Primidone AND Phenobarbital (All indications) 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.
S16802
R70500		 The NAAED (Phenobarbital) (Controls exposed to LTG) (Indications NOS), 2023 Major congenital malformations 1st trimester prospective cohort exposed to other treatment, sick excluded Adjustment: No 2.96 [1.55;5.64] C
excluded (control group) 		12/200   52/2,461 64 200
ref
S16803
R70502		 The NAAED (Phenobarbital) (Controls unexposed, disease free) (Indications NOS), 2023 Major congenital malformations 1st trimester prospective cohort unexposed, disease free Adjustment: No 5.51 [2.54;11.96] C 12/200   15/1,311 27 200
ref
S12841
R48394		 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
S12842
R48402		 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
S12844
R48408		 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
S9587
R33953		 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
S9588
R33954		 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
S9586
R33943		 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
S9485
R33352		 Barroso (Phenobarbital), 2015 Major anomalies during pregnancy (anytime or not specified) excluded retrospective cohort unexposed, disease free Adjustment: No 2.11 [0.68;6.62] C
excluded (exposition period) 		4/32   20/316 24 32
ref
S9506
R33534		 Veiby (Phenobarbital) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2014 Major congenital malformation throughout pregnancy population based cohort retrospective exposed to other treatment, sick excluded Adjustment: No 2.30 [0.52;10.19] C
excluded (control group) 		2/27   28/833 30 27
ref
S9507
R33536		 Veiby (Phenobarbital) (Controls unexposed, disease free) (Mixed indications), 2014 Major malformations throughout pregnancy population based cohort retrospective unexposed, disease free excluded Adjustment: Yes 2.75 [0.65;11.60]
excluded (control group) 		2/27   22,371/771,412 22,373 27
ref
S9566
R33870		 Veiby (Phenobarbital) (Controls unexposed, sick) (Mixed indications), 2014 Major malformations throughout pregnancy population based cohort retrospective unexposed, sick Adjustment: No Controls: epilepsy indication 2.77 [0.65;11.84] C 2/27   106/3,773 108 27
ref
S9515
R33600		 Cassina (Phenobarbital) (Controls exposed to Lamotrigine, sick) (Other indications), 2013 Major congenital anomalies 1st trimester prospective cohort exposed to other treatment, sick excluded Adjustment: No 6.43 [0.11;379.68] C
excluded (control group) 		0/4   0/23 0 4
ref
S9516
R33602		 Cassina (Phenobarbital) (Controls unexposed, disease free) (Other indications), 2013 Major congenital anomalies 1st trimester prospective cohort unexposed, disease free Adjustment: No 4.36 [0.22;86.56] C 0/4   25/803 25 4
ref
S9572
R33909		 Källén (Phenobarbital or Primidone) (Controls exposed to Lamotrigine, sick) (Indications NOS), 2013 Relatively severe malformations early pregnancy population based cohort retrospective exposed to other treatment, sick excluded Adjustment: No 2.36 [0.54;10.35] C
excluded (control group) 		2/26   37/1,084 39 26
ref
S9573
R33911		 Källén (Phenobarbital or Primidone) (Controls unexposed, NOS) (Indications NOS), 2013 Relatively severe malformations early pregnancy population based cohort retrospective unexposed (general population or NOS) Adjustment: No 2.57 [0.61;10.87] C 2/26   49,499/1,575,847 49,501 26
ref
S9575
R33921		 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
S9578
R33930		 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
S9571
R33893		 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
S9497
R33478		 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
S9498
R33487		 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
S9577
R33928		 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
S9584
R33939		 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
S9585
R33941		 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
S9530
R33682		 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
S9522
R33612		 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 13 studies 2.36 [1.71;3.25] 49,854 1,171
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 The NAAED (Phenobarbital) (Controls unexposed, disease free) (Indications NOS), 2023The NAAED, 2023 1 5.51[2.54; 11.96]2720016%ROB confusion: criticalROB selection: unclearROB classification: moderateROB missing: unclearROB mesure: criticalROB reporting: low Thomas (Phenobarbital) (Controls unexposed, sick), 2021Thomas, 2021 2 1.20[0.50; 2.70]2413714%ROB confusion: seriousROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Vajda (Phenobarbital or Primidone) (Controls unexposed, sick), 2019Vajda, 2019 3 4.43[0.20; 96.60]541%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Tomson (Phenobarbital or Primidone), 2018Tomson, 2018 4 2.33[1.42; 3.80]9633436%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Veiby (Phenobarbital) (Controls unexposed, sick) (Mixed indications), 2014Veiby, 2014 5 2.77[0.65; 11.84]108275%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: moderateROB mesure: moderateROB reporting: moderate Cassina (Phenobarbital) (Controls unexposed, disease free) (Other indications), 2013Cassina, 2013 6 4.36[0.22; 86.56]2541%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Källén (Phenobarbital or Primidone) (Controls unexposed, NOS) (Indications NOS), 2013Källén, 2013 7 2.57[0.61; 10.87]49,501265%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Bànhidy (Phenobarbital or Primidone), 2011Bànhidy, 2011 8 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 9 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 10 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 11 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 12 1.78[0.68; 4.65]3419611%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Robert (Phenobarbital), 1986Robert, 1986 13 4.60[0.21; 99.23]2401%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Total (13 studies) I2 = 3% 2.36[1.71; 3.25]49,8541,1710.250.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

1: Phenobarbital) (Controls unexposed, disease free) (Indications NOS; 2: Phenobarbital) (Controls unexposed, sick; 3: Phenobarbital or Primidone) (Controls unexposed, sick; 4: Phenobarbital or Primidone; 5: Phenobarbital) (Controls unexposed, sick) (Mixed indications; 6: Phenobarbital) (Controls unexposed, disease free) (Other indications; 7: Phenobarbital or Primidone) (Controls unexposed, NOS) (Indications NOS; 8: Phenobarbital or Primidone; 9: Phenobarbital or Primidone; 10: Phenobarbital or Primidone; 11: Phenobarbital or Primidone; 12: Phenobarbital or Primidone; 13: Phenobarbital;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 2.50[1.83; 3.41]49,8371,1600%NAThe NAAED (Phenobarbital) (Controls unexposed, disease free) (Indications NOS), 2023 Thomas (Phenobarbital) (Controls unexposed, sick), 2021 Vajda (Phenobarbital or Primidone) (Controls unexposed, sick), 2019 Tomson (Phenobarbital or Primidone), 2018 Veiby (Phenobarbital) (Controls unexposed, sick) (Mixed indications), 2014 Cassina (Phenobarbital) (Controls unexposed, disease free) (Other indications), 2013 Källén (Phenobarbital or Primidone) (Controls unexposed, NOS) (Indications NOS), 2013 Kaaja (Phenobarbital or Primidone), 2003 Dean (Phenobarbital or Primidone), 2002 Canger (Phenobarbital or Primidone), 1999 Samrén (Phenobarbital or Primidone), 1999 Robert (Phenobarbital), 1986 12 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) 3.32[1.80; 6.10]49,58742612%NAThe NAAED (Phenobarbital) (Controls unexposed, disease free) (Indications NOS), 2023 Cassina (Phenobarbital) (Controls unexposed, disease free) (Other indications), 2013 Källén (Phenobarbital or Primidone) (Controls unexposed, NOS) (Indications NOS), 2013 Samrén (Phenobarbital or Primidone), 1999 4 unexposed, sickunexposed, sick 1.64[0.94; 2.87]1714110%NAThomas (Phenobarbital) (Controls unexposed, sick), 2021 Vajda (Phenobarbital or Primidone) (Controls unexposed, sick), 2019 Veiby (Phenobarbital) (Controls unexposed, sick) (Mixed indications), 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 2.61[1.88; 3.63]49,8301,0340%NAThe NAAED (Phenobarbital) (Controls unexposed, disease free) (Indications NOS), 2023 Vajda (Phenobarbital or Primidone) (Controls unexposed, sick), 2019 Tomson (Phenobarbital or Primidone), 2018 Veiby (Phenobarbital) (Controls unexposed, sick) (Mixed indications), 2014 Cassina (Phenobarbital) (Controls unexposed, disease free) (Other indications), 2013 Källén (Phenobarbital or Primidone) (Controls unexposed, NOS) (Indications NOS), 2013 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 12   - Yes  - Yes 1.20[0.52; 2.79]24137 -NAThomas (Phenobarbital) (Controls unexposed, sick), 2021 1 Controls   - epilepsy indication  - epilepsy indication 2.77[0.65; 11.84]10827 -NAVeiby (Phenobarbital) (Controls unexposed, sick) (Mixed indications), 2014 1 MatchedMatched 1.31[0.55; 3.11]5120711%NABànhidy (Phenobarbital or Primidone), 2011 Samrén (Phenobarbital or Primidone), 1999 2 All studiesAll studies 2.36[1.71; 3.25]49,8541,1713%NAThe NAAED (Phenobarbital) (Controls unexposed, disease free) (Indications NOS), 2023 Thomas (Phenobarbital) (Controls unexposed, sick), 2021 Vajda (Phenobarbital or Primidone) (Controls unexposed, sick), 2019 Tomson (Phenobarbital or Primidone), 2018 Veiby (Phenobarbital) (Controls unexposed, sick) (Mixed indications), 2014 Cassina (Phenobarbital) (Controls unexposed, disease free) (Other indications), 2013 Källén (Phenobarbital or Primidone) (Controls unexposed, NOS) (Indications NOS), 2013 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 130.250.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-3.74.61.8870.000The NAAED (Phenobarbital) (Controls unexposed, disease free) (Indications NOS), 2023Thomas (Phenobarbital) (Controls unexposed, sick), 2021Vajda (Phenobarbital or Primidone) (Controls unexposed, sick), 2019Tomson (Phenobarbital or Primidone), 2018Veiby (Phenobarbital) (Controls unexposed, sick) (Mixed indications), 2014Cassina (Phenobarbital) (Controls unexposed, disease free) (Other indications), 2013Källén (Phenobarbital or Primidone) (Controls unexposed, NOS) (Indications NOS), 2013Bànhidy (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 = 0.7251 (by Egger's regression)

slope=0.7651 (0.3069); intercept=0.1970 (0.5459); t=0.3608; p=0.7251

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 9497, 9515, 9572, 9506, 9507, 9587, 12841, 12842, 16802

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 2.75[1.72; 4.42]71,9785827%NAThe NAAED (Phenobarbital) (Controls unexposed, disease free) (Indications NOS), 2023 Thomas (Phenobarbital) (Controls unexposed, disease free), 2021 Veiby (Phenobarbital) (Controls unexposed, disease free) (Mixed indications), 2014 Cassina (Phenobarbital) (Controls unexposed, disease free) (Other indications), 2013 Källén (Phenobarbital or Primidone) (Controls unexposed, NOS) (Indications NOS), 2013 Samrén (Phenobarbital or Primidone), 1999 6 unexposed, sick controlsunexposed, sick controls 1.64[0.94; 2.87]1714110%NAThomas (Phenobarbital) (Controls unexposed, sick), 2021 Vajda (Phenobarbital or Primidone) (Controls unexposed, sick), 2019 Veiby (Phenobarbital) (Controls unexposed, sick) (Mixed indications), 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 2.55[1.78; 3.64]2587320%NAThe NAAED (Phenobarbital) (Controls exposed to LTG) (Indications NOS), 2023 Thomas (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) (Mixed indications), 2014 Cassina (Phenobarbital) (Controls exposed to Lamotrigine, sick) (Other indications), 2013 Källén (Phenobarbital or Primidone) (Controls exposed to Lamotrigine, sick) (Indications NOS), 2013 70.510.01.0