Valproate (All indications)

Language disorders/delay

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.
S15275
R62800		 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
S9391
R32883		 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
S9392
R32901		 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
S9405
R32975		 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
S9406
R32977		 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
S9407
R32979		 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
S9408
R32981		 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
S9409
R32984		 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
S9374
R32781		 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
S9398
R32934		 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
S9942
R35745		 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
S9944
R35757		 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
S9371
R32763		 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
S9372
R32768		 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
S9373
R32774		 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
S9414
R33010		 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
S9450
R33196		 Rihtman (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2013 Stanford Binet Intelligence Scales, Fifth Edition (SB5) - Verbal IQ (VIQ) (mean age 4-5 years old) at least 1st trimester prospective cohort exposed to other treatment, sick excluded Adjustment: No Controls: epilepsy indication extrapolated (cont. endpoint) 1.21 [0.51;2.87]
excluded (control group) 		-/29   -/41 - 29
ref
S9451
R33231		 Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013 Stanford Binet Intelligence Scales, Fifth Edition (SB5) - Verbal IQ (VIQ) (mean age 4-5 years old) at least 1st trimester prospective cohort unexposed (general population or NOS) Adjustment: No extrapolated (cont. endpoint) 1.81 [0.79;4.15] -/29   -/52 - 29
ref
S9415
R33022		 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
S9418
R33046		 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
S9400
R32940		 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
S9278
R32184		 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
S9401
R32942		 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
S9402
R32946		 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 15 studies 2.87 [2.05;4.02] 72,249 1,423
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 Thomas (Valproate), 2022Thomas, 2022 1 1.57[0.45; 5.45]-335%ROB confusion: criticalROB selection: criticalROB classification: criticalROB missing: criticalROB mesure: lowROB reporting: moderate Coste (Valproate) (Controls unexposed, NOS), 2020Coste, 2020 2 1.70[1.40; 2.10]72,10599116%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Husebye (Valproate) (Controls unexposed, sick), 2020Husebye, 2020 3 1.49[0.49; 4.59]40166%ROB confusion: unclearROB selection: lowROB classification: lowROB missing: criticalROB mesure: moderateROB reporting: moderate Kasradze (Valproate) (Controls unexposed, disease free), 2017Kasradze, 2017 4 7.59[2.69; 21.43]-186%ROB confusion: criticalROB selection: lowROB classification: criticalROB missing: criticalROB mesure: lowROB reporting: moderate Bromley (Valproate), 2016Bromley, 2016 5 3.45[1.00; 11.84]14475%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Deshmukh (Valproate), 2016Deshmukh, 2016 6 4.35[0.79; 25.00]17513%ROB confusion: moderateROB selection: lowROB classification: moderateROB missing: criticalROB mesure: moderateROB reporting: moderate Videman (Valproate) (Controls unexposed, disease free), 2016Videman, 2016 7 41.13[6.91; 244.94]-53%ROB confusion: unclearROB selection: lowROB classification: moderateROB missing: criticalROB mesure: lowROB reporting: moderate Baker (Valproate) (Controls unexposed, sick), 2015Baker, 2015 8 3.06[1.26; 7.44]-518%ROB confusion: unclearROB selection: lowROB classification: moderateROB missing: moderateROB mesure: lowROB reporting: moderate Meador (Valproate), 2013Meador, 2013 9 3.77[1.92; 7.41]-4910%ROB confusion: moderateROB selection: lowROB classification: lowROB missing: moderateROB mesure: lowROB reporting: low Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013Rihtman, 2013 10 1.81[0.79; 4.15]-298%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Nadebaum (Valproate), 2011Nadebaum, 2011 11 8.23[0.42; 162.35]7231%ROB confusion: criticalROB selection: lowROB classification: lowROB missing: criticalROB mesure: lowROB reporting: moderate Shallcross (Valproate), 2011Shallcross, 2011 12 3.01[1.56; 5.82]-4410%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Eriksson (Valproate), 2005Eriksson, 2005 13 2.94[0.70; 12.28]-134%ROB confusion: seriousROB selection: lowROB classification: moderateROB missing: moderateROB mesure: lowROB reporting: moderate Adab (Valproate), 2004Adab, 2004 14 2.03[0.93; 4.42]66419%ROB confusion: criticalROB selection: criticalROB classification: lowROB missing: criticalROB mesure: lowROB reporting: moderate Gaily (Valproate) (Controls unexposed, sick), 2004Gaily, 2004 15 3.22[0.99; 10.49]-125%ROB confusion: criticalROB selection: lowROB classification: moderateROB missing: criticalROB mesure: lowROB reporting: moderate Total (15 studies) I2 = 52% 2.87[2.05; 4.02]72,2491,4230.5100.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

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) (Controls unexposed, NOS) (Mixed indications; 11: Valproate; 12: Valproate; 13: Valproate; 14: Valproate; 15: Valproate) (Controls unexposed, sick;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 2.87[2.05; 4.02]72,2491,42352%NAThomas (Valproate), 2022 Coste (Valproate) (Controls unexposed, NOS), 2020 Husebye (Valproate) (Controls unexposed, sick), 2020 Kasradze (Valproate) (Controls unexposed, disease free), 2017 Bromley (Valproate), 2016 Deshmukh (Valproate), 2016 Videman (Valproate) (Controls unexposed, disease free), 2016 Baker (Valproate) (Controls unexposed, sick), 2015 Meador (Valproate), 2013 Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013 Nadebaum (Valproate), 2011 Shallcross (Valproate), 2011 Eriksson (Valproate), 2005 Adab (Valproate), 2004 Gaily (Valproate) (Controls unexposed, sick), 2004 15 case control studiescase control studies 0 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 3.62[1.73; 7.57]72,1051,08781%NACoste (Valproate) (Controls unexposed, NOS), 2020 Kasradze (Valproate) (Controls unexposed, disease free), 2017 Videman (Valproate) (Controls unexposed, disease free), 2016 Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013 Shallcross (Valproate), 2011 5 unexposed, sickunexposed, sick 2.37[1.59; 3.54]1202130%NAThomas (Valproate), 2022 Husebye (Valproate) (Controls unexposed, sick), 2020 Bromley (Valproate), 2016 Baker (Valproate) (Controls unexposed, sick), 2015 Eriksson (Valproate), 2005 Adab (Valproate), 2004 Gaily (Valproate) (Controls unexposed, sick), 2004 7 exposed to other treatment, sickexposed to other treatment, sick 3.97[2.14; 7.34]241230%NADeshmukh (Valproate), 2016 Meador (Valproate), 2013 Nadebaum (Valproate), 2011 3 Tags Adjustment   - No  - No 3.03[2.06; 4.45]12733234%NAThomas (Valproate), 2022 Husebye (Valproate) (Controls unexposed, sick), 2020 Kasradze (Valproate) (Controls unexposed, disease free), 2017 Bromley (Valproate), 2016 Videman (Valproate) (Controls unexposed, disease free), 2016 Baker (Valproate) (Controls unexposed, sick), 2015 Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013 Nadebaum (Valproate), 2011 Shallcross (Valproate), 2011 Eriksson (Valproate), 2005 Adab (Valproate), 2004 Gaily (Valproate) (Controls unexposed, sick), 2004 12   - Yes  - Yes 2.53[1.28; 4.98]72,1221,09166%NACoste (Valproate) (Controls unexposed, NOS), 2020 Deshmukh (Valproate), 2016 Meador (Valproate), 2013 3 extrapolated (cont. endpoint)extrapolated (cont. endpoint) 3.48[2.26; 5.35]-25442%NAThomas (Valproate), 2022 Kasradze (Valproate) (Controls unexposed, disease free), 2017 Videman (Valproate) (Controls unexposed, disease free), 2016 Baker (Valproate) (Controls unexposed, sick), 2015 Meador (Valproate), 2013 Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013 Shallcross (Valproate), 2011 Eriksson (Valproate), 2005 Gaily (Valproate) (Controls unexposed, sick), 2004 9 MatchedMatched 5.40[2.21; 13.17]-319%NAKasradze (Valproate) (Controls unexposed, disease free), 2017 Eriksson (Valproate), 2005 2 All studiesAll studies 2.87[2.05; 4.02]72,2491,42352%NAThomas (Valproate), 2022 Coste (Valproate) (Controls unexposed, NOS), 2020 Husebye (Valproate) (Controls unexposed, sick), 2020 Kasradze (Valproate) (Controls unexposed, disease free), 2017 Bromley (Valproate), 2016 Deshmukh (Valproate), 2016 Videman (Valproate) (Controls unexposed, disease free), 2016 Baker (Valproate) (Controls unexposed, sick), 2015 Meador (Valproate), 2013 Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013 Nadebaum (Valproate), 2011 Shallcross (Valproate), 2011 Eriksson (Valproate), 2005 Adab (Valproate), 2004 Gaily (Valproate) (Controls unexposed, sick), 2004 150.5100.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-4.54.61.8260.000Thomas (Valproate), 2022Coste (Valproate) (Controls unexposed, NOS), 2020Husebye (Valproate) (Controls unexposed, sick), 2020Kasradze (Valproate) (Controls unexposed, disease free), 2017Bromley (Valproate), 2016Deshmukh (Valproate), 2016Videman (Valproate) (Controls unexposed, disease free), 2016Baker (Valproate) (Controls unexposed, sick), 2015Meador (Valproate), 2013Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013Nadebaum (Valproate), 2011Shallcross (Valproate), 2011Eriksson (Valproate), 2005Adab (Valproate), 2004Gaily (Valproate) (Controls unexposed, sick), 2004

Asymetry test p-value = 0.0047 (by Egger's regression)

slope=0.3935 (0.1364); intercept=1.4505 (0.4267); t=3.3996; p=0.0047

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 9401, 9450, 9371, 9372, 9942, 9408, 9391, 9405, 9406

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 3.69[2.11; 6.47]80,3601,16680%NACoste (Valproate) (Controls unexposed, NOS), 2020 Husebye (Valproate) (Controls unexposed, disease free), 2020 Kasradze (Valproate) (Controls unexposed, disease free), 2017 Videman (Valproate) (Controls unexposed, disease free), 2016 Baker (Valproate) (Controls unexposed, disease free), 2015 Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013 Shallcross (Valproate), 2011 Gaily (Valproate) (Controls unexposed, disease free), 2004 8 unexposed, sick controlsunexposed, sick controls 2.37[1.59; 3.54]1202130%NAThomas (Valproate), 2022 Husebye (Valproate) (Controls unexposed, sick), 2020 Bromley (Valproate), 2016 Baker (Valproate) (Controls unexposed, sick), 2015 Eriksson (Valproate), 2005 Adab (Valproate), 2004 Gaily (Valproate) (Controls unexposed, sick), 2004 7 exposed to other treatment, sick controlsexposed to other treatment, sick controls 2.07[1.38; 3.10]2531,23335%NACoste (Valproate) (Controls exposed to Lamotrigine, sick), 2020 Husebye (Valproate) (Controls exposed to Lamotrigine, sick), 2020 Kasradze (Valproate) (Controls exposed to Lamotrigine, sick), 2017 Deshmukh (Valproate), 2016 Videman (Valproate) (Controls exposed to Lamotrigine, sick), 2016 Baker (Valproate) (Controls exposed to Lamotrigine, sick), 2015 Meador (Valproate), 2013 Rihtman (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2013 Nadebaum (Valproate), 2011 90.510.01.0