Serotonin and Noradrenaline Reuptake Inhibitors (SNRI)

Exposed non-exposed, cohort studies

Study Country
Study period
Study design
Data source Exposure definition Non-exposure definition Exposition period Sample size
(exposed/unexposed) Or (case / control)
Remarks Risk of bias
Ankarfeldt - Duloxetine (Controls unexposed, NOS)
2023
Sweden and Denmark
2004 - 2016
population based cohort retrospective
A nationwide observational cohort study, based on Danish and Swedish national registers, Pregnant women with at least one redeemed prescription of duloxetine (ATC: N06AX21) from a community pharmacy during pregnancy (early exposure and/or late exposure) (and no SSRI or venlafaxine comedication). unexposed (general population or NOS)
Pregnant women with not exposed to duloxetine during pregnancy and from 90 days prior to last menstrual period.
early pregnancy, late pregnancy 1589 / 2080880 1589 and 450 were duloxetine exposed in early and late pregnancies, respectively. Few overlapping between Reis 2010 (1995 - 2007) and Ankarfeldt 2023 (2004 - 2016) => the 2 studies were kept.
Information about redeemed prescriptions obtained from the national prescription registers.
Ankarfeldt - Duloxetine (Controls unexposed, sick)
2023
Sweden and Denmark
2004 - 2016
population based cohort retrospective
A nationwide observational cohort study, based on Danish and Swedish national registers, Pregnant women with at least one redeemed prescription of duloxetine (ATC: N06AX21) from a community pharmacy during pregnancy (early exposure and/or late exposure) (and no SSRI or venlafaxine comedication). unexposed, sick
Pregnant women who have discontinued duloxetine, i.e with at least one redeemed prescription of duloxetine between 365 days prior to LMP, but not during the exposure-time window.
early pregnancy, late pregnancy 1589 / 2839 1589 and 450 were duloxetine exposed in early and late pregnancies, respectively. Few overlapping between Reis 2010 (1995 - 2007) and Ankarfeldt 2023 (2004 - 2016) => the 2 studies were kept.
Information about redeemed prescriptions obtained from the national prescription registers.
Ankarfeldt a - Duloxetine (Controls unexposed, NOS)
2021
Sweden and Denmark
2004 - 2016
population based cohort retrospective
Nationwide registers from Sweden and Denmark covering all pregnancies. At least one redeemed prescription of duloxetine from Last menstrual period (LMP) to 90 days after LMP for malformations or to the end of pregnancy (for stillbirth). unexposed (general population or NOS)
No redeemed prescription of duloxetine in the exposure time window (women with duloxetine exposure from 90 days prior to LMP but no exposure from LMP to 90 days after LMP were excluded).
1st trimester, during pregnancy (anytime or not specified) 1512 / 2074652 Cohort for stillbirths: 1668 exposed; 2130495 unexposed. Overlapping: For malformations: 3 studies kept from Sweden: Ankarfeld : Duloxetine (Sweden/Denmark: 2004 - 2016; Furu 2015 (Venlafaxine 2006-2010 with other countries) and Reis 2010 (1995 - 2007).
The prescription registers containing electronically submitted information on prescriptions dispensed by pharmacies, classified according to the global ATC system.
Ankarfeldt a - Duloxetine (Controls unexposed, sick)
2021
Sweden and Denmark
2004 - 2016
population based cohort retrospective
Nationwide registers from Sweden and Denmark covering all pregnancies. At least one redeemed prescription of duloxetine from Last menstrual period (LMP) to 90 days after LMP for malformations or to the end of pregnancy (for stillbirth). unexposed, sick
Duloxetine discontinuers: at least one redeemed prescription of duloxetine between 365 days prior to LMP to LMP and not during pregnancy.
1st trimester, during pregnancy (anytime or not specified) 1512 / 2876 For malformations: 3 studies kept from Sweden: Ankarfeld : Duloxetine (Sweden/Denmark: 2004 - 2016; Furu 2015 (Venlafaxine 2006-2010 with other countries) and Reis 2010 (1995 - 2007). Cohort for stillbirths: 1668 exposed; 2815 discontinuers.
The prescription registers containing electronically submitted information on prescriptions dispensed by pharmacies, classified according to the global ATC system.
Ankarfeldt b - Duloxetine (Controls unexposed, NOS)
2021
Denmark
2004 - 2016
population based cohort retrospective
The Danish National Prescription Register, the Danish National Patient Register, the Medical Birth Register, and registers containing information on education and household income. At least one redeemed prescription of duloxetine from 30 days prior to last menstrual period (LMP) to 140 days post LMP, or the end of the pregnancy, whichever came first. unexposed (general population or NOS)
Duloxetine non-exposed: no redeemed prescriptions of duloxetine in the exposure time window.
during pregnancy (anytime or not specified) 1212 / 1018745 Overlapping: partial overlapping between Ankarfeldt 2021b (2004 - 2016) and Kjaersgaard 2013 (1997 - 2008). Because the 2 study periods are longer than the common period, the 2 studies were kept.
Information on maternal exposure to antidepressant drugs was based on redeemed prescriptions from community pharmacies using the Danish National Prescription Register.
Ankarfeldt b - Duloxetine (Controls unexposed, sick)
2021
Denmark
2004 - 2016
population based cohort retrospective
The Danish National Prescription Register, the Danish National Patient Register, the Medical Birth Register, and registers containing information on education and household income. At least one redeemed prescription of duloxetine from 30 days prior to last menstrual period (LMP) to 140 days post LMP, or the end of the pregnancy, whichever came first. unexposed, sick
Duloxetine discontinuers: at least one redeemed prescription of duloxetine between 365 days prior to LMP to 30 days prior to LMP, but no redeemed prescription of duloxetine in the exposure time window.
during pregnancy (anytime or not specified) 1212 / 1418 Overlapping: partial overlapping between Ankarfeldt 2021b (2004 - 2016) and Kjaersgaard 2013 (1997 - 2008). Because the 2 study periods are longer than the common period, the 2 studies were kept.
Information on maternal exposure to antidepressant drugs was based on redeemed prescriptions from community pharmacies using the Danish National Prescription Register.
Avalos - SNRI (Controls exposed to TCA)
2015
USA
2010 - 2012
retrospective cohort (claims database)
Kaiser Permanente Northern California (KPNC). Pregnant women with at least one dispensing of serotonin-norepinephrine reuptake inhibitor (SNRI) only between the first day of the woman's last menstrual period (LMP) and 20 completed weeks of gestation. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Pregnant women with at least one pharmacy dispensing of tricyclic antidepressants (TCAs) only between the first day of the woman's last menstrual period (LMP) and 20 completed weeks of gestation. (This is a subgroup of exposure among the whole exposed group considered in the study).
during pregnancy (anytime or not specified) 72 / 116 Results of SNRI only reported rather than 'SNRI/SNRI plus other antidepressant'.
Women exposed to antidepressant medications during pregnancy were identified through linkage to information on dates of drug dispensation and days of supply from the pharmacy database.
Avalos - SNRI (Controls unexposed, disease free)
2015
USA
2010 - 2012
retrospective cohort (claims database)
Kaiser Permanente Northern California (KPNC). Pregnant women with at least one dispensing of Serotonin-norepinephrine reuptake inhibitor (SNRI) only between the first day of the woman's last menstrual period (LMP) and 20 completed weeks of gestation. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, disease free
Pregnant women without depression.
during pregnancy (anytime or not specified) 72 / 16402 Results of SNRI only reported rather than 'SNRI/SNRI plus other antidepressant'.
Women exposed to antidepressant medications during pregnancy were identified through linkage to information on dates of drug dispensation and days of supply from the pharmacy database.
Avalos - SNRI (Controls unexposed, sick)
2015
USA
2010 - 2012
retrospective cohort (claims database)
Kaiser Permanente Northern California (KPNC). Pregnant women with at least one dispensing of Serotonin-norepinephrine reuptake inhibitor (SNRI) only between the first day of the woman's last menstrual period (LMP) and 20 completed weeks of gestation. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Pregnant women with untreated depression (diagnosed between 6 months prior to the woman's last menstrual period (LMP) and 20 completed weeks of gestation).
during pregnancy (anytime or not specified) 72 / 1345 Results of SNRI only reported rather than 'SNRI/SNRI plus other antidepressant'.
Women exposed to antidepressant medications during pregnancy were identified through linkage to information on dates of drug dispensation and days of supply from the pharmacy database.
Bahat - Duloxetine
2020
Israel
2001 - 2015
prospective cohort
The Israeli Teratology Information Service (TIS). Pregnant women counseled for duloxetine exposure in the first trimester. unexposed (general population or NOS)
Pregnant women counseled for non-teratogenic exposure in pregnancy.
1st trimester 128 / 511 Major congenital anomalies excluding genetic or cytogenetic not reported because number of cases, exposures and exclusions not provided.
Not specified.
Benevent - SNRI
2023
France
2004 - 2019
retrospective cohort (claims database)
EFEMERIS (Évaluation chez la Femme Enceinte des MÉdicaments et de leurs RISques) database, Haute-Garonne, France. Pregnant women with at least one redeemed prescription of serotonin-norepinephrine reuptake inhibitors (SNRIs) monotherapy at least during the first trimester of pregnancy. unexposed (general population or NOS)
Pregnant women without redeemed prescription of antidepressants 3 months before and during pregnancy.
1st trimester, during pregnancy (anytime or not specified) 210 / 141865 Publication of Benevent 2023 (preeclampsia) completed with data of the unpublished report of Araujo 2022. Exclusion of receipt of both SSRIs and SNRIs 3 months before and during pregnancy. Results versus SSRIs not reported => inadequate control group.
Prescriptions obtained from the French Health Insurance database (Haute Garonne), that included all drug prescriptions dispensed at pharmacies by patients receiving outpatient care, prior to and during pregnancy (names, ATC codes, dispensing dates, etc).
Bérard a - Venlafaxine
2017
Canada
1998 - 2010
population based cohort propective
A register-based cohort study using data from the Quebec Pregnancy Cohort (QPC). Women that had filled at least one prescription for Venlafaxine during the time window of interest (between week 21 and date of birth). (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
Women that did not have filled prescription for antidepressant during the time window of of interest (between week 21 and date of birth).
2nd and/or 3rd trimester 419 / 141097 SNRI (venlafaxine). Duloxetine and desvenlafaxine were not included in the SNRI category as they were not on the list of medications reimbursed in Quebec during the calendar years of the study;
The Quebec Public Prescription Drug Insurance database (drug name, start date, dosage, duration).
Bérard b - SNRI=Venlafaxine (Controls exposed to TCA)
2017
Canada
1998 - 2009
retrospective cohort (claims database)
A register-based cohort study using data from the Quebec Pregnancy Cohort (QPC). Depressed/anxious pregnancies with prescription fillings for Serotonin–norepinephrine reuptake inhibitor (SNRI) (venlafaxine only) dispensed during the first trimester of gestation. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Depressed/anxious pregnancies with prescription fillings for Tricyclic antidepressants (TCA) dispensed during the first trimester of gestation.
1st trimester 738 / 382 Overlapping: results of Ramos 2008 (1998-2002) are included in this larger study.
Prescription fillings dispensed to women identified in the cohort from the Quebec public prescription drug insurance database
Bérard b - SNRI=Venlafaxine (Controls unexposed, sick)
2017
Canada
1998 - 2009
retrospective cohort (claims database)
A register-based cohort study using data from the Quebec Pregnancy Cohort (QPC). Depressed/anxious pregnancies with prescription fillings for Serotonin–norepinephrine reuptake inhibitor (SNRI) (venlafaxine only) dispensed during the first trimester of gestation. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Pregnancies with a diagnosis or were treated with antidepressants in the year before their pregnancy but with no exposure to antidepressants during the first trimester of gestation.
1st trimester 738 / 14847 Overlapping: results of Ramos 2008 (1998-2002) are included in this larger study.
Prescription fillings dispensed to women identified in the cohort from the Quebec public prescription drug insurance database
Bernard - SNRI
2019
Canada
2005 - 2010
prospective cohort
The CHU de Québec-Université Laval. Pregnant women exposed to Serotonin norepinephrine reuptake inhibitors (SNRI) before the 16th week of pregnancy. unexposed, disease free
Pregnant women not exposed to the antidepressant/anxiolytic medication, depression or anxiety.
at least 1st trimester 65 / 6502
Documentation on antidepressant medication was obtained following delivery from a standardized prenatal follow-up form filled at each prenatal visit by the nurse and the physician and included in the hospital records.
Boukhris - SNRI (Controls exposed to TCA)
2016
Canada
1998 - 2009
retrospective cohort (claims database)
The Québec Pregnancy Children Cohort (QPC), a register-based study of an ongoing population-based cohort. Infants whose mother having at least 1 prescription of Serotonin norepinephrine reuptake inhibitor (SNRIs) filled at any time during pregnancy or before pregnancy that overlapped the first day of gestation. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Infants whose mother having at least 1 prescription of Tricyclic antidepressants filled at any time during pregnancy or before pregnancy that overlapped the first day of gestation. (This is a subgroup of exposure among the whole exposed group considered in the study).
2nd and/or 3rd trimester 447 / 229 'Exposure to a single class was defined as the filling of prescriptions for only 1 AD class in the time window of interest.'
The Public Prescription Drug Insurance database of Québec (drug name, start date, dose, and duration). Data on prescription filling for AD were validated against medical records and maternal reports.
Boukhris - SNRI (Controls exposed to TCA)
2017
Canada
1998 - 2009
retrospective cohort (claims database)
A register-based cohort study using data from the Quebec Pregnancy/Children Cohort (QPC). Having at least one prescription filled of Serotonin norepinephrine reuptake inhibitors (SNRIs) during the 2nd/3rd trimesters of pregnancy. (This is a subgroup of exposure among the whole exposed group considered). exposed to other treatment, sick
Having at least one prescription filled of tricyclic antidepressants (TCAs) during the 2nd/3rd trimesters of pregnancy. (This is a subgroup of exposure among the whole exposed group considered).
2nd and/or 3rd trimester 445 / 227 ‘Single class exposure was defined as the filling of prescriptions for only one antidepressant class in the time window of interest.'
The Quebec’s Public Prescription Drug Insurance database (drug name, start date and duration), MedEcho database (diagnoses and procedures).
Boukhris - SNRI (Controls unexposed, NOS)
2016
Canada
1998 - 2009
retrospective cohort (claims database)
The Québec Pregnancy Children Cohort (QPC), a register-based study of an ongoing population-based cohort. Infants whose mother having at least 1 prescription of Serotonin norepinephrine reuptake inhibitor (SNRIs) filled at any time during pregnancy or before pregnancy that overlapped the first day of gestation. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
Infants who were not exposed in utero to antidepressants.
2nd and/or 3rd trimester 447 / 142924 'Exposure to a single class was defined as the filling of prescriptions for only 1 antidepressant class in the time window of interest.'
The Public Prescription Drug Insurance database of Québec (drug name, start date, dose, and duration). Data on prescription filling for antidepressant were validated against medical records and maternal reports.
Boukhris - SNRI (Controls unexposed, NOS)
2017
Canada
1998 - 2009
retrospective cohort (claims database)
A register-based cohort study using data from the Quebec Pregnancy/Children Cohort (QPC). Having at least one prescription filled of Serotonin norepinephrine reuptake inhibitors (SNRIs) during the 2nd/3rd trimesters of pregnancy. (This is a subgroup of exposure among the whole exposed group considered). unexposed (general population or NOS)
Infants who were not exposed in utero to any antidepressants during the 2nd/3rd trimesters of pregnancy.
2nd and/or 3rd trimester 445 / 141905 ‘Single class exposure was defined as the filling of prescriptions for only one antidepressant class in the time window of interest.'
The Quebec’s Public Prescription Drug Insurance database (drug name, start date and duration), MedEcho database (diagnoses and procedures).
Calderon-Margalit - Venlafaxine
2009
USA
1996 - nr
prospective cohort
The ongoing Omega Study, a prospective cohort study of pregnant mothers who attended prenatal care clinics affiliated with Swedish Medical Center (Seattle, Washington) and Tacoma General Hospital (Tacoma, Washington). Pregnant women who used Venlafaxine during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
Pregnant women who did not use psychotropic medications during pregnancy.
during pregnancy (anytime or not specified) 9 / 2493 Of the women who were taking psychotropic medications, 235 (78%) took only one medication, 51 (17%) used two medications, and 14 (5%) used three or more medications.
Participants were interviewed during a prenatal visit prior to 20 weeks of gestation by trained research personnel using a structured questionnaire. Data on medications used during pregnancy were retrieved from both questionnaires and medical records.
Chan (Controls unexposed, sick)
2024
China
2003 - 2018
retrospective cohort (claims database)
The Clinical Data Analysis and Reporting System (CDARS), an electronic health-record database developed by the Hospital-Authority which is a statutory body delivering government-subsidized, universal health coverage to all Hong Kong residents. Infants of women with depression/anxiety who were prescribed with serotonin-norepinephrine-reuptake-inhibitors (SNRI) only filled during the first trimester and prescriptions filled before pregnancy but with duration overlapping the first trimester. unexposed, sick
Infants of pregnant women with depression/anxiety who were not prescribed with any antidepressant within 90 days before the last menstrual period and during the first trimester.
1st trimester 66 / 4413
Study data were obtained from the Clinical Data Analysis and Reporting System, a database that contains prescribing/dispensing records.
Chan - SNRI (Controls exposed to TCA)
2024
China
2003 - 2018
retrospective cohort (claims database)
The Clinical Data Analysis and Reporting System (CDARS), an electronic health-record database developed by the Hospital-Authority which is a statutory body delivering government-subsidized, universal health coverage to all Hong Kong residents. Infants of women with prescription of serotonin-norepinephrine-reuptake-inhibitors (SNRI) only filled during the first trimester and prescriptions filled before pregnancy but with duration overlapping the first trimester. exposed to other treatment, sick
Infants of women who were prescribed with Tricyclic-antidepressants (TCA) only filled during the first trimester and prescriptions filled before pregnancy but with duration overlapping the first trimester.
1st trimester 77 / 322
Study data were obtained from the Clinical Data Analysis and Reporting System, a database that contains prescribing/dispensing records.
Chan - SNRI (Controls unexposed, general pop)
2024
China
2003 - 2018
retrospective cohort (claims database)
The Clinical Data Analysis and Reporting System (CDARS), an electronic health-record database developed by the Hospital-Authority which is a statutory body delivering government-subsidized, universal health coverage to all Hong Kong residents. Infants of women with prescription of serotonin-norepinephrine-reuptake-inhibitors (SNRI) only filled during the first trimester and prescriptions filled before pregnancy but with duration overlapping the first trimester. unexposed (general population or NOS)
Infants of pregnant women who were not prescribed with any antidepressant within 90 days before the last menstrual period and during the first trimester.
1st trimester 77 / 462377
Study data were obtained from the Clinical Data Analysis and Reporting System, a database that contains prescribing/dispensing records.
Chen - SNRI
2021
Taiwan
2000 - 2013
population based cohort retrospective
The Taiwanese National Health Insurance Research Database (NHIRD). Pregnant patients with perinatal depression with serotonin norepinephrine reuptake inhibitors (SNRIs) prescription. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Pregnant patients with perinatal depression with no antidepressant treatment 90 days before the date of their first pregnancy.
during pregnancy (anytime or not specified) 483 / 1789 SNRIs; venlafaxine and duloxetine. Meta-analysis of adjusted HR provided by authors according to defined daily doses.
The National Health Insurance Research Database (NHIRD) which is a medical claims database and that includes drug prescription.
De Ocampo - SNRI
2016
USA and Canada
2004 - 2014
prospective cohort
The MotherToBaby (MTB) USA and Canada and MTB California cohort studies. Pregnant women who use serotonin-norepinephrine reuptake inhibitors (SNRIs) alone during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
Pregnant women who did not use antidepressants at any time during pregnancy.
1st and 2nd trimester, throughout pregnancy 21 / 3119 Two exposed groups: discontinuers (women who discontinued use <20 weeks of gestation) or continuers (women who continued use ≥20 weeks of gestation). Continuers reported here because it maximize the potential effect and there are more pregnancies.
After enrollment, the women completed a comprehensive intake interview and use of prescription and over-the-counter medications were collected. Information on exposures collected at intake was updated at each successive interview (every 3 months until the end of the pregnancy).
Einarson - Venlafaxine
2009
Canada
Not specified.
prospective cohort
The Motherisk Program, a teratogenic information service. Pregnant women who were exposed to Venlafaxine in the first trimester of pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
Pregnant women who were not exposed to antidepressants and who had called Motherisk for information regarding nonteratogenic drugs.
1st trimester 154 / 928
During the initial telephone contact, details of exposure and concurrent exposures are recorded on a standardized questionnaire.
Einarson - Venlafaxine
2001
Italy, UK, USA, Brazil and Canada
Not specfied.
prospective cohort
The Motherisk Program and the other participating Teratology information services. Pregnant women exposed to Venlafaxine at least during organogenesis (4h and 14th week of gestation). unexposed (general population or NOS)
Pregnant women who were given nonteratogenic drugs (loperamide, echinacea, sumatriptan, and dextromethorphan).
at least 1st trimester 150 / 150 Overlapping: malformations not reported because probable overlapping with Einarson 2009 (2 same malformations reported). 'The majority of the women in the venlafaxine group (70% [N=105]) took 75 mg/day of venlafaxine'
On successful contact, information on each woman’s exposure history and pregnancy outcome were obtained, along with other measures of interest, with the aid of a structured questionnaire.
Frayne - SNRI
2021
Australia
Not specified
retrospective cohort
The King Edward Memorial Hospital in Perth and Mercy Hospital for Women in Melbourne, Australia. Pregnant women that use Selective Norepinephrine reuptake inhibitors (SNRIs) during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Pregnant women who were not taking, and had not taken, antidepressant, mood stabilizing and antiepileptic agents during the pregnancy.
throughout pregnancy 68 / 238 'Data were extracted from a larger dataset: Galbally et al. 2020'
Psychotropic medication usage was extracted from the medical records and included information for first trimester and third trimester exposure as well as dosage.
Furu - Venlafaxine
2015
Denmark, Finland, Iceland, Norway, and Sweden
1996 - 2010
population based cohort retrospective
Nordic population (Denmark, Finland, Iceland, Norway, and Sweden) identified from nationwide health registers. Infants born to women who filled a prescription for Venlafaxine from 30 days before the first day of the last menstrual period until the end of the first trimester (defined as 97 days after the last menstrual period). unexposed (general population or NOS)
Infants not exposed to any antidepressant (ATC code N06A) in utero.
1st trimester 2763 / 2266875 Overlapping: For malformations: 3 studies kept from Sweden: Ankarfeld : Duloxetine (Sweden/Denmark: 2004 - 2016; Furu 2015 (Venlafaxine 2006-2010 with other countries) and Reis 2010 (1995 - 2007).
The Nordic prescription registers include data on dispensed drugs, substance, brand name, and formulation, together with date of dispensing.
Hagberg - SNRI (Controls exposed to TCA)
2018
United Kingdom
1989 - 2011
retrospective cohort (claims database)
The UK Clinical Practice Research Datalink (CPRD), a large, population-based electronic medical database. Pregnant women with depression treated with Serotonin and norepinephrine reuptake inhibitors (SNRIs) only (diagnosis and ≥1 antidepressant prescription during the exposure period). (This is a subgroup of exposure among the whole exposed group considered). exposed to other treatment, sick
Pregnant women with depression treated with tricyclic antidepressants (TCAs) only (diagnosis and ≥1 antidepressant prescription during the exposure period). (This is a subgroup of exposure among the whole exposed group considered).
during pregnancy (anytime or not specified) 1246 / 4856 For ASD: Partial overlapping of Hagberg 2018 (1989 - 2011) and Heuvelman 2023 (1995 - 2017), with more uncommon study period (12 years) than common (6 years) => The 2 studies were kept.
The UK Clinical Practice Research Datalink (CPRD) where participating general practitioners (GPs) contributed de-identified data including details of prescription drugs.
Hagberg - SNRI (Controls unexposed, disease free)
2018
United Kingdom
1989 - 2011
retrospective cohort (claims database)
The UK Clinical Practice Research Datalink (CPRD), a large, population-based electronic medical database. Pregnant women with depression treated with Serotonin and norepinephrine reuptake inhibitors (SNRIs) only (diagnosis and ≥1 antidepressant prescription during the exposure period). (This is a subgroup of exposure among the whole exposed group considered). unexposed, disease free
Pregnant women who had neither depression nor prescriptions for antidepressants prior to the baby’s delivery date.
during pregnancy (anytime or not specified) 1246 / 154107 For ASD: Partial overlapping of Hagberg 2018 (1989 - 2011) and Heuvelman 2023 (1995 - 2017), with more uncommon study period (12 years) than common (6 years) => The 2 studies were kept.
The UK Clinical Practice Research Datalink (CPRD) where participating general practitioners (GPs) contributed de-identified data including details of prescription drugs.
Hagberg - SNRI (Controls unexposed, sick)
2018
United Kingdom
1989 - 2011
retrospective cohort (claims database)
The UK Clinical Practice Research Datalink (CPRD), a large, population-based electronic medical database. Pregnant women with depression treated with Serotonin and norepinephrine reuptake inhibitors (SNRIs) only (diagnosis and ≥1 antidepressant prescription during the exposure period). (This is a subgroup of exposure among the whole exposed group considered). unexposed, sick
Pregnant women with untreated depression (recent history of treated depression but no antidepressants during the exposure period).
during pregnancy (anytime or not specified) 1246 / 12994 For ASD: Partial overlapping of Hagberg 2018 (1989 - 2011) and Heuvelman 2023 (1995 - 2017), with more uncommon study period (12 years) than common (6 years) => The 2 studies were kept.
The UK Clinical Practice Research Datalink (CPRD) where participating general practitioners (GPs) contributed de-identified data including details of prescription drugs.
Hanley - SNRI
2016
Canada
2002 - 2011
retrospective cohort (claims database)
A population-based cohort study in British Columbia, Canada. A supply of Serotonin–norepinephrine reuptake inhibitors (SNRIs) during pregnancy (late- or mid-pregnancy exposure). (This is a subgroup of exposure among the whole exposed group considered). unexposed (general population or NOS)
No supply of any antidepressants in the 5 months before delivery (during mid- to late pregnancy).
2nd trimester, late pregnancy 1390 / 310813 'We excluded all women using 'other antidepressants' (such as amitriptyline, bupropion, and trazodone) from our final analyses. Women using combination SSRI and serotonin–norepinephrine reuptake inhibitor therapy were also excluded.'
The British Columbia PharmaNet (a prescription dispensation database into which all prescriptions dispensed must be entered by law).
Heuvelman - Venlafaxine
2023
United Kingdom
1995 - 2017
retrospective cohort (claims database)
The UK Clinical Practice Research Datalink, a large, ongoing database of anonymised primary care medical records for patients registered with a general practice in the United Kingdom. Women who had initiated or continued Lofepramine for the treatment of depressive symptoms during pregnancy. unexposed, sick
Women who did not initiate or who discontinue antidepressants during pregnancy.
during pregnancy (anytime or not specified) 818 / 16330 For ASD: Partial overlapping of Hagberg 2018 (1989 - 2011) and Heuvelman 2023 (1995 - 2017), with more uncommon study period (12 years) than common (6 years) => The 2 studies were kept.
The Clinical Practice Research Datalink (CPRD) contains an extensive code list to identify the name, formulation and dose of medications, which are mandatory fields in the prescription electronic record (according to protocol).
Huybrechts - Duloxetine (Controls unexposed, NOS)
2020
USA
2004 - 2013
retrospective cohort (claims database)
The nationwide Medicaid Analytic eXtract (MAX). Pregnant women who filled at least one outpatient prescription for duloxetine during the etiologically relevant window. unexposed (general population or NOS)
Pregnant women not exposed to duloxetine during the etiologically relevant exposure window.
1st trimester, early pregnancy, late pregnancy 2532 / 1284827 Exclusion of pregnancies exposed to a known teratogenic drug (warfarin, antineoplastic agents, lithium, isotretinoin, misoprostol, thalidomide) 1st trimester. Partial overlapping for preeclampsia and cardiac malfo (Palmsten 2013, Huybrechts 2014 and 2020)
The Medicaid Analytic eXtract (MAX) dataset that contains all filled outpatient drug prescriptions for Medicaid beneficiaries.
Huybrechts - Duloxetine (Controls unexposed, sick)
2020
USA
2004 - 2013
retrospective cohort (claims database)
The nationwide Medicaid Analytic eXtract (MAX). Pregnant women who filled at least one outpatient prescription for duloxetine during the etiologically relevant window. unexposed, sick
Pregnant women exposed to duloxetine before but not during pregnancy (≥1 duloxetine dispensing between 6 months and 60 days before LMP but not during first trimester).
1st trimester 2532 / 2456 Exclusion of pregnancies exposed to a known teratogenic drug (warfarin, antineoplastic agents, lithium, isotretinoin, misoprostol, thalidomide) 1st trimester. Partial overlapping for preeclampsia and cardiac malfo (Palmsten 2013, Huybrechts 2014 and 2020)
The Medicaid Analytic eXtract (MAX) dataset that contains all filled outpatient drug prescriptions for Medicaid beneficiaries.
Huybrechts - SNRI (Controls unexposed, NOS)
2014
USA
2000 - 2007
cohort
Cohort study nested in the nationwide Medicaid Analytic eXtract. Pregnant women who have had exposure to Serotonin– norepinephrine reuptake inhibitors (SNRIs) with the first trimester. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
Pregnant women without exposure to antidepressants during the first trimester.
1st trimester 6904 / 885115 Exclusion of pregnancies with a diagnosis of a chromosomal abnormality and pregnancies in which the mother had been treated with known teratogens during the first trimester (i.e., lithium, antineoplastic agents, retinoids, and thalidomide).
The Medicaid Analytic eXtract data set that contains data on all filled outpatient medication prescriptions.
Huybrechts - SNRI (Controls unexposed, sick)
2014
USA
2000 - 2007
cohort
Cohort study nested in the nationwide Medicaid Analytic eXtract. Pregnant women who have had exposure to Serotonin– norepinephrine reuptake inhibitors (SNRIs) with the first trimester. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Pregnant women with a diagnosis of depression without exposure to antidepressants during the first trimester.
1st trimester 6904 / 180564 Use of High-dimensional propensity-score data (Supplementary Table S15). Exclusion of pregnancies in which the mother had been treated with known teratogens during the first trimester (i.e., lithium, antineoplastic agents, retinoids, and thalidomide).
The Medicaid Analytic eXtract data set that contains data on all filled outpatient medication prescriptions.
Jackson - SNRI
2024
U.S.A
2019 - 2022
retrospective cohort (claims database)
Inpatient electronic medical record system (Sunrise Clinical Manager, Allscripts Corp., Chicago, IL) of 7 hospitals within a large academic health system in New York. Prenatal exposure to a monotherapy of serotonin-norepinephrine reuptake inhibitors (SNRIs: duloxetine, venlafaxine), unexposed, disease free
No prenatal exposure to serotonin-norepinephrine reuptake inhibitors (SNRIs: duloxetine, venlafaxine),
during pregnancy (anytime or not specified) 145 / 106961
Medication exposure was determined by its presence or absence in the medication reconciliation document completed during hospital admission.
Kjaersgaard - Venlafaxine (Controls unexposed, NOS)
2013
Denmark
1997 - 2008
population based cohort retrospective
Danish administrative health registries. Mother that had redeemed a prescription for Venlafaxine at any time from 30 days before conception up to 1 day before the end of pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
Mother that had not redeemed any prescription for antidepressant medication from 6 months before conception up to 1 day before the end of the pregnancy.
during pregnancy (anytime or not specified) -9 / 983258 Unexposed cohort: 1843 plus 981415 = 983258. partial Partial overlapping between Ankarfeldt 2021b (2004 - 2016) and Kjaersgaard 2013 (1997 - 2008) => 4 common years, 13 not common years => the 2 studies were kept.
Information on all redeemed prescriptions was obtained from the Denmark Registry of Medicinal Product Statistics.
Kjaersgaard - Venlafaxine (Controls unexposed, sick)
2013
Denmark
1997 - 2008
population based cohort retrospective
Danish administrative health registries. Mother with a registry-based diagnosis of depressive disorder that had redeemed a prescription for Venlafaxine at any time from 30 days before conception up to 1 day before the end of pregnancy. unexposed, sick
Mother with a registry-based diagnosis of depressive disorder that had not redeemed any prescription for antidepressant medication from 6 months before conception up to 1 day before the end of the pregnancy.
during pregnancy (anytime or not specified) -9 / -9 Molar or ectopic pregnancies (ICD-10: O00.0– O01.9) were excluded from the main analyses. Partial overlapping between Ankarfeldt 2021b (2004 - 2016) and Kjaersgaard 2013 (1997 - 2008) => 4 common years, 13 not common years => the 2 studies were kept.
Information on all redeemed prescriptions was obtained from the Denmark Registry of Medicinal Product Statistics.
Kolding - Venlafaxine (Controls unexposed, disease free)
2021
Denmark
2007 - 2014
population based cohort retrospective
Five nationwide registries and databases: the Danish Fetal Medicine Database, the Danish National Patient Registry, the Danish Medical Birth Registry and the Danish Health Services Prescription Database. Pregnant women with two or more redeemed prescriptions of Venlafaxine from 28 days before through 70 days after the conception date. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, disease free
Pregnant women with absence of redemptions for an antidepressant in the same time window, combined with absence of former use.
1st trimester 847 / 353581 'Pregnancies with fetal chromosomal abnormalities were excluded regardless of presence of other malformations.'
Exposure to antidepressants was measured using redeemed prescriptions through linkage to the Danish Health Services Prescription Database.
Kolding - Venlafaxine (Controls unexposed, sick)
2021
Denmark
2007 - 2014
population based cohort retrospective
Five nationwide registries and databases: the Danish Fetal Medicine Database, the Danish National Patient Registry, the Danish Medical Birth Registry and the Danish Health Services Prescription Database. Pregnant women with two or more redeemed prescriptions of Venlafaxine from 28 days before through 70 days after the conception date. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Pregnant women with untreated- or well treated depression or anxiety without antidepressant use in the pregnancy (one or more redeemed prescription of an antidepressant from 365 to 183 days preconception and no redemptions between 182 days preconception through the first trimester).
1st trimester 847 / 6326 'Pregnancies with fetal chromosomal abnormalities were excluded regardless of presence of other malformations.'
Exposure to antidepressants was measured using redeemed prescriptions through linkage to the Danish Health Services Prescription Database.
Laugesen - SNRI
2013
Denmark
1996 - 2009
population based cohort retrospective
Nationwide Danish medical registries Children born to mother with redemption of a Serotonin-norepinephrine reuptake inhibitor (SNRI) prescription by the mother 30 days prior to or during pregnancy. (This is a subgroup of exposure among the whole exposed group considered). unexposed (general population or NOS)
Children born to mother who had never redeemed a prescription on antidepressants.
during pregnancy (anytime or not specified) 763 / 816792
Prescription identified through the Danish National Prescription.
Lee (Controls exposed to TCAs)
2025
China
2003 - 2018
retrospective cohort (claims database)
The Clinical Data Analysis and Reporting System (CDARS) of the Hospital Authority, Hong Kong. Women filling at least one prescription of any serotonin and norepinephrine reuptake inhibitors (SNRI) only during pregnancy, that is the period between the date of the last menstrual period and the date of delivery. exposed to other treatment, sick
Women filling at least one prescription of any tricyclic antidepressants (TCA) only during pregnancy, that is the period between the date of the last menstrual period and the date of delivery.
during pregnancy (anytime or not specified) 71 / 613
The Clinical Data Analysis and Reporting System (CDARS) that captures and links all clinical data, including prescribing and dispensing records.
Lee (Controls unexposed, general pop)
2025
China
2003 - 2018
retrospective cohort (claims database)
The Clinical Data Analysis and Reporting System (CDARS) of the Hospital Authority, Hong Kong. Women filling at least one prescription of any serotonin and norepinephrine reuptake inhibitors (SNRI) only during pregnancy, that is the period between the date of the last menstrual period and the date of delivery. unexposed (general population or NOS)
Women who were not prescribed with any antidepressant during index pregnancy.
during pregnancy (anytime or not specified) 71 / 463440
The Clinical Data Analysis and Reporting System (CDARS) that captures and links all clinical data, including prescribing and dispensing records.
Lupattelli - SNRI (Controls exposed to TCA)
2017
Norway
1999 - 2008
prospective cohort
The Norwegian Mother and Child Cohort (the MoBa study), a prospective population‐based study, and the Medical Birth Registry of Norway Depressed pregnant women that reported use of Serotonin‐norepinephrine reuptake inhibitors (SNRIs: venlafaxine or duloxetine) monotherapy during pregnancy. exposed to other treatment, sick
Depressed pregnant women that reported use of tricyclic antidepressants (TCAs) monotherapy during pregnancy.
during pregnancy (anytime or not specified) 75 / 21 Data for Early‐onset preeclampsia cannot be reported because nb of exposure to SNRI in gestational weeks 0‐16 is not reported. 'Women on antidepressant polytherapy, ie, exposed to multiple antidepressant groups in pregnancy, were excluded'
Data about antidepressant exposure were gathered prospectively from 2 self‐completed questionnaires at Gestational weeks 17 (Q1) and 30 (Q3). Women reported the name of the medication taken along with timing of use (6 months before pregnancy and during pregnancy by 4‐week intervals).
Lupattelli - SNRI (Controls unexposed, sick)
2017
Norway
1999 - 2008
prospective cohort
The Norwegian Mother and Child Cohort (the MoBa study), a prospective population‐based study, and the Medical Birth Registry of Norway Depressed pregnant women that reported use of Serotonin‐norepinephrine reuptake inhibitors (SNRIs: venlafaxine or duloxetine) monotherapy during pregnancy. unexposed, sick
Depressed pregnant women nonmedicated.
during pregnancy (anytime or not specified) 75 / 5106 Data for Early‐onset preeclampsia cannot be reported because nb of exposure to SNRI in gestational weeks 0‐16 is not reported. 'Women on antidepressant polytherapy, ie, exposed to multiple antidepressant groups in pregnancy, were excluded'
Data about antidepressant exposure were gathered prospectively from 2 self‐completed questionnaires at Gestational weeks 17 (Q1) and 30 (Q3). Women reported the name of the medication taken along with timing of use (6 months before pregnancy and during pregnancy by 4‐week intervals).
Marks - Duloxetine (Controls exposed to Bupropion)
2021
USA
2010 - 2019
retrospective cohort
Electronic medical records (EMRs) through the Regenstrief Institute in Indianapolis, USA. Pregnant women with one (or more) prescription of Duloxetine written during the time period studied. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Pregnant women with one (or more) prescription of Bupropion written during the time period studied.
during pregnancy (anytime or not specified) 139 / 406 '252 women (6.8%) prescribed >1 antidepressant'=> considered as monotherapy. This study assessed several SNRIs, with adjustment => To avoid redundancy of control, only the substance with the higher number of exposure was used in the meta-analysis.
Data were obtained from electronic medical records (EMRs) through the Regenstrief Institute in Indianapolis.
Marks - Duloxetine (Controls unexposed, sick)
2021
USA
2010 - 2019
retrospective cohort
Electronic medical records (EMRs) through the Regenstrief Institute in Indianapolis, USA. Pregnant women with one (or more) prescription of Duloxetine during the third trimester exposure. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Pregnant women who took an antidepressant at some point during pregnancy but did not have a prescription for any antidepressant during the relevant period of exposure.
3rd trimester 59 / -9 '252 women (6.8%) prescribed >1 antidepressant'=> considered as monotherapy. 'Neonatal intensive care unit admission" => not considered here because an exposure in early pregnancy could also lead to NICU admission.
Data were obtained from electronic medical records (EMRs) through the Regenstrief Institute in Indianapolis.
Martin - Venlafaxine
2024
Norway, Sweden and United Kingdom.
1996 - 2020
population based cohort retrospective
The UK’s Clinical Practice Research Datalink (CPRD), the Norway’s Medical Birth Registry and the Sweden’s Medical Birth Register. Singleton deliveries with maternal Venlafaxine (without concurrent prescriptions for different antidepressants) use during pregnancy proxied by prescriptions in the United Kingdom and dispensations in Norway and Sweden. unexposed (general population or NOS)
Singleton deliveries without maternal antidepressants use during pregnancy proxied by prescriptions in the United Kingdom and dispensations in Norway and Sweden.
during pregnancy (anytime or not specified) 6441 / 2408707 A group ‘multiple’ (i.e drug switching or concurrent prescriptions for different antidepressants) is available => thus individual antidepressant considered as monotherapy. Unexposed numbers: Table S4.
In the UK, prescription data were based on the prescriptions written by general practitioners (CPRD GOLD), whereas in Norway and Sweden, dispensation of prescription drugs from all ambulatory pharmacies was used (Norwegian Prescription Database, and Swedish Prescribed Drug Register).
Nulman - Venlafaxine (Controls unexposed, disease free)
2012
Canada
2001 - 2006
prospective cohort
The Motherisk program at the Hospital for Sick Children in Toronto. Depressed women who took Venlafaxine during pregnancy. unexposed, disease free
Nondepressed, healthy pregnant women who called Motherisk to inquire about nonteratogenic exposure (e.g., acetaminophen).
during pregnancy (anytime or not specified) 62 / 62 'Excluded were mothers exposed to polytherapy for depression or known teratogens, mothers with substance abuse, mothers with other psychiatric conditions, prematurity, mothers and/or children with medical conditions that may affect cognitive outcomes.'
At the time of the first contact with Motherisk during pregnancy, information about medications was collected.
Nulman - Venlafaxine (Controls unexposed, sick)
2012
Canada
2001 - 2006
prospective cohort
The Motherisk program at the Hospital for Sick Children in Toronto. Depressed women who took Venlafaxine during pregnancy. unexposed, sick
Depressed women who were untreated during pregnancy (discontinued pharmacotherapy before conception).
during pregnancy (anytime or not specified) 62 / 54 'Excluded were mothers exposed to polytherapy for depression or known teratogens, mothers with substance abuse, mothers with other psychiatric conditions, prematurity, mothers and/or children with medical conditions that may affect cognitive outcomes.'
At the time of the first contact with Motherisk during pregnancy, information about medications was collected.
Oberlander - Venlafaxine
2008
Canada
1997 - 2002
retrospective cohort (claims database)
Population-based health-care utilization databases from the province of British Columbia. Infants exposed to Venlafaxine in the first trimester of pregnancy. unexposed (general population or NOS)
Infants with no exposure to either of these drugs (Serotonin Reuptake Inhibitors (SRI) or benzodiazepine) in the first trimester of pregnancy.
1st trimester 250 / 107320
PharmaNet, a province-wide network recording all prescriptions dispensed by British Columbian pharmacists outside hospitals.
Ozturk - Venlafaxine
2016
Turkey
2007 - 2012
prospective cohort
An observational cohort study based on a prenatal consultation service. Pregnant women exposed to Venlafaxine during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
Pregnant women selected from the non-teratogen exposed pregnancies in the same year.
at least 1st trimester 13 / 275 This study assessed several SNRIs, with potential co-exposures => data of all SNRIs cannot be added. To avoid redundancy of control, only the substance with the higher number of exposure was used in the meta-analysis (i.e Venlafaxine).
At the first contact, initiated via gynecologists, a detailed patient history form was used to notably record all drug exposures (dose, duration and timing in pregnancy).
Palmsten - SNRI (Controls exposed to TCA)
2012
Canada
1997 - 2006
retrospective cohort (claims database)
Population-based health-care utilization databases from the province of British Columbia. Pregnant women with at least 1 pharmacy dispensing record for a serotonin-norepinephrine reuptake inhibitors (SNRI) during estimated gestational weeks 10–20 (Monotherapy). exposed to other treatment, sick
Pregnant women with at least 1 pharmacy dispensing record for a tricyclic antidepressant (TCA) during estimated gestational weeks 10–20 (Monotherapy).
2nd trimester 408 / 146 'Exposure was classified as monotherapy if dispensings for only 1 antidepressant class were present during pregnancy and as polytherapy otherwise.'
PharmaNet database, which contains all non-hospital pharmacy dispensings.
Palmsten - SNRI (Controls unexposed, sick)
2012
Canada
1997 - 2006
retrospective cohort (claims database)
Population-based health-care utilization databases from the province of British Columbia. Pregnant women with at least 1 pharmacy dispensing record for serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressants during estimated gestational weeks 10–20 (Monotherapy). unexposed, sick
Pregnant women with no antidepressant dispensing between the year prior to the last menstrual period and gestational week 20.
2nd trimester 408 / 65392 'Exposure was classified as monotherapy if dispensings for only 1 antidepressant class were present during pregnancy and as polytherapy otherwise.'
PharmaNet database, which contains all non-hospital pharmacy dispensings.
Palmsten a - SNRI (control exposed to TCA)
2013
USA
2000 - 2007
retrospective cohort (claims database)
The US nationwide Medicaid Analytic eXtract (MAX). Pregnant women with a depression diagnosis and a dispensation of serotonin-norepinephrine reuptake inhibitor (SNRI) in monotherapy during the exposure window. exposed to other treatment, sick
Pregnant women with a depression diagnosis and a dispensation of tricyclic antidepressant in monotherapy during the exposure window.
2nd and/or 3rd trimester 1216 / 441 Women who received only one antidepressant class during the window were classified as having either SSRI, SNRI, tricyclic, bupropion or other antidepressant (mirtazapine, nefazodone, trazodone) monotherapy.
Outpatient pharmacy-dispensing data.
Palmsten a - SNRI (Controls unexposed, sick)
2013
USA
2000 - 2007
retrospective cohort (claims database)
The US nationwide Medicaid Analytic eXtract (MAX). Pregnant women with a depression diagnosis and a dispensation of serotonin-norepenephrine reuptake inhibitor (SNRI) in monotherapy during the exposure window. unexposed, sick
Pregnant women with a depression diagnosis and no antidepressant exposure between the LMP and the end of the window.
2nd and/or 3rd trimester 1216 / 59219 Women who received only one antidepressant class during the window were classified as having either SSRI, SNRI, tricyclic, bupropion or other antidepressant (mirtazapine, nefazodone, trazodone) monotherapy.
Outpatient pharmacy-dispensing data.
Palmsten b - SNRI
2013
USA
2000 - 2007
retrospective cohort (claims database)
The Medicaid Analytic eXtract (MAX) data Women with a supply of Serotonin-norepinephrine reuptake inhibitor (SNRI) monotherapy that overlapped with the delivery date. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Women who had no supply of antidepressants in the five months before delivery.
late pregnancy 702 / 69044 Exclusion of women who were exposed to both drugs types (polytherapy) during the five months before delivery.
Data of prescription.
Rai - Venlafaxine (Controls exposed to TCA)
2017
Sweden
2001 - 2011
prospective cohort
The Stockholm youth cohort, an observational prospective cohort study of Stockholm County. Children of mothers who used Venlafaxine during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Children of mothers who used Clomipramine during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study).
during pregnancy (anytime or not specified) 213 / 235 Overlapping: Rai 2017 is an update of Rai 2013. About 3% with co-exposure to SSRI and Non-SSRI antidepressants (91/3342) => considered as SSRI monotherapy and Non-SSRI monotherapy.
Information on maternal use of antidepressants in pregnancy is derived from the medical birth register (as reported by pregnant women at their antenatal interview, at a median of 10 weeks’ gestation) and supplemented it with the prescribed drug register (available from July 2005).
Rai - Venlafaxine (Controls unexposed, disease free)
2017
Sweden
2001 - 2011
prospective cohort
The Stockholm youth cohort, an observational prospective cohort study of Stockholm County. Children of mothers who used Venlafaxine during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, disease free
No maternal psychiatric disorder and unexposed to antidepressants
during pregnancy (anytime or not specified) 213 / 238943 Overlapping: Rai 2017 is an update of Rai 2013. About 3% with co-exposure to SSRI and Non-SSRI antidepressants (91/3342) => considered as SSRI monotherapy and Non-SSRI monotherapy.
Information on maternal use of antidepressants in pregnancy is derived from the medical birth register (as reported by pregnant women at their antenatal interview, at a median of 10 weeks’ gestation) and supplemented it with the prescribed drug register (available from July 2005).
Rai - Venlafaxine (Controls unexposed, sick)
2017
Sweden
2001 - 2011
prospective cohort
The Stockholm youth cohort, an observational prospective cohort study of Stockholm County. Children of mothers who used Venlafaxine during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Children of mothers with psychiatric disorders (any time before the birth of the child) who did not take antidepressants during pregnancy.
during pregnancy (anytime or not specified) 213 / 12325 Overlapping: Rai 2017 is an update of Rai 2013. About 3% with co-exposure to SSRI and Non-SSRI antidepressants (91/3342) => considered as SSRI monotherapy and Non-SSRI monotherapy.
Information on maternal use of antidepressants in pregnancy is derived from the medical birth register (as reported by pregnant women at their antenatal interview, at a median of 10 weeks’ gestation) and supplemented it with the prescribed drug register (available from July 2005).
Rampono - SNRI=Venlafaxine
2009
Australia
Not specified.
prospective cohort
The outpatient clinics of the Department of Psychological Medicine at King Edward Memorial Hospital, Western Australia. Pregnant patients treated with serotonin norepinephrine reuptake inhibitor (SNRI) antidepressants (venlafaxine only) during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Pregnant women untreated with antidepressants during pregnancy.
during pregnancy (anytime or not specified) 11 / 18 Maternal antenatal EPDS scores were not different between cases and controls. Mothers who were known substance abusers, or who took any medication known to alter infant behaviour (apart from those being investigated) were excluded from the study.
The antidepressant and dose for each individual patient was determined by the prescriber (JR) according to the patients needs. The analyses of medicines and metabolites in maternal and infant plasma were carried out by high performance liquid chromatography.
Reis - SNRI (Controls exposed to TCA)
2010
Sweden
1995 - 2007
population based cohort retrospective
The Swedish Medical Birth Register (MBR), Register of Birth Defects and the Patient Register (previous the Hospital Discharge Register). Pregnant women who reported the use of Serotonin-norepinephrine reuptake inhibitor (SNRI) in late pregnancy or were prescribed SNRIs during pregnancy. exposed to other treatment, sick
Pregnant women who reported the use of Tricyclic antidepressant (TCAs) in late pregnancy or were prescribed TCAs during pregnancy.
1st trimester, 2nd and/or 3rd trimester 538 / 784 Overlapping: For malformations: 3 studies kept from Sweden: Ankarfeld : Duloxetine (Sweden/Denmark: 2004 - 2016; Furu 2015 (Venlafaxine 2006-2010 with other countries) and Reis 2010 (1995 - 2007).
Information on drug use is partly based on an interview conducted by the midwife at the first antenatal visit (in 90% of cases before the end of the first trimester) and partly on information from the antenatal care with respect to drugs prescribed later during the pregnancy by the attending doctor.
Reis - SNRI (Controls unexposed, NOS)
2010
Sweden
1995 - 2007
population based cohort retrospective
The Swedish Medical Birth Register (MBR), Register of Birth Defects and the Patient Register (previous the Hospital Discharge Register). Pregnant women who reported the use of Serotonin-norepinephrine reuptake inhibitor (SNRI) in late pregnancy or were prescribed SNRIs during pregnancy. unexposed (general population or NOS)
All other pregnant women in the register (not exposed to antidepressants during pregnancy).
1st trimester, 2nd and/or 3rd trimester 538 / 1062190 Overlapping: For malformations: 3 studies kept from Sweden: Ankarfeld : Duloxetine (Sweden/Denmark: 2004 - 2016; Furu 2015 (Venlafaxine 2006-2010 with other countries) and Reis 2010 (1995 - 2007).
Information on drug use is partly based on an interview conducted by the midwife at the first antenatal visit (in 90% of cases before the end of the first trimester) and partly on information from the antenatal care with respect to drugs prescribed later during the pregnancy by the attending doctor.
Richardson - Venlafaxine
2019
The United Kingdom.
1995 - 2018
prospective cohort
The United Kingdom Teratology Information Service (UKTIS). Pregnancies in which mothers had used venlafaxine at any stage of pregnancy. unexposed (general population or NOS)
Pregnancies unexposed to any antidepressant medications (matching ratio 5:1).
1st trimester, at least 1st trimester, during pregnancy (anytime or not specified) 281 / 1405 Gestational venlafaxine exposure occurred in at least the first trimester for the majority of the venlafaxine exposed study group (n = 270/281, 96.1%). Concomitant psychiatric medication use was common among the venlafaxine exposed pregnancies.
Upon contact with the service, relevant information is collected from the health professional to allow accurate fetal risk assessment. Subsequently, all enquiries which involve maternal exposures in pregnancy are included in the prospective surveillance system.
Robinson-Wolrath - SNRI
2016
Australia
2005 - 2010
retrospective cohort
The King Edward Memorial Hospital, Perth, Australia. Mothers treated with Serotonin noradrenaline reuptake inhibitors (SNRIs) during pregnancy. unexposed (general population or NOS)
Mothers not treated with Selective serotonin inhibitors (SSRIs) nor Serotonin noradrenaline reuptake inhibitors (SNRIs) during pregnancy.
during pregnancy (anytime or not specified) 91 / -9 Number of unexposed pregnancies not specified (thus all data without OR provided by authors cannot be reported here). 75 babies of mothers prescribed multiple psychiatric medications excluded.
Retrospective review of all pregnancies at King Edward Memorial Hospital, using midwifery and neonatal databases and case records.
Suarez - SNRI (Controls unexposed, discontinuers)
2022
USA
2000 - 2015
retrospective cohort (claims database)
The Medicaid Analytic eXtract (MAX) and the MarketScan Commercial Claims Database (MarketScan), USA. Individuals with at least 1 dispensing of serotonin-norepinephrine reuptake inhibitors (SNRIs) from 127 days after LMP (week 19 of gestation) to delivery. unexposed, sick
Individuals that having a dispensing for serotonin-norepinephrine reuptake inhibitors (SNRIs) in the window from 90 to 31 days prior to LMP but not during the window of 30 days prior to LMP through delivery.
2nd and/or 3rd trimester 8540 / 4899 The Medicaid Analytic eXtract (MAX): 2000 to 2014 and the MarketScan Commercial Claims Database (MarketScan): 2003 to 2015.
The Medicaid Analytic eXtract (MAX) and the MarketScan Commercial Claims Database (MarketScan), that include information on dispensed outpatient prescription medications.
Suarez - SNRI (Controls unexposed, general pop)
2022
USA
2000 - 2015
retrospective cohort (claims database)
The Medicaid Analytic eXtract (MAX) and the MarketScan Commercial Claims Database (MarketScan), USA. Individuals with at least 1 dispensing of serotonin-norepinephrine reuptake inhibitors (SNRIs) from 127 days after LMP (week 19 of gestation) to delivery. unexposed (general population or NOS)
Individuals with no antidepressant dispensing from 90 days prior to pregnancy start through the day prior to delivery.
2nd and/or 3rd trimester 8659 / 2910114 The Medicaid Analytic eXtract (MAX): 2000 to 2014 and the MarketScan Commercial Claims Database (MarketScan): 2003 to 2015.
The Medicaid Analytic eXtract (MAX) and the MarketScan Commercial Claims Database (MarketScan), that include information on dispensed outpatient prescription medications.
Sørensen - SNRI (Controls exposed to TCA)
2013
Denmark
1996 - 2006
population based cohort retrospective
The Danish Civil Registration System (CRS), the Danish National Prescription Registry (DNPR) and the Danish Psychiatric Central Register (DPCR). Children of women who filled a prescription for Serotonin–norepinephrine reuptake inhibitors (SNRIs) from 30 days before conception to the day of birth. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Children of women who filled a prescription for Tricyclic antidepressants (TCA) from 30 days before conception to the day of birth. (This is a subgroup of exposure among the whole exposed group considered in the study).
during pregnancy (anytime or not specified) 673 / 642 Overlapping between Gidaya 2014, Hviid 2013 and Sorensen 2013: same outcomes, same dataset, same period (not the same research team). The study of Sorensen 2013 included a larger study period and more pregnancies and was the only one reported.
The Danish National Prescription Registry (DNPR) that holds information on prescriptions filled, written by a general practitioner or medical specialist.
Sørensen - SNRI (Controls unexposed, NOS)
2013
Denmark
1996 - 2006
population based cohort retrospective
The Danish Civil Registration System (CRS), the Danish National Prescription Registry (DNPR) and the Danish Psychiatric Central Register (DPCR). Children of women who filled a prescription for Serotonin–norepinephrine reuptake inhibitors (SNRIs) from 30 days before conception to the day of birth. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
Children of women who not filled antidepressant drugs during pregnancy.
during pregnancy (anytime or not specified) 673 / 646782 Overlapping between Gidaya 2014, Hviid 2013 and Sorensen 2013: same outcomes, same dataset, same period. Sorensen 2013 included more pregnancies=> the only one reported. Low nb of co-exposure SSRI/SNRI/TCS (<5%) => considered as monotherapies.
The Danish National Prescription Registry (DNPR) that holds information on prescriptions filled, written by a general practitioner or medical specialist.
Te Winkel - Venlafaxine
2016
Finland, France, Israel, Italy, Netherlands and Switzerland.
Not specified.
prospective cohort
Nine centers of the European Network of Teratology Information Services (ENTIS). Pregnant women exposed to Venlafaxine during pregnancy. unexposed (general population or NOS)
Pregnant women not exposed to any known teratogen during pregnancy.
1st trimester, during pregnancy (anytime or not specified) 732 / 724 Number of pregnancies in the control group: 656 live births - 6 twins plus 46 spontaneous abortions plus 25 ETOPs plus 3 stillbirths.
Information about the exposure was collected after individual risk counseling. Standardized procedures for data collection and follow up were used by each center.
Tran - SNRI (Controls exposed to TCA)
2022
The Netherlands
2000 - 2010
retrospective cohort (claims database)
The Netherlands Perinatal Registry (PERINED) and the PHARMO Database Network. Pregnant women who received a dispensing of Serotonin-norepinephrine reuptake inhibitors (SNRIs) between weeks 0–20 of gestation or received before pregnancy, but the treatment duration lasted into pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Pregnant women who received a dispensing of tricyclic antidepressants (TCAs) between weeks 0–20 of gestation or received before pregnancy, but the treatment duration lasted into pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study).
1st and 2nd trimester, at least 1st trimester 212 / 214
The PHARMO Database Network, a population-based network of healthcare databases combining data from hospital and community pharmacies in the Netherlands, including the ATC classification of the drug, start and end date of use, strength, dosage regimen and route of administration.
Tran - SNRI (Controls unexposed, NOS)
2022
The Netherlands
2000 - 2010
retrospective cohort (claims database)
The Netherlands Perinatal Registry (PERINED) and the PHARMO Database Network. Pregnant women who received a dispensing of Serotonin-norepinephrine reuptake inhibitors (SNRIs) between weeks 0–20 of gestation or received before pregnancy, but the treatment duration lasted into pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
Pregnant women who did not receive antidepressants in 15 months before delivery.
1st and 2nd trimester, at least 1st trimester 212 / 95376
The PHARMO Database Network, a population-based network of healthcare databases combining data from hospital and community pharmacies in the Netherlands, including the ATC classification of the drug, start and end date of use, strength, dosage regimen and route of administration.
Wall-Wieler - SNRI
2020
USA
2008 - 2015
retrospective cohort (claims database)
The nationwide (American) IBM® MarketScan® Databases, a large administrative claims database. Pregnant women having a Serotonin-norepinephrine reuptake inhibitor (SNRI) prescription that had at least a 1-day supply in the 3 weeks after a woman’s estimated last menstrual period. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Pregnant women who had a prepregnancy depression diagnosis and did not have Selective serotonin reuptake inhibitor (SSRI) prescription, but that could they could be exposed to an antidepressant (but not that class).
early pregnancy 6620 / 100168 Non exposed group: a majority is non exposed to antidepressant (n=66501) whereas the other one are exposed to an other class of antidepressants.
Antidepressant prescriptions were identified from outpatient pharmacy files through National Drug Codes (NDC) from outpatient pharmaceutical claims.
Yang - SNRI
2021
Taiwan
2010 - 2016
retrospective cohort (claims database)
The Health and Welfare Database (HWD) in Taiwan, administrative claims database that incorporates information from the Taiwan National Health Insurance Program, which covers more than 99.6% of Taiwan's population. Pregnant women with depression and at least 1 prescription for an oral serotonin-norepinephrine reuptake inhibitors (SNRI) from the day of pregnancy initiation up to the start of 20 weeks of gestation. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Pregnant women with depression without antidepressant prescription.
1st and 2nd trimester 338 / 2832 'In addition, we restricted the cohort of antidepressant users to patients who were only prescribed 1 consistent antidepressant during the exposure period.'
The Health and Welfare Database (HWD), administrative claims database that incorporates prescription drug utilization.
Yaris - Venlafaxine
2005
Turkey
1999 - 2004
prospective cohort
Toxicology Information and Follow-up Service Women who were exposed to Venlafaxine during pregnancy for depression, anxiety, and psychotic disorders. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
Women who did not use any drug while pregnant.
during pregnancy (anytime or not specified) 11 / 248 Raw data for Intrauterine exitus not reported because the nb of cases in the unexposed group not clearly stated. Raw data for premature delivery not reported because the denominator is not clearly stated.
Data surveyed by the interviews.
Yeh - SNRI
2021
Taiwan
2002 - 2011
retrospective cohort (claims database)
The Taiwan National Health Insurance Research Database (NHIRD). Pregnant women with bipolar disorder receiving serotonin-norepinephrine reuptake inhibitors (SNRI - duloxetine, venlafaxine, milnacipran, mirtazapine) during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Pregnant women with bipolar disorder not receiving any psychotropics before and during the pregnancy.
1st trimester, 2nd trimester, 3rd trimester, during pregnancy (anytime or not specified) 56 / 5243
The Taiwan National Health Insurance Research Database (THIRD) provides prescriptions information about insured individuals.

Case-control studies

Study Country
Study period
Study design
Data source Case Control Exposition Exposition period Sample size
(exposed/unexposed) Or (case / control)
Remarks Risk of bias
Anderson - SNRI
2020
USA
1997 - 2011
case control
The National Birth Defects Prevention Study (NBDPS), a US population-based, multisite case-control study. The case infants were infants born alive or died at 20 SG or more and who had received a diagnosis of at least one selected birth defect. The controls were live-born infants with no major birth defects who were randomly selected from hospital or state birth-certificate records from the same geographic areas. Information on exposure to SSRIs and other potential risk factors during pregnancy were collected by standardized telephone interviews with mothers of case and control infants, conducted 6 weeks to 24 months after the EDD. 1st trimester 30630 / 11478 'Infants with recognized or strongly suspected chromosomal abnormalities or single-gene conditions were excluded from the study.'
Case infants were ascertained through population-based birth-defects surveillance systems in 10 U.S. states. Controls were selected randomly from the same geographic areas. Clinical data were abstracted from medical records and classified by clinician geneticists and other clinicians.
Dandjinou - SNRI
2019
Canada
1998 - 2015
nested case control
The Quebec Pregnancy Cohort (QPC), a Canadian provincial database. Pregnant women with a diagnosis of gestational diabetes mellitus (GDM) identified using diagnosis codes ICD-9: 250.0–250.9, 648.0, 648.8, 790.2, 775.1 or ICD-10: E10–E14, O24, R73.0) or at least one filled prescription for an antidiabetic drug allowed during pregnancy (insulin, glyburide or metformin), both after week 20 of gestation, whichever occurred first. Pregnant women that did not have a diagnosis of gestational diabetes mellitus (GDM) at the index date. The Quebec Prescription Drug Insurance Database (drug name, start date, dosage and duration). during pregnancy (anytime or not specified) 20905 / 209050 The 10 categories of exposure were mutually exclusive.
The medical service database (RAMQ: diagnoses and medical procedures), the Hospitalisation Archive Database (MedEcho: in-hospital diagnoses and procedures) and the Quebec Statistics Database (Institut de la statistique du Québec (ISQ):patient sociodemographic information).
De Vera - SNRI
2012
Canada
1997 - 2003
nested case control
The Quebec Pregnancy Registry (QPR), a longitudinal cohort established with the linkage of three administrative databases. Women with a diagnosis of gestational hypertension (ICD-9: 642.3, 642.0), pre-eclampsia (ICD-9: 642.4, 642.5) or eclampsia (ICD-9: 642.6) after the 20th week of gestation. Women who did not have a diagnosis of pregnancy-induced hypertension at or before the same gestational age. The Quebec’s Public Prescription Drug Insurance Plan. during pregnancy (anytime or not specified) 1216 / 12160 Tricyclic antidepressants (amitriptyline, clomipramine, desipramine, doxepin, imipramine, nortriptyline and trimipramine).
Linkage of three administrative databases: (i) Régie de l’Assurance Maladie du Québec (RAMQ), (ii) MED-ECHO and (iii) Institut de la Statistique du Québec (ISQ).
Kieler - Venlafaxine
2015
Denmark, Finland, and Norway
1996 - 2007
nested case control
National registers of Denmark, Finland, and Norway. Women with elective termination of pregnancy at 12–23 weeks of gestation. Women that continued their pregnancy, randomly selected and matched with cases on key factors. The prescription registers include data on dispensed item, substance, brand name, and formulation, together with date of dispensing for over 95% of the total outpatient population. 3 months (or more) before pregnancy or during pregnancy, during pregnancy (anytime or not specified) 14902 / 148929 The (ORs) are presented for women exposed to only one type of antidepressant during the exposure period.
In the registers the diagnoses and pregnancy complications are classified according to the national version of the International Classification of Diseases (ICD).
Laspro - Venlafaxine
2024
USA
2013 - 2023
nested case control
EPIC Cosmos, a database incorporating health information of 180 million patients, throughout the United States from approximately 180 US institutions utilizing EPIC medical records. Newborns with oral clefts (ICD 10 codes Q35 or Q36 or Q37). Newborns without oral clefts. Gestational medication use was identified by medications, prescribed, provider-administered, or reported use by mothers at any point during pregnancy. during pregnancy (anytime or not specified) 12098 / -9 P-values were calculated, while to account for multiple testing (693 hypotheses) Benjamini- Hochberg (BH) corrections were performed with a false discovery rate (Q) of 0.05.
Oral cleft cohorts were isolated using a combination of ICD codes, from the EPIC medical records.
Nakhai-Pour - Venlafaxine
2010
Canada
1998 - 2003
nested case control
The Quebec Pregnancy Registry, built with the linkage of three administrative databases: the Régie de l’assurance maladie du Québec (RAMQ), the Med-Echo database and the Institut de la statistique du Québec database. Pregnant women with a diagnosis or a procedure for spontaneous abortion between the first day and the 20th week of gestation. Randomly selected pregnant women who did not have a spontaneous abortion at or before the same gestational age as their matched case did. The Régie de l’assurance maladie du Québec (RAMQ) database which provides prospectively collected data on filled prescriptions. during pregnancy (anytime or not specified) 5124 / 51240
The Régie de l’assurance maladie du Québec (RAMQ) (physician-based diagnoses according to the ICD-9), the Med-Echo database (data on acute care hospital admissions) and the Institut de la statistique du Québec database (data on all births and deaths in Quebec).

Risk of bias: : NA;   : low;   : moderate;   : serious;   : critical;   : unclear;  

master protocol