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

All congenital malformations (majors, minors, majors and minors, or unspecified)

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
R77618
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
R77619
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
R77620
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
S18401
R77650
Kernizan (Controls exposed to LTG), 2024 Malformations during pregnancy (anytime or not specified) retrospective cohort exposed to other treatment, sick excluded Adjustment: No 0.27 [0.02;4.58] C
excluded (control group)
1/46   1/13 2 46
ref
S18348
R77613
Kernizan (Controls unexposed, sick), 2024 Malformations during pregnancy (anytime or not specified) excluded retrospective cohort unexposed, sick Adjustment: No 0.32 [0.04;2.60] C
excluded (exposition period)
1/46   9/139 10 46
ref
S14276
R56342
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
R56355
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
R46740
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
R46698
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
R56343
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
R11452
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
R11449
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
R11451
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
R2695
Bellet - Aripiprazole, 2015 All malformations (minor and major) 1st trimester prospective cohort unexposed (general population or NOS) Adjustment: No 2.03 [0.66;6.28] 6/71   7/161 13 71
ref
S2294
R8228
Vigod, 2015 Congenital malformations 1st trimester retrospective cohort (claims database) unexposed, sick Adjustment: Yes Matched 1.37 [0.82;2.29] 40/893   33/893 73 893
ref
S2341
R11445
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
R11446
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
R11450
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
R11455
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
R11457
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
R11458
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
R11453
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
R11454
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
R11448
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 14 studies 1.46 [1.18;1.81] 89,051 22,922
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]4193638%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]12,41117,06823%ROB confusion: moderateROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: unclearROB reporting: moderate Cohen, 2022Cohen, 2022 1.79[0.96; 3.32]418108%ROB confusion: criticalROB selection: unclearROB classification: moderateROB missing: lowROB mesure: criticalROB reporting: low Anderson, 2020Anderson, 2020 1.54[0.80; 2.96]22,387487%ROB confusion: criticalROB selection: criticalROB classification: criticalROB missing: lowROB mesure: moderateROB reporting: moderate Yakuwa, 2019Yakuwa, 2019 0.75[0.30; 1.86]793514%ROB confusion: criticalROB selection: criticalROB classification: moderateROB missing: unclearROB mesure: criticalROB reporting: moderate Raguideau, 2017Raguideau, 2017 1.65[1.19; 2.28]18,7192,28615%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]4,1692036%ROB confusion: criticalROB selection: moderateROB classification: criticalROB missing: unclearROB mesure: criticalROB reporting: moderate Bellet - Aripiprazole, 2015Bellet - Aripiprazole, 2015 2.03[0.66; 6.28]13713%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: moderateROB mesure: unclearROB reporting: moderate Vigod, 2015Vigod, 2015 1.37[0.82; 2.29]7389310%ROB confusion: seriousROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: criticalROB reporting: moderate Habermann (Control unexposed, disease free), 2013Habermann, 2013 4 2.17[1.20; 3.91]474308%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: moderateROB reporting: moderate Vial (Control unexposed, NOS), 2009Vial, 2009 5 1.63[0.27; 9.99]5661%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]30,6851475%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 (14 studies) I2 = 44% 1.46[1.18; 1.81]89,05122,9220.25.01.0ROB: 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 1.46[1.17; 1.83]66,66422,87447%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 Vigod, 2015 Habermann (Control unexposed, disease free), 2013 Peng, 2013 Vial (Control unexposed, NOS), 2009 Reis (Control unexposed, NOS), 2008 McKenna, 2005 13 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) 1.60[1.28; 2.00]76,1073,7880%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 1.33[0.91; 1.94]12,90318,32463%NAChan (Controls unexposed, sick), 2024 Huybrechts (Controls unexposed, sick), 2023 Vigod, 2015 3 exposed to other treatment, sickexposed to other treatment, sick 1.79[0.96; 3.33]41810 -NACohen, 2022 1 Tags Adjustment   - No  - No 1.56[1.25; 1.94]76,1014,1680%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 1.50[1.00; 2.23]12,95018,75472%NAChan (Controls unexposed, sick), 2024 Huybrechts (Controls unexposed, sick), 2023 Vigod, 2015 Habermann (Control unexposed, disease free), 2013 4 MatchedMatched 1.32[0.80; 2.17]761,0790%NAVigod, 2015 Peng, 2013 McKenna, 2005 3 All studiesAll studies 1.46[1.18; 1.81]89,05122,92244%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 Vigod, 2015 Habermann (Control unexposed, disease free), 2013 Peng, 2013 Vial (Control unexposed, NOS), 2009 Reis (Control unexposed, NOS), 2008 McKenna, 2005 140.25.01.0

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, 2015Vigod, 2015Habermann (Control unexposed, disease free), 2013Peng, 2013Vial (Control unexposed, NOS), 2009Reis (Control unexposed, NOS), 2008McKenna, 2005

Asymetry test p-value = 0.0141 (by Egger's regression)

slope=0.0523 (0.0429); intercept=0.9857 (0.3436); t=2.8685; p=0.0141

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 2384, 2391, 2341, 14276, 18393, 18339, 18401

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 1.46[1.13; 1.88]277,18025,95852%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 1.33[0.91; 1.94]12,90318,32463%NAChan (Controls unexposed, sick), 2024 Huybrechts (Controls unexposed, sick), 2023 Vigod, 2015 3 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