Phenytoin (Epilepsy) updated on 04-22-2025

Cognitive developmental disorders/delay (> 6 years old)

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.
S17394
R72936		 Madley-Dowd_SE (Phenytoin) (Controls unexposed, sick), 2024 Intellectual disability (intelligence quotient below 70) - ICD-8/9/10 codes - Mean 5-20 years old (according groups) during pregnancy (anytime or not specified) population based cohort retrospective unexposed, sick Adjustment: Yes 0.73 [0.23;2.30] -/147   194/10,769 - 147
ref
S17253
R72244		 Madley-Dowd_UK (Phenytoin) (Epilepsy), 2024 Intellectual disability - ICD10 codes - Median follow up 10.75 (7.82-13.62) years old during pregnancy (anytime or not specified) retrospective cohort (claims database) unexposed, sick Adjustment: No 3.38 [0.20;57.75] C 0/45   13/4,075 13 45
ref
S12508
R53740		 Adams (Phenytoin), 2022 Full Scale IQ - The Wechsler Intelligence Scale for Children, 3rd Edition (WISC-III) (mean >6 years old) during pregnancy (anytime or not specified) retrospective cohort unexposed, sick Adjustment: No extrapolated (cont. endpoint) Matched 1.91 [0.86;4.27] -/40   -/40 - 40
ref
S15862
R65282		 Thomas a (Phenytoin), 2022 Full-scale IQ - Wechsler Intelligence Scale for Children or Adult - Ages 13 to 21 years (mean of 16.5 ± 2.2 years) during pregnancy (anytime or not specified) prospective cohort unexposed, sick Adjustment: No extrapolated (cont. endpoint) 2.04 [0.42;9.83] -/10   -/11 - 10
ref
S7303
R53742		 Meador (Phenytoin), 2013 IQ <85 (DAS) (at 6 years old) during pregnancy (anytime or not specified) prospective cohort exposed to other treatment, sick Adjustment: Yes 1.89 [0.26;13.99] C 2/40   2/74 4 40
ref
S6118
R53743		 Titze (Phenytoin) (Controls unexposed, disease free), 2008 Learning disability (IQ<70) (German versions of the revised Wechsler Intelligence Scales for children and for adults) during pregnancy (anytime or not specified) prospective cohort unexposed, disease free excluded Adjustment: No Matched 4.22 [0.08;223.98] C
excluded (control group) 		0/12   0/49 0 12
ref
S6119
R53744		 Titze (Phenytoin) (Controls unexposed, sick), 2008 Learning disability (IQ<70) (German versions of the revised Wechsler Intelligence Scales for children and for adults) during pregnancy (anytime or not specified) prospective cohort unexposed, sick Adjustment: No 0.33 [0.01;9.07] C 0/12   1/13 1 12
ref
S7176
R53739		 Adab (Phenytoin), 2004 Mean Full Scale IQ (Wechsler Intelligence Scale for Children (WISC)) (Aged between 6 and 16 years) during pregnancy (anytime or not specified) retrospective cohort unexposed, sick Adjustment: No extrapolated (cont. endpoint) 0.44 [0.18;1.06] -/21   -/80 - 21
ref
Total 7 studies 1.07 [0.58;1.98] 18 315
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 Madley-Dowd_SE (Phenytoin) (Controls unexposed, sick), 2024Madley-Dowd_SE, 2024 1 0.73[0.23; 2.30]-14719%ROB confusion: criticalROB selection: lowROB classification: lowROB missing: lowROB mesure: criticalROB reporting: moderate Madley-Dowd_UK (Phenytoin) (Epilepsy), 2024Madley-Dowd_UK, 2024 2 3.38[0.20; 57.75]13454%ROB confusion: criticalROB selection: lowROB classification: criticalROB missing: unclearROB mesure: criticalROB reporting: moderate Adams (Phenytoin), 2022Adams, 2022 3 1.91[0.86; 4.27]-4028%ROB confusion: seriousROB selection: moderateROB classification: criticalROB missing: lowROB mesure: lowROB reporting: moderate Thomas a (Phenytoin), 2022Thomas a, 2022 4 2.04[0.42; 9.83]-1012%ROB confusion: criticalROB selection: criticalROB classification: criticalROB missing: criticalROB mesure: lowROB reporting: moderate Meador (Phenytoin), 2013Meador, 2013 5 1.89[0.26; 13.99]4408%ROB confusion: moderateROB selection: lowROB classification: lowROB missing: moderateROB mesure: lowROB reporting: low Titze (Phenytoin) (Controls unexposed, sick), 2008Titze, 2008 6 0.33[0.01; 9.07]1123%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: moderateROB mesure: moderateROB reporting: moderate Adab (Phenytoin), 2004Adab, 2004 7 0.44[0.18; 1.06]-2125%ROB confusion: criticalROB selection: criticalROB classification: lowROB missing: criticalROB mesure: lowROB reporting: moderate Total (7 studies) I2 = 28% 1.07[0.58; 1.98]183150.210.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

1: Phenytoin) (Controls unexposed, sick; 2: Phenytoin) (Epilepsy; 3: Phenytoin; 4: Phenytoin; 5: Phenytoin; 6: Phenytoin) (Controls unexposed, sick; 7: Phenytoin;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 1.07[0.58; 1.98]1831528%NAMadley-Dowd_SE (Phenytoin) (Controls unexposed, sick), 2024 Madley-Dowd_UK (Phenytoin) (Epilepsy), 2024 Adams (Phenytoin), 2022 Thomas a (Phenytoin), 2022 Meador (Phenytoin), 2013 Titze (Phenytoin) (Controls unexposed, sick), 2008 Adab (Phenytoin), 2004 7 case control studiescase control studies 0 Type of controls unexposed, sickunexposed, sick 1.02[0.51; 2.04]1427538%NAMadley-Dowd_SE (Phenytoin) (Controls unexposed, sick), 2024 Madley-Dowd_UK (Phenytoin) (Epilepsy), 2024 Adams (Phenytoin), 2022 Thomas a (Phenytoin), 2022 Titze (Phenytoin) (Controls unexposed, sick), 2008 Adab (Phenytoin), 2004 6 exposed to other treatment, sickexposed to other treatment, sick 1.89[0.26; 13.99]440 -NAMeador (Phenytoin), 2013 1 Tags Adjustment   - No  - No 1.13[0.47; 2.73]1412847%NAMadley-Dowd_UK (Phenytoin) (Epilepsy), 2024 Adams (Phenytoin), 2022 Thomas a (Phenytoin), 2022 Titze (Phenytoin) (Controls unexposed, sick), 2008 Adab (Phenytoin), 2004 5   - Yes  - Yes 0.93[0.34; 2.51]41870%NAMadley-Dowd_SE (Phenytoin) (Controls unexposed, sick), 2024 Meador (Phenytoin), 2013 2 extrapolated (cont. endpoint)extrapolated (cont. endpoint) 1.13[0.38; 3.30]-7169%NAAdams (Phenytoin), 2022 Thomas a (Phenytoin), 2022 Adab (Phenytoin), 2004 3 MatchedMatched 1.91[0.86; 4.26]-40 -NAAdams (Phenytoin), 2022 1 All studiesAll studies 1.07[0.58; 1.98]1831528%NAMadley-Dowd_SE (Phenytoin) (Controls unexposed, sick), 2024 Madley-Dowd_UK (Phenytoin) (Epilepsy), 2024 Adams (Phenytoin), 2022 Thomas a (Phenytoin), 2022 Meador (Phenytoin), 2013 Titze (Phenytoin) (Controls unexposed, sick), 2008 Adab (Phenytoin), 2004 70.110.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-4.04.02.0220.000Madley-Dowd_SE (Phenytoin) (Controls unexposed, sick), 2024Madley-Dowd_UK (Phenytoin) (Epilepsy), 2024Adams (Phenytoin), 2022Thomas a (Phenytoin), 2022Meador (Phenytoin), 2013Titze (Phenytoin) (Controls unexposed, sick), 2008Adab (Phenytoin), 2004

Asymetry test p-value = 0.7763 (by Egger's regression)

slope=-0.1436 (0.7165); intercept=0.3359 (1.1201); t=0.2999; p=0.7763

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 6118

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 4.22[0.08; 223.98]-12 -NATitze (Phenytoin) (Controls unexposed, disease free), 2008 1 unexposed, sick controlsunexposed, sick controls 1.02[0.51; 2.04]19927538%NAMadley-Dowd_SE (Phenytoin) (Controls unexposed, sick), 2024 Madley-Dowd_UK (Phenytoin) (Epilepsy), 2024 Adams (Phenytoin), 2022 Thomas a (Phenytoin), 2022 Titze (Phenytoin) (Controls unexposed, sick), 2008 Adab (Phenytoin), 2004 6 exposed to other treatment, sick controlsexposed to other treatment, sick controls 1.89[0.26; 13.99]440 -NAMeador (Phenytoin), 2013 10.510.01.0

Umbrella review (other published meta-analyses)

Published MAControlPeriodTE95% CIn exposedkI2 Veroniki b (NMA) (Cognitive developmental delay)Veroniki b (NMA) (Cognitive developmental delay) 2.47[0.65; 8.25]NA-Wwhatever (meta-analysis)Anyduring pregnancy (anytime or not specified)studies TTT-9 metaPregmetaPreg 1.07[0.58; 1.98]28%315----Madley-Dowd_SE (Phenytoin) (Controls unexposed, sick), 2024 Madley-Dowd_UK (Phenytoin) (Epilepsy), 2024 Adams (Phenytoin), 2022 Thomas a (Phenytoin), 2022 Meador (Phenytoin), 2013 Titze (Phenytoin) (Controls unexposed, sick), 2008 Adab (Phenytoin), 2004 70.510.01.0