Phenytoin (Epilepsy)

Major congenital malformations

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.
S12698
R47934		 Alsfouk (Phenytoin) (Controls exposed to Lamotrigine, sick), 2021 Major congenital malformation during pregnancy (anytime or not specified) retrospective cohort exposed to other treatment, sick excluded Adjustment: No 5.00 [0.08;316.71] C
excluded (control group) 		0/1   2/15 2 1
ref
S12700
R47936		 Alsfouk (Phenytoin) (Controls unexposed, sick), 2021 Major congenital malformation during pregnancy (anytime or not specified) excluded retrospective cohort unexposed, sick Adjustment: No 19.00 [0.27;1331.97] C
excluded (exposition period) 		0/1   1/30 1 1
ref
S12848
R48430		 Thomas (Phenytoin) (Controls exposed to Lamotrigine, sick), 2021 Major congenital malformations 1st trimester prospective cohort exposed to other treatment, sick excluded Adjustment: No 3.06 [0.37;25.57] C
excluded (control group) 		7/119   1/50 8 119
ref
S7552
R22593		 Thomas (Phenytoin) (Controls unexposed, disease free), 2021 Major congenital malformations 1st trimester prospective cohort unexposed, disease free excluded Adjustment: No 1.64 [0.62;4.33]
excluded (control group) 		6/106   11/319 17 106
ref
S12849
R48440		 Thomas (Phenytoin) (Controls unexposed, sick), 2021 Major congenital malformations 1st trimester prospective cohort unexposed, sick Adjustment: Yes 1.21 [0.50;2.90] 7/119   16/340 23 119
ref
S7779
R22988		 Vajda (Phenytoin) (Controls exposed to Lamotrigine, sick), 2019 Fetal malformations at least 1st trimester prospective cohort exposed to other treatment, sick excluded Adjustment: No 0.45 [0.06;3.43] C
excluded (control group) 		1/44   20/406 21 44
ref
S7780
R22989		 Vajda (Phenytoin) (Controls unexposed, sick), 2019 Fetal malformations at least 1st trimester prospective cohort unexposed, sick Adjustment: No 0.80 [0.10;6.61] 1/44   5/176 6 44
ref
S7661
R22667		 Tomson (Phenytoin), 2018 Major congenital malformation at least 1st trimester prospective cohort exposed to other treatment, sick Adjustment: No 2.25 [1.06;4.79] C 8/125   74/2,514 82 125
ref
S8031
R24441		 He (Phenytoin) (Controls exposed to Lamotrigine, sick), 2017 Congenital malformations during pregnancy (anytime or not specified) prospective cohort exposed to other treatment, sick excluded Adjustment: No 2.14 [0.03;131.94] C
excluded (control group) 		0/4   0/8 0 4
ref
S8032
R24442		 He (Phenytoin) (Controls unexposed, sick), 2017 Congenital malformations during pregnancy (anytime or not specified) excluded prospective cohort unexposed, sick Adjustment: No 8.71 [0.15;511.85] C
excluded (exposition period) 		0/4   0/31 0 4
ref
S6254
R16659		 Arkilo (Phenytoin), 2015 Major malformations during pregnancy (anytime or not specified) excluded retrospective cohort exposed to other treatment, sick Adjustment: No 5.22 [0.09;299.04] C
excluded (exposition period) 		0/5   0/24 0 5
ref
S5878
R14626		 Hernández-Díaz (Phenytoin) (Controls exposed to Lamotrigine, sick), 2012 Major congenital malformations 1st trimester prospective cohort exposed to other treatment, sick excluded Adjustment: No Controls: mixed indications 1.40 [0.60;3.40]
excluded (control group) 		-/-   -/- - -
ref
S7932
R24008		 Hernández-Díaz (Phenytoin) (Controls unexposed, disease free), 2012 Major congenital malformations 1st trimester prospective cohort unexposed, disease free Adjustment: No 2.60 [0.90;7.40] 12/416   5/442 17 416
ref
S6501
R17872		 Bànhidy (Phenytoin), 2011 Total congenital abnormalities throughout pregnancy case control unexposed, sick Adjustment: No Matched 0.61 [0.21;1.82] C 14/33   12/22 26 33
ref
S9851
R35378		 Mawer (Phenytoin) (Controls exposed to Lamotrigine, sick), 2010 Major malformations 1st trimester prospective cohort exposed to other treatment, sick excluded Adjustment: No 1.06 [0.05;24.77] C
excluded (control group) 		0/7   2/37 2 7
ref
S9852
R35384		 Mawer (Phenytoin) (Controls unexposed, disease free), 2010 Major malformations 1st trimester prospective cohort unexposed, disease free excluded Adjustment: No Matched 3.30 [0.17;64.87] C
excluded (control group) 		0/7   6/285 6 7
ref
S9853
R35390		 Mawer (Phenytoin) (Controls unexposed, sick), 2010 Major malformations 1st trimester prospective cohort unexposed, sick Adjustment: No 2.03 [0.07;55.28] C 0/7   1/41 1 7
ref
S7182
R20266		 Kini (Phenytoin) (Controls unexposed, sick), 2006 Major malformations during pregnancy (anytime or not specified) excluded retrospective cohort unexposed, sick Adjustment: No 0.97 [0.10;9.07]
excluded (exposition period) 		1/26   4/101 5 26
ref
S6431
R17660		 Meador (Phenytoin), 2006 Congenital malformations during pregnancy (anytime or not specified) excluded prospective cohort exposed to other treatment, sick Adjustment: No 7.46 [0.81;68.50] C
excluded (exposition period) 		4/56   1/98 5 56
ref
S319
R15670		 Morrow (Phenytoin) (Controls exposed to Lamotrigine, sick), 2006 Major congenital malformation 1st trimester prospective cohort exposed to other treatment, sick excluded Adjustment: No 1.13 [0.33;3.88] C
excluded (control group) 		3/82   21/647 24 82
ref
S6057
R15733		 Morrow (Phenytoin) (Controls unexposed, sick), 2006 Major congenital malformation 1st trimester prospective cohort unexposed, sick Adjustment: No 1.04 [0.27;4.02] C 3/82   8/227 11 82
ref
S6173
R16242		 Viinikainen (Phenytoin) (Controls unexposed, sick) a, 2006 Major malformations throughout pregnancy prospective cohort unexposed, sick Adjustment: No 34.33 [0.49;2389.88] C 0/2   0/52 0 2
ref
S6135
R16029		 Kaaja (Phenytoin), 2003 Major malformation 1st trimester prospective cohort unexposed, sick Adjustment: No 2.94 [0.48;17.82] C 3/124   2/239 5 124
ref
S6680
R18513		 Dean (Phenytoin), 2002 Major congenital malformations at least 1st trimester retrospective cohort unexposed, sick Adjustment: No 3.43 [0.58;20.34] C 4/25   2/38 6 25
ref
S354
R14549		 Holmes (Phenytoin) (Controls unexposed, disease free), 2001 Major malformations during pregnancy (anytime or not specified) retrospective cohort unexposed, disease free excluded Adjustment: Yes 1.90 [0.30;9.20]
excluded (control group) 		3/87   9/508 12 87
ref
S5862
R14558		 Holmes (Phenytoin) (Controls unexposed, sick), 2001 Major malformations during pregnancy (anytime or not specified) excluded retrospective cohort unexposed, sick Adjustment: No 8.17 [0.42;160.54] C
excluded (exposition period) 		3/87   0/98 3 87
ref
S8387
R26541		 Hvas (Phenytoin) (Controls unexposed, disease free), 2000 Major congenital malformations 1st trimester retrospective cohort unexposed, disease free excluded Adjustment: No 83.94 [1.66;4238.34] C
excluded (control group) 		0/1   280/23,827 280 1
ref
S8389
R26546		 Hvas (Phenytoin) (Controls unexposed, sick), 2000 Major congenital malformations 1st trimester retrospective cohort unexposed, sick Adjustment: No 211.00 [1.73;25761.82] C 0/1   0/106 0 1
ref
S7173
R26577		 Canger (Phenytoin), 1999 Severe malformations 1st trimester prospective cohort unexposed, sick Adjustment: No 0.80 [0.02;41.97] C 0/31   0/25 0 31
ref
S6712
R18985		 Samrén (Phenytoin), 1999 Major congential abnormalities at least 1st trimester retrospective cohort unexposed, disease free Adjustment: No Matched 0.50 [0.10;3.40] 1/151   29/2,000 30 151
ref
S6709
R18981		 Steegers-Theunissen (Phenytoin), 1994 Major malformations (ICD9 British Paediatric Association System) during pregnancy (anytime or not specified) excluded prospective cohort unexposed, disease free Adjustment: No 2.76 [0.12;62.85] C
excluded (exposition period) 		0/8   2/106 2 8
ref
S368
R19660		 Kelly (Phenytoin), 1984 Major abnormality during pregnancy (anytime or not specified) excluded prospective cohort unexposed, sick Adjustment: No 0.50 [0.03;8.42] C
excluded (exposition period) 		1/41   1/21 2 41
ref
Total 13 studies 1.57 [0.99;2.48] 207 1,160
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 1.21[0.50; 2.90]2311917%ROB confusion: seriousROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Vajda (Phenytoin) (Controls unexposed, sick), 2019Vajda, 2019 2 0.80[0.10; 6.61]6444%ROB confusion: criticalROB selection: moderateROB classification: lowROB missing: moderateROB mesure: moderateROB reporting: moderate Tomson (Phenytoin), 2018Tomson, 2018 3 2.25[1.06; 4.79]8212520%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Hernández-Díaz (Phenytoin) (Controls unexposed, disease free), 2012Hernández-Díaz, 2012 4 2.60[0.90; 7.40]1741613%ROB confusion: moderateROB selection: lowROB classification: moderateROB missing: moderateROB mesure: moderateROB reporting: moderate Bànhidy (Phenytoin), 2011Bànhidy, 2011 5 0.61[0.21; 1.82]263313%ROB confusion: criticalROB selection: criticalROB classification: lowROB missing: lowROB mesure: moderateROB reporting: moderate Mawer (Phenytoin) (Controls unexposed, sick), 2010Mawer, 2010 6 2.03[0.07; 55.28]172%ROB confusion: criticalROB selection: moderateROB classification: lowROB missing: moderateROB mesure: moderateROB reporting: moderate Morrow (Phenytoin) (Controls unexposed, sick), 2006Morrow, 2006 7 1.04[0.27; 4.02]11829%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Viinikainen (Phenytoin) (Controls unexposed, sick) a, 2006Viinikainen, 2006 8 34.33[0.49; 2389.88]021%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Kaaja (Phenytoin), 2003Kaaja, 2003 9 2.94[0.48; 17.82]51246%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Dean (Phenytoin), 2002Dean, 2002 10 3.43[0.58; 20.34]6256%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Hvas (Phenytoin) (Controls unexposed, sick), 2000Hvas, 2000 11 211.00[1.73; 25761.82]011%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Canger (Phenytoin), 1999Canger, 1999 12 0.80[0.02; 41.97]0311%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Samrén (Phenytoin), 1999Samrén, 1999 13 0.50[0.10; 3.40]301516%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Total (13 studies) I2 = 18% 1.57[0.99; 2.48]2071,1600.2500.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

1: Phenytoin) (Controls unexposed, sick; 2: Phenytoin) (Controls unexposed, sick; 3: Phenytoin; 4: Phenytoin) (Controls unexposed, disease free; 5: Phenytoin; 6: Phenytoin) (Controls unexposed, sick; 7: Phenytoin) (Controls unexposed, sick; 8: Phenytoin) (Controls unexposed, sick) ; 9: Phenytoin; 10: Phenytoin; 11: Phenytoin) (Controls unexposed, sick; 12: Phenytoin; 13: Phenytoin;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 1.80[1.17; 2.76]1811,1274%NAThomas (Phenytoin) (Controls unexposed, sick), 2021 Vajda (Phenytoin) (Controls unexposed, sick), 2019 Tomson (Phenytoin), 2018 Hernández-Díaz (Phenytoin) (Controls unexposed, disease free), 2012 Mawer (Phenytoin) (Controls unexposed, sick), 2010 Morrow (Phenytoin) (Controls unexposed, sick), 2006 Viinikainen (Phenytoin) (Controls unexposed, sick) a, 2006 Kaaja (Phenytoin), 2003 Dean (Phenytoin), 2002 Hvas (Phenytoin) (Controls unexposed, sick), 2000 Canger (Phenytoin), 1999 Samrén (Phenytoin), 1999 12 case control studiescase control studies 0.61[0.21; 1.82]2633 -NABànhidy (Phenytoin), 2011 1 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 1.34[0.27; 6.52]4756760%NAHernández-Díaz (Phenytoin) (Controls unexposed, disease free), 2012 Samrén (Phenytoin), 1999 2 unexposed, sickunexposed, sick 1.40[0.76; 2.59]7846817%NAThomas (Phenytoin) (Controls unexposed, sick), 2021 Vajda (Phenytoin) (Controls unexposed, sick), 2019 Bànhidy (Phenytoin), 2011 Mawer (Phenytoin) (Controls unexposed, sick), 2010 Morrow (Phenytoin) (Controls unexposed, sick), 2006 Viinikainen (Phenytoin) (Controls unexposed, sick) a, 2006 Kaaja (Phenytoin), 2003 Dean (Phenytoin), 2002 Hvas (Phenytoin) (Controls unexposed, sick), 2000 Canger (Phenytoin), 1999 10 exposed to other treatment, sickexposed to other treatment, sick 2.25[1.06; 4.79]82125 -NATomson (Phenytoin), 2018 1 Tags Adjustment   - No  - No 1.65[0.96; 2.84]1841,04123%NAVajda (Phenytoin) (Controls unexposed, sick), 2019 Tomson (Phenytoin), 2018 Hernández-Díaz (Phenytoin) (Controls unexposed, disease free), 2012 Bànhidy (Phenytoin), 2011 Mawer (Phenytoin) (Controls unexposed, sick), 2010 Morrow (Phenytoin) (Controls unexposed, sick), 2006 Viinikainen (Phenytoin) (Controls unexposed, sick) a, 2006 Kaaja (Phenytoin), 2003 Dean (Phenytoin), 2002 Hvas (Phenytoin) (Controls unexposed, sick), 2000 Canger (Phenytoin), 1999 Samrén (Phenytoin), 1999 12   - Yes  - Yes 1.21[0.50; 2.91]23119 -NAThomas (Phenytoin) (Controls unexposed, sick), 2021 1 MatchedMatched 0.58[0.23; 1.46]561840%NABànhidy (Phenytoin), 2011 Samrén (Phenytoin), 1999 2 All studiesAll studies 1.57[0.99; 2.48]2071,16018%NAThomas (Phenytoin) (Controls unexposed, sick), 2021 Vajda (Phenytoin) (Controls unexposed, sick), 2019 Tomson (Phenytoin), 2018 Hernández-Díaz (Phenytoin) (Controls unexposed, disease free), 2012 Bànhidy (Phenytoin), 2011 Mawer (Phenytoin) (Controls unexposed, sick), 2010 Morrow (Phenytoin) (Controls unexposed, sick), 2006 Viinikainen (Phenytoin) (Controls unexposed, sick) a, 2006 Kaaja (Phenytoin), 2003 Dean (Phenytoin), 2002 Hvas (Phenytoin) (Controls unexposed, sick), 2000 Canger (Phenytoin), 1999 Samrén (Phenytoin), 1999 130.21000.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-6.46.42.9420.000Thomas (Phenytoin) (Controls unexposed, sick), 2021Vajda (Phenytoin) (Controls unexposed, sick), 2019Tomson (Phenytoin), 2018Hernández-Díaz (Phenytoin) (Controls unexposed, disease free), 2012Bànhidy (Phenytoin), 2011Mawer (Phenytoin) (Controls unexposed, sick), 2010Morrow (Phenytoin) (Controls unexposed, sick), 2006Viinikainen (Phenytoin) (Controls unexposed, sick) a, 2006Kaaja (Phenytoin), 2003Dean (Phenytoin), 2002Hvas (Phenytoin) (Controls unexposed, sick), 2000Canger (Phenytoin), 1999Samrén (Phenytoin), 1999

Asymetry test p-value = 0.3569 (by Egger's regression)

slope=0.0715 (0.4530); intercept=0.6167 (0.6413); t=0.9617; p=0.3569

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 8387, 354, 319, 9851, 9852, 5878, 8031, 7779, 12698, 12848, 7552

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 1.98[0.79; 4.95]35068137%NAThomas (Phenytoin) (Controls unexposed, disease free), 2021 Hernández-Díaz (Phenytoin) (Controls unexposed, disease free), 2012 Mawer (Phenytoin) (Controls unexposed, disease free), 2010 Hvas (Phenytoin) (Controls unexposed, disease free), 2000 Samrén (Phenytoin), 1999 5 unexposed, sick controlsunexposed, sick controls 1.40[0.76; 2.59]7846817%NAThomas (Phenytoin) (Controls unexposed, sick), 2021 Vajda (Phenytoin) (Controls unexposed, sick), 2019 Bànhidy (Phenytoin), 2011 Mawer (Phenytoin) (Controls unexposed, sick), 2010 Morrow (Phenytoin) (Controls unexposed, sick), 2006 Viinikainen (Phenytoin) (Controls unexposed, sick) a, 2006 Kaaja (Phenytoin), 2003 Dean (Phenytoin), 2002 Hvas (Phenytoin) (Controls unexposed, sick), 2000 Canger (Phenytoin), 1999 10 exposed to other treatment, sick controlsexposed to other treatment, sick controls 1.60[0.99; 2.59]1373770%NAThomas (Phenytoin) (Controls exposed to Lamotrigine, sick), 2021 Vajda (Phenytoin) (Controls exposed to Lamotrigine, sick), 2019 Tomson (Phenytoin), 2018 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