Phenobarbital (All indications)

Neuro-developmental disorders (as a whole)

id	Study   Auto Bjørk (Phenobarbital) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2022Bjørk (Phenobarbital) (Controls unexposed NOS) (Mixed indications), 2022Bjørk (Phenobarbital) (Controls unexposed, sick) (Mixed indications), 2022Coste (Phenobarbital) (Controls exposed to Lamotrigine, sick), 2020Coste (Phenobarbital) (Controls unexposed, NOS), 2020Dean (Phenobarbital) (Controls exposed to Lamotrigine, sick), 2007Dean (Phenobarbital) (Controls unexposed, sick), 2007Katz (Phenobarbital), 2001Van der Pol (Phenobarbital) (Controls unexposed, disease free), 1991Van der Pol (Phenobarbital) (Controls unexposed, sick), 1991	Lib. in paper	Exposition period  Auto during pregnancy (anytime or not specified)1st trimester2nd trimester3rd trimester2nd and/or 3rd trimesterthroughout pregnancyearly pregnancydays before deliverylate pregnancypreconception-onlypericonceptionalpreconceptional for kinetic reasonat least 1st trimester3 months (or more) before pregnancy or during pregnancy1st and 2nd trimester3 months or more before pregnancy or1st trimester	Study type  All studies Case control excluded Only case control	Control type    Auto unexposed (general population or NOS)unexposed, sickunexposed, disease freeexposed to other treatment, sicknot specifiedwhatever (meta-analysis)	Tags	OR 95%CI	x1/n1 x0/n0	no cases	no exposed	ROB	Ref.
S12782 R48197	Bjørk (Phenobarbital) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2022	Neurodevelopmental Disorder (ND): any diagnoses of autism spectrum disorder (F84.0, F84.1, F84.5) or intellectual disability (F70, F71, F72, F73) plus F84.3, F84.4, F84.8, F84.9, F79 (between 6.1 and 7.9 years old)	during pregnancy (anytime or not specified)	population based cohort retrospective	exposed to other treatment, sick excluded	Adjustment: No	2.82 [1.36;5.84] C excluded (control group)	8/175   133/7,950	141	175		ref
S12785 R48203	Bjørk (Phenobarbital) (Controls unexposed NOS) (Mixed indications), 2022	Neurodevelopmental Disorder (ND): any diagnoses of autism spectrum disorder (F84.0, F84.1, F84.5) or intellectual disability (F70, F71, F72, F73) plus F84.3, F84.4, F84.8, F84.9, F79 (between 6.1 and 7.9 years old)	during pregnancy (anytime or not specified)	population based cohort retrospective	unexposed (general population or NOS) excluded	Adjustment: Yes	1.23 [0.61;2.46] excluded (control group)	8/175   68,295/4,463,879	68,303	175		ref
S12788 R48209	Bjørk (Phenobarbital) (Controls unexposed, sick) (Mixed indications), 2022	Neurodevelopmental Disorder (ND): any diagnoses of autism spectrum disorder (F84.0, F84.1, F84.5) or intellectual disability (F70, F71, F72, F73) plus F84.3, F84.4, F84.8, F84.9, F79 (between 6.1 and 7.9 years old)	during pregnancy (anytime or not specified)	population based cohort retrospective	unexposed, sick	Adjustment: No Controls: epilepsy indication	2.29 [1.12;4.69] C	8/175   443/21,634	451	175		ref
S9160 R31491	Coste (Phenobarbital) (Controls exposed to Lamotrigine, sick), 2020	Diagnosis Disorders of psychological development (F80–F89) (mean age of 3.6 years old)	during pregnancy (anytime or not specified)	retrospective cohort (claims database)	exposed to other treatment, sick excluded	Adjustment: No Controls: mixed indications	1.24 [0.17;9.26] C excluded (control group)	1/84   27/2,813	28	84		ref
S9161 R31509	Coste (Phenobarbital) (Controls unexposed, NOS), 2020	Diagnosis Disorders of psychological development (F80–F89) (mean age of 3.6 years old)	during pregnancy (anytime or not specified)	retrospective cohort (claims database)	unexposed (general population or NOS)	Adjustment: Yes	0.90 [0.10;6.70]	1/84   10,010/1,710,441	10,011	84		ref
S9127 R31359	Dean (Phenobarbital) (Controls exposed to Lamotrigine, sick), 2007	Neurodevelopmental disorder (mean age in years: m1=16.25 and m0=1.5)	during pregnancy (anytime or not specified)	retrospective cohort	exposed to other treatment, sick excluded	Adjustment: No	1.24 [0.06;26.43] C excluded (control group)	7/50   0/4	7	50		ref
S9128 R31361	Dean (Phenobarbital) (Controls unexposed, sick), 2007	Neurodevelopmental disorder (mean age in years: m1=16.25 and m0=15.25)	during pregnancy (anytime or not specified)	retrospective cohort	unexposed, sick	Adjustment: No	2.33 [0.57;9.62] C	7/50   3/46	10	50		ref
S9113 R31311	Katz (Phenobarbital), 2001	Developmental delay (Based on the DSM-IV-TR criteria)	during pregnancy (anytime or not specified)	retrospective cohort	exposed to other treatment, sick	Adjustment: No	0.56 [0.01;37.57] C	0/5   0/3	0	5		ref
S9172 R31560	Van der Pol (Phenobarbital) (Controls unexposed, disease free), 1991	Nonoptimal school career	throughout pregnancy	prospective cohort	unexposed, disease free excluded	Adjustment: No Matched	2.20 [0.55;8.77] C excluded (control group)	4/12   10/54	14	12		ref
S9173 R31585	Van der Pol (Phenobarbital) (Controls unexposed, sick), 1991	Nonoptimal school career	throughout pregnancy	prospective cohort	unexposed, sick	Adjustment: No	1.70 [0.36;8.09] C	4/12   5/22	9	12		ref
					Total	5 studies	2.01 [1.15;3.54]		10,481	326
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

Sensitivity analysis

Publication bias and p-hacking diagnosis

Sub-groups analysis using all included studies

excluded 9172, 9127, 9160, 12782, 12785