Valproate (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.
S15858 R65273	Li (Valproate) (Controls exposed to LTG), 2023	Major congenital malformation	during pregnancy (anytime or not specified)	prospective cohort	exposed to other treatment, sick excluded	Adjustment: No	6.58 [0.30;142.47] ^C excluded (control group)	2/31 0/38	2	31		ref
S15859 R65275	Li (Valproate) (Controls unexposed, sick), 2023	Major congenital malformation	during pregnancy (anytime or not specified) excluded	prospective cohort	unexposed, sick	Adjustment: No	2.42 [0.48;12.22] ^C excluded (exposition period)	2/31 7/253	9	31		ref
S15839 R65201	Pekoz (Valproate) (Epilepsy) (Controls exposed to LTG), 2023	Congenital malformations (major and minor)	during pregnancy (anytime or not specified)	prospective cohort	exposed to other treatment, sick excluded	Adjustment: No	4.29 [1.08;17.09] ^C excluded (control group)	7/82 3/141	10	82		ref
S15840 R65202	Pekoz (Valproate) (Epilepsy) (Controls unexposed, sick), 2023	Congenital malformations (major and minor)	during pregnancy (anytime or not specified) excluded	prospective cohort	unexposed, sick	Adjustment: No	3.92 [0.47;32.96] ^C excluded (exposition period)	7/82 1/43	8	82		ref
S12690 R48843	Alsfouk (Valproate) (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	0.22 [0.01;5.02] ^C excluded (control group)	0/12 2/15	2	12		ref
S12692 R48842	Alsfouk (Valproate) (Controls unexposed, sick), 2021	Major congenital malformation	during pregnancy (anytime or not specified) excluded	retrospective cohort	unexposed, sick	Adjustment: No	0.83 [0.03;21.80] ^C excluded (exposition period)	0/12 1/30	1	12		ref
S12881 R48682	Hosny (Valproate) (Controls exposed to Lamotrigine, sick), 2021	Major birth defects	1st trimester	prospective cohort	exposed to other treatment, sick excluded	Adjustment: No	0.07 [0.00;8.55] ^C excluded (control group)	0/8 0/1	0	8		ref
S12880 R48679	Hosny (Valproate) (Controls unexposed, sick), 2021	Major birth defects	1st trimester	prospective cohort	unexposed, sick	Adjustment: No	0.87 [0.03;23.72] ^C	0/8 1/21	1	8		ref
S12860 R48517	Thomas (Valproate) (Controls exposed to Lamotrigine, sick), 2021	Major congenital malformations	1st trimester	prospective cohort	exposed to other treatment, sick excluded	Adjustment: No	4.21 [0.56;31.72] ^C excluded (control group)	27/341 1/50	28	341		ref
S7558 R27064	Thomas (Valproate) (Controls unexposed, disease free), 2021	Major congenital malformations	1st trimester	prospective cohort	unexposed, disease free excluded	Adjustment: No	2.60 [1.30;5.20] excluded (control group)	24/268 11/319	35	268		ref
S12861 R48527	Thomas (Valproate) (Controls unexposed, sick), 2021	Major congenital malformations	1st trimester	prospective cohort	unexposed, sick	Adjustment: Yes	1.71 [0.90;3.20]	27/341 16/340	43	341		ref
S8006 R27036	AlSheikh (Valproate) (Controls exposed to Lamotrigine, sick), 2020	Fetal/neonatal malformation	during pregnancy (anytime or not specified)	prospective cohort	exposed to other treatment, sick excluded	Adjustment: No	39.00 [0.31;4841.77] ^C excluded (control group)	0/1 0/20	0	1		ref
S8007 R27037	AlSheikh (Valproate) (Controls unexposed, sick), 2020	Fetal/neonatal malformation	during pregnancy (anytime or not specified) excluded	prospective cohort	unexposed, sick	Adjustment: No	4.33 [0.06;320.42] ^C excluded (exposition period)	0/1 1/8	1	1		ref
S8087 R24748	Aydin (Valproate) (Controls exposed to Lamotrigine, sick), 2020	Congenital chromosomal/structural anomalies	throughout pregnancy	retrospective cohort	exposed to other treatment, sick excluded	Adjustment: No	0.62 [0.01;35.19] ^C excluded (control group)	0/11 0/7	0	11		ref
S7922 R24625	Aydin (Valproate) (Controls unexposed, sick), 2020	Congenital chromosomal/structural anomalies	throughout pregnancy	retrospective cohort	unexposed, sick	Adjustment: No	2.05 [0.04;110.56] ^C	0/11 0/22	0	11		ref
S7508 R27739	Huber-Mollema (Valproate), 2019	Congenital malformations	throughout pregnancy	prospective cohort	exposed to other treatment, sick	Adjustment: No	6.30 [1.62;24.45] ^C	6/26 4/88	10	26		ref
S7460 R25119	Putignano (Valproate), 2019	Congenital malformations (ICD-9 740 to 760 and 658.8)	throughout pregnancy	retrospective cohort	unexposed (general population or NOS)	Adjustment: No Matched	3.17 [1.61;6.25] ^C	12/79 49/917	61	79		ref
S7774 R35177	Vajda (Valproate) (Controls exposed to Lamotrigine, sick), 2019	Fetal malformations	at least 1st trimester	prospective cohort	exposed to other treatment, sick excluded	Adjustment: No	3.36 [1.93;5.85] ^C excluded (control group)	43/290 20/406	63	290		ref
S7775 R35178	Vajda (Valproate) (Controls unexposed, sick), 2019	Fetal malformations	at least 1st trimester	prospective cohort	unexposed, sick	Adjustment: No	5.22 [2.11;12.95]	43/290 5/176	48	290		ref
S7663 R27066	Tomson (Valproate), 2018	Major congenital malformation	at least 1st trimester	prospective cohort	exposed to other treatment, sick	Adjustment: No	3.78 [2.83;5.05] ^C	142/1,381 74/2,514	216	1,381		ref
S9995 R37652	Petersen (Valproate) (Controls exposed to Lamotrigine, sick), 2017	Major congenital malformation	1st trimester	retrospective cohort (claims database)	exposed to other treatment, sick excluded	Adjustment: No	2.53 [1.01;6.36] ^C excluded (control group)	10/157 9/344	19	157		ref
S9993 R37653	Petersen (Valproate) (Controls unexposed NOS), 2017	Major congenital malformation	1st trimester	retrospective cohort (claims database)	unexposed (general population or NOS) excluded	Adjustment: Yes	1.94 [1.05;3.61] excluded (control group)	10/176 5,315/239,151	5,325	176		ref
S9994 R37654	Petersen (Valproate) (Controls unexposed, sick), 2017	Major congenital malformation	1st trimester	retrospective cohort (claims database)	unexposed, sick	Adjustment: Yes	2.14 [1.11;4.13]	10/157 86/2,844	96	157		ref
S10281 R37655	Razaz (Valproate) (Controls exposed to Lamotrigine, sick), 2017	Major malformations	during pregnancy (anytime or not specified)	population based cohort retrospective	exposed to other treatment, sick excluded	Adjustment: No	2.60 [1.39;4.89] ^C excluded (control group)	20/188 22/503	42	188		ref
S10282 R37656	Razaz (Valproate) (Controls unexposed, disease free), 2017	Major malformations	during pregnancy (anytime or not specified)	population based cohort retrospective	unexposed, disease free excluded	Adjustment: No	3.52 [2.21;5.59] ^C excluded (control group)	20/188 46,632/1,424,279	46,652	188		ref
S10279 R37657	Razaz (Valproate) (Controls unexposed, sick), 2017	Major malformations	during pregnancy (anytime or not specified) excluded	population based cohort retrospective	unexposed, sick	Adjustment: No	2.44 [1.46;4.06] ^C excluded (exposition period)	20/188 87/1,868	107	188		ref
S6255 R27038	Arkilo (Valproate), 2015	Major malformations	during pregnancy (anytime or not specified) excluded	retrospective cohort	exposed to other treatment, sick	Adjustment: No	15.67 [0.22;1102.00] ^C excluded (exposition period)	0/2 0/24	0	2		ref
S6962 R27067	Vanya (Valproate) (Controls exposed to Lamotrigine, sick), 2015	Major congenital malformations	throughout pregnancy	retrospective cohort	exposed to other treatment, sick excluded	Adjustment: No	5.21 [0.23;116.22] ^C excluded (control group)	4/14 0/6	4	14		ref
S5527 R27068	Vanya (Valproate) (Controls unexposed, sick), 2015	Major congenital malformations	throughout pregnancy	retrospective cohort	unexposed, sick	Adjustment: No	18.47 [0.90;379.67] ^C	4/14 0/20	4	14		ref
S307 R27039	Babic (Valproate), 2014	Major congential malformations	during pregnancy (anytime or not specified) excluded	prospective cohort	exposed to other treatment, sick	Adjustment: No	1.67 [0.03;99.62] ^C excluded (exposition period)	0/5 0/8	0	5		ref
S318 R27040	Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014	Major malformations	1st trimester	prospective cohort	exposed to other treatment, sick excluded	Adjustment: No	3.00 [2.10;4.00] excluded (control group)	82/1,220 49/2,098	131	1,220		ref
S8232 R27041	Campbell (Valproate) (Controls unexposed, sick), 2014	Major malformations	1st trimester	prospective cohort	unexposed, sick	Adjustment: No	2.93 [1.62;5.30]	82/1,220 13/541	95	1,220		ref
S6317 R27069	Veiby (Valproate) (Controls exposed to Lamotrigine, sick), 2014	Major malformations	throughout pregnancy	population based cohort retrospective	exposed to other treatment, sick excluded	Adjustment: No	1.81 [0.97;3.38] ^C excluded (control group)	19/279 23/593	42	279		ref
S6313 R27070	Veiby (Valproate) (Controls unexposed, disease free), 2014	Major malformations	throughout pregnancy	population based cohort retrospective	unexposed, disease free excluded	Adjustment: Yes	2.71 [1.70;4.32] excluded (control group)	19/279 22,371/771,412	22,390	279		ref
S6314 R27071	Veiby (Valproate) (Controls unexposed, sick), 2014	Major malformations	throughout pregnancy	population based cohort retrospective	unexposed, sick	Adjustment: No	2.53 [1.53;4.19] ^C	19/279 106/3,773	125	279		ref
S6525 R27042	Cassina (Valproate) (Controls exposed to Lamotrigine, sick), 2013	Major congenital anomalies	1st trimester	prospective cohort	exposed to other treatment, sick excluded	Adjustment: No	3.80 [0.19;76.79] ^C excluded (control group)	3/45 0/23	3	45		ref
S330 R27043	Cassina (Valproate) (Controls unexposed, disease free), 2013	Major congenital anomalies	1st trimester	prospective cohort	unexposed, disease free	Adjustment: No	2.22 [0.65;7.66] ^C	3/45 25/803	28	45		ref
S6996 R19845	Arteaga-Vázquez (Valproate), 2012	Congenital malformations	1st trimester	case control	unexposed, sick	Adjustment: No	2.54 [0.55;11.69] ^C	4/8 13/46	17	8		ref
S5940 R27048	Hernández-Díaz (Valproate) (Controls exposed to Lamotrigine, sick), 2012	Major congenital malformations	1st trimester	prospective cohort	exposed to other treatment, sick excluded	Adjustment: No Controls: mixed indications	4.20 [2.10;8.30] excluded (control group)	-/- -/-	-	-		ref
S7935 R27049	Hernández-Díaz (Valproate) (Controls unexposed, disease free), 2012	Major congenital malformations	1st trimester	prospective cohort	unexposed, disease free	Adjustment: No	9.00 [3.40;23.30]	30/323 5/442	35	323		ref
S6505 R35134	Bànhidy (Valproate), 2011	Total congenital abnormalities	throughout pregnancy	case control	unexposed, sick	Adjustment: No Matched	1.17 [0.28;4.84] ^C	7/12 12/22	19	12		ref
S8138 R27044	Charlton (Valproate) (Controls exposed to Lamotrigine, sick), 2011	Major congenital malformations	1st trimester	retrospective cohort (claims database)	exposed to other treatment, sick excluded	Adjustment: No	1.63 [0.44;5.97] ^C excluded (control group)	11/225 3/98	14	225		ref
S8136 R27045	Charlton (Valproate) (Controls unexposed, sick), 2011	Major congenital malformations	1st trimester	retrospective cohort (claims database)	unexposed, sick	Adjustment: No	2.00 [0.99;4.07]	11/225 22/902	33	225		ref
S9848 R35349	Mawer (Valproate) (Controls exposed to Lamotrigine, sick), 2010	Major malformations	1st trimester	prospective cohort	exposed to other treatment, sick excluded	Adjustment: No	2.23 [0.43;11.74] ^C excluded (control group)	6/53 2/37	8	53		ref
S9849 R35355	Mawer (Valproate) (Controls unexposed, disease free), 2010	Major malformations	1st trimester	prospective cohort	unexposed, disease free excluded	Adjustment: No Matched	5.94 [1.84;19.19] excluded (control group)	6/53 6/285	12	53		ref
S9850 R35361	Mawer (Valproate) (Controls unexposed, sick), 2010	Major malformations	1st trimester	prospective cohort	unexposed, sick	Adjustment: No	5.11 [0.59;44.22] ^C	6/53 1/41	7	53		ref
S6623 R18199	Burja (Valproate) (Controls unexposed, disease free), 2006	Congenital malformation	during pregnancy (anytime or not specified)	retrospective cohort (registry)	unexposed, disease free excluded	Adjustment: No	12.45 [0.45;341.34] ^C excluded (control group)	0/2 5/211	5	2		ref
S6619 R18179	Burja (Valproate) (Controls unexposed, sick), 2006	Congenital malformation	during pregnancy (anytime or not specified) excluded	retrospective cohort (registry)	unexposed, sick	Adjustment: No	21.00 [0.30;1469.95] ^C excluded (exposition period)	0/2 0/32	0	2		ref
S371 R27056	Kini (Valproate) (Controls unexposed, sick), 2006	Major malformations	during pregnancy (anytime or not specified) excluded	retrospective cohort	unexposed, sick	Adjustment: No	4.04 [1.19;13.74] excluded (exposition period)	9/63 4/101	13	63		ref
S6432 R27060	Meador (Valproate), 2006	Congenital malformations	during pregnancy (anytime or not specified) excluded	prospective cohort	exposed to other treatment, sick	Adjustment: Yes	22.82 [4.25;424.20] excluded (exposition period)	12/69 1/98	13	69		ref
S6168 R27072	Viinikainen (Valproate) (Controls unexposed, sick) a, 2006	Major malformations	throughout pregnancy	prospective cohort	unexposed, sick	Adjustment: No	5.83 [0.23;148.09] ^C	1/28 0/52	1	28		ref
S6099 R15900	Artama (Valproate), 2005	Malformations	1st trimester	retrospective cohort (registry)	unexposed, sick	Adjustment: No	4.18 [2.31;7.57]	28/263 26/939	54	263		ref
S8221 R25743	Endo (Valproate) (Controls unexposed, disease free), 2004	Congenital malformations	at least 1st trimester	retrospective cohort	unexposed, disease free excluded	Adjustment: No	2.54 [0.13;48.35] ^C excluded (control group)	0/5 27/656	27	5		ref
S8311 R26300	Endo (Valproate) (Controls unexposed, sick), 2004	Congenital malformations	throughout pregnancy	retrospective cohort	unexposed, sick	Adjustment: No	0.11 [0.00;14.76] ^C	0/5 0/1	0	5		ref
S6137 R27053	Kaaja (Valproate), 2003	Major malformation	1st trimester	prospective cohort	unexposed, sick	Adjustment: No	8.32 [1.49;46.53] ^C	4/61 2/239	6	61		ref
S6679 R18512	Dean (Valproate), 2002	Congenital malformations (major and minor)	at least 1st trimester	retrospective cohort	unexposed, sick	Adjustment: No	7.82 [2.84;21.53] ^C	30/47 7/38	37	47		ref
S6929 R27050	Hvas (Valproate) (Controls unexposed, disease free), 2000	Major congenital malformations	1st trimester	retrospective cohort	unexposed, disease free excluded	Adjustment: No	16.82 [3.67;77.12] ^C excluded (control group)	2/12 280/23,827	282	12		ref
S6925 R27051	Hvas (Valproate) (Controls unexposed, sick), 2000	Major congenital malformations	1st trimester	retrospective cohort	unexposed, sick	Adjustment: No	55.53 [2.48;1242.66] ^C	2/12 0/106	2	12		ref
S8349 R26463	Al Bunyan (Valproate), 1999	Congenital malformations	during pregnancy (anytime or not specified) excluded	retrospective cohort	unexposed, sick	Adjustment: No	2.11 [0.04;124.53] ^C excluded (exposition period)	0/5 0/10	0	5		ref
S6510 R26574	Canger (Valproate), 1999	All type of malformation	1st trimester	prospective cohort	unexposed, sick	Adjustment: No	11.73 [0.65;212.86] ^C	8/44 0/25	8	44		ref
S6446 R17700	Kaneko (Valproate), 1999	Malformations	throughout pregnancy	prospective cohort	unexposed, sick	Adjustment: No	3.96 [1.03;15.15] ^C	9/81 3/98	12	81		ref
S6718 R27061	Samrén (Valproate), 1999	Major congential abnormalities	at least 1st trimester	retrospective cohort	unexposed, disease free	Adjustment: No Matched	4.10 [1.90;8.80]	9/158 29/2,000	38	158		ref
S6707 R27062	Steegers-Theunissen (Valproate), 1994	Major malformations (ICD9 British Paediatric Association System)	during pregnancy (anytime or not specified) excluded	prospective cohort	unexposed, disease free	Adjustment: No	9.75 [1.51;62.95] ^C excluded (exposition period)	3/19 2/106	5	19		ref
S6687 R18637	D'Souza (Valproate) (Controls unexposed, disease free), 1991	Congenital anomalies	throughout pregnancy	prospective cohort	unexposed, disease free excluded	Adjustment: No Matched	123.00 [1.00;15058.31] ^C excluded (control group)	0/1 0/62	0	1		ref
S6695 R18798	D'Souza (Valproate) (Controls unexposed, sick), 1991	Congenital anomalies	throughout pregnancy	prospective cohort	unexposed, sick	Adjustment: No	4.33 [0.06;320.42] ^C	0/1 1/8	1	1		ref
S5495 R27052	Jäger-Roman (Valproate), 1986	Major malformations	at least 1st trimester	prospective cohort	unexposed (general population or NOS)	Adjustment: No	6.23 [1.55;24.98] ^C	4/14 7/116	11	14		ref
S6163 R16407	Robert (Valproate), 1986	Congenital malformations (minor and major)	1st trimester	retrospective cohort	unexposed, sick	Adjustment: No	3.88 [0.87;17.29] ^C	5/15 4/35	9	15		ref
					Total	29 studies	3.36 [2.79;4.06]		1,017	5,201
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: Valproate) (Controls unexposed, sick; 2: Valproate) (Controls unexposed, sick; 3: Valproate) (Controls unexposed, sick; 4: Valproate; 5: Valproate; 6: Valproate) (Controls unexposed, sick; 7: Valproate; 8: Valproate) (Controls unexposed, sick; 9: Valproate) (Controls unexposed, sick; 10: Valproate) (Controls unexposed, sick; 11: Valproate) (Controls unexposed, sick; 12: Valproate) (Controls unexposed, disease free; 13: Valproate; 14: Valproate) (Controls unexposed, disease free; 15: Valproate; 16: Valproate) (Controls unexposed, sick; 17: Valproate) (Controls unexposed, sick; 18: Valproate) (Controls unexposed, sick) ; 19: Valproate; 20: Valproate) (Controls unexposed, sick; 21: Valproate; 22: Valproate; 23: Valproate) (Controls unexposed, sick; 24: Valproate; 25: Valproate; 26: Valproate; 27: Valproate) (Controls unexposed, sick; 28: Valproate; 29: Valproate;

Sensitivity analysis

Publication bias and p-hacking diagnosis

funnel plot

Asymetry test p-value = 0.5053 (by Egger's regression)

slope=1.1171 (0.1462); intercept=0.2778 (0.3381); t=0.8217; p=0.5053

p values plot

Sub-groups analysis using all included studies

excluded 6687, 6929, 8221, 6623, 9848, 9849, 8138, 5940, 6525, 318, 6317, 6313, 6962, 9995, 9993, 10281, 10282, 7774, 8006, 8087, 12690, 12881, 12860, 7558, 15858, 15839

S15858 R65273	Li (Valproate) (Controls exposed to LTG), 2023	Major congenital malformation (67)	during pregnancy (anytime or not specified)	exposed to other treatment, sick	6.58 [0.30;142.47]	2/31 0/38
S15859 R65275	Li (Valproate) (Controls unexposed, sick), 2023	Major congenital malformation (67)	during pregnancy (anytime or not specified)	unexposed, sick	2.42 [0.48;12.22]	2/31 7/253
S15839 R65201	Pekoz (Valproate) (Epilepsy) (Controls exposed to LTG), 2023	Congenital malformations (major and minor) (67)	during pregnancy (anytime or not specified)	exposed to other treatment, sick	4.29 [1.08;17.09]	7/82 3/141
S15840 R65202	Pekoz (Valproate) (Epilepsy) (Controls unexposed, sick), 2023	Congenital malformations (major and minor) (67)	during pregnancy (anytime or not specified)	unexposed, sick	3.92 [0.47;32.96]	7/82 1/43
S12690 R48843	Alsfouk (Valproate) (Controls exposed to Lamotrigine, sick), 2021	Major congenital malformation (67)	during pregnancy (anytime or not specified)	exposed to other treatment, sick	0.22 [0.01;5.02]	0/12 2/15
S12692 R48842	Alsfouk (Valproate) (Controls unexposed, sick), 2021	Major congenital malformation (67)	during pregnancy (anytime or not specified)	unexposed, sick	0.83 [0.03;21.80]	0/12 1/30
S12881 R48682	Hosny (Valproate) (Controls exposed to Lamotrigine, sick), 2021	Major birth defects (67)	1st trimester	exposed to other treatment, sick	0.07 [0.00;8.55]	0/8 0/1
S12880 R48679	Hosny (Valproate) (Controls unexposed, sick), 2021	Major birth defects (67)	1st trimester	unexposed, sick	0.87 [0.03;23.72]	0/8 1/21
S12860 R48517	Thomas (Valproate) (Controls exposed to Lamotrigine, sick), 2021	Major congenital malformations (67)	1st trimester	exposed to other treatment, sick	4.21 [0.56;31.72]	27/341 1/50
S7558 R27064	Thomas (Valproate) (Controls unexposed, disease free), 2021	Major congenital malformations (67)	1st trimester	unexposed, disease free	2.60 [1.30;5.20]	24/268 11/319
S12861 R48527	Thomas (Valproate) (Controls unexposed, sick), 2021	Major congenital malformations (67)	1st trimester	unexposed, sick	1.71 [0.90;3.20]	27/341 16/340
S8006 R27036	AlSheikh (Valproate) (Controls exposed to Lamotrigine, sick), 2020	Fetal/neonatal malformation (67)	during pregnancy (anytime or not specified)	exposed to other treatment, sick	39.00 [0.31;4841.77]	0/1 0/20
S8007 R27037	AlSheikh (Valproate) (Controls unexposed, sick), 2020	Fetal/neonatal malformation (67)	during pregnancy (anytime or not specified)	unexposed, sick	4.33 [0.06;320.42]	0/1 1/8
S8087 R24748	Aydin (Valproate) (Controls exposed to Lamotrigine, sick), 2020	Congenital chromosomal/structural anomalies (67)	throughout pregnancy	exposed to other treatment, sick	0.62 [0.01;35.19]	0/11 0/7
S7922 R24625	Aydin (Valproate) (Controls unexposed, sick), 2020	Congenital chromosomal/structural anomalies (67)	throughout pregnancy	unexposed, sick	2.05 [0.04;110.56]	0/11 0/22
S7508 R27739	Huber-Mollema (Valproate), 2019	Congenital malformations (67)	throughout pregnancy	exposed to other treatment, sick	6.30 [1.62;24.45]	6/26 4/88
S7460 R25119	Putignano (Valproate), 2019	Congenital malformations (ICD-9 740 to 760 and 658.8) (67)	throughout pregnancy	unexposed (general population or NOS)	3.17 [1.61;6.25]	12/79 49/917
S7774 R35177	Vajda (Valproate) (Controls exposed to Lamotrigine, sick), 2019	Fetal malformations (67)	at least 1st trimester	exposed to other treatment, sick	3.36 [1.93;5.85]	43/290 20/406
S7775 R35178	Vajda (Valproate) (Controls unexposed, sick), 2019	Fetal malformations (67)	at least 1st trimester	unexposed, sick	5.22 [2.11;12.95]	43/290 5/176
S7663 R27066	Tomson (Valproate), 2018	Major congenital malformation (67)	at least 1st trimester	exposed to other treatment, sick	3.78 [2.83;5.05]	142/1381 74/2514
S9995 R37652	Petersen (Valproate) (Controls exposed to Lamotrigine, sick), 2017	Major congenital malformation (67)	1st trimester	exposed to other treatment, sick	2.53 [1.01;6.36]	10/157 9/344
S9993 R37653	Petersen (Valproate) (Controls unexposed NOS), 2017	Major congenital malformation (67)	1st trimester	unexposed (general population or NOS)	1.94 [1.05;3.61]	10/176 5315/239151
S9994 R37654	Petersen (Valproate) (Controls unexposed, sick), 2017	Major congenital malformation (67)	1st trimester	unexposed, sick	2.14 [1.11;4.13]	10/157 86/2844
S10281 R37655	Razaz (Valproate) (Controls exposed to Lamotrigine, sick), 2017	Major malformations (67)	during pregnancy (anytime or not specified)	exposed to other treatment, sick	2.60 [1.39;4.89]	20/188 22/503
S10282 R37656	Razaz (Valproate) (Controls unexposed, disease free), 2017	Major malformations (67)	during pregnancy (anytime or not specified)	unexposed, disease free	3.52 [2.21;5.59]	20/188 46632/1424279
S10279 R37657	Razaz (Valproate) (Controls unexposed, sick), 2017	Major malformations (67)	during pregnancy (anytime or not specified)	unexposed, sick	2.44 [1.46;4.06]	20/188 87/1868
S6255 R27038	Arkilo (Valproate), 2015	Major malformations (67)	during pregnancy (anytime or not specified)	exposed to other treatment, sick	15.67 [0.22;1102.00]	0/2 0/24
S6962 R27067	Vanya (Valproate) (Controls exposed to Lamotrigine, sick), 2015	Major congenital malformations (67)	throughout pregnancy	exposed to other treatment, sick	5.21 [0.23;116.22]	4/14 0/6
S5527 R27068	Vanya (Valproate) (Controls unexposed, sick), 2015	Major congenital malformations (67)	throughout pregnancy	unexposed, sick	18.47 [0.90;379.67]	4/14 0/20
S307 R27039	Babic (Valproate), 2014	Major congential malformations (67)	during pregnancy (anytime or not specified)	exposed to other treatment, sick	1.67 [0.03;99.62]	0/5 0/8
S318 R27040	Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014	Major malformations (67)	1st trimester	exposed to other treatment, sick	3.00 [2.10;4.00]	82/1220 49/2098
S8232 R27041	Campbell (Valproate) (Controls unexposed, sick), 2014	Major malformations (67)	1st trimester	unexposed, sick	2.93 [1.62;5.30]	82/1220 13/541
S6317 R27069	Veiby (Valproate) (Controls exposed to Lamotrigine, sick), 2014	Major malformations (67)	throughout pregnancy	exposed to other treatment, sick	1.81 [0.97;3.38]	19/279 23/593
S6313 R27070	Veiby (Valproate) (Controls unexposed, disease free), 2014	Major malformations (67)	throughout pregnancy	unexposed, disease free	2.71 [1.70;4.32]	19/279 22371/771412
S6314 R27071	Veiby (Valproate) (Controls unexposed, sick), 2014	Major malformations (67)	throughout pregnancy	unexposed, sick	2.53 [1.53;4.19]	19/279 106/3773
S6525 R27042	Cassina (Valproate) (Controls exposed to Lamotrigine, sick), 2013	Major congenital anomalies (67)	1st trimester	exposed to other treatment, sick	3.80 [0.19;76.79]	3/45 0/23
S330 R27043	Cassina (Valproate) (Controls unexposed, disease free), 2013	Major congenital anomalies (67)	1st trimester	unexposed, disease free	2.22 [0.65;7.66]	3/45 25/803
S6996 R19845	Arteaga-Vázquez (Valproate), 2012	Congenital malformations (67)	1st trimester	unexposed, sick	2.54 [0.55;11.69]	4/8 13/46
S5940 R27048	Hernández-Díaz (Valproate) (Controls exposed to Lamotrigine, sick), 2012	Major congenital malformations (67)	1st trimester	exposed to other treatment, sick	4.20 [2.10;8.30]	-9/-9 -9/-9
S7935 R27049	Hernández-Díaz (Valproate) (Controls unexposed, disease free), 2012	Major congenital malformations (67)	1st trimester	unexposed, disease free	9.00 [3.40;23.30]	30/323 5/442
S6505 R35134	Bànhidy (Valproate), 2011	Total congenital abnormalities (67)	throughout pregnancy	unexposed, sick	1.17 [0.28;4.84]	7/12 12/22
S8138 R27044	Charlton (Valproate) (Controls exposed to Lamotrigine, sick), 2011	Major congenital malformations (67)	1st trimester	exposed to other treatment, sick	1.63 [0.44;5.97]	11/225 3/98
S8136 R27045	Charlton (Valproate) (Controls unexposed, sick), 2011	Major congenital malformations (67)	1st trimester	unexposed, sick	2.00 [0.99;4.07]	11/225 22/902
S9848 R35349	Mawer (Valproate) (Controls exposed to Lamotrigine, sick), 2010	Major malformations (67)	1st trimester	exposed to other treatment, sick	2.23 [0.43;11.74]	6/53 2/37
S9849 R35355	Mawer (Valproate) (Controls unexposed, disease free), 2010	Major malformations (67)	1st trimester	unexposed, disease free	5.94 [1.84;19.19]	6/53 6/285
S9850 R35361	Mawer (Valproate) (Controls unexposed, sick), 2010	Major malformations (67)	1st trimester	unexposed, sick	5.11 [0.59;44.22]	6/53 1/41
S6623 R18199	Burja (Valproate) (Controls unexposed, disease free), 2006	Congenital malformation (67)	during pregnancy (anytime or not specified)	unexposed, disease free	12.45 [0.45;341.34]	0/2 5/211
S6619 R18179	Burja (Valproate) (Controls unexposed, sick), 2006	Congenital malformation (67)	during pregnancy (anytime or not specified)	unexposed, sick	21.00 [0.30;1469.95]	0/2 0/32
S371 R27056	Kini (Valproate) (Controls unexposed, sick), 2006	Major malformations (67)	during pregnancy (anytime or not specified)	unexposed, sick	4.04 [1.19;13.74]	9/63 4/101
S6432 R27060	Meador (Valproate), 2006	Congenital malformations (67)	during pregnancy (anytime or not specified)	exposed to other treatment, sick	22.82 [4.25;424.20]	12/69 1/98
S6168 R27072	Viinikainen (Valproate) (Controls unexposed, sick) a, 2006	Major malformations (67)	throughout pregnancy	unexposed, sick	5.83 [0.23;148.09]	1/28 0/52
S6099 R15900	Artama (Valproate), 2005	Malformations (67)	1st trimester	unexposed, sick	4.18 [2.31;7.57]	28/263 26/939
S8221 R25743	Endo (Valproate) (Controls unexposed, disease free), 2004	Congenital malformations (67)	at least 1st trimester	unexposed, disease free	2.54 [0.13;48.35]	0/5 27/656
S8311 R26300	Endo (Valproate) (Controls unexposed, sick), 2004	Congenital malformations (67)	throughout pregnancy	unexposed, sick	0.11 [0.00;14.76]	0/5 0/1
S6137 R27053	Kaaja (Valproate), 2003	Major malformation (67)	1st trimester	unexposed, sick	8.32 [1.49;46.53]	4/61 2/239
S6679 R18512	Dean (Valproate), 2002	Congenital malformations (major and minor) (67)	at least 1st trimester	unexposed, sick	7.82 [2.84;21.53]	30/47 7/38
S6929 R27050	Hvas (Valproate) (Controls unexposed, disease free), 2000	Major congenital malformations (67)	1st trimester	unexposed, disease free	16.82 [3.67;77.12]	2/12 280/23827
S6925 R27051	Hvas (Valproate) (Controls unexposed, sick), 2000	Major congenital malformations (67)	1st trimester	unexposed, sick	55.53 [2.48;1242.66]	2/12 0/106
S8349 R26463	Al Bunyan (Valproate), 1999	Congenital malformations (67)	during pregnancy (anytime or not specified)	unexposed, sick	2.11 [0.04;124.53]	0/5 0/10
S6510 R26574	Canger (Valproate), 1999	All type of malformation (67)	1st trimester	unexposed, sick	11.73 [0.65;212.86]	8/44 0/25
S6446 R17700	Kaneko (Valproate), 1999	Malformations (67)	throughout pregnancy	unexposed, sick	3.96 [1.03;15.15]	9/81 3/98
S6718 R27061	Samrén (Valproate), 1999	Major congential abnormalities (67)	at least 1st trimester	unexposed, disease free	4.10 [1.90;8.80]	9/158 29/2000
S6707 R27062	Steegers-Theunissen (Valproate), 1994	Major malformations (ICD9 British Paediatric Association System) (67)	during pregnancy (anytime or not specified)	unexposed, disease free	9.75 [1.51;62.95]	3/19 2/106
S6687 R18637	D'Souza (Valproate) (Controls unexposed, disease free), 1991	Congenital anomalies (67)	throughout pregnancy	unexposed, disease free	123.00 [1.00;15058.31]	0/1 0/62
S6695 R18798	D'Souza (Valproate) (Controls unexposed, sick), 1991	Congenital anomalies (67)	throughout pregnancy	unexposed, sick	4.33 [0.06;320.42]	0/1 1/8
S5495 R27052	Jäger-Roman (Valproate), 1986	Major malformations (67)	at least 1st trimester	unexposed (general population or NOS)	6.23 [1.55;24.98]	4/14 7/116
S6163 R16407	Robert (Valproate), 1986	Congenital malformations (minor and major) (67)	1st trimester	unexposed, sick	3.88 [0.87;17.29]	5/15 4/35