Valproate (Epilepsy)

Major congenital malformations

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 R65272	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 R65274	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
S12690 R47926	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 R47928	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 R48680	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 R48677	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 R48516	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 R22596	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 R48526	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 R24380	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 R24382	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
S7508 R27736	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
S7774 R22983	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 R22984	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 R22685	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 R35917	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 R35915	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 R35916	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 R37624	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 R37625	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 R37622	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 R16665	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 R19695	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 R19688	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 R16401	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 R25944	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 R25956	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 R17139	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 R17135	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 R17136	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 R17979	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 R17943	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
S5940 R15202	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 R24011	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 R17916	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 R24994	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 R24988	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 R35348	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 R35354	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 R35360	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
S371 R18040	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 R17663	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 R16229	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
S6137 R16031	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 R18497	Dean (Valproate), 2002	Major congenital malformations	at least 1st trimester	retrospective cohort	unexposed, sick	Adjustment: No	2.14 [0.39;11.72] ^C	5/47 2/38	7	47		ref
S6929 R19482	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 R19478	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
S6510 R26573	Canger (Valproate), 1999	Severe malformations	1st trimester	prospective cohort	unexposed, sick	Adjustment: No	8.49 [0.46;157.67] ^C	6/44 0/25	6	44		ref
S6718 R18991	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 R18979	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
S5495 R16634	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 R16214	Robert (Valproate), 1986	Major malformations	1st trimester	retrospective cohort	unexposed, sick	Adjustment: No	13.80 [0.62;307.74] ^C	2/15 0/35	2	15		ref
					Total	22 studies	3.24 [2.56;4.10]		833	4,753
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; 4: Valproate) (Controls unexposed, sick; 5: Valproate; 6: Valproate) (Controls unexposed, sick; 7: Valproate) (Controls unexposed, sick; 8: Valproate) (Controls unexposed, sick; 9: Valproate) (Controls unexposed, sick; 10: Valproate) (Controls unexposed, disease free; 11: Valproate) (Controls unexposed, disease free; 12: Valproate; 13: Valproate) (Controls unexposed, sick; 14: Valproate) (Controls unexposed, sick; 15: Valproate) (Controls unexposed, sick) ; 16: Valproate; 17: Valproate; 18: Valproate) (Controls unexposed, sick; 19: Valproate; 20: Valproate; 21: Valproate; 22: Valproate;

Sensitivity analysis

Publication bias and p-hacking diagnosis

funnel plot

Asymetry test p-value = 0.1712 (by Egger's regression)

slope=1.0191 (0.1659); intercept=0.4765 (0.3999); t=1.1914; p=0.1712

p values plot

Sub-groups analysis using all included studies

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

S15858 R65272	Li (Valproate) (Controls exposed to LTG), 2023	Major congenital malformation (68)	during pregnancy (anytime or not specified)	exposed to other treatment, sick	6.58 [0.30;142.47]	2/31 0/38
S15859 R65274	Li (Valproate) (Controls unexposed, sick), 2023	Major congenital malformation (68)	during pregnancy (anytime or not specified)	unexposed, sick	2.42 [0.48;12.22]	2/31 7/253
S12690 R47926	Alsfouk (Valproate) (Controls exposed to Lamotrigine, sick), 2021	Major congenital malformation (68)	during pregnancy (anytime or not specified)	exposed to other treatment, sick	0.22 [0.01;5.02]	0/12 2/15
S12692 R47928	Alsfouk (Valproate) (Controls unexposed, sick), 2021	Major congenital malformation (68)	during pregnancy (anytime or not specified)	unexposed, sick	0.83 [0.03;21.80]	0/12 1/30
S12881 R48680	Hosny (Valproate) (Controls exposed to Lamotrigine, sick), 2021	Major birth defects (68)	1st trimester	exposed to other treatment, sick	0.07 [0.00;8.55]	0/8 0/1
S12880 R48677	Hosny (Valproate) (Controls unexposed, sick), 2021	Major birth defects (68)	1st trimester	unexposed, sick	0.87 [0.03;23.72]	0/8 1/21
S12860 R48516	Thomas (Valproate) (Controls exposed to Lamotrigine, sick), 2021	Major congenital malformations (68)	1st trimester	exposed to other treatment, sick	4.21 [0.56;31.72]	27/341 1/50
S7558 R22596	Thomas (Valproate) (Controls unexposed, disease free), 2021	Major congenital malformations (68)	1st trimester	unexposed, disease free	2.60 [1.30;5.20]	24/268 11/319
S12861 R48526	Thomas (Valproate) (Controls unexposed, sick), 2021	Major congenital malformations (68)	1st trimester	unexposed, sick	1.71 [0.90;3.20]	27/341 16/340
S8006 R24380	AlSheikh (Valproate) (Controls exposed to Lamotrigine, sick), 2020	Fetal/neonatal malformation (68)	during pregnancy (anytime or not specified)	exposed to other treatment, sick	39.00 [0.31;4841.77]	0/1 0/20
S8007 R24382	AlSheikh (Valproate) (Controls unexposed, sick), 2020	Fetal/neonatal malformation (68)	during pregnancy (anytime or not specified)	unexposed, sick	4.33 [0.06;320.42]	0/1 1/8
S7508 R27736	Huber-Mollema (Valproate), 2019	Congenital malformations (68)	throughout pregnancy	exposed to other treatment, sick	6.30 [1.62;24.45]	6/26 4/88
S7774 R22983	Vajda (Valproate) (Controls exposed to Lamotrigine, sick), 2019	Fetal malformations (68)	at least 1st trimester	exposed to other treatment, sick	3.36 [1.93;5.85]	43/290 20/406
S7775 R22984	Vajda (Valproate) (Controls unexposed, sick), 2019	Fetal malformations (68)	at least 1st trimester	unexposed, sick	5.22 [2.11;12.95]	43/290 5/176
S7663 R22685	Tomson (Valproate), 2018	Major congenital malformation (68)	at least 1st trimester	exposed to other treatment, sick	3.78 [2.83;5.05]	142/1381 74/2514
S9995 R35917	Petersen (Valproate) (Controls exposed to Lamotrigine, sick), 2017	Major congenital malformation (68)	1st trimester	exposed to other treatment, sick	2.53 [1.01;6.36]	10/157 9/344
S9993 R35915	Petersen (Valproate) (Controls unexposed NOS), 2017	Major congenital malformation (68)	1st trimester	unexposed (general population or NOS)	1.94 [1.05;3.61]	10/176 5315/239151
S9994 R35916	Petersen (Valproate) (Controls unexposed, sick), 2017	Major congenital malformation (68)	1st trimester	unexposed, sick	2.14 [1.11;4.13]	10/157 86/2844
S10281 R37624	Razaz (Valproate) (Controls exposed to Lamotrigine, sick), 2017	Major malformations (68)	during pregnancy (anytime or not specified)	exposed to other treatment, sick	2.60 [1.39;4.89]	20/188 22/503
S10282 R37625	Razaz (Valproate) (Controls unexposed, disease free), 2017	Major malformations (68)	during pregnancy (anytime or not specified)	unexposed, disease free	3.52 [2.21;5.59]	20/188 46632/1424279
S10279 R37622	Razaz (Valproate) (Controls unexposed, sick), 2017	Major malformations (68)	during pregnancy (anytime or not specified)	unexposed, sick	2.44 [1.46;4.06]	20/188 87/1868
S6255 R16665	Arkilo (Valproate), 2015	Major malformations (68)	during pregnancy (anytime or not specified)	exposed to other treatment, sick	15.67 [0.22;1102.00]	0/2 0/24
S6962 R19695	Vanya (Valproate) (Controls exposed to Lamotrigine, sick), 2015	Major congenital malformations (68)	throughout pregnancy	exposed to other treatment, sick	5.21 [0.23;116.22]	4/14 0/6
S5527 R19688	Vanya (Valproate) (Controls unexposed, sick), 2015	Major congenital malformations (68)	throughout pregnancy	unexposed, sick	18.47 [0.90;379.67]	4/14 0/20
S307 R16401	Babic (Valproate), 2014	Major congential malformations (68)	during pregnancy (anytime or not specified)	exposed to other treatment, sick	1.67 [0.03;99.62]	0/5 0/8
S318 R25944	Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014	Major malformations (68)	1st trimester	exposed to other treatment, sick	3.00 [2.10;4.00]	82/1220 49/2098
S8232 R25956	Campbell (Valproate) (Controls unexposed, sick), 2014	Major malformations (68)	1st trimester	unexposed, sick	2.93 [1.62;5.30]	82/1220 13/541
S6317 R17139	Veiby (Valproate) (Controls exposed to Lamotrigine, sick), 2014	Major malformations (68)	throughout pregnancy	exposed to other treatment, sick	1.81 [0.97;3.38]	19/279 23/593
S6313 R17135	Veiby (Valproate) (Controls unexposed, disease free), 2014	Major malformations (68)	throughout pregnancy	unexposed, disease free	2.71 [1.70;4.32]	19/279 22371/771412
S6314 R17136	Veiby (Valproate) (Controls unexposed, sick), 2014	Major malformations (68)	throughout pregnancy	unexposed, sick	2.53 [1.53;4.19]	19/279 106/3773
S6525 R17979	Cassina (Valproate) (Controls exposed to Lamotrigine, sick), 2013	Major congenital anomalies (68)	1st trimester	exposed to other treatment, sick	3.80 [0.19;76.79]	3/45 0/23
S330 R17943	Cassina (Valproate) (Controls unexposed, disease free), 2013	Major congenital anomalies (68)	1st trimester	unexposed, disease free	2.22 [0.65;7.66]	3/45 25/803
S5940 R15202	Hernández-Díaz (Valproate) (Controls exposed to Lamotrigine, sick), 2012	Major congenital malformations (68)	1st trimester	exposed to other treatment, sick	4.20 [2.10;8.30]	-9/-9 -9/-9
S7935 R24011	Hernández-Díaz (Valproate) (Controls unexposed, disease free), 2012	Major congenital malformations (68)	1st trimester	unexposed, disease free	9.00 [3.40;23.30]	30/323 5/442
S6505 R17916	Bànhidy (Valproate), 2011	Total congenital abnormalities (68)	throughout pregnancy	unexposed, sick	1.17 [0.28;4.84]	7/12 12/22
S8138 R24994	Charlton (Valproate) (Controls exposed to Lamotrigine, sick), 2011	Major congenital malformations (68)	1st trimester	exposed to other treatment, sick	1.63 [0.44;5.97]	11/225 3/98
S8136 R24988	Charlton (Valproate) (Controls unexposed, sick), 2011	Major congenital malformations (68)	1st trimester	unexposed, sick	2.00 [0.99;4.07]	11/225 22/902
S9848 R35348	Mawer (Valproate) (Controls exposed to Lamotrigine, sick), 2010	Major malformations (68)	1st trimester	exposed to other treatment, sick	2.23 [0.43;11.74]	6/53 2/37
S9849 R35354	Mawer (Valproate) (Controls unexposed, disease free), 2010	Major malformations (68)	1st trimester	unexposed, disease free	5.94 [1.84;19.19]	6/53 6/285
S9850 R35360	Mawer (Valproate) (Controls unexposed, sick), 2010	Major malformations (68)	1st trimester	unexposed, sick	5.11 [0.59;44.22]	6/53 1/41
S371 R18040	Kini (Valproate) (Controls unexposed, sick), 2006	Major malformations (68)	during pregnancy (anytime or not specified)	unexposed, sick	4.04 [1.19;13.74]	9/63 4/101
S6432 R17663	Meador (Valproate), 2006	Congenital malformations (68)	during pregnancy (anytime or not specified)	exposed to other treatment, sick	22.82 [4.25;424.20]	12/69 1/98
S6168 R16229	Viinikainen (Valproate) (Controls unexposed, sick) a, 2006	Major malformations (68)	throughout pregnancy	unexposed, sick	5.83 [0.23;148.09]	1/28 0/52
S6137 R16031	Kaaja (Valproate), 2003	Major malformation (68)	1st trimester	unexposed, sick	8.32 [1.49;46.53]	4/61 2/239
S6679 R18497	Dean (Valproate), 2002	Major congenital malformations (68)	at least 1st trimester	unexposed, sick	2.14 [0.39;11.72]	5/47 2/38
S6929 R19482	Hvas (Valproate) (Controls unexposed, disease free), 2000	Major congenital malformations (68)	1st trimester	unexposed, disease free	16.82 [3.67;77.12]	2/12 280/23827
S6925 R19478	Hvas (Valproate) (Controls unexposed, sick), 2000	Major congenital malformations (68)	1st trimester	unexposed, sick	55.53 [2.48;1242.66]	2/12 0/106
S6510 R26573	Canger (Valproate), 1999	Severe malformations (68)	1st trimester	unexposed, sick	8.49 [0.46;157.67]	6/44 0/25
S6718 R18991	Samrén (Valproate), 1999	Major congential abnormalities (68)	at least 1st trimester	unexposed, disease free	4.10 [1.90;8.80]	9/158 29/2000
S6707 R18979	Steegers-Theunissen (Valproate), 1994	Major malformations (ICD9 British Paediatric Association System) (68)	during pregnancy (anytime or not specified)	unexposed, disease free	9.75 [1.51;62.95]	3/19 2/106
S5495 R16634	Jäger-Roman (Valproate), 1986	Major malformations (68)	at least 1st trimester	unexposed (general population or NOS)	6.23 [1.55;24.98]	4/14 7/116
S6163 R16214	Robert (Valproate), 1986	Major malformations (68)	1st trimester	unexposed, sick	13.80 [0.62;307.74]	2/15 0/35