Valproate (Paternal exposure)

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.
S18649
R79264		 Colas_Norway, 2025 Congenital malformations (major and/or minor) Paternal exposure: genotoxic/epigenetic window (0–xxx months preconception) population based cohort retrospective exposed to other treatment, sick Adjustment: No Matched Paternal ASMs: monotherapy 0.75 [0.39;1.43] C 14/136   40/301 54 136
ref
S18646
R79296		 Christensen (Controls exposed to LTG/LEV), 2024 Major congenital malformations Paternal exposure: genotoxic/epigenetic window (0–xxx months preconception) population based cohort retrospective exposed to other treatment, sick excluded Adjustment: Yes Paternal ASMs: mono/polytherapy or not specified 0.67 [0.46;0.98]
excluded (control group) 		48/1,336   84/1,663 132 1,336
ref
S18644
R79297		 Christensen (Controls unexposed, general pop), 2024 Major congenital malformations Paternal exposure: genotoxic/epigenetic window (0–xxx months preconception) population based cohort retrospective unexposed (general population or NOS) excluded Adjustment: Yes Paternal ASMs: monotherapy 0.83 [0.59;1.17]
excluded (control group) 		-/1,017   43,855/1,234,017 - 1,017
ref
S18647
R79298		 Christensen (Controls unexposed, sibling), 2024 Major congenital malformations Paternal exposure: genotoxic/epigenetic window (0–xxx months preconception) population based cohort retrospective sibling excluded Adjustment: Yes Paternal ASMs: mono/polytherapy or not specified 0.72 [0.30;1.70]
excluded (control group) 		10/303   16/381 26 303
ref
S18645
R79299		 Christensen (Controls unexposed, sick), 2024 Major congenital malformations Paternal exposure: genotoxic/epigenetic window (0–xxx months preconception) population based cohort retrospective unexposed, sick Adjustment: Yes Paternal ASMs: mono/polytherapy or not specified 0.81 [0.58;1.14] 35/1,052   481/11,308 516 1,052
ref
S18640
R79300		 Tomson, 2020 Major malformations Paternal exposure: genotoxic/epigenetic window (0–xxx months preconception) population based cohort retrospective unexposed, sick Adjustment: Yes Paternal ASMs: monotherapy 0.90 [0.60;1.50] 22/458   121/2,457 143 458
ref
Total 3 studies 0.83 [0.64;1.06] 713 1,646
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 Colas_Norway, 2025Colas_Norway, 2025 0.75[0.39; 1.43]5413615%ROB confusion: seriousROB selection: unclearROB classification: criticalROB missing: unclearROB mesure: moderateROB reporting: moderate Christensen (Controls unexposed, sick), 2024Christensen, 2024 1 0.81[0.58; 1.14]5161,05255%ROB confusion: seriousROB selection: moderateROB classification: criticalROB missing: unclearROB mesure: moderateROB reporting: moderate Tomson, 2020Tomson, 2020 0.90[0.60; 1.50]14345830%ROB confusion: criticalROB selection: unclearROB classification: criticalROB missing: lowROB mesure: moderateROB reporting: moderate Total (3 studies) I2 = 0% 0.83[0.64; 1.06]7131,6460.22.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

1: Controls unexposed, sick;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 0.83[0.64; 1.06]7131,6460%NAColas_Norway, 2025 Christensen (Controls unexposed, sick), 2024 Tomson, 2020 3 case control studiescase control studies 0 Type of controls unexposed, sickunexposed, sick 0.84[0.64; 1.10]6591,5100%NAChristensen (Controls unexposed, sick), 2024 Tomson, 2020 2 exposed to other treatment, sickexposed to other treatment, sick 0.75[0.39; 1.43]54136 -NAColas_Norway, 2025 1 Tags Adjustment   - No  - No 0.75[0.39; 1.43]54136 -NAColas_Norway, 2025 1   - Yes  - Yes 0.84[0.64; 1.10]6591,5100%NAChristensen (Controls unexposed, sick), 2024 Tomson, 2020 2 MatchedMatched 0.75[0.39; 1.43]54136 -NAColas_Norway, 2025 1 Paternal ASMs   - mono/polytherapy or not specified  - mono/polytherapy or not specified 0.81[0.58; 1.14]5161,052 -NAChristensen (Controls unexposed, sick), 2024 1   - monotherapy  - monotherapy 0.85[0.58; 1.23]1975940%NAColas_Norway, 2025 Tomson, 2020 2 All studiesAll studies 0.83[0.64; 1.06]7131,6460%NAColas_Norway, 2025 Christensen (Controls unexposed, sick), 2024 Tomson, 2020 30.210.01.0

Publication bias and p-hacking diagnosis

funnel plot

Funnel plot not drawn. Less than 3 points.

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

not enought points

p values plot

Funnel plot not drawn. Less than 3 points.

Sub-groups analysis using all included studies

excluded 18646, 18644, 18647

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 0.83[0.59; 1.17]43,8461,017 -NAChristensen (Controls unexposed, general pop), 2024 1 unexposed, sick controlsunexposed, sick controls 0.84[0.64; 1.10]6591,5100%NAChristensen (Controls unexposed, sick), 2024 Tomson, 2020 2 exposed to other treatment, sick controlsexposed to other treatment, sick controls 0.69[0.50; 0.96]1861,4720%NAColas_Norway, 2025 Christensen (Controls exposed to LTG/LEV), 2024 2 siblingssiblings 0.72[0.30; 1.71]26303 -NAChristensen (Controls unexposed, sibling), 2024 10.510.01.0