Tramadol (versus unexposed) updated on 07-09-2025

Major congenital malformations

id	Study   Auto Ferrer, 2025Bowie, 2022Sørensen, 2022Källén, 2015Gouraud, 2010	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.
S18427 R78018	Ferrer, 2025	Major congenital anomalies	at least 1st trimester	retrospective cohort (claims database)	unexposed (general population or NOS)	Adjustment: Yes	1.24 [0.86;1.79]	30/999   3,719/152,811	3,749	999		ref
S13279 R51136	Bowie, 2022	Any major congenital anomalies	at least 1st trimester	population based cohort retrospective	unexposed (general population or NOS)	Adjustment: Yes	1.94 [1.28;2.92]	30/781   9,264/587,676	9,294	781		ref
S13280 R51152	Sørensen, 2022	Any major congenital malformation (chromosome abnormality or syndrome excluded)	1st trimester	population based cohort retrospective	unexposed (general population or NOS)	Adjustment: Yes	1.04 [0.87;1.24]	151/3,796   579/15,111	730	3,796		ref
S13036 R49439	Källén, 2015	Relatively severe malformation	early pregnancy	population based cohort retrospective	unexposed (general population or NOS)	Adjustment: Yes	1.33 [1.05;1.70]	70/1,776   52,195/1,797,678	52,265	1,776		ref
S13270 R51121	Gouraud, 2010	Major malformations (without chromosomal malformations - among examinable fetuses or liveborn)	1st trimester	prospective cohort	unexposed (general population or NOS)	Adjustment: No	1.33 [0.39;4.60] C	3/115   18/915	21	115		ref
					Total	5 studies	1.29 [1.04;1.60]		66,059	7,467
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