Valproate (All indications) updated on 04-22-2025

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.
S18030
R75971		 Hao (Valproate) (Epilepsy) (Controls exposed to LTG), 2025 Major congenital malformation (MCM) 1st trimester prospective cohort exposed to other treatment, sick excluded Adjustment: No 1.06 [0.17;6.56] C
excluded (control group) 		2/53   3/84 5 53
ref
S18029
R75970		 Hao (Valproate) (Epilepsy) (Controls unexposed, sick), 2025 Major congenital malformation (MCM) 1st trimester prospective cohort unexposed, sick Adjustment: No 0.86 [0.21;3.42] 2/53   10/261 12 53
ref
S16099
R66790		 Battino (Valproate) (Epilepsy), 2024 Major congenital malformations (MCMs) early pregnancy prospective cohort exposed to other treatment, sick Adjustment: No 3.46 [2.69;4.46] C 153/1,549   110/3,584 263 1,549
ref
S16109
R66804		 Fietz (Valproate), 2024 Major birth defects (excluding genetic disorders) 1st trimester prospective cohort unexposed (general population or NOS) Adjustment: Yes 2.36 [1.27;4.38] 20/256   44/1,306 64 256
ref
S18045
R76011		 Vajda b (Valproate) (Epilepsy) (Controls exposed to Lamotrigine, sick), 2024 Fetal malformations early pregnancy prospective cohort exposed to other treatment, sick excluded Adjustment: No 3.97 [2.27;6.96] C
excluded (control group) 		40/268   20/473 60 268
ref
S18046
R76013		 Vajda b (Valproate) (Epilepsy) (Controls unexposed, sick), 2024 Fetal malformations at least 1st trimester prospective cohort unexposed, sick Adjustment: No 4.50 [2.06;9.81] 40/268   7/201 47 268
ref
S17499
R73517		 Wiggs (Epilepsy) (Valproate), 2024 Major birth defects early pregnancy population based cohort retrospective unexposed, sick Adjustment: Yes 2.70 [1.88;3.89] -/624   -/12,666 - 624
ref
S15200
R62348		 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
R62349		 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
R62749		 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
R62750		 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
S16172
R67061		 The NAAED (Valproate) (Controls exposed to LTG) (Indications NOS), 2023 Major congenital malformations 1st trimester prospective cohort exposed to other treatment, sick excluded Adjustment: No 4.69 [2.96;7.44] C
excluded (control group) 		31/337   52/2,461 83 337
ref
S16173
R67063		 The NAAED (Valproate) (Controls unexposed, disease free) (Indications NOS), 2023 Major congenital malformations 1st trimester prospective cohort unexposed, disease free Adjustment: No 8.75 [4.67;16.42] C 31/337   15/1,311 46 337
ref
S12689
R47925		 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
R47927		 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
R48683		 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
R48686		 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
R48536		 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
R48544		 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
R48548		 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
S16157
R67050		 Alsaadi (Valproate) (Epilepsy) (Controls exposed to LTG), 2020 Major congenital malformations 1st trimester retrospective cohort exposed to other treatment, sick excluded Adjustment: No 2.80 [0.12;63.59] C
excluded (control group) 		2/23   0/12 2 23
ref
S16154
R67038		 Alsaadi (Valproate) (Epilepsy) (Controls unexposed sick), 2020 Major congenital malformations 1st trimester retrospective cohort unexposed, sick Adjustment: No 3.33 [0.28;39.04] C 2/23   1/36 3 23
ref
S9280
R32189		 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
R32192		 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
S16169
R67060		 Zhang (Valproate) (Epilepsy), 2020 Major congenital malformations (MCMs) 1st trimester retrospective cohort unexposed, sick Adjustment: No 6.96 [1.16;41.91] C 2/14   4/171 6 14
ref
S9314
R32450		 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
S16162
R67053		 Guveli (Valproate) (Epilepsy), 2017 Major malformations during pregnancy (anytime or not specified) excluded retrospective cohort unexposed, sick Adjustment: No 2.59 [0.25;26.46] C
excluded (exposition period) 		3/32   1/26 4 32
ref
S10210
R37402		 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
R37403		 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
R37404		 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
R32195		 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
R32746		 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
R32748		 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
R32259		 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
R32568		 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
R32570		 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
R32518		 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
R32522		 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
R32525		 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
R32580		 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
R32582		 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
S9331
R32555		 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
R32277		 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
R32280		 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
R32441		 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
R32466		 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
R32468		 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
R33166		 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
S9346
R32595		 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
R32470		 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
R32528		 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
S9342
R32590		 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
R32355		 Dean (Valproate), 2002 Major congenital malformations at least 1st trimester retrospective cohort unexposed, sick Adjustment: No 2.14 [0.39;11.72] C 5/47   2/38 7 47
ref
S9306
R32413		 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
R32415		 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
S9335
R32578		 Canger (Valproate), 1999 Severe malformations 1st trimester prospective cohort unexposed, sick Adjustment: No 8.49 [0.46;157.67] C 6/44   0/25 6 44
ref
S9353
R32723		 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
R32725		 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
S9308
R32422		 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
R32720		 Robert (Valproate), 1986 Major malformations 1st trimester retrospective cohort unexposed, sick Adjustment: No 13.80 [0.62;307.74] C 2/15   0/35 2 15
ref
Total 28 studies 2.91 [2.44;3.48] 149,091 8,088
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 Hao (Valproate) (Epilepsy) (Controls unexposed, sick), 2025Hao, 2025 1 0.86[0.21; 3.42]12531%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: lowROB mesure: moderateROB reporting: moderate Battino (Valproate) (Epilepsy), 2024Battino, 2024 2 3.46[2.69; 4.46]2631,54913%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: moderateROB mesure: moderateROB reporting: moderate Fietz (Valproate), 2024Fietz, 2024 3 2.36[1.27; 4.38]642566%ROB confusion: seriousROB selection: moderateROB classification: moderateROB missing: moderateROB mesure: criticalROB reporting: low Vajda b (Valproate) (Epilepsy) (Controls unexposed, sick), 2024Vajda b, 2024 4 4.50[2.06; 9.81]472684%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: moderateROB mesure: moderateROB reporting: moderate Wiggs (Epilepsy) (Valproate), 2024Wiggs, 2024 5 2.70[1.88; 3.89]-62410%ROB confusion: seriousROB selection: moderateROB classification: moderateROB missing: lowROB mesure: moderateROB reporting: moderate Cohen (Valproate) (Mixed indications) (Controls unexposed, NOS), 2023Cohen, 2023 6 2.71[2.30; 3.19]148,0872,03115%ROB confusion: criticalROB selection: lowROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate The NAAED (Valproate) (Controls unexposed, disease free) (Indications NOS), 2023The NAAED, 2023 7 8.75[4.67; 16.42]463375%ROB confusion: criticalROB selection: unclearROB classification: moderateROB missing: unclearROB mesure: criticalROB reporting: low Hosny (Valproate) (Controls unexposed, sick), 2021Hosny, 2021 8 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 9 1.71[0.90; 3.20]433415%ROB confusion: seriousROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Alsaadi (Valproate) (Epilepsy) (Controls unexposed sick), 2020Alsaadi, 2020 10 3.33[0.28; 39.04]3231%ROB confusion: criticalROB selection: unclearROB classification: criticalROB missing: lowROB mesure: criticalROB reporting: moderate Zhang (Valproate) (Epilepsy), 2020Zhang, 2020 11 6.96[1.16; 41.91]6141%ROB confusion: criticalROB selection: unclearROB classification: criticalROB missing: lowROB mesure: moderateROB reporting: moderate Petersen (Valproate) (Controls unexposed, sick), 2017Petersen, 2017 12 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 13 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 14 2.93[1.62; 5.30]951,2206%ROB confusion: unclearROB selection: lowROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Veiby (Valproate) (Controls unexposed, sick) (Mixed indications), 2014Veiby, 2014 15 2.33[1.44; 3.77]1273338%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: moderateROB mesure: moderateROB reporting: moderate Cassina (Valproate) (Controls unexposed, disease free) (Mixed indications), 2013Cassina, 2013 16 1.64[0.66; 4.08]311203%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Bànhidy (Valproate), 2011Bànhidy, 2011 17 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 18 2.00[0.99; 4.07]332255%ROB confusion: criticalROB selection: moderateROB classification: criticalROB missing: unclearROB mesure: moderateROB reporting: moderate Mawer (Valproate) (Controls unexposed, sick), 2010Mawer, 2010 19 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 20 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 21 5.83[0.23; 148.09]1280%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Kaaja (Valproate), 2003Kaaja, 2003 22 8.32[1.49; 46.53]6611%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Dean (Valproate), 2002Dean, 2002 23 2.14[0.39; 11.72]7471%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Hvas (Valproate) (Controls unexposed, sick), 2000Hvas, 2000 24 55.53[2.48; 1242.66]2120%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Canger (Valproate), 1999Canger, 1999 25 8.49[0.46; 157.67]6440%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Samrén (Valproate), 1999Samrén, 1999 26 4.10[1.90; 8.80]381584%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Jäger-Roman (Valproate), 1986Jäger-Roman, 1986 27 6.23[1.55; 24.98]11141%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Robert (Valproate), 1986Robert, 1986 28 13.80[0.62; 307.74]2150%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Total (28 studies) I2 = 33% 2.91[2.44; 3.48]149,0918,0880.2500.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

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

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 2.95[2.47; 3.52]149,0728,07632%NAHao (Valproate) (Epilepsy) (Controls unexposed, sick), 2025 Battino (Valproate) (Epilepsy), 2024 Fietz (Valproate), 2024 Vajda b (Valproate) (Epilepsy) (Controls unexposed, sick), 2024 Wiggs (Epilepsy) (Valproate), 2024 Cohen (Valproate) (Mixed indications) (Controls unexposed, NOS), 2023 The NAAED (Valproate) (Controls unexposed, disease free) (Indications NOS), 2023 Hosny (Valproate) (Controls unexposed, sick), 2021 Thomas (Valproate) (Controls unexposed, sick), 2021 Alsaadi (Valproate) (Epilepsy) (Controls unexposed sick), 2020 Zhang (Valproate) (Epilepsy), 2020 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 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 Kaaja (Valproate), 2003 Dean (Valproate), 2002 Hvas (Valproate) (Controls unexposed, sick), 2000 Canger (Valproate), 1999 Samrén (Valproate), 1999 Jäger-Roman (Valproate), 1986 Robert (Valproate), 1986 27 case control studiescase control studies 1.17[0.28; 4.84]1912 -NABànhidy (Valproate), 2011 1 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 3.28[2.14; 5.00]148,3112,98765%NAFietz (Valproate), 2024 Cohen (Valproate) (Mixed indications) (Controls unexposed, NOS), 2023 The NAAED (Valproate) (Controls unexposed, disease free) (Indications NOS), 2023 Cassina (Valproate) (Controls unexposed, disease free) (Mixed indications), 2013 Diav-Citrin (Valproate) (Mixed indications), 2008 Samrén (Valproate), 1999 Jäger-Roman (Valproate), 1986 7 unexposed, sickunexposed, sick 2.57[2.10; 3.16]5173,5523%NAHao (Valproate) (Epilepsy) (Controls unexposed, sick), 2025 Vajda b (Valproate) (Epilepsy) (Controls unexposed, sick), 2024 Wiggs (Epilepsy) (Valproate), 2024 Hosny (Valproate) (Controls unexposed, sick), 2021 Thomas (Valproate) (Controls unexposed, sick), 2021 Alsaadi (Valproate) (Epilepsy) (Controls unexposed sick), 2020 Zhang (Valproate) (Epilepsy), 2020 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 Bànhidy (Valproate), 2011 Charlton (Valproate) (Controls unexposed, sick), 2011 Mawer (Valproate) (Controls unexposed, sick), 2010 Viinikainen (Valproate) (Controls unexposed, sick) a, 2006 Kaaja (Valproate), 2003 Dean (Valproate), 2002 Hvas (Valproate) (Controls unexposed, sick), 2000 Canger (Valproate), 1999 Robert (Valproate), 1986 20 exposed to other treatment, sickexposed to other treatment, sick 3.46[2.69; 4.46]2631,549 -NABattino (Valproate) (Epilepsy), 2024 1 Tags Adjustment   - No  - No 3.19[2.56; 3.97]148,8886,71036%NAHao (Valproate) (Epilepsy) (Controls unexposed, sick), 2025 Battino (Valproate) (Epilepsy), 2024 Vajda b (Valproate) (Epilepsy) (Controls unexposed, sick), 2024 Cohen (Valproate) (Mixed indications) (Controls unexposed, NOS), 2023 The NAAED (Valproate) (Controls unexposed, disease free) (Indications NOS), 2023 Hosny (Valproate) (Controls unexposed, sick), 2021 Alsaadi (Valproate) (Epilepsy) (Controls unexposed sick), 2020 Zhang (Valproate) (Epilepsy), 2020 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 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 Kaaja (Valproate), 2003 Dean (Valproate), 2002 Hvas (Valproate) (Controls unexposed, sick), 2000 Canger (Valproate), 1999 Samrén (Valproate), 1999 Jäger-Roman (Valproate), 1986 Robert (Valproate), 1986 24   - Yes  - Yes 2.36[1.82; 3.05]2031,3780%NAFietz (Valproate), 2024 Wiggs (Epilepsy) (Valproate), 2024 Thomas (Valproate) (Controls unexposed, sick), 2021 Petersen (Valproate) (Controls unexposed, sick), 2017 4 Controls   - epilepsy indication  - epilepsy indication 2.33[1.44; 3.77]127333 -NAVeiby (Valproate) (Controls unexposed, sick) (Mixed indications), 2014 1 MatchedMatched 2.54[0.77; 8.40]5717057%NABànhidy (Valproate), 2011 Samrén (Valproate), 1999 2 Partial overlappingPartial overlapping 2.33[1.44; 3.77]127333 -NAVeiby (Valproate) (Controls unexposed, sick) (Mixed indications), 2014 1 All studiesAll studies 2.91[2.44; 3.48]149,0918,08833%NAHao (Valproate) (Epilepsy) (Controls unexposed, sick), 2025 Battino (Valproate) (Epilepsy), 2024 Fietz (Valproate), 2024 Vajda b (Valproate) (Epilepsy) (Controls unexposed, sick), 2024 Wiggs (Epilepsy) (Valproate), 2024 Cohen (Valproate) (Mixed indications) (Controls unexposed, NOS), 2023 The NAAED (Valproate) (Controls unexposed, disease free) (Indications NOS), 2023 Hosny (Valproate) (Controls unexposed, sick), 2021 Thomas (Valproate) (Controls unexposed, sick), 2021 Alsaadi (Valproate) (Epilepsy) (Controls unexposed sick), 2020 Zhang (Valproate) (Epilepsy), 2020 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 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 Kaaja (Valproate), 2003 Dean (Valproate), 2002 Hvas (Valproate) (Controls unexposed, sick), 2000 Canger (Valproate), 1999 Samrén (Valproate), 1999 Jäger-Roman (Valproate), 1986 Robert (Valproate), 1986 280.21000.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-4.85.02.0260.000Hao (Valproate) (Epilepsy) (Controls unexposed, sick), 2025Battino (Valproate) (Epilepsy), 2024Fietz (Valproate), 2024Vajda b (Valproate) (Epilepsy) (Controls unexposed, sick), 2024Wiggs (Epilepsy) (Valproate), 2024Cohen (Valproate) (Mixed indications) (Controls unexposed, NOS), 2023The NAAED (Valproate) (Controls unexposed, disease free) (Indications NOS), 2023Hosny (Valproate) (Controls unexposed, sick), 2021Thomas (Valproate) (Controls unexposed, sick), 2021Alsaadi (Valproate) (Epilepsy) (Controls unexposed sick), 2020Zhang (Valproate) (Epilepsy), 2020Petersen (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), 2013Bànhidy (Valproate), 2011Charlton (Valproate) (Controls unexposed, sick), 2011Mawer (Valproate) (Controls unexposed, sick), 2010Diav-Citrin (Valproate) (Mixed indications), 2008Viinikainen (Valproate) (Controls unexposed, sick) a, 2006Kaaja (Valproate), 2003Dean (Valproate), 2002Hvas (Valproate) (Controls unexposed, sick), 2000Canger (Valproate), 1999Samrén (Valproate), 1999Jäger-Roman (Valproate), 1986Robert (Valproate), 1986

Asymetry test p-value = 0.4308 (by Egger's regression)

slope=0.9962 (0.0939); intercept=0.2939 (0.3285); t=0.8946; p=0.4308

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 9306, 9312, 9317, 9293, 9336, 9333, 9325, 9326, 9362, 10210, 10211, 16157, 9280, 12689, 12882, 12862, 12863, 15200, 15264, 16172, 18045, 18030

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 3.16[2.36; 4.23]176,3573,82957%NAFietz (Valproate), 2024 Cohen (Valproate) (Mixed indications) (Controls unexposed, NOS), 2023 The NAAED (Valproate) (Controls unexposed, disease free) (Indications NOS), 2023 Thomas (Valproate) (Controls unexposed, disease free), 2021 Petersen (Valproate) (Controls unexposed NOS), 2017 Veiby (Valproate) (Controls unexposed, disease free) (Mixed indications), 2014 Cassina (Valproate) (Controls unexposed, disease free) (Mixed indications), 2013 Mawer (Valproate) (Controls unexposed, disease free), 2010 Diav-Citrin (Valproate) (Mixed indications), 2008 Hvas (Valproate) (Controls unexposed, disease free), 2000 Samrén (Valproate), 1999 Jäger-Roman (Valproate), 1986 12 unexposed, sick controlsunexposed, sick controls 2.57[2.10; 3.16]5173,5523%NAHao (Valproate) (Epilepsy) (Controls unexposed, sick), 2025 Vajda b (Valproate) (Epilepsy) (Controls unexposed, sick), 2024 Wiggs (Epilepsy) (Valproate), 2024 Hosny (Valproate) (Controls unexposed, sick), 2021 Thomas (Valproate) (Controls unexposed, sick), 2021 Alsaadi (Valproate) (Epilepsy) (Controls unexposed sick), 2020 Zhang (Valproate) (Epilepsy), 2020 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 Bànhidy (Valproate), 2011 Charlton (Valproate) (Controls unexposed, sick), 2011 Mawer (Valproate) (Controls unexposed, sick), 2010 Viinikainen (Valproate) (Controls unexposed, sick) a, 2006 Kaaja (Valproate), 2003 Dean (Valproate), 2002 Hvas (Valproate) (Controls unexposed, sick), 2000 Canger (Valproate), 1999 Robert (Valproate), 1986 20 exposed to other treatment, sick controlsexposed to other treatment, sick controls 2.84[2.25; 3.58]1,1456,73246%NAHao (Valproate) (Epilepsy) (Controls exposed to LTG), 2025 Battino (Valproate) (Epilepsy), 2024 Vajda b (Valproate) (Epilepsy) (Controls exposed to Lamotrigine, sick), 2024 Cohen (Valproate) (Mixed indications) (Controls exposed to LTG), 2023 The NAAED (Valproate) (Controls exposed to LTG) (Indications NOS), 2023 Hosny (Valproate) (Controls exposed to Lamotrigine, sick), 2021 Thomas (Valproate) (Controls exposed to Lamotrigine, sick), 2021 Alsaadi (Valproate) (Epilepsy) (Controls exposed to LTG), 2020 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 Charlton (Valproate) (Controls exposed to Lamotrigine, sick), 2011 Mawer (Valproate) (Controls exposed to Lamotrigine, sick), 2010 150.510.01.0

Umbrella review (other published meta-analyses)

Published MAControlPeriodTE95% CIn exposedkI2 Tanoshima (Epilepsy) (Major congenital malfor ...Tanoshima (Epilepsy) (Major congenital malformations) 2.44[2.13; 2.80]0%-Wwhatever (meta-analysis)Anyduring pregnancy (anytime or not specified)studies TTT28 Veroniki a (MA) (All indications) (Overall Ma ...Veroniki a (MA) (All indications) (Overall Major Congenital Malformations) 2.62[2.04; 3.38]NA-Wwhatever (meta-analysis)T11st trimesterstudies TTT28 Veroniki a (NMA) (All indications) (Overall m ...Veroniki a (NMA) (All indications) (Overall major congenital malformations) 2.93[2.36; 3.69]NA-Wwhatever (meta-analysis)T11st trimesterstudies TTT-9 metaPregmetaPreg 2.91[2.44; 3.48]33%8,088----Hao (Valproate) (Epilepsy) (Controls unexposed, sick), 2025 Battino (Valproate) (Epilepsy), 2024 Fietz (Valproate), 2024 Vajda b (Valproate) (Epilepsy) (Controls unexposed, sick), 2024 Wiggs (Epilepsy) (Valproate), 2024 Cohen (Valproate) (Mixed indications) (Controls unexposed, NOS), 2023 The NAAED (Valproate) (Controls unexposed, disease free) (Indications NOS), 2023 Hosny (Valproate) (Controls unexposed, sick), 2021 Thomas (Valproate) (Controls unexposed, sick), 2021 Alsaadi (Valproate) (Epilepsy) (Controls unexposed sick), 2020 Zhang (Valproate) (Epilepsy), 2020 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 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 Kaaja (Valproate), 2003 Dean (Valproate), 2002 Hvas (Valproate) (Controls unexposed, sick), 2000 Canger (Valproate), 1999 Samrén (Valproate), 1999 Jäger-Roman (Valproate), 1986 Robert (Valproate), 1986 280.510.01.0