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

Nervous system anomalies

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
R76357		 Chan (Controls exposed to TCA), 2024 Nervous system malformations 1st trimester retrospective cohort (claims database) exposed to other treatment, sick excluded Adjustment: No Monotherapy: SSRI only 0.90 [0.24;3.40] C
excluded (control group) 		8/956   3/322 11 956
ref
S18138
R76243		 Chan (Controls unexposed, general pop), 2024 Nervous system malformations 1st trimester retrospective cohort (claims database) unexposed (general population or NOS) excluded Adjustment: Yes Monotherapy: SSRI only 0.83 [0.19;3.52]
excluded (control group) 		8/956   1,899/462,377 1,907 956
ref
S18139
R76249		 Chan (Controls unexposed, sick), 2024 Nervous system 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 0.91 [0.26;3.14] 8/714   36/4,413 44 714
ref
S12482
R47056		 Benevent, 2023 Nervous system anomalies 1st trimester retrospective cohort (claims database) unexposed (general population or NOS) Adjustment: No Monotherapy: SSRI only 2.05 [0.91;4.60] C 6/1,653   261/146,855 267 1,653
ref
S6704
R18909		 Bérard - Non Sertraline SSRI, 2015 Nervous system 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) 1.24 [0.77;2.00] 20/1,963   117/14,868 137 1,963
ref
S5881
R14675		 Ban (Controls exposed to TCA), 2014 Nervous system malformations 1st trimester retrospective cohort (claims database) exposed to other treatment, sick excluded Adjustment: No Monotherapy: SSRI only 0.68 [0.28;1.66] C
excluded (control group) 		15/7,683   7/2,428 22 7,683
ref
S517
R14653		 Ban (Controls unexposed, disease free), 2014 Nervous system malformations 1st trimester retrospective cohort (claims database) unexposed, disease free excluded Adjustment: Yes Monotherapy: SSRI only 1.39 [0.82;2.34]
excluded (control group) 		15/7,683   465/325,294 480 7,683
ref
S6700
R18880		 Ban (Controls unexposed, sick), 2014 Nervous system malformations 1st trimester retrospective cohort (claims database) unexposed, sick Adjustment: No Monotherapy: SSRI only Unexposed sick: intermediate history of illness/treatment (3-12 months before pregnancy) 1.09 [0.57;2.08] C 15/7,683   24/13,432 39 7,683
ref
S10216
R37423		 De Jonge - Paroxetine only, 2013 Central nervous system anomalies 1st trimester case control unexposed (general population or NOS) Adjustment: No Monotherapy: no or not specified 0.39 [0.02;6.21] C 0/181   208/29,250 208 181
ref
S6989
R19775		 Vasilakis-Scaramozza (Controls exposed to TCA), 2013 Central nervous system anomalies 1st trimester retrospective cohort exposed to other treatment, sick excluded Adjustment: No Monotherapy: SSRI only 0.88 [0.12;6.26] C
excluded (control group) 		2/1,825   2/1,608 4 1,825
ref
S5362
R16694		 Vasilakis-Scaramozza (Controls unexposed, NOS), 2013 Central nervous system anomalies 1st trimester retrospective cohort (claims database) unexposed (general population or NOS) Adjustment: No Matched Monotherapy: SSRI only 3.60 [0.50;25.60] 2/1,825   2/6,617 4 1,825
ref
S6013
R15470		 Jimenez-Solem (Controls unexposed, NOS), 2012 Malformations of the nervous system 1st trimester population based cohort retrospective unexposed (general population or NOS) Adjustment: Yes Monotherapy: no or not specified 1.13 [0.54;2.39] 7/4,183   -/843,797 - 4,183
ref
S493
R15235		 Colvin, 2011 Nervous system defects 1st trimester retrospective cohort (claims database) unexposed (general population or NOS) Adjustment: No Monotherapy: no or not specified 0.85 [0.40;1.80] 7/2,701   289/94,561 296 2,701
ref
S497
R16467		 Malm, 2011 Central nervous system 1st trimester population based cohort retrospective unexposed (general population or NOS) Adjustment: Yes Monotherapy: no or not specified 1.03 [0.68;1.57] -/6,976   -/628,607 - 6,976
ref
S495
R76909		 Källén, 2007 Any central nervous system malformation early pregnancy population based cohort retrospective unexposed (general population or NOS) Adjustment: Yes Monotherapy: SSRI only 0.85 [0.51;1.39] 16/6,555   5,331/873,876 5,347 6,555
ref
Total 10 studies 1.09 [0.88;1.34] 6,342 34,434
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 0.91[0.26; 3.14]447143%ROB confusion: seriousROB selection: moderateROB classification: moderateROB missing: lowROB mesure: moderateROB reporting: moderate Benevent, 2023Benevent, 2023 2.05[0.91; 4.60]2671,6537%ROB confusion: criticalROB selection: lowROB classification: criticalROB missing: unclearROB mesure: moderateROB reporting: moderate Bérard - Non Sertraline SSRI, 2015Bérard - Non Sertraline SSRI, 2015 1.24[0.77; 2.00]1371,96319%ROB confusion: seriousROB selection: moderateROB classification: criticalROB missing: unclearROB mesure: moderateROB reporting: moderate Ban (Controls unexposed, sick), 2014Ban, 2014 2 1.09[0.57; 2.08]397,68311%ROB confusion: criticalROB selection: moderateROB classification: criticalROB missing: lowROB mesure: criticalROB reporting: moderate De Jonge - Paroxetine only, 2013De Jonge - Paroxetine only, 2013 0.39[0.02; 6.21]2081811%ROB confusion: criticalROB selection: criticalROB classification: criticalROB missing: lowROB mesure: moderateROB reporting: moderate Vasilakis-Scaramozza (Controls unexposed, NOS), 2013Vasilakis-Scaramozza, 2013 3 3.60[0.50; 25.60]41,8251%ROB confusion: seriousROB selection: moderateROB classification: criticalROB missing: moderateROB mesure: moderateROB reporting: moderate Jimenez-Solem (Controls unexposed, NOS), 2012Jimenez-Solem, 2012 4 1.13[0.54; 2.39]-4,1838%ROB confusion: criticalROB selection: moderateROB classification: criticalROB missing: lowROB mesure: moderateROB reporting: critical Colvin, 2011Colvin, 2011 0.85[0.40; 1.80]2962,7018%ROB confusion: criticalROB selection: moderateROB classification: criticalROB missing: unclearROB mesure: moderateROB reporting: moderate Malm, 2011Malm, 2011 1.03[0.68; 1.57]-6,97625%ROB confusion: criticalROB selection: lowROB classification: criticalROB missing: lowROB mesure: criticalROB reporting: moderate Källén, 2007Källén, 2007 0.85[0.51; 1.39]5,3476,55518%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: lowROB mesure: unclearROB reporting: moderate Total (10 studies) I2 = 0% 1.09[0.88; 1.34]6,34234,4340.210.01.0ROB: 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, NOS; 4: Controls unexposed, NOS;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 1.09[0.88; 1.35]6,13434,2530%NAChan (Controls unexposed, sick), 2024 Benevent, 2023 Bérard - Non Sertraline SSRI, 2015 Ban (Controls unexposed, sick), 2014 Vasilakis-Scaramozza (Controls unexposed, NOS), 2013 Jimenez-Solem (Controls unexposed, NOS), 2012 Colvin, 2011 Malm, 2011 Källén, 2007 9 case control studiescase control studies 0.39[0.02; 6.21]208181 -NADe Jonge - Paroxetine only, 2013 1 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 1.05[0.81; 1.36]6,12224,0740%NABenevent, 2023 De Jonge - Paroxetine only, 2013 Vasilakis-Scaramozza (Controls unexposed, NOS), 2013 Jimenez-Solem (Controls unexposed, NOS), 2012 Colvin, 2011 Malm, 2011 Källén, 2007 7 unexposed, sickunexposed, sick 1.16[0.80; 1.67]22010,3600%NAChan (Controls unexposed, sick), 2024 Bérard - Non Sertraline SSRI, 2015 Ban (Controls unexposed, sick), 2014 3 Tags Adjustment   - No  - No 1.23[0.79; 1.91]81414,0439%NABenevent, 2023 Ban (Controls unexposed, sick), 2014 De Jonge - Paroxetine only, 2013 Vasilakis-Scaramozza (Controls unexposed, NOS), 2013 Colvin, 2011 5   - Yes  - Yes 1.04[0.81; 1.33]5,52820,3910%NAChan (Controls unexposed, sick), 2024 Bérard - Non Sertraline SSRI, 2015 Jimenez-Solem (Controls unexposed, NOS), 2012 Malm, 2011 Källén, 2007 5 MatchedMatched 3.60[0.50; 25.76]41,825 -NAVasilakis-Scaramozza (Controls unexposed, NOS), 2013 1 Monotherapy   - no or not specified  - no or not specified 1.00[0.72; 1.38]50414,0410%NADe Jonge - Paroxetine only, 2013 Jimenez-Solem (Controls unexposed, NOS), 2012 Colvin, 2011 Malm, 2011 4   - SSRI only  - SSRI only 1.15[0.87; 1.52]5,83820,3930%NAChan (Controls unexposed, sick), 2024 Benevent, 2023 Bérard - Non Sertraline SSRI, 2015 Ban (Controls unexposed, sick), 2014 Vasilakis-Scaramozza (Controls unexposed, NOS), 2013 Källén, 2007 6 Unexposed sick   - intermediate history of illness/tre ...  - intermediate history of illness/treatment (3-12 months before pregnancy) 1.19[0.81; 1.74]1769,6460%NABérard - Non Sertraline SSRI, 2015 Ban (Controls unexposed, sick), 2014 2   - old history of illness/treatment (> ...  - old history of illness/treatment (> 12 months before pregnancy) or not specified 0.91[0.26; 3.16]44714 -NAChan (Controls unexposed, sick), 2024 1 All studiesAll studies 1.09[0.88; 1.34]6,34234,4340%NAChan (Controls unexposed, sick), 2024 Benevent, 2023 Bérard - Non Sertraline SSRI, 2015 Ban (Controls unexposed, sick), 2014 De Jonge - Paroxetine only, 2013 Vasilakis-Scaramozza (Controls unexposed, NOS), 2013 Jimenez-Solem (Controls unexposed, NOS), 2012 Colvin, 2011 Malm, 2011 Källén, 2007 100.110.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-3.33.41.7010.000Chan (Controls unexposed, sick), 2024Benevent, 2023Bérard - Non Sertraline SSRI, 2015Ban (Controls unexposed, sick), 2014De Jonge - Paroxetine only, 2013Vasilakis-Scaramozza (Controls unexposed, NOS), 2013Jimenez-Solem (Controls unexposed, NOS), 2012Colvin, 2011Malm, 2011Källén, 2007

Asymetry test p-value = 0.6412 (by Egger's regression)

slope=-0.0131 (0.2166); intercept=0.3091 (0.6383); t=0.4842; p=0.6412

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 6989, 5881, 517, 18158, 18138

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 1.10[0.88; 1.38]8,50932,7130%NAChan (Controls unexposed, general pop), 2024 Benevent, 2023 Ban (Controls unexposed, disease free), 2014 De Jonge - Paroxetine only, 2013 Vasilakis-Scaramozza (Controls unexposed, NOS), 2013 Jimenez-Solem (Controls unexposed, NOS), 2012 Colvin, 2011 Malm, 2011 Källén, 2007 9 unexposed, sick controlsunexposed, sick controls 1.16[0.80; 1.67]22010,3600%NAChan (Controls unexposed, sick), 2024 Bérard - Non Sertraline SSRI, 2015 Ban (Controls unexposed, sick), 2014 3 exposed to other treatment, sick controlsexposed to other treatment, sick controls 0.76[0.38; 1.52]3710,4640%NAChan (Controls exposed to TCA), 2024 Ban (Controls exposed to TCA), 2014 Vasilakis-Scaramozza (Controls exposed to TCA), 2013 30.510.01.0

Umbrella review (other published meta-analyses)

Published MAControlPeriodTE95% CIn exposedkI2 Huang - SSRIs (Congenital malformations of th ...Huang - SSRIs (Congenital malformations of the nervous system) 1.07[0.93; 1.23]32%-U,GPunexposed (general population or NOS)Anyduring pregnancy (anytime or not specified)studies TTT-9 Gao - SSRI (Nervous system malformations)Gao - SSRI (Nervous system malformations) 1.09[0.87; 1.36]-U,GPunexposed (general population or NOS)T11st trimesterstudies TTT7 metaPregmetaPreg 1.09[0.88; 1.34]0%34,434----Chan (Controls unexposed, sick), 2024 Benevent, 2023 Bérard - Non Sertraline SSRI, 2015 Ban (Controls unexposed, sick), 2014 De Jonge - Paroxetine only, 2013 Vasilakis-Scaramozza (Controls unexposed, NOS), 2013 Jimenez-Solem (Controls unexposed, NOS), 2012 Colvin, 2011 Malm, 2011 Källén, 2007 100.510.01.0