Phenobarbital (All indications)

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.
S10233
R37488		 The NAAED (Controls exposed to Lamotrigine, sick) (Indications NOS), 2022 Major congenital malformations 1st trimester prospective cohort exposed to other treatment, sick excluded Adjustment: No 3.32 [1.72;6.40] C
excluded (control group) 		12/200   44/2,333 56 200
ref
S10234
R37494		 The NAAED (Controls unexposed, disease free) (Indications NOS), 2022 Major congenital malformations 1st trimester prospective cohort unexposed, disease free Adjustment: No 6.32 [2.80;14.29] C 12/200   12/1,201 24 200
ref
S12836
R48361		 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
S12837
R48369		 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
S12838
R48373		 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
S9152
R31466		 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
S9153
R31467		 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
S9151
R31456		 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
S9098
R31164		 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
S9118
R31330		 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
S9119
R31332		 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
S9120
R31334		 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
S9175
R31621		 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
S9176
R31623		 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
S9111
R31307		 Källén (Phenobarbital) (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 3.77 [0.83;17.10] C
excluded (control group) 		2/17   37/1,084 39 17
ref
S9112
R31309		 Källén (Phenobarbital) (Controls unexposed, NOS) (Indications NOS), 2013 Relatively severe malformations early pregnancy population based cohort retrospective unexposed (general population or NOS) Adjustment: No 4.11 [0.94;17.98] C 2/17   49,499/1,575,847 49,501 17
ref
S9124
R31350		 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
S9130
R31364		 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
S9103
R31234		 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
S9109
R31289		 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
S9110
R31298		 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
S9126
R31357		 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
S9145
R31445		 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
S9146
R31447		 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
S9144
R31442		 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
S9132
R31367		 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 2.58 [1.87;3.56] 49,841 1,049
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 (Controls unexposed, disease free) (Indications NOS), 2022The NAAED, 2022 1 6.32[2.80; 14.29]2420016%ROB confusion: criticalROB selection: unclearROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: low Thomas (Phenobarbital) (Controls unexposed, sick), 2021Thomas, 2021 2 1.20[0.50; 2.70]2413715%ROB confusion: seriousROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Vajda (Phenobarbital) (Controls unexposed, sick), 2019Vajda, 2019 3 10.33[0.38; 283.37]521%ROB confusion: criticalROB selection: moderateROB classification: lowROB missing: moderateROB mesure: moderateROB reporting: moderate Tomson (Phenobarbital), 2018Tomson, 2018 4 2.28[1.36; 3.83]9329439%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) (Controls unexposed, NOS) (Indications NOS), 2013Källén, 2013 7 4.11[0.94; 17.98]49,501175%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Bànhidy (Phenobarbital), 2011Bànhidy, 2011 8 2.48[0.09; 68.14]1311%ROB confusion: criticalROB selection: criticalROB classification: lowROB missing: lowROB mesure: moderateROB reporting: moderate Kaaja (Phenobarbital), 2003Kaaja, 2003 9 10.51[0.44; 251.86]251%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Dean (Phenobarbital), 2002Dean, 2002 10 1.96[0.38; 10.27]8614%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Canger (Phenobarbital), 1999Canger, 1999 11 1.52[0.07; 32.78]2831%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Samrén (Phenobarbital), 1999Samrén, 1999 12 1.96[0.75; 5.14]3417811%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 = 0% 2.58[1.87; 3.56]49,8411,0490.550.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

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

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 2.58[1.86; 3.57]49,8281,0480%NAThe NAAED (Controls unexposed, disease free) (Indications NOS), 2022 Thomas (Phenobarbital) (Controls unexposed, sick), 2021 Vajda (Phenobarbital) (Controls unexposed, sick), 2019 Tomson (Phenobarbital), 2018 Veiby (Phenobarbital) (Controls unexposed, sick) (Mixed indications), 2014 Cassina (Phenobarbital) (Controls unexposed, disease free) (Other indications), 2013 Källén (Phenobarbital) (Controls unexposed, NOS) (Indications NOS), 2013 Kaaja (Phenobarbital), 2003 Dean (Phenobarbital), 2002 Canger (Phenobarbital), 1999 Samrén (Phenobarbital), 1999 Robert (Phenobarbital), 1986 12 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) 3.89[2.11; 7.16]49,58439910%NAThe NAAED (Controls unexposed, disease free) (Indications NOS), 2022 Cassina (Phenobarbital) (Controls unexposed, disease free) (Other indications), 2013 Källén (Phenobarbital) (Controls unexposed, NOS) (Indications NOS), 2013 Samrén (Phenobarbital), 1999 4 unexposed, sickunexposed, sick 1.87[1.02; 3.43]1643560%NAThomas (Phenobarbital) (Controls unexposed, sick), 2021 Vajda (Phenobarbital) (Controls unexposed, sick), 2019 Veiby (Phenobarbital) (Controls unexposed, sick) (Mixed indications), 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 2.94[2.07; 4.17]49,8179120%NAThe NAAED (Controls unexposed, disease free) (Indications NOS), 2022 Vajda (Phenobarbital) (Controls unexposed, sick), 2019 Tomson (Phenobarbital), 2018 Veiby (Phenobarbital) (Controls unexposed, sick) (Mixed indications), 2014 Cassina (Phenobarbital) (Controls unexposed, disease free) (Other indications), 2013 Källén (Phenobarbital) (Controls unexposed, NOS) (Indications NOS), 2013 Bànhidy (Phenobarbital), 2011 Kaaja (Phenobarbital), 2003 Dean (Phenobarbital), 2002 Canger (Phenobarbital), 1999 Samrén (Phenobarbital), 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 2.00[0.79; 5.04]471790%NABànhidy (Phenobarbital), 2011 Samrén (Phenobarbital), 1999 2 All studiesAll studies 2.58[1.87; 3.56]49,8411,0490%NAThe NAAED (Controls unexposed, disease free) (Indications NOS), 2022 Thomas (Phenobarbital) (Controls unexposed, sick), 2021 Vajda (Phenobarbital) (Controls unexposed, sick), 2019 Tomson (Phenobarbital), 2018 Veiby (Phenobarbital) (Controls unexposed, sick) (Mixed indications), 2014 Cassina (Phenobarbital) (Controls unexposed, disease free) (Other indications), 2013 Källén (Phenobarbital) (Controls unexposed, NOS) (Indications NOS), 2013 Bànhidy (Phenobarbital), 2011 Kaaja (Phenobarbital), 2003 Dean (Phenobarbital), 2002 Canger (Phenobarbital), 1999 Samrén (Phenobarbital), 1999 Robert (Phenobarbital), 1986 130.550.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-4.04.92.0290.000The NAAED (Controls unexposed, disease free) (Indications NOS), 2022Thomas (Phenobarbital) (Controls unexposed, sick), 2021Vajda (Phenobarbital) (Controls unexposed, sick), 2019Tomson (Phenobarbital), 2018Veiby (Phenobarbital) (Controls unexposed, sick) (Mixed indications), 2014Cassina (Phenobarbital) (Controls unexposed, disease free) (Other indications), 2013Källén (Phenobarbital) (Controls unexposed, NOS) (Indications NOS), 2013Bànhidy (Phenobarbital), 2011Kaaja (Phenobarbital), 2003Dean (Phenobarbital), 2002Canger (Phenobarbital), 1999Samrén (Phenobarbital), 1999Robert (Phenobarbital), 1986

Asymetry test p-value = 0.3671 (by Egger's regression)

slope=0.7305 (0.2778); intercept=0.4402 (0.4680); t=0.9405; p=0.3671

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 9109, 9175, 9111, 9118, 9119, 9152, 12836, 12837, 10233

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 3.00[1.78; 5.06]71,97555518%NAThe NAAED (Controls unexposed, disease free) (Indications NOS), 2022 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) (Controls unexposed, NOS) (Indications NOS), 2013 Samrén (Phenobarbital), 1999 6 unexposed, sick controlsunexposed, sick controls 1.87[1.02; 3.43]1643560%NAThomas (Phenobarbital) (Controls unexposed, sick), 2021 Vajda (Phenobarbital) (Controls unexposed, sick), 2019 Veiby (Phenobarbital) (Controls unexposed, sick) (Mixed indications), 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 2.73[1.89; 3.95]2476810%NAThe NAAED (Controls exposed to Lamotrigine, sick) (Indications NOS), 2022 Thomas (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) (Mixed indications), 2014 Cassina (Phenobarbital) (Controls exposed to Lamotrigine, sick) (Other indications), 2013 Källén (Phenobarbital) (Controls exposed to Lamotrigine, sick) (Indications NOS), 2013 70.510.01.0