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

Early intrauterine deaths (< 22 weeks) / Spontaneous abortions

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.
S12954
R49163		 Kitchin, 2022 Miscarriage (pregnancy losses between 4-22 weeks) 1st trimester case control unexposed (general population or NOS) Adjustment: Yes Monotherapy: no or not specified 1.21 [1.04;1.40] 266/863   17,804/71,416 18,070 863
ref
S7479
R22384		 Richardson, 2019 Spontaneous abortion (prior to 24 weeks) during pregnancy (anytime or not specified) prospective cohort unexposed (general population or NOS) Adjustment: No Monotherapy: no or not specified 1.49 [1.13;1.95] C 114/566   140/965 254 566
ref
S7454
R22009		 Wu, 2019 Spontaneous abortion (before 20 completed weeks’ gestation° 1st trimester prospective cohort unexposed (general population or NOS) Adjustment: Yes Monotherapy: SSRI only 1.44 [1.01;2.05] 35/179   617/5,228 652 179
ref
S7518
R22534		 Ozturk - Escitalopram, 2016 Miscarriages at least 1st trimester prospective cohort unexposed (general population or NOS) Adjustment: No Monotherapy: no or not specified 1.09 [0.24;5.02] C 2/32   15/261 17 32
ref
S7865
R23808		 Andersen (Controls unexposed, NOS), 2014 Miscarriage (O021 and O03) early pregnancy population based cohort retrospective unexposed (general population or NOS) excluded Adjustment: Yes Monotherapy: no or not specified 1.27 [1.22;1.33]
excluded (control group) 		2,883/22,884   139,210/1,256,956 142,093 22,884
ref
S7577
R23807		 Andersen (Controls unexposed, sick), 2014 Miscarriage (O021 and O03) early pregnancy 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) 0.90 [0.85;0.96] C 2,883/22,884   1,936/14,016 4,819 22,884
ref
S11224
R41301		 Ban (Controls exposed to TCA), 2012 Miscarriage (NOS) during pregnancy (anytime or not specified) population based cohort retrospective exposed to other treatment, sick excluded Adjustment: No Monotherapy: SSRI only 0.97 [0.88;1.07] C
excluded (control group) 		2,069/14,191   650/4,349 2,719 14,191
ref
S11225
R41304		 Ban (Controls unexposed, disease free), 2012 Miscarriage (NOS) during pregnancy (anytime or not specified) population based cohort retrospective unexposed, disease free excluded Adjustment: Yes Monotherapy: SSRI only 1.50 [1.30;1.60]
excluded (control group) 		2,069/14,191   -/- - 14,191
ref
S11226
R41307		 Ban (Controls unexposed, sick), 2012 Miscarriage (NOS) during pregnancy (anytime or not specified) population based cohort retrospective unexposed, sick Adjustment: Yes Monotherapy: SSRI only Unexposed sick: recent illness/treatment (during or juste before pregnancy or treatment stopped in view of pregnancy) 1.40 [1.20;1.70] 2,069/14,191   -/- - 14,191
ref
S5395
R16283		 Klieger-Grossmann - Escitalopram, 2012 Spontaneous abortion during pregnancy (anytime or not specified) prospective cohort unexposed (general population or NOS) Adjustment: No Matched Monotherapy: SSRI only 1.91 [1.03;3.51] C 32/213   18/212 50 213
ref
S7579
R23157		 Manakova, 2011 Spontaneous abortions (NOS) 1st trimester prospective cohort unexposed (general population or NOS) Adjustment: No Monotherapy: no or not specified 1.70 [0.47;6.19] C 5/52   5/85 10 52
ref
S7588
R25333		 Nakhai-Pour, 2010 Spontaneous abortions (< 20th week of gestation) during pregnancy (anytime or not specified) nested case control unexposed (general population or NOS) Adjustment: Yes Matched Monotherapy: SSRI only 1.61 [1.28;2.04] 161/-   4,963/- 5,124 -
ref
S5958
R15300		 Diav-Citrin - Fluoxetine or Paroxetine, 2008 Miscarriage during pregnancy (anytime or not specified) prospective cohort unexposed (general population or NOS) Adjustment: Yes Monotherapy: no or not specified 0.85 [0.52;1.40] 42/463   97/1,467 139 463
ref
S507
R343		 Vial - Paroxetine, 2006 Spontaneous abortion 1st trimester prospective cohort unexposed (general population or NOS) Adjustment: No Matched Monotherapy: no or not specified 2.60 [1.80;4.30] 80/683   31/683 111 683
ref
S508
R344		 Sivojelezova - Citalopram, 2005 Spontaneous abortion during pregnancy (anytime or not specified) prospective cohort unexposed (general population or NOS) Adjustment: No Matched Monotherapy: no or not specified 1.09 [0.49;2.41] C 14/132   13/132 27 132
ref
S7883
R23834		 Yaris, 2005 Spontaneous abortions during pregnancy (anytime or not specified) prospective cohort unexposed (general population or NOS) Adjustment: No Monotherapy: no or not specified 2.12 [0.63;7.17] C 4/54   9/248 13 54
ref
S512
R348		 Einarson, 2001 Spontaneous abortion during pregnancy (anytime or not specified) prospective cohort unexposed (general population or NOS) Adjustment: No Monotherapy: no or not specified 1.51 [0.68;3.37] C 16/150   11/150 27 150
ref
S513
R347		 Kulin, 1998 Spontaneous abortion 1st trimester prospective cohort unexposed (general population or NOS) Adjustment: No Monotherapy: no or not specified 1.48 [0.83;2.66] C 30/267   21/267 51 267
ref
S490
R15186		 Chambers - Fluoxetine, 1996 Spontaneous abortion 1st trimester prospective cohort unexposed (general population or NOS) Adjustment: No Monotherapy: no or not specified 1.66 [0.89;3.09] C 23/169   22/254 45 169
ref
S6197
R16359		 Pastuszak - Fluoxetine (Controls exposed to TCA), 1993 Spontaneous abortion (NOS) 1st trimester prospective cohort exposed to other treatment, sick excluded Adjustment: No Matched Monotherapy: SSRI only 1.13 [0.43;2.96] C
excluded (control group) 		10/74   9/74 19 74
ref
S515
R16349		 Pastuszak - Fluoxetine (Controls unexposed, NOS), 1993 Spontaneous abortion (NOS) 1st trimester prospective cohort unexposed (general population or NOS) Adjustment: No Matched Monotherapy: SSRI only 1.90 [0.92;3.92] 19/128   10/128 29 128
ref
Total 17 studies 1.42 [1.17;1.71] 29,438 41,026
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 Kitchin, 2022Kitchin, 2022 1.21[1.04; 1.40]18,07086310%ROB confusion: seriousROB selection: lowROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Richardson, 2019Richardson, 2019 1.49[1.13; 1.95]2545669%ROB confusion: seriousROB selection: moderateROB classification: moderateROB missing: moderateROB mesure: moderateROB reporting: moderate Wu, 2019Wu, 2019 1.44[1.01; 2.05]6521798%ROB confusion: seriousROB selection: lowROB classification: moderateROB missing: lowROB mesure: moderateROB reporting: moderate Ozturk - Escitalopram, 2016Ozturk - Escitalopram, 2016 1.09[0.24; 5.02]17321%ROB confusion: criticalROB selection: unclearROB classification: moderateROB missing: lowROB mesure: criticalROB reporting: moderate Andersen (Controls unexposed, sick), 2014Andersen, 2014 1 0.90[0.85; 0.96]4,81922,88411%ROB confusion: seriousROB selection: lowROB classification: criticalROB missing: lowROB mesure: criticalROB reporting: moderate Ban (Controls unexposed, sick), 2012Ban, 2012 2 1.40[1.20; 1.70]-14,19110%ROB confusion: seriousROB selection: criticalROB classification: moderateROB missing: lowROB mesure: criticalROB reporting: moderate Klieger-Grossmann - Escitalopram, 2012Klieger-Grossmann - Escitalopram, 2012 1.91[1.03; 3.51]502135%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Manakova, 2011Manakova, 2011 1.70[0.47; 6.19]10522%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: criticalROB reporting: moderate Nakhai-Pour, 2010Nakhai-Pour, 2010 1.61[1.28; 2.04]5,124-9%ROB confusion: seriousROB selection: lowROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Diav-Citrin - Fluoxetine or Paroxetine, 2008Diav-Citrin - Fluoxetine or Paroxetine, 2008 0.85[0.52; 1.40]1394636%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: unclearROB reporting: moderate Vial - Paroxetine, 2006Vial - Paroxetine, 2006 2.60[1.80; 4.30]1116837%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: unclearROB reporting: unclear Sivojelezova - Citalopram, 2005Sivojelezova - Citalopram, 2005 1.09[0.49; 2.41]271324%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: criticalROB reporting: moderate Yaris, 2005Yaris, 2005 2.12[0.63; 7.17]13542%ROB confusion: criticalROB selection: unclearROB classification: moderateROB missing: unclearROB mesure: unclearROB reporting: moderate Einarson, 2001Einarson, 2001 1.51[0.68; 3.37]271504%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: criticalROB reporting: moderate Kulin, 1998Kulin, 1998 1.48[0.83; 2.66]512675%ROB confusion: seriousROB selection: moderateROB classification: moderateROB missing: lowROB mesure: criticalROB reporting: moderate Chambers - Fluoxetine, 1996Chambers - Fluoxetine, 1996 1.66[0.89; 3.09]451695%ROB confusion: criticalROB selection: criticalROB classification: lowROB missing: lowROB mesure: moderateROB reporting: moderate Pastuszak - Fluoxetine (Controls unexposed, NOS), 1993Pastuszak - Fluoxetine, 1993 3 1.90[0.92; 3.92]291284%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: lowROB mesure: criticalROB reporting: moderate Total (17 studies) I2 = 82% 1.42[1.17; 1.71]29,43841,0260.210.01.0ROB: 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;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 1.43[1.14; 1.80]6,24440,16380%NARichardson, 2019 Wu, 2019 Ozturk - Escitalopram, 2016 Andersen (Controls unexposed, sick), 2014 Ban (Controls unexposed, sick), 2012 Klieger-Grossmann - Escitalopram, 2012 Manakova, 2011 Diav-Citrin - Fluoxetine or Paroxetine, 2008 Vial - Paroxetine, 2006 Sivojelezova - Citalopram, 2005 Yaris, 2005 Einarson, 2001 Kulin, 1998 Chambers - Fluoxetine, 1996 Pastuszak - Fluoxetine (Controls unexposed, NOS), 1993 15 case control studiescase control studies 1.38[1.04; 1.82]23,19486376%NAKitchin, 2022 Nakhai-Pour, 2010 2 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 1.47[1.28; 1.70]24,6193,95130%NAKitchin, 2022 Richardson, 2019 Wu, 2019 Ozturk - Escitalopram, 2016 Klieger-Grossmann - Escitalopram, 2012 Manakova, 2011 Nakhai-Pour, 2010 Diav-Citrin - Fluoxetine or Paroxetine, 2008 Vial - Paroxetine, 2006 Sivojelezova - Citalopram, 2005 Yaris, 2005 Einarson, 2001 Kulin, 1998 Chambers - Fluoxetine, 1996 Pastuszak - Fluoxetine (Controls unexposed, NOS), 1993 15 unexposed, sickunexposed, sick 1.11[0.72; 1.72]4,81937,07595%NAAndersen (Controls unexposed, sick), 2014 Ban (Controls unexposed, sick), 2012 2 Tags Adjustment   - No  - No 1.53[1.13; 2.08]5,45325,33079%NARichardson, 2019 Ozturk - Escitalopram, 2016 Andersen (Controls unexposed, sick), 2014 Klieger-Grossmann - Escitalopram, 2012 Manakova, 2011 Vial - Paroxetine, 2006 Sivojelezova - Citalopram, 2005 Yaris, 2005 Einarson, 2001 Kulin, 1998 Chambers - Fluoxetine, 1996 Pastuszak - Fluoxetine (Controls unexposed, NOS), 1993 12   - Yes  - Yes 1.33[1.15; 1.55]23,98515,69649%NAKitchin, 2022 Wu, 2019 Ban (Controls unexposed, sick), 2012 Nakhai-Pour, 2010 Diav-Citrin - Fluoxetine or Paroxetine, 2008 5 MatchedMatched 1.80[1.42; 2.29]5,3411,15623%NAKlieger-Grossmann - Escitalopram, 2012 Nakhai-Pour, 2010 Vial - Paroxetine, 2006 Sivojelezova - Citalopram, 2005 Pastuszak - Fluoxetine (Controls unexposed, NOS), 1993 5 Monotherapy   - no or not specified  - no or not specified 1.33[1.06; 1.67]23,58326,31579%NAKitchin, 2022 Richardson, 2019 Ozturk - Escitalopram, 2016 Andersen (Controls unexposed, sick), 2014 Manakova, 2011 Diav-Citrin - Fluoxetine or Paroxetine, 2008 Vial - Paroxetine, 2006 Sivojelezova - Citalopram, 2005 Yaris, 2005 Einarson, 2001 Kulin, 1998 Chambers - Fluoxetine, 1996 12   - SSRI only  - SSRI only 1.50[1.32; 1.69]5,85514,7110%NAWu, 2019 Ban (Controls unexposed, sick), 2012 Klieger-Grossmann - Escitalopram, 2012 Nakhai-Pour, 2010 Pastuszak - Fluoxetine (Controls unexposed, NOS), 1993 5 Unexposed sick   - intermediate history of illness/tre ...  - intermediate history of illness/treatment (3-12 months before pregnancy) 0.90[0.85; 0.96]4,81922,884 -NAAndersen (Controls unexposed, sick), 2014 1   - recent illness/treatment (during o ...  - recent illness/treatment (during or juste before pregnancy or treatment stopped in view of pregnancy) 1.40[1.18; 1.67]-14,191 -NABan (Controls unexposed, sick), 2012 1 All studiesAll studies 1.42[1.17; 1.71]29,43841,02682%NAKitchin, 2022 Richardson, 2019 Wu, 2019 Ozturk - Escitalopram, 2016 Andersen (Controls unexposed, sick), 2014 Ban (Controls unexposed, sick), 2012 Klieger-Grossmann - Escitalopram, 2012 Manakova, 2011 Nakhai-Pour, 2010 Diav-Citrin - Fluoxetine or Paroxetine, 2008 Vial - Paroxetine, 2006 Sivojelezova - Citalopram, 2005 Yaris, 2005 Einarson, 2001 Kulin, 1998 Chambers - Fluoxetine, 1996 Pastuszak - Fluoxetine (Controls unexposed, NOS), 1993 170.210.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-1.82.20.9330.000Kitchin, 2022Richardson, 2019Wu, 2019Ozturk - Escitalopram, 2016Andersen (Controls unexposed, sick), 2014Ban (Controls unexposed, sick), 2012Klieger-Grossmann - Escitalopram, 2012Manakova, 2011Nakhai-Pour, 2010Diav-Citrin - Fluoxetine or Paroxetine, 2008Vial - Paroxetine, 2006Sivojelezova - Citalopram, 2005Yaris, 2005Einarson, 2001Kulin, 1998Chambers - Fluoxetine, 1996Pastuszak - Fluoxetine (Controls unexposed, NOS), 1993

Asymetry test p-value = 0.0024 (by Egger's regression)

slope=-0.0951 (0.0604); intercept=2.1032 (0.5765); t=3.6484; p=0.0024

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 6197, 11224, 11225, 7865

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 1.42[1.29; 1.57]168,77241,17847%NAKitchin, 2022 Richardson, 2019 Wu, 2019 Ozturk - Escitalopram, 2016 Andersen (Controls unexposed, NOS), 2014 Ban (Controls unexposed, disease free), 2012 Klieger-Grossmann - Escitalopram, 2012 Manakova, 2011 Nakhai-Pour, 2010 Diav-Citrin - Fluoxetine or Paroxetine, 2008 Vial - Paroxetine, 2006 Sivojelezova - Citalopram, 2005 Yaris, 2005 Einarson, 2001 Kulin, 1998 Chambers - Fluoxetine, 1996 Pastuszak - Fluoxetine (Controls unexposed, NOS), 1993 17 unexposed, sick controlsunexposed, sick controls 1.11[0.72; 1.72]6,87937,07595%NAAndersen (Controls unexposed, sick), 2014 Ban (Controls unexposed, sick), 2012 2 exposed to other treatment, sick controlsexposed to other treatment, sick controls 0.97[0.88; 1.07]2,73814,2650%NABan (Controls exposed to TCA), 2012 Pastuszak - Fluoxetine (Controls exposed to TCA), 1993 20.510.01.0

Umbrella review (other published meta-analyses)

Published MAControlPeriodTE95% CIn exposedkI2 Smith - SSRI (Miscarriage (spontaneous aborti ...Smith - SSRI (Miscarriage (spontaneous abortion, defined as pregnancy loss before viability)) 1.29[1.15; 1.44]81%-U,GPunexposed (general population or NOS)Anyduring pregnancy (anytime or not specified)studies TTT12 Smith - SSRI (Miscarriage (spontaneous aborti ...Smith - SSRI (Miscarriage (spontaneous abortion, defined as pregnancy loss before viability)) 1.03[0.93; 1.15]0%-Eexposed to other treatment, sickAnyduring pregnancy (anytime or not specified)studies TTT5 Nikfar - SSRI (Spontaneous abortion)Nikfar - SSRI (Spontaneous abortion) 1.87[1.50; 2.33]NA-Wwhatever (meta-analysis)Anyduring pregnancy (anytime or not specified)studies TTT7 Rahimi - SSRI (Spontaneous abortion)Rahimi - SSRI (Spontaneous abortion) 1.70[1.28; 2.25]NA-Wwhatever (meta-analysis)T1+at least 1st trimesterstudies TTT5 metaPregmetaPreg 1.42[1.17; 1.71]82%41,026----Kitchin, 2022 Richardson, 2019 Wu, 2019 Ozturk - Escitalopram, 2016 Andersen (Controls unexposed, sick), 2014 Ban (Controls unexposed, sick), 2012 Klieger-Grossmann - Escitalopram, 2012 Manakova, 2011 Nakhai-Pour, 2010 Diav-Citrin - Fluoxetine or Paroxetine, 2008 Vial - Paroxetine, 2006 Sivojelezova - Citalopram, 2005 Yaris, 2005 Einarson, 2001 Kulin, 1998 Chambers - Fluoxetine, 1996 Pastuszak - Fluoxetine (Controls unexposed, NOS), 1993 170.510.01.0