Topiramate (Epilepsy)

Major congenital malformations

id	Study   Auto Li (Topiramate) (Controls exposed to LTG), 2023Li (Topiramate) (Controls unexposed, sick), 2023Alsfouk (Topiramate) (Controls exposed to Lamotrigine, sick), 2021Alsfouk (Topiramate) (Controls unexposed, sick), 2021Thomas (Topiramate) (Controls exposed to Lamotrigine, sick), 2021Thomas (Topiramate) (Controls unexposed, disease free), 2021Thomas (Topiramate) (Controls unexposed, sick), 2021AlSheikh (Topiramate) (Controls exposed to Lamotrigine, sick), 2020AlSheikh (Topiramate) (Controls unexposed, sick), 2020Meador (Topiramate) (Controls exposed to Lamotrigine, sick), 2020Meador (Topiramate) (Controls unexposed, disease free), 2020Meador (Topiramate) (Controls unexposed, sick), 2020Vajda (Topiramate) (Controls exposed to Lamotrigine, sick), 2019Vajda (Topiramate) (Controls unexposed, sick), 2019Tomson (Topiramate), 2018Razaz (Topiramate) (Controls exposed to Lamotrigine, sick), 2017Razaz (Topiramate) (Controls unexposed, disease free), 2017Razaz (Topiramate) (Controls unexposed, sick), 2017Arkilo (Topiramate), 2015Babic (Topiramate), 2014Veiby (Topiramate) (Controls exposed to Lamotrigine, sick), 2014Veiby (Topiramate) (Controls unexposed, disease free), 2014Veiby (Topiramate) (Controls unexposed, sick), 2014Hernández-Díaz (Topiramate), 2012Mawer (Topiramate) (Controls exposed to Lamotrigine, sick), 2010Mawer (Topiramate) (Controls unexposed, disease free), 2010Mawer (Topiramate) (Controls unexposed, sick), 2010Ornoy (Topiramate), 2008Morrow (Topiramate) (Controls exposed to Lamotrigine, sick), 2006Morrow (Topiramate) (Controls unexposed, sick), 2006	Lib. in paper	Exposition period  Auto during pregnancy (anytime or not specified)1st trimester2nd trimester3rd trimester2nd and/or 3rd trimesterthroughout pregnancyearly pregnancydays before deliverylate pregnancypreconception-onlypericonceptionalpreconceptional for kinetic reasonat least 1st trimester3 months (or more) before pregnancy or during pregnancy1st and 2nd trimester3 months or more before pregnancy or1st trimester	Study type  All studies Case control excluded Only case control	Control type    Auto unexposed (general population or NOS)unexposed, sickunexposed, disease freeexposed to other treatment, sicknot specifiedwhatever (meta-analysis)	Tags	OR 95%CI	x1/n1 x0/n0	no cases	no exposed	ROB	Ref.
S15860 R65276	Li (Topiramate) (Controls exposed to LTG), 2023	Major congenital malformation	during pregnancy (anytime or not specified)	prospective cohort	exposed to other treatment, sick excluded	Adjustment: No	20.45 [0.74;567.72] C excluded (control group)	1/7   0/38	1	7		ref
S15861 R65278	Li (Topiramate) (Controls unexposed, sick), 2023	Major congenital malformation	during pregnancy (anytime or not specified) excluded	prospective cohort	unexposed, sick	Adjustment: No	5.86 [0.62;55.37] C excluded (exposition period)	1/7   7/253	8	7		ref
S12694 R47930	Alsfouk (Topiramate) (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	1.67 [0.05;53.93] C excluded (control group)	0/2   2/15	2	2		ref
S12696 R47932	Alsfouk (Topiramate) (Controls unexposed, sick), 2021	Major congenital malformation	during pregnancy (anytime or not specified) excluded	retrospective cohort	unexposed, sick	Adjustment: No	6.33 [0.17;231.15] C excluded (exposition period)	0/2   1/30	1	2		ref
S12871 R48601	Thomas (Topiramate) (Controls exposed to Lamotrigine, sick), 2021	Major congenital malformations	1st trimester	prospective cohort	exposed to other treatment, sick excluded	Adjustment: No	1.90 [0.07;50.68] C excluded (control group)	0/9   1/50	1	9		ref
S7555 R22594	Thomas (Topiramate) (Controls unexposed, disease free), 2021	Major congenital malformations	1st trimester	prospective cohort	unexposed, disease free excluded	Adjustment: No	2.43 [0.13;46.65] C excluded (control group)	0/6   11/319	11	6		ref
S12872 R48611	Thomas (Topiramate) (Controls unexposed, sick), 2021	Major congenital malformations	1st trimester	prospective cohort	unexposed, sick	Adjustment: No	1.15 [0.06;20.85] C	0/9   16/340	16	9		ref
S8004 R24376	AlSheikh (Topiramate) (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
S8005 R24378	AlSheikh (Topiramate) (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
S7507 R22458	Meador (Topiramate) (Controls exposed to Lamotrigine, sick), 2020	Major congenital malformations	1st trimester	prospective cohort	exposed to other treatment, sick excluded	Adjustment: No	4.20 [0.41;43.04] C excluded (control group)	1/6   5/110	6	6		ref
S7498 R22431	Meador (Topiramate) (Controls unexposed, disease free), 2020	Major congenital malformations	1st trimester	prospective cohort	unexposed, disease free excluded	Adjustment: No	10.40 [0.80;134.90] C excluded (control group)	1/6   2/106	3	6		ref
S7503 R22446	Meador (Topiramate) (Controls unexposed, sick), 2020	Major congenital malformations	1st trimester	prospective cohort	unexposed, sick	Adjustment: No	2.80 [0.15;53.71] C	1/6   1/15	2	6		ref
S7781 R22990	Vajda (Topiramate) (Controls exposed to Lamotrigine, sick), 2019	Fetal malformations	at least 1st trimester	prospective cohort	exposed to other treatment, sick excluded	Adjustment: No	0.37 [0.05;2.82] C excluded (control group)	1/53   20/406	21	53		ref
S7782 R22991	Vajda (Topiramate) (Controls unexposed, sick), 2019	Fetal malformations	at least 1st trimester	prospective cohort	unexposed, sick	Adjustment: No	0.66 [0.09;5.96]	1/53   5/176	6	53		ref
S7662 R22676	Tomson (Topiramate), 2018	Major congenital malformation	at least 1st trimester	prospective cohort	exposed to other treatment, sick	Adjustment: No	1.36 [0.58;3.17] C	6/152   74/2,514	80	152		ref
S10275 R37618	Razaz (Topiramate) (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	3.12 [0.87;11.27] C excluded (control group)	3/24   22/503	25	24		ref
S10274 R37617	Razaz (Topiramate) (Controls unexposed, disease free), 2017	Major malformations	during pregnancy (anytime or not specified)	population based cohort retrospective	unexposed, disease free excluded	Adjustment: No	4.22 [1.26;14.15] C excluded (control group)	3/24   46,632/1,424,279	46,635	24		ref
S10273 R37616	Razaz (Topiramate) (Controls unexposed, sick), 2017	Major malformations	during pregnancy (anytime or not specified) excluded	population based cohort retrospective	unexposed, sick	Adjustment: No	2.92 [0.86;9.99] C excluded (exposition period)	3/24   87/1,868	90	24		ref
S6251 R16641	Arkilo (Topiramate), 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
S6239 R16451	Babic (Topiramate), 2014	Major congential malformations	during pregnancy (anytime or not specified) excluded	prospective cohort	exposed to other treatment, sick	Adjustment: No	15.00 [0.12;1923.88] C excluded (exposition period)	0/1   0/8	0	1		ref
S6315 R17137	Veiby (Topiramate) (Controls exposed to Lamotrigine, sick), 2014	Major malformations	throughout pregnancy	population based cohort retrospective	exposed to other treatment, sick excluded	Adjustment: No	1.21 [0.28;5.31] C excluded (control group)	2/43   23/593	25	43		ref
S5528 R17091	Veiby (Topiramate) (Controls unexposed, disease free), 2014	Major malformations	throughout pregnancy	population based cohort retrospective	unexposed, disease free excluded	Adjustment: Yes	1.84 [0.44;7.62] excluded (control group)	2/43   22,371/771,412	22,373	43		ref
S6312 R17134	Veiby (Topiramate) (Controls unexposed, sick), 2014	Major malformations	throughout pregnancy	population based cohort retrospective	unexposed, sick	Adjustment: No	1.69 [0.40;7.07] C	2/43   106/3,773	108	43		ref
S8253 R26071	Hernández-Díaz (Topiramate), 2012	Major congenital malformations	1st trimester	prospective cohort	exposed to other treatment, sick	Adjustment: No Controls: mixed indications	3.10 [1.60;5.90]	-/-   -/-	-	-		ref
S8289 R26231	Mawer (Topiramate) (Controls exposed to Lamotrigine, sick), 2010	Major malformations	1st trimester	prospective cohort	exposed to other treatment, sick excluded	Adjustment: No	2.76 [0.10;74.58] C excluded (control group)	0/3   2/37	2	3		ref
S8290 R26232	Mawer (Topiramate) (Controls unexposed, disease free), 2010	Major malformations	1st trimester	prospective cohort	unexposed, disease free excluded	Adjustment: No Matched	8.57 [0.37;196.88] C excluded (control group)	0/3   6/285	6	3		ref
S8294 R26238	Mawer (Topiramate) (Controls unexposed, sick), 2010	Major malformations	1st trimester	prospective cohort	unexposed, sick	Adjustment: No	5.27 [0.17;165.32] C	0/3   1/41	1	3		ref
S5510 R18922	Ornoy (Topiramate), 2008	Non-genetic anomalies	at least 1st trimester	prospective cohort	unexposed (general population or NOS)	Adjustment: No	1.44 [0.16;12.74] C	1/29   5/206	6	29		ref
S6061 R15757	Morrow (Topiramate) (Controls exposed to Lamotrigine, sick), 2006	Major congenital malformation	1st trimester	prospective cohort	exposed to other treatment, sick excluded	Adjustment: No	2.29 [0.51;10.30] C excluded (control group)	2/28   21/647	23	28		ref
S6062 R15764	Morrow (Topiramate) (Controls unexposed, sick), 2006	Major congenital malformation	1st trimester	prospective cohort	unexposed, sick	Adjustment: No	2.11 [0.42;10.45] C	2/28   8/227	10	28		ref
					Total	9 studies	2.06 [1.34;3.17]		229	323
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

Sensitivity analysis

Publication bias and p-hacking diagnosis

Sub-groups analysis using all included studies

excluded 6061, 8289, 8290, 6315, 5528, 10275, 10274, 7781, 8004, 7507, 7498, 12694, 12871, 7555, 15860