Paroxetine

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
Andersen
2014 		Denmark
1997 - 2010
population based cohort retrospective 		The Danish administrative health registries and linked through the CPR-number, a unique identification number given to all citizens. Pregnant women dispensing of a prescription of Paroxetine (at least the first 35 days of pregnancy). unexposed (general population or NOS)
Pregnant women without dispensation of Selective Serotonin Reuptake Inhibitors (SSRIs) during the first 35 days of pregnancy. 		early pregnancy 2739 / 1256956
Information on use of prescription medication was collected from the National Prescription Register (the Register of Medicinal Product Statistics), that contains individual-level data on all prescribed drugs dispensed at all pharmacies in Denmark.
Ban (Controls unexposed, disease free)
2014 		United Kingdom
1990 - 2009
retrospective cohort (claims database) 		The Health Improvement Network (THIN), a nationally representative database of computerised primary care records. Pregnant women with Paroxetine prescriptions from 4 weeks before to 12 weeks after the first day of the estimated last menstrual period. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, disease free
Pregnant women without diagnosis of depression. 		1st trimester 1200 / 325294 Exclusion of 9096 children (2.5% of the study population) whose mothers had bipolar disorder, schizophrenia, other serious psychotic disorders, or prescriptions for antimanic and antipsychotic drugs before childbirth.
The Health Improvement Network (THIN), a nationally representative database that contains drug prescriptions.
Ban (Controls unexposed, sick)
2014 		United Kingdom
1990 - 2009
retrospective cohort (claims database) 		The Health Improvement Network (THIN), a nationally representative database of computerised primary care records. Pregnant women with Paroxetine prescriptions from 4 weeks before to 12 weeks after the first day of the estimated last menstrual period. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Pregnant women with diagnosed depression (in the year before conception up to the end of the first trimester) but with no antidepressant drug prescriptions in the first trimester. 		1st trimester 1200 / 13432 Exclusion of 9096 children (2.5% of the study population) whose mothers had bipolar disorder, schizophrenia, other serious psychotic disorders, or prescriptions for antimanic and antipsychotic drugs before childbirth.
The Health Improvement Network (THIN), a nationally representative database that contains drug prescriptions.
Bérard
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 Paroxetine dispensed during the first trimester of gestation. unexposed, sick
Depressed/anxious pregnancies with no exposure to any antidepressants during the first trimester of gestation. 		1st trimester 1132 / 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.
Bérard
2016 		Canada
1998 - 2009
retrospective cohort (claims database) 		The Québec Pregnancy Children Cohort (QPC), a register-based study of an ongoing population-based cohort. Pregnant women having at least 1 prescription of Paroxetine filled at any time during the second/third trimester of pregnancy. (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 at any time throughout gestation. 		2nd and/or 3rd trimester 744 / 142716 Material and methods based on description provided by Boukhris et al 2016.
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.
Brown
2017 		Canada
2002 - 2010
retrospective cohort (claims database) 		Retrospective cohort study using health administrative data sets from Ontario, Canada. Pregnant women with 2 or more consecutive prescriptions for paroxetine filled between conception and delivery. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
Pregnant women with no serotonergic antidepressants prescribed during pregnancy or within 90 days prior to conception. 		during pregnancy (anytime or not specified) 577 / 33069
Ontario Drug Benefit database.
Calderon-Margalit
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 Paroxetine 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) 31 / 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 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 Paroxetine 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 with prescription of Tricyclic antidepressants (TCA) only filled during the first trimester and prescriptions filled before pregnancy but with duration overlapping the first trimester. 		1st trimester 48 / 322
Study data were obtained from the Clinical Data Analysis and Reporting System, a database that contains prescribing/dispensing records.
Chan (Controls unexposed, pop general)
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 Paroxetine 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 48 / 462377
Study data were obtained from the Clinical Data Analysis and Reporting System, a database that contains prescribing/dispensing records.
Colvin
2011 		Australia
2002 - 2005
retrospective cohort (claims database) 		A population-based linked datasets for the state of Western Australia. Pregnant women who were dispensed Paroxetine during their pregnancy. unexposed (general population or NOS)
All other pregnant women and children of the women who were not dispensed a Selective Serotonin Reuptake Inhibitor (SSRI). 		1st trimester, 2nd and/or 3rd trimester, during pregnancy (anytime or not specified) 676 / 92995
The national Pharmaceutical Benefits Scheme (PBS), including dispensing in the community, private hospitals, and, since late 2004, public hospitals.
Colvin
2012 		Australia
2002 - 2005
retrospective cohort (claims database) 		A population-based study of all pregnancy events in Western Australia (WA). Children born to women who had been dispensed Paroxetine at any time during their pregnancy. unexposed (general population or NOS)
Children born to women who had not been dispensed a selective serotonin reuptake inhibitor (SSRI) at any time during their pregnancy. 		during pregnancy (anytime or not specified) -9 / 94561 Nb of exposed children not reported. Overlapping with Colvin 2011, for which a similar result was obtained for Late intrauterine death (not reported here).
The national Pharmaceutical Benefits Scheme (PBS), a claims database that includes 80% of all prescriptions dispensed in Australia.
Costei (Controls unexposed, NOS)
2002 		Canada
1996 - 1999
prospective cohort 		The Motherisk program Pregnant women exposed to paroxetine throughout the third trimester. unexposed (general population or NOS)
Pregnant women who used nonteratogenic drugs. 		3rd trimester 55 / 27 Authors also considered a mixed control group: women who used paroxetine only during the 1st and/or 2nd trimesters and women who used nonteratogenic drugs. => Not considered here because the 2 separate control group seem more relevant.
At the time of counseling (during pregnancy), detailed exposure data and information on all other drugs used concomitantly were collected by maternal interview.
Costei (Controls unexposed, sick)
2002 		Canada
1996 - 1999
prospective cohort 		The Motherisk program Pregnant women exposed to paroxetine throughout the third trimester. unexposed, sick
Pregnant women who used paroxetine only during the first and/or second trimesters. 		3rd trimester 55 / 27 Authors also considered a mixed control group: women who used paroxetine only during the 1st and/or 2nd trimesters and women who used nonteratogenic drugs. => Not considered here because the 2 separate control group seem more relevant.
At the time of counseling (during pregnancy), detailed exposure data and information on all other drugs used concomitantly were collected by maternal interview.
Davis
2007 		USA
1996 - 2000
retrospective cohort (claims database) 		A population-based cohort based on five health maintenance organizations (HMOs) participating in the HMO Research Network’s Center for Education and Research on Therapeutics (CERTs). Fullterm infants exposed in utero to Paroxetine during first trimester of pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
Fullterm infants unexposed to Paroxetine. 		1st trimester 182 / 49654 'Group Health Cooperative (Seattle, Washington), Harvard Pilgrim Health Care (Boston, Massachusetts), Henry Ford Health System (Detroit, Michigan), Kaiser Permanente Colorado (Denver, Colorado), and Kaiser Permanente Northwest (Portland, Oregon).'
Information on prescribed antidepressant medications was derived from the pharmacy database files available at each health system.
Diav-Citrin
2008 		Israel, Italy and Germany
1994 - 2005
prospective cohort 		The Israeli Teratology Information Service, Servizio di Informazione Teratologica, or Pharmakovigilanz-und Beratungszentrum für Embryonaltoxikologie. Pregnant women who contacted one TIS regarding exposures to Paroxetine. unexposed (general population or NOS)
Pregnant women who contacted one TIS regarding exposures known not to be teratogenic in similar time frames. 		1st trimester, during pregnancy (anytime or not specified) 463 / 1467
Details of exposure were collected at the initial contact with the TIS and before pregnancy outcome was known using a structured questionnaire. SSRIs and other exposures were also ascertained after delivery.
Dubnov-Raz
2008 		Israel
2000 - 2005
prospective cohort 		The Rabin Medical Center Department of Neonatology, Israel. Newborns exposed to Paroxetine in the immediate antepartum period. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, disease free
Newborns born to healthy mothers who took no medications before delivery. 		days before delivery 25 / 52
Not specified.
Einarson
2008 		Italy, Switzerland, Australia, Canada, Germany, Israel, USA and Finland
Not specified.
prospective cohort 		Data of eight teratology information services (TIS). First-trimester paroxetine exposure. unexposed (general population or NOS)
Other women who called teratology information services inquiring about exposures to drugs that are considered safe in pregnancy. 		1st trimester 1174 / -9 Only the 1,174 unpublished cases of first-trimester paroxetine exposure from eight teratology information services were reported here. The other 2,061 cases from five previously published database studies are not reported here.
During the initial telephone contact, details of exposure and concurrent exposures are recorded on a standardized questionnaire form. Details about the exposure include duration, timing in pregnancy, dose, frequency, and medical indication for use of the drug.
Einarson
2009 		Canada
Not specified.
prospective cohort 		The Motherisk Program, a teratogenic information service. Pregnant women who were exposed to Paroxetine 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 148 / 928
During the initial telephone contact, details of exposure and concurrent exposures are recorded on a standardized questionnaire.
Furu
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 Paroxetine 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 LMP). (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
Infants not exposed to any antidepressant (ATC code N06A) in utero. 		1st trimester 2879 / 2266875
The Nordic prescription registers include data on dispensed drugs, substance, brand name, and formulation, together with date of dispensing.
Heuvelman
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 Paroxetine 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) 982 / 16330 Dose–response relationships, sibling design and negative control for antidepressants use as a whole (not for the class of antidepressants).
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 (Controls unexposed, NOS)
2014 		USA
2000 - 2007
cohort 		Cohort study nested in the nationwide Medicaid Analytic eXtract. Pregnant women who have had exposure to Paroxetine 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 11126 / 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 (Controls unexposed, sick)
2014 		USA
2000 - 2007
cohort 		Cohort study nested in the nationwide Medicaid Analytic eXtract. Pregnant women who have had exposure to Paroxetine 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 8756 / 180564 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.
Jimenez-Solem (Controls unexposed, NOS)
2012 		Denmark
1997 - 2009
population based cohort retrospective 		Register-based retrospective nationwide cohort study, using the Danish Medical Birth Registry. Pregnancies with a continuous exposure to Paroxetine at least 1 month before conception until day 84 of pregnancy (last day of the first trimester). unexposed (general population or NOS)
Pregnancies with no exposure to a selective serotonin reuptake inhibitor (SSRI) during pregnancy. 		1st trimester 568 / 843797 Overlapping: this study included data published by Kornum 2010. Overlapping: Data related to Major and cardiac malformations not reported because an overlapping Furu 2015 a larger study including data from 5 nordic countries, including Denmark.
The drug redemptions were identified using the Register of Medicinal Product Statistics which has recorded drugs dispensed from Danish pharmacies.
Jimenez-Solem (Controls unexposed, sick)
2012 		Denmark
1997 - 2009
population based cohort retrospective 		Register-based retrospective nationwide cohort study, using the Danish Medical Birth Registry. Pregnancies with a continuous exposure to Paroxetine, at least 1 month before conception until day 84 of pregnancy (last day of the first trimester). unexposed, sick
Pregnancies with paused exposure during pregnancy (an SSRI 3-12 months before conception and 1-12 months after giving birth but with no expo- sure to an SSRI between 3 months before conception to 1 month after giving birth). 		1st trimester 568 / 806 Overlapping: this study included data published by Kornum 2010. Overlapping: Data related to Major and cardiac malformations not reported because an overlapping Furu 2015 a larger study including data from 5 nordic countries, including Denmark.
The drug redemptions were identified using the Register of Medicinal Product Statistics which has recorded drugs dispensed from Danish pharmacies.
Jordan
2016 		Norway, Wales and Denmark.
2000 - 2010
retrospective cohort (registry) 		Three population-based EUROCAT congenital anomaly registries- Norway, Wales and Funen, Denmark. Prescription of Paroxetine in the 91 days either side of the 1st day of last menstrual period (LMP). (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
No prescription of selective serotonin reuptake inhibitors (SSRIs) during pregancy. 		3 months or more before pregnancy or1st trimester 1069 / 506155 Overlapping: The results of outcomes also reported in the largest study published by Wemakor 2015 (EUROCAT data in 12 countries; 1995-2009) are not reported here. Overlapping: Jordan 2016 included results of Knudsen 2014.
Anomalies registries were linked with prescription and healthcare databases covering their source populations (Danish national Prescription and Patient register; Norway National Prescription Database; and Wales’ health and social care linked electronic databank).
Kieler
2012 		Denmark, Finland, Iceland, Norway, and Sweden
1996 - 2007
population based cohort retrospective 		Population based cohort study using data from the national health registers from the five Nordic countries. A filled prescription of Paroxetine during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
No filled prescription of selective serotonin reuptake inhibitors (SSRIs) during pregnancy. 		2nd and/or 3rd trimester, 3 months or more before pregnancy or1st trimester 3798 / 1588140
The prescription registers.
Kivistö
2016 		Finland
2002 - 2012
retrospective cohort 		Retrospective study conducted at the Kuopio University Hospital. Pregnant women that used only Paroxetine during pregnancy. unexposed (general population or NOS)
Pregnant women not using any antidepressant medication. 		during pregnancy (anytime or not specified) 32 / 24402 'Eleven women were excluded from the SSRI group due to combined therapy with an SSRI and an antidepressant belonging to another pharmacological group. '
The data were gathered retrospectively from the hospital birth register.
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 Paroxetine 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) 77 / 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 Paroxetine 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) 77 / 463440
The Clinical Data Analysis and Reporting System (CDARS) that captures and links all clinical data, including prescribing and dispensing records.
Levinson-Castiel
2006 		Israel
2002 - 2004
retrospective cohort 		The Rabin Medical Center in Israel, a tertiary care facility housing a neonatology department. Neonates exposed to Paroxetine in utero during the entire pregnancy or at least during the third trimester. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, disease free
Neonates not exposed to selective serotonin reuptake inhibitors (SSRIs) in utero, born to healthy mothers. 		3rd trimester 37 / 60
The infants were identified from the delivery room records as they arrived at the nursery or from a medical history form completed by all mothers at admittance to the nursery. This form included notably type, dosage, and duration of treatment with SSRIs or other drugs.
Liu
2017 		Denmark
1998 - 2012
population based cohort retrospective 		Data from Danish national registers A prescription of Paroxetine monotherapy dispensed on any date from one month before pregnancy until delivery. (This is a subgroup of exposure among the whole exposed group considered). unexposed, sick
Antidepressant discontinuation (use before but not during pregnancy). 		during pregnancy (anytime or not specified) 1111 / 30079 Results for Psychiatric disorders (ICD-10 codes F00-F99) in the offspring (mean age at diagnosis: 8.5 years) not reported here because not only neurodevelopmental disorders but also psychiatric disorders.
Information on antidepressant use came from the Danish National Prescription Registry, that covers all prescriptions dispensed in Denmark since 1995.
Malm
2011 		Finland
1996 - 2006
population based cohort retrospective 		An ongoing national joint project, Drugs and Pregnancy, based on three national health registers: The Medical Birth Register and the Register of Congenital Malformations and the Drug Reimbursement Register. Offspring of mothers with at least one purchase of Paroxetine during the period of 1 month before pregnancy and first trimester. unexposed (general population or NOS)
Offspring of mothers without purchase of one or more selective serotonin reuptake inhibitor drugs. 		1st trimester 968 / 618727 Major malformations and cardiovascular malformations (excepted ASV, VSD and transpo of great vessels) updated in a larger study published by Furu 2015 (1996-2010). Thus only the not updated malformations are reported here.
The Drug Reimbursement Register that contains data on 98% of reimbursed prescription drug purchases.
Marks (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 Paroxetine 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) 55 / 406 '252 women (6.8%) prescribed >1 antidepressant'=> considered as monotherapy.
Data were obtained from electronic medical records (EMRs) through the Regenstrief Institute in Indianapolis.
Marks (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 Paroxetine 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 10 / -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
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 Paroxetine (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) 2794 / 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).
Maschi
2008 		Italy
1995 - 2003
prospective cohort 		A Drug and Health Information Centre in Milan, Italy. Women who took Paroxetine during pregnancy and delivered liveborn children. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
Pregnant women who were counselled at the Centre on the use of nonteratogenic drugs or drugs that do not cause neonatal adverse effects, such as antibiotics or paracetamol. 		during pregnancy (anytime or not specified) 58 / 348 'In all, 33 women (17%) had taken more than one antidepressant drug and 86 (43%) had received these medications in combination with a benzodiazepine.'
Maternal demographic data, indication for treatment and time of exposure were collected using a structured questionnaire.
Merlob
2009 		Israel
2000 - 2007
prospective cohort 		The Departments of Neonatology in Rabin Medical Center and Schneider Children’s Medical Center of Israel (affiliated with ENTIS). Pregnant women who reported using Paroxetine during 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 who not reported using Selective serotonin reuptake inhibitors (SSRIs). 		1st trimester 92 / 67636 'Any infant with multiple congenital anomalies or dysmorphic features underwent genetic evaluation by a trained expert to exclude a congenital syndrome.'
A standardized pregnancy questionnaire is administered to all women on admittance to the maternity ward and reviewed by the attending neonatologist. The use of any drug during pregnancy is routinely recorded.
Nijenhuis (Controls exposed to TCA)
2012 		The Netherlands
1995 - 2009
retrospective cohort (claims database) 		The ‘Pregnancy IADB’, extracted from the main pharmacy prescription database IADB.nl Children of mothers exposed to Paroxetine 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 exposed to tricyclic antidepressants (TCAs) during pregnancy. 		1st trimester, 2nd and/or 3rd trimester, at least 1st trimester, during pregnancy (anytime or not specified), throughout pregnancy 301 / 76 The group exposed to both a SSRI and a TCA was excluded from the TCA exposed group and SSRI exposed group.
The pharmacy prescription database IADB.nl which contains pharmacy prescription data of an estimated population of 500 000 individuals from the Netherlands.
Nijenhuis (Controls unexposed, NOS)
2012 		The Netherlands
1995 - 2009
retrospective cohort (claims database) 		The ‘Pregnancy IADB’, extracted from the main pharmacy prescription database IADB.nl Children of mothers exposed to Paroxetine during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
Children of mothers who did not use any selective serotonin re-uptake inhibitors (SSRIs) or tricyclic antidepressants (TCAs) during pregnancy and during a period of 7 days before pregnancy. 		1st trimester, 2nd and/or 3rd trimester, at least 1st trimester, during pregnancy (anytime or not specified), throughout pregnancy 301 / 34908 The group exposed to both a SSRI and a TCA was excluded from the TCA exposed group and SSRI exposed group.
The pharmacy prescription database IADB.nl which contains pharmacy prescription data of an estimated population of 500 000 individuals from the Netherlands.
Nordeng (Controls unexposed, NOS)
2012 		Norway
2000 - 2006
cohort 		The Norwegian Mother and Child Cohort Study (the MoBa study). Exposure to Paroxetine during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
No reported use of any antidepressants in the 6 months before or during pregnancy. 		1st trimester 76 / 61648 Little overlapping between Nordeng 2012 (2000 - 2006) and Furu 2015 (including Norway 2005-10) => the 2 studies kept.
The pregnant women completed 2 questionnaires during pregnancy at around gestational weeks 17 and 30, which included notably questions regarding medication use.
Nordeng (Controls unexposed, sick)
2012 		Norway
2000 - 2006
cohort 		The Norwegian Mother and Child Cohort Study (the MoBa study). Exposure to Paroxetine during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Pregnancies that reported use of an antidepressant during the 6 months before pregnancy, but not during pregnancy. 		1st trimester 76 / 1048 Little overlapping between Nordeng 2012 (2000 - 2006) and Furu 2015 (including Norway 2005-10) => the 2 studies kept.
The pregnant women completed 2 questionnaires during pregnancy at around gestational weeks 17 and 30, which included notably questions regarding medication use.
Oberlander
2004 		Canada
1996 - 2000
prospective cohort 		The British Columbia Women's Hospital (Vancouver, British Columbia). Infants prenatally exposed to Paroxetine alone. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, disease free
Term-born healthy infants whose mother did not use psychotropic or antidepressant medications during pregnancy and without history of maternal mental illness. 		during pregnancy (anytime or not specified) 17 / 23
Measure of plasma level of maternal SSRI medications.
Oberlander
2008 		Canada
1997 - 2002
retrospective cohort (claims database) 		Population-based health-care utilization databases from the province of British Columbia. Infants exposed to Paroxetine monotherapy in the first trimester of pregnancy. unexposed (general population or NOS)
Infants with no exposure to either of these drugs (SRI or benzodiazepine) in the first trimester of pregnancy. 		1st trimester 993 / 107320
PharmaNet, a province-wide network recording all prescriptions dispensed by British Columbian pharmacists outside hospitals.
Ozturk
2016 		Turkey
2007 - 2012
prospective cohort 		An observational cohort study based on a prenatal consultation service. Pregnant women exposed to Paroxetine 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 14 / 275 'Drug exposures took place in 81% during the first trimester, and 11% in all three trimesters. Medical treatments were discontinued in most of recognized pregnancies.'=> considered as 'At least first trimester'.
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 (Controls 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 Paroxetine 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 3517 / 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 (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 paroxetine 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 3517 / 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
2013 		USA
2000 - 2007
retrospective cohort (claims database) 		The Medicaid Analytic eXtract (MAX) data Women with a supply of Paroxetine 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 2055 / 69044 Exclusion of women who were exposed to both drugs types (polytherapy) during the five months before delivery.
Data of prescription.
Rai (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 Paroxetine 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) 264 / 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 (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 Paroxetine 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) 264 / 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 (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 Paroxetine 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) 264 / 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).
Reis (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 Paroxetine in early pregnancy. exposed to other treatment, sick
Pregnant women who reported the use of tricyclic antidepressants (TCAs) in early pregnancy. 		early pregnancy 1208 / 1662
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 (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 Paroxetine in early pregnancy. unexposed (general population or NOS)
All other pregnant women in the register (not exposed to antidepressants during pregnancy). 		early pregnancy 1208 / 1062190 Overlapping: Kallen 2007 totally included in Reis 2010. Minor overlapping with Furu 2015 (including Sweden 2006-2010).
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.
Stephansson
2013 		Nordic countries (Denmark, Finland, Iceland, Norway, and Sweden)
1996 - 2007
population based cohort retrospective 		A registry-based cohort study based on national registries of the 5 Nordic countries. One or more filled prescriptions for Paroxetine from 3 months before the start of pregnancy until birth (different analysis according to period of exposure). unexposed (general population or NOS)
No prescriptions for an Selective serotonin reuptake inhibitors (SSRIs). 		3 months (or more) before pregnancy or during pregnancy 3745 / 1604649 Exclusion of pregnancies and births of mothers who had used other antidepressants with an effect on serotonin or norepinephrine activity (but not other antidepressants). Overlapping: Jimenez-Solem 2013 (not reported because included in Stephansson 2013).
The prescription registries in the Nordic countries include data on the dispensed item, substance, brand name, and formulation together with date of dispensing for more than 95% of the total outpatient population.
Van der Veere
2020 		The Netherlands
2007 - 2010
prospective cohort 		A prospective, longitudinal cohort design for the Dutch ‘SSRI in pregnant mothers, outcome of the kids’ study, abbreviated to SMOK. Children who had been exposed to Paroxetine during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
Children who had not been exposed to psychotropic medication during pregnancy, with adjustment for maternal psychopathology. 		during pregnancy (anytime or not specified) 27 / 41
Not specified (but prospective cohort).
Vial
2006 		France
1994 - 2005
prospective cohort 		A French multicentre prospective study (25 participating centers: pharmacovigilance and teratology information service). Pregnant women exposed to paroxetine during early pregnancy (i.e. 3 to 10 weeks after the last menstrual period). unexposed (general population or NOS)
Pregnant women who were unexposed or exposed to a non-teratogenic agent during organogenesis. 		1st trimester 683 / -9
Maternal data and detailed history of drug exposures were collected during the first contact for individual risk counseling.
Viktorin (Controls unexposed, NOS)
2017 		Sweden
2006 - 2014
population based cohort retrospective 		A birth cohort established by linkage of Swedish National registers. Offspring that were born to mothers with at least 2 dispensations of Paroxetine overlapping the pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
Offspring that were born to mothers without any dispensation of an antidepressant with a medication period overlapping the pregnancy. 		during pregnancy (anytime or not specified) 173 / 172646
Dispensations identified in the Swedish Prescribed Drug Register that holds information on all dispensed prescription drugs in Sweden.
Viktorin (Controls unexposed, sick)
2017 		Sweden
2006 - 2014
population based cohort retrospective 		A birth cohort established by linkage of Swedish National registers. Offspring that were born to mothers with a history of depression or anxiety with at least 2 dispensations of Paroxetine overlapping the pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Offspring that were born to mothers with a history of depression or anxiety without any dispensation of an antidepressant with a medication period overlapping the pregnancy. 		during pregnancy (anytime or not specified) 108 / -9
Dispensations identified in the Swedish Prescribed Drug Register that holds information on all dispensed prescription drugs in Sweden.
Yaris
2005 		Turkey
1999 - 2004
prospective cohort 		Toxicology Information and Follow-up Service, Turkey Women who were exposed to Paroxetine 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) 4 / 248 Multiple drug exposure. Raw data for Intrauterine exitus not reported because the nb of cases in the unexposed group not clearly stated.
Data surveyed by the interviews.

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
Alwan
2007 		USA
1997 - 2002
case control 		The National Birth Defects Prevention Study (NBDPS). 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 in English or Spanish. 1st trimester 9622 / 4092 Overlapping: individual malformations not reported because updated by Anderson 2020. '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 eight U.S. states. Controls were selected randomly from the same geographic areas. Information on the case infants was reviewed by clinical geneticists unaware of the infants’ exposure status
Ames
2021 		USA
2003 - 2011
case control 		The Study to Explore Early Development (SEED): a multisite case-control study of autism by the Centers for Autism and Developmental Disabilities Research and Epidemiology (CADDRE) network. Children with Autism spectrum disorder (ASD) or with other developmental delays or disorders (DDs) such as language delay or intellectual disability (ID) recruited from educational and clinical settings that serve children with developmental disorders. Children from the general population randomly sampled state birth records at each study site who either scored <11 on the SCQ or scored >=11 but did not meet ASD criteria after the in-person assessment. Maternal use of SSRIs during pregnancy were ascertained from all participants in three ways: self-report in a telephone interview shortly after study enrollment (SEED Caregiver Interview), self-report on the SEED maternal medical history form, and abstraction from prenatal medical records. 3 months (or more) before pregnancy or during pregnancy 1750 / 1671 The final analytic sample comprised 1367 children with ASD, 1750 with DDs, and 1671 POP controls. No age specified in article but in CDC website: 'The study will include children with ASD, with other DDs, and with typical development, ages 2-5 years'.
Children completed a multistage process. 1) Mother (mainly) completed the Social Communication Questionnaire. 2) Gold standard clinical assessments: Autism Diagnostic Observation Schedule, Autism Diagnostic Interview Revised, Mullen Scales of Early Learning and Vineland Adaptive Behavior Scales.
Anderson
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 Overlapping: this study is an update of Alwan 2007, Werler 2018 (gastroschisis) and Lind 2013 (hypospadias). '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.
Bakker
2010 		The Netherlands
1997 - 2006
case control 		The EUROCAT Northern Netherlands database, a population-based birth defects registry for the northern part of the Netherlands Fetuses or children born with isolated congenital heart defects (included fetuses or children with simple or complex heart defects only and excluded fetuses or children with associated genetic or other syndromes or those with extracardiac malformations.) Fetuses and children with a chromosomal or single gene disorder as controls (with exclusion of children with an associated heart defect ) Information regarding medications dispensed before and during pregnancy is obtained from community pharmacies which keep complete records of dispersed medications. The use of the prescribed medications and the use of over-the-counter medication is verified in a telephone interview with the mother. 1st trimester 678 / 615 Overlapping with Wemakor 2015, a larger study based on 12 EUROCAT registries (included The Netherlands) for VSD, ASD, septal defects and cardiac malformations. Results not reported here.
The registry is notified of infants and fetuses with a congenital malformation by physicians and midwifes on a voluntary basis. Reports are actively collected from obstetric, pediatric, pathology, cytogenetic departments. Data on malformations is obtained from the medical files and is coded (ICD).
Chambers
2006 		USA and Canada
1998 - 2003
nested case control 		The Birth Defects Study of the Slone Epidemiology Center. Mothers of subjects with Persistent pulmonary hypertension of the newborn (PPHN). Mothers of subjects without Persistent pulmonary hypertension of the newborn (PPHN). Trained study nurses who were unaware of the study hypothesis interviewed all the mothers. The telephone interview was detailed and structured, and included questions on the use of all medications (prescription and over-the-counter) from 2 months before conception to the end of the pregnancy. 2nd and/or 3rd trimester 377 / 836
Admission and discharge records from major referral hospitals and clinics were reviewed, logbooks from neonatal intensive care units were examined, and weekly telephone calls were made to collaborators at newborn nurseries in community hospitals.
Dandjinou
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 Jonge
2013 		The Netherlands
1998 - 2008
case control 		EUROCAT NNL, a population-based birth defect registry in the northern part of the Netherlands and the IADB pregnancy database. All malformed foetuses and children (live births, stillbirths, spontaneous abortions and terminations of pregnancy) excluding chromosomal and genetic disorders. From the IADB, a population-based prescription database that contains prescription data from approximately 55 community pharmacies in The Netherlands, we selected the population controls. The IADB covers an estimated population of 500,000 individuals, which is considered representative of the general population. For controls: from the IADB, a population-based prescription database. For cases: the pharmacy records for 3 months before conception until delivery were obtained and verified in a telephone interview and only the actually used medication is registered. 1st trimester 3212 / 29223 Overlapping with Wemakor 2015, a larger study based on 12 EUROCAT registries (included The Netherlands) for cardiac, respiratory and digestive malformations => thus these results not reported here.
Information on congenital malformations is obtained from the medical files, including pathology reports, and coded afterwards, according to the International Classification of Diseases (ICD) coding system by trained registry staff.
De Vera
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
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).
Kerr
2018 		USA and Canada
1993 - 2015
case control 		Slone Epidemiology Center Birth Defects Study (BDS) Infants with microcephaly alone (“isolated”) and microcephaly that included other major birth defects (“non-isolated”), Nonmalformed live-born infants. Within 6 months of delivery, trained Birth Defects Study (BDS) nurse- interviewers contacted mothers to complete a roughly 1-hr computer-assisted telephone interview, including medications during pregnancy. 1st trimester, 2nd trimester, 3rd trimester 166 / 12059 Authors analyzed separately “isolated” microcephaly and “non-isolated” microcephaly. Only isolated microcephaly are indexed in MetaPreg.
Cases and controls were ascertained at participating hospitals or birth defect registries in the same areas.
Kitchin
2022 		Spain
2002 - 2015
case control 		The Spanish database BIFAP (Base de Datos para la Investigacion Farmacoepidemiologica en Atencion Primaria, Database for Pharmacoepidemiological Research in Primary Care) Pregnant woman suffering a miscarriage. Pregnant woman randomly selected from the whole cohort among women who were still at risk within follow-up, by risk-set sampling and individually matched to cases. Database for Pharmacoepidemiological Research in Primary Care, a computerized medical longitudinal population database of electronic medical records from 10.153 primary care practitioners and pediatricians distributed on nine Autonomous Regions (out of 17), which contains prescriptions. 1st trimester 18070 / 54209
Database for Pharmacoepidemiological Research in Primary Care, a computerized medical longitudinal population database of electronic medical records from 10.153 primary care practitioners and pediatricians, which contains medical diagnoses, medical visits, hospital admissions.
Louik
2007 		USA and Canada
1993 - 2004
case control 		The Slone Epidemiology Center Birth Defects Study. Infants with any of a wide range of malformations with exclusion of isolated minor defects (e.g., accessory nipples, dislocatable hips, and low-set ears). Nonmalformed infants. Detailed data are collected on all medications (prescription, over-the-counter, vitamins and minerals, and herbal products) used at any time from 2 months before conception through the end of the pregnancy, by mother completion of a 45-to-60-minute interview. 1st trimester 9849 / 5860 Exclusion of subjects whose infants had chromosomal defects, known mendelian inherited disorders, syndromes, defects with a known cause (e.g., fetal alcohol syndrome), metabolic disorders. No overlapping: Yazdy 2014 (2006-2011) - Louik 2007 (1993 - 2004)
Research staff identify subjects by reviewing clinical and surgical logs, reviewing admission and discharge lists, and contacting newborn nurseries and labor and delivery rooms. Nonmalformed infants were identified in a population-based random sample of newborns in Massachusetts.
Nakhai-Pour
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).
Wemakor
2015 		Belgium, Spain, Ireland, Malta, Netherlands, Norway, Denmark, FR, Germany, Italy, Switzerland, UK
1995 - 2009
case control 		Case-malformed control study based on 12 population-based European Surveillance of Congenital Anomalies (EUROCAT) congenital anomaly registries. Babies with congenital heart defects (CHD) or with congenital anomalies other than CHD identified as significantly associated with SSRI exposure (‘‘signals’’) in at least one previous study. All other registrations. Medication exposure information came from maternal medical/midwifery notes, created prospectively. Other additional data sources include paediatrician records (postnatal), medical geneticist records (postnatal), GP records of mother (prenatal), and maternal interviews (postnatal). 1st trimester 12876 / 17083 'Women were excluded if they took non-SSRI antidepressants or unspecified antidepressants and for the specific SSRI analyses, if they took more than one specific SSRI'. '12,876 with CHD, 13,024 with one or more of the 15 ‘signal’ subgroups'.
EUROCAT registries collect data using multiple sources of information: maternity, neonatal, and paediatric records; fetal medicine, cytogenetic, pathology, and medical genetics records; paediatric cardiology services; and hospital discharge and child health records. ICD 9 or 10 classification.
Yazdy
2014 		USA
2006 - 2011
case control 		The Slone epidemiology center at Boston University, a population-based case-control study, based on registries in Massachusetts, north carolina, and new York. Infants with a diagnosis of talipes equinovarus ('clubfoot') without a known syndrome. Infants with no major malformations or foot problems, drawn from the same birth population as cases and selected from either birth certificates (Massachusetts and north carolina) or hospital medical records (new York). The telephone interview were conducted by trained nurses within 1 year after delivery. It consisted in questions notably on illnesses and medications. If a mother reported using any medications, the timing and indication for use were noted. 1st trimester 622 / 2002 No overlapping between Yazdy 2014 (2006 - 2011) and Louik 2007 (1993 - 2004).
Diagnosis of structural clubfoot was confirmed primarily by orthopedic records (77%); when medical records were not available, maternal report of 3 or more castings for the clubfoot was used to confirm a true structural clubfoot (23%).

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

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