Phenytoin (Epilepsy)

All congenital malformations (majors, minors, majors and minors, or unspecified)

R analysis

id	Study	Lib. in paper	Exposition period	Study type All studies Case control excluded Only case control	Control type	Tags	OR 95%CI	x1/n1 x0/n0	no cases	no exposed	ROB	Ref.
S12698 R48808	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 R48809	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 R48431	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 R26989	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 R48441	Thomas (Phenytoin) (Controls unexposed, sick), 2021	Major congenital malformations	1st trimester	prospective cohort	unexposed, sick	Adjustment: Yes	1.27 [0.51;3.16] ^C	7/119 16/340	23	119		ref
S8086 R24726	Aydin (Phenytoin) (Controls exposed to Lamotrigine, sick), 2020	Congenital chromosomal/structural anomalies	throughout pregnancy	retrospective cohort	exposed to other treatment, sick excluded	Adjustment: No	13.00 [0.10;1680.94] ^C excluded (control group)	0/1 0/7	0	1		ref
S8079 R24665	Aydin (Phenytoin) (Controls unexposed, sick), 2020	Congenital chromosomal/structural anomalies	throughout pregnancy	retrospective cohort	unexposed, sick	Adjustment: No	43.00 [0.35;5328.22] ^C	0/1 0/22	0	1		ref
S7779 R35161	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 R35162	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 R26991	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 R26967	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 R26968	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 R26966	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
S306 R19772	Arteaga-Vázquez (Phenytoin), 2012	Congenital malformations	1st trimester	case control	unexposed, sick	Adjustment: No	2.01 [0.83;4.84] ^C	19/43 13/46	32	43		ref
S5878 R26969	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 R26970	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 R35124	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 R35379	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 R35385	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 R35391	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 R26979	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 R26983	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 R26984	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 R26985	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 R26992	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
S6098 R15886	Artama (Phenytoin), 2005	Malformations	1st trimester	retrospective cohort (registry)	unexposed, sick	Adjustment: No	0.95 [0.02;6.11]	1/38 26/939	27	38		ref
S6135 R26975	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 R18528	Dean (Phenytoin), 2002	Congenital malformations (major and minor)	at least 1st trimester	retrospective cohort	unexposed, sick	Adjustment: No	4.80 [1.54;14.93] ^C	13/25 7/38	20	25		ref
S354 R26971	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 R26972	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 R26973	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 R26974	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
S8350 R26464	Al Bunyan (Phenytoin), 1999	Congenital malformations	during pregnancy (anytime or not specified) excluded	retrospective cohort	unexposed, sick	Adjustment: No	1.12 [0.02;62.74] ^C excluded (exposition period)	0/9 0/10	0	9		ref
S7173 R26578	Canger (Phenytoin), 1999	All type of malformation	1st trimester	prospective cohort	unexposed, sick	Adjustment: No	6.24 [0.31;126.88] ^C	3/31 0/25	3	31		ref
S365 R17688	Kaneko (Phenytoin), 1999	Malformations	throughout pregnancy	prospective cohort	unexposed, sick	Adjustment: No	3.17 [0.87;11.54] ^C	12/132 3/98	15	132		ref
S6712 R26986	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 R26987	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
S341 R18224	D'Souza (Phenytoin) (Controls unexposed, disease free), 1991	Congenital anomalies	throughout pregnancy	prospective cohort	unexposed, disease free excluded	Adjustment: No Matched	161.84 [8.83;2965.43] ^C excluded (control group)	12/22 0/62	12	22		ref
S6690 R18724	D'Souza (Phenytoin) (Controls unexposed, sick), 1991	Congenital anomalies	throughout pregnancy	prospective cohort	unexposed, sick	Adjustment: No	8.40 [0.88;80.27] ^C	12/22 1/8	13	22		ref
S368 R26978	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
S379 R18062	Lowe (Phenytoin) (Controls unexposed, disease free), 1973	Malformations	1st trimester	population based cohort retrospective	unexposed, disease free excluded	Adjustment: No	10.16 [2.11;48.99] ^C excluded (control group)	2/9 865/31,632	867	9		ref
S6588 R18068	Lowe (Phenytoin) (Controls unexposed, sick), 1973	Malformations	1st trimester	population based cohort retrospective	unexposed, sick	Adjustment: No	10.29 [1.47;71.98] ^C	2/9 3/111	5	9		ref
					Total	19 studies	2.13 [1.41;3.22]		316	1,405
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

1: Phenytoin) (Controls unexposed, sick; 2: Phenytoin) (Controls unexposed, sick; 3: Phenytoin) (Controls unexposed, sick; 4: Phenytoin; 5: Phenytoin; 6: Phenytoin) (Controls unexposed, disease free; 7: Phenytoin; 8: Phenytoin) (Controls unexposed, sick; 9: Phenytoin) (Controls unexposed, sick; 10: Phenytoin) (Controls unexposed, sick) ; 11: Phenytoin; 12: Phenytoin; 13: Phenytoin; 14: Phenytoin) (Controls unexposed, sick; 15: Phenytoin; 16: Phenytoin; 17: Phenytoin; 18: Phenytoin) (Controls unexposed, sick; 19: Phenytoin) (Controls unexposed, sick;

Sensitivity analysis

Publication bias and p-hacking diagnosis

funnel plot

Asymetry test p-value = 0.0875 (by Egger's regression)

slope=0.0922 (0.3879); intercept=0.9855 (0.5434); t=1.8135; p=0.0875

p values plot

Sub-groups analysis using all included studies

excluded 379, 341, 8387, 354, 319, 9851, 9852, 5878, 8031, 7779, 8086, 12698, 12848, 7552

S12698 R48808	Alsfouk (Phenytoin) (Controls exposed to Lamotrigine, sick), 2021	Major congenital malformation (67)	during pregnancy (anytime or not specified)	exposed to other treatment, sick	5.00 [0.08;316.71]	0/1 2/15
S12700 R48809	Alsfouk (Phenytoin) (Controls unexposed, sick), 2021	Major congenital malformation (67)	during pregnancy (anytime or not specified)	unexposed, sick	19.00 [0.27;1331.97]	0/1 1/30
S12848 R48431	Thomas (Phenytoin) (Controls exposed to Lamotrigine, sick), 2021	Major congenital malformations (67)	1st trimester	exposed to other treatment, sick	3.06 [0.37;25.57]	7/119 1/50
S7552 R26989	Thomas (Phenytoin) (Controls unexposed, disease free), 2021	Major congenital malformations (67)	1st trimester	unexposed, disease free	1.64 [0.62;4.33]	6/106 11/319
S12849 R48441	Thomas (Phenytoin) (Controls unexposed, sick), 2021	Major congenital malformations (67)	1st trimester	unexposed, sick	1.27 [0.51;3.16]	7/119 16/340
S8086 R24726	Aydin (Phenytoin) (Controls exposed to Lamotrigine, sick), 2020	Congenital chromosomal/structural anomalies (67)	throughout pregnancy	exposed to other treatment, sick	13.00 [0.10;1680.94]	0/1 0/7
S8079 R24665	Aydin (Phenytoin) (Controls unexposed, sick), 2020	Congenital chromosomal/structural anomalies (67)	throughout pregnancy	unexposed, sick	43.00 [0.35;5328.22]	0/1 0/22
S7779 R35161	Vajda (Phenytoin) (Controls exposed to Lamotrigine, sick), 2019	Fetal malformations (67)	at least 1st trimester	exposed to other treatment, sick	0.45 [0.06;3.43]	1/44 20/406
S7780 R35162	Vajda (Phenytoin) (Controls unexposed, sick), 2019	Fetal malformations (67)	at least 1st trimester	unexposed, sick	0.80 [0.10;6.61]	1/44 5/176
S7661 R26991	Tomson (Phenytoin), 2018	Major congenital malformation (67)	at least 1st trimester	exposed to other treatment, sick	2.25 [1.06;4.79]	8/125 74/2514
S8031 R26967	He (Phenytoin) (Controls exposed to Lamotrigine, sick), 2017	Congenital malformations (67)	during pregnancy (anytime or not specified)	exposed to other treatment, sick	2.14 [0.03;131.94]	0/4 0/8
S8032 R26968	He (Phenytoin) (Controls unexposed, sick), 2017	Congenital malformations (67)	during pregnancy (anytime or not specified)	unexposed, sick	8.71 [0.15;511.85]	0/4 0/31
S6254 R26966	Arkilo (Phenytoin), 2015	Major malformations (67)	during pregnancy (anytime or not specified)	exposed to other treatment, sick	5.22 [0.09;299.04]	0/5 0/24
S306 R19772	Arteaga-Vázquez (Phenytoin), 2012	Congenital malformations (67)	1st trimester	unexposed, sick	2.01 [0.83;4.84]	19/43 13/46
S5878 R26969	Hernández-Díaz (Phenytoin) (Controls exposed to Lamotrigine, sick), 2012	Major congenital malformations (67)	1st trimester	exposed to other treatment, sick	1.40 [0.60;3.40]	-9/-9 -9/-9
S7932 R26970	Hernández-Díaz (Phenytoin) (Controls unexposed, disease free), 2012	Major congenital malformations (67)	1st trimester	unexposed, disease free	2.60 [0.90;7.40]	12/416 5/442
S6501 R35124	Bànhidy (Phenytoin), 2011	Total congenital abnormalities (67)	throughout pregnancy	unexposed, sick	0.61 [0.21;1.82]	14/33 12/22
S9851 R35379	Mawer (Phenytoin) (Controls exposed to Lamotrigine, sick), 2010	Major malformations (67)	1st trimester	exposed to other treatment, sick	1.06 [0.05;24.77]	0/7 2/37
S9852 R35385	Mawer (Phenytoin) (Controls unexposed, disease free), 2010	Major malformations (67)	1st trimester	unexposed, disease free	3.30 [0.17;64.87]	0/7 6/285
S9853 R35391	Mawer (Phenytoin) (Controls unexposed, sick), 2010	Major malformations (67)	1st trimester	unexposed, sick	2.03 [0.07;55.28]	0/7 1/41
S7182 R26979	Kini (Phenytoin) (Controls unexposed, sick), 2006	Major malformations (67)	during pregnancy (anytime or not specified)	unexposed, sick	0.97 [0.10;9.07]	1/26 4/101
S6431 R26983	Meador (Phenytoin), 2006	Congenital malformations (67)	during pregnancy (anytime or not specified)	exposed to other treatment, sick	7.46 [0.81;68.50]	4/56 1/98
S319 R26984	Morrow (Phenytoin) (Controls exposed to Lamotrigine, sick), 2006	Major congenital malformation (67)	1st trimester	exposed to other treatment, sick	1.13 [0.33;3.88]	3/82 21/647
S6057 R26985	Morrow (Phenytoin) (Controls unexposed, sick), 2006	Major congenital malformation (67)	1st trimester	unexposed, sick	1.04 [0.27;4.02]	3/82 8/227
S6173 R26992	Viinikainen (Phenytoin) (Controls unexposed, sick) a, 2006	Major malformations (67)	throughout pregnancy	unexposed, sick	34.33 [0.49;2389.88]	0/2 0/52
S6098 R15886	Artama (Phenytoin), 2005	Malformations (67)	1st trimester	unexposed, sick	0.95 [0.02;6.11]	1/38 26/939
S6135 R26975	Kaaja (Phenytoin), 2003	Major malformation (67)	1st trimester	unexposed, sick	2.94 [0.48;17.82]	3/124 2/239
S6680 R18528	Dean (Phenytoin), 2002	Congenital malformations (major and minor) (67)	at least 1st trimester	unexposed, sick	4.80 [1.54;14.93]	13/25 7/38
S354 R26971	Holmes (Phenytoin) (Controls unexposed, disease free), 2001	Major malformations (67)	during pregnancy (anytime or not specified)	unexposed, disease free	1.90 [0.30;9.20]	3/87 9/508
S5862 R26972	Holmes (Phenytoin) (Controls unexposed, sick), 2001	Major malformations (67)	during pregnancy (anytime or not specified)	unexposed, sick	8.17 [0.42;160.54]	3/87 0/98
S8387 R26973	Hvas (Phenytoin) (Controls unexposed, disease free), 2000	Major congenital malformations (67)	1st trimester	unexposed, disease free	83.94 [1.66;4238.34]	0/1 280/23827
S8389 R26974	Hvas (Phenytoin) (Controls unexposed, sick), 2000	Major congenital malformations (67)	1st trimester	unexposed, sick	211.00 [1.73;25761.82]	0/1 0/106
S8350 R26464	Al Bunyan (Phenytoin), 1999	Congenital malformations (67)	during pregnancy (anytime or not specified)	unexposed, sick	1.12 [0.02;62.74]	0/9 0/10
S7173 R26578	Canger (Phenytoin), 1999	All type of malformation (67)	1st trimester	unexposed, sick	6.24 [0.31;126.88]	3/31 0/25
S365 R17688	Kaneko (Phenytoin), 1999	Malformations (67)	throughout pregnancy	unexposed, sick	3.17 [0.87;11.54]	12/132 3/98
S6712 R26986	Samrén (Phenytoin), 1999	Major congential abnormalities (67)	at least 1st trimester	unexposed, disease free	0.50 [0.10;3.40]	1/151 29/2000
S6709 R26987	Steegers-Theunissen (Phenytoin), 1994	Major malformations (ICD9 British Paediatric Association System) (67)	during pregnancy (anytime or not specified)	unexposed, disease free	2.76 [0.12;62.85]	0/8 2/106
S341 R18224	D'Souza (Phenytoin) (Controls unexposed, disease free), 1991	Congenital anomalies (67)	throughout pregnancy	unexposed, disease free	161.84 [8.83;2965.43]	12/22 0/62
S6690 R18724	D'Souza (Phenytoin) (Controls unexposed, sick), 1991	Congenital anomalies (67)	throughout pregnancy	unexposed, sick	8.40 [0.88;80.27]	12/22 1/8
S368 R26978	Kelly (Phenytoin), 1984	Major abnormality (67)	during pregnancy (anytime or not specified)	unexposed, sick	0.50 [0.03;8.42]	1/41 1/21
S379 R18062	Lowe (Phenytoin) (Controls unexposed, disease free), 1973	Malformations (67)	1st trimester	unexposed, disease free	10.16 [2.11;48.99]	2/9 865/31632
S6588 R18068	Lowe (Phenytoin) (Controls unexposed, sick), 1973	Malformations (67)	1st trimester	unexposed, sick	10.29 [1.47;71.98]	2/9 3/111