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

Limb defects

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.
S18317
R77151		 Chan (Controls unexposed, sick), 2024 Musculoskeletal 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 2.92 [0.39;22.09] 1/66   68/4,413 69 66
ref
S18315
R77127		 Chan - SNRI (Controls exposed to TCA), 2024 Musculoskeletal malformations 1st trimester retrospective cohort (claims database) exposed to other treatment, sick excluded Adjustment: No Monotherapy: SNRI only 0.59 [0.07;4.89] C
excluded (control group) 		1/77   7/322 8 77
ref
S18316
R77139		 Chan - SNRI (Controls unexposed, general pop), 2024 Musculoskeletal malformations 1st trimester retrospective cohort (claims database) unexposed (general population or NOS) excluded Adjustment: Yes Monotherapy: SNRI only 1.07 [0.15;7.71]
excluded (control group) 		1/77   5,767/462,377 5,768 77
ref
S15171
R62289		 Benevent - SNRI, 2023 Musculoskeletal defects 1st trimester retrospective cohort (claims database) unexposed (general population or NOS) Adjustment: No Monotherapy: SNRI only 0.94 [0.13;6.73] C 1/314   496/146,855 497 314
ref
S11684
R42947		 Ankarfeldt a - Duloxetine (Controls unexposed, NOS), 2021 Limb malformations 1st trimester population based cohort retrospective unexposed (general population or NOS) excluded Adjustment: Yes Monotherapy: no or not specified 0.67 [0.42;1.06]
excluded (control group) 		21/1,438   125/5,751 146 1,438
ref
S11685
R42963		 Ankarfeldt a - Duloxetine (Controls unexposed, sick), 2021 Limb 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) 0.56 [0.32;0.96] 20/1,434   36/1,435 56 1,434
ref
S11745
R43138		 Huybrechts - Duloxetine (Controls unexposed, NOS), 2020 Limb defects 1st trimester retrospective cohort (claims database) unexposed (general population or NOS) excluded Adjustment: Yes Monotherapy: no or not specified 0.60 [0.25;1.43]
excluded (control group) 		-/2,532   -/- - 2,532
ref
S11746
R43152		 Huybrechts - Duloxetine (Controls unexposed, sick), 2020 Limb defects 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) 0.48 [0.16;1.42] -/2,532   -/2,456 - 2,532
ref
S11696
R43031		 Bérard b - SNRI=Venlafaxine (Controls unexposed, sick), 2017 Musculoskeletal system malformations 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) 1.30 [0.93;1.80] -/738   -/14,847 - 738
ref
Total 5 studies 0.87 [0.49;1.57] 622 5,084
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 Chan (Controls unexposed, sick), 2024Chan, 2024 1 2.92[0.39; 22.09]69667%ROB confusion: seriousROB selection: moderateROB classification: moderateROB missing: lowROB mesure: moderateROB reporting: moderate Benevent - SNRI, 2023Benevent - SNRI, 2023 0.94[0.13; 6.73]4973147%ROB confusion: criticalROB selection: lowROB classification: criticalROB missing: unclearROB mesure: moderateROB reporting: moderate Ankarfeldt a - Duloxetine (Controls unexposed, sick), 2021Ankarfeldt a - Duloxetine, 2021 2 0.56[0.32; 0.96]561,43431%ROB confusion: seriousROB selection: moderateROB classification: criticalROB missing: lowROB mesure: moderateROB reporting: low Huybrechts - Duloxetine (Controls unexposed, sick), 2020Huybrechts - Duloxetine, 2020 3 0.48[0.16; 1.42]-2,53217%ROB confusion: moderateROB selection: moderateROB classification: criticalROB missing: unclearROB mesure: moderateROB reporting: low Bérard b - SNRI=Venlafaxine (Controls unexposed, sick), 2017Bérard b - SNRI=Venlafaxine, 2017 4 1.30[0.93; 1.80]-73838%ROB confusion: seriousROB selection: moderateROB classification: criticalROB missing: lowROB mesure: moderateROB reporting: moderate Total (5 studies) I2 = 58% 0.87[0.49; 1.57]6225,0840.210.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

1: Controls unexposed, sick; 2: Controls unexposed, sick; 3: Controls unexposed, sick; 4: Controls unexposed, sick;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 0.87[0.49; 1.57]6225,08458%NAChan (Controls unexposed, sick), 2024 Benevent - SNRI, 2023 Ankarfeldt a - Duloxetine (Controls unexposed, sick), 2021 Huybrechts - Duloxetine (Controls unexposed, sick), 2020 Bérard b - SNRI=Venlafaxine (Controls unexposed, sick), 2017 5 case control studiescase control studies 0 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 0.94[0.13; 6.73]497314 -NABenevent - SNRI, 2023 1 unexposed, sickunexposed, sick 0.87[0.45; 1.67]1254,77068%NAChan (Controls unexposed, sick), 2024 Ankarfeldt a - Duloxetine (Controls unexposed, sick), 2021 Huybrechts - Duloxetine (Controls unexposed, sick), 2020 Bérard b - SNRI=Venlafaxine (Controls unexposed, sick), 2017 4 Tags Adjustment   - No  - No 0.94[0.13; 6.73]497314 -NABenevent - SNRI, 2023 1   - Yes  - Yes 0.87[0.45; 1.67]1254,77068%NAChan (Controls unexposed, sick), 2024 Ankarfeldt a - Duloxetine (Controls unexposed, sick), 2021 Huybrechts - Duloxetine (Controls unexposed, sick), 2020 Bérard b - SNRI=Venlafaxine (Controls unexposed, sick), 2017 4 Monotherapy   - no or not specified  - no or not specified 0.54[0.33; 0.89]563,9660%NAAnkarfeldt a - Duloxetine (Controls unexposed, sick), 2021 Huybrechts - Duloxetine (Controls unexposed, sick), 2020 2   - SNRI only  - SNRI only 1.32[0.95; 1.81]5661,1180%NAChan (Controls unexposed, sick), 2024 Benevent - SNRI, 2023 Bérard b - SNRI=Venlafaxine (Controls unexposed, sick), 2017 3 Unexposed sick   - intermediate history of illness/tre ...  - intermediate history of illness/treatment (3-12 months before pregnancy) 0.77[0.38; 1.55]564,70476%NAAnkarfeldt a - Duloxetine (Controls unexposed, sick), 2021 Huybrechts - Duloxetine (Controls unexposed, sick), 2020 Bérard b - SNRI=Venlafaxine (Controls unexposed, sick), 2017 3   - old history of illness/treatment (> ...  - old history of illness/treatment (> 12 months before pregnancy) or not specified 2.92[0.39; 21.98]6966 -NAChan (Controls unexposed, sick), 2024 1 All studiesAll studies 0.87[0.49; 1.57]6225,08458%NAChan (Controls unexposed, sick), 2024 Benevent - SNRI, 2023 Ankarfeldt a - Duloxetine (Controls unexposed, sick), 2021 Huybrechts - Duloxetine (Controls unexposed, sick), 2020 Bérard b - SNRI=Venlafaxine (Controls unexposed, sick), 2017 50.210.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-2.42.31.2360.000Chan (Controls unexposed, sick), 2024Benevent - SNRI, 2023Ankarfeldt a - Duloxetine (Controls unexposed, sick), 2021Huybrechts - Duloxetine (Controls unexposed, sick), 2020Bérard b - SNRI=Venlafaxine (Controls unexposed, sick), 2017

Asymetry test p-value = 0.6981 (by Egger's regression)

slope=0.1505 (0.4087); intercept=-0.5690 (1.3322); t=0.4271; p=0.6981

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 11745, 11684, 18315, 18316

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 0.68[0.46; 1.00]6,4114,3610%NAChan - SNRI (Controls unexposed, general pop), 2024 Benevent - SNRI, 2023 Ankarfeldt a - Duloxetine (Controls unexposed, NOS), 2021 Huybrechts - Duloxetine (Controls unexposed, NOS), 2020 4 unexposed, sick controlsunexposed, sick controls 0.87[0.45; 1.67]1254,77068%NAChan (Controls unexposed, sick), 2024 Ankarfeldt a - Duloxetine (Controls unexposed, sick), 2021 Huybrechts - Duloxetine (Controls unexposed, sick), 2020 Bérard b - SNRI=Venlafaxine (Controls unexposed, sick), 2017 4 exposed to other treatment, sick controlsexposed to other treatment, sick controls 0.59[0.07; 4.89]877 -NAChan - SNRI (Controls exposed to TCA), 2024 10.510.01.0

Umbrella review (other published meta-analyses)

Published MAControlPeriodTE95% CIn exposedkI2 Huang - SNRIs (Musculoskeletal congenital mal ...Huang - SNRIs (Musculoskeletal congenital malformations) 1.01[0.73; 1.40]15%-U,GPunexposed (general population or NOS)Anyduring pregnancy (anytime or not specified)studies TTT-9 metaPregmetaPreg 0.87[0.49; 1.57]58%5,084----Chan (Controls unexposed, sick), 2024 Benevent - SNRI, 2023 Ankarfeldt a - Duloxetine (Controls unexposed, sick), 2021 Huybrechts - Duloxetine (Controls unexposed, sick), 2020 Bérard b - SNRI=Venlafaxine (Controls unexposed, sick), 2017 50.510.01.0