Serotonin and Noradrenaline Reuptake Inhibitors (SNRI) updated on 07-01-2025

Major congenital malformations

id	Study   Auto Chan (Controls unexposed, sick), 2024Chan - SNRI (Controls exposed to TCA), 2024Chan - SNRI (Controls unexposed, general pop), 2024Benevent - SNRI, 2023Ankarfeldt a - Duloxetine (Controls unexposed, NOS), 2021Ankarfeldt a - Duloxetine (Controls unexposed, sick), 2021Anderson - SNRI, 2020Bahat - Duloxetine, 2020Huybrechts - Duloxetine (Controls unexposed, NOS), 2020Huybrechts - Duloxetine (Controls unexposed, sick), 2020Richardson - Venlafaxine, 2019Bérard b - SNRI=Venlafaxine (Controls exposed to TCA), 2017Bérard b - SNRI=Venlafaxine (Controls unexposed, sick), 2017Ozturk - Venlafaxine, 2016Te Winkel - Venlafaxine, 2016Furu - Venlafaxine, 2015Reis - SNRI (Controls exposed to TCA), 2010Reis - SNRI (Controls unexposed, NOS), 2010Einarson - Venlafaxine, 2009Oberlander - Venlafaxine, 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.
S18317 R77146	Chan (Controls unexposed, sick), 2024	Any major malformations	1st trimester	retrospective cohort (claims database)	unexposed, sick	Adjustment: Yes Monotherapy: SNRI only Unexposed sick: old history of illness/treatment (> 12 months before pregnancy) or not specified	2.51 [0.70;9.04]	6/66   269/4,413	275	66		ref
S18315 R77122	Chan - SNRI (Controls exposed to TCA), 2024	Any major malformations	1st trimester	retrospective cohort (claims database)	exposed to other treatment, sick excluded	Adjustment: No Monotherapy: SNRI only	1.19 [0.49;2.86] C excluded (control group)	7/77   25/322	32	77		ref
S18316 R77134	Chan - SNRI (Controls unexposed, general pop), 2024	Any major malformations	1st trimester	retrospective cohort (claims database)	unexposed (general population or NOS) excluded	Adjustment: Yes Monotherapy: SNRI only	1.44 [0.56;3.72] excluded (control group)	7/77   22,628/462,377	22,635	77		ref
S15171 R62278	Benevent - SNRI, 2023	Major congenital malformations	1st trimester	retrospective cohort (claims database)	unexposed (general population or NOS)	Adjustment: No Monotherapy: SNRI only	0.83 [0.37;1.86] C	6/314   3,365/146,855	3,371	314		ref
S11684 R42938	Ankarfeldt a - Duloxetine (Controls unexposed, NOS), 2021	Major malformations	1st trimester	population based cohort retrospective	unexposed (general population or NOS) excluded	Adjustment: Yes Monotherapy: no or not specified	0.96 [0.75;1.24] excluded (control group)	63/1,430   75,879/1,965,441	75,942	1,430		ref
S11685 R42954	Ankarfeldt a - Duloxetine (Controls unexposed, sick), 2021	Major malformations	1st trimester	population based cohort retrospective	unexposed, sick	Adjustment: Yes Monotherapy: no or not specified Unexposed sick: intermediate history of illness/treatment (3-12 months before pregnancy)	0.91 [0.66;1.24]	63/1,430   130/2,766	193	1,430		ref
S11771 R43272	Anderson - SNRI, 2020	Major birth defects	1st trimester	case control	unexposed (general population or NOS)	Adjustment: No Monotherapy: SNRI only	1.92 [1.27;2.90] C	138/165   30,492/41,943	30,630	165		ref
S11707 R43058	Bahat - Duloxetine, 2020	Major congenital anomalies	1st trimester	prospective cohort	unexposed (general population or NOS)	Adjustment: Yes Monotherapy: no or not specified	1.02 [0.33;3.15]	5/128   20/511	25	128		ref
S11745 R43120	Huybrechts - Duloxetine (Controls unexposed, NOS), 2020	Major congenital malformations overall	1st trimester	retrospective cohort (claims database)	unexposed (general population or NOS) excluded	Adjustment: Yes Monotherapy: no or not specified	1.11 [0.93;1.33] excluded (control group)	128/2,532   47,001/1,284,827	47,129	2,532		ref
S11746 R43141	Huybrechts - Duloxetine (Controls unexposed, sick), 2020	Major congenital malformations overall	1st trimester	retrospective cohort (claims database)	unexposed, sick	Adjustment: Yes Monotherapy: no or not specified Unexposed sick: intermediate history of illness/treatment (3-12 months before pregnancy)	1.09 [0.84;1.42]	128/2,532   114/2,456	242	2,532		ref
S11774 R43316	Richardson - Venlafaxine, 2019	Major congenital malformation (genetic conditions excluded)	1st trimester	prospective cohort	unexposed (general population or NOS)	Adjustment: Yes Matched Monotherapy: no or not specified	1.10 [0.32;2.97]	4/270   19/1,400	23	270		ref
S11695 R43020	Bérard b - SNRI=Venlafaxine (Controls exposed to TCA), 2017	Major congenital malformations overall	1st trimester	retrospective cohort (claims database)	exposed to other treatment, sick excluded	Adjustment: No Monotherapy: SNRI only	0.91 [0.63;1.32] C excluded (control group)	91/738   51/382	142	738		ref
S11696 R43022	Bérard b - SNRI=Venlafaxine (Controls unexposed, sick), 2017	Major congenital malformations overall	1st trimester	retrospective cohort (claims database)	unexposed, sick	Adjustment: Yes Monotherapy: SNRI only Unexposed sick: intermediate history of illness/treatment (3-12 months before pregnancy)	1.10 [0.87;1.38]	91/738   1,650/14,847	1,741	738		ref
S11791 R43384	Ozturk - Venlafaxine, 2016	Major congenital defects	at least 1st trimester	prospective cohort	unexposed (general population or NOS)	Adjustment: No Monotherapy: no or not specified	3.30 [0.16;68.08] C	0/11   3/246	3	11		ref
S11776 R43332	Te Winkel - Venlafaxine, 2016	Major congenital malformation (excluding chromosomal and genetic disorders)	1st trimester	prospective cohort	unexposed (general population or NOS)	Adjustment: No Monotherapy: no or not specified	1.34 [0.67;2.69]	17/523   16/656	33	523		ref
S11688 R42974	Furu - Venlafaxine, 2015	Major birth defects	1st trimester	population based cohort retrospective	unexposed (general population or NOS)	Adjustment: Yes Monotherapy: SNRI only	1.06 [0.86;1.32]	95/2,763   71,374/2,266,875	71,469	2,763		ref
S11693 R76989	Reis - SNRI (Controls exposed to TCA), 2010	Relatively severe malformation	1st trimester	population based cohort retrospective	exposed to other treatment, sick excluded	Adjustment: No Monotherapy: SNRI only	0.68 [0.46;0.99] C excluded (control group)	43/1,351   77/1,662	120	1,351		ref
S11694 R76984	Reis - SNRI (Controls unexposed, NOS), 2010	Relatively severe malformation	1st trimester	population based cohort retrospective	unexposed (general population or NOS)	Adjustment: Yes Monotherapy: SNRI only	1.00 [0.73;1.37]	43/1,351   36,321/1,062,190	36,364	1,351		ref
S11753 R43198	Einarson - Venlafaxine, 2009	Major malformations	1st trimester	prospective cohort	unexposed (general population or NOS)	Adjustment: No Monotherapy: no or not specified	0.48 [0.11;2.03] C	2/154   25/928	27	154		ref
S11796 R43397	Oberlander - Venlafaxine, 2008	Major congenital anomalies	1st trimester	retrospective cohort (claims database)	unexposed (general population or NOS)	Adjustment: No Monotherapy: SNRI only	0.76 [0.34;1.71] C	6/250   3,369/107,320	3,375	250		ref
					Total	14 studies	1.09 [0.97;1.22]		147,771	10,695
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 11693, 11695, 11745, 11684, 18315, 18316

Umbrella review (other published meta-analyses)