Valproate (Epilepsy)

Congenital heart 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.
S12860
R48519		 Thomas (Valproate) (Controls exposed to Lamotrigine, sick), 2021 Cardiac malformations 1st trimester prospective cohort exposed to other treatment, sick excluded Adjustment: No 3.05 [0.40;23.26] C
excluded (control group) 		20/341   1/50 21 341
ref
S12861
R48529		 Thomas (Valproate) (Controls unexposed, sick), 2021 Cardiac malformations 1st trimester prospective cohort unexposed, sick Adjustment: No 2.29 [1.03;5.11] C 20/341   9/340 29 341
ref
S7663
R22686		 Tomson (Valproate), 2018 Cardiac malformations at least 1st trimester prospective cohort exposed to other treatment, sick Adjustment: No 4.21 [2.28;7.75] C 34/1,381   15/2,514 49 1,381
ref
S318
R14441		 Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014 Cardiac defects 1st trimester prospective cohort exposed to other treatment, sick Adjustment: No 2.69 [1.16;6.25] 14/1,220   9/2,098 23 1,220
ref
S10293
R37693		 Vajda (Valproate) (Controls exposed to Lamotrigine, sick), 2013 Cardiac Malformations at least 1st trimester prospective cohort exposed to other treatment, sick excluded Adjustment: No 3.98 [1.09;14.63] C
excluded (control group) 		10/271   3/315 13 271
ref
S10294
R37699		 Vajda (Valproate) (Controls unexposed, sick), 2013 Cardiac Malformations at least 1st trimester prospective cohort unexposed, sick Adjustment: No 5.59 [0.71;44.14] C 10/271   1/147 11 271
ref
S5940
R23801		 Hernández-Díaz (Valproate) (Controls exposed to Lamotrigine, sick), 2012 Cardiovascular anomalies 1st trimester prospective cohort exposed to other treatment, sick Adjustment: No Controls: mixed indications 13.20 [3.48;50.02] C 8/323   3/1,562 11 323
ref
S6505
R17909		 Bànhidy (Valproate), 2011 Cardiovascular congenital abnormalities throughout pregnancy case control unexposed, sick Adjustment: No Matched 0.19 [0.01;4.28] C 0/5   5/15 5 5
ref
S9848
R35351		 Mawer (Valproate) (Controls exposed to Lamotrigine, sick), 2010 Cardiac Malformations 1st trimester prospective cohort exposed to other treatment, sick excluded Adjustment: No 6.77 [0.35;129.82] C
excluded (control group) 		4/53   0/37 4 53
ref
S9849
R35357		 Mawer (Valproate) (Controls unexposed, disease free), 2010 Cardiac Malformations 1st trimester prospective cohort unexposed, disease free excluded Adjustment: No Matched 23.18 [2.54;211.81] C
excluded (control group) 		4/53   1/285 5 53
ref
S9850
R35363		 Mawer (Valproate) (Controls unexposed, sick), 2010 Cardiac Malformations 1st trimester prospective cohort unexposed, sick Adjustment: No 7.52 [0.39;143.80] C 4/53   0/41 4 53
ref
S6099
R15906		 Artama (Valproate), 2005 Cardiovascular 1st trimester retrospective cohort (registry) unexposed, sick Adjustment: No 2.06 [0.60;7.08] C 4/263   7/939 11 263
ref
S6510
R17935		 Canger (Valproate), 1999 Cardiac malformations 1st trimester prospective cohort unexposed, sick Adjustment: No 0.56 [0.01;29.28] C 0/44   0/25 0 44
ref
S6687
R18642		 D'Souza (Valproate) (Controls unexposed, disease free), 1991 Heart disease throughout pregnancy prospective cohort unexposed, disease free excluded Adjustment: No Matched 123.00 [1.00;15058.31] C
excluded (control group) 		0/1   0/62 0 1
ref
S6695
R18803		 D'Souza (Valproate) (Controls unexposed, sick), 1991 Heart disease throughout pregnancy prospective cohort unexposed, sick Adjustment: No 4.33 [0.06;320.42] C 0/1   1/8 1 1
ref
Total 10 studies 3.30 [2.11;5.17] 144 3,902
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 2.29[1.03; 5.11]2934121%ROB confusion: seriousROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Tomson (Valproate), 2018Tomson, 2018 2 4.21[2.28; 7.75]491,38129%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014Campbell, 2014 3 2.69[1.16; 6.25]231,22019%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Vajda (Valproate) (Controls unexposed, sick), 2013Vajda, 2013 4 5.59[0.71; 44.14]112714%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Hernández-Díaz (Valproate) (Controls exposed to Lamotrigine, sick), 2012Hernández-Díaz, 2012 5 13.20[3.48; 50.02]1132310%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: moderateROB mesure: moderateROB reporting: moderate Bànhidy (Valproate), 2011Bànhidy, 2011 6 0.19[0.01; 4.28]552%ROB confusion: criticalROB selection: criticalROB classification: lowROB missing: lowROB mesure: moderateROB reporting: moderate Mawer (Valproate) (Controls unexposed, sick), 2010Mawer, 2010 7 7.52[0.39; 143.80]4532%ROB confusion: criticalROB selection: moderateROB classification: lowROB missing: moderateROB mesure: moderateROB reporting: moderate Artama (Valproate), 2005Artama, 2005 8 2.06[0.60; 7.08]1126311%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Canger (Valproate), 1999Canger, 1999 9 0.56[0.01; 29.28]0441%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA D'Souza (Valproate) (Controls unexposed, sick), 1991D'Souza, 1991 10 4.33[0.06; 320.42]111%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Total (10 studies) I2 = 17% 3.30[2.11; 5.17]1443,9020.050.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

1: Valproate) (Controls unexposed, sick; 2: Valproate; 3: Valproate) (Controls exposed to Lamotrigine, sick; 4: Valproate) (Controls unexposed, sick; 5: Valproate) (Controls exposed to Lamotrigine, sick; 6: Valproate; 7: Valproate) (Controls unexposed, sick; 8: Valproate; 9: Valproate; 10: Valproate) (Controls unexposed, sick;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 3.48[2.40; 5.03]1393,8970%NAThomas (Valproate) (Controls unexposed, sick), 2021 Tomson (Valproate), 2018 Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014 Vajda (Valproate) (Controls unexposed, sick), 2013 Hernández-Díaz (Valproate) (Controls exposed to Lamotrigine, sick), 2012 Mawer (Valproate) (Controls unexposed, sick), 2010 Artama (Valproate), 2005 Canger (Valproate), 1999 D'Souza (Valproate) (Controls unexposed, sick), 1991 9 case control studiescase control studies 0.19[0.01; 4.28]55 -NABànhidy (Valproate), 2011 1 Type of controls unexposed, sickunexposed, sick 2.26[1.24; 4.12]619780%NAThomas (Valproate) (Controls unexposed, sick), 2021 Vajda (Valproate) (Controls unexposed, sick), 2013 Bànhidy (Valproate), 2011 Mawer (Valproate) (Controls unexposed, sick), 2010 Artama (Valproate), 2005 Canger (Valproate), 1999 D'Souza (Valproate) (Controls unexposed, sick), 1991 7 exposed to other treatment, sickexposed to other treatment, sick 4.52[2.23; 9.18]832,92449%NATomson (Valproate), 2018 Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014 Hernández-Díaz (Valproate) (Controls exposed to Lamotrigine, sick), 2012 3 Tags Adjustment   - No  - No 3.30[2.11; 5.17]1443,90217%NAThomas (Valproate) (Controls unexposed, sick), 2021 Tomson (Valproate), 2018 Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014 Vajda (Valproate) (Controls unexposed, sick), 2013 Hernández-Díaz (Valproate) (Controls exposed to Lamotrigine, sick), 2012 Bànhidy (Valproate), 2011 Mawer (Valproate) (Controls unexposed, sick), 2010 Artama (Valproate), 2005 Canger (Valproate), 1999 D'Souza (Valproate) (Controls unexposed, sick), 1991 10 Controls   - mixed indications  - mixed indications 13.20[3.48; 50.02]11323 -NAHernández-Díaz (Valproate) (Controls exposed to Lamotrigine, sick), 2012 1 MatchedMatched 0.19[0.01; 4.28]55 -NABànhidy (Valproate), 2011 1 All studiesAll studies 3.30[2.11; 5.17]1443,90217%NAThomas (Valproate) (Controls unexposed, sick), 2021 Tomson (Valproate), 2018 Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014 Vajda (Valproate) (Controls unexposed, sick), 2013 Hernández-Díaz (Valproate) (Controls exposed to Lamotrigine, sick), 2012 Bànhidy (Valproate), 2011 Mawer (Valproate) (Controls unexposed, sick), 2010 Artama (Valproate), 2005 Canger (Valproate), 1999 D'Souza (Valproate) (Controls unexposed, sick), 1991 100.050.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-5.26.42.6350.000Thomas (Valproate) (Controls unexposed, sick), 2021Tomson (Valproate), 2018Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014Vajda (Valproate) (Controls unexposed, sick), 2013Hernández-Díaz (Valproate) (Controls exposed to Lamotrigine, sick), 2012Bànhidy (Valproate), 2011Mawer (Valproate) (Controls unexposed, sick), 2010Artama (Valproate), 2005Canger (Valproate), 1999D'Souza (Valproate) (Controls unexposed, sick), 1991

Asymetry test p-value = 0.6330 (by Egger's regression)

slope=1.3727 (0.3991); intercept=-0.3347 (0.6744); t=0.4963; p=0.6330

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 6687, 9848, 9849, 10293, 12860

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) Out of scale31.03[4.16; 231.53]5540%NAMawer (Valproate) (Controls unexposed, disease free), 2010 D'Souza (Valproate) (Controls unexposed, disease free), 1991 2 unexposed, sick controlsunexposed, sick controls 2.26[1.24; 4.12]619780%NAThomas (Valproate) (Controls unexposed, sick), 2021 Vajda (Valproate) (Controls unexposed, sick), 2013 Bànhidy (Valproate), 2011 Mawer (Valproate) (Controls unexposed, sick), 2010 Artama (Valproate), 2005 Canger (Valproate), 1999 D'Souza (Valproate) (Controls unexposed, sick), 1991 7 exposed to other treatment, sick controlsexposed to other treatment, sick controls 4.17[2.74; 6.37]1213,5890%NAThomas (Valproate) (Controls exposed to Lamotrigine, sick), 2021 Tomson (Valproate), 2018 Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014 Vajda (Valproate) (Controls exposed to Lamotrigine, sick), 2013 Hernández-Díaz (Valproate) (Controls exposed to Lamotrigine, sick), 2012 Mawer (Valproate) (Controls exposed to Lamotrigine, sick), 2010 60.510.01.0