Selective Serotonin Reuptake Inhibitor (SSRI) updated on 07-01-2025

Limb defects

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.
S18158
R76360		 Chan (Controls exposed to TCA), 2024 Musculoskeletal malformations 1st trimester retrospective cohort (claims database) exposed to other treatment, sick excluded Adjustment: No Monotherapy: SSRI only 0.57 [0.22;1.47] C
excluded (control group) 		12/956   7/322 19 956
ref
S18138
R76246		 Chan (Controls unexposed, general pop), 2024 Musculoskeletal malformations 1st trimester retrospective cohort (claims database) unexposed (general population or NOS) excluded Adjustment: Yes Monotherapy: SSRI only 1.07 [0.51;2.24]
excluded (control group) 		12/956   5,767/462,377 5,779 956
ref
S18139
R76252		 Chan (Controls unexposed, sick), 2024 Musculoskeletal malformations 1st trimester retrospective cohort (claims database) unexposed, sick Adjustment: Yes Monotherapy: SSRI only Unexposed sick: old history of illness/treatment (> 12 months before pregnancy) or not specified 0.94 [0.34;2.61] 6/714   68/4,413 74 714
ref
S12482
R47066		 Benevent, 2023 Musculoskeletal defects 1st trimester retrospective cohort (claims database) unexposed (general population or NOS) Adjustment: No Monotherapy: SSRI only 0.36 [0.09;1.43] C 2/1,653   496/146,855 498 1,653
ref
S7467
R22131		 Anderson, 2020 Any limb deficiency 1st trimester case control unexposed (general population or NOS) Adjustment: Yes Monotherapy: SSRI only 1.25 [0.90;1.73] -/-   0/- - -
ref
S6704
R18916		 Bérard - Non Sertraline SSRI, 2015 Musculoskeletal system 1st trimester retrospective cohort (claims database) unexposed, sick Adjustment: Yes Monotherapy: SSRI only Unexposed sick: intermediate history of illness/treatment (3-12 months before pregnancy) 1.28 [1.03;1.58] 104/1,963   619/14,868 723 1,963
ref
S5881
R14670		 Ban (Controls exposed to TCA), 2014 Limb malformations 1st trimester retrospective cohort (claims database) exposed to other treatment, sick excluded Adjustment: No Monotherapy: SSRI only 0.74 [0.40;1.39] C
excluded (control group) 		33/7,683   14/2,428 47 7,683
ref
S517
R14648		 Ban (Controls unexposed, disease free), 2014 Limb malformations 1st trimester retrospective cohort (claims database) unexposed, disease free excluded Adjustment: Yes Monotherapy: SSRI only 0.88 [0.62;1.25]
excluded (control group) 		33/7,683   1,750/325,294 1,783 7,683
ref
S6700
R18875		 Ban (Controls unexposed, sick), 2014 Limb malformations 1st trimester retrospective cohort (claims database) unexposed, sick Adjustment: Yes Monotherapy: SSRI only Unexposed sick: intermediate history of illness/treatment (3-12 months before pregnancy) 0.82 [0.54;1.25] 33/7,683   71/13,432 104 7,683
ref
S10216
R37428		 De Jonge - Paroxetine only, 2013 Limb malformations 1st trimester case control unexposed (general population or NOS) Adjustment: No Monotherapy: no or not specified 0.44 [0.03;7.02] C 0/181   184/29,226 184 181
ref
S6013
R15469		 Jimenez-Solem (Controls unexposed, NOS), 2012 Congenital malformations of the limbs 1st trimester population based cohort retrospective unexposed (general population or NOS) excluded Adjustment: Yes Monotherapy: no or not specified 0.93 [0.71;1.23]
excluded (control group) 		53/4,183   11,785/843,797 11,838 4,183
ref
S518
R15460		 Jimenez-Solem (Controls unexposed, sick), 2012 Congenital malformations of the limbs 1st trimester population based cohort retrospective unexposed, sick Adjustment: No Monotherapy: no or not specified Unexposed sick: intermediate history of illness/treatment (3-12 months before pregnancy) 0.73 [0.40;1.31] C 53/4,183   14/806 67 4,183
ref
S493
R15243		 Colvin, 2011 Musculoskeletal defects (ICD 754–756) 1st trimester retrospective cohort (claims database) unexposed (general population or NOS) Adjustment: No Monotherapy: no or not specified 0.80 [0.53;1.20] 24/2,701   1,052/94,561 1,076 2,701
ref
S497
R16474		 Malm, 2011 Musculoskeletal malformations (including limb defects) 1st trimester population based cohort retrospective unexposed (general population or NOS) Adjustment: Yes Monotherapy: no or not specified 0.96 [0.75;1.23] -/6,976   -/628,607 - 6,976
ref
S6994
R19837		 Simon (Controls exposed to TCA), 2002 Skeletal malformations during pregnancy (anytime or not specified) retrospective cohort (claims database) exposed to other treatment, sick excluded Adjustment: No Monotherapy: SSRI only 0.56 [0.10;3.09] C
excluded (control group) 		2/185   4/209 6 185
ref
S492
R17425		 Simon (Controls unexposed, NOS), 2002 Skeletal malformations during pregnancy (anytime or not specified) excluded retrospective cohort (claims database) unexposed (general population or NOS) Adjustment: No Matched Monotherapy: SSRI only 0.24 [0.05;1.15]
excluded (exposition period) 		2/185   8/185 10 185
ref
Total 9 studies 0.99 [0.83;1.19] 2,726 26,054
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 0.94[0.34; 2.61]747143%ROB confusion: seriousROB selection: moderateROB classification: moderateROB missing: lowROB mesure: moderateROB reporting: moderate Benevent, 2023Benevent, 2023 0.36[0.09; 1.43]4981,6532%ROB confusion: criticalROB selection: lowROB classification: criticalROB missing: unclearROB mesure: moderateROB reporting: moderate Anderson, 2020Anderson, 2020 1.25[0.90; 1.73]--17%ROB confusion: seriousROB selection: criticalROB classification: criticalROB missing: lowROB mesure: criticalROB reporting: moderate Bérard - Non Sertraline SSRI, 2015Bérard - Non Sertraline SSRI, 2015 1.28[1.03; 1.58]7231,96324%ROB confusion: seriousROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Ban (Controls unexposed, sick), 2014Ban, 2014 2 0.82[0.54; 1.25]1047,68312%ROB confusion: seriousROB selection: moderateROB classification: criticalROB missing: lowROB mesure: criticalROB reporting: moderate De Jonge - Paroxetine only, 2013De Jonge - Paroxetine only, 2013 0.44[0.03; 7.02]1841810%ROB confusion: criticalROB selection: criticalROB classification: criticalROB missing: lowROB mesure: moderateROB reporting: moderate Jimenez-Solem (Controls unexposed, sick), 2012Jimenez-Solem, 2012 3 0.73[0.40; 1.31]674,1837%ROB confusion: criticalROB selection: moderateROB classification: criticalROB missing: lowROB mesure: moderateROB reporting: critical Colvin, 2011Colvin, 2011 0.80[0.53; 1.20]1,0762,70113%ROB confusion: criticalROB selection: moderateROB classification: criticalROB missing: unclearROB mesure: moderateROB reporting: moderate Malm, 2011Malm, 2011 0.96[0.75; 1.23]-6,97622%ROB confusion: criticalROB selection: lowROB classification: criticalROB missing: lowROB mesure: criticalROB reporting: moderate Total (9 studies) I2 = 34% 0.99[0.83; 1.19]2,72626,0540.25.01.0ROB: 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;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 0.94[0.76; 1.16]2,54225,87342%NAChan (Controls unexposed, sick), 2024 Benevent, 2023 Bérard - Non Sertraline SSRI, 2015 Ban (Controls unexposed, sick), 2014 Jimenez-Solem (Controls unexposed, sick), 2012 Colvin, 2011 Malm, 2011 7 case control studiescase control studies 1.23[0.89; 1.70]1841810%NAAnderson, 2020 De Jonge - Paroxetine only, 2013 2 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 0.97[0.76; 1.22]1,75811,51127%NABenevent, 2023 Anderson, 2020 De Jonge - Paroxetine only, 2013 Colvin, 2011 Malm, 2011 5 unexposed, sickunexposed, sick 0.99[0.72; 1.36]96814,54348%NAChan (Controls unexposed, sick), 2024 Bérard - Non Sertraline SSRI, 2015 Ban (Controls unexposed, sick), 2014 Jimenez-Solem (Controls unexposed, sick), 2012 4 Tags Adjustment   - No  - No 0.74[0.53; 1.02]1,8258,7180%NABenevent, 2023 De Jonge - Paroxetine only, 2013 Jimenez-Solem (Controls unexposed, sick), 2012 Colvin, 2011 4   - Yes  - Yes 1.09[0.92; 1.30]90117,33629%NAChan (Controls unexposed, sick), 2024 Anderson, 2020 Bérard - Non Sertraline SSRI, 2015 Ban (Controls unexposed, sick), 2014 Malm, 2011 5 Monotherapy   - no or not specified  - no or not specified 0.89[0.73; 1.08]1,32714,0410%NADe Jonge - Paroxetine only, 2013 Jimenez-Solem (Controls unexposed, sick), 2012 Colvin, 2011 Malm, 2011 4   - SSRI only  - SSRI only 1.09[0.85; 1.40]1,39912,01339%NAChan (Controls unexposed, sick), 2024 Benevent, 2023 Anderson, 2020 Bérard - Non Sertraline SSRI, 2015 Ban (Controls unexposed, sick), 2014 5 Unexposed sick   - intermediate history of illness/tre ...  - intermediate history of illness/treatment (3-12 months before pregnancy) 0.97[0.67; 1.42]89413,82965%NABérard - Non Sertraline SSRI, 2015 Ban (Controls unexposed, sick), 2014 Jimenez-Solem (Controls unexposed, sick), 2012 3   - old history of illness/treatment (> ...  - old history of illness/treatment (> 12 months before pregnancy) or not specified 0.94[0.34; 2.60]74714 -NAChan (Controls unexposed, sick), 2024 1 All studiesAll studies 0.99[0.83; 1.19]2,72626,05434%NAChan (Controls unexposed, sick), 2024 Benevent, 2023 Anderson, 2020 Bérard - Non Sertraline SSRI, 2015 Ban (Controls unexposed, sick), 2014 De Jonge - Paroxetine only, 2013 Jimenez-Solem (Controls unexposed, sick), 2012 Colvin, 2011 Malm, 2011 90.15.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-3.33.31.7020.000Chan (Controls unexposed, sick), 2024Benevent, 2023Anderson, 2020Bérard - Non Sertraline SSRI, 2015Ban (Controls unexposed, sick), 2014De Jonge - Paroxetine only, 2013Jimenez-Solem (Controls unexposed, sick), 2012Colvin, 2011Malm, 2011

Asymetry test p-value = 0.0512 (by Egger's regression)

slope=0.2819 (0.1196); intercept=-1.4643 (0.6237); t=2.3479; p=0.0512

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 6994, 6013, 5881, 517, 18158, 18138

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 0.96[0.84; 1.09]21,15824,3330%NAChan (Controls unexposed, general pop), 2024 Benevent, 2023 Anderson, 2020 Ban (Controls unexposed, disease free), 2014 De Jonge - Paroxetine only, 2013 Jimenez-Solem (Controls unexposed, NOS), 2012 Colvin, 2011 Malm, 2011 8 unexposed, sick controlsunexposed, sick controls 0.99[0.72; 1.36]96814,54348%NAChan (Controls unexposed, sick), 2024 Bérard - Non Sertraline SSRI, 2015 Ban (Controls unexposed, sick), 2014 Jimenez-Solem (Controls unexposed, sick), 2012 4 exposed to other treatment, sick controlsexposed to other treatment, sick controls 0.69[0.41; 1.16]668,6390%NAChan (Controls exposed to TCA), 2024 Ban (Controls exposed to TCA), 2014 20.510.01.0

Umbrella review (other published meta-analyses)

Published MAControlPeriodTE95% CIn exposedkI2 Gao - SSRI (Limb defects)Gao - SSRI (Limb defects) Out of scale1.00[0.82; -9.00]-U,GPunexposed (general population or NOS)T11st trimesterstudies TTT8 Huang - SSRIs (Musculoskeletal congenital mal ...Huang - SSRIs (Musculoskeletal congenital malformations) 1.44[1.32; 1.56]43%-U,GPunexposed (general population or NOS)Anyduring pregnancy (anytime or not specified)studies TTT-9 metaPregmetaPreg 0.99[0.83; 1.19]34%26,054----Chan (Controls unexposed, sick), 2024 Benevent, 2023 Anderson, 2020 Bérard - Non Sertraline SSRI, 2015 Ban (Controls unexposed, sick), 2014 De Jonge - Paroxetine only, 2013 Jimenez-Solem (Controls unexposed, sick), 2012 Colvin, 2011 Malm, 2011 90.510.01.0