Primidone AND Phenobarbital (Epilepsy) updated on 04-22-2025

Major congenital malformations

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.
S12840
R48384		 Thomas (Phenobarbital) (Controls exposed to Lamotrigine, sick), 2021 Major congenital malformations 1st trimester prospective cohort exposed to other treatment, sick excluded Adjustment: No 3.04 [0.37;24.93] C
excluded (control group) 		8/137   1/50 9 137
ref
S12843
R48404		 Thomas (Phenobarbital) (Controls unexposed, disease free), 2021 Major congenital malformations 1st trimester prospective cohort unexposed, disease free excluded Adjustment: No 1.57 [0.62;3.97]
excluded (control group) 		7/129   11/319 18 129
ref
S12845
R48418		 Thomas (Phenobarbital) (Controls unexposed, sick), 2021 Major congenital malformations 1st trimester prospective cohort unexposed, sick Adjustment: Yes 1.20 [0.50;2.70] 8/137   16/340 24 137
ref
S8695
R29321		 Vajda (Phenobarbital or Primidone) (Controls exposed to Lamotrigine, sick), 2019 Fetal malformations at least 1st trimester prospective cohort exposed to other treatment, sick excluded Adjustment: No 2.69 [0.13;53.76] C
excluded (control group) 		0/4   20/406 20 4
ref
S8696
R29322		 Vajda (Phenobarbital or Primidone) (Controls unexposed, sick), 2019 Fetal malformations at least 1st trimester prospective cohort unexposed, sick Adjustment: No 4.43 [0.20;96.60] C 0/4   5/176 5 4
ref
S8694
R29311		 Tomson (Phenobarbital or Primidone), 2018 Major congenital malformation at least 1st trimester prospective cohort exposed to other treatment, sick Adjustment: No 2.33 [1.42;3.80] C 22/334   74/2,514 96 334
ref
S8666
R29189		 Veiby (Phenobarbital) (Controls exposed to Lamotrigine, sick), 2014 Major malformations throughout pregnancy population based cohort retrospective exposed to other treatment, sick excluded Adjustment: No 0.69 [0.04;11.87] C
excluded (control group) 		0/18   23/593 23 18
ref
S8667
R29193		 Veiby (Phenobarbital) (Controls unexposed, disease free), 2014 Major malformations throughout pregnancy population based cohort retrospective unexposed, disease free excluded Adjustment: No 0.96 [0.06;15.91] C
excluded (control group) 		0/18   22,371/771,412 22,371 18
ref
S8668
R29195		 Veiby (Phenobarbital) (Controls unexposed, sick), 2014 Major malformations throughout pregnancy population based cohort retrospective unexposed, sick Adjustment: No 0.98 [0.06;16.47] C 0/18   106/3,773 106 18
ref
S8656
R29146		 Hernández-Díaz (Phenobarbital) (Controls exposed to Lamotrigine, sick), 2012 Major congenital malformations 1st trimester prospective cohort exposed to other treatment, sick excluded Adjustment: No Controls: mixed indications 2.50 [0.90;6.80]
excluded (control group) 		-/-   -/- - -
ref
S8657
R29152		 Hernández-Díaz (Phenobarbital) (Controls unexposed, disease free), 2012 Major congenital malformations 1st trimester prospective cohort unexposed, disease free Adjustment: No 5.10 [1.80;14.90] 11/199   5/442 16 199
ref
S8671
R29210		 Bànhidy (Phenobarbital or Primidone), 2011 Total congenital abnormalities throughout pregnancy case control unexposed, sick Adjustment: No Matched 0.69 [0.16;2.97] C 5/11   12/22 17 11
ref
S8678
R29225		 Kaaja (Phenobarbital or Primidone), 2003 Major malformation 1st trimester prospective cohort unexposed, sick Adjustment: No 11.85 [0.99;141.86] C 1/11   2/239 3 11
ref
S8652
R29099		 Dean (Phenobarbital or Primidone), 2002 Major congenital malformations at least 1st trimester retrospective cohort unexposed, sick Adjustment: No 1.89 [0.36;9.90] C 6/63   2/38 8 63
ref
S8658
R29154		 Holmes (Phenobarbital) (Controls unexposed, disease free), 2001 Major malformations during pregnancy (anytime or not specified) retrospective cohort unexposed, disease free excluded Adjustment: Yes 2.70 [0.60;16.40]
excluded (control group) 		3/64   9/508 12 64
ref
S8659
R29163		 Holmes (Phenobarbital) (Controls unexposed, sick), 2001 Major malformations during pregnancy (anytime or not specified) excluded retrospective cohort unexposed, sick Adjustment: No 11.28 [0.57;222.22] C
excluded (exposition period) 		3/64   0/98 3 64
ref
S8673
R29217		 Canger (Phenobarbital or Primidone), 1999 Severe malformations 1st trimester prospective cohort unexposed, sick Adjustment: No 1.94 [0.10;37.28] C 4/118   0/25 4 118
ref
S8688
R29300		 Samrén (Phenobarbital or Primidone), 1999 Major congential abnormalities at least 1st trimester retrospective cohort unexposed, disease free Adjustment: No Matched 1.78 [0.68;4.65] C 5/196   29/2,000 34 196
ref
S8689
R29302		 Steegers-Theunissen (Phenobarbital or Primidone), 1994 Major malformations (ICD9 British Paediatric Association System) during pregnancy (anytime or not specified) excluded prospective cohort unexposed, disease free Adjustment: No 4.33 [0.37;51.42] C
excluded (exposition period) 		1/13   2/106 3 13
ref
S8687
R29297		 Robert (Phenobarbital), 1986 Major malformations 1st trimester retrospective cohort unexposed, sick Adjustment: No 4.60 [0.21;99.23] C 2/40   0/35 2 40
ref
S8680
R29228		 Kelly (Phenobarbital), 1984 Major abnormality during pregnancy (anytime or not specified) excluded prospective cohort unexposed, sick Adjustment: No 0.52 [0.02;13.80] C
excluded (exposition period) 		0/13   1/21 1 13
ref
Total 11 studies 2.11 [1.51;2.94] 315 1,131
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 (Phenobarbital) (Controls unexposed, sick), 2021Thomas, 2021 1 1.20[0.50; 2.70]2413716%ROB confusion: seriousROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Vajda (Phenobarbital or Primidone) (Controls unexposed, sick), 2019Vajda, 2019 2 4.43[0.20; 96.60]541%ROB confusion: criticalROB selection: moderateROB classification: lowROB missing: moderateROB mesure: moderateROB reporting: moderate Tomson (Phenobarbital or Primidone), 2018Tomson, 2018 3 2.33[1.42; 3.80]9633446%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Veiby (Phenobarbital) (Controls unexposed, sick), 2014Veiby, 2014 4 0.98[0.06; 16.47]106181%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: moderateROB mesure: moderateROB reporting: moderate Hernández-Díaz (Phenobarbital) (Controls unexposed, disease free), 2012Hernández-Díaz, 2012 5 5.10[1.80; 14.90]1619910%ROB confusion: moderateROB selection: lowROB classification: moderateROB missing: moderateROB mesure: moderateROB reporting: moderate Bànhidy (Phenobarbital or Primidone), 2011Bànhidy, 2011 6 0.69[0.16; 2.97]17115%ROB confusion: criticalROB selection: criticalROB classification: lowROB missing: lowROB mesure: moderateROB reporting: moderate Kaaja (Phenobarbital or Primidone), 2003Kaaja, 2003 7 11.85[0.99; 141.86]3112%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Dean (Phenobarbital or Primidone), 2002Dean, 2002 8 1.89[0.36; 9.90]8634%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Canger (Phenobarbital or Primidone), 1999Canger, 1999 9 1.94[0.10; 37.28]41181%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Samrén (Phenobarbital or Primidone), 1999Samrén, 1999 10 1.78[0.68; 4.65]3419612%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Robert (Phenobarbital), 1986Robert, 1986 11 4.60[0.21; 99.23]2401%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Total (11 studies) I2 = 0% 2.11[1.51; 2.94]3151,1310.250.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

1: Phenobarbital) (Controls unexposed, sick; 2: Phenobarbital or Primidone) (Controls unexposed, sick; 3: Phenobarbital or Primidone; 4: Phenobarbital) (Controls unexposed, sick; 5: Phenobarbital) (Controls unexposed, disease free; 6: Phenobarbital or Primidone; 7: Phenobarbital or Primidone; 8: Phenobarbital or Primidone; 9: Phenobarbital or Primidone; 10: Phenobarbital or Primidone; 11: Phenobarbital;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 2.24[1.59; 3.16]2981,1200%NAThomas (Phenobarbital) (Controls unexposed, sick), 2021 Vajda (Phenobarbital or Primidone) (Controls unexposed, sick), 2019 Tomson (Phenobarbital or Primidone), 2018 Veiby (Phenobarbital) (Controls unexposed, sick), 2014 Hernández-Díaz (Phenobarbital) (Controls unexposed, disease free), 2012 Kaaja (Phenobarbital or Primidone), 2003 Dean (Phenobarbital or Primidone), 2002 Canger (Phenobarbital or Primidone), 1999 Samrén (Phenobarbital or Primidone), 1999 Robert (Phenobarbital), 1986 10 case control studiescase control studies 0.69[0.16; 2.97]1711 -NABànhidy (Phenobarbital or Primidone), 2011 1 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 2.94[1.05; 8.25]5039552%NAHernández-Díaz (Phenobarbital) (Controls unexposed, disease free), 2012 Samrén (Phenobarbital or Primidone), 1999 2 unexposed, sickunexposed, sick 1.47[0.82; 2.66]1694020%NAThomas (Phenobarbital) (Controls unexposed, sick), 2021 Vajda (Phenobarbital or Primidone) (Controls unexposed, sick), 2019 Veiby (Phenobarbital) (Controls unexposed, sick), 2014 Bànhidy (Phenobarbital or Primidone), 2011 Kaaja (Phenobarbital or Primidone), 2003 Dean (Phenobarbital or Primidone), 2002 Canger (Phenobarbital or Primidone), 1999 Robert (Phenobarbital), 1986 8 exposed to other treatment, sickexposed to other treatment, sick 2.33[1.42; 3.80]96334 -NATomson (Phenobarbital or Primidone), 2018 1 Tags Adjustment   - No  - No 2.34[1.63; 3.36]2919940%NAVajda (Phenobarbital or Primidone) (Controls unexposed, sick), 2019 Tomson (Phenobarbital or Primidone), 2018 Veiby (Phenobarbital) (Controls unexposed, sick), 2014 Hernández-Díaz (Phenobarbital) (Controls unexposed, disease free), 2012 Bànhidy (Phenobarbital or Primidone), 2011 Kaaja (Phenobarbital or Primidone), 2003 Dean (Phenobarbital or Primidone), 2002 Canger (Phenobarbital or Primidone), 1999 Samrén (Phenobarbital or Primidone), 1999 Robert (Phenobarbital), 1986 10   - Yes  - Yes 1.20[0.52; 2.79]24137 -NAThomas (Phenobarbital) (Controls unexposed, sick), 2021 1 MatchedMatched 1.31[0.55; 3.11]5120711%NABànhidy (Phenobarbital or Primidone), 2011 Samrén (Phenobarbital or Primidone), 1999 2 All studiesAll studies 2.11[1.51; 2.94]3151,1310%NAThomas (Phenobarbital) (Controls unexposed, sick), 2021 Vajda (Phenobarbital or Primidone) (Controls unexposed, sick), 2019 Tomson (Phenobarbital or Primidone), 2018 Veiby (Phenobarbital) (Controls unexposed, sick), 2014 Hernández-Díaz (Phenobarbital) (Controls unexposed, disease free), 2012 Bànhidy (Phenobarbital or Primidone), 2011 Kaaja (Phenobarbital or Primidone), 2003 Dean (Phenobarbital or Primidone), 2002 Canger (Phenobarbital or Primidone), 1999 Samrén (Phenobarbital or Primidone), 1999 Robert (Phenobarbital), 1986 110.250.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-3.74.41.8870.000Thomas (Phenobarbital) (Controls unexposed, sick), 2021Vajda (Phenobarbital or Primidone) (Controls unexposed, sick), 2019Tomson (Phenobarbital or Primidone), 2018Veiby (Phenobarbital) (Controls unexposed, sick), 2014Hernández-Díaz (Phenobarbital) (Controls unexposed, disease free), 2012Bànhidy (Phenobarbital or Primidone), 2011Kaaja (Phenobarbital or Primidone), 2003Dean (Phenobarbital or Primidone), 2002Canger (Phenobarbital or Primidone), 1999Samrén (Phenobarbital or Primidone), 1999Robert (Phenobarbital), 1986

Asymetry test p-value = 0.7940 (by Egger's regression)

slope=0.6753 (0.3123); intercept=0.1489 (0.5536); t=0.2691; p=0.7940

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 8658, 8656, 8666, 8667, 8695, 12840, 12843

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 2.22[1.21; 4.09]22,43954213%NAThomas (Phenobarbital) (Controls unexposed, disease free), 2021 Veiby (Phenobarbital) (Controls unexposed, disease free), 2014 Hernández-Díaz (Phenobarbital) (Controls unexposed, disease free), 2012 Samrén (Phenobarbital or Primidone), 1999 4 unexposed, sick controlsunexposed, sick controls 1.47[0.82; 2.66]1694020%NAThomas (Phenobarbital) (Controls unexposed, sick), 2021 Vajda (Phenobarbital or Primidone) (Controls unexposed, sick), 2019 Veiby (Phenobarbital) (Controls unexposed, sick), 2014 Bànhidy (Phenobarbital or Primidone), 2011 Kaaja (Phenobarbital or Primidone), 2003 Dean (Phenobarbital or Primidone), 2002 Canger (Phenobarbital or Primidone), 1999 Robert (Phenobarbital), 1986 8 exposed to other treatment, sick controlsexposed to other treatment, sick controls 2.32[1.52; 3.55]1484930%NAThomas (Phenobarbital) (Controls exposed to Lamotrigine, sick), 2021 Vajda (Phenobarbital or Primidone) (Controls exposed to Lamotrigine, sick), 2019 Tomson (Phenobarbital or Primidone), 2018 Veiby (Phenobarbital) (Controls exposed to Lamotrigine, sick), 2014 Hernández-Díaz (Phenobarbital) (Controls exposed to Lamotrigine, sick), 2012 50.510.01.0