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

Preterm (< 37 weeks)

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.
S18440
R78232		 Lee (Controls exposed to TCAs), 2025 Preterm birth (infant born at gestational age <37 weeks) during pregnancy (anytime or not specified) retrospective cohort (claims database) exposed to other treatment, sick excluded Adjustment: No Monotherapy: SNRI only 1.95 [0.99;3.83] C
excluded (control group) 		12/71   58/613 70 71
ref
S18441
R78253		 Lee (Controls unexposed, general pop), 2025 Preterm birth (infant born at gestational age <37 weeks) during pregnancy (anytime or not specified) retrospective cohort (claims database) unexposed (general population or NOS) Adjustment: Yes Monotherapy: SNRI only 1.56 [0.84;2.91] 12/71   28,543/463,440 28,555 71
ref
S18310
R77107		 Martin - Venlafaxine, 2024 Preterm delivery (delivery at <259 days (37 weeks’)) during pregnancy (anytime or not specified) population based cohort retrospective unexposed (general population or NOS) Adjustment: Yes Monotherapy: substance alone among all Antidep (SSRI, SNRI, ...) 1.74 [1.60;1.91] 679/6,441   119,950/2,408,707 120,629 6,441
ref
S15178
R62303		 Ankarfeldt - Duloxetine (Controls unexposed, NOS), 2023 Preterm births (< 37 weeks of gestation) late pregnancy population based cohort retrospective unexposed (general population or NOS) excluded Adjustment: Yes Monotherapy: substance alone among all Antidep (SSRI, SNRI, ...) 1.90 [1.44;2.49]
excluded (control group) 		65/450   116,041/2,082,019 116,106 450
ref
S15179
R62307		 Ankarfeldt - Duloxetine (Controls unexposed, sick), 2023 Preterm births (< 37 weeks of gestation) late pregnancy population based cohort retrospective unexposed, sick Adjustment: Yes Monotherapy: substance alone among all Antidep (SSRI, SNRI, ...) Unexposed sick: intermediate history of illness/treatment (3-12 months before pregnancy) 1.67 [1.24;2.23] 69/450   335/3,772 404 450
ref
S15171
R62273		 Benevent - SNRI, 2023 Preterm (< 37 weeks) during pregnancy (anytime or not specified) retrospective cohort (claims database) unexposed (general population or NOS) Adjustment: No Monotherapy: SNRI only 1.65 [1.05;2.59] C 21/215   8,813/143,301 8,834 215
ref
S11701
R43052		 Chen - SNRI, 2021 Preterm birth (<37 completed weeks of gestation) during pregnancy (anytime or not specified) population based cohort retrospective 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) 1.43 [1.22;1.67] 22/483   55/1,789 77 483
ref
S13145
R50181		 Marks - Duloxetine (Controls exposed to Bupropion), 2021 Preterm Birth during pregnancy (anytime or not specified) retrospective cohort exposed to other treatment, sick Adjustment: No Monotherapy: SNRI only 1.69 [1.05;2.73] C 32/139   61/406 93 139
ref
S11707
R43059		 Bahat - Duloxetine, 2020 Preterm birth (NOS) 1st trimester prospective cohort unexposed (general population or NOS) Adjustment: Yes Monotherapy: no or not specified 4.84 [2.31;10.15] -/-   -/- - -
ref
S11745
R43123		 Huybrechts - Duloxetine (Controls unexposed, NOS), 2020 Preterm birth late pregnancy retrospective cohort (claims database) unexposed (general population or NOS) Adjustment: Yes Monotherapy: no or not specified 1.19 [1.04;1.37] 179/880   147,007/1,364,101 147,186 880
ref
S11774
R43310		 Richardson - Venlafaxine, 2019 Preterm birth at least 1st trimester prospective cohort unexposed (general population or NOS) Adjustment: Yes Matched Monotherapy: no or not specified 1.51 [0.98;2.27] 33/198   125/1,081 158 198
ref
S11791
R43387		 Ozturk - Venlafaxine, 2016 Preterm Births (<37 weeks) at least 1st trimester prospective cohort unexposed (general population or NOS) Adjustment: No Monotherapy: no or not specified 1.33 [0.07;24.63] C 0/11   8/246 8 11
ref
S14993
R61352		 Robinson-Wolrath - SNRI, 2016 Preterm birth during pregnancy (anytime or not specified) retrospective cohort unexposed (general population or NOS) Adjustment: Yes Monotherapy: SNRI only 1.28 [0.69;2.40] -/91   -/- - 91
ref
S11776
R43333		 Te Winkel - Venlafaxine, 2016 Preterm deliveries during pregnancy (anytime or not specified) prospective cohort unexposed (general population or NOS) Adjustment: No Monotherapy: no or not specified 2.02 [1.32;3.10] C 62/590   36/656 98 590
ref
S11693
R42999		 Reis - SNRI (Controls exposed to TCA), 2010 Preterm birth (<37 weeks) 2nd and/or 3rd trimester population based cohort retrospective exposed to other treatment, sick excluded Adjustment: No Monotherapy: SNRI only 0.89 [0.62;1.28] C
excluded (control group) 		54/538   87/784 141 538
ref
S11694
R43011		 Reis - SNRI (Controls unexposed, NOS), 2010 Preterm birth (<37 weeks) 2nd and/or 3rd trimester population based cohort retrospective unexposed (general population or NOS) Adjustment: Yes Monotherapy: SNRI only 1.98 [1.49;2.63] 54/538   57,946/1,062,190 58,000 538
ref
S13352
R51468		 Calderon-Margalit - Venlafaxine, 2009 Preterm delivery (before 37 weeks of gestation) during pregnancy (anytime or not specified) prospective cohort unexposed (general population or NOS) Adjustment: Yes Monotherapy: no or not specified 3.78 [0.81;17.60] 4/9   234/2,493 238 9
ref
Total 14 studies 1.64 [1.43;1.89] 364,280 10,116
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 Lee (Controls unexposed, general pop), 2025Lee, 2025 1 1.56[0.84; 2.91]28,555714%ROB confusion: seriousROB selection: lowROB classification: criticalROB missing: lowROB mesure: moderateROB reporting: moderate Martin - Venlafaxine, 2024Martin - Venlafaxine, 2024 1.74[1.60; 1.91]120,6296,44115%ROB confusion: seriousROB selection: lowROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Ankarfeldt - Duloxetine (Controls unexposed, sick), 2023Ankarfeldt - Duloxetine, 2023 2 1.67[1.24; 2.23]40445010%ROB confusion: seriousROB selection: lowROB classification: moderateROB missing: lowROB mesure: moderateROB reporting: low Benevent - SNRI, 2023Benevent - SNRI, 2023 1.65[1.05; 2.59]8,8342156%ROB confusion: criticalROB selection: lowROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Chen - SNRI, 2021Chen - SNRI, 2021 1.43[1.22; 1.67]7748314%ROB confusion: moderateROB selection: lowROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Marks - Duloxetine (Controls exposed to Bupropion), 2021Marks - Duloxetine, 2021 3 1.69[1.05; 2.73]931396%ROB confusion: criticalROB selection: lowROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Bahat - Duloxetine, 2020Bahat - Duloxetine, 2020 4.84[2.31; 10.15]--3%ROB confusion: unclearROB selection: unclearROB classification: moderateROB missing: unclearROB mesure: unclearROB reporting: unclear Huybrechts - Duloxetine (Controls unexposed, NOS), 2020Huybrechts - Duloxetine, 2020 4 1.19[1.04; 1.37]147,18688014%ROB confusion: moderateROB selection: lowROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: low Richardson - Venlafaxine, 2019Richardson - Venlafaxine, 2019 1.51[0.98; 2.27]1581987%ROB confusion: seriousROB selection: moderateROB classification: moderateROB missing: criticalROB mesure: moderateROB reporting: moderate Ozturk - Venlafaxine, 2016Ozturk - Venlafaxine, 2016 1.33[0.07; 24.63]8110%ROB confusion: criticalROB selection: unclearROB classification: moderateROB missing: lowROB mesure: moderateROB reporting: moderate Robinson-Wolrath - SNRI, 2016Robinson-Wolrath - SNRI, 2016 1.28[0.69; 2.40]-914%ROB confusion: criticalROB selection: unclearROB classification: criticalROB missing: unclearROB mesure: moderateROB reporting: unclear Te Winkel - Venlafaxine, 2016Te Winkel - Venlafaxine, 2016 2.02[1.32; 3.10]985907%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: unclearROB reporting: moderate Reis - SNRI (Controls unexposed, NOS), 2010Reis - SNRI, 2010 5 1.98[1.49; 2.63]58,00053810%ROB confusion: seriousROB selection: lowROB classification: moderateROB missing: lowROB mesure: moderateROB reporting: moderate Calderon-Margalit - Venlafaxine, 2009Calderon-Margalit - Venlafaxine, 2009 3.78[0.81; 17.60]23891%ROB confusion: seriousROB selection: moderateROB classification: moderateROB missing: lowROB mesure: moderateROB reporting: moderate Total (14 studies) I2 = 65% 1.64[1.43; 1.89]364,28010,1160.510.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

1: Controls unexposed, general pop; 2: Controls unexposed, sick; 3: Controls exposed to Bupropion; 4: Controls unexposed, NOS; 5: Controls unexposed, NOS;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 1.64[1.43; 1.89]364,28010,11665%NALee (Controls unexposed, general pop), 2025 Martin - Venlafaxine, 2024 Ankarfeldt - Duloxetine (Controls unexposed, sick), 2023 Benevent - SNRI, 2023 Chen - SNRI, 2021 Marks - Duloxetine (Controls exposed to Bupropion), 2021 Bahat - Duloxetine, 2020 Huybrechts - Duloxetine (Controls unexposed, NOS), 2020 Richardson - Venlafaxine, 2019 Ozturk - Venlafaxine, 2016 Robinson-Wolrath - SNRI, 2016 Te Winkel - Venlafaxine, 2016 Reis - SNRI (Controls unexposed, NOS), 2010 Calderon-Margalit - Venlafaxine, 2009 14 case control studiescase control studies 0 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 1.71[1.41; 2.08]363,7069,04471%NALee (Controls unexposed, general pop), 2025 Martin - Venlafaxine, 2024 Benevent - SNRI, 2023 Bahat - Duloxetine, 2020 Huybrechts - Duloxetine (Controls unexposed, NOS), 2020 Richardson - Venlafaxine, 2019 Ozturk - Venlafaxine, 2016 Robinson-Wolrath - SNRI, 2016 Te Winkel - Venlafaxine, 2016 Reis - SNRI (Controls unexposed, NOS), 2010 Calderon-Margalit - Venlafaxine, 2009 11 unexposed, sickunexposed, sick 1.48[1.29; 1.70]4819330%NAAnkarfeldt - Duloxetine (Controls unexposed, sick), 2023 Chen - SNRI, 2021 2 exposed to other treatment, sickexposed to other treatment, sick 1.69[1.05; 2.73]93139 -NAMarks - Duloxetine (Controls exposed to Bupropion), 2021 1 Tags Adjustment   - No  - No 1.79[1.38; 2.32]9,0339550%NABenevent - SNRI, 2023 Marks - Duloxetine (Controls exposed to Bupropion), 2021 Ozturk - Venlafaxine, 2016 Te Winkel - Venlafaxine, 2016 4   - Yes  - Yes 1.62[1.37; 1.92]355,2479,16175%NALee (Controls unexposed, general pop), 2025 Martin - Venlafaxine, 2024 Ankarfeldt - Duloxetine (Controls unexposed, sick), 2023 Chen - SNRI, 2021 Bahat - Duloxetine, 2020 Huybrechts - Duloxetine (Controls unexposed, NOS), 2020 Richardson - Venlafaxine, 2019 Robinson-Wolrath - SNRI, 2016 Reis - SNRI (Controls unexposed, NOS), 2010 Calderon-Margalit - Venlafaxine, 2009 10 MatchedMatched 1.51[0.99; 2.30]158198 -NARichardson - Venlafaxine, 2019 1 Monotherapy   - no or not specified  - no or not specified 1.66[1.28; 2.15]147,7652,17171%NAChen - SNRI, 2021 Bahat - Duloxetine, 2020 Huybrechts - Duloxetine (Controls unexposed, NOS), 2020 Richardson - Venlafaxine, 2019 Ozturk - Venlafaxine, 2016 Te Winkel - Venlafaxine, 2016 Calderon-Margalit - Venlafaxine, 2009 7   - SNRI only  - SNRI only 1.75[1.44; 2.12]95,4821,0540%NALee (Controls unexposed, general pop), 2025 Benevent - SNRI, 2023 Marks - Duloxetine (Controls exposed to Bupropion), 2021 Robinson-Wolrath - SNRI, 2016 Reis - SNRI (Controls unexposed, NOS), 2010 5   - substance alone among all Antidep ( ...  - substance alone among all Antidep (SSRI, SNRI, ...) 1.73[1.59; 1.89]121,0336,8910%NAMartin - Venlafaxine, 2024 Ankarfeldt - Duloxetine (Controls unexposed, sick), 2023 2 Unexposed sick   - intermediate history of illness/tre ...  - intermediate history of illness/treatment (3-12 months before pregnancy) 1.67[1.25; 2.24]404450 -NAAnkarfeldt - Duloxetine (Controls unexposed, sick), 2023 1   - recent illness/treatment (during o ...  - recent illness/treatment (during or juste before pregnancy or treatment stopped in view of pregnancy) 1.43[1.22; 1.67]77483 -NAChen - SNRI, 2021 1 All studiesAll studies 1.64[1.43; 1.89]364,28010,11665%NALee (Controls unexposed, general pop), 2025 Martin - Venlafaxine, 2024 Ankarfeldt - Duloxetine (Controls unexposed, sick), 2023 Benevent - SNRI, 2023 Chen - SNRI, 2021 Marks - Duloxetine (Controls exposed to Bupropion), 2021 Bahat - Duloxetine, 2020 Huybrechts - Duloxetine (Controls unexposed, NOS), 2020 Richardson - Venlafaxine, 2019 Ozturk - Venlafaxine, 2016 Robinson-Wolrath - SNRI, 2016 Te Winkel - Venlafaxine, 2016 Reis - SNRI (Controls unexposed, NOS), 2010 Calderon-Margalit - Venlafaxine, 2009 140.510.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-3.54.01.7870.000Lee (Controls unexposed, general pop), 2025Martin - Venlafaxine, 2024Ankarfeldt - Duloxetine (Controls unexposed, sick), 2023Benevent - SNRI, 2023Chen - SNRI, 2021Marks - Duloxetine (Controls exposed to Bupropion), 2021Bahat - Duloxetine, 2020Huybrechts - Duloxetine (Controls unexposed, NOS), 2020Richardson - Venlafaxine, 2019Ozturk - Venlafaxine, 2016Robinson-Wolrath - SNRI, 2016Te Winkel - Venlafaxine, 2016Reis - SNRI (Controls unexposed, NOS), 2010Calderon-Margalit - Venlafaxine, 2009

Asymetry test p-value = 0.4394 (by Egger's regression)

slope=0.4101 (0.0799); intercept=0.5531 (0.6916); t=0.7997; p=0.4394

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 11693, 15178, 18440

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 1.73[1.45; 2.06]479,8129,49470%NALee (Controls unexposed, general pop), 2025 Martin - Venlafaxine, 2024 Ankarfeldt - Duloxetine (Controls unexposed, NOS), 2023 Benevent - SNRI, 2023 Bahat - Duloxetine, 2020 Huybrechts - Duloxetine (Controls unexposed, NOS), 2020 Richardson - Venlafaxine, 2019 Ozturk - Venlafaxine, 2016 Robinson-Wolrath - SNRI, 2016 Te Winkel - Venlafaxine, 2016 Reis - SNRI (Controls unexposed, NOS), 2010 Calderon-Margalit - Venlafaxine, 2009 12 unexposed, sick controlsunexposed, sick controls 1.48[1.29; 1.70]4819330%NAAnkarfeldt - Duloxetine (Controls unexposed, sick), 2023 Chen - SNRI, 2021 2 exposed to other treatment, sick controlsexposed to other treatment, sick controls 1.36[0.82; 2.28]30474869%NALee (Controls exposed to TCAs), 2025 Marks - Duloxetine (Controls exposed to Bupropion), 2021 Reis - SNRI (Controls exposed to TCA), 2010 30.510.01.0

Umbrella review (other published meta-analyses)

Published MAControlPeriodTE95% CIn exposedkI2 Xing (Preterm birth)Xing (Preterm birth) 1.79[1.45; 2.20]4%-Wwhatever (meta-analysis)Anyduring pregnancy (anytime or not specified)studies TTT2 metaPregmetaPreg 1.64[1.43; 1.89]65%10,116----Lee (Controls unexposed, general pop), 2025 Martin - Venlafaxine, 2024 Ankarfeldt - Duloxetine (Controls unexposed, sick), 2023 Benevent - SNRI, 2023 Chen - SNRI, 2021 Marks - Duloxetine (Controls exposed to Bupropion), 2021 Bahat - Duloxetine, 2020 Huybrechts - Duloxetine (Controls unexposed, NOS), 2020 Richardson - Venlafaxine, 2019 Ozturk - Venlafaxine, 2016 Robinson-Wolrath - SNRI, 2016 Te Winkel - Venlafaxine, 2016 Reis - SNRI (Controls unexposed, NOS), 2010 Calderon-Margalit - Venlafaxine, 2009 140.510.01.0