Phenytoin (All indications)

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.
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 (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 5 studies 1.11 [0.49;2.53] 5 123
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 Adams (Phenytoin), 2022Adams, 2022 1 1.91[0.86; 4.27]-4033%ROB confusion: seriousROB selection: moderateROB classification: criticalROB missing: lowROB mesure: lowROB reporting: moderate Thomas (Phenytoin), 2022Thomas, 2022 2 2.04[0.42; 9.83]-1017%ROB confusion: criticalROB selection: criticalROB classification: criticalROB missing: criticalROB mesure: lowROB reporting: moderate Meador (Phenytoin), 2013Meador, 2013 3 1.89[0.26; 13.99]44013%ROB confusion: moderateROB selection: lowROB classification: lowROB missing: moderateROB mesure: lowROB reporting: low Titze (Phenytoin) (Controls unexposed, sick), 2008Titze, 2008 4 0.33[0.01; 9.07]1126%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: moderateROB mesure: moderateROB reporting: moderate Adab (Phenytoin), 2004Adab, 2004 5 0.44[0.18; 1.06]-2131%ROB confusion: criticalROB selection: criticalROB classification: lowROB missing: criticalROB mesure: lowROB reporting: moderate Total (5 studies) I2 = 45% 1.11[0.49; 2.53]51230.25.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

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

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 1.11[0.49; 2.53]512345%NAAdams (Phenytoin), 2022 Thomas (Phenytoin), 2022 Meador (Phenytoin), 2013 Titze (Phenytoin) (Controls unexposed, sick), 2008 Adab (Phenytoin), 2004 5 case control studiescase control studies 0 Type of controls unexposed, sickunexposed, sick 1.02[0.39; 2.71]18357%NAAdams (Phenytoin), 2022 Thomas (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 1.02[0.39; 2.71]18357%NAAdams (Phenytoin), 2022 Thomas (Phenytoin), 2022 Titze (Phenytoin) (Controls unexposed, sick), 2008 Adab (Phenytoin), 2004 4   - Yes  - Yes 1.89[0.26; 13.99]440 -NAMeador (Phenytoin), 2013 1 extrapolated (cont. endpoint)extrapolated (cont. endpoint) 1.13[0.38; 3.30]-7169%NAAdams (Phenytoin), 2022 Thomas (Phenytoin), 2022 Adab (Phenytoin), 2004 3 MatchedMatched 1.91[0.86; 4.26]-40 -NAAdams (Phenytoin), 2022 1 All studiesAll studies 1.11[0.49; 2.53]512345%NAAdams (Phenytoin), 2022 Thomas (Phenytoin), 2022 Meador (Phenytoin), 2013 Titze (Phenytoin) (Controls unexposed, sick), 2008 Adab (Phenytoin), 2004 50.15.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-4.04.12.0220.000Adams (Phenytoin), 2022Thomas (Phenytoin), 2022Meador (Phenytoin), 2013Titze (Phenytoin) (Controls unexposed, sick), 2008Adab (Phenytoin), 2004

Asymetry test p-value = 0.9911 (by Egger's regression)

slope=0.0973 (0.9753); intercept=-0.0196 (1.6162); t=0.0121; p=0.9911

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 9269

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[0.39; 2.71]18357%NAAdams (Phenytoin), 2022 Thomas (Phenytoin), 2022 Titze (Phenytoin) (Controls unexposed, sick), 2008 Adab (Phenytoin), 2004 4 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