Phenytoin (All indications) updated on 04-22-2025

ASD (Autism spectrum disorder): Diagnosis/Risk

id	Study   Auto Straub (Controls exposed to LTG) (Phenytoin) (Epilepsy), 2026Straub (Controls unexposed, sick) (Phenytoin) (Epilepsy), 2026Madley-Dowd_SE (Phenytoin) (Controls exposed to LTG) (Mixed indications), 2024Madley-Dowd_SE (Phenytoin) (Controls unexposed, general pop) (Mixed indications), 2024Madley-Dowd_SE (Phenytoin) (Controls unexposed, sibling) (Mixed indications), 2024Madley-Dowd_UK (Phenytoin) (Controls exposed to LTG) (Mixed indications), 2024Madley-Dowd_UK (Phenytoin) (Controls unexposed, general pop) (Mixed indications), 2024Madley-Dowd_UK (Phenytoin) (Controls unexposed, sibling) (Mixed indications), 2024Bromley (Phenytoin) (Controls exposed to Lamotrigine, sick), 2008Bromley (Phenytoin) (Controls unexposed, disease free), 2008Bromley (Phenytoin) (Controls unexposed, sick), 2008	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 trimesterPaternal exp. genotoxic window only (0–3 months preconception)Paternal exposure: epigenetic window only (3–xxx months preconception)Paternal exposure: genotoxic/epigenetic window (0–xxx months preconception)Paternal exposure: other window	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 specifiedsiblingwhatever (meta-analysis)	Tags	OR 95%CI	x1/n1 x0/n0	no cases	no exposed	ROB	Ref.
S19381 R82468	Straub (Controls exposed to LTG) (Phenytoin) (Epilepsy), 2026	Autism spectrum disorder - ICD-10 codes: F84.x (except F84.2, F84.3) - Mean follow up (full cohort): 3.4 years	during pregnancy (anytime or not specified)	retrospective cohort (claims database)	exposed to other treatment, sick excluded	Adjustment: No	0.90 [0.47;1.71] C excluded (control group)	13/1,390   34/3,273	47	1,390		ref
S19370 R82475	Straub (Controls unexposed, sick) (Phenytoin) (Epilepsy), 2026	Autism spectrum disorder - ICD-10 codes: F84.x (except F84.2, F84.3) - Mean follow up (full cohort): 3.4 years	during pregnancy (anytime or not specified)	retrospective cohort (claims database)	unexposed, sick	Adjustment: Yes	0.54 [0.29;0.98]	13/1,390   106/8,887	119	1,390		ref
S17390 R72908	Madley-Dowd_SE (Phenytoin) (Controls exposed to LTG) (Mixed indications), 2024	Autism - ICD-8/9/10 codes - Mean 5-20 years old (according groups)	during pregnancy (anytime or not specified)	population based cohort retrospective	exposed to other treatment, sick excluded	Adjustment: Yes	1.18 [0.62;2.24] excluded (control group)	10/194   134/5,035	144	194		ref
S17391 R72914	Madley-Dowd_SE (Phenytoin) (Controls unexposed, general pop) (Mixed indications), 2024	Autism - ICD-8/9/10 codes - Mean 5-20 years old (according groups)	during pregnancy (anytime or not specified)	population based cohort retrospective	unexposed (general population or NOS)	Adjustment: Yes	0.97 [0.52;1.82]	10/194   68,788/2,651,210	68,798	194		ref
S17392 R72920	Madley-Dowd_SE (Phenytoin) (Controls unexposed, sibling) (Mixed indications), 2024	Autism - ICD-8/9/10 codes - Mean 5-20 years old (according groups)	during pregnancy (anytime or not specified)	population based cohort retrospective	sibling excluded	Adjustment: Yes	5.34 [0.70;40.88] excluded (control group)	-/-   -/-	-	-		ref
S17283 R72392	Madley-Dowd_UK (Phenytoin) (Controls exposed to LTG) (Mixed indications), 2024	Autism - ICD10 codes - Median follow up 10.75 (7.82-13.62) years old	during pregnancy (anytime or not specified)	retrospective cohort (claims database)	exposed to other treatment, sick excluded	Adjustment: Yes	1.09 [0.15;7.66] excluded (control group)	-/46   20/939	-	46		ref
S17268 R72393	Madley-Dowd_UK (Phenytoin) (Controls unexposed, general pop) (Mixed indications), 2024	Autism - ICD10 codes - Median follow up 10.75 (7.82-13.62) years old	during pregnancy (anytime or not specified)	retrospective cohort (claims database)	unexposed (general population or NOS)	Adjustment: Yes	1.19 [0.18;8.05]	-/46   7,657/514,066	-	46		ref
S17276 R72394	Madley-Dowd_UK (Phenytoin) (Controls unexposed, sibling) (Mixed indications), 2024	Autism - ICD10 codes - Median follow up 10.75 (7.82-13.62) years old	during pregnancy (anytime or not specified)	retrospective cohort (claims database)	sibling excluded	Adjustment: Yes	15.33 [4.45;52.85] excluded (control group)	-/-   -/-	-	-		ref
S9256 R48804	Bromley (Phenytoin) (Controls exposed to Lamotrigine, sick), 2008	Autism spectrum disorder (a majority aged 6 and above)	early pregnancy	prospective cohort	exposed to other treatment, sick excluded	Adjustment: No	5.38 [0.30;95.06] C excluded (control group)	1/9   1/44	2	9		ref
S9257 R48805	Bromley (Phenytoin) (Controls unexposed, disease free), 2008	Autism spectrum disorder (a majority aged 6 and above)	early pregnancy	prospective cohort	unexposed, disease free excluded	Adjustment: No	13.88 [1.30;148.33] C excluded (control group)	1/9   3/336	4	9		ref
S9258 R48806	Bromley (Phenytoin) (Controls unexposed, sick), 2008	Autism spectrum disorder (a majority aged 6 and above)	early pregnancy	prospective cohort	unexposed, sick	Adjustment: No	18.60 [0.69;500.42] C	1/9   0/47	1	9		ref
					Total	4 studies	0.88 [0.43;1.80]		68,918	1,639
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 9256, 9257, 17390, 17392, 17283, 17276, 19381

Umbrella review (other published meta-analyses)