Valproate (All indications)

Oro-facial clefts

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.
S15201
R62352		 Cohen (Valproate) (Mixed indications) (Controls unexposed, NOS), 2023 Orofacial clefts 1st trimester population based cohort retrospective unexposed (general population or NOS) Adjustment: Yes 3.21 [1.73;5.96] -/2,031   -/4,866,362 - 2,031
ref
S10174
R46500		 Blotière (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2019 Oro-facial clefts 1st trimester retrospective cohort (claims database) exposed to other treatment, sick excluded Adjustment: No 4.95 [1.39;17.58] C
excluded (control group) 		6/913   4/2,997 10 913
ref
S10051
R46495		 Blotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019 Oro-facial clefts 1st trimester retrospective cohort (claims database) unexposed (general population or NOS) Adjustment: No 4.40 [1.97;9.83] C 6/913   2,815/1,875,733 2,821 913
ref
S9359
R32737		 Tomson (Valproate), 2018 Cleft lip or palate at least 1st trimester prospective cohort exposed to other treatment, sick Adjustment: No 3.65 [0.91;14.63] C 6/1,381   3/2,514 9 1,381
ref
S9333
R32559		 Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014 Facial cleft 1st trimester prospective cohort exposed to other treatment, sick Adjustment: No 11.29 [2.54;50.12] 13/1,220   2/2,098 15 1,220
ref
S9325
R32517		 Veiby (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2014 Orofacial clefts throughout pregnancy population based cohort retrospective exposed to other treatment, sick Adjustment: No 0.83 [0.03;20.52] C 0/333   1/833 1 333
ref
S9309
R32425		 Källén (Valproate) (Controls exposed to Lamotrigine, sick) (Indications NOS), 2013 Orofacial cleft early pregnancy population based cohort retrospective exposed to other treatment, sick excluded Adjustment: No 1.95 [0.52;7.29] C
excluded (control group) 		5/697   4/1,084 9 697
ref
S9310
R32433		 Källén (Valproate) (Controls unexposed, NOS) (Indications NOS), 2013 Orofacial cleft early pregnancy population based cohort retrospective unexposed (general population or NOS) Adjustment: Yes 3.33 [1.08;7.78] 5/697   2,756/1,575,847 2,761 697
ref
S10231
R37484		 Hernández-Díaz (Valproate) (Controls exposed to Lamotrigine, sick), 2012 Oral clefts 1st trimester prospective cohort exposed to other treatment, sick Adjustment: No Controls: mixed indications 2.79 [0.81;9.57] C 4/323   7/1,562 11 323
ref
Total 7 studies 3.67 [2.51;5.38] 5,618 6,898
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 3.21[1.73; 5.96]-2,03138%ROB confusion: seriousROB selection: lowROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Blotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019Blotière, 2019 2 4.40[1.97; 9.83]2,82191322%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Tomson (Valproate), 2018Tomson, 2018 3 3.65[0.91; 14.63]91,3818%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014Campbell, 2014 4 11.29[2.54; 50.12]151,2207%ROB confusion: criticalROB selection: lowROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Veiby (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2014Veiby, 2014 5 0.83[0.03; 20.52]13331%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: moderateROB mesure: moderateROB reporting: moderate Källén (Valproate) (Controls unexposed, NOS) (Indications NOS), 2013Källén, 2013 6 3.33[1.08; 7.78]2,76169715%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Hernández-Díaz (Valproate) (Controls exposed to Lamotrigine, sick), 2012Hernández-Díaz, 2012 7 2.79[0.81; 9.57]113239%ROB confusion: moderateROB selection: lowROB classification: moderateROB missing: moderateROB mesure: moderateROB reporting: moderate Total (7 studies) I2 = 0% 3.67[2.51; 5.38]5,6186,8980.250.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

1: Valproate) (Mixed indications) (Controls unexposed, NOS; 2: Valproate) (Controls unexposed NOS) (Mixed indications; 3: Valproate; 4: Valproate) (Controls exposed to Lamotrigine, sick; 5: Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications; 6: Valproate) (Controls unexposed, NOS) (Indications NOS; 7: Valproate) (Controls exposed to Lamotrigine, sick;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 3.67[2.51; 5.38]5,6186,8980%NACohen (Valproate) (Mixed indications) (Controls unexposed, NOS), 2023 Blotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019 Tomson (Valproate), 2018 Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014 Veiby (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2014 Källén (Valproate) (Controls unexposed, NOS) (Indications NOS), 2013 Hernández-Díaz (Valproate) (Controls exposed to Lamotrigine, sick), 2012 7 case control studiescase control studies 0 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 3.55[2.29; 5.51]5,5823,6410%NACohen (Valproate) (Mixed indications) (Controls unexposed, NOS), 2023 Blotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019 Källén (Valproate) (Controls unexposed, NOS) (Indications NOS), 2013 3 exposed to other treatment, sickexposed to other treatment, sick 4.07[1.86; 8.90]363,2574%NATomson (Valproate), 2018 Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014 Veiby (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2014 Hernández-Díaz (Valproate) (Controls exposed to Lamotrigine, sick), 2012 4 Tags Adjustment   - No  - No 4.22[2.43; 7.34]2,8574,1700%NABlotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019 Tomson (Valproate), 2018 Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014 Veiby (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2014 Hernández-Díaz (Valproate) (Controls exposed to Lamotrigine, sick), 2012 5   - Yes  - Yes 3.24[1.92; 5.48]2,7612,7280%NACohen (Valproate) (Mixed indications) (Controls unexposed, NOS), 2023 Källén (Valproate) (Controls unexposed, NOS) (Indications NOS), 2013 2 Controls   - mixed indications  - mixed indications 2.79[0.81; 9.57]11323 -NAHernández-Díaz (Valproate) (Controls exposed to Lamotrigine, sick), 2012 1 All studiesAll studies 3.67[2.51; 5.38]5,6186,8980%NACohen (Valproate) (Mixed indications) (Controls unexposed, NOS), 2023 Blotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019 Tomson (Valproate), 2018 Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014 Veiby (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2014 Källén (Valproate) (Controls unexposed, NOS) (Indications NOS), 2013 Hernández-Díaz (Valproate) (Controls exposed to Lamotrigine, sick), 2012 70.250.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-3.85.11.9610.000Cohen (Valproate) (Mixed indications) (Controls unexposed, NOS), 2023Blotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019Tomson (Valproate), 2018Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014Veiby (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2014Källén (Valproate) (Controls unexposed, NOS) (Indications NOS), 2013Hernández-Díaz (Valproate) (Controls exposed to Lamotrigine, sick), 2012

Asymetry test p-value = 0.9446 (by Egger's regression)

slope=1.3294 (0.4165); intercept=-0.0593 (0.8111); t=0.0731; p=0.9446

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 9309, 10174

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 3.55[2.29; 5.51]5,5823,6410%NACohen (Valproate) (Mixed indications) (Controls unexposed, NOS), 2023 Blotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019 Källén (Valproate) (Controls unexposed, NOS) (Indications NOS), 2013 3 exposed to other treatment, sick controlsexposed to other treatment, sick controls 3.67[2.04; 6.59]554,8670%NABlotière (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2019 Tomson (Valproate), 2018 Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014 Veiby (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2014 Källén (Valproate) (Controls exposed to Lamotrigine, sick) (Indications NOS), 2013 Hernández-Díaz (Valproate) (Controls exposed to Lamotrigine, sick), 2012 60.510.01.0