Tricyclic antidepressants

Table   Graphic  
individual studies
OutcomeTE95% CIn casesn exposedkPub. bias Congenital malformations All congenital malformations (majors, minors, majors and minors, or unspecified) Kullander - Imipramine, 1976 Greenberg, 1977 Pastuszak (Controls unexposed, NOS), 1993 Nulman (Controls unexposed, NOS), 1997 Davis, 2007 Vasilakis-Scaramozza (Controls unexposed, NOS), 2013 Källen, 2013 Ban (Controls unexposed, sick), 2014 Ozturk - Amitriptyline, 2016 Bérard (Controls unexposed, sick), 2017 Anderson, 2020 Bahat, 2020 Chan (Controls unexposed, sick), 2024 131.05[0.93; 1.18]41,8457,205low Major congenital malformations Kullander - Imipramine, 1976 Greenberg, 1977 Pastuszak (Controls unexposed, NOS), 1993 Nulman (Controls unexposed, NOS), 1997 Vasilakis-Scaramozza (Controls unexposed, NOS), 2013 Källen, 2013 Ban (Controls unexposed, sick), 2014 Ozturk - Amitriptyline, 2016 Bérard (Controls unexposed, sick), 2017 Anderson, 2020 Bahat, 2020 Chan (Controls unexposed, sick), 2024 121.06[0.93; 1.20]34,4637,035low Congenital heart defects Davis, 2007 Vasilakis-Scaramozza (Controls unexposed, NOS), 2013 Källen, 2013 Huybrechts (Controls unexposed, sick), 2014 Ban (Controls unexposed, sick), 2014 Bérard (Controls unexposed, sick), 2017 Chan (Controls unexposed, sick), 2024 71.02[0.80; 1.30]3,00810,192not evaluable Urinary malformations Davis, 2007 Vasilakis-Scaramozza (Controls unexposed, NOS), 2013 Ban (Controls unexposed, sick), 2014 Bérard (Controls unexposed, sick), 2017 Chan (Controls unexposed, sick), 2024 51.12[0.66; 1.91]5754,766not evaluable Limb defects Ban (Controls unexposed, sick), 2014 Bérard (Controls unexposed, sick), 2017 Chan (Controls unexposed, sick), 2024 31.02[0.70; 1.49]1562,991not evaluable Nervous system anomalies Vasilakis-Scaramozza (Controls unexposed, NOS), 2013 Ban (Controls unexposed, sick), 2014 Bérard (Controls unexposed, sick), 2017 Chan (Controls unexposed, sick), 2024 41.31[0.66; 2.61]724,599not evaluable Respiratory system anomalies Davis, 2007 Ban (Controls unexposed, sick), 2014 Bérard (Controls unexposed, sick), 2017 Chan (Controls unexposed, sick), 2024 41.69[0.70; 4.07]2813,158not evaluable Cardiac septal defects Davis, 2007 Källen, 2013 Ban (Controls unexposed, disease free), 2014 Bérard (Controls unexposed, sick), 2017 Chan (Controls unexposed, sick), 2024 51.31[1.00; 1.73]7805,297not evaluable Genital anomalies Davis, 2007 Vasilakis-Scaramozza (Controls unexposed, NOS), 2013 Ban (Controls unexposed, sick), 2014 Bérard (Controls unexposed, sick), 2017 40.70[0.45; 1.08]1,3114,585not evaluable Ventricular septal defect Ban (Controls unexposed, disease free), 2014 Huybrechts (Controls unexposed, sick), 2014 Louik, 2014 Chan (Controls unexposed, sick), 2024 40.85[0.59; 1.22]3,5025,953not evaluable Atrial septal defect Ban (Controls unexposed, disease free), 2014 Louik, 2014 Chan (Controls unexposed, sick), 2024 31.34[0.74; 2.45]1,1992,647not evaluable Digestive system anomalies Davis, 2007 Ban (Controls unexposed, sick), 2014 Bérard (Controls unexposed, sick), 2017 32.33[1.38; 3.94]1532,977not evaluable Chromosomal abnormalities Davis, 2007 Ban (Controls unexposed, sick), 2014 20.89[0.33; 2.38]1232,595not evaluable Ear, face and neck anomalies Davis, 2007 Ban (Controls unexposed, sick), 2014 20.51[0.07; 3.77]2182,595not evaluable Eye defects Davis, 2007 Ban (Controls unexposed, sick), 2014 21.05[0.11; 9.88]6622,595not evaluable Oro-facial clefts Davis, 2007 Ban (Controls unexposed, sick), 2014 20.67[0.18; 2.41]1162,595not evaluable Abdominal wall defects Ban (Controls unexposed, sick), 2014 11.11[0.05; 23.05]22,428not evaluable Eye, ear, face and neck malformations Vasilakis-Scaramozza (Controls unexposed, NOS), 2013 Bérard (Controls unexposed, sick), 2017 21.48[0.44; 4.93]141,990not evaluable Minor congenital malformations Kullander - Imipramine, 1976 13.04[0.82; 11.25]55112not evaluable Atrioventricular septal defect Louik, 2014 10.70[0.10; 4.85]52133not evaluable Coarctation of aorta Louik, 2014 11.30[0.30; 5.57]47134not evaluable Craniosynostosis Bérard (Controls unexposed, sick), 2017 11.05[0.25; 4.39]-382not evaluable Hypoplastic left heart (HLH/HLHS) Louik, 2014 10.90[0.11; 7.58]28133not evaluable Hypospadias Källen, 2013 11.38[0.70; 2.71]12,139not evaluable Spina bifida Davis, 2007 112.43[1.70; 90.77]29167not evaluable Growth parameters and prematurity Preterm (< 37 weeks) Simon (Controls unexposed, NOS), 2002 Pearson (Controls unexposed, NOS), 2007 Davis, 2007 Reis (Controls unexposed, NOS), 2010 Ozturk - Amitriptyline, 2016 Bahat, 2020 Chen, 2021 Martin - Amitriptyline, 2024 Lee (Controls unexposed, general pop), 2025 91.53[1.23; 1.89]212,5617,181not evaluable Low birth weight (< 2500g) Simon (Controls unexposed, NOS), 2002 Pearson (Controls exposed to SSRIs), 2007 Reis (Controls unexposed, NOS), 2010 Lee (Controls unexposed, general pop), 2025 41.20[0.99; 1.47]68,5781,643not evaluable Small for gestational age (weight) Reis (Controls unexposed, NOS), 2010 Martin - Amitriptyline, 2024 Lee (Controls unexposed, general pop), 2025 30.99[0.90; 1.10]261,3165,256not evaluable Large for gestational age (weight) Reis (Controls unexposed, NOS), 2010 Lee (Controls unexposed, general pop), 2025 20.83[0.42; 1.66]78,6261,397not evaluable Macrosomia (> 4000g) Reis (Controls unexposed, NOS), 2010 10.62[0.40; 0.96]46,071784not evaluable Maternal consequences Preeclampsia De Vera, 2012 Palmsten (Controls unexposed, sick), 2012 Palmsten a (Controls unexposed, sick), 2013 Avalos (Controls unexposed, sick), 2015 Lupattelli (Controls unexposed, sick), 2017 Zakiyah, 2018 Bernard, 2019 Yang, 2021 Tran (Controls unexposed, NOS), 2022 91.80[1.24; 2.63]9,4641,137not evaluable Caesarean Solé, 2020 Lee (Controls unexposed, general pop), 2025 21.00[0.84; 1.19]111,874618not evaluable Assisted deliveries (forceps, vacuum, ...) Lee (Controls unexposed, general pop), 2025 10.89[0.67; 1.19]46,086613not evaluable Postpartum hemorrhage Palmsten b, 2013 Källen, 2013 Lee (Controls unexposed, general pop), 2025 31.19[0.88; 1.60]21,6921,182not evaluable Maternal consequences (as a whole) Lee (Controls unexposed, general pop), 2025 11.01[0.84; 1.21]311,547613not evaluable Gestational diabetes Dandjinou, 2019 11.47[1.22; 1.77]20,905971not evaluable Neonatal disorders Neonatal medical care Davis, 2007 Pearson (Controls unexposed, NOS), 2007 Reis (Controls unexposed, NOS), 2010 Lee (Controls unexposed, general pop), 2025 42.03[1.32; 3.11]71,5971,570not evaluable Low Apgar score (< 7) (at 5 min) Simon (Controls unexposed, NOS), 2002 Källen, 2013 Martin - Amitriptyline, 2024 Lee (Controls unexposed, general pop), 2025 41.36[0.87; 2.14]32,8004,115not evaluable Neonatal disorders (as a whole) Källen, 2013 Lee (Controls unexposed, general pop), 2025 21.58[1.18; 2.13]161,8011,007not evaluable Jaundice / Icterus Reis (Controls unexposed, NOS), 2010 11.39[1.03; 1.88]52,050784not evaluable Low Apgar score (< 7) (at 1 min) Lee (Controls unexposed, general pop), 2025 11.33[0.93; 1.90]14,917613not evaluable Low Apgar score (< 7) (NOS) Reis (Controls unexposed, NOS), 2010 12.75[1.91; 3.96]15,570784not evaluable Neonatal death (< 28 days of life) Lee (Controls unexposed, general pop), 2025 10.60[0.04; 9.65]627613not evaluable Neonatal hypoglycemia Reis (Controls unexposed, NOS), 2010 11.83[1.38; 2.43]34,844784not evaluable Neonatal intracranial hemorrhage Reis (Controls unexposed, NOS), 2010 10.83[0.12; 5.89]1,636784not evaluable Very low Apgar score (< 5) (at 1 min) Simon (Controls unexposed, NOS), 2002 11.16[0.50; 2.70]27209not evaluable Feeding difficulty Davis, 2007 11.69[0.96; 2.97]3,496136not evaluable Fetal distress Davis, 2007 15.90[0.36; 96.15]47136not evaluable Metabolic disorders in neonate/infant Davis, 2007 12.15[1.04; 4.44]1,805136not evaluable Long term consequences Child/Infant death (> 28 days of life) Lee (Controls unexposed, general pop), 2025 12.90[0.18; 46.64]130613not evaluable Childhood asthma Liu, 2015 11.28[1.06; 1.55]1,718409not evaluable Intrauterine deaths Early intrauterine deaths (< 22 weeks) / Spontaneous abortions Pastuszak (Controls unexposed, NOS), 1993 Yaris, 2005 Nakhai-Pour, 2010 Ban (Controls unexposed, sick), 2012 Kjaersgaard (Controls unexposed, sick), 2013 Abadie, 2015 Ozturk - Amitriptyline, 2016 Kitchin, 2022 81.38[1.17; 1.62]24,7124,716not evaluable Elective/induced termination of pregnancy Pastuszak (Controls unexposed, NOS), 1993 Ban (Controls unexposed, sick), 2012 Kieler, 2015 Ozturk - Amitriptyline, 2016 41.40[1.19; 1.64]15,6224,427not evaluable Perinatal death Ban (Controls unexposed, sick), 2012 11.20[0.52; 2.79]134,349not evaluable Ectopic pregnancy Wall-Wieler, 2020 11.44[1.00; 2.07]2,2891,037not evaluable Therapeutic terminations of pregnancy Kieler, 2015 11.00[0.50; 2.00]--not evaluable Neuro-developmental disorders ASD (Autism spectrum disorder): Diagnosis Sørensen (Controls unexposed, NOS), 2013 Boukhris (Controls unexposed, NOS), 2016 Rai - Clomipramine only (Controls unexposed, sick), 2017 Hagberg (Controls unexposed, sick), 2018 Suarez (Controls unexposed, discontinuers), 2022 Heuvelman, 2023 61.42[1.20; 1.68]7,09412,417not evaluable ASD (Autism spectrum disorder): Diagnosis/Risk Sørensen (Controls unexposed, NOS), 2013 Boukhris (Controls unexposed, NOS), 2016 Rai - Clomipramine only (Controls unexposed, sick), 2017 Hagberg (Controls unexposed, sick), 2018 Suarez (Controls unexposed, discontinuers), 2022 Heuvelman, 2023 61.42[1.20; 1.68]7,09412,417not evaluable ADHD (Attention deficit hyperactivity disorder): Diagnosis Laugesen, 2013 Boukhris (Controls unexposed, NOS), 2017 Suarez (Controls unexposed, discontinuers), 2022 Hartwig, 2022 Heuvelman, 2023 51.19[0.98; 1.45]4,7987,398not evaluable ADHD (Attention deficit hyperactivity disorder): Diagnosis/Risk Laugesen, 2013 Boukhris (Controls unexposed, NOS), 2017 Suarez (Controls unexposed, discontinuers), 2022 Hartwig, 2022 Heuvelman, 2023 51.19[0.98; 1.45]4,7987,398not evaluable Psychomotor developmental disorders/delay Simon (Controls unexposed, NOS), 2002 Nulman (Controls unexposed, disease free), 2002 Pedersen, 2010 Suarez (Controls unexposed, discontinuers), 2022 41.05[0.56; 1.97]2984,544not evaluable Language disorders/delay Simon (Controls unexposed, NOS), 2002 Nulman (Controls unexposed, disease free), 2002 Suarez (Controls unexposed, discontinuers), 2022 30.90[0.71; 1.14]3614,561not evaluable Cognitive developmental disorders/delay (3-6 years old) Nulman (Controls unexposed, disease free), 2002 Suarez (Controls unexposed, discontinuers), 2022 21.03[0.44; 2.41]-3,512not evaluable Childhood autism (F84.0) Sørensen (Controls unexposed, NOS), 2013 10.99[0.25; 3.98]2,032642not evaluable Cognitive developmental disorders/delay (< 3 years old) Nulman (Controls unexposed, disease free), 2002 10.48[0.16; 1.43]-28not evaluable Learning disorders Suarez (Controls unexposed, discontinuers), 2022 10.82[0.39; 1.72]343,494not evaluable Neuro-developmental disorders (as a whole) Suarez (Controls unexposed, discontinuers), 2022 10.95[0.79; 1.14]7624,307not evaluable Severe cognitive developmental delay (Mental retardation) (3-6 years old) Suarez (Controls unexposed, discontinuers), 2022 10.95[0.29; 3.14]-3,494not evaluable Cognitive developmental disorders/delay (> 6 years old) Heuvelman, 2023 10.90[0.46; 1.77]-2,148not evaluable Severe cognitive developmental delay (Mental retardation) (> 6 years old) Heuvelman, 2023 10.90[0.46; 1.77]-2,148not evaluable0.0100.01.0