Valproate (All indications) - Medication and Pregnancy KB

Valproate (All indications) updated on 04-22-2025

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.
S18030 R75988	Hao (Valproate) (Epilepsy) (Controls exposed to LTG), 2025	Major congenital malformation (MCM)	1st trimester	prospective cohort	exposed to other treatment, sick excluded	Adjustment: No	1.06 [0.17;6.56] ^C excluded (control group)	2/53 3/84	5	53		ref
S18029 R75989	Hao (Valproate) (Epilepsy) (Controls unexposed, sick), 2025	Major congenital malformation (MCM)	1st trimester	prospective cohort	unexposed, sick	Adjustment: No	0.86 [0.21;3.42]	2/53 10/261	12	53		ref
S16099 R67092	Battino (Valproate) (Epilepsy), 2024	Major congenital malformations (MCMs)	early pregnancy	prospective cohort	exposed to other treatment, sick	Adjustment: No	3.46 [2.69;4.46] ^C	153/1,549 110/3,584	263	1,549		ref
S16109 R67095	Fietz (Valproate), 2024	Major birth defects (excluding genetic disorders)	1st trimester	prospective cohort	unexposed (general population or NOS)	Adjustment: Yes	2.36 [1.27;4.38]	20/256 44/1,306	64	256		ref
S18045 R76012	Vajda b (Valproate) (Epilepsy) (Controls exposed to Lamotrigine, sick), 2024	Fetal malformations	early pregnancy	prospective cohort	exposed to other treatment, sick excluded	Adjustment: No	3.97 [2.27;6.96] ^C excluded (control group)	40/268 20/473	60	268		ref
S18046 R76014	Vajda b (Valproate) (Epilepsy) (Controls unexposed, sick), 2024	Fetal malformations	at least 1st trimester	prospective cohort	unexposed, sick	Adjustment: No	4.50 [2.06;9.81]	40/268 7/201	47	268		ref
S17499 R73570	Wiggs (Epilepsy) (Valproate), 2024	Major birth defects	early pregnancy	population based cohort retrospective	unexposed, sick	Adjustment: Yes	2.70 [1.88;3.89]	-/624 -/12,666	-	624		ref
S15200 R62383	Cohen (Valproate) (Mixed indications) (Controls exposed to LTG), 2023	Major congenital malformations (excluding genetic/chromosomal)	1st trimester	population based cohort retrospective	exposed to other treatment, sick excluded	Adjustment: Yes Partial overlapping	2.05 [1.70;2.46] excluded (control group)	159/2,031 314/8,339	473	2,031		ref
S15201 R62384	Cohen (Valproate) (Mixed indications) (Controls unexposed, NOS), 2023	Major congenital malformations (excluding genetic/chromosomal)	1st trimester	population based cohort retrospective	unexposed (general population or NOS)	Adjustment: No	2.71 [2.30;3.19] ^C	159/2,031 147,928/4,866,362	148,087	2,031		ref
S15264 R62770	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
S15265 R62771	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
S15216 R62390	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
S15217 R62391	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
S16172 R67062	The NAAED (Valproate) (Controls exposed to LTG) (Indications NOS), 2023	Major congenital malformations	1st trimester	prospective cohort	exposed to other treatment, sick excluded	Adjustment: No	4.69 [2.96;7.44] ^C excluded (control group)	31/337 52/2,461	83	337		ref
S16173 R67064	The NAAED (Valproate) (Controls unexposed, disease free) (Indications NOS), 2023	Major congenital malformations	1st trimester	prospective cohort	unexposed, disease free	Adjustment: No	8.75 [4.67;16.42] ^C	31/337 15/1,311	46	337		ref
S12689 R48835	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
S12691 R48836	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
S12882 R48685	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
S12883 R48688	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
S12862 R48537	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
S12863 R48545	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
S12864 R48549	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
S16157 R67049	Alsaadi (Valproate) (Epilepsy) (Controls exposed to LTG), 2020	All congenital malformations (majors and minors)	1st trimester	retrospective cohort	exposed to other treatment, sick excluded	Adjustment: No	1.05 [0.09;12.88] ^C excluded (control group)	2/23 1/12	3	23		ref
S16154 R67037	Alsaadi (Valproate) (Epilepsy) (Controls unexposed sick), 2020	All congenital malformations (majors and minors)	1st trimester	retrospective cohort	unexposed, sick	Adjustment: No	3.33 [0.28;39.04] ^C	2/23 1/36	3	23		ref
S9280 R32191	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
S9281 R32194	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
S9287 R32246	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
S9288 R32256	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
S16169 R67123	Zhang (Valproate) (Epilepsy), 2020	Major congenital malformations (MCMs)	1st trimester	retrospective cohort	unexposed, sick	Adjustment: No	6.96 [1.16;41.91] ^C	2/14 4/171	6	14		ref
S9324 R32498	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
S9452 R33252	Elkjaer (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2018	Malformation in child within first year of life (ICD-10 Q0 to Q99)	during pregnancy (anytime or not specified)	population based cohort propective	exposed to other treatment, sick excluded	Adjustment: No Controls: mixed indications	2.16 [1.24;3.78] ^C excluded (control group)	31/253 24/396	55	253		ref
S9453 R33256	Elkjaer (Valproate) (Controls unexposed NOS) (Mixed indications), 2018	Malformation in child within first year of life (ICD-10 Q0 to Q99)	during pregnancy (anytime or not specified) excluded	population based cohort propective	unexposed (general population or NOS)	Adjustment: No	2.65 [1.82;3.86] ^C excluded (exposition period)	31/253 23,858/477,162	23,889	253		ref
S9314 R32451	Bank (Valproate) (Mixed indications), 2017	Major Malformation	during pregnancy (anytime or not specified) excluded	prospective cohort	exposed to other treatment, sick	Adjustment: No	6.45 [0.12;360.09] ^C excluded (exposition period)	0/6 0/36	0	6		ref
S16162 R67100	Guveli (Valproate) (Epilepsy), 2017	Major malformations	during pregnancy (anytime or not specified) excluded	retrospective cohort	unexposed, sick	Adjustment: No	2.59 [0.25;26.46] ^C excluded (exposition period)	3/32 1/26	4	32		ref
S10210 R37661	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
S10211 R37662	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
S10212 R37663	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
S9282 R32201	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
S9362 R32747	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
S9363 R32749	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
S9289 R32261	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
S9333 R32569	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
S9334 R32571	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
S9325 R32519	Veiby (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2014	Major congenital malformation	throughout pregnancy	population based cohort retrospective	exposed to other treatment, sick excluded	Adjustment: No Partial overlapping	1.94 [1.08;3.46] ^C excluded (control group)	21/333 28/833	49	333		ref
S9326 R32523	Veiby (Valproate) (Controls unexposed, disease free) (Mixed indications), 2014	Major malformations	throughout pregnancy	population based cohort retrospective	unexposed, disease free excluded	Adjustment: Yes Partial overlapping	2.47 [1.58;3.84] excluded (control group)	21/333 22,371/771,412	22,392	333		ref
S9327 R32526	Veiby (Valproate) (Controls unexposed, sick) (Mixed indications), 2014	Major malformations	throughout pregnancy	population based cohort retrospective	unexposed, sick	Adjustment: No Controls: epilepsy indication Partial overlapping	2.33 [1.44;3.77] ^C	21/333 106/3,773	127	333		ref
S9336 R32581	Cassina (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2013	Major congenital anomalies	1st trimester	prospective cohort	exposed to other treatment, sick excluded	Adjustment: No	5.21 [0.29;94.43] ^C excluded (control group)	6/120 0/46	6	120		ref
S9337 R32583	Cassina (Valproate) (Controls unexposed, disease free) (Mixed indications), 2013	Major congenital anomalies	1st trimester	prospective cohort	unexposed, disease free	Adjustment: No	1.64 [0.66;4.08] ^C	6/120 25/803	31	120		ref
S9450 R33186	Rihtman (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2013	Children: born with congenital deformation	at least 1st trimester	prospective cohort	exposed to other treatment, sick excluded	Adjustment: No Controls: epilepsy indication	6.31 [0.67;59.59] ^C excluded (control group)	4/30 1/42	5	30		ref
S9451 R33221	Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013	Children: born with congenital deformation	at least 1st trimester	prospective cohort	unexposed (general population or NOS)	Adjustment: No	18.18 [0.94;350.80] ^C	4/30 0/52	4	30		ref
S9286 R32238	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
S9331 R35133	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
S9293 R32279	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
S9294 R32282	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
S9312 R32442	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
S9317 R32467	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
S9318 R32469	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
S9444 R33169	Diav-Citrin (Valproate) (Mixed indications), 2008	Major anomalies without chromosomal or genetic anomalies	at least 1st trimester	prospective cohort	unexposed (general population or NOS)	Adjustment: No	1.71 [0.51;5.75] ^C	3/71 31/1,236	34	71		ref
S9290 R32264	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
S9292 R32274	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
S9346 R32608	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
S9319 R32473	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
S9329 R32533	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
S9330 R32534	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
S9300 R32383	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
S9301 R32398	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
S9342 R32591	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
S9299 R32370	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
S9306 R32414	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
S9307 R32416	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
S9279 R32188	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
S9335 R32579	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
S9344 R32593	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
S9353 R32724	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
S9354 R32726	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
S9297 R32297	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
S9298 R32326	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
S9308 R32423	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
S9352 R32722	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	36 studies	3.06 [2.61;3.59]		149,279	8,566
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) (Epilepsy) (Controls unexposed, sick; 2: Valproate) (Epilepsy; 3: Valproate; 4: Valproate) (Epilepsy) (Controls unexposed, sick; 5: Epilepsy) (Valproate; 6: Valproate) (Mixed indications) (Controls unexposed, NOS; 7: Valproate) (Controls unexposed, disease free) (Indications NOS; 8: Valproate) (Controls unexposed, sick; 9: Valproate) (Controls unexposed, sick; 10: Valproate) (Epilepsy) (Controls unexposed sick; 11: Valproate) (Controls unexposed, sick; 12: Valproate) (Epilepsy; 13: Valproate; 14: Valproate) (Controls unexposed, sick; 15: Valproate) (Controls unexposed, sick; 16: Valproate) (Controls unexposed, sick; 17: Valproate) (Controls unexposed, sick) (Mixed indications; 18: Valproate) (Controls unexposed, disease free) (Mixed indications; 19: Valproate) (Controls unexposed, NOS) (Mixed indications; 20: Valproate; 21: Valproate; 22: Valproate) (Controls unexposed, sick; 23: Valproate) (Controls unexposed, sick; 24: Valproate) (Mixed indications; 25: Valproate) (Controls unexposed, sick) ; 26: Valproate; 27: Valproate) (Controls unexposed, sick; 28: Valproate; 29: Valproate; 30: Valproate) (Controls unexposed, sick; 31: Valproate; 32: Valproate; 33: Valproate; 34: Valproate) (Controls unexposed, sick; 35: Valproate; 36: Valproate;

Sensitivity analysis

Publication bias and p-hacking diagnosis

funnel plot

Asymetry test p-value = 0.2132 (by Egger's regression)

slope=1.0136 (0.0862); intercept=0.3114 (0.2765); t=1.1263; p=0.2132

p values plot

Sub-groups analysis using all included studies

excluded 9297, 9306, 9300, 9290, 9312, 9317, 9293, 9336, 9450, 9333, 9325, 9326, 9362, 10210, 10211, 9452, 16157, 9280, 9287, 12689, 12882, 12862, 12863, 15200, 15264, 15216, 16172, 18045, 18030

S18030 R75988	Hao (Valproate) (Epilepsy) (Controls exposed to LTG), 2025	Major congenital malformation (MCM) (67)	1st trimester	exposed to other treatment, sick	1.06 [0.17;6.56]	2/53 3/84
S18029 R75989	Hao (Valproate) (Epilepsy) (Controls unexposed, sick), 2025	Major congenital malformation (MCM) (67)	1st trimester	unexposed, sick	0.86 [0.21;3.42]	2/53 10/261
S16099 R67092	Battino (Valproate) (Epilepsy), 2024	Major congenital malformations (MCMs) (67)	early pregnancy	exposed to other treatment, sick	3.46 [2.69;4.46]	153/1549 110/3584
S16109 R67095	Fietz (Valproate), 2024	Major birth defects (excluding genetic disorders) (67)	1st trimester	unexposed (general population or NOS)	2.36 [1.27;4.38]	20/256 44/1306
S18045 R76012	Vajda b (Valproate) (Epilepsy) (Controls exposed to Lamotrigine, sick), 2024	Fetal malformations (67)	early pregnancy	exposed to other treatment, sick	3.97 [2.27;6.96]	40/268 20/473
S18046 R76014	Vajda b (Valproate) (Epilepsy) (Controls unexposed, sick), 2024	Fetal malformations (67)	at least 1st trimester	unexposed, sick	4.50 [2.06;9.81]	40/268 7/201
S17499 R73570	Wiggs (Epilepsy) (Valproate), 2024	Major birth defects (67)	early pregnancy	unexposed, sick	2.70 [1.88;3.89]	-9/624 -9/12666
S15200 R62383	Cohen (Valproate) (Mixed indications) (Controls exposed to LTG), 2023	Major congenital malformations (excluding genetic/chromosomal) (67)	1st trimester	exposed to other treatment, sick	2.05 [1.70;2.46]	159/2031 314/8339
S15201 R62384	Cohen (Valproate) (Mixed indications) (Controls unexposed, NOS), 2023	Major congenital malformations (excluding genetic/chromosomal) (67)	1st trimester	unexposed (general population or NOS)	2.71 [2.30;3.19]	159/2031 147928/4866362
S15264 R62770	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
S15265 R62771	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
S15216 R62390	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
S15217 R62391	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
S16172 R67062	The NAAED (Valproate) (Controls exposed to LTG) (Indications NOS), 2023	Major congenital malformations (67)	1st trimester	exposed to other treatment, sick	4.69 [2.96;7.44]	31/337 52/2461
S16173 R67064	The NAAED (Valproate) (Controls unexposed, disease free) (Indications NOS), 2023	Major congenital malformations (67)	1st trimester	unexposed, disease free	8.75 [4.67;16.42]	31/337 15/1311
S12689 R48835	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
S12691 R48836	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
S12882 R48685	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
S12883 R48688	Hosny (Valproate) (Controls unexposed, sick), 2021	Major birth defects (67)	1st trimester	unexposed, sick	0.87 [0.03;23.72]	0/8 1/21
S12862 R48537	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
S12863 R48545	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
S12864 R48549	Thomas (Valproate) (Controls unexposed, sick), 2021	Major congenital malformations (67)	1st trimester	unexposed, sick	1.71 [0.90;3.20]	27/341 16/340
S16157 R67049	Alsaadi (Valproate) (Epilepsy) (Controls exposed to LTG), 2020	All congenital malformations (majors and minors) (67)	1st trimester	exposed to other treatment, sick	1.05 [0.09;12.88]	2/23 1/12
S16154 R67037	Alsaadi (Valproate) (Epilepsy) (Controls unexposed sick), 2020	All congenital malformations (majors and minors) (67)	1st trimester	unexposed, sick	3.33 [0.28;39.04]	2/23 1/36
S9280 R32191	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
S9281 R32194	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
S9287 R32246	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
S9288 R32256	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
S16169 R67123	Zhang (Valproate) (Epilepsy), 2020	Major congenital malformations (MCMs) (67)	1st trimester	unexposed, sick	6.96 [1.16;41.91]	2/14 4/171
S9324 R32498	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
S9452 R33252	Elkjaer (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2018	Malformation in child within first year of life (ICD-10 Q0 to Q99) (67)	during pregnancy (anytime or not specified)	exposed to other treatment, sick	2.16 [1.24;3.78]	31/253 24/396
S9453 R33256	Elkjaer (Valproate) (Controls unexposed NOS) (Mixed indications), 2018	Malformation in child within first year of life (ICD-10 Q0 to Q99) (67)	during pregnancy (anytime or not specified)	unexposed (general population or NOS)	2.65 [1.82;3.86]	31/253 23858/477162
S9314 R32451	Bank (Valproate) (Mixed indications), 2017	Major Malformation (67)	during pregnancy (anytime or not specified)	exposed to other treatment, sick	6.45 [0.12;360.09]	0/6 0/36
S16162 R67100	Guveli (Valproate) (Epilepsy), 2017	Major malformations (67)	during pregnancy (anytime or not specified)	unexposed, sick	2.59 [0.25;26.46]	3/32 1/26
S10210 R37661	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
S10211 R37662	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
S10212 R37663	Petersen (Valproate) (Controls unexposed, sick), 2017	Major congenital malformation (67)	1st trimester	unexposed, sick	2.14 [1.11;4.13]	10/157 86/2844
S9282 R32201	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
S9362 R32747	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
S9363 R32749	Vanya (Valproate) (Controls unexposed, sick), 2015	Major congenital malformations (67)	throughout pregnancy	unexposed, sick	18.47 [0.90;379.67]	4/14 0/20
S9289 R32261	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
S9333 R32569	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
S9334 R32571	Campbell (Valproate) (Controls unexposed, sick), 2014	Major malformations (67)	1st trimester	unexposed, sick	2.93 [1.62;5.30]	82/1220 13/541
S9325 R32519	Veiby (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2014	Major congenital malformation (67)	throughout pregnancy	exposed to other treatment, sick	1.94 [1.08;3.46]	21/333 28/833
S9326 R32523	Veiby (Valproate) (Controls unexposed, disease free) (Mixed indications), 2014	Major malformations (67)	throughout pregnancy	unexposed, disease free	2.47 [1.58;3.84]	21/333 22371/771412
S9327 R32526	Veiby (Valproate) (Controls unexposed, sick) (Mixed indications), 2014	Major malformations (67)	throughout pregnancy	unexposed, sick	2.33 [1.44;3.77]	21/333 106/3773
S9336 R32581	Cassina (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2013	Major congenital anomalies (67)	1st trimester	exposed to other treatment, sick	5.21 [0.29;94.43]	6/120 0/46
S9337 R32583	Cassina (Valproate) (Controls unexposed, disease free) (Mixed indications), 2013	Major congenital anomalies (67)	1st trimester	unexposed, disease free	1.64 [0.66;4.08]	6/120 25/803
S9450 R33186	Rihtman (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2013	Children: born with congenital deformation (67)	at least 1st trimester	exposed to other treatment, sick	6.31 [0.67;59.59]	4/30 1/42
S9451 R33221	Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013	Children: born with congenital deformation (67)	at least 1st trimester	unexposed (general population or NOS)	18.18 [0.94;350.80]	4/30 0/52
S9286 R32238	Arteaga-Vázquez (Valproate), 2012	Congenital malformations (67)	1st trimester	unexposed, sick	2.54 [0.55;11.69]	4/8 13/46
S9331 R35133	Bànhidy (Valproate), 2011	Total congenital abnormalities (67)	throughout pregnancy	unexposed, sick	1.17 [0.28;4.84]	7/12 12/22
S9293 R32279	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
S9294 R32282	Charlton (Valproate) (Controls unexposed, sick), 2011	Major congenital malformations (67)	1st trimester	unexposed, sick	2.00 [0.99;4.07]	11/225 22/902
S9312 R32442	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
S9317 R32467	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
S9318 R32469	Mawer (Valproate) (Controls unexposed, sick), 2010	Major malformations (67)	1st trimester	unexposed, sick	5.11 [0.59;44.22]	6/53 1/41
S9444 R33169	Diav-Citrin (Valproate) (Mixed indications), 2008	Major anomalies without chromosomal or genetic anomalies (67)	at least 1st trimester	unexposed (general population or NOS)	1.71 [0.51;5.75]	3/71 31/1236
S9290 R32264	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
S9292 R32274	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
S9346 R32608	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
S9319 R32473	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
S9329 R32533	Viinikainen (Valproate) (Controls unexposed, sick) a, 2006	Major malformations (67)	throughout pregnancy	unexposed, sick	5.83 [0.23;148.09]	1/28 0/52
S9330 R32534	Artama (Valproate), 2005	Malformations (67)	1st trimester	unexposed, sick	4.18 [2.31;7.57]	28/263 26/939
S9300 R32383	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
S9301 R32398	Endo (Valproate) (Controls unexposed, sick), 2004	Congenital malformations (67)	throughout pregnancy	unexposed, sick	0.11 [0.00;14.76]	0/5 0/1
S9342 R32591	Kaaja (Valproate), 2003	Major malformation (67)	1st trimester	unexposed, sick	8.32 [1.49;46.53]	4/61 2/239
S9299 R32370	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
S9306 R32414	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
S9307 R32416	Hvas (Valproate) (Controls unexposed, sick), 2000	Major congenital malformations (67)	1st trimester	unexposed, sick	55.53 [2.48;1242.66]	2/12 0/106
S9279 R32188	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
S9335 R32579	Canger (Valproate), 1999	All type of malformation (67)	1st trimester	unexposed, sick	11.73 [0.65;212.86]	8/44 0/25
S9344 R32593	Kaneko (Valproate), 1999	Malformations (67)	throughout pregnancy	unexposed, sick	3.96 [1.03;15.15]	9/81 3/98
S9353 R32724	Samrén (Valproate), 1999	Major congential abnormalities (67)	at least 1st trimester	unexposed, disease free	4.10 [1.90;8.80]	9/158 29/2000
S9354 R32726	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
S9297 R32297	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
S9298 R32326	D'Souza (Valproate) (Controls unexposed, sick), 1991	Congenital anomalies (67)	throughout pregnancy	unexposed, sick	4.33 [0.06;320.42]	0/1 1/8
S9308 R32423	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
S9352 R32722	Robert (Valproate), 1986	Congenital malformations (minor and major) (67)	1st trimester	unexposed, sick	3.88 [0.87;17.29]	5/15 4/35