Valproate (All indications)

Hypospadias

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.
S15201
R62354		 Cohen (Valproate) (Mixed indications) (Controls unexposed, NOS), 2023 Hypospadias 1st trimester population based cohort retrospective unexposed (general population or NOS) Adjustment: Yes 6.47 [4.32;9.69] -/2,031   -/4,866,362 - 2,031
ref
S10174
R37217		 Blotière (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2019 Hypospadias 1st trimester retrospective cohort (claims database) exposed to other treatment, sick excluded Adjustment: No 3.78 [1.37;10.44] C
excluded (control group) 		8/913   7/2,997 15 913
ref
S10051
R36491		 Blotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019 Hypospadias 1st trimester retrospective cohort (claims database) unexposed (general population or NOS) Adjustment: Yes 4.80 [2.40;9.80] 8/913   3,371/1,875,733 3,379 913
ref
S9359
R32736		 Tomson (Valproate), 2018 Hypospadias at least 1st trimester prospective cohort exposed to other treatment, sick Adjustment: No 6.77 [2.74;16.73] C 22/1,381   6/2,514 28 1,381
ref
S9333
R32557		 Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014 Hypospadias and genitourinary tract defects 1st trimester prospective cohort exposed to other treatment, sick Adjustment: No 2.60 [1.16;5.81] 15/1,220   10/2,098 25 1,220
ref
S9325
R32514		 Veiby (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2014 Hypospadias throughout pregnancy population based cohort retrospective exposed to other treatment, sick excluded Adjustment: No 2.52 [0.63;10.13] C
excluded (control group) 		4/333   4/833 8 333
ref
S9326
R32521		 Veiby (Valproate) (Controls unexposed, disease free) (Mixed indications), 2014 Hypospadias throughout pregnancy population based cohort retrospective unexposed, disease free Adjustment: Yes 5.71 [2.13;15.30] 4/333   1,543/771,412 1,547 333
ref
S9309
R32428		 Källén (Valproate) (Controls exposed to Lamotrigine, sick) (Indications NOS), 2013 Hypospadias early pregnancy population based cohort retrospective exposed to other treatment, sick excluded Adjustment: No 10.65 [3.15;35.96] C
excluded (control group) 		20/697   3/1,084 23 697
ref
S9310
R32436		 Källén (Valproate) (Controls unexposed, NOS) (Indications NOS), 2013 Hypospadias early pregnancy population based cohort retrospective unexposed (general population or NOS) Adjustment: Yes 7.33 [4.48;11.30] 20/697   4,552/1,575,847 4,572 697
ref
S10231
R37481		 Hernández-Díaz (Valproate) (Controls exposed to Lamotrigine, sick), 2012 Hypospadias 1st trimester prospective cohort exposed to other treatment, sick Adjustment: No Controls: mixed indications 54.10 [2.98;980.87] C 5/323   0/1,562 5 323
ref
S9331
R32552		 Bànhidy (Valproate), 2011 Hypospadias throughout pregnancy case control unexposed, sick Adjustment: No Matched 2.00 [0.29;13.74] C 3/8   3/13 6 8
ref
S9444
R33168		 Diav-Citrin (Valproate) (Mixed indications), 2008 Hypospadias at least 1st trimester prospective cohort unexposed (general population or NOS) Adjustment: No 4.40 [0.49;39.89] C 1/71   4/1,236 5 71
ref
S9297
R32306		 D'Souza (Valproate) (Controls unexposed, disease free), 1991 Hypospadias throughout pregnancy prospective cohort unexposed, disease free excluded Adjustment: No Matched 123.00 [1.00;15058.31] C
excluded (control group) 		0/1   0/62 0 1
ref
S9298
R32335		 D'Souza (Valproate) (Controls unexposed, sick), 1991 Hypospadias throughout pregnancy prospective cohort unexposed, sick Adjustment: No 15.00 [0.12;1923.88] C 0/1   0/8 0 1
ref
Total 10 studies 5.88 [4.60;7.51] 9,567 6,978
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 (Valproate) (Mixed indications) (Controls unexposed, NOS), 2023Cohen, 2023 1 6.47[4.32; 9.69]-2,03135%ROB confusion: seriousROB selection: lowROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Blotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019Blotière, 2019 2 4.80[2.40; 9.80]3,37991312%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Tomson (Valproate), 2018Tomson, 2018 3 6.77[2.74; 16.73]281,3817%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014Campbell, 2014 4 2.60[1.16; 5.81]251,2209%ROB confusion: criticalROB selection: lowROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Veiby (Valproate) (Controls unexposed, disease free) (Mixed indications), 2014Veiby, 2014 5 5.71[2.13; 15.30]1,5473336%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: moderateROB mesure: moderateROB reporting: moderate Källén (Valproate) (Controls unexposed, NOS) (Indications NOS), 2013Källén, 2013 6 7.33[4.48; 11.30]4,57269727%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Hernández-Díaz (Valproate) (Controls exposed to Lamotrigine, sick), 2012Hernández-Díaz, 2012 7 54.10[2.98; 980.87]53231%ROB confusion: moderateROB selection: lowROB classification: moderateROB missing: moderateROB mesure: moderateROB reporting: moderate Bànhidy (Valproate), 2011Bànhidy, 2011 8 2.00[0.29; 13.74]682%ROB confusion: criticalROB selection: criticalROB classification: lowROB missing: lowROB mesure: moderateROB reporting: moderate Diav-Citrin (Valproate) (Mixed indications), 2008Diav-Citrin, 2008 9 4.40[0.49; 39.89]5711%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA D'Souza (Valproate) (Controls unexposed, sick), 1991D'Souza, 1991 10 15.00[0.12; 1923.88]010%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Total (10 studies) I2 = 1% 5.88[4.60; 7.51]9,5676,9780.9500.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

1: Valproate) (Mixed indications) (Controls unexposed, NOS; 2: Valproate) (Controls unexposed NOS) (Mixed indications; 3: Valproate; 4: Valproate) (Controls exposed to Lamotrigine, sick; 5: Valproate) (Controls unexposed, disease free) (Mixed indications; 6: Valproate) (Controls unexposed, NOS) (Indications NOS; 7: Valproate) (Controls exposed to Lamotrigine, sick; 8: Valproate; 9: Valproate) (Mixed indications; 10: Valproate) (Controls unexposed, sick;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 6.00[4.70; 7.64]9,5616,9700%NACohen (Valproate) (Mixed indications) (Controls unexposed, NOS), 2023 Blotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019 Tomson (Valproate), 2018 Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014 Veiby (Valproate) (Controls unexposed, disease free) (Mixed indications), 2014 Källén (Valproate) (Controls unexposed, NOS) (Indications NOS), 2013 Hernández-Díaz (Valproate) (Controls exposed to Lamotrigine, sick), 2012 Diav-Citrin (Valproate) (Mixed indications), 2008 D'Souza (Valproate) (Controls unexposed, sick), 1991 9 case control studiescase control studies 2.00[0.29; 13.74]68 -NABànhidy (Valproate), 2011 1 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 6.37[4.88; 8.31]9,5034,0450%NACohen (Valproate) (Mixed indications) (Controls unexposed, NOS), 2023 Blotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019 Veiby (Valproate) (Controls unexposed, disease free) (Mixed indications), 2014 Källén (Valproate) (Controls unexposed, NOS) (Indications NOS), 2013 Diav-Citrin (Valproate) (Mixed indications), 2008 5 unexposed, sickunexposed, sick 2.63[0.44; 15.78]690%NABànhidy (Valproate), 2011 D'Souza (Valproate) (Controls unexposed, sick), 1991 2 exposed to other treatment, sickexposed to other treatment, sick 5.66[1.82; 17.62]582,92463%NATomson (Valproate), 2018 Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014 Hernández-Díaz (Valproate) (Controls exposed to Lamotrigine, sick), 2012 3 Tags Adjustment   - No  - No 4.45[2.24; 8.84]693,00420%NATomson (Valproate), 2018 Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014 Hernández-Díaz (Valproate) (Controls exposed to Lamotrigine, sick), 2012 Bànhidy (Valproate), 2011 Diav-Citrin (Valproate) (Mixed indications), 2008 D'Souza (Valproate) (Controls unexposed, sick), 1991 6   - Yes  - Yes 6.40[4.89; 8.37]9,4983,9740%NACohen (Valproate) (Mixed indications) (Controls unexposed, NOS), 2023 Blotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019 Veiby (Valproate) (Controls unexposed, disease free) (Mixed indications), 2014 Källén (Valproate) (Controls unexposed, NOS) (Indications NOS), 2013 4 Controls   - mixed indications  - mixed indications 54.10[2.98; 980.87]5323 -NAHernández-Díaz (Valproate) (Controls exposed to Lamotrigine, sick), 2012 1 MatchedMatched 2.00[0.29; 13.74]68 -NABànhidy (Valproate), 2011 1 All studiesAll studies 5.88[4.60; 7.51]9,5676,9781%NACohen (Valproate) (Mixed indications) (Controls unexposed, NOS), 2023 Blotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019 Tomson (Valproate), 2018 Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014 Veiby (Valproate) (Controls unexposed, disease free) (Mixed indications), 2014 Källén (Valproate) (Controls unexposed, NOS) (Indications NOS), 2013 Hernández-Díaz (Valproate) (Controls exposed to Lamotrigine, sick), 2012 Bànhidy (Valproate), 2011 Diav-Citrin (Valproate) (Mixed indications), 2008 D'Souza (Valproate) (Controls unexposed, sick), 1991 100.51000.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-5.87.62.9720.000Cohen (Valproate) (Mixed indications) (Controls unexposed, NOS), 2023Blotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019Tomson (Valproate), 2018Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014Veiby (Valproate) (Controls unexposed, disease free) (Mixed indications), 2014Källén (Valproate) (Controls unexposed, NOS) (Indications NOS), 2013Hernández-Díaz (Valproate) (Controls exposed to Lamotrigine, sick), 2012Bànhidy (Valproate), 2011Diav-Citrin (Valproate) (Mixed indications), 2008D'Souza (Valproate) (Controls unexposed, sick), 1991

Asymetry test p-value = 0.8201 (by Egger's regression)

slope=1.8204 (0.2363); intercept=-0.1429 (0.6082); t=0.2350; p=0.8201

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 9297, 9309, 9325, 10174

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 6.42[4.92; 8.38]9,5034,0460%NACohen (Valproate) (Mixed indications) (Controls unexposed, NOS), 2023 Blotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019 Veiby (Valproate) (Controls unexposed, disease free) (Mixed indications), 2014 Källén (Valproate) (Controls unexposed, NOS) (Indications NOS), 2013 Diav-Citrin (Valproate) (Mixed indications), 2008 D'Souza (Valproate) (Controls unexposed, disease free), 1991 6 unexposed, sick controlsunexposed, sick controls 2.63[0.44; 15.78]690%NABànhidy (Valproate), 2011 D'Souza (Valproate) (Controls unexposed, sick), 1991 2 exposed to other treatment, sick controlsexposed to other treatment, sick controls 4.86[2.67; 8.84]1044,86738%NABlotière (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2019 Tomson (Valproate), 2018 Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014 Veiby (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2014 Källén (Valproate) (Controls exposed to Lamotrigine, sick) (Indications NOS), 2013 Hernández-Díaz (Valproate) (Controls exposed to Lamotrigine, sick), 2012 60.510.01.0