04 6.23 Venlafaxine Pyelonephritis 17 17.91 38.64 1.58 6.83 Withdrawal syndrome 11 11.59 27.78 1.16 5.4 Congenital vesicoureteric reflux 9 10.95 29.23 0.89 4.96 Poor weight gain neonatal 8 10.57 30.31 0.73 4.7 Temperature regulation disorder 14 6.67 12.73 1.46 4.42 NaSSA Mirtazapine Neonatal hyponatraemia 5 22.98 69.34 0.63 13.99 Adactyly 4 12.96 40.34 0.45 9.44 Neonatal seizure 5 8.59 22.19 0.83 7.08 Congenital inguinal hernia 4 5.6 15.85 0.49 4.87 Plagiocephaly 5 4.94 12.33 0.74 4.41 SSRI Citalopram Attention deficit/Hyperactivity disorder 30 11.28 20.48 1.68 7.77 Otitis media chronic 12 6.72 16.38 0.86 7.15 Congenital scoliosis 8 6.59 21.84 0.32 7.95 Congenital aortic valve incompetence 6 4.63 16.38 0.07 7.15 Arnold-chiari malformation 12 4.34 9.36 0.87 5.50 Paroxetine Attention deficit/Hyperactivity disorder 30 11.28 20.48 1.68 4.23 Otitis media chronic 12 6.72 16.38 0.86 2.92 Congenital scoliosis 8 6.59 21.84 0.32 2.39 Congenital aortic valve incompetence 6 4.63 16.38 0.07 2.02 Arnold-chiari malformation 12 4.34 9.36 0.87 2.54 Sertraline Coordination abnormal 9 9.18 22.99 0.97 4.75 Electrocardiogram QT prolonged 7 9.05 26.83 0.60 4.34 Infantile haemangioma 7 9.05 26.83 0.60 4.34 Neonatal infection 7 9.05 26.83 0.60 4.34 Right ventricular failure 6 8.45 27.59 0.39 3.99 Fluoxetine Meconium in amniotic fluid 5 4.58 15.79 0.09 2.43 Seizure 16 3.40 6.02 1.10 2.60 # Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs), Atypical Antipsychotics (AAs), Selective Serotonin Reuptake Inhibitors (SSRIs),Non-Selective Serotonin and Norepinephrine Reuptake Inhibitor (NaSSA) 4 DISCUSSION 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. 5 CONCLUSION Few studies have investigated drug exposure in pregnant women and newborns, with the majority relying on cohort and case-control designs. Our study utilizes signal mining in extensive databases, offering a novel approach to clinical evidence. Through analysis of publicly accessible FAERS databases, we identified a potential link between commonly prescribed psychotropic medications, including SSRIs, AAs, SNRIs, and NaSSA, and congenital abnormalities. Despite inherent limitations stemming from the voluntary reporting system in the FDA FAERS database, the presence of associated risks cannot be overlooked. In conclusion, acquiring comprehensive data on the potential risks of psychotropic medication use during pregnancy is imperative to safeguard embryos and fetuses. Such information is vital for healthcare professionals to make well-informed prescribing decisions and offer appropriate counseling to pregnant patients concerning their treatment choices. Declarations Acknowledgement Thanks to all the individuals who assisted and facilitated the research, those who provided suggestions and assistance throughout the research process, and the owners of materials, pictures, documents, and research ideas who granted permission for reproduction and citation. Authors’ Contributions J.Zheng, L. Ma, Z.Zhang, Y.Liang, Q.Wu, C.Din, Y.Wang, J.Lyu and L.Su conceived and executed the research project. J.Zheng designed and executed the statistical analysis. L.Ma collated the data. J.Zheng, L.Ma, Z.Zhang, Y.Liang, Q.Wu, C.Din, Y.Wang, J.Lyu and L.Su reviewed and critiqued the statistical analysis. All the authors contributed to the interpretation of data. Regarding article preparation, the writing of the first draft was executed by J.Zheng and L.Ma, all the authors contributed to the review and critique. All the authors approved the final version. Availability of Data and Material The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. Additional Information Ethics approval and consent to participate Anonymized data were collected from a publicly available database and do not require ethics committee approval. Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. References Ertekin, P.S., et al., Effect of stress management training on depression, stress and coping strategies in pregnant women: a randomised controlled trial. J Psychosom Obstet Gynaecol, 2018. 39(3): p. 203–210. Monteiro, F., et al., Exploring factors associated with complete mental health of pregnant women during the COVID-19 pandemic. Midwifery, 2023. 116: p. 103521. 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Ankarfeldt, M.Z., et al., Duloxetine Exposure During Pregnancy and the Risk of Offspring Being Born Small for Gestational Age or Prematurely: A Nationwide Danish and Swedish Safety Study. Drugs Real World Outcomes, 2023. 10(1): p. 69–81. Smit, M., et al., Mirtazapine in pregnancy and lactation: data from a case series. J Clin Psychopharmacol, 2015. 35(2): p. 163–7. Smit, M., K.M. Dolman and A. Honig, Mirtazapine in pregnancy and lactation - A systematic review. Eur Neuropsychopharmacol, 2016. 26(1): p. 126–135. Ostenfeld, A., et al., Mirtazapine exposure in pregnancy and fetal safety: A nationwide cohort study. Acta Psychiatr Scand, 2022. 145(6): p. 557–567. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4333094","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":299739863,"identity":"b429f260-0276-40cd-b342-20ecc1709707","order_by":0,"name":"Jingping Zheng","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAr0lEQVRIie3PMQqDQBCF4ZEBq43bZiCH2C4IYq6yEEiVQwwInsFcJFiOCFaSHMAiV1jJBaI5wdgFsn81xfuKAYjFfrU9FMZa1s7TL7kcqJEtBKAvHHulyF6MIW+fxoEkYb4qCA0AjsbJHJGRbncFcQvxVE8mZ0lxpyVC9cM48XqSMNWygdDgEWg8G2q6SvdL1gu+qS1P1lZdmDUExAYkXq+ENfuVLNtZO47FYrH/7APCnDPIs2l55wAAAABJRU5ErkJggg==","orcid":"","institution":"Jinan University","correspondingAuthor":true,"prefix":"","firstName":"Jingping","middleName":"","lastName":"Zheng","suffix":""},{"id":299739864,"identity":"9aa9a52d-6846-4f3e-9417-27e72f11a182","order_by":1,"name":"Lin Ma","email":"","orcid":"","institution":"University of Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Lin","middleName":"","lastName":"Ma","suffix":""},{"id":299739866,"identity":"0e85e089-0810-4085-86ad-07e82332db4d","order_by":2,"name":"Yankun Liang","email":"","orcid":"","institution":"Jinan University","correspondingAuthor":false,"prefix":"","firstName":"Yankun","middleName":"","lastName":"Liang","suffix":""},{"id":299739869,"identity":"7d5dbc12-c0d1-4eeb-9469-0916f000bac1","order_by":3,"name":"Zhenpo Zhang","email":"","orcid":"","institution":"Jinan University","correspondingAuthor":false,"prefix":"","firstName":"Zhenpo","middleName":"","lastName":"Zhang","suffix":""},{"id":299739873,"identity":"78bc0b66-d02e-4450-bacd-62c107a51fce","order_by":4,"name":"Qimin Wu","email":"","orcid":"","institution":"Jinan University","correspondingAuthor":false,"prefix":"","firstName":"Qimin","middleName":"","lastName":"Wu","suffix":""},{"id":299739875,"identity":"947ab4bb-09df-4536-aca8-91d628485c7a","order_by":5,"name":"Chufeng Din","email":"","orcid":"","institution":"Jinan University","correspondingAuthor":false,"prefix":"","firstName":"Chufeng","middleName":"","lastName":"Din","suffix":""},{"id":299739876,"identity":"dc57c3c2-6302-4e4f-8ba6-a3b20b648e78","order_by":6,"name":"Yuting Wang","email":"","orcid":"","institution":"Jinan University","correspondingAuthor":false,"prefix":"","firstName":"Yuting","middleName":"","lastName":"Wang","suffix":""},{"id":299739878,"identity":"c3117c48-ab51-4499-a3e5-01601ee36885","order_by":7,"name":"Jun Lyu","email":"","orcid":"","institution":"Guangdong Provincial Key Laboratory of Traditional Chinese Medicine Information","correspondingAuthor":false,"prefix":"","firstName":"Jun","middleName":"","lastName":"Lyu","suffix":""},{"id":299739880,"identity":"6bd432c9-8d95-4c68-a64d-00c6a74576d7","order_by":8,"name":"Ling Su","email":"","orcid":"","institution":"Jinan University","correspondingAuthor":false,"prefix":"","firstName":"Ling","middleName":"","lastName":"Su","suffix":""}],"badges":[],"createdAt":"2024-04-27 08:24:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4333094/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4333094/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":56409504,"identity":"76235432-6028-499e-842b-b9c6b8e2eb2d","added_by":"auto","created_at":"2024-05-13 20:00:44","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":26322,"visible":true,"origin":"","legend":"\u003cp\u003eAnnual quantity of congenital anomaly reports in newborn.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-4333094/v1/c81f7ae1029e9024478ee12a.png"},{"id":56409507,"identity":"ea37fb74-7e62-40ac-8257-f3b5e26bd234","added_by":"auto","created_at":"2024-05-13 20:00:54","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":85662,"visible":true,"origin":"","legend":"\u003cp\u003eNumber of signals distributed across System Organ Classes.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-4333094/v1/616b3037dacc5ea6e9210dd8.png"},{"id":58175329,"identity":"48148f13-8e11-4fb1-8076-96480f0beffd","added_by":"auto","created_at":"2024-06-12 04:31:49","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":780461,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4333094/v1/3944205c-42a4-461d-9273-ea2d746c1581.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Risk of Congenital Anomalies Associated with Psychotropic Medications: A Review of Neonatal Reports in the FDA Adverse Event Reporting System (FAERS)","fulltext":[{"header":"1 INTRODUCTION","content":"\u003cp\u003ePregnancy leads to substantial biological and psychosocial changes in women, frequently causing increased anxiety and stress[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Pregnant women experienced a notably higher prevalence of depression, anxiety, and other mood disorders during the COVID-19 pandemic[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], leading to a greater reliance on psychotropic medications. Common psychotropic medications comprise antidepressants, anxiolytics, and antipsychotics[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The safety of psychotropic medications in pregnancy has garnered significant attention.\u003c/p\u003e \u003cp\u003eCurrently, divergent perspectives exist regarding the association between prenatal exposure to psychotropic drugs and congenital abnormalities in newborns. For example, a cohort study that included 1,341,715 pregnant women reported that antipsychotic use in early pregnancy generally did not significantly increase the overall risk of congenital malformations[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Conversely, a separate cohort study involving 28,122 pregnant women with early exposure to antipsychotics suggests that the observed increased risk of cleft lip associated with olanzapine, gastroschisis, and specific brain abnormalities caused by other atypical antipsychotics[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Hence, comprehensive comprehension of the safety and potential risks associated with these medications during pregnancy is imperative, necessitating proactive identification and mitigation of any adverse effects on both maternal and fetal health. Our study aimed to achieve three primary objectives: (1) Identify safety signals for individual psychotropic medications and their potential correlation with congenital anomalies in the FAERS database. (2) Discover new or robust adverse event (AE) signals potentially linked with a specific drug or drug class. (3) Perform a comparative analysis of AE risks among different medications.\u003c/p\u003e"},{"header":"2 METHODS","content":"\u003cp\u003eWe conducted a retrospective pharmacovigilance study to explore whether there is an association between congenital abnormalities in newborns and psychotropic drugs. Specifically, we reviewed cases in the FAERS database from the first quarter of 2004 to the second quarter of 2023. We screened cases of infants under 28 days of age resulting from \u0026ldquo;congenital abnormalities\u0026rdquo;.\u003c/p\u003e \u003cp\u003eWe used four different signal detection methods, such as Reporting Odds Ratio (ROR), Medicines and Healthcare products Regulatory Agency (MHRA), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinker (MGPS) to calculate all signals associated with congenital abnormalities for psychoactive drugs[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The combination of these four methods can not only effectively detect signals but also reduce the interference of false positive signals. Only when a signal meets the criteria of all four methods simultaneously, will it be judged as a positive signal.\u003c/p\u003e \u003cp\u003eFinally, we utilized MedDRA to define preferred terms (PT) and System Organ Class (SOC) to classify and discuss the signals. We focused on signals with high rankings or unknown signal.\u003c/p\u003e"},{"header":"3 RESULTS","content":"\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Annual data analysis\u003c/h2\u003e \u003cp\u003eAs illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, from January 2004 to June 2023, the FAERS database documented 21,605 cases related to newborns, of which 6,208 cases indicated \u0026ldquo;congenital anomaly\u0026rdquo; as the outcome. Among these cases, 53.58% were male offspring, 36.50% were female offspring, and 9.92% had an undisclosed gender. Typically, the annual count of reports for males exceeded that of females. Generally, the annual report count showed a rapid increase followed by fluctuations. Reports of congenital anomalies experienced a significant rise between 2013 and 2014, increasing from 427 cases in 2013 to 809 cases in 2014, subsequently followed by a decrease.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Psychotropic medications and congenital Anomalies\u003c/h2\u003e \u003cp\u003eAs presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, out of 6,208 reports concerning congenital anomalies submitted to the FDA, 6,164 (99.29%) clearly attributed adverse events (AE) to medications. After performing calculations using four signal detection methods, the top ten psychiatric drugs associated with congenital abnormalities in newborns were Venlafaxine, Quetiapine, Olanzapine, Sertraline, Citalopram, Mirtazapine, Duloxetine, Paroxetine, Aripiprazole, and Fluoxetine. Among these drugs, Venlafaxine and Quetiapine exhibited the highest number of signals, both at 27, followed by Olanzapine (26) and Sertraline (25). Conversely, Paroxetine had the highest incidence of congenital Anomalies, with Citalopram and Sertraline following suit. It is essential to stress that these cases were relatively infrequent in the complete dataset. These medications were classified into Atypical Antipsychotics (AAs), Selective Serotonin Reuptake Inhibitors (SSRIs), Serotonin Norepinephrine Reuptake Inhibitors (SNRIs), and Non-Selective Serotonin and Norepinephrine Reuptake Inhibitors (NaSSA) based on their pharmacological properties. These ten medications consist of four SSRIs, three AAs, two SNRIs, and one NaSSA.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePsychotropic Medications Related Congenital Anomaly Reports in FAERS Database from 2004Q1-2023Q2.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDrug Name\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSignals\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAdverse Event Reports (%) (n\u0026thinsp;=\u0026thinsp;6164)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eClass#\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVenlafaxine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e266 (4.32%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSNRIs\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eQuetiapine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e245 (3.97%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAAs\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOlanzapine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e90 (1.46%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAAs\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSertraline\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e285 (4.62%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSSRIs\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCitalopram\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e339 (5.50%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSSRIs\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMirtazapine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e74 (1.20%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNaSSA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuloxetine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e71 (1.15%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSNRIs\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParoxetine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e360 (5.84%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSSRIs\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAripiprazole\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e141 (2.29%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAAs\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFluoxetine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e246 (3.99%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSSRIs\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e# Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs), Atypical Antipsychotics (AAs), Selective Serotonin Reuptake Inhibitors (SSRIs),Non-Selective Serotonin and Norepinephrine Reuptake Inhibitor (NaSSA)\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Signals distributed across System Organ Classes\u003c/h2\u003e \u003cp\u003eOverall, the signals of psychotropic drugs were concentrated in the SOC categories of heart disease, musculoskeletal-connective tissue disease, neurological disease, and respiratory-thoracic-mediastinal disease, as illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Specifically, upon comparing the signals of three Atypical Antipsychotics (AAs) within SOCs, quetiapine predominantly displayed signals linked to cardiovascular issues, olanzapine demonstrated the highest number of signals related to the nervous and musculoskeletal systems, and aripiprazole exhibited the most signals associated with respiratory conditions. When comparing four Selective Serotonin Reuptake Inhibitors (SSRIs), with the exception of fluoxetine, the signals identified by the other three SSRIs (Sertraline, Citalopram, Paroxetine) displayed notable associations with cardiac organs. Of the two Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs), venlafaxine signaling was predominantly linked to respiratory-thoracic-mediastinal diseases, whereas duloxetine did not exhibit notable prominence across various SOCs. As a Noradrenergic and Specific Serotonergic Antidepressant (NaSSA), mirtazapine signals primarily concentrate in musculoskeletal tissues and various neurological systems.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e3.4 The top5 signals of ten psychotropic drugs\u003c/h2\u003e \u003cp\u003eGiven ROR's superior sensitivity among the four signal detection methods[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], we focus on analyzing the top five signals for ten psychotropic drugs using the lower bound of the 95% confidence interval (95% CI\u003csub\u003elower\u003c/sub\u003e ROR), As presented in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Among all signals, the most notable intensity was observed in \u0026ldquo;Blood creatine phosphokinase MB increased\u0026rdquo; (95% CI\u003csub\u003elower\u003c/sub\u003e ROR\u0026thinsp;=\u0026thinsp;35.41) and \u0026ldquo;Myoglobin blood increased\u0026rdquo; (95% CI\u003csub\u003elower\u003c/sub\u003e ROR\u0026thinsp;=\u0026thinsp;35.41) associated with Olanzapine. Additionally, Duloxetine demonstrated its most prominent signal with \u0026ldquo;Telangiectasia congenital\u0026rdquo; (95% CI\u003csub\u003elower\u003c/sub\u003e ROR\u0026thinsp;=\u0026thinsp;33.15). Mirtazapine exhibited its most prominent signal with \u0026ldquo;Neonatal hyponatremia\u0026rdquo; (95% CI\u003csub\u003elower\u003c/sub\u003e ROR\u0026thinsp;=\u0026thinsp;22.98), whereas Quetiapine's most significant signal related to \u0026ldquo;Junctional ectopic tachycardia\u0026rdquo; (95% CI\u003csub\u003elower\u003c/sub\u003e ROR\u0026thinsp;=\u0026thinsp;18.01). Venlafaxine displayed the strongest signal associated with \u0026ldquo;Pyelonephritis\u0026rdquo; 95% CI\u003csub\u003elower\u003c/sub\u003e ROR\u0026thinsp;=\u0026thinsp;17.91). Citalopram and Paroxetine exhibited their most notable signal intensity concerning \u0026ldquo;Attention deficit/Hyperactivity disorder\u0026rdquo; (95% CI\u003csub\u003elower\u003c/sub\u003e ROR\u0026thinsp;=\u0026thinsp;11.28). Aripiprazole's most notable signal pertained to \u0026ldquo;Enterococcal sepsis\u0026rdquo; (95% CI\u003csub\u003elower\u003c/sub\u003e ROR\u0026thinsp;=\u0026thinsp;9.73), while Sertraline's most notable signal intensity was associated with \u0026ldquo;Coordination abnormal\u0026rdquo; (95% CI\u003csub\u003elower\u003c/sub\u003e ROR\u0026thinsp;=\u0026thinsp;9.18). Fluoxetine exhibited only two signals, with the strongest signal being \u0026ldquo;Meconium in amniotic fluid\u0026rdquo; (95% CI\u003csub\u003elower\u003c/sub\u003e ROR\u0026thinsp;=\u0026thinsp;4.58).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThe top5 signals of ten psychotropic drugs\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClass#\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDrug\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePT\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ea\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e95%CI\u003csub\u003elower\u003c/sub\u003e ROR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePRR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eIC-2SD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003e95%CI\u003csub\u003elower\u003c/sub\u003e EGBM\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"14\" rowspan=\"15\"\u003e \u003cp\u003eAA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003eOlanzapine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBlood creatine phosphokinase MB increased\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e35.41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e173.72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e8.89\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMyoglobin blood increased\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e35.41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e173.72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e8.89\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFever neonatal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e35.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e115.81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e11.78\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBlood lactate dehydrogenase increased\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e29.24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e115.81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e9.79\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOesophageal stenosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e24.74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e86.86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e9.94\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003eQuetiapine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eJunctional ectopic tachycardia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e18.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e86.23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e4.14\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMitral valve atresia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e17.53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e65.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e4.94\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAortic valve atresia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e12.97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e39.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e5.15\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEnterococcal sepsis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e10.47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e36.96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e4.33\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRight ventricular false tendon\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e10.47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e36.96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e4.33\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003eAripiprazole\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEnterococcal sepsis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e9.73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e34.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e5.91\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRight ventricular false tendon\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e9.73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e34.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e5.91\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBreech presentation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e5.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e12.88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e4.28\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePulmonary arterial hypertension\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e14.72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e3.83\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMeconium aspiration syndrome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e10.85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e3.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"9\" rowspan=\"10\"\u003e \u003cp\u003eSNRI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003eDuloxetine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTelangiectasia congenital\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e33.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e33.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e14.64\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGastroschisis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e16.93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e16.93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e11.84\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eThrombocytopenia neonatal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e9.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e9.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e7.35\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLiver disorder\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e8.85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e8.85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e6.64\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNeonatal hyponatraemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e8.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e8.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e6.23\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003eVenlafaxine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePyelonephritis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e17.91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e38.64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e6.83\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eWithdrawal syndrome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e11.59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e27.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e5.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCongenital vesicoureteric reflux\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e10.95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e29.23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e4.96\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePoor weight gain neonatal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e10.57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e30.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e4.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTemperature regulation disorder\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e6.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e12.73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e4.42\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003eNaSSA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003eMirtazapine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNeonatal hyponatraemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e22.98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e69.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e13.99\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAdactyly\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e12.96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e40.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e9.44\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNeonatal seizure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e8.59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e22.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e7.08\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCongenital inguinal hernia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e5.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e15.85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e4.87\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePlagiocephaly\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e12.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e4.41\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"16\" rowspan=\"17\"\u003e \u003cp\u003eSSRI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003eCitalopram\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAttention deficit/Hyperactivity disorder\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e11.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e20.48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e7.77\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOtitis media chronic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e6.72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e16.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e7.15\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCongenital scoliosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e6.59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e21.84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e7.95\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCongenital aortic valve incompetence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e16.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e7.15\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eArnold-chiari malformation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e9.36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e5.50\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003eParoxetine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAttention deficit/Hyperactivity disorder\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e11.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e20.48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e4.23\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOtitis media chronic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e6.72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e16.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e2.92\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCongenital scoliosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e6.59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e21.84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e2.39\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCongenital aortic valve incompetence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e16.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e2.02\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eArnold-chiari malformation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e9.36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e2.54\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003eSertraline\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCoordination abnormal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e9.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e22.99\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e4.75\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eElectrocardiogram QT prolonged\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e9.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e26.83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e4.34\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eInfantile haemangioma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e9.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e26.83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e4.34\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNeonatal infection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e9.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e26.83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e4.34\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRight ventricular failure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e8.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e27.59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e3.99\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eFluoxetine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMeconium in amniotic fluid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e15.79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e2.43\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSeizure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e6.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e2.60\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"8\"\u003e# Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs), Atypical Antipsychotics (AAs), Selective Serotonin Reuptake Inhibitors (SSRIs),Non-Selective Serotonin and Norepinephrine Reuptake Inhibitor (NaSSA)\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"4 DISCUSSION","content":"\u003cp\u003eIn recent years, many scholars have conducted data mining research based on large pharmacovigilance databases[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. 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.\u003c/p\u003e \u003cp\u003eOur 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.\u003c/p\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e4.1 Atypical Antipsychotics (Quetiapine, Olanzapine, Aripiprazole)\u003c/h2\u003e \u003cp\u003eOur 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[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Existing data indicate that antipsychotic drugs exhibit different adverse drug reactions (ADR) across different age groups, including children and pregnant women[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. 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.\u003c/p\u003e \u003cp\u003eUpon 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[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Additionally, the musculoskeletal muscle abnormal signal results of Olanzapine are consistent with existing research conclusions[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. 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[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. 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.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e4.2 Selective Serotonin Reuptake Inhibitors (Sertraline, Citalopram, Paroxetine, Fluoxetine)\u003c/h2\u003e \u003cp\u003eSertraline, 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[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. 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[\u003cspan additionalcitationids=\"CR17 CR18\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. 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.\u003c/p\u003e \u003cp\u003eFurthermore, 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[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. With no satisfactory treatment methods currently available, vigilance regarding the potential risks posed by SSRIs is warranted.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e4.3 Serotonin-Norepinephrine Reuptake Inhibitors (Venlafaxine, Duloxetine)\u003c/h2\u003e \u003cp\u003eOur research identified signals of neonatal adverse respiratory events linked to venlafaxine. Extensive literature supports the notion that venlafaxine induces neonatal withdrawal syndrome[\u003cspan additionalcitationids=\"CR23\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e], marked by symptoms such as tachycardia, rapid breathing, respiratory distress, dystonia, and others[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. 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.\u003c/p\u003e \u003cp\u003eDespite 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[\u003cspan additionalcitationids=\"CR27\" citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. 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[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Our findings are not fully consistent with the conclusions drawn in these studies.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e4.4 Norepinephrine Reuptake Inhibitor (Mirtazapine)\u003c/h2\u003e \u003cp\u003eOur 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[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. 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[\u003cspan additionalcitationids=\"CR30\" citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Furthermore, we found that mirtazapine was strongly linked to neonatal hyponatremia, neonatal seizures, and congenital inguinal hernia.\u003c/p\u003e \u003c/div\u003e"},{"header":"5 CONCLUSION","content":"\u003cp\u003eFew studies have investigated drug exposure in pregnant women and newborns, with the majority relying on cohort and case-control designs. Our study utilizes signal mining in extensive databases, offering a novel approach to clinical evidence. Through analysis of publicly accessible FAERS databases, we identified a potential link between commonly prescribed psychotropic medications, including SSRIs, AAs, SNRIs, and NaSSA, and congenital abnormalities. Despite inherent limitations stemming from the voluntary reporting system in the FDA FAERS database, the presence of associated risks cannot be overlooked.\u003c/p\u003e \u003cp\u003eIn conclusion, acquiring comprehensive data on the potential risks of psychotropic medication use during pregnancy is imperative to safeguard embryos and fetuses. Such information is vital for healthcare professionals to make well-informed prescribing decisions and offer appropriate counseling to pregnant patients concerning their treatment choices.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAcknowledgement\u003c/h2\u003e\n\u003cp\u003eThanks to all the individuals who assisted and facilitated the research, those who provided suggestions and assistance throughout the research process, and the owners of materials, pictures, documents, and research ideas who granted permission for reproduction and citation.\u003c/p\u003e\n\u003ch2\u003eAuthors\u0026rsquo; Contributions\u003c/h2\u003e\n\u003cp\u003eJ.Zheng,\u0026nbsp;L. Ma, Z.Zhang, Y.Liang, Q.Wu, C.Din, Y.Wang, J.Lyu and L.Su conceived and executed the research project. \u0026nbsp;J.Zheng designed and executed the statistical analysis. \u0026nbsp;L.Ma collated the data. \u0026nbsp; J.Zheng, L.Ma, Z.Zhang, Y.Liang, Q.Wu, C.Din, Y.Wang, J.Lyu and L.Su reviewed and critiqued the statistical analysis. \u0026nbsp;All the authors contributed to the interpretation of data. \u0026nbsp;Regarding article preparation, the writing of the first draft was executed by J.Zheng and L.Ma, all the authors contributed to the review and critique. \u0026nbsp;All the authors approved the final version.\u003c/p\u003e\n\u003ch2\u003eAvailability of Data and Material\u003c/h2\u003e\n\u003cp\u003eThe datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003ch2\u003eAdditional Information\u003c/h2\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate \u0026nbsp;\u003c/strong\u003eAnonymized data were collected from a publicly available database and do not require ethics committee approval.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp;\u003c/strong\u003eThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eErtekin, P.S., et al., Effect of stress management training on depression, stress and coping strategies in pregnant women: a randomised controlled trial. J Psychosom Obstet Gynaecol, 2018. 39(3): p. 203\u0026ndash;210.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMonteiro, F., et al., Exploring factors associated with complete mental health of pregnant women during the COVID-19 pandemic. Midwifery, 2023. 116: p. 103521.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMcAllister-Williams, R.H., et al., British Association for Psychopharmacology consensus guidance on the use of psychotropic medication preconception, in pregnancy and postpartum 2017. J Psychopharmacol, 2017. 31(5): p. 519\u0026ndash;552.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHuybrechts, K.F., et al., Antipsychotic Use in Pregnancy and the Risk for Congenital Malformations. JAMA Psychiatry, 2016. 73(9): p. 938\u0026ndash;46.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHuybrechts, K.F., et al., Association of In Utero Antipsychotic Medication Exposure With Risk of Congenital Malformations in Nordic Countries and the US. JAMA Psychiatry, 2023. 80(2): p. 156\u0026ndash;166.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSakaeda, T., et al., Data mining of the public version of the FDA Adverse Event Reporting System. Int J Med Sci, 2013. 10(7): p. 796\u0026ndash;803.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAng, P.S., et al., Data mining spontaneous adverse drug event reports for safety signals in Singapore - a comparison of three different disproportionality measures. Expert Opin Drug Saf, 2016. 15(5): p. 583\u0026ndash;90.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTan, G., et al., Drug repurposing using real-world data. Drug Discov Today, 2023. 28(1): p. 103422.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMcCauley-Elsom, K., et al., Antipsychotics in pregnancy. J Psychiatr Ment Health Nurs, 2010. 17(2): p. 97\u0026ndash;104.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKulkarni, J., et al., Antipsychotic use in pregnancy. Expert Opin Pharmacother, 2015. 16(9): p. 1335\u0026ndash;45.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSagreiya, H., et al., Differences in Antipsychotic-Related Adverse Events in Adult, Pediatric, and Geriatric Populations. Cureus, 2017. 9(2): p. e1059.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu, X., et al., Maternal antipsychotic use during pregnancy and congenital malformations. Am J Obstet Gynecol MFM, 2023. 5(6): p. 100950.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAndrade, C., Major Congenital Malformations Associated With Exposure to Second-Generation Antipsychotic Drugs During Pregnancy. J Clin Psychiatry, 2021. 82(5).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStraub, L., et al., Association of Antipsychotic Drug Exposure in Pregnancy With Risk of Neurodevelopmental Disorders: A National Birth Cohort Study. JAMA Intern Med, 2022. 182(5): p. 522\u0026ndash;533.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBruggeman, C. and C.S. O'Day, Selective Serotonin Reuptake Inhibitor Toxicity. 2024.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSadler, T.W., Selective serotonin reuptake inhibitors (SSRIs) and heart defects: potential mechanisms for the observed associations. Reprod Toxicol, 2011. 32(4): p. 484\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWatanabe, N., et al., Mirtazapine versus other antidepressive agents for depression. Cochrane Database Syst Rev, 2011(12): p. CD006528.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGao, S.Y., et al., Selective serotonin reuptake inhibitor use during early pregnancy and congenital malformations: a systematic review and meta-analysis of cohort studies of more than 9 million births. BMC Med, 2018. 16(1): p. 205.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShad, M.U., et al., How to identify and manage non-response to clozapine? Asian J Psychiatr, 2019. 45: p. 50\u0026ndash;52.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKelly, M.P., T.J. Guillaume and L.G. Lenke, Spinal Deformity Associated with Chiari Malformation. Neurosurg Clin N Am, 2015. 26(4): p. 579\u0026ndash;85.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFons, K. and A.J. Jnah, Arnold-Chiari Malformation: Core Concepts. Neonatal Netw, 2021. 40(5): p. 313\u0026ndash;320.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHolland, J. and R. Brown, Neonatal venlafaxine discontinuation syndrome: A mini-review. Eur J Paediatr Neurol, 2017. 21(2): p. 264\u0026ndash;268.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFava, G.A., et al., Withdrawal Symptoms after Serotonin-Noradrenaline Reuptake Inhibitor Discontinuation: Systematic Review. Psychother Psychosom, 2018. 87(4): p. 195\u0026ndash;203.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMarks, C., et al., Comparing newborn outcomes after prenatal exposure to individual antidepressants: A retrospective cohort study. Pharmacotherapy, 2021. 41(11): p. 907\u0026ndash;914.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang, J. and F. Cosci, Neonatal Withdrawal Syndrome following Late in utero Exposure to Selective Serotonin Reuptake Inhibitors: A Systematic Review and Meta-Analysis of Observational Studies. Psychother Psychosom, 2021. 90(5): p. 299\u0026ndash;307.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHuybrechts, K.F., et al., Maternal and fetal outcomes following exposure to duloxetine in pregnancy: cohort study. BMJ, 2020. 368: p. m237.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAnkarfeldt, M.Z., et al., Exposure to duloxetine during pregnancy and risk of congenital malformations and stillbirth: A nationwide cohort study in Denmark and Sweden. PLoS Med, 2021. 18(11): p. e1003851.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAnkarfeldt, M.Z., et al., Duloxetine Exposure During Pregnancy and the Risk of Offspring Being Born Small for Gestational Age or Prematurely: A Nationwide Danish and Swedish Safety Study. Drugs Real World Outcomes, 2023. 10(1): p. 69\u0026ndash;81.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSmit, M., et al., Mirtazapine in pregnancy and lactation: data from a case series. J Clin Psychopharmacol, 2015. 35(2): p. 163\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSmit, M., K.M. Dolman and A. Honig, Mirtazapine in pregnancy and lactation - A systematic review. Eur Neuropsychopharmacol, 2016. 26(1): p. 126\u0026ndash;135.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOstenfeld, A., et al., Mirtazapine exposure in pregnancy and fetal safety: A nationwide cohort study. Acta Psychiatr Scand, 2022. 145(6): p. 557\u0026ndash;567.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Antipsychotics, pregnancy, newborn, adverse event, pharmacovigilance","lastPublishedDoi":"10.21203/rs.3.rs-4333094/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4333094/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eThe objective of this article is to explore commonly prescribed psychotropic medications, such as atypical antipsychotics (AAs), selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), regarding their potential association with congenital anomalies in newborns. This analysis will be based on data obtained from the Food and Drug Administration Adverse Event Reporting System (FAERS).\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eSpontaneously reported cases involving congenital anomalies in newborns (under 28 days old) were extracted and reviewed from the FAERS database covering the period from January 2004 to June 2023. We employed four methods (ROR, PRR, BCPMM, MGPS) to identify signals associated with neonatal deformities caused by specific drugs in newborns.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe FAERS database encompassed 21,605 reported cases involving newborns, of which 6,208 reported congenital abnormalities. Among these cases, 6,164 (99.29%) explicitly attributed the adverse event to the drug. Following calculations utilizing four signal detection methods, the top ten psychiatric drugs associated with congenital abnormalities in newborns were Venlafaxine, Quetiapine, Olanzapine, Sertraline, Citalopram, Mirtazapine, Duloxetine, Paroxetine, Aripiprazole, and Fluoxetine. These drugs demonstrated heightened signal frequencies concerning heart disease, neurological disorders, respiratory-chest-mediastinal conditions, and musculoskeletal-connective tissue disorders.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eThe use of psychotropic medications during pregnancy has been observed to correlate with the potential risk of specific congenital abnormalities. Pregnant women with psychiatric disorders are advised to use psychotropic drugs with caution. Healthcare professionals should actively understand the potential risks of specific psychotropic medications in causing particular congenital abnormalities, enabling them to provide informed counseling and explore more suitable treatment options for patients.\u003c/p\u003e","manuscriptTitle":"Risk of Congenital Anomalies Associated with Psychotropic Medications: A Review of Neonatal Reports in the FDA Adverse Event Reporting System (FAERS)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-13 20:00:35","doi":"10.21203/rs.3.rs-4333094/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d2a0438d-0a3e-4bc5-a58d-d26529ff7aa7","owner":[],"postedDate":"May 13th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":31623835,"name":"Biological sciences/Drug discovery/Drug regulation"},{"id":31623836,"name":"Biological sciences/Drug discovery/Drug safety"}],"tags":[],"updatedAt":"2024-06-12T04:23:42+00:00","versionOfRecord":[],"versionCreatedAt":"2024-05-13 20:00:35","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4333094","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4333094","identity":"rs-4333094","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}