Phenytoin (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.
S12848
R48433		 Thomas (Phenytoin) (Controls exposed to Lamotrigine, sick), 2021 Cardiac malformations 1st trimester prospective cohort exposed to other treatment, sick excluded Adjustment: No 2.15 [0.24;18.88] C
excluded (control group) 		5/119   1/50 6 119
ref
S12849
R48443		 Thomas (Phenytoin) (Controls unexposed, sick), 2021 Cardiac malformations 1st trimester prospective cohort unexposed, sick Adjustment: No 1.61 [0.53;4.91] C 5/119   9/340 14 119
ref
S7661
R22668		 Tomson (Phenytoin), 2018 Cardiac malformations at least 1st trimester prospective cohort exposed to other treatment, sick Adjustment: No 6.94 [2.48;19.42] C 5/125   15/2,514 20 125
ref
S10299
R37736		 Vajda (Phenytoin) (Controls exposed to Lamotrigine, sick), 2013 Cardiac Malformations at least 1st trimester prospective cohort exposed to other treatment, sick excluded Adjustment: No 2.42 [0.25;23.78] C
excluded (control group) 		1/44   3/315 4 44
ref
S9842
R37740		 Vajda (Phenytoin) (Controls unexposed, sick), 2013 Cardiac Malformations at least 1st trimester prospective cohort unexposed, sick Adjustment: No 3.40 [0.21;55.43] C 1/44   1/147 2 44
ref
S5878
R23785		 Hernández-Díaz (Phenytoin) (Controls exposed to Lamotrigine, sick), 2012 Cardiovascular anomalies 1st trimester prospective cohort exposed to other treatment, sick Adjustment: No Controls: mixed indications 5.05 [1.12;22.63] C 4/416   3/1,562 7 416
ref
S6501
R17865		 Bànhidy (Phenytoin), 2011 Cardiovascular congenital abnormalities throughout pregnancy case control unexposed, sick Adjustment: No Matched 0.32 [0.06;1.60] C 3/22   5/15 8 22
ref
S9851
R35381		 Mawer (Phenytoin) (Controls exposed to Lamotrigine, sick), 2010 Cardiac Malformations 1st trimester prospective cohort exposed to other treatment, sick excluded Adjustment: No 5.62 [0.10;309.00] C
excluded (control group) 		0/7   0/37 0 7
ref
S9852
R35387		 Mawer (Phenytoin) (Controls unexposed, disease free), 2010 Cardiac Malformations 1st trimester prospective cohort unexposed, disease free excluded Adjustment: No Matched 14.54 [0.54;391.72] C
excluded (control group) 		0/7   1/285 1 7
ref
S9853
R35393		 Mawer (Phenytoin) (Controls unexposed, sick), 2010 Cardiac Malformations 1st trimester prospective cohort unexposed, sick Adjustment: No 6.23 [0.11;342.42] C 0/7   0/41 0 7
ref
S319
R15723		 Morrow (Phenytoin) (Controls exposed to Lamotrigine, sick), 2006 Cardiac 1st trimester prospective cohort exposed to other treatment, sick Adjustment: No 1.98 [0.22;17.97] C 1/82   4/647 5 82
ref
S6098
R15890		 Artama (Phenytoin), 2005 Cardiovascular 1st trimester retrospective cohort (registry) unexposed, sick Adjustment: No 1.66 [0.09;29.54] C 0/38   7/939 7 38
ref
S341
R18229		 D'Souza (Phenytoin) (Controls unexposed, disease free), 1991 Heart disease throughout pregnancy prospective cohort unexposed, disease free excluded Adjustment: No Matched 9.00 [0.35;229.68] C
excluded (control group) 		1/22   0/62 1 22
ref
S6690
R18729		 D'Souza (Phenytoin) (Controls unexposed, sick), 1991 Heart disease throughout pregnancy prospective cohort unexposed, sick Adjustment: No 0.33 [0.02;6.06] C 1/22   1/8 2 22
ref
Total 9 studies 2.10 [0.93;4.72] 65 875
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 (Phenytoin) (Controls unexposed, sick), 2021Thomas, 2021 1 1.61[0.53; 4.91]1411919%ROB confusion: seriousROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Tomson (Phenytoin), 2018Tomson, 2018 2 6.94[2.48; 19.42]2012520%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Vajda (Phenytoin) (Controls unexposed, sick), 2013Vajda, 2013 3 3.40[0.21; 55.43]2447%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Hernández-Díaz (Phenytoin) (Controls exposed to Lamotrigine, sick), 2012Hernández-Díaz, 2012 4 5.05[1.12; 22.63]741615%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: moderateROB mesure: moderateROB reporting: moderate Bànhidy (Phenytoin), 2011Bànhidy, 2011 5 0.32[0.06; 1.60]82214%ROB confusion: criticalROB selection: criticalROB classification: lowROB missing: lowROB mesure: moderateROB reporting: moderate Mawer (Phenytoin) (Controls unexposed, sick), 2010Mawer, 2010 6 6.23[0.11; 342.42]074%ROB confusion: criticalROB selection: moderateROB classification: lowROB missing: moderateROB mesure: moderateROB reporting: moderate Morrow (Phenytoin) (Controls exposed to Lamotrigine, sick), 2006Morrow, 2006 7 1.98[0.22; 17.97]5829%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Artama (Phenytoin), 2005Artama, 2005 8 1.66[0.09; 29.54]7386%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA D'Souza (Phenytoin) (Controls unexposed, sick), 1991D'Souza, 1991 9 0.33[0.02; 6.06]2226%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Total (9 studies) I2 = 41% 2.10[0.93; 4.72]658750.220.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

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

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 3.18[1.76; 5.77]578530%NAThomas (Phenytoin) (Controls unexposed, sick), 2021 Tomson (Phenytoin), 2018 Vajda (Phenytoin) (Controls unexposed, sick), 2013 Hernández-Díaz (Phenytoin) (Controls exposed to Lamotrigine, sick), 2012 Mawer (Phenytoin) (Controls unexposed, sick), 2010 Morrow (Phenytoin) (Controls exposed to Lamotrigine, sick), 2006 Artama (Phenytoin), 2005 D'Souza (Phenytoin) (Controls unexposed, sick), 1991 8 case control studiescase control studies 0.32[0.06; 1.60]822 -NABànhidy (Phenytoin), 2011 1 Type of controls unexposed, sickunexposed, sick 1.10[0.50; 2.41]332520%NAThomas (Phenytoin) (Controls unexposed, sick), 2021 Vajda (Phenytoin) (Controls unexposed, sick), 2013 Bànhidy (Phenytoin), 2011 Mawer (Phenytoin) (Controls unexposed, sick), 2010 Artama (Phenytoin), 2005 D'Souza (Phenytoin) (Controls unexposed, sick), 1991 6 exposed to other treatment, sickexposed to other treatment, sick 5.40[2.45; 11.93]326230%NATomson (Phenytoin), 2018 Hernández-Díaz (Phenytoin) (Controls exposed to Lamotrigine, sick), 2012 Morrow (Phenytoin) (Controls exposed to Lamotrigine, sick), 2006 3 Tags Adjustment   - No  - No 2.10[0.93; 4.72]6587541%NAThomas (Phenytoin) (Controls unexposed, sick), 2021 Tomson (Phenytoin), 2018 Vajda (Phenytoin) (Controls unexposed, sick), 2013 Hernández-Díaz (Phenytoin) (Controls exposed to Lamotrigine, sick), 2012 Bànhidy (Phenytoin), 2011 Mawer (Phenytoin) (Controls unexposed, sick), 2010 Morrow (Phenytoin) (Controls exposed to Lamotrigine, sick), 2006 Artama (Phenytoin), 2005 D'Souza (Phenytoin) (Controls unexposed, sick), 1991 9 Controls   - mixed indications  - mixed indications 5.05[1.12; 22.63]7416 -NAHernández-Díaz (Phenytoin) (Controls exposed to Lamotrigine, sick), 2012 1 MatchedMatched 0.32[0.06; 1.60]822 -NABànhidy (Phenytoin), 2011 1 All studiesAll studies 2.10[0.93; 4.72]6587541%NAThomas (Phenytoin) (Controls unexposed, sick), 2021 Tomson (Phenytoin), 2018 Vajda (Phenytoin) (Controls unexposed, sick), 2013 Hernández-Díaz (Phenytoin) (Controls exposed to Lamotrigine, sick), 2012 Bànhidy (Phenytoin), 2011 Mawer (Phenytoin) (Controls unexposed, sick), 2010 Morrow (Phenytoin) (Controls exposed to Lamotrigine, sick), 2006 Artama (Phenytoin), 2005 D'Souza (Phenytoin) (Controls unexposed, sick), 1991 90.120.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-4.85.52.4530.000Thomas (Phenytoin) (Controls unexposed, sick), 2021Tomson (Phenytoin), 2018Vajda (Phenytoin) (Controls unexposed, sick), 2013Hernández-Díaz (Phenytoin) (Controls exposed to Lamotrigine, sick), 2012Bànhidy (Phenytoin), 2011Mawer (Phenytoin) (Controls unexposed, sick), 2010Morrow (Phenytoin) (Controls exposed to Lamotrigine, sick), 2006Artama (Phenytoin), 2005D'Souza (Phenytoin) (Controls unexposed, sick), 1991

Asymetry test p-value = 0.4594 (by Egger's regression)

slope=1.5514 (0.9333); intercept=-0.8553 (1.0926); t=0.7828; p=0.4594

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 341, 9851, 9852, 10299, 12848

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) Out of scale11.39[1.13; 114.74]2290%NAMawer (Phenytoin) (Controls unexposed, disease free), 2010 D'Souza (Phenytoin) (Controls unexposed, disease free), 1991 2 unexposed, sick controlsunexposed, sick controls 1.10[0.50; 2.41]332520%NAThomas (Phenytoin) (Controls unexposed, sick), 2021 Vajda (Phenytoin) (Controls unexposed, sick), 2013 Bànhidy (Phenytoin), 2011 Mawer (Phenytoin) (Controls unexposed, sick), 2010 Artama (Phenytoin), 2005 D'Souza (Phenytoin) (Controls unexposed, sick), 1991 6 exposed to other treatment, sick controlsexposed to other treatment, sick controls 4.57[2.28; 9.17]427930%NAThomas (Phenytoin) (Controls exposed to Lamotrigine, sick), 2021 Tomson (Phenytoin), 2018 Vajda (Phenytoin) (Controls exposed to Lamotrigine, sick), 2013 Hernández-Díaz (Phenytoin) (Controls exposed to Lamotrigine, sick), 2012 Mawer (Phenytoin) (Controls exposed to Lamotrigine, sick), 2010 Morrow (Phenytoin) (Controls exposed to Lamotrigine, sick), 2006 60.510.01.0