Levetiracetam (All indications)

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.
S15220 R62422	Bromley (Levetiracetam) (Epilepsy) (Controls exposed to LTG), 2023	Any congenital anomaly	during pregnancy (anytime or not specified)	prospective cohort	exposed to other treatment, sick excluded	Adjustment: No	0.52 [0.16;1.71] ^C excluded (control group)	4/70 11/106	15	70		ref
S15219 R62409	Bromley (Levetiracetam) (Epilepsy) (Controls unexposed, sick), 2023	Any congenital anomaly	during pregnancy (anytime or not specified) excluded	prospective cohort	unexposed, sick	Adjustment: No	1.15 [0.28;4.79] ^C excluded (exposition period)	4/70 4/80	8	70		ref
S15204 R62377	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
S15205 R62378	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
S15260 R62764	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
S15259 R62765	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
S15212 R62386	Pekoz (Levetiracetam) (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	3.24 [0.87;12.02] ^C excluded (control group)	10/152 3/141	13	152		ref
S15211 R62385	Pekoz (Levetiracetam) (Epilepsy) (Controls unexposed, sick), 2023	Congenital malformations (major and minor)	during pregnancy (anytime or not specified) excluded	prospective cohort	unexposed, sick	Adjustment: No	2.96 [0.37;23.78] ^C excluded (exposition period)	10/152 1/43	11	152		ref
S12676 R48761	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
S10227 R37467	The NAAED (Controls exposed to Lamotrigine, sick) (Indications NOS), 2022	Major congenital malformations	1st trimester	prospective cohort	exposed to other treatment, sick excluded	Adjustment: No	0.99 [0.59;1.66] ^C excluded (control group)	22/1,179 44/2,333	66	1,179		ref
S10228 R37469	The NAAED (Controls unexposed, disease free) (Indications NOS), 2022	Major congenital malformations	1st trimester	prospective cohort	unexposed, disease free	Adjustment: No	1.88 [0.93;3.82] ^C	22/1,179 12/1,201	34	1,179		ref
S12687 R48758	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
S12685 R48759	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
S12886 R48697	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
S12887 R48700	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
S12825 R48276	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
S12826 R48284	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
S12827 R48288	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
S8980 R30464	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
S8981 R30467	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
S8986 R30518	Aydin (Levetiracetam) (Controls exposed to Lamotrigine, sick), 2020	Congenital chromosomal/structural anomalies	throughout pregnancy	retrospective cohort	exposed to other treatment, sick excluded	Adjustment: No	0.68 [0.01;39.07] ^C excluded (control group)	0/10 0/7	0	10		ref
S8987 R30528	Aydin (Levetiracetam) (Controls unexposed, sick), 2020	Congenital chromosomal/structural anomalies	throughout pregnancy	retrospective cohort	unexposed, sick	Adjustment: No	2.26 [0.04;122.79] ^C	0/10 0/22	0	10		ref
S8995 R30553	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
S8996 R30557	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
S8997 R30561	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
S9022 R30761	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
S9011 R35149	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
S9012 R35150	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
S9001 R30574	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
S9010 R30656	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
S9029 R30785	Bank (Levetiracetam) (Mixed indications), 2017	Major Malformation	during pregnancy (anytime or not specified) excluded	prospective cohort	exposed to other treatment, sick	Adjustment: No	5.46 [0.10;300.64] ^C excluded (exposition period)	0/7 0/36	0	7		ref
S8982 R30474	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
S8988 R30533	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
S8998 R30565	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
S8999 R30567	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
S9000 R30570	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
S8993 R30547	Källén (Levetiracetam) (Controls exposed to Lamotrigine, sick) (Indications NOS), 2013	Relatively severe malformations	early pregnancy	population based cohort retrospective	exposed to other treatment, sick excluded	Adjustment: No Partial overlapping	0.51 [0.07;3.75] ^C excluded (control group)	1/57 37/1,084	38	57		ref
S8994 R30549	Källén (Levetiracetam) (Controls unexposed, NOS) (Indications NOS), 2013	Relatively severe malformations	early pregnancy	population based cohort retrospective	unexposed (general population or NOS)	Adjustment: No Partial overlapping	0.55 [0.08;3.98] ^C	1/57 49,499/1,575,847	49,500	57		ref
S9002 R30582	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
S9003 R30584	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	13 studies	1.04 [0.81;1.33]		197,745	3,477
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: Controls unexposed, disease free) (Indications NOS; 4: Levetiracetam) (Controls unexposed, sick; 5: Levetiracetam) (Controls unexposed, sick; 6: Levetiracetam) (Controls unexposed, sick; 7: Levetiracetam) (Controls unexposed, sick; 8: Levetiracetam; 9: Levetiracetam) (Controls unexposed, sick; 10: Levetiracetam; 11: Levetiracetam) (Controls unexposed, sick; 12: Levetiracetam) (Controls unexposed, NOS) (Indications NOS; 13: Levetiracetam) (Controls unexposed, sick;

Sensitivity analysis

Publication bias and p-hacking diagnosis

funnel plot

Asymetry test p-value = 0.7916 (by Egger's regression)

slope=0.0636 (0.1323); intercept=-0.0789 (0.2913); t=0.2708; p=0.7916

p values plot

Sub-groups analysis using all included studies

excluded 9002, 8993, 8998, 8999, 9011, 8980, 8986, 8995, 8996, 12687, 12886, 12825, 12826, 10227, 15220, 15204, 15260, 15212

S15220 R62422	Bromley (Levetiracetam) (Epilepsy) (Controls exposed to LTG), 2023	Any congenital anomaly (67)	during pregnancy (anytime or not specified)	exposed to other treatment, sick	0.52 [0.16;1.71]	4/70 11/106
S15219 R62409	Bromley (Levetiracetam) (Epilepsy) (Controls unexposed, sick), 2023	Any congenital anomaly (67)	during pregnancy (anytime or not specified)	unexposed, sick	1.15 [0.28;4.79]	4/70 4/80
S15204 R62377	Cohen (Levetiracetam) (Epilepsy) (Controls exposed to LTG), 2023	Major congenital malformations (excluding genetic/chromosomal) (67)	1st trimester	exposed to other treatment, sick	0.78 [0.53;1.13]	30/1040 314/8339
S15205 R62378	Cohen (Levetiracetam) (Epilepsy) (Controls unexposed, NOS), 2023	Major congenital malformations (excluding genetic/chromosomal) (67)	1st trimester	unexposed (general population or NOS)	0.95 [0.66;1.36]	30/1040 147928/4866362
S15260 R62764	Li (Levetiracetam) (Controls exposed to LTG), 2023	Major congenital malformation (67)	during pregnancy (anytime or not specified)	exposed to other treatment, sick	0.35 [0.01;18.06]	0/107 0/38
S15259 R62765	Li (Levetiracetam) (Controls unexposed, sick), 2023	Major congenital malformation (67)	during pregnancy (anytime or not specified)	unexposed, sick	0.15 [0.01;2.72]	0/107 7/253
S15212 R62386	Pekoz (Levetiracetam) (Epilepsy) (Controls exposed to LTG), 2023	Congenital malformations (major and minor) (67)	during pregnancy (anytime or not specified)	exposed to other treatment, sick	3.24 [0.87;12.02]	10/152 3/141
S15211 R62385	Pekoz (Levetiracetam) (Epilepsy) (Controls unexposed, sick), 2023	Congenital malformations (major and minor) (67)	during pregnancy (anytime or not specified)	unexposed, sick	2.96 [0.37;23.78]	10/152 1/43
S12676 R48761	Mari (Levetiracetam), 2022	Major foetal malformation (67)	throughout pregnancy	exposed to other treatment, sick	0.64 [0.01;34.59]	0/17 0/11
S10227 R37467	The NAAED (Controls exposed to Lamotrigine, sick) (Indications NOS), 2022	Major congenital malformations (67)	1st trimester	exposed to other treatment, sick	0.99 [0.59;1.66]	22/1179 44/2333
S10228 R37469	The NAAED (Controls unexposed, disease free) (Indications NOS), 2022	Major congenital malformations (67)	1st trimester	unexposed, disease free	1.88 [0.93;3.82]	22/1179 12/1201
S12687 R48758	Alsfouk (Levetiracetam) (Controls exposed to Lamotrigine, sick), 2021	Major congenital malformation (67)	during pregnancy (anytime or not specified)	exposed to other treatment, sick	0.11 [0.00;2.39]	0/24 2/15
S12685 R48759	Alsfouk (Levetiracetam) (Controls unexposed, sick), 2021	Major congenital malformation (67)	during pregnancy (anytime or not specified)	unexposed, sick	0.40 [0.02;10.39]	0/24 1/30
S12886 R48697	Hosny (Levetiracetam) (Controls exposed to Lamotrigine, sick), 2021	Major birth defects (67)	1st trimester	exposed to other treatment, sick	0.04 [0.00;2.38]	2/67 0/1
S12887 R48700	Hosny (Levetiracetam) (Controls unexposed, sick), 2021	Major birth defects (67)	1st trimester	unexposed, sick	0.62 [0.05;7.15]	2/67 1/21
S12825 R48276	Thomas (Levetiracetam) (Controls exposed to Lamotrigine, sick), 2021	Major congenital malformations (67)	1st trimester	exposed to other treatment, sick	2.43 [0.28;21.33]	5/106 1/50
S12826 R48284	Thomas (Levetiracetam) (Controls unexposed, disease free), 2021	Major congenital malformations (67)	1st trimester	unexposed, disease free	0.97 [0.13;7.23]	1/30 11/319
S12827 R48288	Thomas (Levetiracetam) (Controls unexposed, sick), 2021	Major congenital malformations (67)	1st trimester	unexposed, sick	1.16 [0.40;3.10]	5/106 16/340
S8980 R30464	AlSheikh (Levetiracetam) (Controls exposed to Lamotrigine, sick), 2020	Fetal/neonatal malformation (67)	during pregnancy (anytime or not specified)	exposed to other treatment, sick	2.29 [0.04;125.50]	0/9 0/20
S8981 R30467	AlSheikh (Levetiracetam) (Controls unexposed, sick), 2020	Fetal/neonatal malformation (67)	during pregnancy (anytime or not specified)	unexposed, sick	0.25 [0.01;7.34]	0/9 1/8
S8986 R30518	Aydin (Levetiracetam) (Controls exposed to Lamotrigine, sick), 2020	Congenital chromosomal/structural anomalies (67)	throughout pregnancy	exposed to other treatment, sick	0.68 [0.01;39.07]	0/10 0/7
S8987 R30528	Aydin (Levetiracetam) (Controls unexposed, sick), 2020	Congenital chromosomal/structural anomalies (67)	throughout pregnancy	unexposed, sick	2.26 [0.04;122.79]	0/10 0/22
S8995 R30553	Meador (Levetiracetam) (Controls exposed to Lamotrigine, sick), 2020	Major congenital malformations (67)	1st trimester	exposed to other treatment, sick	1.14 [0.32;4.07]	5/97 5/110
S8996 R30557	Meador (Levetiracetam) (Controls unexposed, disease free), 2020	Major congenital malformations (67)	1st trimester	unexposed, disease free	2.83 [0.54;14.92]	5/97 2/106
S8997 R30561	Meador (Levetiracetam) (Controls unexposed, sick), 2020	Major congenital malformations (67)	1st trimester	unexposed, sick	0.76 [0.08;7.00]	5/97 1/15
S9022 R30761	Huber-Mollema (Levetiracetam), 2019	Congenital malformations (67)	throughout pregnancy	exposed to other treatment, sick	1.50 [0.26;8.64]	2/30 4/88
S9011 R35149	Vajda (Levetiracetam) (Controls exposed to Lamotrigine, sick), 2019	Fetal malformations (67)	at least 1st trimester	exposed to other treatment, sick	0.72 [0.27;1.96]	5/139 20/406
S9012 R35150	Vajda (Levetiracetam) (Controls unexposed, sick), 2019	Fetal malformations (67)	at least 1st trimester	unexposed, sick	1.27 [0.37;4.29]	5/139 5/176
S9001 R30574	Koc (Levetiracetam), 2018	Major congenital malformations (67)	during pregnancy (anytime or not specified)	unexposed, sick	1.11 [0.02;57.82]	0/28 0/31
S9010 R30656	Tomson (Levetiracetam), 2018	Major congenital malformation (67)	at least 1st trimester	exposed to other treatment, sick	0.96 [0.56;1.64]	17/599 74/2514
S9029 R30785	Bank (Levetiracetam) (Mixed indications), 2017	Major Malformation (67)	during pregnancy (anytime or not specified)	exposed to other treatment, sick	5.46 [0.10;300.64]	0/7 0/36
S8982 R30474	Arkilo (Levetiracetam), 2015	Major malformations (67)	during pregnancy (anytime or not specified)	exposed to other treatment, sick	2.24 [0.04;120.61]	0/11 0/24
S8988 R30533	Babic (Levetiracetam), 2014	Major congential malformations (67)	during pregnancy (anytime or not specified)	exposed to other treatment, sick	2.14 [0.03;131.94]	0/4 0/8
S8998 R30565	Veiby (Levetiracetam) (Controls exposed to Lamotrigine, sick), 2014	Major malformations (67)	throughout pregnancy	exposed to other treatment, sick	0.44 [0.10;1.90]	2/114 23/593
S8999 R30567	Veiby (Levetiracetam) (Controls unexposed, disease free), 2014	Major malformations (67)	throughout pregnancy	unexposed, disease free	0.66 [0.16;2.67]	2/114 22371/771412
S9000 R30570	Veiby (Levetiracetam) (Controls unexposed, sick), 2014	Major malformations (67)	throughout pregnancy	unexposed, sick	0.62 [0.15;2.53]	2/114 106/3773
S8993 R30547	Källén (Levetiracetam) (Controls exposed to Lamotrigine, sick) (Indications NOS), 2013	Relatively severe malformations (67)	early pregnancy	exposed to other treatment, sick	0.51 [0.07;3.75]	1/57 37/1084
S8994 R30549	Källén (Levetiracetam) (Controls unexposed, NOS) (Indications NOS), 2013	Relatively severe malformations (67)	early pregnancy	unexposed (general population or NOS)	0.55 [0.08;3.98]	1/57 49499/1575847
S9002 R30582	Morrow (Levetiracetam) (Controls exposed to Lamotrigine, sick), 2006	Major congenital malformation (67)	1st trimester	exposed to other treatment, sick	0.68 [0.04;11.54]	0/22 21/647
S9003 R30584	Morrow (Levetiracetam) (Controls unexposed, sick), 2006	Major congenital malformation (67)	1st trimester	unexposed, sick	0.60 [0.03;10.72]	0/22 8/227