Phenytoin (All indications) 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.
S17390
R72909		 Madley-Dowd_SE (Phenytoin) (Controls exposed to LTG) (Mixed indications), 2024 Intellectual disability - ICD-8/9/10 codes and/or ADHD medication prescription - Mean 5-20 years old (according groups) during pregnancy (anytime or not specified) population based cohort retrospective exposed to other treatment, sick excluded Adjustment: Yes 0.61 [0.19;1.96]
excluded (control group) 		-/194   60/5,035 - 194
ref
S17391
R72915		 Madley-Dowd_SE (Phenytoin) (Controls unexposed, general pop) (Mixed indications), 2024 Intellectual disability - ICD-8/9/10 codes and/or ADHD medication prescription - Mean 5-20 years old (according groups) during pregnancy (anytime or not specified) population based cohort retrospective unexposed (general population or NOS) Adjustment: Yes 0.67 [0.22;2.10] -/194   24,323/2,651,210 - 194
ref
S17392
R72921		 Madley-Dowd_SE (Phenytoin) (Controls unexposed, sibling) (Mixed indications), 2024 Intellectual disability - ICD-8/9/10 codes and/or ADHD medication prescription - Mean 5-20 years old (according groups) during pregnancy (anytime or not specified) population based cohort retrospective sibling excluded Adjustment: Yes 0.53 [0.03;8.50]
excluded (control group) 		-/-   -/- - -
ref
S17268
R72350		 Madley-Dowd_UK (Phenytoin) (Controls unexposed, general pop) (Mixed indications), 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 (general population or NOS) Adjustment: No 5.04 [0.31;81.78] C 0/46   1,119/514,066 1,119 46
ref
S12898
R53734		 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
S15272
R62775		 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
S9266
R53736		 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
S9269
R53737		 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
S9270
R53738		 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
S9184
R53733		 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 1.08 [0.56;2.07] 1,124 363
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, general pop) (Mixed indications), 2024Madley-Dowd_SE, 2024 1 0.67[0.22; 2.10]-19419%ROB confusion: seriousROB selection: lowROB classification: lowROB missing: lowROB mesure: criticalROB reporting: moderate Madley-Dowd_UK (Phenytoin) (Controls unexposed, general pop) (Mixed indications), 2024Madley-Dowd_UK, 2024 2 5.04[0.31; 81.78]1,119465%ROB confusion: criticalROB selection: lowROB classification: criticalROB missing: unclearROB mesure: criticalROB reporting: moderate Adams (Phenytoin), 2022Adams, 2022 3 1.91[0.86; 4.27]-4027%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]4409%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]1124%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 = 34% 1.08[0.56; 2.07]1,1243630.220.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

1: Phenytoin) (Controls unexposed, general pop) (Mixed indications; 2: Phenytoin) (Controls unexposed, general pop) (Mixed indications; 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 1.08[0.56; 2.07]1,12436334%NAMadley-Dowd_SE (Phenytoin) (Controls unexposed, general pop) (Mixed indications), 2024 Madley-Dowd_UK (Phenytoin) (Controls unexposed, general pop) (Mixed indications), 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 (disease free or unspecified)unexposed (disease free or unspecified) 1.21[0.20; 7.29]1,11924042%NAMadley-Dowd_SE (Phenytoin) (Controls unexposed, general pop) (Mixed indications), 2024 Madley-Dowd_UK (Phenytoin) (Controls unexposed, general pop) (Mixed indications), 2024 2 unexposed, sickunexposed, sick 1.02[0.39; 2.71]18357%NAAdams (Phenytoin), 2022 Thomas a (Phenytoin), 2022 Titze (Phenytoin) (Controls unexposed, sick), 2008 Adab (Phenytoin), 2004 4 exposed to other treatment, sickexposed to other treatment, sick 1.89[0.26; 13.99]440 -NAMeador (Phenytoin), 2013 1 Tags Adjustment   - No  - No 1.18[0.47; 2.95]1,12012951%NAMadley-Dowd_UK (Phenytoin) (Controls unexposed, general pop) (Mixed indications), 2024 Adams (Phenytoin), 2022 Thomas a (Phenytoin), 2022 Titze (Phenytoin) (Controls unexposed, sick), 2008 Adab (Phenytoin), 2004 5   - Yes  - Yes 0.86[0.32; 2.30]42340%NAMadley-Dowd_SE (Phenytoin) (Controls unexposed, general pop) (Mixed indications), 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 1.08[0.56; 2.07]1,12436334%NAMadley-Dowd_SE (Phenytoin) (Controls unexposed, general pop) (Mixed indications), 2024 Madley-Dowd_UK (Phenytoin) (Controls unexposed, general pop) (Mixed indications), 2024 Adams (Phenytoin), 2022 Thomas a (Phenytoin), 2022 Meador (Phenytoin), 2013 Titze (Phenytoin) (Controls unexposed, sick), 2008 Adab (Phenytoin), 2004 70.120.01.0

Publication bias and p-hacking diagnosis

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

Asymetry test p-value = 0.6988 (by Egger's regression)

slope=-0.2299 (0.7435); intercept=0.4785 (1.1669); t=0.4100; p=0.6988

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 9269, 17390, 17392

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 1.14[0.33; 3.97]25,43325212%NAMadley-Dowd_SE (Phenytoin) (Controls unexposed, general pop) (Mixed indications), 2024 Madley-Dowd_UK (Phenytoin) (Controls unexposed, general pop) (Mixed indications), 2024 Titze (Phenytoin) (Controls unexposed, disease free), 2008 3 unexposed, sick controlsunexposed, sick controls 1.02[0.39; 2.71]18357%NAAdams (Phenytoin), 2022 Thomas a (Phenytoin), 2022 Titze (Phenytoin) (Controls unexposed, sick), 2008 Adab (Phenytoin), 2004 4 exposed to other treatment, sick controlsexposed to other treatment, sick controls 0.81[0.30; 2.23]552340%NAMadley-Dowd_SE (Phenytoin) (Controls exposed to LTG) (Mixed indications), 2024 Meador (Phenytoin), 2013 2 siblingssiblings 0.53[0.03; 8.92]-- -NAMadley-Dowd_SE (Phenytoin) (Controls unexposed, sibling) (Mixed indications), 2024 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) 2.55[0.72; 8.55]NA-Wwhatever (meta-analysis)Anyduring pregnancy (anytime or not specified)studies TTT-9 metaPregmetaPreg 1.08[0.56; 2.07]34%363----Madley-Dowd_SE (Phenytoin) (Controls unexposed, general pop) (Mixed indications), 2024 Madley-Dowd_UK (Phenytoin) (Controls unexposed, general pop) (Mixed indications), 2024 Adams (Phenytoin), 2022 Thomas a (Phenytoin), 2022 Meador (Phenytoin), 2013 Titze (Phenytoin) (Controls unexposed, sick), 2008 Adab (Phenytoin), 2004 70.510.01.0