Valproate (All indications)

Limb defects

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.
S12862
R48542		 Thomas (Valproate) (Controls exposed to Lamotrigine, sick), 2021 Skeletal malformations 1st trimester prospective cohort exposed to other treatment, sick excluded Adjustment: No 1.32 [0.07;24.97] C
excluded (control group) 		4/341   0/50 4 341
ref
S12864
R48554		 Thomas (Valproate) (Controls unexposed, sick), 2021 Skeletal malformations 1st trimester prospective cohort unexposed, sick Adjustment: No 2.01 [0.36;11.03] C 4/341   2/340 6 341
ref
S9442
R33158		 Ban (Valproate) (Mixed indications) (Controls exposed to Lamotrigine, sick), 2015 Limb anomaly 1st trimester prospective cohort exposed to other treatment, sick excluded Adjustment: No 1.93 [0.32;11.63] C
excluded (control group) 		3/214   2/273 5 214
ref
S9443
R33163		 Ban (Valproate) (Mixed indications) (Controls unexposed NOS), 2015 Limb anomaly 1st trimester prospective cohort unexposed (general population or NOS) Adjustment: No 2.88 [0.92;9.02] C 3/214   1,263/257,153 1,266 214
ref
S9333
R32562		 Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014 Skeletal defects 1st trimester prospective cohort exposed to other treatment, sick Adjustment: No 5.77 [1.59;21.02] 10/1,220   3/2,098 13 1,220
ref
S9325
R32512		 Veiby (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2014 Musculoskeletal throughout pregnancy population based cohort retrospective exposed to other treatment, sick Adjustment: No 1.86 [0.85;4.10] C 11/333   15/833 26 333
ref
S10295
R37705		 Vajda (Valproate) (Controls exposed to Lamotrigine, sick), 2013 Skeletal / Limb Malformations at least 1st trimester prospective cohort exposed to other treatment, sick excluded Adjustment: No 15.46 [0.87;275.68] C
excluded (control group) 		6/271   0/315 6 271
ref
S10296
R37709		 Vajda (Valproate) (Controls unexposed, sick), 2013 Skeletal / Limb Malformations at least 1st trimester prospective cohort unexposed, sick Adjustment: No 3.31 [0.39;27.72] C 6/271   1/147 7 271
ref
S9312
R35339		 Mawer (Valproate) (Controls exposed to Lamotrigine, sick), 2010 Skeletal / Limb Malformations 1st trimester prospective cohort exposed to other treatment, sick excluded Adjustment: No 0.69 [0.04;11.43] C
excluded (control group) 		1/53   1/37 2 53
ref
S9317
R35343		 Mawer (Valproate) (Controls unexposed, disease free), 2010 Skeletal / Limb Malformations 1st trimester prospective cohort unexposed, disease free excluded Adjustment: No Matched 16.57 [0.67;412.47] C
excluded (control group) 		1/53   0/285 1 53
ref
S9318
R35347		 Mawer (Valproate) (Controls unexposed, sick), 2010 Skeletal / Limb Malformations 1st trimester prospective cohort unexposed, sick Adjustment: No 2.36 [0.09;59.46] C 1/53   0/41 1 53
ref
S9330
R35926		 Artama (Valproate), 2005 Certain musculoskeletal deformities and Other anomalies of limbs 1st trimester retrospective cohort (registry) unexposed, sick Adjustment: No 4.18 [1.50;11.63] C 8/263   7/939 15 263
ref
Total 7 studies 2.85 [1.79;4.55] 1,334 2,695
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 Thomas (Valproate) (Controls unexposed, sick), 2021Thomas, 2021 1 2.01[0.36; 11.03]63417%ROB confusion: seriousROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Ban (Valproate) (Mixed indications) (Controls unexposed NOS), 2015Ban, 2015 2 2.88[0.92; 9.02]1,26621417%ROB confusion: criticalROB selection: moderateROB classification: criticalROB missing: unclearROB mesure: moderateROB reporting: moderate Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014Campbell, 2014 3 5.77[1.59; 21.02]131,22013%ROB confusion: criticalROB selection: lowROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Veiby (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2014Veiby, 2014 4 1.86[0.85; 4.10]2633335%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: moderateROB mesure: moderateROB reporting: moderate Vajda (Valproate) (Controls unexposed, sick), 2013Vajda, 2013 5 3.31[0.39; 27.72]72715%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Mawer (Valproate) (Controls unexposed, sick), 2010Mawer, 2010 6 2.36[0.09; 59.46]1532%ROB confusion: criticalROB selection: moderateROB classification: lowROB missing: moderateROB mesure: moderateROB reporting: moderate Artama (Valproate), 2005Artama, 2005 7 4.18[1.50; 11.63]1526321%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Total (7 studies) I2 = 0% 2.85[1.79; 4.55]1,3342,6950.520.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

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

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 2.85[1.79; 4.55]1,3342,6950%NAThomas (Valproate) (Controls unexposed, sick), 2021 Ban (Valproate) (Mixed indications) (Controls unexposed NOS), 2015 Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014 Veiby (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2014 Vajda (Valproate) (Controls unexposed, sick), 2013 Mawer (Valproate) (Controls unexposed, sick), 2010 Artama (Valproate), 2005 7 case control studiescase control studies 0 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 2.88[0.92; 9.02]1,266214 -NABan (Valproate) (Mixed indications) (Controls unexposed NOS), 2015 1 unexposed, sickunexposed, sick 3.34[1.52; 7.35]299280%NAThomas (Valproate) (Controls unexposed, sick), 2021 Vajda (Valproate) (Controls unexposed, sick), 2013 Mawer (Valproate) (Controls unexposed, sick), 2010 Artama (Valproate), 2005 4 exposed to other treatment, sickexposed to other treatment, sick 2.91[0.98; 8.58]391,55353%NACampbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014 Veiby (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2014 2 Tags Adjustment   - No  - No 2.85[1.79; 4.55]1,3342,6950%NAThomas (Valproate) (Controls unexposed, sick), 2021 Ban (Valproate) (Mixed indications) (Controls unexposed NOS), 2015 Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014 Veiby (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2014 Vajda (Valproate) (Controls unexposed, sick), 2013 Mawer (Valproate) (Controls unexposed, sick), 2010 Artama (Valproate), 2005 7 All studiesAll studies 2.85[1.79; 4.55]1,3342,6950%NAThomas (Valproate) (Controls unexposed, sick), 2021 Ban (Valproate) (Mixed indications) (Controls unexposed NOS), 2015 Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014 Veiby (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2014 Vajda (Valproate) (Controls unexposed, sick), 2013 Mawer (Valproate) (Controls unexposed, sick), 2010 Artama (Valproate), 2005 70.520.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-3.94.91.9760.000Thomas (Valproate) (Controls unexposed, sick), 2021Ban (Valproate) (Mixed indications) (Controls unexposed NOS), 2015Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014Veiby (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2014Vajda (Valproate) (Controls unexposed, sick), 2013Mawer (Valproate) (Controls unexposed, sick), 2010Artama (Valproate), 2005

Asymetry test p-value = 0.6413 (by Egger's regression)

slope=0.8262 (0.4838); intercept=0.3805 (0.7680); t=0.4954; p=0.6413

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 9312, 9317, 10295, 9442, 12862

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 3.53[1.18; 10.59]1,2672671%NABan (Valproate) (Mixed indications) (Controls unexposed NOS), 2015 Mawer (Valproate) (Controls unexposed, disease free), 2010 2 unexposed, sick controlsunexposed, sick controls 3.34[1.52; 7.35]299280%NAThomas (Valproate) (Controls unexposed, sick), 2021 Vajda (Valproate) (Controls unexposed, sick), 2013 Mawer (Valproate) (Controls unexposed, sick), 2010 Artama (Valproate), 2005 4 exposed to other treatment, sick controlsexposed to other treatment, sick controls 2.44[1.35; 4.40]562,4320%NAThomas (Valproate) (Controls exposed to Lamotrigine, sick), 2021 Ban (Valproate) (Mixed indications) (Controls exposed to Lamotrigine, sick), 2015 Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014 Veiby (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2014 Vajda (Valproate) (Controls exposed to Lamotrigine, sick), 2013 Mawer (Valproate) (Controls exposed to Lamotrigine, sick), 2010 60.510.01.0