Valproate (Epilepsy)

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.
S15866 R65316	Thomas (Valproate), 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)	1.57 [0.45;5.45]	-/33 -/11	-	33		ref
S10070 R36647	Coste (Valproate) (Controls exposed to Lamotrigine, sick), 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	1.50 [1.10;1.90] excluded (control group)	93/991 122/2,108	215	991		ref
S7799 R23034	Coste (Valproate) (Controls unexposed, NOS), 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	1.70 [1.40;2.10]	93/991 72,012/1,710,441	72,105	991		ref
S7711 R22899	Husebye (Valproate) (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	1.62 [0.44;5.87] ^C excluded (control group)	5/16 9/41	14	16		ref
S7697 R22875	Husebye (Valproate) (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	2.20 [0.70;6.40] excluded (control group)	5/16 8,250/42,550	8,255	16		ref
S7705 R22887	Husebye (Valproate) (Controls unexposed, sick), 2020	Language impairment age 8 years (Language 20)	during pregnancy (anytime or not specified)	population based cohort propective	unexposed, sick	Adjustment: No	1.49 [0.49;4.59] ^C	5/16 35/150	40	16		ref
S7281 R21067	Kasradze (Valproate) (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)	0.48 [0.05;4.50] excluded (control group)	-/18 -/3	-	18		ref
S6938 R19574	Kasradze (Valproate) (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	7.59 [2.69;21.43]	-/18 -/50	-	18		ref
S7309 R21208	Bromley (Valproate), 2016	Verbal abilities <85 (Wechsler Preschool and Primary Scale of Intelligence (WPPSI) / Wechsler Intelligence Scale for Children (WISC)) (5-9 years old)	during pregnancy (anytime or not specified)	retrospective cohort (registry)	unexposed, sick	Adjustment: No	3.45 [1.00;11.84] ^C	10/47 4/55	14	47		ref
S8117 R24931	Deshmukh (Valproate), 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	4.35 [0.79;25.00]	9/51 8/104	17	51		ref
S9943 R35751	Videman (Valproate) (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)	4.00 [0.48;33.44] excluded (control group)	-/5 -/8	-	5		ref
S9945 R35763	Videman (Valproate) (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)	41.13 [6.91;244.94]	-/5 -/59	-	5		ref
S8321 R26339	Baker (Valproate) (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)	2.96 [1.27;6.89] excluded (control group)	-/51 -/29	-	51		ref
S8320 R26333	Baker (Valproate) (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)	5.60 [3.16;9.96] excluded (control group)	-/51 -/210	-	51		ref
S8328 R26376	Baker (Valproate) (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)	3.06 [1.26;7.44]	-/51 -/25	-	51		ref
S7304 R21158	Meador (Valproate), 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)	3.77 [1.92;7.41]	-/49 -/74	-	49		ref
S7168 R20073	Nadebaum (Valproate), 2011	Total language delay (CELF-4) (core language ≤ 85)	during pregnancy (anytime or not specified)	prospective cohort	exposed to other treatment, sick	Adjustment: No	8.23 [0.42;162.35] ^C	7/23 0/9	7	23		ref
S5567 R19101	Shallcross (Valproate), 2011	Hearing and language (Griffiths scale)	throughout pregnancy	prospective cohort	unexposed, disease free	Adjustment: No extrapolated (cont. endpoint)	3.01 [1.56;5.82]	-/44 -/97	-	44		ref
S7225 R20639	Eriksson (Valproate), 2005	Mean Verbal IQ (VIQ) (Wechsler Intelligence Scale for Children (WISC-III))	throughout pregnancy	prospective cohort	unexposed, sick	Adjustment: No extrapolated (cont. endpoint) Matched	2.94 [0.70;12.28]	-/13 -/13	-	13		ref
S7175 R24951	Adab (Valproate), 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	2.03 [0.93;4.42] ^C	27/41 39/80	66	41		ref
S7235 R20857	Gaily (Valproate) (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)	4.31 [1.46;12.73] excluded (control group)	-/12 -/139	-	12		ref
S7237 R20872	Gaily (Valproate) (Controls unexposed, sick), 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, sick	Adjustment: No extrapolated (cont. endpoint)	3.22 [0.99;10.49]	-/12 -/44	-	12		ref
					Total	14 studies	3.02 [2.10;4.36]		72,249	1,394
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: Valproate; 2: Valproate) (Controls unexposed, NOS; 3: Valproate) (Controls unexposed, sick; 4: Valproate) (Controls unexposed, disease free; 5: Valproate; 6: Valproate; 7: Valproate) (Controls unexposed, disease free; 8: Valproate) (Controls unexposed, sick; 9: Valproate; 10: Valproate; 11: Valproate; 12: Valproate; 13: Valproate; 14: Valproate) (Controls unexposed, sick;

Sensitivity analysis

Publication bias and p-hacking diagnosis

funnel plot

Asymetry test p-value = 0.0045 (by Egger's regression)

slope=0.3936 (0.1372); intercept=1.5201 (0.4355); t=3.4903; p=0.0045

p values plot

Sub-groups analysis using all included studies

excluded 7235, 8321, 8320, 9943, 7281, 10070, 7711, 7697

S15866 R65316	Thomas (Valproate), 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	1.57 [0.45;5.45]	-9/33 -9/11
S10070 R36647	Coste (Valproate) (Controls exposed to Lamotrigine, sick), 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	1.50 [1.10;1.90]	93/991 122/2108
S7799 R23034	Coste (Valproate) (Controls unexposed, NOS), 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)	1.70 [1.40;2.10]	93/991 72012/1710441
S7711 R22899	Husebye (Valproate) (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	1.62 [0.44;5.87]	5/16 9/41
S7697 R22875	Husebye (Valproate) (Controls unexposed, disease free), 2020	Language impairment age 8 years (Language 20) (298)	during pregnancy (anytime or not specified)	unexposed, disease free	2.20 [0.70;6.40]	5/16 8250/42550
S7705 R22887	Husebye (Valproate) (Controls unexposed, sick), 2020	Language impairment age 8 years (Language 20) (298)	during pregnancy (anytime or not specified)	unexposed, sick	1.49 [0.49;4.59]	5/16 35/150
S7281 R21067	Kasradze (Valproate) (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	0.48 [0.05;4.50]	-9/18 -9/3
S6938 R19574	Kasradze (Valproate) (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	7.59 [2.69;21.43]	-9/18 -9/50
S7309 R21208	Bromley (Valproate), 2016	Verbal abilities <85 (Wechsler Preschool and Primary Scale of Intelligence (WPPSI) / Wechsler Intelligence Scale for Children (WISC)) (5-9 years old) (298)	during pregnancy (anytime or not specified)	unexposed, sick	3.45 [1.00;11.84]	10/47 4/55
S8117 R24931	Deshmukh (Valproate), 2016	Vineland-II Adaptative Behavior Scales - Low and moderately low in the communication domain (298)	throughout pregnancy	exposed to other treatment, sick	4.35 [0.79;25.00]	9/51 8/104
S9943 R35751	Videman (Valproate) (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	4.00 [0.48;33.44]	-9/5 -9/8
S9945 R35763	Videman (Valproate) (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	41.13 [6.91;244.94]	-9/5 -9/59
S8321 R26339	Baker (Valproate) (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	2.96 [1.27;6.89]	-9/51 -9/29
S8320 R26333	Baker (Valproate) (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	5.60 [3.16;9.96]	-9/51 -9/210
S8328 R26376	Baker (Valproate) (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	3.06 [1.26;7.44]	-9/51 -9/25
S7304 R21158	Meador (Valproate), 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	3.77 [1.92;7.41]	-9/49 -9/74
S7168 R20073	Nadebaum (Valproate), 2011	Total language delay (CELF-4) (core language ≤ 85) (298)	during pregnancy (anytime or not specified)	exposed to other treatment, sick	8.23 [0.42;162.35]	7/23 0/9
S5567 R19101	Shallcross (Valproate), 2011	Hearing and language (Griffiths scale) (298)	throughout pregnancy	unexposed, disease free	3.01 [1.56;5.82]	-9/44 -9/97
S7225 R20639	Eriksson (Valproate), 2005	Mean Verbal IQ (VIQ) (Wechsler Intelligence Scale for Children (WISC-III)) (298)	throughout pregnancy	unexposed, sick	2.94 [0.70;12.28]	-9/13 -9/13
S7175 R24951	Adab (Valproate), 2004	Verbal IQ (VIQ) less than low average (≤ 89) (Wechsler Intelligence Scale for Children (WISC)) (298)	during pregnancy (anytime or not specified)	unexposed, sick	2.03 [0.93;4.42]	27/41 39/80
S7235 R20857	Gaily (Valproate) (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	4.31 [1.46;12.73]	-9/12 -9/139
S7237 R20872	Gaily (Valproate) (Controls unexposed, sick), 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, sick	3.22 [0.99;10.49]	-9/12 -9/44