Tricyclic antidepressants updated on 07-01-2025

Major congenital malformations

R analysis
id Study   Lib. in paper Exposition period    Study type 
 Control type 
 
Tags OR 95%CI x1/n1 x0/n0 no cases no exposed ROB Ref.
S18161
R76379		 Chan (Controls exposed to SSRIs), 2024 Any major malformations 1st trimester retrospective cohort (claims database) exposed to other treatment, sick excluded Adjustment: No Monotherapy: TCA only 1.07 [0.66;1.71] C
excluded (control group) 		25/322   70/956 95 322
ref
S18156
R76333		 Chan (Controls unexposed, general pop), 2024 Any major malformations 1st trimester retrospective cohort (claims database) unexposed (general population or NOS) excluded Adjustment: Yes Monotherapy: TCA only 1.39 [0.90;2.15]
excluded (control group) 		25/322   22,628/462,377 22,653 322
ref
S18157
R76344		 Chan (Controls unexposed, sick), 2024 Any major malformations 1st trimester retrospective cohort (claims database) unexposed, sick Adjustment: Yes Monotherapy: TCA only Unexposed sick: old history of illness/treatment (> 12 months before pregnancy) or not specified 1.25 [0.61;2.56] 10/181   269/4,413 279 181
ref
S11187
R41233		 Anderson, 2020 Major birth defects 1st trimester case control unexposed (general population or NOS) Adjustment: No Monotherapy: TCA only 0.72 [0.39;1.35] C 29/44   30,601/42,064 30,630 44
ref
S11453
R42093		 Bahat, 2020 Major congenital anomalies 1st trimester prospective cohort unexposed (general population or NOS) Adjustment: Yes Monotherapy: no or not specified 1.00 [0.29;3.51] 3/83   20/511 23 83
ref
S11053
R40990		 Bérard (Controls exposed to SSRIs), 2017 Major congenital malformations overall 1st trimester retrospective cohort (claims database) exposed to other treatment, sick excluded Adjustment: No Monotherapy: TCA only 1.13 [0.82;1.56] C
excluded (control group) 		51/382   279/2,327 330 382
ref
S11052
R40977		 Bérard (Controls unexposed, sick), 2017 Major congenital malformations overall 1st trimester retrospective cohort (claims database) unexposed, sick Adjustment: Yes Monotherapy: TCA only Unexposed sick: intermediate history of illness/treatment (3-12 months before pregnancy) 1.16 [0.86;1.56] 51/382   1,650/14,847 1,701 382
ref
S11594
R42480		 Ozturk - Amitriptyline, 2016 Major congenital defects at least 1st trimester prospective cohort unexposed (general population or NOS) Adjustment: No Monotherapy: no or not specified 9.90 [0.43;229.94] C 0/4   3/246 3 4
ref
S10937
R40702		 Ban (Controls exposed to SSRIs), 2014 Major congenital anomalies 1st trimester retrospective cohort (claims database) exposed to other treatment, sick excluded Adjustment: No Monotherapy: TCA only 1.15 [0.88;1.51] C
excluded (control group) 		74/2,428   204/7,683 278 2,428
ref
S10938
R40718		 Ban (Controls unexposed, disease free), 2014 Major congenital anomalies 1st trimester retrospective cohort (claims database) unexposed, disease free excluded Adjustment: Yes Monotherapy: TCA only 1.09 [0.87;1.38]
excluded (control group) 		74/2,428   8,731/325,294 8,805 2,428
ref
S10939
R40740		 Ban (Controls unexposed, sick), 2014 Major congenital anomalies 1st trimester retrospective cohort (claims database) unexposed, sick Adjustment: Yes Monotherapy: TCA only Unexposed sick: intermediate history of illness/treatment (3-12 months before pregnancy) 1.02 [0.79;1.32] 74/2,428   380/13,432 454 2,428
ref
S11668
R42771		 Källen, 2013 Relatively severe malformations early pregnancy population based cohort retrospective unexposed (general population or NOS) Adjustment: Yes Monotherapy: no or not specified 1.09 [0.88;1.34] 92/2,139   -/- - 2,139
ref
S10943
R40768		 Vasilakis-Scaramozza (Controls exposed to SSRIs), 2013 Congenital Anomalies (chromosomal and minor anomalies excluded) 1st trimester retrospective cohort exposed to other treatment, sick excluded Adjustment: No Monotherapy: TCA only 0.93 [0.62;1.41] C
excluded (control group) 		42/1,608   51/1,825 93 1,608
ref
S10944
R40776		 Vasilakis-Scaramozza (Controls unexposed, NOS), 2013 Congenital Anomalies (chromosomal and minor anomalies excluded) 1st trimester retrospective cohort (claims database) unexposed (general population or NOS) Adjustment: Yes Matched Monotherapy: TCA only 0.90 [0.60;1.20] 42/1,608   205/6,617 247 1,608
ref
S10935
R40674		 Simon (Controls exposed to SSRIs), 2002 Major malformations during pregnancy (anytime or not specified) retrospective cohort (claims database) exposed to other treatment, sick excluded Adjustment: No Monotherapy: TCA only 0.72 [0.31;1.72] C
excluded (control group) 		10/209   12/185 22 209
ref
S10936
R40690		 Simon (Controls unexposed, NOS), 2002 Major malformations during pregnancy (anytime or not specified) excluded retrospective cohort (claims database) unexposed (general population or NOS) Adjustment: No Matched Monotherapy: TCA only 0.82 [0.35;1.95]
excluded (exposition period) 		10/209   12/209 22 209
ref
S10952
R40791		 Nulman (Controls exposed to Fluoxetine), 1997 Major malformations at least 1st trimester prospective cohort exposed to other treatment, sick excluded Adjustment: No Monotherapy: TCA only 1.03 [0.17;6.39] C
excluded (control group) 		3/80   2/55 5 80
ref
S10955
R40805		 Nulman (Controls unexposed, NOS), 1997 Major malformations at least 1st trimester prospective cohort unexposed (general population or NOS) Adjustment: No Monotherapy: TCA only 1.60 [0.26;9.82] C 3/80   2/84 5 80
ref
S10931
R40645		 Pastuszak (Controls exposed to Fluoxetine), 1993 Major malformations 1st trimester prospective cohort exposed to other treatment, sick excluded Adjustment: No Matched Monotherapy: TCA only 0.19 [0.01;3.97] C
excluded (control group) 		0/60   2/58 2 60
ref
S10932
R40653		 Pastuszak (Controls unexposed, NOS), 1993 Major malformations 1st trimester prospective cohort unexposed (general population or NOS) Adjustment: No Matched Monotherapy: TCA only 0.22 [0.01;4.61] C 0/60   2/67 2 60
ref
S14629
R59143		 Greenberg, 1977 Congenital abnormalities (minor abnormalities excluded) 1st trimester case control unexposed (general population or NOS) Adjustment: No Monotherapy: no or not specified 1.67 [0.61;4.63] C 10/16   826/1,656 836 16
ref
S15445
R63529		 Kullander - Imipramine, 1976 Major malformations (gross and insignificant major malfo) 1st trimester nested case control unexposed (general population or NOS) Adjustment: No 2.79 [0.35;22.11] C 1/10   199/5,192 200 10
ref
Total 12 studies 1.06 [0.93;1.20] 34,380 7,035
x1: number of endpoints among exposed, n1: number of exposed; x0: number of endpoints among non exposed, n0: number of non exposed; C: calculated odds ratio from numbers of events and effectives

Forest plot

StudyTE95% CIn casesn exposedweightROBABCDEF Chan (Controls unexposed, sick), 2024Chan, 2024 1 1.25[0.61; 2.56]2791813%ROB confusion: seriousROB selection: moderateROB classification: moderateROB missing: lowROB mesure: moderateROB reporting: moderate Anderson, 2020Anderson, 2020 0.72[0.39; 1.35]30,630444%ROB confusion: criticalROB selection: criticalROB classification: criticalROB missing: lowROB mesure: unclearROB reporting: moderate Bahat, 2020Bahat, 2020 1.00[0.29; 3.51]23831%ROB confusion: unclearROB selection: unclearROB classification: moderateROB missing: unclearROB mesure: unclearROB reporting: unclear Bérard (Controls unexposed, sick), 2017Bérard, 2017 2 1.16[0.86; 1.56]1,70138218%ROB confusion: seriousROB selection: moderateROB classification: criticalROB missing: lowROB mesure: moderateROB reporting: moderate Ozturk - Amitriptyline, 2016Ozturk - Amitriptyline, 2016 9.90[0.43; 229.94]340%ROB confusion: criticalROB selection: unclearROB classification: moderateROB missing: lowROB mesure: moderateROB reporting: moderate Ban (Controls unexposed, sick), 2014Ban, 2014 3 1.02[0.79; 1.32]4542,42824%ROB confusion: seriousROB selection: moderateROB classification: criticalROB missing: lowROB mesure: criticalROB reporting: moderate Källen, 2013Källen, 2013 1.09[0.88; 1.34]-2,13935%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: criticalROB reporting: moderate Vasilakis-Scaramozza (Controls unexposed, NOS), 2013Vasilakis-Scaramozza, 2013 4 0.90[0.60; 1.20]2471,60813%ROB confusion: seriousROB selection: moderateROB classification: criticalROB missing: moderateROB mesure: moderateROB reporting: moderate Nulman (Controls unexposed, NOS), 1997Nulman, 1997 5 1.60[0.26; 9.82]5800%ROB confusion: criticalROB selection: criticalROB classification: moderateROB missing: moderateROB mesure: criticalROB reporting: moderate Pastuszak (Controls unexposed, NOS), 1993Pastuszak, 1993 6 0.22[0.01; 4.61]2600%ROB confusion: criticalROB selection: criticalROB classification: moderateROB missing: lowROB mesure: moderateROB reporting: moderate Greenberg, 1977Greenberg, 1977 1.67[0.61; 4.63]836162%ROB confusion: criticalROB selection: criticalROB classification: criticalROB missing: criticalROB mesure: unclearROB reporting: moderate Kullander - Imipramine, 1976Kullander - Imipramine, 1976 2.79[0.35; 22.11]200100%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Total (12 studies) I2 = 0% 1.06[0.93; 1.20]34,3807,0350.220.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

1: Controls unexposed, sick; 2: Controls unexposed, sick; 3: Controls unexposed, sick; 4: Controls unexposed, NOS; 5: Controls unexposed, NOS; 6: Controls unexposed, NOS;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 1.06[0.93; 1.21]2,7146,9650%NAChan (Controls unexposed, sick), 2024 Bahat, 2020 Bérard (Controls unexposed, sick), 2017 Ozturk - Amitriptyline, 2016 Ban (Controls unexposed, sick), 2014 Källen, 2013 Vasilakis-Scaramozza (Controls unexposed, NOS), 2013 Nulman (Controls unexposed, NOS), 1997 Pastuszak (Controls unexposed, NOS), 1993 9 case control studiescase control studies 1.11[0.54; 2.28]31,6667032%NAAnderson, 2020 Greenberg, 1977 Kullander - Imipramine, 1976 3 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 1.03[0.87; 1.22]31,9464,0440%NAAnderson, 2020 Bahat, 2020 Ozturk - Amitriptyline, 2016 Källen, 2013 Vasilakis-Scaramozza (Controls unexposed, NOS), 2013 Nulman (Controls unexposed, NOS), 1997 Pastuszak (Controls unexposed, NOS), 1993 Greenberg, 1977 Kullander - Imipramine, 1976 9 unexposed, sickunexposed, sick 1.09[0.90; 1.31]2,4342,9910%NAChan (Controls unexposed, sick), 2024 Bérard (Controls unexposed, sick), 2017 Ban (Controls unexposed, sick), 2014 3 Tags Adjustment   - No  - No 1.16[0.62; 2.20]31,67621419%NAAnderson, 2020 Ozturk - Amitriptyline, 2016 Nulman (Controls unexposed, NOS), 1997 Pastuszak (Controls unexposed, NOS), 1993 Greenberg, 1977 Kullander - Imipramine, 1976 6   - Yes  - Yes 1.06[0.93; 1.21]2,7046,8210%NAChan (Controls unexposed, sick), 2024 Bahat, 2020 Bérard (Controls unexposed, sick), 2017 Ban (Controls unexposed, sick), 2014 Källen, 2013 Vasilakis-Scaramozza (Controls unexposed, NOS), 2013 6 MatchedMatched 0.88[0.63; 1.25]2491,6680%NAVasilakis-Scaramozza (Controls unexposed, NOS), 2013 Pastuszak (Controls unexposed, NOS), 1993 2 Monotherapy   - no or not specified  - no or not specified 1.12[0.91; 1.37]8622,2420%NABahat, 2020 Ozturk - Amitriptyline, 2016 Källen, 2013 Greenberg, 1977 4   - TCA only  - TCA only 1.02[0.87; 1.19]33,3184,7830%NAChan (Controls unexposed, sick), 2024 Anderson, 2020 Bérard (Controls unexposed, sick), 2017 Ban (Controls unexposed, sick), 2014 Vasilakis-Scaramozza (Controls unexposed, NOS), 2013 Nulman (Controls unexposed, NOS), 1997 Pastuszak (Controls unexposed, NOS), 1993 7 Unexposed sick   - intermediate history of illness/tre ...  - intermediate history of illness/treatment (3-12 months before pregnancy) 1.08[0.89; 1.31]2,1552,8100%NABérard (Controls unexposed, sick), 2017 Ban (Controls unexposed, sick), 2014 2   - old history of illness/treatment (> ...  - old history of illness/treatment (> 12 months before pregnancy) or not specified 1.25[0.61; 2.56]279181 -NAChan (Controls unexposed, sick), 2024 1 All studiesAll studies 1.06[0.93; 1.20]34,3807,0350%NAChan (Controls unexposed, sick), 2024 Anderson, 2020 Bahat, 2020 Bérard (Controls unexposed, sick), 2017 Ozturk - Amitriptyline, 2016 Ban (Controls unexposed, sick), 2014 Källen, 2013 Vasilakis-Scaramozza (Controls unexposed, NOS), 2013 Nulman (Controls unexposed, NOS), 1997 Pastuszak (Controls unexposed, NOS), 1993 Greenberg, 1977 Kullander - Imipramine, 1976 120.120.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-3.83.81.9260.000Chan (Controls unexposed, sick), 2024Anderson, 2020Bahat, 2020Bérard (Controls unexposed, sick), 2017Ozturk - Amitriptyline, 2016Ban (Controls unexposed, sick), 2014Källen, 2013Vasilakis-Scaramozza (Controls unexposed, NOS), 2013Nulman (Controls unexposed, NOS), 1997Pastuszak (Controls unexposed, NOS), 1993Greenberg, 1977Kullander - Imipramine, 1976

Asymetry test p-value = 0.4455 (by Egger's regression)

slope=0.0039 (0.0852); intercept=0.3071 (0.3866); t=0.7943; p=0.4455

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 10931, 10952, 10935, 10943, 10937, 10938, 11053, 18161, 18156

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 1.08[0.95; 1.23]63,4876,7940%NAChan (Controls unexposed, general pop), 2024 Anderson, 2020 Bahat, 2020 Ozturk - Amitriptyline, 2016 Ban (Controls unexposed, disease free), 2014 Källen, 2013 Vasilakis-Scaramozza (Controls unexposed, NOS), 2013 Nulman (Controls unexposed, NOS), 1997 Pastuszak (Controls unexposed, NOS), 1993 Greenberg, 1977 Kullander - Imipramine, 1976 11 unexposed, sick controlsunexposed, sick controls 1.09[0.90; 1.31]2,4342,9910%NAChan (Controls unexposed, sick), 2024 Bérard (Controls unexposed, sick), 2017 Ban (Controls unexposed, sick), 2014 3 exposed to other treatment, sick controlsexposed to other treatment, sick controls 1.09[0.92; 1.29]8034,8800%NAChan (Controls exposed to SSRIs), 2024 Bérard (Controls exposed to SSRIs), 2017 Ban (Controls exposed to SSRIs), 2014 Vasilakis-Scaramozza (Controls exposed to SSRIs), 2013 Nulman (Controls exposed to Fluoxetine), 1997 Pastuszak (Controls exposed to Fluoxetine), 1993 60.510.01.0

Umbrella review (other published meta-analyses)

Published MAControlPeriodTE95% CIn exposedkI2 McDonagh (Major malformations)McDonagh (Major malformations) 1.31[1.04; 1.65]NA-NAnot specifiedstudies TTT-9 metaPregmetaPreg 1.06[0.93; 1.20]0%7,035----Chan (Controls unexposed, sick), 2024 Anderson, 2020 Bahat, 2020 Bérard (Controls unexposed, sick), 2017 Ozturk - Amitriptyline, 2016 Ban (Controls unexposed, sick), 2014 Källen, 2013 Vasilakis-Scaramozza (Controls unexposed, NOS), 2013 Nulman (Controls unexposed, NOS), 1997 Pastuszak (Controls unexposed, NOS), 1993 Greenberg, 1977 Kullander - Imipramine, 1976 120.510.01.0