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

ASD (Autism spectrum disorder): Diagnosis/Risk

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.
S18387
R77532		 Heuvelman - Venlafaxine, 2023 Autism spectrum disorder - Validated Read code list among primary care clinical and referral records - Mean age at end of follow-up 10.04 years, range 4–22 years during pregnancy (anytime or not specified) retrospective cohort (claims database) unexposed, sick Adjustment: Yes Monotherapy: no or not specified Partial overlapping Unexposed sick: intermediate history of illness/treatment (3-12 months before pregnancy) 1.46 [0.78;2.73] -/818   -/16,330 - 818
ref
S18333
R77345		 Suarez - SNRI (Controls unexposed, discontinuers), 2022 Autism Spectrum Disorder - ≥ 2 dates with ICD-9 Dx 299.xx (except 299.1x) - At ≥ 1 year of age 2nd and/or 3rd trimester retrospective cohort (claims database) unexposed, sick Adjustment: Yes Monotherapy: no or not specified Unexposed sick: recent illness/treatment (during or juste before pregnancy or treatment stopped in view of pregnancy) 1.79 [1.08;2.99] 66/8,540   28/4,899 94 8,540
ref
S18334
R77356		 Suarez - SNRI (Controls unexposed, general pop), 2022 Autism Spectrum Disorder - ≥ 2 dates with ICD-9 Dx 299.xx (except 299.1x) - At ≥ 1 year of age 2nd and/or 3rd trimester retrospective cohort (claims database) unexposed (general population or NOS) excluded Adjustment: Yes Monotherapy: no or not specified 1.04 [0.79;1.37]
excluded (control group) 		67/8,659   11,270/2,910,114 11,337 8,659
ref
S11813
R46838		 Hagberg - SNRI (Controls exposed to TCA), 2018 Autism spectrum disorder (diagnostic code including codes for autism, Asperger’s syndrome, and pervasive developmental disorder (PDD)) - Median diagnosis 5.8 years during pregnancy (anytime or not specified) retrospective cohort (claims database) exposed to other treatment, sick excluded Adjustment: No Monotherapy: SNRI only Partial overlapping 0.51 [0.29;0.92] C
excluded (control group) 		13/1,246   98/4,856 111 1,246
ref
S11814
R46839		 Hagberg - SNRI (Controls unexposed, disease free), 2018 Autism spectrum disorder (diagnostic code including codes for autism, Asperger’s syndrome, and pervasive developmental disorder (PDD)) - Median diagnosis 5.8 years during pregnancy (anytime or not specified) retrospective cohort (claims database) unexposed, disease free excluded Adjustment: Yes Matched Monotherapy: SNRI only Partial overlapping 1.03 [0.60;1.78]
excluded (control group) 		13/1,246   1,500/154,107 1,513 1,246
ref
S11815
R46840		 Hagberg - SNRI (Controls unexposed, sick), 2018 Autism spectrum disorder (diagnostic code including codes for autism, Asperger’s syndrome, and pervasive developmental disorder (PDD)) - Median diagnosis 5.8 years during pregnancy (anytime or not specified) retrospective cohort (claims database) unexposed, sick Adjustment: No Monotherapy: SNRI only Partial overlapping Unexposed sick: intermediate history of illness/treatment (3-12 months before pregnancy) 0.69 [0.39;1.21] C 13/1,246   196/12,994 209 1,246
ref
S11816
R46841		 Rai - Venlafaxine (Controls exposed to TCA), 2017 Autism spectrum disorder (ICD-9 (299), ICD-10 (F84), or DSM-IV (299) codes) - At 4-17 years during pregnancy (anytime or not specified) prospective cohort exposed to other treatment, sick excluded Adjustment: No Monotherapy: SNRI only 0.75 [0.34;1.64] C
excluded (control group) 		11/213   16/235 27 213
ref
S11817
R46842		 Rai - Venlafaxine (Controls unexposed, disease free), 2017 Autism spectrum disorder (ICD-9 (299), ICD-10 (F84), or DSM-IV (299) codes) - At 4-17 years during pregnancy (anytime or not specified) prospective cohort unexposed, disease free excluded Adjustment: No Monotherapy: SNRI only 2.61 [1.42;4.79] C
excluded (control group) 		11/213   4,889/238,943 4,900 213
ref
S11818
R46843		 Rai - Venlafaxine (Controls unexposed, sick), 2017 Autism spectrum disorder (ICD-9 (299), ICD-10 (F84), or DSM-IV (299) codes) - At 4-17 years during pregnancy (anytime or not specified) prospective cohort unexposed, sick Adjustment: Yes Monotherapy: SNRI only Unexposed sick: old history of illness/treatment (> 12 months before pregnancy) or not specified 1.81 [0.89;3.71] 11/213   353/12,325 364 213
ref
S11702
R46836		 Boukhris - SNRI (Controls exposed to TCA), 2016 Autism spectrum disorder (ICD-9 codes 299.0, 299.8, 299.9; ICD-10 codes F84.0, F84.1, F84.5, F84.8, F84.9) - End follow-up: mean 6.2 years (median 7.0 years) 2nd and/or 3rd trimester retrospective cohort (claims database) exposed to other treatment, sick excluded Adjustment: No Monotherapy: SNRI only 0.51 [0.07;3.65] C
excluded (control group) 		2/447   2/229 4 447
ref
S11703
R46837		 Boukhris - SNRI (Controls unexposed, NOS), 2016 Autism spectrum disorder (ICD-9 codes 299.0, 299.8, 299.9; ICD-10 codes F84.0, F84.1, F84.5, F84.8, F84.9) - End follow-up: mean 6.2 years (median 7.0 years) 2nd and/or 3rd trimester retrospective cohort (claims database) unexposed (general population or NOS) Adjustment: Yes Monotherapy: SNRI only 1.04 [0.20;5.46] 2/447   1,023/142,924 1,025 447
ref
S11782
R46844		 Sørensen - SNRI (Controls exposed to TCA), 2013 Autism spectrum disorder (ICD-10, codes F84.0, F84.1, F84.5, F84.8, and F84.9) - At 4-14 years (mean 8.8 years) during pregnancy (anytime or not specified) population based cohort retrospective exposed to other treatment, sick excluded Adjustment: No Monotherapy: TCA only 0.74 [0.27;2.00] C
excluded (control group) 		7/673   9/642 16 673
ref
S11783
R46845		 Sørensen - SNRI (Controls unexposed, NOS), 2013 Autism spectrum disorder (ICD-10, codes F84.0, F84.1, F84.5, F84.8, and F84.9) - At 4-14 years (mean 8.8 years) during pregnancy (anytime or not specified) population based cohort retrospective unexposed (general population or NOS) Adjustment: Yes Monotherapy: SNRI only 1.70 [0.80;3.50] 7/673   5,333/646,782 5,340 673
ref
Total 6 studies 1.36 [0.96;1.94] 7,032 11,937
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 Heuvelman - Venlafaxine, 2023Heuvelman - Venlafaxine, 2023 1.46[0.78; 2.73]-81819%ROB confusion: seriousROB selection: lowROB classification: criticalROB missing: criticalROB mesure: criticalROB reporting: low Suarez - SNRI (Controls unexposed, discontinuers), 2022Suarez - SNRI, 2022 1 1.79[1.08; 2.99]948,54024%ROB confusion: seriousROB selection: lowROB classification: moderateROB missing: lowROB mesure: criticalROB reporting: moderate Hagberg - SNRI (Controls unexposed, sick), 2018Hagberg - SNRI, 2018 2 0.69[0.39; 1.21]2091,24621%ROB confusion: unclearROB selection: lowROB classification: criticalROB missing: moderateROB mesure: moderateROB reporting: moderate Rai - Venlafaxine (Controls unexposed, sick), 2017Rai - Venlafaxine, 2017 3 1.81[0.89; 3.71]36421316%ROB confusion: unclearROB selection: lowROB classification: moderateROB missing: lowROB mesure: moderateROB reporting: moderate Boukhris - SNRI (Controls unexposed, NOS), 2016Boukhris - SNRI, 2016 4 1.04[0.20; 5.46]1,0254474%ROB confusion: seriousROB selection: lowROB classification: criticalROB missing: unclearROB mesure: criticalROB reporting: moderate Sørensen - SNRI (Controls unexposed, NOS), 2013Sørensen - SNRI, 2013 5 1.70[0.80; 3.50]5,34067315%ROB confusion: seriousROB selection: lowROB classification: criticalROB missing: lowROB mesure: moderateROB reporting: moderate Total (6 studies) I2 = 36% 1.36[0.96; 1.94]7,03211,9370.25.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

1: Controls unexposed, discontinuers; 2: Controls unexposed, sick; 3: Controls unexposed, sick; 4: Controls unexposed, NOS; 5: Controls unexposed, NOS;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 1.36[0.96; 1.94]7,03211,93736%NAHeuvelman - Venlafaxine, 2023 Suarez - SNRI (Controls unexposed, discontinuers), 2022 Hagberg - SNRI (Controls unexposed, sick), 2018 Rai - Venlafaxine (Controls unexposed, sick), 2017 Boukhris - SNRI (Controls unexposed, NOS), 2016 Sørensen - SNRI (Controls unexposed, NOS), 2013 6 case control studiescase control studies 0 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 1.57[0.80; 3.07]6,3651,1200%NABoukhris - SNRI (Controls unexposed, NOS), 2016 Sørensen - SNRI (Controls unexposed, NOS), 2013 2 unexposed, sickunexposed, sick 1.33[0.83; 2.12]66710,81759%NAHeuvelman - Venlafaxine, 2023 Suarez - SNRI (Controls unexposed, discontinuers), 2022 Hagberg - SNRI (Controls unexposed, sick), 2018 Rai - Venlafaxine (Controls unexposed, sick), 2017 4 Tags Adjustment   - No  - No 0.69[0.39; 1.21]2091,246 -NAHagberg - SNRI (Controls unexposed, sick), 2018 1   - Yes  - Yes 1.66[1.22; 2.26]6,82310,6910%NAHeuvelman - Venlafaxine, 2023 Suarez - SNRI (Controls unexposed, discontinuers), 2022 Rai - Venlafaxine (Controls unexposed, sick), 2017 Boukhris - SNRI (Controls unexposed, NOS), 2016 Sørensen - SNRI (Controls unexposed, NOS), 2013 5 Monotherapy   - no or not specified  - no or not specified 1.65[1.11; 2.45]949,3580%NAHeuvelman - Venlafaxine, 2023 Suarez - SNRI (Controls unexposed, discontinuers), 2022 2   - SNRI only  - SNRI only 1.21[0.69; 2.10]6,9382,57948%NAHagberg - SNRI (Controls unexposed, sick), 2018 Rai - Venlafaxine (Controls unexposed, sick), 2017 Boukhris - SNRI (Controls unexposed, NOS), 2016 Sørensen - SNRI (Controls unexposed, NOS), 2013 4 Partial overlappingPartial overlapping 0.99[0.47; 2.07]2092,06467%NAHeuvelman - Venlafaxine, 2023 Hagberg - SNRI (Controls unexposed, sick), 2018 2 Unexposed sick   - intermediate history of illness/tre ...  - intermediate history of illness/treatment (3-12 months before pregnancy) 0.99[0.47; 2.07]2092,06467%NAHeuvelman - Venlafaxine, 2023 Hagberg - SNRI (Controls unexposed, sick), 2018 2   - old history of illness/treatment (> ...  - old history of illness/treatment (> 12 months before pregnancy) or not specified 1.81[0.89; 3.70]364213 -NARai - Venlafaxine (Controls unexposed, sick), 2017 1   - recent illness/treatment (during o ...  - recent illness/treatment (during or juste before pregnancy or treatment stopped in view of pregnancy) 1.79[1.08; 2.98]948,540 -NASuarez - SNRI (Controls unexposed, discontinuers), 2022 1 All studiesAll studies 1.36[0.96; 1.94]7,03211,93736%NAHeuvelman - Venlafaxine, 2023 Suarez - SNRI (Controls unexposed, discontinuers), 2022 Hagberg - SNRI (Controls unexposed, sick), 2018 Rai - Venlafaxine (Controls unexposed, sick), 2017 Boukhris - SNRI (Controls unexposed, NOS), 2016 Sørensen - SNRI (Controls unexposed, NOS), 2013 60.25.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-2.02.31.0120.000Heuvelman - Venlafaxine, 2023Suarez - SNRI (Controls unexposed, discontinuers), 2022Hagberg - SNRI (Controls unexposed, sick), 2018Rai - Venlafaxine (Controls unexposed, sick), 2017Boukhris - SNRI (Controls unexposed, NOS), 2016Sørensen - SNRI (Controls unexposed, NOS), 2013

Asymetry test p-value = 0.9963 (by Egger's regression)

slope=0.3025 (0.6758); intercept=0.0098 (2.0024); t=0.0049; p=0.9963

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 11782, 11702, 11816, 11817, 11813, 11814, 18334

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 1.36[0.92; 2.01]24,11511,23853%NASuarez - SNRI (Controls unexposed, general pop), 2022 Hagberg - SNRI (Controls unexposed, disease free), 2018 Rai - Venlafaxine (Controls unexposed, disease free), 2017 Boukhris - SNRI (Controls unexposed, NOS), 2016 Sørensen - SNRI (Controls unexposed, NOS), 2013 5 unexposed, sick controlsunexposed, sick controls 1.33[0.83; 2.12]66710,81759%NAHeuvelman - Venlafaxine, 2023 Suarez - SNRI (Controls unexposed, discontinuers), 2022 Hagberg - SNRI (Controls unexposed, sick), 2018 Rai - Venlafaxine (Controls unexposed, sick), 2017 4 exposed to other treatment, sick controlsexposed to other treatment, sick controls 0.60[0.40; 0.92]1582,5790%NAHagberg - SNRI (Controls exposed to TCA), 2018 Rai - Venlafaxine (Controls exposed to TCA), 2017 Boukhris - SNRI (Controls exposed to TCA), 2016 Sørensen - SNRI (Controls exposed to TCA), 2013 40.510.01.0