Levetiracetam (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.
S15842 R65221	Bromley (Levetiracetam) (Controls exposed to LTG), 2023	Major congenital anomaly	during pregnancy (anytime or not specified)	prospective cohort	exposed to other treatment, sick excluded	Adjustment: No	1.01 [0.16;6.20] ^C excluded (control group)	2/70 3/106	5	70		ref
S15843 R65234	Bromley (Levetiracetam) (Controls unexposed, sick), 2023	Major congenital anomaly	during pregnancy (anytime or not specified) excluded	prospective cohort	unexposed, sick	Adjustment: No	0.75 [0.12;4.65] ^C excluded (exposition period)	2/70 3/80	5	70		ref
S15825 R65173	Cohen (Levetiracetam) (Epilepsy) (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	0.78 [0.53;1.13] excluded (control group)	30/1,040 314/8,339	344	1,040		ref
S15826 R65175	Cohen (Levetiracetam) (Epilepsy) (Controls unexposed, NOS), 2023	Major congenital malformations (excluding genetic/chromosomal)	1st trimester	population based cohort retrospective	unexposed (general population or NOS)	Adjustment: No Partial overlapping	0.95 [0.66;1.36] ^C	30/1,040 147,928/4,866,362	147,958	1,040		ref
S15854 R65264	Li (Levetiracetam) (Controls exposed to LTG), 2023	Major congenital malformation	during pregnancy (anytime or not specified)	prospective cohort	exposed to other treatment, sick excluded	Adjustment: No	0.35 [0.01;18.06] ^C excluded (control group)	0/107 0/38	0	107		ref
S15855 R65266	Li (Levetiracetam) (Controls unexposed, sick), 2023	Major congenital malformation	during pregnancy (anytime or not specified) excluded	prospective cohort	unexposed, sick	Adjustment: No	0.15 [0.01;2.72] ^C excluded (exposition period)	0/107 7/253	7	107		ref
S12502 R47876	Mari (Levetiracetam), 2022	Major foetal malformation	throughout pregnancy	retrospective cohort	exposed to other treatment, sick	Adjustment: No	0.64 [0.01;34.59] ^C	0/17 0/11	0	17		ref
S12688 R47924	Alsfouk (Levetiracetam) (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	0.11 [0.00;2.39] ^C excluded (control group)	0/24 2/15	2	24		ref
S12686 R47922	Alsfouk (Levetiracetam) (Controls unexposed, sick), 2021	Major congenital malformation	during pregnancy (anytime or not specified) excluded	retrospective cohort	unexposed, sick	Adjustment: No	0.40 [0.02;10.39] ^C excluded (exposition period)	0/24 1/30	1	24		ref
S12884 R48689	Hosny (Levetiracetam) (Controls exposed to Lamotrigine, sick), 2021	Major birth defects	1st trimester	prospective cohort	exposed to other treatment, sick excluded	Adjustment: No	0.04 [0.00;2.38] ^C excluded (control group)	2/67 0/1	2	67		ref
S12885 R48692	Hosny (Levetiracetam) (Controls unexposed, sick), 2021	Major birth defects	1st trimester	prospective cohort	unexposed, sick	Adjustment: No	0.62 [0.05;7.15] ^C	2/67 1/21	3	67		ref
S12824 R48265	Thomas (Levetiracetam) (Controls exposed to Lamotrigine, sick), 2021	Major congenital malformations	1st trimester	prospective cohort	exposed to other treatment, sick excluded	Adjustment: No	2.43 [0.28;21.33] ^C excluded (control group)	5/106 1/50	6	106		ref
S7547 R22590	Thomas (Levetiracetam) (Controls unexposed, disease free), 2021	Major congenital malformations	1st trimester	prospective cohort	unexposed, disease free excluded	Adjustment: No	0.97 [0.13;7.23] excluded (control group)	1/30 11/319	12	30		ref
S12823 R48255	Thomas (Levetiracetam) (Controls unexposed, sick), 2021	Major congenital malformations	1st trimester	prospective cohort	unexposed, sick	Adjustment: Yes	1.16 [0.40;3.10]	5/106 16/340	21	106		ref
S7999 R24366	AlSheikh (Levetiracetam) (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	2.29 [0.04;125.50] ^C excluded (control group)	0/9 0/20	0	9		ref
S8000 R24368	AlSheikh (Levetiracetam) (Controls unexposed, sick), 2020	Fetal/neonatal malformation	during pregnancy (anytime or not specified) excluded	prospective cohort	unexposed, sick	Adjustment: No	0.25 [0.01;7.34] ^C excluded (exposition period)	0/9 1/8	1	9		ref
S7505 R22452	Meador (Levetiracetam) (Controls exposed to Lamotrigine, sick), 2020	Major congenital malformations	1st trimester	prospective cohort	exposed to other treatment, sick excluded	Adjustment: No	1.14 [0.32;4.07] ^C excluded (control group)	5/97 5/110	10	97		ref
S7495 R22422	Meador (Levetiracetam) (Controls unexposed, disease free), 2020	Major congenital malformations	1st trimester	prospective cohort	unexposed, disease free excluded	Adjustment: No	2.83 [0.54;14.92] ^C excluded (control group)	5/97 2/106	7	97		ref
S7501 R22440	Meador (Levetiracetam) (Controls unexposed, sick), 2020	Major congenital malformations	1st trimester	prospective cohort	unexposed, sick	Adjustment: No	0.76 [0.08;7.00] ^C	5/97 1/15	6	97		ref
S7511 R27734	Huber-Mollema (Levetiracetam), 2019	Congenital malformations	throughout pregnancy	prospective cohort	exposed to other treatment, sick	Adjustment: No	1.50 [0.26;8.64] ^C	2/30 4/88	6	30		ref
S7772 R22981	Vajda (Levetiracetam) (Controls exposed to Lamotrigine, sick), 2019	Fetal malformations	at least 1st trimester	prospective cohort	exposed to other treatment, sick excluded	Adjustment: No	0.72 [0.27;1.96] ^C excluded (control group)	5/139 20/406	25	139		ref
S7773 R22982	Vajda (Levetiracetam) (Controls unexposed, sick), 2019	Fetal malformations	at least 1st trimester	prospective cohort	unexposed, sick	Adjustment: No	1.27 [0.37;4.29]	5/139 5/176	10	139		ref
S8038 R24455	Koc (Levetiracetam), 2018	Major congenital malformations	during pregnancy (anytime or not specified) excluded	retrospective cohort	unexposed, sick	Adjustment: No	1.11 [0.02;57.82] ^C excluded (exposition period)	0/28 0/31	0	28		ref
S7651 R22630	Tomson (Levetiracetam), 2018	Major congenital malformation	at least 1st trimester	prospective cohort	exposed to other treatment, sick	Adjustment: No	0.96 [0.56;1.64] ^C	17/599 74/2,514	91	599		ref
S10278 R37621	Razaz (Levetiracetam) (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	1.15 [0.26;5.08] ^C excluded (control group)	2/40 22/503	24	40		ref
S10277 R37620	Razaz (Levetiracetam) (Controls unexposed, disease free), 2017	Major malformations	during pregnancy (anytime or not specified)	population based cohort retrospective	unexposed, disease free excluded	Adjustment: No	1.55 [0.38;6.45] ^C excluded (control group)	2/40 46,632/1,424,279	46,634	40		ref
S10276 R37619	Razaz (Levetiracetam) (Controls unexposed, sick), 2017	Major malformations	during pregnancy (anytime or not specified) excluded	population based cohort retrospective	unexposed, sick	Adjustment: No	1.08 [0.26;4.54] ^C excluded (exposition period)	2/40 87/1,868	89	40		ref
S301 R16635	Arkilo (Levetiracetam), 2015	Major malformations	during pregnancy (anytime or not specified) excluded	retrospective cohort	exposed to other treatment, sick	Adjustment: No	2.24 [0.04;120.61] ^C excluded (exposition period)	0/11 0/24	0	11		ref
S6240 R16453	Babic (Levetiracetam), 2014	Major congential malformations	during pregnancy (anytime or not specified) excluded	prospective cohort	exposed to other treatment, sick	Adjustment: No	2.14 [0.03;131.94] ^C excluded (exposition period)	0/4 0/8	0	4		ref
S6330 R17152	Veiby (Levetiracetam) (Controls exposed to Lamotrigine, sick), 2014	Major malformations	throughout pregnancy	population based cohort retrospective	exposed to other treatment, sick excluded	Adjustment: No Partial overlapping	0.44 [0.10;1.90] ^C excluded (control group)	2/114 23/593	25	114		ref
S6331 R17153	Veiby (Levetiracetam) (Controls unexposed, disease free), 2014	Major malformations	throughout pregnancy	population based cohort retrospective	unexposed, disease free excluded	Adjustment: Yes Partial overlapping	0.66 [0.16;2.67] excluded (control group)	2/114 22,371/771,412	22,373	114		ref
S6332 R17154	Veiby (Levetiracetam) (Controls unexposed, sick), 2014	Major malformations	throughout pregnancy	population based cohort retrospective	unexposed, sick	Adjustment: No Partial overlapping	0.62 [0.15;2.53] ^C	2/114 106/3,773	108	114		ref
S5938 R15200	Hernández-Díaz (Levetiracetam) (Controls exposed to Lamotrigine, sick), 2012	Major congenital malformations	1st trimester	prospective cohort	exposed to other treatment, sick excluded	Adjustment: No Controls: mixed indications	0.80 [0.30;2.10] excluded (control group)	-/- -/-	-	-		ref
S7933 R24009	Hernández-Díaz (Levetiracetam) (Controls unexposed, disease free), 2012	Major congenital malformations	1st trimester	prospective cohort	unexposed, disease free	Adjustment: No	2.20 [0.80;6.40]	11/450 5/442	16	450		ref
S6063 R15765	Morrow (Levetiracetam) (Controls exposed to Lamotrigine, sick), 2006	Major congenital malformation	1st trimester	prospective cohort	exposed to other treatment, sick excluded	Adjustment: No	0.68 [0.04;11.54] ^C excluded (control group)	0/22 21/647	21	22		ref
S6064 R15772	Morrow (Levetiracetam) (Controls unexposed, sick), 2006	Major congenital malformation	1st trimester	prospective cohort	unexposed, sick	Adjustment: No	0.60 [0.03;10.72] ^C	0/22 8/227	8	22		ref
					Total	11 studies	1.01 [0.78;1.31]		148,227	2,681
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: Levetiracetam) (Epilepsy) (Controls unexposed, NOS; 2: Levetiracetam; 3: Levetiracetam) (Controls unexposed, sick; 4: Levetiracetam) (Controls unexposed, sick; 5: Levetiracetam) (Controls unexposed, sick; 6: Levetiracetam; 7: Levetiracetam) (Controls unexposed, sick; 8: Levetiracetam; 9: Levetiracetam) (Controls unexposed, sick; 10: Levetiracetam) (Controls unexposed, disease free; 11: Levetiracetam) (Controls unexposed, sick;

Sensitivity analysis

Publication bias and p-hacking diagnosis

funnel plot

Asymetry test p-value = 0.9365 (by Egger's regression)

slope=0.0016 (0.1344); intercept=0.0252 (0.3077); t=0.0819; p=0.9365

p values plot

Sub-groups analysis using all included studies

excluded 6063, 5938, 6330, 6331, 10278, 10277, 7772, 7999, 7505, 7495, 12688, 12884, 12824, 7547, 15842, 15825, 15854

S15842 R65221	Bromley (Levetiracetam) (Controls exposed to LTG), 2023	Major congenital anomaly (68)	during pregnancy (anytime or not specified)	exposed to other treatment, sick	1.01 [0.16;6.20]	2/70 3/106
S15843 R65234	Bromley (Levetiracetam) (Controls unexposed, sick), 2023	Major congenital anomaly (68)	during pregnancy (anytime or not specified)	unexposed, sick	0.75 [0.12;4.65]	2/70 3/80
S15825 R65173	Cohen (Levetiracetam) (Epilepsy) (Controls exposed to LTG), 2023	Major congenital malformations (excluding genetic/chromosomal) (68)	1st trimester	exposed to other treatment, sick	0.78 [0.53;1.13]	30/1040 314/8339
S15826 R65175	Cohen (Levetiracetam) (Epilepsy) (Controls unexposed, NOS), 2023	Major congenital malformations (excluding genetic/chromosomal) (68)	1st trimester	unexposed (general population or NOS)	0.95 [0.66;1.36]	30/1040 147928/4866362
S15854 R65264	Li (Levetiracetam) (Controls exposed to LTG), 2023	Major congenital malformation (68)	during pregnancy (anytime or not specified)	exposed to other treatment, sick	0.35 [0.01;18.06]	0/107 0/38
S15855 R65266	Li (Levetiracetam) (Controls unexposed, sick), 2023	Major congenital malformation (68)	during pregnancy (anytime or not specified)	unexposed, sick	0.15 [0.01;2.72]	0/107 7/253
S12502 R47876	Mari (Levetiracetam), 2022	Major foetal malformation (68)	throughout pregnancy	exposed to other treatment, sick	0.64 [0.01;34.59]	0/17 0/11
S12688 R47924	Alsfouk (Levetiracetam) (Controls exposed to Lamotrigine, sick), 2021	Major congenital malformation (68)	during pregnancy (anytime or not specified)	exposed to other treatment, sick	0.11 [0.00;2.39]	0/24 2/15
S12686 R47922	Alsfouk (Levetiracetam) (Controls unexposed, sick), 2021	Major congenital malformation (68)	during pregnancy (anytime or not specified)	unexposed, sick	0.40 [0.02;10.39]	0/24 1/30
S12884 R48689	Hosny (Levetiracetam) (Controls exposed to Lamotrigine, sick), 2021	Major birth defects (68)	1st trimester	exposed to other treatment, sick	0.04 [0.00;2.38]	2/67 0/1
S12885 R48692	Hosny (Levetiracetam) (Controls unexposed, sick), 2021	Major birth defects (68)	1st trimester	unexposed, sick	0.62 [0.05;7.15]	2/67 1/21
S12824 R48265	Thomas (Levetiracetam) (Controls exposed to Lamotrigine, sick), 2021	Major congenital malformations (68)	1st trimester	exposed to other treatment, sick	2.43 [0.28;21.33]	5/106 1/50
S7547 R22590	Thomas (Levetiracetam) (Controls unexposed, disease free), 2021	Major congenital malformations (68)	1st trimester	unexposed, disease free	0.97 [0.13;7.23]	1/30 11/319
S12823 R48255	Thomas (Levetiracetam) (Controls unexposed, sick), 2021	Major congenital malformations (68)	1st trimester	unexposed, sick	1.16 [0.40;3.10]	5/106 16/340
S7999 R24366	AlSheikh (Levetiracetam) (Controls exposed to Lamotrigine, sick), 2020	Fetal/neonatal malformation (68)	during pregnancy (anytime or not specified)	exposed to other treatment, sick	2.29 [0.04;125.50]	0/9 0/20
S8000 R24368	AlSheikh (Levetiracetam) (Controls unexposed, sick), 2020	Fetal/neonatal malformation (68)	during pregnancy (anytime or not specified)	unexposed, sick	0.25 [0.01;7.34]	0/9 1/8
S7505 R22452	Meador (Levetiracetam) (Controls exposed to Lamotrigine, sick), 2020	Major congenital malformations (68)	1st trimester	exposed to other treatment, sick	1.14 [0.32;4.07]	5/97 5/110
S7495 R22422	Meador (Levetiracetam) (Controls unexposed, disease free), 2020	Major congenital malformations (68)	1st trimester	unexposed, disease free	2.83 [0.54;14.92]	5/97 2/106
S7501 R22440	Meador (Levetiracetam) (Controls unexposed, sick), 2020	Major congenital malformations (68)	1st trimester	unexposed, sick	0.76 [0.08;7.00]	5/97 1/15
S7511 R27734	Huber-Mollema (Levetiracetam), 2019	Congenital malformations (68)	throughout pregnancy	exposed to other treatment, sick	1.50 [0.26;8.64]	2/30 4/88
S7772 R22981	Vajda (Levetiracetam) (Controls exposed to Lamotrigine, sick), 2019	Fetal malformations (68)	at least 1st trimester	exposed to other treatment, sick	0.72 [0.27;1.96]	5/139 20/406
S7773 R22982	Vajda (Levetiracetam) (Controls unexposed, sick), 2019	Fetal malformations (68)	at least 1st trimester	unexposed, sick	1.27 [0.37;4.29]	5/139 5/176
S8038 R24455	Koc (Levetiracetam), 2018	Major congenital malformations (68)	during pregnancy (anytime or not specified)	unexposed, sick	1.11 [0.02;57.82]	0/28 0/31
S7651 R22630	Tomson (Levetiracetam), 2018	Major congenital malformation (68)	at least 1st trimester	exposed to other treatment, sick	0.96 [0.56;1.64]	17/599 74/2514
S10278 R37621	Razaz (Levetiracetam) (Controls exposed to Lamotrigine, sick), 2017	Major malformations (68)	during pregnancy (anytime or not specified)	exposed to other treatment, sick	1.15 [0.26;5.08]	2/40 22/503
S10277 R37620	Razaz (Levetiracetam) (Controls unexposed, disease free), 2017	Major malformations (68)	during pregnancy (anytime or not specified)	unexposed, disease free	1.55 [0.38;6.45]	2/40 46632/1424279
S10276 R37619	Razaz (Levetiracetam) (Controls unexposed, sick), 2017	Major malformations (68)	during pregnancy (anytime or not specified)	unexposed, sick	1.08 [0.26;4.54]	2/40 87/1868
S301 R16635	Arkilo (Levetiracetam), 2015	Major malformations (68)	during pregnancy (anytime or not specified)	exposed to other treatment, sick	2.24 [0.04;120.61]	0/11 0/24
S6240 R16453	Babic (Levetiracetam), 2014	Major congential malformations (68)	during pregnancy (anytime or not specified)	exposed to other treatment, sick	2.14 [0.03;131.94]	0/4 0/8
S6330 R17152	Veiby (Levetiracetam) (Controls exposed to Lamotrigine, sick), 2014	Major malformations (68)	throughout pregnancy	exposed to other treatment, sick	0.44 [0.10;1.90]	2/114 23/593
S6331 R17153	Veiby (Levetiracetam) (Controls unexposed, disease free), 2014	Major malformations (68)	throughout pregnancy	unexposed, disease free	0.66 [0.16;2.67]	2/114 22371/771412
S6332 R17154	Veiby (Levetiracetam) (Controls unexposed, sick), 2014	Major malformations (68)	throughout pregnancy	unexposed, sick	0.62 [0.15;2.53]	2/114 106/3773
S5938 R15200	Hernández-Díaz (Levetiracetam) (Controls exposed to Lamotrigine, sick), 2012	Major congenital malformations (68)	1st trimester	exposed to other treatment, sick	0.80 [0.30;2.10]	-9/-9 -9/-9
S7933 R24009	Hernández-Díaz (Levetiracetam) (Controls unexposed, disease free), 2012	Major congenital malformations (68)	1st trimester	unexposed, disease free	2.20 [0.80;6.40]	11/450 5/442
S6063 R15765	Morrow (Levetiracetam) (Controls exposed to Lamotrigine, sick), 2006	Major congenital malformation (68)	1st trimester	exposed to other treatment, sick	0.68 [0.04;11.54]	0/22 21/647
S6064 R15772	Morrow (Levetiracetam) (Controls unexposed, sick), 2006	Major congenital malformation (68)	1st trimester	unexposed, sick	0.60 [0.03;10.72]	0/22 8/227