Valproate (All indications)

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.
S15200
R62383		 Cohen (Valproate) (Mixed indications) (Controls exposed to LTG), 2023 Major congenital malformations (excluding genetic/chromosomal) 1st trimester population based cohort retrospective exposed to other treatment, sick excluded Adjustment: Yes Partial overlapping 2.05 [1.70;2.46]
excluded (control group) 		159/2,031   314/8,339 473 2,031
ref
S15201
R62384		 Cohen (Valproate) (Mixed indications) (Controls unexposed, NOS), 2023 Major congenital malformations (excluding genetic/chromosomal) 1st trimester population based cohort retrospective unexposed (general population or NOS) Adjustment: No 2.71 [2.30;3.19] C 159/2,031   147,928/4,866,362 148,087 2,031
ref
S15264
R62770		 Li (Valproate) (Controls exposed to LTG), 2023 Major congenital malformation during pregnancy (anytime or not specified) prospective cohort exposed to other treatment, sick excluded Adjustment: No 6.58 [0.30;142.47] C
excluded (control group) 		2/31   0/38 2 31
ref
S15265
R62771		 Li (Valproate) (Controls unexposed, sick), 2023 Major congenital malformation during pregnancy (anytime or not specified) excluded prospective cohort unexposed, sick Adjustment: No 2.42 [0.48;12.22] C
excluded (exposition period) 		2/31   7/253 9 31
ref
S15216
R62390		 Pekoz (Valproate) (Epilepsy) (Controls exposed to LTG), 2023 Congenital malformations (major and minor) during pregnancy (anytime or not specified) prospective cohort exposed to other treatment, sick excluded Adjustment: No 4.29 [1.08;17.09] C
excluded (control group) 		7/82   3/141 10 82
ref
S15217
R62391		 Pekoz (Valproate) (Epilepsy) (Controls unexposed, sick), 2023 Congenital malformations (major and minor) during pregnancy (anytime or not specified) excluded prospective cohort unexposed, sick Adjustment: No 3.92 [0.47;32.96] C
excluded (exposition period) 		7/82   1/43 8 82
ref
S9304
R32410		 The NAAED (Controls exposed to Lamotrigine, sick) (Indications NOS), 2022 Major congenital malformations 1st trimester prospective cohort exposed to other treatment, sick excluded Adjustment: No 5.29 [3.29;8.50] C
excluded (control group) 		31/336   44/2,333 75 336
ref
S9305
R32412		 The NAAED (Controls unexposed, disease free) (Indications NOS), 2022 Major congenital malformations 1st trimester prospective cohort unexposed, disease free Adjustment: No 10.07 [5.11;19.84] C 31/336   12/1,201 43 336
ref
S12689
R48835		 Alsfouk (Valproate) (Controls exposed to Lamotrigine, sick), 2021 Major congenital malformation during pregnancy (anytime or not specified) retrospective cohort exposed to other treatment, sick excluded Adjustment: No 0.22 [0.01;5.02] C
excluded (control group) 		0/12   2/15 2 12
ref
S12691
R48836		 Alsfouk (Valproate) (Controls unexposed, sick), 2021 Major congenital malformation during pregnancy (anytime or not specified) excluded retrospective cohort unexposed, sick Adjustment: No 0.83 [0.03;21.80] C
excluded (exposition period) 		0/12   1/30 1 12
ref
S12882
R48685		 Hosny (Valproate) (Controls exposed to Lamotrigine, sick), 2021 Major birth defects 1st trimester prospective cohort exposed to other treatment, sick excluded Adjustment: No 0.07 [0.00;8.55] C
excluded (control group) 		0/8   0/1 0 8
ref
S12883
R48688		 Hosny (Valproate) (Controls unexposed, sick), 2021 Major birth defects 1st trimester prospective cohort unexposed, sick Adjustment: No 0.87 [0.03;23.72] C 0/8   1/21 1 8
ref
S12862
R48537		 Thomas (Valproate) (Controls exposed to Lamotrigine, sick), 2021 Major congenital malformations 1st trimester prospective cohort exposed to other treatment, sick excluded Adjustment: No 4.21 [0.56;31.72] C
excluded (control group) 		27/341   1/50 28 341
ref
S12863
R48545		 Thomas (Valproate) (Controls unexposed, disease free), 2021 Major congenital malformations 1st trimester prospective cohort unexposed, disease free excluded Adjustment: No 2.60 [1.30;5.20]
excluded (control group) 		24/268   11/319 35 268
ref
S12864
R48549		 Thomas (Valproate) (Controls unexposed, sick), 2021 Major congenital malformations 1st trimester prospective cohort unexposed, sick Adjustment: Yes 1.71 [0.90;3.20] 27/341   16/340 43 341
ref
S9280
R32191		 AlSheikh (Valproate) (Controls exposed to Lamotrigine, sick), 2020 Fetal/neonatal malformation during pregnancy (anytime or not specified) prospective cohort exposed to other treatment, sick excluded Adjustment: No 39.00 [0.31;4841.77] C
excluded (control group) 		0/1   0/20 0 1
ref
S9281
R32194		 AlSheikh (Valproate) (Controls unexposed, sick), 2020 Fetal/neonatal malformation during pregnancy (anytime or not specified) excluded prospective cohort unexposed, sick Adjustment: No 4.33 [0.06;320.42] C
excluded (exposition period) 		0/1   1/8 1 1
ref
S9287
R32246		 Aydin (Valproate) (Controls exposed to Lamotrigine, sick), 2020 Congenital chromosomal/structural anomalies throughout pregnancy retrospective cohort exposed to other treatment, sick excluded Adjustment: No 0.62 [0.01;35.19] C
excluded (control group) 		0/11   0/7 0 11
ref
S9288
R32256		 Aydin (Valproate) (Controls unexposed, sick), 2020 Congenital chromosomal/structural anomalies throughout pregnancy retrospective cohort unexposed, sick Adjustment: No 2.05 [0.04;110.56] C 0/11   0/22 0 11
ref
S9404
R32973		 Huber-Mollema (Valproate), 2019 Congenital malformations throughout pregnancy prospective cohort exposed to other treatment, sick Adjustment: No 6.30 [1.62;24.45] C 6/26   4/88 10 26
ref
S9324
R32498		 Putignano (Valproate), 2019 Congenital malformations (ICD-9 740 to 760 and 658.8) throughout pregnancy retrospective cohort unexposed (general population or NOS) Adjustment: No Matched 3.17 [1.61;6.25] C 12/79   49/917 61 79
ref
S9360
R35175		 Vajda (Valproate) (Controls exposed to Lamotrigine, sick), 2019 Fetal malformations at least 1st trimester prospective cohort exposed to other treatment, sick excluded Adjustment: No 3.36 [1.93;5.85] C
excluded (control group) 		43/290   20/406 63 290
ref
S9361
R35176		 Vajda (Valproate) (Controls unexposed, sick), 2019 Fetal malformations at least 1st trimester prospective cohort unexposed, sick Adjustment: No 5.22 [2.11;12.95] 43/290   5/176 48 290
ref
S9452
R33252		 Elkjaer (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2018 Malformation in child within first year of life (ICD-10 Q0 to Q99) during pregnancy (anytime or not specified) population based cohort propective exposed to other treatment, sick excluded Adjustment: No Controls: mixed indications 2.16 [1.24;3.78] C
excluded (control group) 		31/253   24/396 55 253
ref
S9453
R33256		 Elkjaer (Valproate) (Controls unexposed NOS) (Mixed indications), 2018 Malformation in child within first year of life (ICD-10 Q0 to Q99) during pregnancy (anytime or not specified) excluded population based cohort propective unexposed (general population or NOS) Adjustment: No 2.65 [1.82;3.86] C
excluded (exposition period) 		31/253   23,858/477,162 23,889 253
ref
S9359
R32743		 Tomson (Valproate), 2018 Major congenital malformation at least 1st trimester prospective cohort exposed to other treatment, sick Adjustment: No 3.78 [2.83;5.05] C 142/1,381   74/2,514 216 1,381
ref
S9314
R32451		 Bank (Valproate) (Mixed indications), 2017 Major Malformation during pregnancy (anytime or not specified) excluded prospective cohort exposed to other treatment, sick Adjustment: No 6.45 [0.12;360.09] C
excluded (exposition period) 		0/6   0/36 0 6
ref
S10210
R37661		 Petersen (Valproate) (Controls exposed to Lamotrigine, sick), 2017 Major congenital malformation 1st trimester retrospective cohort (claims database) exposed to other treatment, sick excluded Adjustment: No 2.53 [1.01;6.36] C
excluded (control group) 		10/157   9/344 19 157
ref
S10211
R37662		 Petersen (Valproate) (Controls unexposed NOS), 2017 Major congenital malformation 1st trimester retrospective cohort (claims database) unexposed (general population or NOS) excluded Adjustment: Yes 1.94 [1.05;3.61]
excluded (control group) 		10/176   5,315/239,151 5,325 176
ref
S10212
R37663		 Petersen (Valproate) (Controls unexposed, sick), 2017 Major congenital malformation 1st trimester retrospective cohort (claims database) unexposed, sick Adjustment: Yes 2.14 [1.11;4.13] 10/157   86/2,844 96 157
ref
S9282
R32201		 Arkilo (Valproate), 2015 Major malformations during pregnancy (anytime or not specified) excluded retrospective cohort exposed to other treatment, sick Adjustment: No 15.67 [0.22;1102.00] C
excluded (exposition period) 		0/2   0/24 0 2
ref
S9362
R32747		 Vanya (Valproate) (Controls exposed to Lamotrigine, sick), 2015 Major congenital malformations throughout pregnancy retrospective cohort exposed to other treatment, sick excluded Adjustment: No 5.21 [0.23;116.22] C
excluded (control group) 		4/14   0/6 4 14
ref
S9363
R32749		 Vanya (Valproate) (Controls unexposed, sick), 2015 Major congenital malformations throughout pregnancy retrospective cohort unexposed, sick Adjustment: No 18.47 [0.90;379.67] C 4/14   0/20 4 14
ref
S9289
R32261		 Babic (Valproate), 2014 Major congential malformations during pregnancy (anytime or not specified) excluded prospective cohort exposed to other treatment, sick Adjustment: No 1.67 [0.03;99.62] C
excluded (exposition period) 		0/5   0/8 0 5
ref
S9333
R32569		 Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014 Major malformations 1st trimester prospective cohort exposed to other treatment, sick excluded Adjustment: No 3.00 [2.10;4.00]
excluded (control group) 		82/1,220   49/2,098 131 1,220
ref
S9334
R32571		 Campbell (Valproate) (Controls unexposed, sick), 2014 Major malformations 1st trimester prospective cohort unexposed, sick Adjustment: No 2.93 [1.62;5.30] 82/1,220   13/541 95 1,220
ref
S9325
R32519		 Veiby (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2014 Major congenital malformation throughout pregnancy population based cohort retrospective exposed to other treatment, sick excluded Adjustment: No Partial overlapping 1.94 [1.08;3.46] C
excluded (control group) 		21/333   28/833 49 333
ref
S9326
R32523		 Veiby (Valproate) (Controls unexposed, disease free) (Mixed indications), 2014 Major malformations throughout pregnancy population based cohort retrospective unexposed, disease free excluded Adjustment: Yes Partial overlapping 2.47 [1.58;3.84]
excluded (control group) 		21/333   22,371/771,412 22,392 333
ref
S9327
R32526		 Veiby (Valproate) (Controls unexposed, sick) (Mixed indications), 2014 Major malformations throughout pregnancy population based cohort retrospective unexposed, sick Adjustment: No Controls: epilepsy indication Partial overlapping 2.33 [1.44;3.77] C 21/333   106/3,773 127 333
ref
S9336
R32581		 Cassina (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2013 Major congenital anomalies 1st trimester prospective cohort exposed to other treatment, sick excluded Adjustment: No 5.21 [0.29;94.43] C
excluded (control group) 		6/120   0/46 6 120
ref
S9337
R32583		 Cassina (Valproate) (Controls unexposed, disease free) (Mixed indications), 2013 Major congenital anomalies 1st trimester prospective cohort unexposed, disease free Adjustment: No 1.64 [0.66;4.08] C 6/120   25/803 31 120
ref
S9309
R32431		 Källén (Valproate) (Controls exposed to Lamotrigine, sick) (Indications NOS), 2013 Relatively severe malformations early pregnancy population based cohort retrospective exposed to other treatment, sick excluded Adjustment: No Partial overlapping 2.76 [1.82;4.20] C
excluded (control group) 		62/697   37/1,084 99 697
ref
S9310
R32439		 Källén (Valproate) (Controls unexposed, NOS) (Indications NOS), 2013 Relatively severe malformations early pregnancy population based cohort retrospective unexposed (general population or NOS) Adjustment: Yes Partial overlapping 2.30 [1.82;2.91] 62/697   49,499/1,575,847 49,561 697
ref
S9450
R33186		 Rihtman (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2013 Children: born with congenital deformation at least 1st trimester prospective cohort exposed to other treatment, sick excluded Adjustment: No Controls: epilepsy indication 6.31 [0.67;59.59] C
excluded (control group) 		4/30   1/42 5 30
ref
S9451
R33221		 Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013 Children: born with congenital deformation at least 1st trimester prospective cohort unexposed (general population or NOS) Adjustment: No 18.18 [0.94;350.80] C 4/30   0/52 4 30
ref
S9286
R32238		 Arteaga-Vázquez (Valproate), 2012 Congenital malformations 1st trimester case control unexposed, sick Adjustment: No 2.54 [0.55;11.69] C 4/8   13/46 17 8
ref
S9331
R35133		 Bànhidy (Valproate), 2011 Total congenital abnormalities throughout pregnancy case control unexposed, sick Adjustment: No Matched 1.17 [0.28;4.84] C 7/12   12/22 19 12
ref
S9293
R32279		 Charlton (Valproate) (Controls exposed to Lamotrigine, sick), 2011 Major congenital malformations 1st trimester retrospective cohort (claims database) exposed to other treatment, sick excluded Adjustment: No 1.63 [0.44;5.97] C
excluded (control group) 		11/225   3/98 14 225
ref
S9294
R32282		 Charlton (Valproate) (Controls unexposed, sick), 2011 Major congenital malformations 1st trimester retrospective cohort (claims database) unexposed, sick Adjustment: No 2.00 [0.99;4.07] 11/225   22/902 33 225
ref
S9312
R32442		 Mawer (Valproate) (Controls exposed to Lamotrigine, sick), 2010 Major malformations 1st trimester prospective cohort exposed to other treatment, sick excluded Adjustment: No 2.23 [0.43;11.74] C
excluded (control group) 		6/53   2/37 8 53
ref
S9317
R32467		 Mawer (Valproate) (Controls unexposed, disease free), 2010 Major malformations 1st trimester prospective cohort unexposed, disease free excluded Adjustment: No Matched 5.94 [1.84;19.19]
excluded (control group) 		6/53   6/285 12 53
ref
S9318
R32469		 Mawer (Valproate) (Controls unexposed, sick), 2010 Major malformations 1st trimester prospective cohort unexposed, sick Adjustment: No 5.11 [0.59;44.22] C 6/53   1/41 7 53
ref
S9444
R33169		 Diav-Citrin (Valproate) (Mixed indications), 2008 Major anomalies without chromosomal or genetic anomalies at least 1st trimester prospective cohort unexposed (general population or NOS) Adjustment: No 1.71 [0.51;5.75] C 3/71   31/1,236 34 71
ref
S9290
R32264		 Burja (Valproate) (Controls unexposed, disease free), 2006 Congenital malformation during pregnancy (anytime or not specified) retrospective cohort (registry) unexposed, disease free excluded Adjustment: No 12.45 [0.45;341.34] C
excluded (control group) 		0/2   5/211 5 2
ref
S9292
R32274		 Burja (Valproate) (Controls unexposed, sick), 2006 Congenital malformation during pregnancy (anytime or not specified) excluded retrospective cohort (registry) unexposed, sick Adjustment: No 21.00 [0.30;1469.95] C
excluded (exposition period) 		0/2   0/32 0 2
ref
S9346
R32608		 Kini (Valproate) (Controls unexposed, sick), 2006 Major malformations during pregnancy (anytime or not specified) excluded retrospective cohort unexposed, sick Adjustment: No 4.04 [1.19;13.74]
excluded (exposition period) 		9/63   4/101 13 63
ref
S9319
R32473		 Meador (Valproate), 2006 Congenital malformations during pregnancy (anytime or not specified) excluded prospective cohort exposed to other treatment, sick Adjustment: Yes 22.82 [4.25;424.20]
excluded (exposition period) 		12/69   1/98 13 69
ref
S9329
R32533		 Viinikainen (Valproate) (Controls unexposed, sick) a, 2006 Major malformations throughout pregnancy prospective cohort unexposed, sick Adjustment: No 5.83 [0.23;148.09] C 1/28   0/52 1 28
ref
S9330
R32534		 Artama (Valproate), 2005 Malformations 1st trimester retrospective cohort (registry) unexposed, sick Adjustment: No 4.18 [2.31;7.57] 28/263   26/939 54 263
ref
S9300
R32383		 Endo (Valproate) (Controls unexposed, disease free), 2004 Congenital malformations at least 1st trimester retrospective cohort unexposed, disease free excluded Adjustment: No 2.54 [0.13;48.35] C
excluded (control group) 		0/5   27/656 27 5
ref
S9301
R32398		 Endo (Valproate) (Controls unexposed, sick), 2004 Congenital malformations throughout pregnancy retrospective cohort unexposed, sick Adjustment: No 0.11 [0.00;14.76] C 0/5   0/1 0 5
ref
S9342
R32591		 Kaaja (Valproate), 2003 Major malformation 1st trimester prospective cohort unexposed, sick Adjustment: No 8.32 [1.49;46.53] C 4/61   2/239 6 61
ref
S9299
R32370		 Dean (Valproate), 2002 Congenital malformations (major and minor) at least 1st trimester retrospective cohort unexposed, sick Adjustment: No 7.82 [2.84;21.53] C 30/47   7/38 37 47
ref
S9306
R32414		 Hvas (Valproate) (Controls unexposed, disease free), 2000 Major congenital malformations 1st trimester retrospective cohort unexposed, disease free excluded Adjustment: No 16.82 [3.67;77.12] C
excluded (control group) 		2/12   280/23,827 282 12
ref
S9307
R32416		 Hvas (Valproate) (Controls unexposed, sick), 2000 Major congenital malformations 1st trimester retrospective cohort unexposed, sick Adjustment: No 55.53 [2.48;1242.66] C 2/12   0/106 2 12
ref
S9279
R32188		 Al Bunyan (Valproate), 1999 Congenital malformations during pregnancy (anytime or not specified) excluded retrospective cohort unexposed, sick Adjustment: No 2.11 [0.04;124.53] C
excluded (exposition period) 		0/5   0/10 0 5
ref
S9335
R32579		 Canger (Valproate), 1999 All type of malformation 1st trimester prospective cohort unexposed, sick Adjustment: No 11.73 [0.65;212.86] C 8/44   0/25 8 44
ref
S9344
R32593		 Kaneko (Valproate), 1999 Malformations throughout pregnancy prospective cohort unexposed, sick Adjustment: No 3.96 [1.03;15.15] C 9/81   3/98 12 81
ref
S9353
R32724		 Samrén (Valproate), 1999 Major congential abnormalities at least 1st trimester retrospective cohort unexposed, disease free Adjustment: No Matched 4.10 [1.90;8.80] 9/158   29/2,000 38 158
ref
S9354
R32726		 Steegers-Theunissen (Valproate), 1994 Major malformations (ICD9 British Paediatric Association System) during pregnancy (anytime or not specified) excluded prospective cohort unexposed, disease free Adjustment: No 9.75 [1.51;62.95] C
excluded (exposition period) 		3/19   2/106 5 19
ref
S9297
R32297		 D'Souza (Valproate) (Controls unexposed, disease free), 1991 Congenital anomalies throughout pregnancy prospective cohort unexposed, disease free excluded Adjustment: No Matched 123.00 [1.00;15058.31] C
excluded (control group) 		0/1   0/62 0 1
ref
S9298
R32326		 D'Souza (Valproate) (Controls unexposed, sick), 1991 Congenital anomalies throughout pregnancy prospective cohort unexposed, sick Adjustment: No 4.33 [0.06;320.42] C 0/1   1/8 1 1
ref
S9308
R32423		 Jäger-Roman (Valproate), 1986 Major malformations at least 1st trimester prospective cohort unexposed (general population or NOS) Adjustment: No 6.23 [1.55;24.98] C 4/14   7/116 11 14
ref
S9352
R32722		 Robert (Valproate), 1986 Congenital malformations (minor and major) 1st trimester retrospective cohort unexposed, sick Adjustment: No 3.88 [0.87;17.29] C 5/15   4/35 9 15
ref
Total 33 studies 3.16 [2.64;3.78] 198,716 8,172
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 Cohen (Valproate) (Mixed indications) (Controls unexposed, NOS), 2023Cohen, 2023 1 2.71[2.30; 3.19]148,0872,03112%ROB confusion: criticalROB selection: lowROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate The NAAED (Controls unexposed, disease free) (Indications NOS), 2022The NAAED, 2022 2 10.07[5.11; 19.84]433365%ROB confusion: criticalROB selection: unclearROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: low Hosny (Valproate) (Controls unexposed, sick), 2021Hosny, 2021 3 0.87[0.03; 23.72]180%ROB confusion: criticalROB selection: moderateROB classification: unclearROB missing: lowROB mesure: unclearROB reporting: moderate Thomas (Valproate) (Controls unexposed, sick), 2021Thomas, 2021 4 1.71[0.90; 3.20]433415%ROB confusion: seriousROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Aydin (Valproate) (Controls unexposed, sick), 2020Aydin, 2020 5 2.05[0.04; 110.56]0110%ROB confusion: criticalROB selection: criticalROB classification: moderateROB missing: lowROB mesure: moderateROB reporting: moderate Huber-Mollema (Valproate), 2019Huber-Mollema, 2019 6 6.30[1.62; 24.45]10262%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: criticalROB mesure: moderateROB reporting: moderate Putignano (Valproate), 2019Putignano, 2019 7 3.17[1.61; 6.25]61795%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Vajda (Valproate) (Controls unexposed, sick), 2019Vajda, 2019 8 5.22[2.11; 12.95]482903%ROB confusion: criticalROB selection: moderateROB classification: lowROB missing: moderateROB mesure: moderateROB reporting: moderate Tomson (Valproate), 2018Tomson, 2018 9 3.78[2.83; 5.05]2161,38110%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Petersen (Valproate) (Controls unexposed, sick), 2017Petersen, 2017 10 2.14[1.11; 4.13]961575%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Vanya (Valproate) (Controls unexposed, sick), 2015Vanya, 2015 11 18.47[0.90; 379.67]4140%ROB confusion: criticalROB selection: criticalROB classification: unclearROB missing: unclearROB mesure: unclearROB reporting: moderate Campbell (Valproate) (Controls unexposed, sick), 2014Campbell, 2014 12 2.93[1.62; 5.30]951,2205%ROB confusion: unclearROB selection: lowROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Veiby (Valproate) (Controls unexposed, sick) (Mixed indications), 2014Veiby, 2014 13 2.33[1.44; 3.77]1273337%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: moderateROB mesure: moderateROB reporting: moderate Cassina (Valproate) (Controls unexposed, disease free) (Mixed indications), 2013Cassina, 2013 14 1.64[0.66; 4.08]311203%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Källén (Valproate) (Controls unexposed, NOS) (Indications NOS), 2013Källén, 2013 15 2.30[1.82; 2.91]49,56169711%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013Rihtman, 2013 16 18.18[0.94; 350.80]4300%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Arteaga-Vázquez (Valproate), 2012Arteaga-Vázquez, 2012 17 2.54[0.55; 11.69]1781%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Bànhidy (Valproate), 2011Bànhidy, 2011 18 1.17[0.28; 4.84]19121%ROB confusion: criticalROB selection: criticalROB classification: lowROB missing: lowROB mesure: moderateROB reporting: moderate Charlton (Valproate) (Controls unexposed, sick), 2011Charlton, 2011 19 2.00[0.99; 4.07]332254%ROB confusion: criticalROB selection: moderateROB classification: criticalROB missing: unclearROB mesure: moderateROB reporting: moderate Mawer (Valproate) (Controls unexposed, sick), 2010Mawer, 2010 20 5.11[0.59; 44.22]7531%ROB confusion: criticalROB selection: moderateROB classification: lowROB missing: moderateROB mesure: moderateROB reporting: moderate Diav-Citrin (Valproate) (Mixed indications), 2008Diav-Citrin, 2008 21 1.71[0.51; 5.75]34712%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Viinikainen (Valproate) (Controls unexposed, sick) a, 2006Viinikainen, 2006 22 5.83[0.23; 148.09]1280%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Artama (Valproate), 2005Artama, 2005 23 4.18[2.31; 7.57]542635%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Endo (Valproate) (Controls unexposed, sick), 2004Endo, 2004 24 0.11[0.00; 14.76]050%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Kaaja (Valproate), 2003Kaaja, 2003 25 8.32[1.49; 46.53]6611%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Dean (Valproate), 2002Dean, 2002 26 7.82[2.84; 21.53]37473%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Hvas (Valproate) (Controls unexposed, sick), 2000Hvas, 2000 27 55.53[2.48; 1242.66]2120%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Canger (Valproate), 1999Canger, 1999 28 11.73[0.65; 212.86]8440%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Kaneko (Valproate), 1999Kaneko, 1999 29 3.96[1.03; 15.15]12812%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Samrén (Valproate), 1999Samrén, 1999 30 4.10[1.90; 8.80]381584%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA D'Souza (Valproate) (Controls unexposed, sick), 1991D'Souza, 1991 31 4.33[0.06; 320.42]110%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Jäger-Roman (Valproate), 1986Jäger-Roman, 1986 32 6.23[1.55; 24.98]11141%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Robert (Valproate), 1986Robert, 1986 33 3.88[0.87; 17.29]9151%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Total (33 studies) I2 = 38% 3.16[2.64; 3.78]198,7168,1720.0500.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

1: Valproate) (Mixed indications) (Controls unexposed, NOS; 2: Controls unexposed, disease free) (Indications NOS; 3: Valproate) (Controls unexposed, sick; 4: Valproate) (Controls unexposed, sick; 5: Valproate) (Controls unexposed, sick; 6: Valproate; 7: Valproate; 8: Valproate) (Controls unexposed, sick; 9: Valproate; 10: Valproate) (Controls unexposed, sick; 11: Valproate) (Controls unexposed, sick; 12: Valproate) (Controls unexposed, sick; 13: Valproate) (Controls unexposed, sick) (Mixed indications; 14: Valproate) (Controls unexposed, disease free) (Mixed indications; 15: Valproate) (Controls unexposed, NOS) (Indications NOS; 16: Valproate) (Controls unexposed, NOS) (Mixed indications; 17: Valproate; 18: Valproate; 19: Valproate) (Controls unexposed, sick; 20: Valproate) (Controls unexposed, sick; 21: Valproate) (Mixed indications; 22: Valproate) (Controls unexposed, sick) ; 23: Valproate; 24: Valproate) (Controls unexposed, sick; 25: Valproate; 26: Valproate; 27: Valproate) (Controls unexposed, sick; 28: Valproate; 29: Valproate; 30: Valproate; 31: Valproate) (Controls unexposed, sick; 32: Valproate; 33: Valproate;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 3.22[2.68; 3.87]198,6808,15240%NACohen (Valproate) (Mixed indications) (Controls unexposed, NOS), 2023 The NAAED (Controls unexposed, disease free) (Indications NOS), 2022 Hosny (Valproate) (Controls unexposed, sick), 2021 Thomas (Valproate) (Controls unexposed, sick), 2021 Aydin (Valproate) (Controls unexposed, sick), 2020 Huber-Mollema (Valproate), 2019 Putignano (Valproate), 2019 Vajda (Valproate) (Controls unexposed, sick), 2019 Tomson (Valproate), 2018 Petersen (Valproate) (Controls unexposed, sick), 2017 Vanya (Valproate) (Controls unexposed, sick), 2015 Campbell (Valproate) (Controls unexposed, sick), 2014 Veiby (Valproate) (Controls unexposed, sick) (Mixed indications), 2014 Cassina (Valproate) (Controls unexposed, disease free) (Mixed indications), 2013 Källén (Valproate) (Controls unexposed, NOS) (Indications NOS), 2013 Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013 Charlton (Valproate) (Controls unexposed, sick), 2011 Mawer (Valproate) (Controls unexposed, sick), 2010 Diav-Citrin (Valproate) (Mixed indications), 2008 Viinikainen (Valproate) (Controls unexposed, sick) a, 2006 Artama (Valproate), 2005 Endo (Valproate) (Controls unexposed, sick), 2004 Kaaja (Valproate), 2003 Dean (Valproate), 2002 Hvas (Valproate) (Controls unexposed, sick), 2000 Canger (Valproate), 1999 Kaneko (Valproate), 1999 Samrén (Valproate), 1999 D'Souza (Valproate) (Controls unexposed, sick), 1991 Jäger-Roman (Valproate), 1986 Robert (Valproate), 1986 31 case control studiescase control studies 1.67[0.59; 4.74]36200%NAArteaga-Vázquez (Valproate), 2012 Bànhidy (Valproate), 2011 2 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 3.21[2.34; 4.40]197,8703,53664%NACohen (Valproate) (Mixed indications) (Controls unexposed, NOS), 2023 The NAAED (Controls unexposed, disease free) (Indications NOS), 2022 Putignano (Valproate), 2019 Cassina (Valproate) (Controls unexposed, disease free) (Mixed indications), 2013 Källén (Valproate) (Controls unexposed, NOS) (Indications NOS), 2013 Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013 Diav-Citrin (Valproate) (Mixed indications), 2008 Samrén (Valproate), 1999 Jäger-Roman (Valproate), 1986 9 unexposed, sickunexposed, sick 2.96[2.31; 3.78]6203,22913%NAHosny (Valproate) (Controls unexposed, sick), 2021 Thomas (Valproate) (Controls unexposed, sick), 2021 Aydin (Valproate) (Controls unexposed, sick), 2020 Vajda (Valproate) (Controls unexposed, sick), 2019 Petersen (Valproate) (Controls unexposed, sick), 2017 Vanya (Valproate) (Controls unexposed, sick), 2015 Campbell (Valproate) (Controls unexposed, sick), 2014 Veiby (Valproate) (Controls unexposed, sick) (Mixed indications), 2014 Arteaga-Vázquez (Valproate), 2012 Bànhidy (Valproate), 2011 Charlton (Valproate) (Controls unexposed, sick), 2011 Mawer (Valproate) (Controls unexposed, sick), 2010 Viinikainen (Valproate) (Controls unexposed, sick) a, 2006 Artama (Valproate), 2005 Endo (Valproate) (Controls unexposed, sick), 2004 Kaaja (Valproate), 2003 Dean (Valproate), 2002 Hvas (Valproate) (Controls unexposed, sick), 2000 Canger (Valproate), 1999 Kaneko (Valproate), 1999 D'Souza (Valproate) (Controls unexposed, sick), 1991 Robert (Valproate), 1986 22 exposed to other treatment, sickexposed to other treatment, sick 3.86[2.91; 5.13]2261,4070%NAHuber-Mollema (Valproate), 2019 Tomson (Valproate), 2018 2 Tags Adjustment   - No  - No 3.51[2.87; 4.29]149,0166,97732%NACohen (Valproate) (Mixed indications) (Controls unexposed, NOS), 2023 The NAAED (Controls unexposed, disease free) (Indications NOS), 2022 Hosny (Valproate) (Controls unexposed, sick), 2021 Aydin (Valproate) (Controls unexposed, sick), 2020 Huber-Mollema (Valproate), 2019 Putignano (Valproate), 2019 Vajda (Valproate) (Controls unexposed, sick), 2019 Tomson (Valproate), 2018 Vanya (Valproate) (Controls unexposed, sick), 2015 Campbell (Valproate) (Controls unexposed, sick), 2014 Veiby (Valproate) (Controls unexposed, sick) (Mixed indications), 2014 Cassina (Valproate) (Controls unexposed, disease free) (Mixed indications), 2013 Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013 Arteaga-Vázquez (Valproate), 2012 Bànhidy (Valproate), 2011 Charlton (Valproate) (Controls unexposed, sick), 2011 Mawer (Valproate) (Controls unexposed, sick), 2010 Diav-Citrin (Valproate) (Mixed indications), 2008 Viinikainen (Valproate) (Controls unexposed, sick) a, 2006 Artama (Valproate), 2005 Endo (Valproate) (Controls unexposed, sick), 2004 Kaaja (Valproate), 2003 Dean (Valproate), 2002 Hvas (Valproate) (Controls unexposed, sick), 2000 Canger (Valproate), 1999 Kaneko (Valproate), 1999 Samrén (Valproate), 1999 D'Souza (Valproate) (Controls unexposed, sick), 1991 Jäger-Roman (Valproate), 1986 Robert (Valproate), 1986 30   - Yes  - Yes 2.21[1.79; 2.72]49,7001,1950%NAThomas (Valproate) (Controls unexposed, sick), 2021 Petersen (Valproate) (Controls unexposed, sick), 2017 Källén (Valproate) (Controls unexposed, NOS) (Indications NOS), 2013 3 Controls   - epilepsy indication  - epilepsy indication 2.33[1.44; 3.77]127333 -NAVeiby (Valproate) (Controls unexposed, sick) (Mixed indications), 2014 1 MatchedMatched 3.08[1.81; 5.23]11824914%NAPutignano (Valproate), 2019 Bànhidy (Valproate), 2011 Samrén (Valproate), 1999 3 Partial overlappingPartial overlapping 2.31[1.87; 2.85]49,6881,0300%NAVeiby (Valproate) (Controls unexposed, sick) (Mixed indications), 2014 Källén (Valproate) (Controls unexposed, NOS) (Indications NOS), 2013 2 All studiesAll studies 3.16[2.64; 3.78]198,7168,17238%NACohen (Valproate) (Mixed indications) (Controls unexposed, NOS), 2023 The NAAED (Controls unexposed, disease free) (Indications NOS), 2022 Hosny (Valproate) (Controls unexposed, sick), 2021 Thomas (Valproate) (Controls unexposed, sick), 2021 Aydin (Valproate) (Controls unexposed, sick), 2020 Huber-Mollema (Valproate), 2019 Putignano (Valproate), 2019 Vajda (Valproate) (Controls unexposed, sick), 2019 Tomson (Valproate), 2018 Petersen (Valproate) (Controls unexposed, sick), 2017 Vanya (Valproate) (Controls unexposed, sick), 2015 Campbell (Valproate) (Controls unexposed, sick), 2014 Veiby (Valproate) (Controls unexposed, sick) (Mixed indications), 2014 Cassina (Valproate) (Controls unexposed, disease free) (Mixed indications), 2013 Källén (Valproate) (Controls unexposed, NOS) (Indications NOS), 2013 Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013 Arteaga-Vázquez (Valproate), 2012 Bànhidy (Valproate), 2011 Charlton (Valproate) (Controls unexposed, sick), 2011 Mawer (Valproate) (Controls unexposed, sick), 2010 Diav-Citrin (Valproate) (Mixed indications), 2008 Viinikainen (Valproate) (Controls unexposed, sick) a, 2006 Artama (Valproate), 2005 Endo (Valproate) (Controls unexposed, sick), 2004 Kaaja (Valproate), 2003 Dean (Valproate), 2002 Hvas (Valproate) (Controls unexposed, sick), 2000 Canger (Valproate), 1999 Kaneko (Valproate), 1999 Samrén (Valproate), 1999 D'Souza (Valproate) (Controls unexposed, sick), 1991 Jäger-Roman (Valproate), 1986 Robert (Valproate), 1986 330.01000.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-5.97.02.9930.000Cohen (Valproate) (Mixed indications) (Controls unexposed, NOS), 2023The NAAED (Controls unexposed, disease free) (Indications NOS), 2022Hosny (Valproate) (Controls unexposed, sick), 2021Thomas (Valproate) (Controls unexposed, sick), 2021Aydin (Valproate) (Controls unexposed, sick), 2020Huber-Mollema (Valproate), 2019Putignano (Valproate), 2019Vajda (Valproate) (Controls unexposed, sick), 2019Tomson (Valproate), 2018Petersen (Valproate) (Controls unexposed, sick), 2017Vanya (Valproate) (Controls unexposed, sick), 2015Campbell (Valproate) (Controls unexposed, sick), 2014Veiby (Valproate) (Controls unexposed, sick) (Mixed indications), 2014Cassina (Valproate) (Controls unexposed, disease free) (Mixed indications), 2013Källén (Valproate) (Controls unexposed, NOS) (Indications NOS), 2013Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013Arteaga-Vázquez (Valproate), 2012Bànhidy (Valproate), 2011Charlton (Valproate) (Controls unexposed, sick), 2011Mawer (Valproate) (Controls unexposed, sick), 2010Diav-Citrin (Valproate) (Mixed indications), 2008Viinikainen (Valproate) (Controls unexposed, sick) a, 2006Artama (Valproate), 2005Endo (Valproate) (Controls unexposed, sick), 2004Kaaja (Valproate), 2003Dean (Valproate), 2002Hvas (Valproate) (Controls unexposed, sick), 2000Canger (Valproate), 1999Kaneko (Valproate), 1999Samrén (Valproate), 1999D'Souza (Valproate) (Controls unexposed, sick), 1991Jäger-Roman (Valproate), 1986Robert (Valproate), 1986

Asymetry test p-value = 0.0041 (by Egger's regression)

slope=0.9529 (0.0879); intercept=0.5270 (0.2992); t=1.7613; p=0.0041

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 9297, 9306, 9300, 9290, 9312, 9317, 9293, 9336, 9309, 9450, 9333, 9325, 9326, 9362, 10210, 10211, 9452, 9360, 9280, 9287, 12689, 12882, 12862, 12863, 9304, 15200, 15264, 15216

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 3.14[2.45; 4.03]225,9434,38455%NACohen (Valproate) (Mixed indications) (Controls unexposed, NOS), 2023 The NAAED (Controls unexposed, disease free) (Indications NOS), 2022 Thomas (Valproate) (Controls unexposed, disease free), 2021 Putignano (Valproate), 2019 Petersen (Valproate) (Controls unexposed NOS), 2017 Veiby (Valproate) (Controls unexposed, disease free) (Mixed indications), 2014 Cassina (Valproate) (Controls unexposed, disease free) (Mixed indications), 2013 Källén (Valproate) (Controls unexposed, NOS) (Indications NOS), 2013 Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013 Mawer (Valproate) (Controls unexposed, disease free), 2010 Diav-Citrin (Valproate) (Mixed indications), 2008 Endo (Valproate) (Controls unexposed, disease free), 2004 Hvas (Valproate) (Controls unexposed, disease free), 2000 Samrén (Valproate), 1999 D'Souza (Valproate) (Controls unexposed, disease free), 1991 Jäger-Roman (Valproate), 1986 16 unexposed, sick controlsunexposed, sick controls 2.96[2.31; 3.78]6203,22913%NAHosny (Valproate) (Controls unexposed, sick), 2021 Thomas (Valproate) (Controls unexposed, sick), 2021 Aydin (Valproate) (Controls unexposed, sick), 2020 Vajda (Valproate) (Controls unexposed, sick), 2019 Petersen (Valproate) (Controls unexposed, sick), 2017 Vanya (Valproate) (Controls unexposed, sick), 2015 Campbell (Valproate) (Controls unexposed, sick), 2014 Veiby (Valproate) (Controls unexposed, sick) (Mixed indications), 2014 Arteaga-Vázquez (Valproate), 2012 Bànhidy (Valproate), 2011 Charlton (Valproate) (Controls unexposed, sick), 2011 Mawer (Valproate) (Controls unexposed, sick), 2010 Viinikainen (Valproate) (Controls unexposed, sick) a, 2006 Artama (Valproate), 2005 Endo (Valproate) (Controls unexposed, sick), 2004 Kaaja (Valproate), 2003 Dean (Valproate), 2002 Hvas (Valproate) (Controls unexposed, sick), 2000 Canger (Valproate), 1999 Kaneko (Valproate), 1999 D'Souza (Valproate) (Controls unexposed, sick), 1991 Robert (Valproate), 1986 22 exposed to other treatment, sick controlsexposed to other treatment, sick controls 2.95[2.36; 3.69]1,2007,27346%NACohen (Valproate) (Mixed indications) (Controls exposed to LTG), 2023 The NAAED (Controls exposed to Lamotrigine, sick) (Indications NOS), 2022 Hosny (Valproate) (Controls exposed to Lamotrigine, sick), 2021 Thomas (Valproate) (Controls exposed to Lamotrigine, sick), 2021 Aydin (Valproate) (Controls exposed to Lamotrigine, sick), 2020 Huber-Mollema (Valproate), 2019 Vajda (Valproate) (Controls exposed to Lamotrigine, sick), 2019 Tomson (Valproate), 2018 Petersen (Valproate) (Controls exposed to Lamotrigine, sick), 2017 Vanya (Valproate) (Controls exposed to Lamotrigine, sick), 2015 Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014 Veiby (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2014 Cassina (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2013 Källén (Valproate) (Controls exposed to Lamotrigine, sick) (Indications NOS), 2013 Rihtman (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2013 Charlton (Valproate) (Controls exposed to Lamotrigine, sick), 2011 Mawer (Valproate) (Controls exposed to Lamotrigine, sick), 2010 170.510.01.0