Lamotrigine (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.
S15218
R62397		 Bromley (Lamotrigine) (Epilepsy), 2023 Major congenital anomaly during pregnancy (anytime or not specified) excluded prospective cohort unexposed, sick Adjustment: No 0.75 [0.15;3.81] C
excluded (exposition period) 		3/106   3/80 6 106
ref
S15197
R62327		 Cohen (Lamotrigine) (Mixed indications), 2023 Major congenital malformations (excluding genetic/chromosomal) 1st trimester population based cohort retrospective unexposed (general population or NOS) Adjustment: Yes Partial overlapping 0.97 [0.87;1.08] 314/8,339   147,928/4,866,362 148,242 8,339
ref
S15263
R62748		 Li (Lamotrigine) (Epilepsy), 2023 Major congenital malformation during pregnancy (anytime or not specified) excluded prospective cohort unexposed, sick Adjustment: No 0.44 [0.02;7.80] C
excluded (exposition period) 		0/38   7/253 7 38
ref
S8968
R30371		 The NAAED (Indications NOS), 2022 Major congenital malformations 1st trimester prospective cohort unexposed, disease free Adjustment: No 1.90 [1.00;3.62] C 44/2,333   12/1,201 56 2,333
ref
S12678
R47913		 Alsfouk (Lamotrigine), 2021 Major congenital malformation during pregnancy (anytime or not specified) excluded retrospective cohort unexposed, sick Adjustment: No 4.46 [0.37;53.71] C
excluded (exposition period) 		2/15   1/30 3 15
ref
S12677
R47909		 Hosny, 2021 Major birth defects 1st trimester prospective cohort unexposed, sick Adjustment: No 2.60 [0.08;82.80] C 0/3   1/21 1 3
ref
S8923
R30161		 Thomas (Lamotrigine) (Controls unexposed, disease free), 2021 Major congenital malformations 1st trimester prospective cohort unexposed, disease free excluded Adjustment: No 0.76 [0.10;5.75]
excluded (control group) 		1/38   11/319 12 38
ref
S8924
R48246		 Thomas (Lamotrigine) (Controls unexposed, sick), 2021 Major congenital malformations 1st trimester prospective cohort unexposed, sick Adjustment: Yes 0.50 [0.10;3.70] 1/50   16/340 17 50
ref
S8901
R30052		 AlSheikh (Lamotrigine), 2020 Fetal/neonatal malformation during pregnancy (anytime or not specified) excluded prospective cohort unexposed, sick Adjustment: No 0.11 [0.00;3.08] C
excluded (exposition period) 		0/20   1/8 1 20
ref
S8911
R30115		 Meador (Lamotrigine) (Controls unexposed, disease free), 2020 Major congenital malformations 1st trimester prospective cohort unexposed, disease free excluded Adjustment: No 2.48 [0.47;13.05] C
excluded (control group) 		5/110   2/106 7 110
ref
S8912
R30119		 Meador (Lamotrigine) (Controls unexposed, sick), 2020 Major congenital malformations 1st trimester prospective cohort unexposed, sick Adjustment: No 0.67 [0.07;6.13] C 5/110   1/15 6 110
ref
S8925
R30165		 Vajda (Lamotrigine), 2019 Fetal malformations at least 1st trimester prospective cohort unexposed, sick Adjustment: No 1.75 [0.66;4.55] 20/406   5/176 25 406
ref
S8920
R30146		 Diav-Citrin (Lamotrigine), 2017 Major anomalies excluding chromosomal or genetic anomalies at least 1st trimester prospective cohort unexposed, disease free Adjustment: No 2.04 [0.81;5.13] C 6/114   22/828 28 114
ref
S10208
R37400		 Petersen (Lamotrigine) (Controls unexposed NOS), 2017 Major congenital malformation 1st trimester retrospective cohort (claims database) unexposed (general population or NOS) excluded Adjustment: Yes 0.95 [0.51;1.79]
excluded (control group) 		10/357   5,315/239,151 5,325 357
ref
S10209
R37401		 Petersen (Lamotrigine) (Controls unexposed, sick), 2017 Major congenital malformation 1st trimester retrospective cohort (claims database) unexposed, sick Adjustment: Yes 0.88 [0.44;1.75] 9/344   86/2,844 95 344
ref
S8926
R30166		 Vanya (Lamotrigine) (Controls unexposed, sick), 2015 Major congenital malformations throughout pregnancy retrospective cohort unexposed, sick Adjustment: No 3.55 [0.06;199.99] C 0/6   0/20 0 6
ref
S8917
R30138		 Campbell (Lamotrigine), 2014 Major malformations 1st trimester prospective cohort unexposed, sick Adjustment: No 0.97 [0.52;1.80] C 49/2,098   13/541 62 2,098
ref
S8964
R30360		 Veiby (Lamotrigine) (Controls unexposed, disease free) (Mixed indications), 2014 Major malformations throughout pregnancy population based cohort retrospective unexposed, disease free excluded Adjustment: Yes Partial overlapping 1.26 [0.87;1.84]
excluded (control group) 		28/833   22,371/771,412 22,399 833
ref
S8965
R30363		 Veiby (Lamotrigine) (Controls unexposed, sick) (Mixed indications), 2014 Major malformations throughout pregnancy population based cohort retrospective unexposed, sick Adjustment: No Controls: epilepsy indication Partial overlapping 1.20 [0.79;1.84] C 28/833   106/3,773 134 833
ref
S8966
R30365		 Cassina (Lamotrigine) (Mixed indications), 2013 Major congenital anomalies 1st trimester prospective cohort unexposed, disease free Adjustment: No 0.34 [0.02;5.59] C 0/46   25/803 25 46
ref
S8908
R30101		 Källén (Lamotrigine) (Indications NOS), 2013 Relatively severe malformations early pregnancy population based cohort retrospective unexposed (general population or NOS) Adjustment: Yes Partial overlapping 1.08 [0.78;1.50] 37/1,084   49,499/1,575,847 49,536 1,084
ref
S8905
R30089		 Charlton (Lamotrigine), 2011 Major congenital malformations 1st trimester retrospective cohort (claims database) unexposed, sick Adjustment: No 1.26 [0.38;4.17] 3/98   22/902 25 98
ref
S8909
R30109		 Mawer (Lamotrigine) (Controls unexposed, disease free), 2010 Major malformations 1st trimester prospective cohort unexposed, disease free excluded Adjustment: No Matched 2.66 [0.52;13.68]
excluded (control group) 		2/37   6/285 8 37
ref
S8910
R30111		 Mawer (Lamotrigine) (Controls unexposed, sick), 2010 Major malformations 1st trimester prospective cohort unexposed, sick Adjustment: No 2.29 [0.20;26.30] C 2/37   1/41 3 37
ref
S8919
R30144		 Dean (Lamotrigine), 2007 Major malformation during pregnancy (anytime or not specified) excluded retrospective cohort unexposed, sick Adjustment: No 1.73 [0.07;40.78] C
excluded (exposition period) 		0/4   3/46 3 4
ref
Total 15 studies 1.02 [0.92;1.12] 198,255 15,901
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 (Lamotrigine) (Mixed indications), 2023Cohen, 2023 1 0.97[0.87; 1.08]148,2428,33977%ROB confusion: seriousROB selection: lowROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate The NAAED (Indications NOS), 2022The NAAED, 2022 2 1.90[1.00; 3.62]562,3332%ROB confusion: criticalROB selection: unclearROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: low Hosny, 2021Hosny, 2021 2.60[0.08; 82.80]130%ROB confusion: criticalROB selection: moderateROB classification: unclearROB missing: lowROB mesure: unclearROB reporting: moderate Thomas (Lamotrigine) (Controls unexposed, sick), 2021Thomas, 2021 3 0.50[0.10; 3.70]17500%ROB confusion: seriousROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Meador (Lamotrigine) (Controls unexposed, sick), 2020Meador, 2020 4 0.67[0.07; 6.13]61100%ROB confusion: unclearROB selection: lowROB classification: lowROB missing: lowROB mesure: moderateROB reporting: low Vajda (Lamotrigine), 2019Vajda, 2019 5 1.75[0.66; 4.55]254061%ROB confusion: criticalROB selection: moderateROB classification: lowROB missing: moderateROB mesure: moderateROB reporting: moderate Diav-Citrin (Lamotrigine), 2017Diav-Citrin, 2017 6 2.04[0.81; 5.13]281141%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Petersen (Lamotrigine) (Controls unexposed, sick), 2017Petersen, 2017 7 0.88[0.44; 1.75]953442%ROB confusion: criticalROB selection: moderateROB classification: criticalROB missing: unclearROB mesure: moderateROB reporting: moderate Vanya (Lamotrigine) (Controls unexposed, sick), 2015Vanya, 2015 8 3.55[0.06; 199.99]060%ROB confusion: criticalROB selection: criticalROB classification: unclearROB missing: unclearROB mesure: unclearROB reporting: moderate Campbell (Lamotrigine), 2014Campbell, 2014 9 0.97[0.52; 1.80]622,0982%ROB confusion: unclearROB selection: lowROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Veiby (Lamotrigine) (Controls unexposed, sick) (Mixed indications), 2014Veiby, 2014 10 1.20[0.79; 1.84]1348335%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: moderateROB mesure: moderateROB reporting: moderate Cassina (Lamotrigine) (Mixed indications), 2013Cassina, 2013 11 0.34[0.02; 5.59]25460%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Källén (Lamotrigine) (Indications NOS), 2013Källén, 2013 12 1.08[0.78; 1.50]49,5361,0848%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Charlton (Lamotrigine), 2011Charlton, 2011 13 1.26[0.38; 4.17]25981%ROB confusion: criticalROB selection: moderateROB classification: criticalROB missing: unclearROB mesure: moderateROB reporting: moderate Mawer (Lamotrigine) (Controls unexposed, sick), 2010Mawer, 2010 14 2.29[0.20; 26.30]3370%ROB confusion: criticalROB selection: moderateROB classification: lowROB missing: moderateROB mesure: moderateROB reporting: moderate Total (15 studies) I2 = 0% 1.02[0.92; 1.12]198,25515,9010.210.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

1: Lamotrigine) (Mixed indications; 2: Indications NOS; 3: Lamotrigine) (Controls unexposed, sick; 4: Lamotrigine) (Controls unexposed, sick; 5: Lamotrigine; 6: Lamotrigine; 7: Lamotrigine) (Controls unexposed, sick; 8: Lamotrigine) (Controls unexposed, sick; 9: Lamotrigine; 10: Lamotrigine) (Controls unexposed, sick) (Mixed indications; 11: Lamotrigine) (Mixed indications; 12: Lamotrigine) (Indications NOS; 13: Lamotrigine; 14: Lamotrigine) (Controls unexposed, sick;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 1.02[0.92; 1.12]198,25515,9010%NACohen (Lamotrigine) (Mixed indications), 2023 The NAAED (Indications NOS), 2022 Hosny, 2021 Thomas (Lamotrigine) (Controls unexposed, sick), 2021 Meador (Lamotrigine) (Controls unexposed, sick), 2020 Vajda (Lamotrigine), 2019 Diav-Citrin (Lamotrigine), 2017 Petersen (Lamotrigine) (Controls unexposed, sick), 2017 Vanya (Lamotrigine) (Controls unexposed, sick), 2015 Campbell (Lamotrigine), 2014 Veiby (Lamotrigine) (Controls unexposed, sick) (Mixed indications), 2014 Cassina (Lamotrigine) (Mixed indications), 2013 Källén (Lamotrigine) (Indications NOS), 2013 Charlton (Lamotrigine), 2011 Mawer (Lamotrigine) (Controls unexposed, sick), 2010 15 case control studiescase control studies 0 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 1.15[0.87; 1.50]197,88711,91645%NACohen (Lamotrigine) (Mixed indications), 2023 The NAAED (Indications NOS), 2022 Diav-Citrin (Lamotrigine), 2017 Cassina (Lamotrigine) (Mixed indications), 2013 Källén (Lamotrigine) (Indications NOS), 2013 5 unexposed, sickunexposed, sick 1.12[0.85; 1.48]3683,9850%NAHosny, 2021 Thomas (Lamotrigine) (Controls unexposed, sick), 2021 Meador (Lamotrigine) (Controls unexposed, sick), 2020 Vajda (Lamotrigine), 2019 Petersen (Lamotrigine) (Controls unexposed, sick), 2017 Vanya (Lamotrigine) (Controls unexposed, sick), 2015 Campbell (Lamotrigine), 2014 Veiby (Lamotrigine) (Controls unexposed, sick) (Mixed indications), 2014 Charlton (Lamotrigine), 2011 Mawer (Lamotrigine) (Controls unexposed, sick), 2010 10 Tags Adjustment   - No  - No 1.34[1.03; 1.75]3656,0840%NAThe NAAED (Indications NOS), 2022 Hosny, 2021 Meador (Lamotrigine) (Controls unexposed, sick), 2020 Vajda (Lamotrigine), 2019 Diav-Citrin (Lamotrigine), 2017 Vanya (Lamotrigine) (Controls unexposed, sick), 2015 Campbell (Lamotrigine), 2014 Veiby (Lamotrigine) (Controls unexposed, sick) (Mixed indications), 2014 Cassina (Lamotrigine) (Mixed indications), 2013 Charlton (Lamotrigine), 2011 Mawer (Lamotrigine) (Controls unexposed, sick), 2010 11   - Yes  - Yes 0.98[0.88; 1.08]197,8909,8170%NACohen (Lamotrigine) (Mixed indications), 2023 Thomas (Lamotrigine) (Controls unexposed, sick), 2021 Petersen (Lamotrigine) (Controls unexposed, sick), 2017 Källén (Lamotrigine) (Indications NOS), 2013 4 Controls   - epilepsy indication  - epilepsy indication 1.20[0.79; 1.84]134833 -NAVeiby (Lamotrigine) (Controls unexposed, sick) (Mixed indications), 2014 1 Partial overlappingPartial overlapping 0.99[0.90; 1.10]197,91210,2560%NACohen (Lamotrigine) (Mixed indications), 2023 Veiby (Lamotrigine) (Controls unexposed, sick) (Mixed indications), 2014 Källén (Lamotrigine) (Indications NOS), 2013 3 All studiesAll studies 1.02[0.92; 1.12]198,25515,9010%NACohen (Lamotrigine) (Mixed indications), 2023 The NAAED (Indications NOS), 2022 Hosny, 2021 Thomas (Lamotrigine) (Controls unexposed, sick), 2021 Meador (Lamotrigine) (Controls unexposed, sick), 2020 Vajda (Lamotrigine), 2019 Diav-Citrin (Lamotrigine), 2017 Petersen (Lamotrigine) (Controls unexposed, sick), 2017 Vanya (Lamotrigine) (Controls unexposed, sick), 2015 Campbell (Lamotrigine), 2014 Veiby (Lamotrigine) (Controls unexposed, sick) (Mixed indications), 2014 Cassina (Lamotrigine) (Mixed indications), 2013 Källén (Lamotrigine) (Indications NOS), 2013 Charlton (Lamotrigine), 2011 Mawer (Lamotrigine) (Controls unexposed, sick), 2010 150.110.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-4.84.92.4690.000Cohen (Lamotrigine) (Mixed indications), 2023The NAAED (Indications NOS), 2022Hosny, 2021Thomas (Lamotrigine) (Controls unexposed, sick), 2021Meador (Lamotrigine) (Controls unexposed, sick), 2020Vajda (Lamotrigine), 2019Diav-Citrin (Lamotrigine), 2017Petersen (Lamotrigine) (Controls unexposed, sick), 2017Vanya (Lamotrigine) (Controls unexposed, sick), 2015Campbell (Lamotrigine), 2014Veiby (Lamotrigine) (Controls unexposed, sick) (Mixed indications), 2014Cassina (Lamotrigine) (Mixed indications), 2013Källén (Lamotrigine) (Indications NOS), 2013Charlton (Lamotrigine), 2011Mawer (Lamotrigine) (Controls unexposed, sick), 2010

Asymetry test p-value = 0.1100 (by Egger's regression)

slope=-0.0359 (0.0507); intercept=0.4648 (0.2710); t=1.7152; p=0.1100

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 8909, 8964, 10208, 8911, 8923

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 1.12[0.94; 1.32]225,63813,29119%NACohen (Lamotrigine) (Mixed indications), 2023 The NAAED (Indications NOS), 2022 Thomas (Lamotrigine) (Controls unexposed, disease free), 2021 Meador (Lamotrigine) (Controls unexposed, disease free), 2020 Diav-Citrin (Lamotrigine), 2017 Petersen (Lamotrigine) (Controls unexposed NOS), 2017 Veiby (Lamotrigine) (Controls unexposed, disease free) (Mixed indications), 2014 Cassina (Lamotrigine) (Mixed indications), 2013 Källén (Lamotrigine) (Indications NOS), 2013 Mawer (Lamotrigine) (Controls unexposed, disease free), 2010 10 unexposed, sick controlsunexposed, sick controls 1.12[0.85; 1.48]3683,9850%NAHosny, 2021 Thomas (Lamotrigine) (Controls unexposed, sick), 2021 Meador (Lamotrigine) (Controls unexposed, sick), 2020 Vajda (Lamotrigine), 2019 Petersen (Lamotrigine) (Controls unexposed, sick), 2017 Vanya (Lamotrigine) (Controls unexposed, sick), 2015 Campbell (Lamotrigine), 2014 Veiby (Lamotrigine) (Controls unexposed, sick) (Mixed indications), 2014 Charlton (Lamotrigine), 2011 Mawer (Lamotrigine) (Controls unexposed, sick), 2010 100.510.01.0

Umbrella review (other published meta-analyses)

Published MATE95% CIn exposedkI2Control groupExposition period Veroniki (NMA)Veroniki (NMA) 0.96[0.72; 1.25]-whatever (meta-analysis)during pregnancy (anytime or not specified)studies17 WestonWeston 1.68[0.78; 3.65]0-unexposed, disease freeduring pregnancy (anytime or not specified)studies3 WestonWeston 1.07[0.64; 1.77]0-unexposed, sickduring pregnancy (anytime or not specified)studies3 metaPregmetaPreg 1.02[0.92; 1.12]0%15,901--Cohen (Lamotrigine) (Mixed indications), 2023 The NAAED (Indications NOS), 2022 Hosny, 2021 Thomas (Lamotrigine) (Controls unexposed, sick), 2021 Meador (Lamotrigine) (Controls unexposed, sick), 2020 Vajda (Lamotrigine), 2019 Diav-Citrin (Lamotrigine), 2017 Petersen (Lamotrigine) (Controls unexposed, sick), 2017 Vanya (Lamotrigine) (Controls unexposed, sick), 2015 Campbell (Lamotrigine), 2014 Veiby (Lamotrigine) (Controls unexposed, sick) (Mixed indications), 2014 Cassina (Lamotrigine) (Mixed indications), 2013 Källén (Lamotrigine) (Indications NOS), 2013 Charlton (Lamotrigine), 2011 Mawer (Lamotrigine) (Controls unexposed, sick), 2010 150.510.01.0