Lamotrigine (All indications) updated on 04-22-2025

Cognitive developmental disorders/delay (> 6 years old)

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.
S17412
R73053		 Madley-Dowd_SE (Lamotrigine) (Controls unexposed, general pop) (Mixed indications), 2024 Intellectual disability (intelligence quotient below 70) - ICD-8/9/10 codes - Mean 5-20 years old (according groups) during pregnancy (anytime or not specified) population based cohort retrospective unexposed (general population or NOS) Adjustment: Yes 1.09 [0.83;1.44] 60/5,035   24,323/2,651,210 24,383 5,035
ref
S17413
R73059		 Madley-Dowd_SE (Lamotrigine) (Controls unexposed, sibling) (Mixed indications), 2024 Intellectual disability (intelligence quotient below 70) - ICD-8/9/10 codes - Mean 5-20 years old (according groups) during pregnancy (anytime or not specified) population based cohort retrospective sibling excluded Adjustment: Yes 1.04 [0.52;2.10]
excluded (control group) 		-/-   -/- - -
ref
S17266
R72347		 Madley-Dowd_UK (Lamotrigine) (Controls unexposed, general pop) (Mixed indications), 2024 Intellectual disability - ICD10 codes - Median 6.18 (3.53-9.94) years old during pregnancy (anytime or not specified) retrospective cohort (claims database) unexposed (general population or NOS) Adjustment: Yes 1.57 [0.57;4.38] -/939   1,119/514,066 - 939
ref
S17274
R72348		 Madley-Dowd_UK (Lamotrigine) (Controls unexposed, sibling) (Mixed indications), 2024 Intellectual disability - ICD10 codes - Median 6.18 (3.53-9.94) years old during pregnancy (anytime or not specified) retrospective cohort (claims database) sibling excluded Adjustment: Yes 2.42 [0.46;12.72]
excluded (control group) 		-/-   -/- - -
ref
S17470
R73449		 Dreier (Lamotrigine) (Epilepsy), 2023 Intellectual disability - Corresponding ICD-10 F-chapter - Up to 22 years of age during pregnancy (anytime or not specified) population based cohort propective unexposed, sick Adjustment: Yes 0.85 [0.58;1.24] 34/5,288   184/22,203 218 5,288
ref
S8941
R53702		 Cohen-Israel (Lamotrigine), 2018 Developmental delay (a majority between 6-12 years old) 1st trimester retrospective cohort unexposed, disease free Adjustment: No Matched 0.57 [0.26;1.26] C 12/83   19/83 31 83
ref
S8929
R53700		 Baker (Lamotrigine) (Controls unexposed, disease free), 2015 Mean child Full scale IQ - Differential ability scales (DAS) (age mean >6 years old) during pregnancy (anytime or not specified) prospective cohort unexposed, disease free excluded Adjustment: No extrapolated (cont. endpoint) 1.84 [0.91;3.72]
excluded (control group) 		-/29   -/210 - 29
ref
S8930
R53701		 Baker (Lamotrigine) (Controls unexposed, sick), 2015 Mean child Full scale IQ - Differential ability scales (DAS) (age mean >6 years old) during pregnancy (anytime or not specified) prospective cohort unexposed, sick Adjustment: No extrapolated (cont. endpoint) 1.16 [0.44;3.07] -/29   -/25 - 29
ref
S8945
R53703		 Gopinath (Lamotrigine), 2015 Full Scale IQ < 86 (Wechsler Intelligence Scale for Children (WISC-IV)) (at 10–12 years of age) during pregnancy (anytime or not specified) retrospective cohort (registry) unexposed, sick Adjustment: No 0.39 [0.01;22.88] C 0/1   11/16 11 1
ref
Total 6 studies 0.99 [0.80;1.21] 24,643 11,375
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 Madley-Dowd_SE (Lamotrigine) (Controls unexposed, general pop) (Mixed indications), 2024Madley-Dowd_SE, 2024 1 1.09[0.83; 1.44]24,3835,03555%ROB confusion: seriousROB selection: lowROB classification: lowROB missing: lowROB mesure: criticalROB reporting: moderate Madley-Dowd_UK (Lamotrigine) (Controls unexposed, general pop) (Mixed indications), 2024Madley-Dowd_UK, 2024 2 1.57[0.57; 4.38]-9394%ROB confusion: seriousROB selection: lowROB classification: criticalROB missing: unclearROB mesure: criticalROB reporting: moderate Dreier (Lamotrigine) (Epilepsy), 2023Dreier, 2023 3 0.85[0.58; 1.24]2185,28829%ROB confusion: seriousROB selection: lowROB classification: criticalROB missing: lowROB mesure: criticalROB reporting: moderate Cohen-Israel (Lamotrigine), 2018Cohen-Israel, 2018 4 0.57[0.26; 1.26]31837%ROB confusion: criticalROB selection: moderateROB classification: criticalROB missing: unclearROB mesure: criticalROB reporting: moderate Baker (Lamotrigine) (Controls unexposed, sick), 2015Baker, 2015 5 1.16[0.44; 3.07]-294%ROB confusion: unclearROB selection: lowROB classification: moderateROB missing: moderateROB mesure: lowROB reporting: moderate Gopinath (Lamotrigine), 2015Gopinath, 2015 6 0.39[0.01; 22.88]1110%ROB confusion: criticalROB selection: lowROB classification: moderateROB missing: criticalROB mesure: moderateROB reporting: moderate Total (6 studies) I2 = 0% 0.99[0.80; 1.21]24,64311,3750.25.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

1: Lamotrigine) (Controls unexposed, general pop) (Mixed indications; 2: Lamotrigine) (Controls unexposed, general pop) (Mixed indications; 3: Lamotrigine) (Epilepsy; 4: Lamotrigine; 5: Lamotrigine) (Controls unexposed, sick; 6: Lamotrigine;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 0.99[0.80; 1.21]24,64311,3750%NAMadley-Dowd_SE (Lamotrigine) (Controls unexposed, general pop) (Mixed indications), 2024 Madley-Dowd_UK (Lamotrigine) (Controls unexposed, general pop) (Mixed indications), 2024 Dreier (Lamotrigine) (Epilepsy), 2023 Cohen-Israel (Lamotrigine), 2018 Baker (Lamotrigine) (Controls unexposed, sick), 2015 Gopinath (Lamotrigine), 2015 6 case control studiescase control studies 0 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 1.00[0.65; 1.53]24,4146,05732%NAMadley-Dowd_SE (Lamotrigine) (Controls unexposed, general pop) (Mixed indications), 2024 Madley-Dowd_UK (Lamotrigine) (Controls unexposed, general pop) (Mixed indications), 2024 Cohen-Israel (Lamotrigine), 2018 3 unexposed, sickunexposed, sick 0.88[0.62; 1.25]2295,3180%NADreier (Lamotrigine) (Epilepsy), 2023 Baker (Lamotrigine) (Controls unexposed, sick), 2015 Gopinath (Lamotrigine), 2015 3 Tags Adjustment   - No  - No 0.75[0.41; 1.37]421130%NACohen-Israel (Lamotrigine), 2018 Baker (Lamotrigine) (Controls unexposed, sick), 2015 Gopinath (Lamotrigine), 2015 3   - Yes  - Yes 1.02[0.82; 1.27]24,60111,2620%NAMadley-Dowd_SE (Lamotrigine) (Controls unexposed, general pop) (Mixed indications), 2024 Madley-Dowd_UK (Lamotrigine) (Controls unexposed, general pop) (Mixed indications), 2024 Dreier (Lamotrigine) (Epilepsy), 2023 3 extrapolated (cont. endpoint)extrapolated (cont. endpoint) 1.16[0.44; 3.06]-29 -NABaker (Lamotrigine) (Controls unexposed, sick), 2015 1 MatchedMatched 0.57[0.26; 1.26]3183 -NACohen-Israel (Lamotrigine), 2018 1 All studiesAll studies 0.99[0.80; 1.21]24,64311,3750%NAMadley-Dowd_SE (Lamotrigine) (Controls unexposed, general pop) (Mixed indications), 2024 Madley-Dowd_UK (Lamotrigine) (Controls unexposed, general pop) (Mixed indications), 2024 Dreier (Lamotrigine) (Epilepsy), 2023 Cohen-Israel (Lamotrigine), 2018 Baker (Lamotrigine) (Controls unexposed, sick), 2015 Gopinath (Lamotrigine), 2015 60.15.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-4.94.92.4910.000Madley-Dowd_SE (Lamotrigine) (Controls unexposed, general pop) (Mixed indications), 2024Madley-Dowd_UK (Lamotrigine) (Controls unexposed, general pop) (Mixed indications), 2024Dreier (Lamotrigine) (Epilepsy), 2023Cohen-Israel (Lamotrigine), 2018Baker (Lamotrigine) (Controls unexposed, sick), 2015Gopinath (Lamotrigine), 2015

Asymetry test p-value = 0.6759 (by Egger's regression)

slope=0.0513 (0.1782); intercept=-0.3129 (0.6950); t=0.4502; p=0.6759

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 8929, 17413, 17274

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 1.14[0.75; 1.71]25,5246,08642%NAMadley-Dowd_SE (Lamotrigine) (Controls unexposed, general pop) (Mixed indications), 2024 Madley-Dowd_UK (Lamotrigine) (Controls unexposed, general pop) (Mixed indications), 2024 Cohen-Israel (Lamotrigine), 2018 Baker (Lamotrigine) (Controls unexposed, disease free), 2015 4 unexposed, sick controlsunexposed, sick controls 0.88[0.62; 1.25]2295,3180%NADreier (Lamotrigine) (Epilepsy), 2023 Baker (Lamotrigine) (Controls unexposed, sick), 2015 Gopinath (Lamotrigine), 2015 3 siblingssiblings 1.18[0.62; 2.25]--0%NAMadley-Dowd_SE (Lamotrigine) (Controls unexposed, sibling) (Mixed indications), 2024 Madley-Dowd_UK (Lamotrigine) (Controls unexposed, sibling) (Mixed indications), 2024 20.510.01.0

Umbrella review (other published meta-analyses)

Published MAControlPeriodTE95% CIn exposedkI2 Veroniki b (NMA) (Cognitive developmental delay)Veroniki b (NMA) (Cognitive developmental delay) 0.93[0.09; 5.10]NA-Wwhatever (meta-analysis)Anyduring pregnancy (anytime or not specified)studies TTT-9 Peron (Epilepsy) (Cognitive developmental del ...Peron (Epilepsy) (Cognitive developmental delay (>6 years old)) 0.75[0.41; 1.37]0%-Wwhatever (meta-analysis)Anyduring pregnancy (anytime or not specified)studies TTT3 metaPregmetaPreg 0.99[0.80; 1.21]0%11,375----Madley-Dowd_SE (Lamotrigine) (Controls unexposed, general pop) (Mixed indications), 2024 Madley-Dowd_UK (Lamotrigine) (Controls unexposed, general pop) (Mixed indications), 2024 Dreier (Lamotrigine) (Epilepsy), 2023 Cohen-Israel (Lamotrigine), 2018 Baker (Lamotrigine) (Controls unexposed, sick), 2015 Gopinath (Lamotrigine), 2015 60.510.01.0