Fluoxetine 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.
S18167
R76400		 Chan (Controls exposed to TCA), 2024 Any major malformations 1st trimester retrospective cohort (claims database) exposed to other treatment, sick excluded Adjustment: No Monotherapy: substance alone among all Antidep (SSRI, SNRI, ...) 0.70 [0.40;1.24] C
excluded (control group) 		26/467   25/322 51 467
ref
S18146
R76285		 Chan (Controls unexposed, pop general), 2024 Any major malformations 1st trimester retrospective cohort (claims database) unexposed (general population or NOS) Adjustment: Yes Monotherapy: substance alone among all Antidep (SSRI, SNRI, ...) 0.90 [0.57;1.41] 26/467   22,628/462,377 22,654 467
ref
S7469
R41455		 Anderson, 2020 Major birth defects 1st trimester case control unexposed (general population or NOS) Adjustment: No Monotherapy: substance alone among all Antidep (SSRI, SNRI, ...) 1.27 [0.99;1.63] C 275/356   30,355/41,752 30,630 356
ref
S7438
R21950		 Bérard, 2017 Major congenital malformations overall 1st trimester retrospective cohort (claims database) unexposed, sick Adjustment: Yes Monotherapy: substance alone among all Antidep (SSRI, SNRI, ...) Unexposed sick: intermediate history of illness/treatment (3-12 months before pregnancy) 0.80 [0.49;1.31] -/191   -/14,847 - 191
ref
S7354
R21583		 Jordan, 2016 All major congenital anomalies 3 months or more before pregnancy or1st trimester excluded retrospective cohort (registry) unexposed (general population or NOS) Adjustment: No Monotherapy: no or not specified 1.05 [0.84;1.31]
excluded (exposition period) 		81/2,601   13,536/506,155 13,617 2,601
ref
S7525
R22560		 Ozturk, 2016 Major congenital defects at least 1st trimester prospective cohort unexposed (general population or NOS) Adjustment: No Monotherapy: no or not specified 4.08 [0.19;85.30] C 0/9   3/246 3 9
ref
S6004
R15364		 Furu, 2015 Major birth defects 1st trimester population based cohort retrospective unexposed (general population or NOS) Adjustment: Yes Monotherapy: substance alone among all Antidep (SSRI, SNRI, ...) 1.25 [1.10;1.42] 255/6,250   71,374/2,266,875 71,629 6,250
ref
S5882
R14689		 Ban (Controls unexposed, disease free), 2014 Major congenital anomalies 1st trimester retrospective cohort (claims database) unexposed, disease free excluded Adjustment: Yes Monotherapy: substance alone among the specific class of antidep (SSRI, SNRI, ...) 0.91 [0.73;1.15]
excluded (control group) 		-/3,189   8,731/325,294 - 3,189
ref
S5883
R14710		 Ban (Controls unexposed, sick), 2014 Major congenital anomalies 1st trimester retrospective cohort (claims database) unexposed, sick Adjustment: Yes Monotherapy: substance alone among the specific class of antidep (SSRI, SNRI, ...) Unexposed sick: intermediate history of illness/treatment (3-12 months before pregnancy) 0.85 [0.66;1.09] -/3,189   380/13,432 - 3,189
ref
S6388
R61460		 Nordeng (Controls unexposed, NOS), 2012 Major malformations 1st trimester cohort unexposed (general population or NOS) excluded Adjustment: No Monotherapy: no or not specified 1.58 [0.38;6.51] C
excluded (control group) 		2/51   1,550/61,648 1,552 51
ref
S7831
R61474		 Nordeng (Controls unexposed, sick), 2012 Major malformations 1st trimester cohort unexposed, sick Adjustment: No Monotherapy: no or not specified Unexposed sick: intermediate history of illness/treatment (3-12 months before pregnancy) 1.39 [0.32;5.96] C 2/51   30/1,048 32 51
ref
S7194
R20418		 Colvin, 2011 Any major birth defects 1st trimester retrospective cohort (claims database) unexposed (general population or NOS) Adjustment: No Monotherapy: substance alone among the specific class of antidep (SSRI, SNRI, ...) 1.29 [0.76;2.16] 15/291   3,834/94,561 3,849 291
ref
S18282
R76937		 Reis (Controls exposed to TCA), 2010 Relatively severe malformation early pregnancy population based cohort retrospective exposed to other treatment, sick excluded Adjustment: No Monotherapy: substance alone among the specific class of antidep (SSRI, SNRI, ...) 0.84 [0.60;1.19] C
excluded (control group) 		60/1,522   77/1,662 137 1,522
ref
S18281
R76930		 Reis (Controls unexposed, NOS), 2010 Relatively severe malformation early pregnancy population based cohort retrospective unexposed (general population or NOS) Adjustment: Yes Monotherapy: substance alone among the specific class of antidep (SSRI, SNRI, ...) 1.29 [1.00;1.67] 60/1,522   -/1,062,190 - 1,522
ref
S5964
R15340		 Einarson, 2009 Major malformations 1st trimester prospective cohort unexposed (general population or NOS) Adjustment: No Monotherapy: no or not specified 1.87 [0.55;6.37] C 3/61   25/928 28 61
ref
S6733
R19034		 Diav-Citrin, 2008 Major anomalies 1st trimester prospective cohort unexposed (general population or NOS) Adjustment: No Monotherapy: no or not specified 2.08 [1.13;3.82] C 15/253   40/1,359 55 253
ref
S6426
R17644		 Oberlander, 2008 Major congenital anomalies 1st trimester retrospective cohort (claims database) unexposed (general population or NOS) Adjustment: No Monotherapy: substance alone among the specific class of antidep (SSRI, SNRI, ...) 1.05 [0.68;1.62] C 21/638   3,369/107,320 3,390 638
ref
S15003
R61424		 Nulman - Fluoxetine (Controls exposed to TCA), 1997 Major malformations at least 1st trimester prospective cohort exposed to other treatment, sick excluded Adjustment: No Monotherapy: SSRI only 0.97 [0.16;6.00] C
excluded (control group) 		2/55   3/80 5 55
ref
S15004
R61428		 Nulman - Fluoxetine (Controls unexposed, NOS), 1997 Major malformations at least 1st trimester prospective cohort unexposed (general population or NOS) Adjustment: No Monotherapy: SSRI only 1.55 [0.21;11.32] C 2/55   2/84 4 55
ref
S15005
R61444		 Chambers, 1996 All major structural anomalies 1st trimester prospective cohort unexposed (general population or NOS) Adjustment: No Monotherapy: no or not specified 1.40 [0.54;3.61] C 9/164   9/226 18 164
ref
S6202
R16361		 Pastuszak (Controls exposed to TCA), 1993 Major malformations 1st trimester prospective cohort exposed to other treatment, sick excluded Adjustment: No Matched Monotherapy: substance alone among all Antidep (SSRI, SNRI, ...) 5.36 [0.25;114.14] C
excluded (control group) 		2/58   0/60 2 58
ref
S6952
R19650		 Pastuszak (Controls unexposed, NOS), 1993 Major malformations 1st trimester prospective cohort unexposed (general population or NOS) Adjustment: No Matched Monotherapy: substance alone among all Antidep (SSRI, SNRI, ...) 1.13 [0.16;8.14] C 2/98   2/110 4 98
ref
Total 15 studies 1.16 [1.03;1.31] 132,296 13,595
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, pop general), 2024Chan, 2024 1 0.90[0.57; 1.41]22,6544676%ROB confusion: seriousROB selection: moderateROB classification: moderateROB missing: lowROB mesure: moderateROB reporting: moderate Anderson, 2020Anderson, 2020 1.27[0.99; 1.63]30,63035615%ROB confusion: criticalROB selection: criticalROB classification: criticalROB missing: lowROB mesure: unclearROB reporting: moderate Bérard, 2017Bérard, 2017 0.80[0.49; 1.31]-1915%ROB confusion: seriousROB selection: moderateROB classification: criticalROB missing: lowROB mesure: moderateROB reporting: moderate Ozturk, 2016Ozturk, 2016 4.08[0.19; 85.30]390%ROB confusion: criticalROB selection: unclearROB classification: moderateROB missing: lowROB mesure: moderateROB reporting: moderate Furu, 2015Furu, 2015 1.25[1.10; 1.42]71,6296,25028%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: lowROB mesure: moderateROB reporting: moderate Ban (Controls unexposed, sick), 2014Ban, 2014 2 0.85[0.66; 1.09]-3,18914%ROB confusion: seriousROB selection: moderateROB classification: criticalROB missing: lowROB mesure: criticalROB reporting: moderate Nordeng (Controls unexposed, sick), 2012Nordeng, 2012 3 1.39[0.32; 5.96]32511%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: lowROB mesure: unclearROB reporting: moderate Colvin, 2011Colvin, 2011 1.29[0.76; 2.16]3,8492914%ROB confusion: criticalROB selection: moderateROB classification: criticalROB missing: unclearROB mesure: moderateROB reporting: moderate Reis (Controls unexposed, NOS), 2010Reis, 2010 4 1.29[1.00; 1.67]-1,52214%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: lowROB mesure: unclearROB reporting: moderate Einarson, 2009Einarson, 2009 1.87[0.55; 6.37]28611%ROB confusion: criticalROB selection: criticalROB classification: moderateROB missing: unclearROB mesure: criticalROB reporting: moderate Diav-Citrin, 2008Diav-Citrin, 2008 2.08[1.13; 3.82]552533%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: unclearROB reporting: moderate Oberlander, 2008Oberlander, 2008 1.05[0.68; 1.62]3,3906386%ROB confusion: criticalROB selection: moderateROB classification: criticalROB missing: unclearROB mesure: criticalROB reporting: moderate Nulman - Fluoxetine (Controls unexposed, NOS), 1997Nulman - Fluoxetine, 1997 5 1.55[0.21; 11.32]4550%ROB confusion: criticalROB selection: criticalROB classification: moderateROB missing: moderateROB mesure: criticalROB reporting: moderate Chambers, 1996Chambers, 1996 1.40[0.54; 3.61]181641%ROB confusion: criticalROB selection: criticalROB classification: lowROB missing: lowROB mesure: criticalROB reporting: moderate Pastuszak (Controls unexposed, NOS), 1993Pastuszak, 1993 6 1.13[0.16; 8.14]4980%ROB confusion: criticalROB selection: criticalROB classification: moderateROB missing: lowROB mesure: criticalROB reporting: moderate Total (15 studies) I2 = 18% 1.16[1.03; 1.31]132,29613,5950.210.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

1: Controls unexposed, pop general; 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 1.14[1.00; 1.31]101,66613,23922%NAChan (Controls unexposed, pop general), 2024 Bérard, 2017 Ozturk, 2016 Furu, 2015 Ban (Controls unexposed, sick), 2014 Nordeng (Controls unexposed, sick), 2012 Colvin, 2011 Reis (Controls unexposed, NOS), 2010 Einarson, 2009 Diav-Citrin, 2008 Oberlander, 2008 Nulman - Fluoxetine (Controls unexposed, NOS), 1997 Chambers, 1996 Pastuszak (Controls unexposed, NOS), 1993 14 case control studiescase control studies 1.27[0.99; 1.63]30,630356 -NAAnderson, 2020 1 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 1.25[1.14; 1.38]132,26410,1640%NAChan (Controls unexposed, pop general), 2024 Anderson, 2020 Ozturk, 2016 Furu, 2015 Colvin, 2011 Reis (Controls unexposed, NOS), 2010 Einarson, 2009 Diav-Citrin, 2008 Oberlander, 2008 Nulman - Fluoxetine (Controls unexposed, NOS), 1997 Chambers, 1996 Pastuszak (Controls unexposed, NOS), 1993 12 unexposed, sickunexposed, sick 0.85[0.68; 1.06]323,4310%NABérard, 2017 Ban (Controls unexposed, sick), 2014 Nordeng (Controls unexposed, sick), 2012 3 Tags Adjustment   - No  - No 1.31[1.10; 1.57]38,0131,9760%NAAnderson, 2020 Ozturk, 2016 Nordeng (Controls unexposed, sick), 2012 Colvin, 2011 Einarson, 2009 Diav-Citrin, 2008 Oberlander, 2008 Nulman - Fluoxetine (Controls unexposed, NOS), 1997 Chambers, 1996 Pastuszak (Controls unexposed, NOS), 1993 10   - Yes  - Yes 1.05[0.86; 1.29]94,28311,61964%NAChan (Controls unexposed, pop general), 2024 Bérard, 2017 Furu, 2015 Ban (Controls unexposed, sick), 2014 Reis (Controls unexposed, NOS), 2010 5 MatchedMatched 1.13[0.16; 8.14]498 -NAPastuszak (Controls unexposed, NOS), 1993 1 Monotherapy   - no or not specified  - no or not specified 1.83[1.18; 2.86]1365380%NAOzturk, 2016 Nordeng (Controls unexposed, sick), 2012 Einarson, 2009 Diav-Citrin, 2008 Chambers, 1996 5   - SSRI only  - SSRI only 1.55[0.21; 11.32]455 -NANulman - Fluoxetine (Controls unexposed, NOS), 1997 1   - substance alone among all Antidep ( ...  - substance alone among all Antidep (SSRI, SNRI, ...) 1.18[1.02; 1.36]124,9177,36216%NAChan (Controls unexposed, pop general), 2024 Anderson, 2020 Bérard, 2017 Furu, 2015 Pastuszak (Controls unexposed, NOS), 1993 5   - substance alone among the specific ...  - substance alone among the specific class of antidep (SSRI, SNRI, ...) 1.08[0.85; 1.37]7,2395,64048%NABan (Controls unexposed, sick), 2014 Colvin, 2011 Reis (Controls unexposed, NOS), 2010 Oberlander, 2008 4 Unexposed sick   - intermediate history of illness/tre ...  - intermediate history of illness/treatment (3-12 months before pregnancy) 0.85[0.68; 1.06]323,4310%NABérard, 2017 Ban (Controls unexposed, sick), 2014 Nordeng (Controls unexposed, sick), 2012 3 All studiesAll studies 1.16[1.03; 1.31]132,29613,59518%NAChan (Controls unexposed, pop general), 2024 Anderson, 2020 Bérard, 2017 Ozturk, 2016 Furu, 2015 Ban (Controls unexposed, sick), 2014 Nordeng (Controls unexposed, sick), 2012 Colvin, 2011 Reis (Controls unexposed, NOS), 2010 Einarson, 2009 Diav-Citrin, 2008 Oberlander, 2008 Nulman - Fluoxetine (Controls unexposed, NOS), 1997 Chambers, 1996 Pastuszak (Controls unexposed, NOS), 1993 150.210.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-3.63.81.8620.000Chan (Controls unexposed, pop general), 2024Anderson, 2020Bérard, 2017Ozturk, 2016Furu, 2015Ban (Controls unexposed, sick), 2014Nordeng (Controls unexposed, sick), 2012Colvin, 2011Reis (Controls unexposed, NOS), 2010Einarson, 2009Diav-Citrin, 2008Oberlander, 2008Nulman - Fluoxetine (Controls unexposed, NOS), 1997Chambers, 1996Pastuszak (Controls unexposed, NOS), 1993

Asymetry test p-value = 0.7748 (by Egger's regression)

slope=0.1483 (0.0777); intercept=0.1320 (0.4520); t=0.2921; p=0.7748

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 6202, 15003, 18282, 6388, 5882, 18167

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 1.20[1.09; 1.31]142,58913,4041%NAChan (Controls unexposed, pop general), 2024 Anderson, 2020 Ozturk, 2016 Furu, 2015 Ban (Controls unexposed, disease free), 2014 Nordeng (Controls unexposed, NOS), 2012 Colvin, 2011 Reis (Controls unexposed, NOS), 2010 Einarson, 2009 Diav-Citrin, 2008 Oberlander, 2008 Nulman - Fluoxetine (Controls unexposed, NOS), 1997 Chambers, 1996 Pastuszak (Controls unexposed, NOS), 1993 14 unexposed, sick controlsunexposed, sick controls 0.85[0.68; 1.06]4033,4310%NABérard, 2017 Ban (Controls unexposed, sick), 2014 Nordeng (Controls unexposed, sick), 2012 3 exposed to other treatment, sick controlsexposed to other treatment, sick controls 0.82[0.61; 1.10]1952,1020%NAChan (Controls exposed to TCA), 2024 Reis (Controls exposed to TCA), 2010 Nulman - Fluoxetine (Controls exposed to TCA), 1997 Pastuszak (Controls exposed to TCA), 1993 40.510.01.0

Umbrella review (other published meta-analyses)

Published MAControlPeriodTE95% CIn exposedkI2 Myles (Major congenital malformation)Myles (Major congenital malformation) 1.14[1.01; 1.30]12%-Wwhatever (meta-analysis)T1+at least 1st trimesterstudies TTT9 Myles (Major congenital malformation _ Qualit ...Myles (Major congenital malformation _ Quality samples only, i.e. more than three quality points) 1.22[1.01; 1.47]0%-Wwhatever (meta-analysis)T1+at least 1st trimesterstudies TTT5 Gao (Major congenital malformations)Gao (Major congenital malformations) 1.17[1.07; 1.28]0%-U,GPunexposed (general population or NOS)T11st trimesterstudies TTT11 Gao (Major congenital malformations)Gao (Major congenital malformations) 0.84[0.67; 1.05]0%-U,Sunexposed, sickT11st trimesterstudies TTT2 Gao (Major congenital malformations)Gao (Major congenital malformations) 1.18[1.08; 1.29]0%-Wwhatever (meta-analysis)T11st trimesterstudies TTT12 McDonagh (Major malformations)McDonagh (Major malformations) 1.14[1.01; 1.30]NA-U,GPunexposed (general population or NOS)Anyduring pregnancy (anytime or not specified)studies TTT-9 Grigoriadis (Major malformations (studies abo ...Grigoriadis (Major malformations (studies above quality threshold)) 1.20[0.98; 1.48]3.6%-Wwhatever (meta-analysis)Anyduring pregnancy (anytime or not specified)studies TTT4 Riggin (Major malformations _ Case control st ...Riggin (Major malformations _ Case control studies) 3.72[0.74; 18.79]NA-Wwhatever (meta-analysis)T11st trimesterstudies TTT3 Riggin (Major malformations _ Cohort studies)Riggin (Major malformations _ Cohort studies) 1.12[0.98; 1.28]NA-Wwhatever (meta-analysis)T11st trimesterstudies TTT18 Einarson (Major structural or functional malf ...Einarson (Major structural or functional malformations) 1.19[0.47; 3.00]NA-Wwhatever (meta-analysis)T11st trimesterstudies TTT3 metaPregmetaPreg 1.16[1.03; 1.31]18%13,595----Chan (Controls unexposed, pop general), 2024 Anderson, 2020 Bérard, 2017 Ozturk, 2016 Furu, 2015 Ban (Controls unexposed, sick), 2014 Nordeng (Controls unexposed, sick), 2012 Colvin, 2011 Reis (Controls unexposed, NOS), 2010 Einarson, 2009 Diav-Citrin, 2008 Oberlander, 2008 Nulman - Fluoxetine (Controls unexposed, NOS), 1997 Chambers, 1996 Pastuszak (Controls unexposed, NOS), 1993 150.510.01.0