Valproate (Epilepsy)

ASD (Autism spectrum disorder): Diagnosis/Risk

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.
S15877
R65489		 Dreier (Valproate) (Epilepsy) (Controls exposed to LTG), 2023 Autism spectrum disorder - Corresponding ICD-10 F-chapter - Up to 22 years of age during pregnancy (anytime or not specified) population based cohort propective exposed to other treatment, sick excluded Adjustment: No 4.08 [2.96;5.64] C
excluded (control group) 		93/1,952   64/5,288 157 1,952
ref
S15878
R65484		 Dreier (Valproate) (Epilepsy) (Controls unexposed, sick), 2023 Autism spectrum disorder - Corresponding ICD-10 F-chapter - Up to 22 years of age during pregnancy (anytime or not specified) population based cohort propective unexposed, sick Adjustment: Yes 2.45 [1.84;3.26] 93/1,952   323/22,203 416 1,952
ref
S10070
R46576		 Coste (Valproate) (Controls exposed to Lamotrigine, sick), 2020 Diagnosis Pervasive developmental disorders (F84) (mean age of 3.7 years old) during pregnancy (anytime or not specified) retrospective cohort (claims database) exposed to other treatment, sick excluded Adjustment: Yes 4.70 [1.90;11.40]
excluded (control group) 		17/991   7/2,108 24 991
ref
S7799
R46577		 Coste (Valproate) (Controls unexposed, NOS), 2020 Diagnosis Pervasive developmental disorders (F84) (mean age of 3.6 years old) during pregnancy (anytime or not specified) retrospective cohort (claims database) unexposed (general population or NOS) Adjustment: Yes 4.60 [2.90;7.50] 17/991   4,280/1,710,441 4,297 991
ref
S8008
R46580		 Wiggs (Valproate), 2020 Austism Spectrum Disorder (after 2 years of age) at least 1st trimester population based cohort retrospective unexposed, sick Adjustment: Yes 2.30 [1.53;3.47] -/-   -/11,298 - -
ref
S7508
R46579		 Huber-Mollema (Valproate), 2019 Diagnosis of autism spectrum disorder throughout pregnancy prospective cohort exposed to other treatment, sick Adjustment: No 2.74 [0.57;13.12] C 3/26   4/88 7 26
ref
S9984
R46582		 Bjørk (Valproate) (Controls exposed to Lamotrigine, sick), 2018 Autistic traits at 18 months and/or at 36 months (M-CHAT <2/6 critical or <3/23 or SCQ >13) during pregnancy (anytime or not specified) population based cohort propective exposed to other treatment, sick excluded Adjustment: No 0.61 [0.16;2.31] C
excluded (control group) 		3/27   13/76 16 27
ref
S9985
R46583		 Bjørk (Valproate) (Controls unexposed, disease free), 2018 Autistic traits at 18 months and/or at 36 months (M-CHAT <2/6 critical or <3/23 or SCQ >13) during pregnancy (anytime or not specified) population based cohort propective unexposed, disease free excluded Adjustment: No 1.24 [0.37;4.12] C
excluded (control group) 		3/27   6,907/75,497 6,910 27
ref
S9986
R46584		 Bjørk (Valproate) (Controls unexposed, sick), 2018 Autistic traits at 18 months and/or at 36 months (M-CHAT <2/6 critical or <3/23 or SCQ >13) during pregnancy (anytime or not specified) population based cohort propective unexposed, sick Adjustment: No 1.13 [0.32;4.02] C 3/27   27/272 30 27
ref
S5549
R46581		 Wood (Valproate), 2015 Score >30 (CARS) during pregnancy (anytime or not specified) prospective cohort exposed to other treatment, sick Adjustment: No 1.04 [0.04;28.06] C 1/26   0/9 1 26
ref
S6662
R46573		 Bromley (Valproate) (Controls exposed to Lamotrigine, sick), 2013 Autistic Spectrum Disorders (at 6 years old) during pregnancy (anytime or not specified) prospective cohort exposed to other treatment, sick excluded Adjustment: No 2.52 [0.27;23.69] C
excluded (control group) 		4/50   1/30 5 50
ref
S6659
R46574		 Bromley (Valproate) (Controls unexposed, disease free), 2013 Autistic Spectrum Disorders (at 6 years old) during pregnancy (anytime or not specified) prospective cohort unexposed, disease free excluded Adjustment: No 4.57 [1.10;18.93] C
excluded (control group) 		4/50   4/214 8 50
ref
S6602
R46575		 Bromley (Valproate) (Controls unexposed, sick), 2013 Autistic Spectrum Disorders (at 6 years old) during pregnancy (anytime or not specified) prospective cohort unexposed, sick Adjustment: No 5.04 [0.26;97.51] C 4/50   0/26 4 50
ref
S7175
R46572		 Adab (Valproate), 2004 Asperger’s syndrome during pregnancy (anytime or not specified) retrospective cohort unexposed, sick Adjustment: No 4.90 [0.20;122.25] C 1/63   0/101 1 63
ref
Total 8 studies 2.71 [2.08;3.52] 4,756 3,135
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 Dreier (Valproate) (Epilepsy) (Controls unexposed, sick), 2023Dreier, 2023 1 2.45[1.84; 3.26]4161,95242%ROB confusion: seriousROB selection: lowROB classification: moderateROB missing: lowROB mesure: criticalROB reporting: moderate Coste (Valproate) (Controls unexposed, NOS), 2020Coste, 2020 2 4.60[2.90; 7.50]4,29799122%ROB confusion: moderateROB selection: moderateROB classification: moderateROB missing: moderateROB mesure: criticalROB reporting: moderate Wiggs (Valproate), 2020Wiggs, 2020 3 2.30[1.53; 3.47]--27%ROB confusion: seriousROB selection: lowROB classification: lowROB missing: moderateROB mesure: moderateROB reporting: moderate Huber-Mollema (Valproate), 2019Huber-Mollema, 2019 4 2.74[0.57; 13.12]7263%ROB confusion: criticalROB selection: lowROB classification: moderateROB missing: criticalROB mesure: moderateROB reporting: moderate Bjørk (Valproate) (Controls unexposed, sick), 2018Bjørk, 2018 5 1.13[0.32; 4.02]30274%ROB confusion: unclearROB selection: lowROB classification: lowROB missing: lowROB mesure: moderateROB reporting: moderate Wood (Valproate), 2015Wood, 2015 6 1.04[0.04; 28.06]1261%ROB confusion: criticalROB selection: lowROB classification: moderateROB missing: criticalROB mesure: lowROB reporting: moderate Bromley (Valproate) (Controls unexposed, sick), 2013Bromley, 2013 7 5.04[0.26; 97.51]4501%ROB confusion: criticalROB selection: lowROB classification: lowROB missing: moderateROB mesure: moderateROB reporting: moderate Adab (Valproate), 2004Adab, 2004 8 4.90[0.20; 122.25]1631%ROB confusion: criticalROB selection: criticalROB classification: lowROB missing: criticalROB mesure: lowROB reporting: moderate Total (8 studies) I2 = 16% 2.71[2.08; 3.52]4,7563,1350.520.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

1: Valproate) (Epilepsy) (Controls unexposed, sick; 2: Valproate) (Controls unexposed, NOS; 3: Valproate; 4: Valproate; 5: Valproate) (Controls unexposed, sick; 6: Valproate; 7: Valproate) (Controls unexposed, sick; 8: Valproate;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 2.71[2.08; 3.52]4,7563,13516%NADreier (Valproate) (Epilepsy) (Controls unexposed, sick), 2023 Coste (Valproate) (Controls unexposed, NOS), 2020 Wiggs (Valproate), 2020 Huber-Mollema (Valproate), 2019 Bjørk (Valproate) (Controls unexposed, sick), 2018 Wood (Valproate), 2015 Bromley (Valproate) (Controls unexposed, sick), 2013 Adab (Valproate), 2004 8 case control studiescase control studies 0 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 4.60[2.86; 7.40]4,297991 -NACoste (Valproate) (Controls unexposed, NOS), 2020 1 unexposed, sickunexposed, sick 2.36[1.88; 2.97]4512,0920%NADreier (Valproate) (Epilepsy) (Controls unexposed, sick), 2023 Wiggs (Valproate), 2020 Bjørk (Valproate) (Controls unexposed, sick), 2018 Bromley (Valproate) (Controls unexposed, sick), 2013 Adab (Valproate), 2004 5 exposed to other treatment, sickexposed to other treatment, sick 2.29[0.56; 9.43]8520%NAHuber-Mollema (Valproate), 2019 Wood (Valproate), 2015 2 Tags Adjustment   - No  - No 1.86[0.78; 4.43]431920%NAHuber-Mollema (Valproate), 2019 Bjørk (Valproate) (Controls unexposed, sick), 2018 Wood (Valproate), 2015 Bromley (Valproate) (Controls unexposed, sick), 2013 Adab (Valproate), 2004 5   - Yes  - Yes 2.87[1.96; 4.20]4,7132,94366%NADreier (Valproate) (Epilepsy) (Controls unexposed, sick), 2023 Coste (Valproate) (Controls unexposed, NOS), 2020 Wiggs (Valproate), 2020 3 All studiesAll studies 2.71[2.08; 3.52]4,7563,13516%NADreier (Valproate) (Epilepsy) (Controls unexposed, sick), 2023 Coste (Valproate) (Controls unexposed, NOS), 2020 Wiggs (Valproate), 2020 Huber-Mollema (Valproate), 2019 Bjørk (Valproate) (Controls unexposed, sick), 2018 Wood (Valproate), 2015 Bromley (Valproate) (Controls unexposed, sick), 2013 Adab (Valproate), 2004 80.520.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-4.04.92.0170.000Dreier (Valproate) (Epilepsy) (Controls unexposed, sick), 2023Coste (Valproate) (Controls unexposed, NOS), 2020Wiggs (Valproate), 2020Huber-Mollema (Valproate), 2019Bjørk (Valproate) (Controls unexposed, sick), 2018Wood (Valproate), 2015Bromley (Valproate) (Controls unexposed, sick), 2013Adab (Valproate), 2004

Asymetry test p-value = 0.9603 (by Egger's regression)

slope=0.9889 (0.1861); intercept=-0.0328 (0.6312); t=0.0519; p=0.9603

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 6662, 6659, 9984, 9985, 10070, 15877

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 3.25[1.46; 7.26]11,2151,06850%NACoste (Valproate) (Controls unexposed, NOS), 2020 Bjørk (Valproate) (Controls unexposed, disease free), 2018 Bromley (Valproate) (Controls unexposed, disease free), 2013 3 unexposed, sick controlsunexposed, sick controls 2.36[1.88; 2.97]4512,0920%NADreier (Valproate) (Epilepsy) (Controls unexposed, sick), 2023 Wiggs (Valproate), 2020 Bjørk (Valproate) (Controls unexposed, sick), 2018 Bromley (Valproate) (Controls unexposed, sick), 2013 Adab (Valproate), 2004 5 exposed to other treatment, sick controlsexposed to other treatment, sick controls 2.84[1.54; 5.24]2103,07241%NADreier (Valproate) (Epilepsy) (Controls exposed to LTG), 2023 Coste (Valproate) (Controls exposed to Lamotrigine, sick), 2020 Huber-Mollema (Valproate), 2019 Bjørk (Valproate) (Controls exposed to Lamotrigine, sick), 2018 Wood (Valproate), 2015 Bromley (Valproate) (Controls exposed to Lamotrigine, sick), 2013 60.510.01.0