Valproate (All indications)

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.
S15201
R62351		 Cohen (Valproate) (Mixed indications) (Controls unexposed, NOS), 2023 Cardiac system malformation 1st trimester population based cohort retrospective unexposed (general population or NOS) Adjustment: Yes 2.46 [1.97;3.07] -/2,031   -/4,866,362 - 2,031
ref
S12862
R48539		 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
S12864
R48551		 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
S9359
R32735		 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
S9442
R33157		 Ban (Valproate) (Mixed indications) (Controls exposed to Lamotrigine, sick), 2015 Heart anomaly 1st trimester prospective cohort exposed to other treatment, sick excluded Adjustment: No 0.54 [0.14;2.11] C
excluded (control group) 		3/214   7/273 10 214
ref
S9443
R33162		 Ban (Valproate) (Mixed indications) (Controls unexposed NOS), 2015 Heart anomaly 1st trimester prospective cohort unexposed (general population or NOS) Adjustment: No 1.78 [0.57;5.56] C 3/214   2,041/257,153 2,044 214
ref
S9333
R32560		 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
S9325
R32508		 Veiby (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2014 Circulatory throughout pregnancy population based cohort retrospective exposed to other treatment, sick Adjustment: No 1.75 [0.74;4.14] C 9/333   13/833 22 333
ref
S9309
R32426		 Källén (Valproate) (Controls exposed to Lamotrigine, sick) (Indications NOS), 2013 Any cardiac defect early pregnancy population based cohort retrospective exposed to other treatment, sick excluded Adjustment: No 3.66 [1.73;7.75] C
excluded (control group) 		23/697   10/1,084 33 697
ref
S9310
R32434		 Källén (Valproate) (Controls unexposed, NOS) (Indications NOS), 2013 Any cardiac defect early pregnancy population based cohort retrospective unexposed (general population or NOS) Adjustment: Yes 2.67 [1.68;4.04] 23/697   16,145/1,575,847 16,168 697
ref
S10295
R37703		 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
S10296
R37707		 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
S10231
R37483		 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
S9331
R32551		 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
S9312
R35337		 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
S9317
R35341		 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
S9318
R35345		 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
S9444
R33167		 Diav-Citrin (Valproate) (Mixed indications), 2008 Cardiovascular anomalies at least 1st trimester prospective cohort unexposed (general population or NOS) Adjustment: No 6.77 [1.76;26.10] C 3/71   8/1,236 11 71
ref
S9330
R32540		 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
S9335
R32574		 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
S9297
R32302		 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
S9298
R32331		 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 15 studies 2.74 [2.19;3.44] 18,389 7,248
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 2.46[1.97; 3.07]-2,03136%ROB confusion: seriousROB selection: lowROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Thomas (Valproate) (Controls unexposed, sick), 2021Thomas, 2021 2 2.29[1.03; 5.11]293417%ROB confusion: seriousROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Tomson (Valproate), 2018Tomson, 2018 3 4.21[2.28; 7.75]491,38111%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Ban (Valproate) (Mixed indications) (Controls unexposed NOS), 2015Ban, 2015 4 1.78[0.57; 5.56]2,0442144%ROB confusion: criticalROB selection: moderateROB classification: criticalROB missing: unclearROB mesure: moderateROB reporting: moderate Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014Campbell, 2014 5 2.69[1.16; 6.25]231,2206%ROB confusion: criticalROB selection: lowROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Veiby (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2014Veiby, 2014 6 1.75[0.74; 4.14]223336%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: moderateROB mesure: moderateROB reporting: moderate Källén (Valproate) (Controls unexposed, NOS) (Indications NOS), 2013Källén, 2013 7 2.67[1.68; 4.04]16,16869718%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Vajda (Valproate) (Controls unexposed, sick), 2013Vajda, 2013 8 5.59[0.71; 44.14]112711%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Hernández-Díaz (Valproate) (Controls exposed to Lamotrigine, sick), 2012Hernández-Díaz, 2012 9 13.20[3.48; 50.02]113233%ROB confusion: moderateROB selection: lowROB classification: moderateROB missing: moderateROB mesure: moderateROB reporting: moderate Bànhidy (Valproate), 2011Bànhidy, 2011 10 0.19[0.01; 4.28]551%ROB confusion: criticalROB selection: criticalROB classification: lowROB missing: lowROB mesure: moderateROB reporting: moderate Mawer (Valproate) (Controls unexposed, sick), 2010Mawer, 2010 11 7.52[0.39; 143.80]4531%ROB confusion: criticalROB selection: moderateROB classification: lowROB missing: moderateROB mesure: moderateROB reporting: moderate Diav-Citrin (Valproate) (Mixed indications), 2008Diav-Citrin, 2008 12 6.77[1.76; 26.10]11713%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Artama (Valproate), 2005Artama, 2005 13 2.06[0.60; 7.08]112633%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Canger (Valproate), 1999Canger, 1999 14 0.56[0.01; 29.28]0440%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA D'Souza (Valproate) (Controls unexposed, sick), 1991D'Souza, 1991 15 4.33[0.06; 320.42]110%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Total (15 studies) I2 = 13% 2.74[2.19; 3.44]18,3897,2480.050.01.0ROB: 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, sick; 3: Valproate; 4: Valproate) (Mixed indications) (Controls unexposed NOS; 5: Valproate) (Controls exposed to Lamotrigine, sick; 6: Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications; 7: Valproate) (Controls unexposed, NOS) (Indications NOS; 8: Valproate) (Controls unexposed, sick; 9: Valproate) (Controls exposed to Lamotrigine, sick; 10: Valproate; 11: Valproate) (Controls unexposed, sick; 12: Valproate) (Mixed indications; 13: Valproate; 14: Valproate; 15: Valproate) (Controls unexposed, sick;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 2.69[2.24; 3.23]18,3847,2432%NACohen (Valproate) (Mixed indications) (Controls unexposed, NOS), 2023 Thomas (Valproate) (Controls unexposed, sick), 2021 Tomson (Valproate), 2018 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 Källén (Valproate) (Controls unexposed, NOS) (Indications NOS), 2013 Vajda (Valproate) (Controls unexposed, sick), 2013 Hernández-Díaz (Valproate) (Controls exposed to Lamotrigine, sick), 2012 Mawer (Valproate) (Controls unexposed, sick), 2010 Diav-Citrin (Valproate) (Mixed indications), 2008 Artama (Valproate), 2005 Canger (Valproate), 1999 D'Souza (Valproate) (Controls unexposed, sick), 1991 14 case control studiescase control studies 0.19[0.01; 4.28]55 -NABànhidy (Valproate), 2011 1 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 2.53[2.08; 3.07]18,2233,0130%NACohen (Valproate) (Mixed indications) (Controls unexposed, NOS), 2023 Ban (Valproate) (Mixed indications) (Controls unexposed NOS), 2015 Källén (Valproate) (Controls unexposed, NOS) (Indications NOS), 2013 Diav-Citrin (Valproate) (Mixed indications), 2008 4 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 3.59[1.85; 6.96]1053,25757%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 3.01[2.06; 4.41]2,2214,52020%NAThomas (Valproate) (Controls unexposed, sick), 2021 Tomson (Valproate), 2018 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 Hernández-Díaz (Valproate) (Controls exposed to Lamotrigine, sick), 2012 Bànhidy (Valproate), 2011 Mawer (Valproate) (Controls unexposed, sick), 2010 Diav-Citrin (Valproate) (Mixed indications), 2008 Artama (Valproate), 2005 Canger (Valproate), 1999 D'Souza (Valproate) (Controls unexposed, sick), 1991 13   - Yes  - Yes 2.50[2.05; 3.05]16,1682,7280%NACohen (Valproate) (Mixed indications) (Controls unexposed, NOS), 2023 Källén (Valproate) (Controls unexposed, NOS) (Indications NOS), 2013 2 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 2.74[2.19; 3.44]18,3897,24813%NACohen (Valproate) (Mixed indications) (Controls unexposed, NOS), 2023 Thomas (Valproate) (Controls unexposed, sick), 2021 Tomson (Valproate), 2018 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 Källén (Valproate) (Controls unexposed, NOS) (Indications NOS), 2013 Vajda (Valproate) (Controls unexposed, sick), 2013 Hernández-Díaz (Valproate) (Controls exposed to Lamotrigine, sick), 2012 Bànhidy (Valproate), 2011 Mawer (Valproate) (Controls unexposed, sick), 2010 Diav-Citrin (Valproate) (Mixed indications), 2008 Artama (Valproate), 2005 Canger (Valproate), 1999 D'Souza (Valproate) (Controls unexposed, sick), 1991 150.050.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-5.26.22.6350.000Cohen (Valproate) (Mixed indications) (Controls unexposed, NOS), 2023Thomas (Valproate) (Controls unexposed, sick), 2021Tomson (Valproate), 2018Ban (Valproate) (Mixed indications) (Controls unexposed NOS), 2015Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014Veiby (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2014Källén (Valproate) (Controls unexposed, NOS) (Indications NOS), 2013Vajda (Valproate) (Controls unexposed, sick), 2013Hernández-Díaz (Valproate) (Controls exposed to Lamotrigine, sick), 2012Bànhidy (Valproate), 2011Mawer (Valproate) (Controls unexposed, sick), 2010Diav-Citrin (Valproate) (Mixed indications), 2008Artama (Valproate), 2005Canger (Valproate), 1999D'Souza (Valproate) (Controls unexposed, sick), 1991

Asymetry test p-value = 0.6103 (by Egger's regression)

slope=0.9194 (0.1373); intercept=0.2165 (0.4146); t=0.5223; p=0.6103

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 9297, 9312, 9317, 9309, 10295, 9442, 12862

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 2.95[1.93; 4.50]18,2283,06743%NACohen (Valproate) (Mixed indications) (Controls unexposed, NOS), 2023 Ban (Valproate) (Mixed indications) (Controls unexposed NOS), 2015 Källén (Valproate) (Controls unexposed, NOS) (Indications NOS), 2013 Mawer (Valproate) (Controls unexposed, disease free), 2010 Diav-Citrin (Valproate) (Mixed indications), 2008 D'Souza (Valproate) (Controls unexposed, disease free), 1991 6 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 3.10[1.92; 5.01]1864,83344%NAThomas (Valproate) (Controls exposed to Lamotrigine, sick), 2021 Tomson (Valproate), 2018 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 Källén (Valproate) (Controls exposed to Lamotrigine, sick) (Indications NOS), 2013 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 90.510.01.0