Atypical antipsychotics (Second generation) updated on 06-10-2025

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.
S18393
R77586		 Chan (Controls exposed to FGA), 2024 Major congenital malformations at least 1st trimester retrospective cohort (claims database) exposed to other treatment, sick excluded Adjustment: No 1.51 [0.90;2.54] C
excluded (control group) 		38/419   26/420 64 419
ref
S18339
R77368		 Chan (Controls unexposed, general pop), 2024 Major congenital malformations at least 1st trimester retrospective cohort (claims database) unexposed (general population or NOS) excluded Adjustment: Yes 2.11 [1.19;3.86]
excluded (control group) 		38/419   22,929/464,017 22,967 419
ref
S18392
R77580		 Chan (Controls unexposed, sick), 2024 Major congenital malformations at least 1st trimester retrospective cohort (claims database) unexposed, sick Adjustment: Yes 2.14 [1.16;4.12] 34/363   385/6,476 419 363
ref
S14276
R56121		 Huybrechts (Controls unexposed, NOS), 2023 Major congenital malformations overall (excluding chromosomal abnormality) 1st trimester population based cohort retrospective unexposed (general population or NOS) excluded Adjustment: Yes 1.05 [0.98;1.11]
excluded (control group) 		941/21,751   177,165/6,455,324 178,106 21,751
ref
S14299
R56344		 Huybrechts (Controls unexposed, sick), 2023 Major congenital malformations overall (excluding chromosomal abnormality) 1st trimester population based cohort retrospective unexposed, sick Adjustment: Yes 1.07 [1.00;1.15] 764/17,068   11,647/318,731 12,411 17,068
ref
S12456
R46739		 Cohen, 2022 Major malformations 1st trimester prospective cohort exposed to other treatment, sick Adjustment: No 1.79 [0.96;3.32] 22/810   19/1,234 41 810
ref
S12436
R46673		 Anderson, 2020 Major birth defects (one of the 30 studied) 1st trimester case control unexposed (general population or NOS) Adjustment: No 1.54 [0.80;2.96] C 36/48   22,351/33,809 22,387 48
ref
S12447
R46714		 Yakuwa, 2019 Major malformation (in live births) 1st trimester prospective cohort unexposed (general population or NOS) Adjustment: No 0.75 [0.30;1.86] C 5/351   74/3,901 79 351
ref
S2360
R2836		 Raguideau, 2017 26 major malformations early pregnancy retrospective cohort (claims database) unexposed (general population or NOS) Adjustment: No 1.65 [1.19;2.28] C 37/2,286   18,682/1,888,130 18,719 2,286
ref
S3876
R8234		 Ozturk, 2016 Major birth defects during pregnancy (anytime or not specified) excluded retrospective cohort unexposed (general population or NOS) Adjustment: No 3.01 [0.15;61.83] C
excluded (exposition period) 		0/12   3/246 3 12
ref
S2398
R3011		 Petersen (Control unexposed, disease free), 2016 Major malformations 1st trimester retrospective cohort (claims database) unexposed, disease free Adjustment: No 1.77 [0.83;3.77] C 7/203   4,162/210,966 4,169 203
ref
S2329
R2694		 Bellet - Aripiprazole, 2015 Major malformations 1st trimester prospective cohort unexposed (general population or NOS) Adjustment: No 2.30 [0.32;16.70] 2/71   2/161 4 71
ref
S2341
R2752		 Habermann (Control exposed to FGA), 2013 Major malformations 1st trimester prospective cohort exposed to other treatment, sick excluded Adjustment: Yes 1.27 [0.57;2.82]
excluded (control group) 		22/430   9/213 31 430
ref
S2385
R2930		 Habermann (Control unexposed, disease free), 2013 Major malformations 1st trimester prospective cohort unexposed, disease free Adjustment: Yes 2.17 [1.20;3.91] 22/430   25/1,014 47 430
ref
S2332
R2733		 Peng, 2013 Major malformations throughout pregnancy prospective cohort unexposed, disease free Adjustment: No Matched 1.00 [0.02;51.06] C 0/76   0/76 0 76
ref
S2286
R2662		 Sadowski, 2013 Major malformations during pregnancy (anytime or not specified) excluded prospective cohort unexposed, disease free Adjustment: No Matched 2.49 [0.63;9.87] C
excluded (exposition period) 		7/113   3/116 10 113
ref
S2391
R2958		 Vial (Control exposed to FGA), 2009 Major malformations 1st trimester prospective cohort exposed to other treatment, sick excluded Adjustment: No Matched 0.42 [0.09;2.03]
excluded (control group) 		2/66   8/117 10 66
ref
S2390
R2957		 Vial (Control unexposed, NOS), 2009 Major malformations 1st trimester prospective cohort unexposed (general population or NOS) Adjustment: No 1.63 [0.27;9.99] 2/66   3/159 5 66
ref
S2384
R2928		 Reis (Control exposed to FGA), 2008 Relatively severe malformations early pregnancy population based cohort retrospective exposed to other treatment, sick excluded Adjustment: No 0.84 [0.33;2.12] C
excluded (control group) 		6/147   21/435 27 147
ref
S2333
R2735		 Reis (Control unexposed, NOS), 2008 Relative severe malformations early pregnancy population based cohort retrospective unexposed (general population or NOS) Adjustment: No 1.31 [0.58;2.96] C 6/147   30,679/973,767 30,685 147
ref
S2305
R2678		 McKenna, 2005 Major malformations 1st trimester prospective cohort unexposed, disease free Adjustment: No Matched 0.61 [0.05;6.82] C 1/110   2/135 3 110
ref
Total 13 studies 1.47 [1.17;1.86] 88,969 22,029
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 2.14[1.16; 4.12]4193639%ROB confusion: seriousROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Huybrechts (Controls unexposed, sick), 2023Huybrechts, 2023 2 1.07[1.00; 1.15]12,41117,06825%ROB confusion: moderateROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: unclearROB reporting: moderate Cohen, 2022Cohen, 2022 1.79[0.96; 3.32]418109%ROB confusion: criticalROB selection: unclearROB classification: moderateROB missing: lowROB mesure: criticalROB reporting: low Anderson, 2020Anderson, 2020 1.54[0.80; 2.96]22,387488%ROB confusion: criticalROB selection: criticalROB classification: criticalROB missing: lowROB mesure: moderateROB reporting: moderate Yakuwa, 2019Yakuwa, 2019 0.75[0.30; 1.86]793515%ROB confusion: criticalROB selection: criticalROB classification: moderateROB missing: unclearROB mesure: criticalROB reporting: moderate Raguideau, 2017Raguideau, 2017 1.65[1.19; 2.28]18,7192,28617%ROB confusion: criticalROB selection: lowROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Petersen (Control unexposed, disease free), 2016Petersen, 2016 3 1.77[0.83; 3.77]4,1692037%ROB confusion: criticalROB selection: moderateROB classification: criticalROB missing: unclearROB mesure: criticalROB reporting: moderate Bellet - Aripiprazole, 2015Bellet - Aripiprazole, 2015 2.30[0.32; 16.70]4711%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: moderateROB mesure: unclearROB reporting: moderate Habermann (Control unexposed, disease free), 2013Habermann, 2013 4 2.17[1.20; 3.91]4743010%ROB confusion: seriousROB selection: moderateROB classification: moderateROB missing: moderateROB mesure: criticalROB reporting: low Peng, 2013Peng, 2013 1.00[0.02; 51.06]0760%ROB confusion: seriousROB selection: unclearROB classification: moderateROB missing: unclearROB mesure: lowROB reporting: moderate Vial (Control unexposed, NOS), 2009Vial, 2009 5 1.63[0.27; 9.99]5662%ROB confusion: unclearROB selection: unclearROB classification: moderateROB missing: unclearROB mesure: unclearROB reporting: unclear Reis (Control unexposed, NOS), 2008Reis, 2008 6 1.31[0.58; 2.96]30,6851476%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: lowROB mesure: unclearROB reporting: moderate McKenna, 2005McKenna, 2005 0.61[0.05; 6.82]31101%ROB confusion: criticalROB selection: criticalROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Total (13 studies) I2 = 46% 1.47[1.17; 1.86]88,96922,0290.25.01.0ROB: 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: Control unexposed, disease free; 4: Control unexposed, disease free; 5: Control unexposed, NOS; 6: Control unexposed, NOS;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 1.47[1.15; 1.90]66,58221,98148%NAChan (Controls unexposed, sick), 2024 Huybrechts (Controls unexposed, sick), 2023 Cohen, 2022 Yakuwa, 2019 Raguideau, 2017 Petersen (Control unexposed, disease free), 2016 Bellet - Aripiprazole, 2015 Habermann (Control unexposed, disease free), 2013 Peng, 2013 Vial (Control unexposed, NOS), 2009 Reis (Control unexposed, NOS), 2008 McKenna, 2005 12 case control studiescase control studies 1.54[0.80; 2.96]22,38748 -NAAnderson, 2020 1 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 1.59[1.27; 1.99]76,0983,7880%NAAnderson, 2020 Yakuwa, 2019 Raguideau, 2017 Petersen (Control unexposed, disease free), 2016 Bellet - Aripiprazole, 2015 Habermann (Control unexposed, disease free), 2013 Peng, 2013 Vial (Control unexposed, NOS), 2009 Reis (Control unexposed, NOS), 2008 McKenna, 2005 10 unexposed, sickunexposed, sick 1.40[0.72; 2.73]12,83017,43178%NAChan (Controls unexposed, sick), 2024 Huybrechts (Controls unexposed, sick), 2023 2 exposed to other treatment, sickexposed to other treatment, sick 1.79[0.96; 3.33]41810 -NACohen, 2022 1 Tags Adjustment   - No  - No 1.55[1.23; 1.94]76,0924,1680%NACohen, 2022 Anderson, 2020 Yakuwa, 2019 Raguideau, 2017 Petersen (Control unexposed, disease free), 2016 Bellet - Aripiprazole, 2015 Peng, 2013 Vial (Control unexposed, NOS), 2009 Reis (Control unexposed, NOS), 2008 McKenna, 2005 10   - Yes  - Yes 1.60[0.91; 2.82]12,87717,86180%NAChan (Controls unexposed, sick), 2024 Huybrechts (Controls unexposed, sick), 2023 Habermann (Control unexposed, disease free), 2013 3 MatchedMatched 0.70[0.09; 5.46]31860%NAPeng, 2013 McKenna, 2005 2 All studiesAll studies 1.47[1.17; 1.86]88,96922,02946%NAChan (Controls unexposed, sick), 2024 Huybrechts (Controls unexposed, sick), 2023 Cohen, 2022 Anderson, 2020 Yakuwa, 2019 Raguideau, 2017 Petersen (Control unexposed, disease free), 2016 Bellet - Aripiprazole, 2015 Habermann (Control unexposed, disease free), 2013 Peng, 2013 Vial (Control unexposed, NOS), 2009 Reis (Control unexposed, NOS), 2008 McKenna, 2005 130.25.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-4.75.12.4080.000Chan (Controls unexposed, sick), 2024Huybrechts (Controls unexposed, sick), 2023Cohen, 2022Anderson, 2020Yakuwa, 2019Raguideau, 2017Petersen (Control unexposed, disease free), 2016Bellet - Aripiprazole, 2015Habermann (Control unexposed, disease free), 2013Peng, 2013Vial (Control unexposed, NOS), 2009Reis (Control unexposed, NOS), 2008McKenna, 2005

Asymetry test p-value = 0.0257 (by Egger's regression)

slope=0.0541 (0.0446); intercept=0.9482 (0.3679); t=2.5776; p=0.0257

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 2384, 2391, 2341, 14276, 18393, 18339

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 1.45[1.12; 1.87]277,17125,95850%NAChan (Controls unexposed, general pop), 2024 Huybrechts (Controls unexposed, NOS), 2023 Anderson, 2020 Yakuwa, 2019 Raguideau, 2017 Petersen (Control unexposed, disease free), 2016 Bellet - Aripiprazole, 2015 Habermann (Control unexposed, disease free), 2013 Peng, 2013 Vial (Control unexposed, NOS), 2009 Reis (Control unexposed, NOS), 2008 McKenna, 2005 12 unexposed, sick controlsunexposed, sick controls 1.40[0.72; 2.73]12,83017,43178%NAChan (Controls unexposed, sick), 2024 Huybrechts (Controls unexposed, sick), 2023 2 exposed to other treatment, sick controlsexposed to other treatment, sick controls 1.35[0.96; 1.88]1731,8724%NAChan (Controls exposed to FGA), 2024 Cohen, 2022 Habermann (Control exposed to FGA), 2013 Vial (Control exposed to FGA), 2009 Reis (Control exposed to FGA), 2008 50.510.01.0

Umbrella review (other published meta-analyses)

Published MAControlPeriodTE95% CIn exposedkI2 Wang (Congenital malformations (major))Wang (Congenital malformations (major)) 1.35[0.73; 2.47]65%-Wwhatever (meta-analysis)T11st trimesterstudies TTT3 Berard (Major congenital malformations)Berard (Major congenital malformations) 1.42[1.07; 1.89]NA-Wwhatever (meta-analysis)T11st trimesterstudies TTT12 Berard (Major congenital malformations)Berard (Major congenital malformations) 1.22[0.96; 1.54]NA-U,Sunexposed, sickT11st trimesterstudies TTT-9 Terrana (Major congenital malformations)Terrana (Major congenital malformations) 2.03[1.41; 2.93]0%-U,DFunexposed, disease freeT11st trimesterstudies TTT8 Coughlin (Major malformations (compared to un ...Coughlin (Major malformations (compared to unexposed)) 1.39[0.66; 2.93]NA-Wwhatever (meta-analysis)Anyduring pregnancy (anytime or not specified)studies TTT3 metaPregmetaPreg 1.47[1.17; 1.86]46%22,029----Chan (Controls unexposed, sick), 2024 Huybrechts (Controls unexposed, sick), 2023 Cohen, 2022 Anderson, 2020 Yakuwa, 2019 Raguideau, 2017 Petersen (Control unexposed, disease free), 2016 Bellet - Aripiprazole, 2015 Habermann (Control unexposed, disease free), 2013 Peng, 2013 Vial (Control unexposed, NOS), 2009 Reis (Control unexposed, NOS), 2008 McKenna, 2005 130.510.01.0