Topiramate (All indications)

Major congenital malformations

R analysis
id Study   Lib. in paper Exposition period    Study type 
 Control type 
 
Tags OR 95%CI x1/n1 x0/n0 no cases no exposed ROB Ref.
S15206
R62366		 Cohen (Topiramate) (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 1.81 [1.26;2.60]
excluded (control group) 		32/509   314/8,339 346 509
ref
S15207
R62367		 Cohen (Topiramate) (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 Partial overlapping 2.14 [1.50;3.06] C 32/509   147,928/4,866,362 147,960 509
ref
S15268
R62753		 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
S15269
R62754		 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
S8597
R28619		 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 2.61 [1.57;4.33] C
excluded (control group) 		24/503   44/2,333 68 503
ref
S8598
R28625		 The NAAED (Controls unexposed, disease free) (Indications NOS), 2022 Major congenital malformations 1st trimester prospective cohort unexposed, disease free Adjustment: No 4.96 [2.46;10.01] C 24/503   12/1,201 36 503
ref
S12693
R47929		 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
S12695
R47931		 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
S12873
R48621		 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
S12874
R48629		 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
S12875
R48633		 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
S8552
R28452		 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
S8553
R28455		 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
S8564
R28486		 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
S8565
R28490		 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
S8566
R28494		 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
S8576
R28535		 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
S8577
R28536		 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
S8575
R28525		 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
S8602
R28639		 Bank (Topiramate) (Mixed indications) , 2017 Major Malformation during pregnancy (anytime or not specified) excluded prospective cohort exposed to other treatment, sick Adjustment: No 23.67 [0.34;1653.93] C
excluded (exposition period) 		0/2   0/36 0 2
ref
S8554
R28458		 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
S8555
R28465		 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
S8594
R28609		 Veiby (Topiramate) (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 1.25 [0.29;5.41] C
excluded (control group) 		2/48   28/833 30 48
ref
S8595
R28613		 Veiby (Topiramate) (Controls unexposed, disease free) (Mixed indications), 2014 Major malformations throughout pregnancy population based cohort retrospective unexposed, disease free excluded Adjustment: Yes Partial overlapping 1.66 [0.40;6.85]
excluded (control group) 		2/48   22,371/771,412 22,373 48
ref
S8596
R28616		 Veiby (Topiramate) (Controls unexposed, sick) (Mixed indications), 2014 Major malformations throughout pregnancy population based cohort retrospective unexposed, sick Adjustment: No Controls: epilepsy indication Partial overlapping 1.50 [0.36;6.28] C 2/48   106/3,773 108 48
ref
S8559
R28474		 Källén (Topiramate) (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 3.95 [1.58;9.86] C
excluded (control group) 		6/49   37/1,084 43 49
ref
S8560
R28476		 Källén (Topiramate) (Controls unexposed, NOS) (Indications NOS), 2013 Relatively severe malformations early pregnancy population based cohort retrospective unexposed (general population or NOS) Adjustment: Yes Partial overlapping 3.73 [1.97;8.11] 6/49   49,499/1,575,847 49,505 49
ref
S8568
R28502		 Margulis (Topiramate) (Mixed indication), 2012 Major congenital malformations 1st trimester case control unexposed (general population or NOS) Adjustment: No Matched 1.01 [0.37;3.22] 15/21   33,605/48,972 33,620 21
ref
S8561
R28478		 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
S8562
R28480		 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
S8563
R28482		 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
S8571
R28517		 Ornoy (Topiramate), 2008 Non-genetic anomalies at least 1st trimester prospective cohort unexposed (general population or NOS) 1.44 [0.16;12.74] C 1/29   5/206 6 29
ref
S8569
R28507		 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
S8570
R28515		 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 12 studies 2.27 [1.66;3.10] 231,350 1,410
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

StudyTE95% CIn casesn exposedweightROBABCDEF Cohen (Topiramate) (Mixed indications) (Controls unexposed, NOS), 2023Cohen, 2023 1 2.14[1.50; 3.06]147,96050936%ROB confusion: criticalROB selection: lowROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate The NAAED (Controls unexposed, disease free) (Indications NOS), 2022The NAAED, 2022 2 4.96[2.46; 10.01]3650315%ROB confusion: criticalROB selection: unclearROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: low Thomas (Topiramate) (Controls unexposed, sick), 2021Thomas, 2021 3 1.15[0.06; 20.85]1691%ROB confusion: seriousROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Meador (Topiramate) (Controls unexposed, sick), 2020Meador, 2020 4 2.80[0.15; 53.71]261%ROB confusion: unclearROB selection: lowROB classification: lowROB missing: lowROB mesure: moderateROB reporting: low Vajda (Topiramate) (Controls unexposed, sick), 2019Vajda, 2019 5 0.66[0.09; 5.96]6532%ROB confusion: criticalROB selection: moderateROB classification: lowROB missing: moderateROB mesure: moderateROB reporting: moderate Tomson (Topiramate), 2018Tomson, 2018 6 1.36[0.58; 3.17]8015211%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Veiby (Topiramate) (Controls unexposed, sick) (Mixed indications), 2014Veiby, 2014 7 1.50[0.36; 6.28]108484%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: moderateROB mesure: moderateROB reporting: moderate Källén (Topiramate) (Controls unexposed, NOS) (Indications NOS), 2013Källén, 2013 8 3.73[1.97; 8.11]49,5054915%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Margulis (Topiramate) (Mixed indication), 2012Margulis, 2012 9 1.01[0.37; 3.22]33,620217%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Mawer (Topiramate) (Controls unexposed, sick), 2010Mawer, 2010 10 5.27[0.17; 165.32]131%ROB confusion: criticalROB selection: moderateROB classification: lowROB missing: moderateROB mesure: moderateROB reporting: moderate Ornoy (Topiramate), 2008Ornoy, 2008 11 1.44[0.16; 12.74]6292%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Morrow (Topiramate) (Controls unexposed, sick), 2006Morrow, 2006 12 2.11[0.42; 10.45]10284%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Total (12 studies) I2 = 13% 2.27[1.66; 3.10]231,3501,4100.220.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

1: Topiramate) (Mixed indications) (Controls unexposed, NOS; 2: Controls unexposed, disease free) (Indications NOS; 3: Topiramate) (Controls unexposed, sick; 4: Topiramate) (Controls unexposed, sick; 5: Topiramate) (Controls unexposed, sick; 6: Topiramate; 7: Topiramate) (Controls unexposed, sick) (Mixed indications; 8: Topiramate) (Controls unexposed, NOS) (Indications NOS; 9: Topiramate) (Mixed indication; 10: Topiramate) (Controls unexposed, sick; 11: Topiramate; 12: Topiramate) (Controls unexposed, sick;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 2.41[1.83; 3.18]197,7301,3893%NACohen (Topiramate) (Mixed indications) (Controls unexposed, NOS), 2023 The NAAED (Controls unexposed, disease free) (Indications NOS), 2022 Thomas (Topiramate) (Controls unexposed, sick), 2021 Meador (Topiramate) (Controls unexposed, sick), 2020 Vajda (Topiramate) (Controls unexposed, sick), 2019 Tomson (Topiramate), 2018 Veiby (Topiramate) (Controls unexposed, sick) (Mixed indications), 2014 Källén (Topiramate) (Controls unexposed, NOS) (Indications NOS), 2013 Mawer (Topiramate) (Controls unexposed, sick), 2010 Ornoy (Topiramate), 2008 Morrow (Topiramate) (Controls unexposed, sick), 2006 11 case control studiescase control studies 1.01[0.34; 2.98]33,62021 -NAMargulis (Topiramate) (Mixed indication), 2012 1 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 2.60[1.57; 4.32]231,1271,11153%NACohen (Topiramate) (Mixed indications) (Controls unexposed, NOS), 2023 The NAAED (Controls unexposed, disease free) (Indications NOS), 2022 Källén (Topiramate) (Controls unexposed, NOS) (Indications NOS), 2013 Margulis (Topiramate) (Mixed indication), 2012 Ornoy (Topiramate), 2008 5 unexposed, sickunexposed, sick 1.60[0.69; 3.70]1431470%NAThomas (Topiramate) (Controls unexposed, sick), 2021 Meador (Topiramate) (Controls unexposed, sick), 2020 Vajda (Topiramate) (Controls unexposed, sick), 2019 Veiby (Topiramate) (Controls unexposed, sick) (Mixed indications), 2014 Mawer (Topiramate) (Controls unexposed, sick), 2010 Morrow (Topiramate) (Controls unexposed, sick), 2006 6 exposed to other treatment, sickexposed to other treatment, sick 1.36[0.58; 3.17]80152 -NATomson (Topiramate), 2018 1 Tags Adjustment   - No  - No 2.09[1.47; 2.97]181,8391,33214%NACohen (Topiramate) (Mixed indications) (Controls unexposed, NOS), 2023 The NAAED (Controls unexposed, disease free) (Indications NOS), 2022 Thomas (Topiramate) (Controls unexposed, sick), 2021 Meador (Topiramate) (Controls unexposed, sick), 2020 Vajda (Topiramate) (Controls unexposed, sick), 2019 Tomson (Topiramate), 2018 Veiby (Topiramate) (Controls unexposed, sick) (Mixed indications), 2014 Margulis (Topiramate) (Mixed indication), 2012 Mawer (Topiramate) (Controls unexposed, sick), 2010 Morrow (Topiramate) (Controls unexposed, sick), 2006 10   - Yes  - Yes 3.73[1.84; 7.57]49,50549 -NAKällén (Topiramate) (Controls unexposed, NOS) (Indications NOS), 2013 1 Controls   - epilepsy indication  - epilepsy indication 1.50[0.36; 6.28]10848 -NAVeiby (Topiramate) (Controls unexposed, sick) (Mixed indications), 2014 1 MatchedMatched 1.01[0.34; 2.98]33,62021 -NAMargulis (Topiramate) (Mixed indication), 2012 1 Partial overlappingPartial overlapping 2.39[1.65; 3.46]197,57360612%NACohen (Topiramate) (Mixed indications) (Controls unexposed, NOS), 2023 Veiby (Topiramate) (Controls unexposed, sick) (Mixed indications), 2014 Källén (Topiramate) (Controls unexposed, NOS) (Indications NOS), 2013 3 All studiesAll studies 2.27[1.66; 3.10]231,3501,41013%NACohen (Topiramate) (Mixed indications) (Controls unexposed, NOS), 2023 The NAAED (Controls unexposed, disease free) (Indications NOS), 2022 Thomas (Topiramate) (Controls unexposed, sick), 2021 Meador (Topiramate) (Controls unexposed, sick), 2020 Vajda (Topiramate) (Controls unexposed, sick), 2019 Tomson (Topiramate), 2018 Veiby (Topiramate) (Controls unexposed, sick) (Mixed indications), 2014 Källén (Topiramate) (Controls unexposed, NOS) (Indications NOS), 2013 Margulis (Topiramate) (Mixed indication), 2012 Mawer (Topiramate) (Controls unexposed, sick), 2010 Ornoy (Topiramate), 2008 Morrow (Topiramate) (Controls unexposed, sick), 2006 120.220.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-4.15.02.1100.000Cohen (Topiramate) (Mixed indications) (Controls unexposed, NOS), 2023The NAAED (Controls unexposed, disease free) (Indications NOS), 2022Thomas (Topiramate) (Controls unexposed, sick), 2021Meador (Topiramate) (Controls unexposed, sick), 2020Vajda (Topiramate) (Controls unexposed, sick), 2019Tomson (Topiramate), 2018Veiby (Topiramate) (Controls unexposed, sick) (Mixed indications), 2014Källén (Topiramate) (Controls unexposed, NOS) (Indications NOS), 2013Margulis (Topiramate) (Mixed indication), 2012Mawer (Topiramate) (Controls unexposed, sick), 2010Ornoy (Topiramate), 2008Morrow (Topiramate) (Controls unexposed, sick), 2006

Asymetry test p-value = 0.4873 (by Egger's regression)

slope=0.9626 (0.2345); intercept=-0.3794 (0.5260); t=0.7212; p=0.4873

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 8569, 8561, 8562, 8559, 8594, 8595, 8576, 8552, 8564, 8565, 12693, 12873, 12874, 8597, 15206, 15268

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 2.67[1.80; 3.96]253,5201,17425%NACohen (Topiramate) (Mixed indications) (Controls unexposed, NOS), 2023 The NAAED (Controls unexposed, disease free) (Indications NOS), 2022 Thomas (Topiramate) (Controls unexposed, disease free), 2021 Meador (Topiramate) (Controls unexposed, disease free), 2020 Veiby (Topiramate) (Controls unexposed, disease free) (Mixed indications), 2014 Källén (Topiramate) (Controls unexposed, NOS) (Indications NOS), 2013 Margulis (Topiramate) (Mixed indication), 2012 Mawer (Topiramate) (Controls unexposed, disease free), 2010 Ornoy (Topiramate), 2008 9 unexposed, sick controlsunexposed, sick controls 1.60[0.69; 3.70]1431470%NAThomas (Topiramate) (Controls unexposed, sick), 2021 Meador (Topiramate) (Controls unexposed, sick), 2020 Vajda (Topiramate) (Controls unexposed, sick), 2019 Veiby (Topiramate) (Controls unexposed, sick) (Mixed indications), 2014 Mawer (Topiramate) (Controls unexposed, sick), 2010 Morrow (Topiramate) (Controls unexposed, sick), 2006 6 exposed to other treatment, sick controlsexposed to other treatment, sick controls 2.02[1.57; 2.60]6201,3600%NACohen (Topiramate) (Mixed indications) (Controls exposed to LTG), 2023 The NAAED (Controls exposed to Lamotrigine, sick) (Indications NOS), 2022 Thomas (Topiramate) (Controls exposed to Lamotrigine, sick), 2021 Meador (Topiramate) (Controls exposed to Lamotrigine, sick), 2020 Vajda (Topiramate) (Controls exposed to Lamotrigine, sick), 2019 Tomson (Topiramate), 2018 Veiby (Topiramate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2014 Källén (Topiramate) (Controls exposed to Lamotrigine, sick) (Indications NOS), 2013 Mawer (Topiramate) (Controls exposed to Lamotrigine, sick), 2010 Morrow (Topiramate) (Controls exposed to Lamotrigine, sick), 2006 100.510.01.0