Phenobarbital (Epilepsy)

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.
S12834
R48341		 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
S7550
R22592		 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
S12835
R48351		 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
S7786
R23004		 Vajda (Phenobarbital) (Controls exposed to Lamotrigine, sick), 2019 Fetal malformations at least 1st trimester prospective cohort exposed to other treatment, sick excluded Adjustment: No 6.27 [0.25;158.67] C
excluded (control group) 		0/2   20/406 20 2
ref
S7787
R23005		 Vajda (Phenobarbital) (Controls unexposed, sick), 2019 Fetal malformations at least 1st trimester prospective cohort unexposed, sick Adjustment: No 10.33 [0.38;283.37] C 0/2   5/176 5 2
ref
S7660
R22658		 Tomson (Phenobarbital), 2018 Major congenital malformation at least 1st trimester prospective cohort exposed to other treatment, sick Adjustment: No 2.28 [1.36;3.83] C 19/294   74/2,514 93 294
ref
S6723
R19005		 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
S6321
R17143		 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
S6322
R17144		 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
S6323
R17145		 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
S5941
R15203		 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
S7936
R24012		 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
S6500
R17861		 Bànhidy (Phenobarbital), 2011 Total congenital abnormalities throughout pregnancy case control unexposed, sick Adjustment: No Matched 2.48 [0.09;68.14] C 1/1   12/22 13 1
ref
S6139
R16033		 Kaaja (Phenobarbital), 2003 Major malformation 1st trimester prospective cohort unexposed, sick Adjustment: No 10.51 [0.44;251.86] C 0/5   2/239 2 5
ref
S6678
R18480		 Dean (Phenobarbital), 2002 Major congenital malformations at least 1st trimester retrospective cohort unexposed, sick Adjustment: No 1.96 [0.38;10.27] C 6/61   2/38 8 61
ref
S5865
R14585		 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
S5866
R14593		 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
S7171
R26575		 Canger (Phenobarbital), 1999 Severe malformations 1st trimester prospective cohort unexposed, sick Adjustment: No 1.52 [0.07;32.78] C 2/83   0/25 2 83
ref
S5515
R18983		 Samrén (Phenobarbital), 1999 Major congential abnormalities at least 1st trimester retrospective cohort unexposed, disease free Adjustment: No Matched 1.96 [0.75;5.14] C 5/178   29/2,000 34 178
ref
S6708
R18980		 Steegers-Theunissen (Phenobarbital), 1994 Major malformations (ICD9 British Paediatric Association System) during pregnancy (anytime or not specified) excluded prospective cohort unexposed, disease free Adjustment: No 1.80 [0.08;39.83] C
excluded (exposition period) 		0/12   2/106 2 12
ref
S5514
R16205		 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
S6953
R19666		 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 2.23 [1.57;3.17] 305 1,018
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]2413717%ROB confusion: seriousROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Vajda (Phenobarbital) (Controls unexposed, sick), 2019Vajda, 2019 2 10.33[0.38; 283.37]521%ROB confusion: criticalROB selection: moderateROB classification: lowROB missing: moderateROB mesure: moderateROB reporting: moderate Tomson (Phenobarbital), 2018Tomson, 2018 3 2.28[1.36; 3.83]9329446%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]106182%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]1619911%ROB confusion: moderateROB selection: lowROB classification: moderateROB missing: moderateROB mesure: moderateROB reporting: moderate Bànhidy (Phenobarbital), 2011Bànhidy, 2011 6 2.48[0.09; 68.14]1311%ROB confusion: criticalROB selection: criticalROB classification: lowROB missing: lowROB mesure: moderateROB reporting: moderate Kaaja (Phenobarbital), 2003Kaaja, 2003 7 10.51[0.44; 251.86]251%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Dean (Phenobarbital), 2002Dean, 2002 8 1.96[0.38; 10.27]8615%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Canger (Phenobarbital), 1999Canger, 1999 9 1.52[0.07; 32.78]2831%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Samrén (Phenobarbital), 1999Samrén, 1999 10 1.96[0.75; 5.14]3417813%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% 2.23[1.57; 3.17]3051,0180.250.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

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

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 2.23[1.56; 3.17]2921,0170%NAThomas (Phenobarbital) (Controls unexposed, sick), 2021 Vajda (Phenobarbital) (Controls unexposed, sick), 2019 Tomson (Phenobarbital), 2018 Veiby (Phenobarbital) (Controls unexposed, sick), 2014 Hernández-Díaz (Phenobarbital) (Controls unexposed, disease free), 2012 Kaaja (Phenobarbital), 2003 Dean (Phenobarbital), 2002 Canger (Phenobarbital), 1999 Samrén (Phenobarbital), 1999 Robert (Phenobarbital), 1986 10 case control studiescase control studies 2.48[0.09; 68.14]131 -NABànhidy (Phenobarbital), 2011 1 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 3.08[1.21; 7.84]5037742%NAHernández-Díaz (Phenobarbital) (Controls unexposed, disease free), 2012 Samrén (Phenobarbital), 1999 2 unexposed, sickunexposed, sick 1.68[0.88; 3.20]1623470%NAThomas (Phenobarbital) (Controls unexposed, sick), 2021 Vajda (Phenobarbital) (Controls unexposed, sick), 2019 Veiby (Phenobarbital) (Controls unexposed, sick), 2014 Bànhidy (Phenobarbital), 2011 Kaaja (Phenobarbital), 2003 Dean (Phenobarbital), 2002 Canger (Phenobarbital), 1999 Robert (Phenobarbital), 1986 8 exposed to other treatment, sickexposed to other treatment, sick 2.28[1.36; 3.83]93294 -NATomson (Phenobarbital), 2018 1 Tags Adjustment   - No  - No 2.54[1.73; 3.74]2818810%NAVajda (Phenobarbital) (Controls unexposed, sick), 2019 Tomson (Phenobarbital), 2018 Veiby (Phenobarbital) (Controls unexposed, sick), 2014 Hernández-Díaz (Phenobarbital) (Controls unexposed, disease free), 2012 Bànhidy (Phenobarbital), 2011 Kaaja (Phenobarbital), 2003 Dean (Phenobarbital), 2002 Canger (Phenobarbital), 1999 Samrén (Phenobarbital), 1999 Robert (Phenobarbital), 1986 10   - Yes  - Yes 1.20[0.52; 2.79]24137 -NAThomas (Phenobarbital) (Controls unexposed, sick), 2021 1 MatchedMatched 2.00[0.79; 5.04]471790%NABànhidy (Phenobarbital), 2011 Samrén (Phenobarbital), 1999 2 All studiesAll studies 2.23[1.57; 3.17]3051,0180%NAThomas (Phenobarbital) (Controls unexposed, sick), 2021 Vajda (Phenobarbital) (Controls unexposed, sick), 2019 Tomson (Phenobarbital), 2018 Veiby (Phenobarbital) (Controls unexposed, sick), 2014 Hernández-Díaz (Phenobarbital) (Controls unexposed, disease free), 2012 Bànhidy (Phenobarbital), 2011 Kaaja (Phenobarbital), 2003 Dean (Phenobarbital), 2002 Canger (Phenobarbital), 1999 Samrén (Phenobarbital), 1999 Robert (Phenobarbital), 1986 110.250.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-4.04.82.0290.000Thomas (Phenobarbital) (Controls unexposed, sick), 2021Vajda (Phenobarbital) (Controls unexposed, sick), 2019Tomson (Phenobarbital), 2018Veiby (Phenobarbital) (Controls unexposed, sick), 2014Hernández-Díaz (Phenobarbital) (Controls unexposed, disease free), 2012Bànhidy (Phenobarbital), 2011Kaaja (Phenobarbital), 2003Dean (Phenobarbital), 2002Canger (Phenobarbital), 1999Samrén (Phenobarbital), 1999Robert (Phenobarbital), 1986

Asymetry test p-value = 0.4360 (by Egger's regression)

slope=0.6322 (0.2575); intercept=0.3526 (0.4325); t=0.8152; p=0.4360

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 5865, 5941, 6321, 6322, 7786, 12834, 7550

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 2.30[1.27; 4.15]22,4395249%NAThomas (Phenobarbital) (Controls unexposed, disease free), 2021 Veiby (Phenobarbital) (Controls unexposed, disease free), 2014 Hernández-Díaz (Phenobarbital) (Controls unexposed, disease free), 2012 Samrén (Phenobarbital), 1999 4 unexposed, sick controlsunexposed, sick controls 1.68[0.88; 3.20]1623470%NAThomas (Phenobarbital) (Controls unexposed, sick), 2021 Vajda (Phenobarbital) (Controls unexposed, sick), 2019 Veiby (Phenobarbital) (Controls unexposed, sick), 2014 Bànhidy (Phenobarbital), 2011 Kaaja (Phenobarbital), 2003 Dean (Phenobarbital), 2002 Canger (Phenobarbital), 1999 Robert (Phenobarbital), 1986 8 exposed to other treatment, sick controlsexposed to other treatment, sick controls 2.33[1.50; 3.62]1454510%NAThomas (Phenobarbital) (Controls exposed to Lamotrigine, sick), 2021 Vajda (Phenobarbital) (Controls exposed to Lamotrigine, sick), 2019 Tomson (Phenobarbital), 2018 Veiby (Phenobarbital) (Controls exposed to Lamotrigine, sick), 2014 Hernández-Díaz (Phenobarbital) (Controls exposed to Lamotrigine, sick), 2012 50.510.01.0