Carbamazepine (All indications)

Language disorders/delay

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.
S15367 R63242	Bromley (Carbamazepine) (Epilepsy) (Controls exposed to LTG), 2023	Language mean score ≤ 86 (below average performance of the cohort mean) - Bayley Scales of Infant and Toddler Development - At 24 months of age	during pregnancy (anytime or not specified)	prospective cohort	exposed to other treatment, sick excluded	Adjustment: No	1.82 [0.31;10.68] ^C excluded (control group)	2/21 4/73	6	21		ref
S15368 R63255	Bromley (Carbamazepine) (Epilepsy) (Controls unexposed, sick), 2023	Language mean score ≤ 86 (below average performance of the cohort mean) - Bayley Scales of Infant and Toddler Development - At 24 months of age	during pregnancy (anytime or not specified)	prospective cohort	unexposed, sick	Adjustment: No	1.58 [0.24;10.22] ^C	2/21 3/48	5	21		ref
S12897 R48731	Adams (Carbamazepine), 2022	Verbal IQ - The Wechsler Intelligence Scale for Children, 3rd Edition (WISC-III) (mean >6 years old)	during pregnancy (anytime or not specified)	retrospective cohort	unexposed, sick	Adjustment: No extrapolated (cont. endpoint) Matched	2.72 [1.22;6.06]	-/41 -/41	-	41		ref
S15378 R63360	Thomas (Carbamazepine), 2022	Verbal IQ/Verbal comprehension index (VCI) - Wechsler Intelligence Scale for Children or Adult - Ages 13 to 21 years (mean of 16.5 ± 2.2 years)	during pregnancy (anytime or not specified)	prospective cohort	unexposed, sick	Adjustment: No extrapolated (cont. endpoint)	2.61 [0.76;8.95]	-/38 -/11	-	38		ref
S12802 R48225	Meador (Carbamazepine) (Controls exposed to Lamotrigine, sick), 2021	Language Score in 2 years old children with the Bayley Scales of Infant and Toddler Development (BSID-III)	3rd trimester	prospective cohort	exposed to other treatment, sick excluded	Adjustment: Yes extrapolated (cont. endpoint)	1.18 [0.40;3.52] excluded (control group)	-/12 -/93	-	12		ref
S12803 R48226	Meador (Carbamazepine) (Controls unexposed, disease free), 2021	Language Score in 2 years old children with the Bayley Scales of Infant and Toddler Development (BSID-III)	3rd trimester	prospective cohort	unexposed, disease free	Adjustment: Yes extrapolated (cont. endpoint)	1.15 [0.39;3.45]	-/12 -/87	-	12		ref
S9776 R34967	Coste (Carbamazepine) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2020	Visits to a speech therapist (mean age of 3.7 years old)	during pregnancy (anytime or not specified)	retrospective cohort (claims database)	exposed to other treatment, sick excluded	Adjustment: Yes	0.90 [0.60;1.40] excluded (control group)	31/502 157/2,916	188	502		ref
S9777 R34985	Coste (Carbamazepine) (Controls unexposed, NOS) (Mixed indications), 2020	Health care utilization: Speech therapy (mean age of 3.6 years old)	during pregnancy (anytime or not specified)	retrospective cohort (claims database)	unexposed (general population or NOS)	Adjustment: Yes	1.20 [0.80;1.70]	29/468 71,832/1,707,707	71,861	468		ref
S9724 R34627	Husebye (Carbamazepine) (Controls exposed to Lamotrigine, sick), 2020	Language impairment age 8 years (Language 20)	during pregnancy (anytime or not specified)	population based cohort propective	exposed to other treatment, sick excluded	Adjustment: No	2.74 [0.90;8.28] ^C excluded (control group)	10/23 9/41	19	23		ref
S9725 R34629	Husebye (Carbamazepine) (Controls unexposed, disease free), 2020	Language impairment age 8 years (Language 20)	during pregnancy (anytime or not specified)	population based cohort propective	unexposed, disease free excluded	Adjustment: Yes	3.80 [1.60;9.00] excluded (control group)	10/23 8,250/42,550	8,260	23		ref
S9726 R34631	Husebye (Carbamazepine) (Controls unexposed, sick), 2020	Language impairment age 8 years	during pregnancy (anytime or not specified)	population based cohort propective	unexposed, sick	Adjustment: No	2.53 [1.02;6.26] ^C	10/23 35/150	45	23		ref
S9727 R34633	Kasradze (Carbamazepine) (Controls exposed to Lamotrigine, sick), 2017	Verbal comprehension (VCI) (WPPSI-4) (mean age 4-4.5 years old)	during pregnancy (anytime or not specified)	prospective cohort	exposed to other treatment, sick excluded	Adjustment: No extrapolated (cont. endpoint)	0.13 [0.01;1.41] excluded (control group)	-/16 -/3	-	16		ref
S9728 R34636	Kasradze (Carbamazepine) (Controls unexposed, disease free), 2017	Verbal comprehension (VCI) (WPPSI-4) (mean age 4-4.5 years old)	during pregnancy (anytime or not specified)	prospective cohort	unexposed, disease free	Adjustment: No extrapolated (cont. endpoint) Matched	3.53 [1.24;10.04]	-/16 -/50	-	16		ref
S9716 R34580	Deshmukh (Carbamazepine), 2016	Vineland-II Adaptative Behavior Scales - Low and moderately low in the communication domain	throughout pregnancy	prospective cohort	exposed to other treatment, sick	Adjustment: Yes	2.91 [0.64;13.21]	10/97 8/104	18	97		ref
S9937 R35715	Videman (Carbamazepine) (Controls exposed to Lamotrigine, sick), 2016	Griffiths Mental Developmental Scale - Hearing and speech (at the age of 7 months)	during pregnancy (anytime or not specified)	prospective cohort	exposed to other treatment, sick excluded	Adjustment: No extrapolated (cont. endpoint)	2.69 [0.46;15.78] excluded (control group)	-/9 -/8	-	9		ref
S9936 R35709	Videman (Carbamazepine) (Controls unexposed, disease free), 2016	Griffiths Mental Developmental Scale - Hearing and speech (at the age of 7 months)	during pregnancy (anytime or not specified)	prospective cohort	unexposed, disease free	Adjustment: No extrapolated (cont. endpoint)	15.07 [3.88;58.47]	-/9 -/59	-	9		ref
S9691 R34479	Baker (Carbamazepine) (Controls exposed to Lamotrigine, sick), 2015	Mean child verbal IQ - Differential ability scales (DAS) (age mean >6 years old)	during pregnancy (anytime or not specified)	prospective cohort	exposed to other treatment, sick excluded	Adjustment: No extrapolated (cont. endpoint)	1.13 [0.49;2.60] excluded (control group)	-/50 -/29	-	50		ref
S9692 R34484	Baker (Carbamazepine) (Controls unexposed, disease free), 2015	Mean child verbal 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)	2.05 [1.17;3.59] excluded (control group)	-/50 -/210	-	50		ref
S9693 R34490	Baker (Carbamazepine) (Controls unexposed, sick), 2015	Mean child verbal 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)	1.14 [0.48;2.71]	-/50 -/25	-	50		ref
S9732 R34658	Meador (Carbamazepine), 2013	Verbal index score (at age 6 years old) (Created by averaging standard scores)	during pregnancy (anytime or not specified)	prospective cohort	exposed to other treatment, sick	Adjustment: Yes extrapolated (cont. endpoint)	1.19 [0.64;2.20]	-/61 -/74	-	61		ref
S9733 R34670	Nadebaum (Carbamazepine), 2011	Total language delay (CELF-4) (core language ≤ 85)	during pregnancy (anytime or not specified)	prospective cohort	exposed to other treatment, sick	Adjustment: No	4.02 [0.20;78.92] ^C	6/34 0/9	6	34		ref
S9718 R34588	Eriksson (Carbamazepine), 2005	Mean Verbal IQ (VIQ) (Wechsler Intelligence Scale for Children (WISC-III))	throughout pregnancy	prospective cohort	unexposed, sick	Adjustment: No extrapolated (cont. endpoint)	1.21 [0.30;4.90]	-/13 -/13	-	13		ref
S9593 R33976	Adab (Carbamazepine), 2004	Verbal IQ (VIQ) less than low average (≤ 89) (Wechsler Intelligence Scale for Children (WISC))	during pregnancy (anytime or not specified)	retrospective cohort	unexposed, sick	Adjustment: No	0.56 [0.27;1.14] ^C	18/52 39/80	57	52		ref
S9720 R34594	Gaily (Carbamazepine) (Controls unexposed, disease free), 2004	Verbal IQ score (Wechsler Preschool and Primary Scale of Intelligence Revised (WPPSI-R) or Wechsler Intelligence Scale for Children Revised (WISC-R))	2nd and/or 3rd trimester	prospective cohort	unexposed, disease free excluded	Adjustment: No extrapolated (cont. endpoint)	0.86 [0.53;1.40] excluded (control group)	-/86 -/139	-	86		ref
S9721 R34598	Gaily (Carbamazepine) (Controls unexposed, sick), 2004	Verbal IQ score (WPPSI-R or WISC-R)	2nd and/or 3rd trimester	prospective cohort	unexposed, sick	Adjustment: No extrapolated (cont. endpoint)	0.82 [0.43;1.59]	-/86 -/44	-	86		ref
					Total	15 studies	1.62 [1.13;2.33]		71,992	1,021
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: Carbamazepine) (Epilepsy) (Controls unexposed, sick; 2: Carbamazepine; 3: Carbamazepine; 4: Carbamazepine) (Controls unexposed, disease free; 5: Carbamazepine) (Controls unexposed, NOS) (Mixed indications; 6: Carbamazepine) (Controls unexposed, sick; 7: Carbamazepine) (Controls unexposed, disease free; 8: Carbamazepine; 9: Carbamazepine) (Controls unexposed, disease free; 10: Carbamazepine) (Controls unexposed, sick; 11: Carbamazepine; 12: Carbamazepine; 13: Carbamazepine; 14: Carbamazepine; 15: Carbamazepine) (Controls unexposed, sick;

Sensitivity analysis

Publication bias and p-hacking diagnosis

funnel plot

Asymetry test p-value = 0.0638 (by Egger's regression)

slope=-0.2692 (0.3273); intercept=1.5866 (0.7831); t=2.0261; p=0.0638

p values plot

Sub-groups analysis using all included studies

excluded 9720, 9691, 9692, 9937, 9727, 9776, 9724, 9725, 12802, 15367

S15367 R63242	Bromley (Carbamazepine) (Epilepsy) (Controls exposed to LTG), 2023	Language mean score ≤ 86 (below average performance of the cohort mean) - Bayley Scales of Infant and Toddler Development - At 24 months of age (298)	during pregnancy (anytime or not specified)	exposed to other treatment, sick	1.82 [0.31;10.68]	2/21 4/73
S15368 R63255	Bromley (Carbamazepine) (Epilepsy) (Controls unexposed, sick), 2023	Language mean score ≤ 86 (below average performance of the cohort mean) - Bayley Scales of Infant and Toddler Development - At 24 months of age (298)	during pregnancy (anytime or not specified)	unexposed, sick	1.58 [0.24;10.22]	2/21 3/48
S12897 R48731	Adams (Carbamazepine), 2022	Verbal IQ - The Wechsler Intelligence Scale for Children, 3rd Edition (WISC-III) (mean >6 years old) (298)	during pregnancy (anytime or not specified)	unexposed, sick	2.72 [1.22;6.06]	-9/41 -9/41
S15378 R63360	Thomas (Carbamazepine), 2022	Verbal IQ/Verbal comprehension index (VCI) - Wechsler Intelligence Scale for Children or Adult - Ages 13 to 21 years (mean of 16.5 ± 2.2 years) (298)	during pregnancy (anytime or not specified)	unexposed, sick	2.61 [0.76;8.95]	-9/38 -9/11
S12802 R48225	Meador (Carbamazepine) (Controls exposed to Lamotrigine, sick), 2021	Language Score in 2 years old children with the Bayley Scales of Infant and Toddler Development (BSID-III) (298)	3rd trimester	exposed to other treatment, sick	1.18 [0.40;3.52]	-9/12 -9/93
S12803 R48226	Meador (Carbamazepine) (Controls unexposed, disease free), 2021	Language Score in 2 years old children with the Bayley Scales of Infant and Toddler Development (BSID-III) (298)	3rd trimester	unexposed, disease free	1.15 [0.39;3.45]	-9/12 -9/87
S9776 R34967	Coste (Carbamazepine) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2020	Visits to a speech therapist (mean age of 3.7 years old) (298)	during pregnancy (anytime or not specified)	exposed to other treatment, sick	0.90 [0.60;1.40]	31/502 157/2916
S9777 R34985	Coste (Carbamazepine) (Controls unexposed, NOS) (Mixed indications), 2020	Health care utilization: Speech therapy (mean age of 3.6 years old) (298)	during pregnancy (anytime or not specified)	unexposed (general population or NOS)	1.20 [0.80;1.70]	29/468 71832/1707707
S9724 R34627	Husebye (Carbamazepine) (Controls exposed to Lamotrigine, sick), 2020	Language impairment age 8 years (Language 20) (298)	during pregnancy (anytime or not specified)	exposed to other treatment, sick	2.74 [0.90;8.28]	10/23 9/41
S9725 R34629	Husebye (Carbamazepine) (Controls unexposed, disease free), 2020	Language impairment age 8 years (Language 20) (298)	during pregnancy (anytime or not specified)	unexposed, disease free	3.80 [1.60;9.00]	10/23 8250/42550
S9726 R34631	Husebye (Carbamazepine) (Controls unexposed, sick), 2020	Language impairment age 8 years (298)	during pregnancy (anytime or not specified)	unexposed, sick	2.53 [1.02;6.26]	10/23 35/150
S9727 R34633	Kasradze (Carbamazepine) (Controls exposed to Lamotrigine, sick), 2017	Verbal comprehension (VCI) (WPPSI-4) (mean age 4-4.5 years old) (298)	during pregnancy (anytime or not specified)	exposed to other treatment, sick	0.13 [0.01;1.41]	-9/16 -9/3
S9728 R34636	Kasradze (Carbamazepine) (Controls unexposed, disease free), 2017	Verbal comprehension (VCI) (WPPSI-4) (mean age 4-4.5 years old) (298)	during pregnancy (anytime or not specified)	unexposed, disease free	3.53 [1.24;10.04]	-9/16 -9/50
S9716 R34580	Deshmukh (Carbamazepine), 2016	Vineland-II Adaptative Behavior Scales - Low and moderately low in the communication domain (298)	throughout pregnancy	exposed to other treatment, sick	2.91 [0.64;13.21]	10/97 8/104
S9937 R35715	Videman (Carbamazepine) (Controls exposed to Lamotrigine, sick), 2016	Griffiths Mental Developmental Scale - Hearing and speech (at the age of 7 months) (298)	during pregnancy (anytime or not specified)	exposed to other treatment, sick	2.69 [0.46;15.78]	-9/9 -9/8
S9936 R35709	Videman (Carbamazepine) (Controls unexposed, disease free), 2016	Griffiths Mental Developmental Scale - Hearing and speech (at the age of 7 months) (298)	during pregnancy (anytime or not specified)	unexposed, disease free	15.07 [3.88;58.47]	-9/9 -9/59
S9691 R34479	Baker (Carbamazepine) (Controls exposed to Lamotrigine, sick), 2015	Mean child verbal IQ - Differential ability scales (DAS) (age mean >6 years old) (298)	during pregnancy (anytime or not specified)	exposed to other treatment, sick	1.13 [0.49;2.60]	-9/50 -9/29
S9692 R34484	Baker (Carbamazepine) (Controls unexposed, disease free), 2015	Mean child verbal IQ - Differential ability scales (DAS) (age mean >6 years old) (298)	during pregnancy (anytime or not specified)	unexposed, disease free	2.05 [1.17;3.59]	-9/50 -9/210
S9693 R34490	Baker (Carbamazepine) (Controls unexposed, sick), 2015	Mean child verbal IQ - Differential ability scales (DAS) (age mean >6 years old) (298)	during pregnancy (anytime or not specified)	unexposed, sick	1.14 [0.48;2.71]	-9/50 -9/25
S9732 R34658	Meador (Carbamazepine), 2013	Verbal index score (at age 6 years old) (Created by averaging standard scores) (298)	during pregnancy (anytime or not specified)	exposed to other treatment, sick	1.19 [0.64;2.20]	-9/61 -9/74
S9733 R34670	Nadebaum (Carbamazepine), 2011	Total language delay (CELF-4) (core language ≤ 85) (298)	during pregnancy (anytime or not specified)	exposed to other treatment, sick	4.02 [0.20;78.92]	6/34 0/9
S9718 R34588	Eriksson (Carbamazepine), 2005	Mean Verbal IQ (VIQ) (Wechsler Intelligence Scale for Children (WISC-III)) (298)	throughout pregnancy	unexposed, sick	1.21 [0.30;4.90]	-9/13 -9/13
S9593 R33976	Adab (Carbamazepine), 2004	Verbal IQ (VIQ) less than low average (≤ 89) (Wechsler Intelligence Scale for Children (WISC)) (298)	during pregnancy (anytime or not specified)	unexposed, sick	0.56 [0.27;1.14]	18/52 39/80
S9720 R34594	Gaily (Carbamazepine) (Controls unexposed, disease free), 2004	Verbal IQ score (Wechsler Preschool and Primary Scale of Intelligence Revised (WPPSI-R) or Wechsler Intelligence Scale for Children Revised (WISC-R)) (298)	2nd and/or 3rd trimester	unexposed, disease free	0.86 [0.53;1.40]	-9/86 -9/139
S9721 R34598	Gaily (Carbamazepine) (Controls unexposed, sick), 2004	Verbal IQ score (WPPSI-R or WISC-R) (298)	2nd and/or 3rd trimester	unexposed, sick	0.82 [0.43;1.59]	-9/86 -9/44