| 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 Fluoxetine (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 | 4111 / 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 Fluoxetine 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 | 3189 / 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 Fluoxetine 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 | 3189 / 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 Fluoxetine 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 | 191 / 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 Fluoxetine 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 | 171 / 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 fluoxetine 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) | 361 / 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 Fluoxetine 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) | 36 / 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. | ||||||||
|
Chambers 1996 |
USA 1989 - 1995 prospective cohort |
The California Teratogen Information Service and Clinical Research Program. | Pregnant women exposed to fluoxetine during pregnancy. |
unexposed (general population or NOS)
Pregnant women who called the program with questions about drugs and procedures not considered teratogenic. |
1st trimester, late pregnancy | 228 / 254 | ||
| Each woman who enrolled in the study completed a questionnaire that included notably exposures during the current pregnancy. Each woman was provided with a diary in which she was asked to keep a record of any additional exposures that might occur before delivery. | ||||||||
|
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 Fluoxetine 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 | 467 / 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 Fluoxetine 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 | 467 / 462377 | ||
| Study data were obtained from the Clinical Data Analysis and Reporting System, a database that contains prescribing/dispensing records. | ||||||||
|
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 Fluoxetine 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. | ||||||||
|
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 Fluoxetine 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) | 364 / 92995 | ||
| The national Pharmaceutical Benefits Scheme (PBS), including dispensing in the community, private hospitals, and, since late 2004, public hospitals. | ||||||||
|
Cornet 2024 |
USA 2011 - 2019 retrospective cohort (claims database) |
The 15 Kaiser Permanente Northern California (KPNC) hospitals. | Infants with any maternal Fluoxetine monotherapy (among Selective serotonin reuptake inhibitor (SSRI)) dispensing by a KPNC pharmacy during late pregnancy, that is, after 20 weeks’ gestation. |
unexposed (general population or NOS)
Infants with no maternal Selective serotonin reuptake inhibitor (SSRI) dispensing by a KPNC pharmacy during late pregnancy, that is, after 20 weeks’ gestation. |
late pregnancy | 982 / 272517 | Dose-dependent relationship of individuals substances: no conclusion provided by authors. | |
| Prescription files of Kaiser Permanente Northern California pharmacies. For each prescription, dispensation date, daily dosage and number of pills dispensed were collected. | ||||||||
|
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 Teratology Information Service regarding exposures to Fluoxetine. |
unexposed (general population or NOS)
Pregnant women who contacted one Teratology Information Service regarding exposures known not to be teratogenic in similar time frames. |
1st trimester, during pregnancy (anytime or not specified) | 346 / 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 Fluoxetine 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 | 12 / 52 | ||
| Not specified. | ||||||||
|
Einarson 2009 |
Canada Not specified. prospective cohort |
The Motherisk Program, a teratogenic information service. | Pregnant women who were exposed to Fluoxetine 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 | 61 / 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 Fluoxetine 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 | 6250 / 2266875 | Overlapping: Furu et al. 2015 included a large part of Kornum 2010. | |
| The Nordic prescription registers include data on dispensed drugs, substance, brand name, and formulation, together with date of dispensing. | ||||||||
|
Heikkinen 2003 |
Finland Not specified prospective cohort |
University of Turku and Turku University Central Hospital. Finland. | Pregnant women taking fluoxetine during pregnancy and lactation. |
unexposed (general population or NOS)
Pregnant women with no psychotropic medication was prospectively matched at the time of delivery. |
during pregnancy (anytime or not specified) | 11 / 10 | Five women started taking fluoxetine later during pregnancy. | |
| Pregnant women taking fluoxetine recruited (NOS). Fluoxetine concentrations detected from the blood samples during gestation. | ||||||||
|
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 Fluoxetine 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) | 4767 / 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 Fluoxetine 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 | 11048 / 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 Fluoxetine 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 | 8676 / 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 Fluoxetine 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 | 928 / 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 Fluoxetine, 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 | 928 / 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 Fluoxetine 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 | 2601 / -9 | Overlapping: The results of outcomes also reported in the largest study published by Wemakor 2015 (EUROCAT data in 12 countries; 1995-2009) or Given 2017 (gastroschisis) 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 Fluoxetine 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 | 7988 / 1588140 | ||
| The prescription registers. | ||||||||
|
Kivistö 2016 |
Finland 2002 - 2012 retrospective cohort |
Retrospective study conducted at the Kuopio University Hospital. | Pregnant women that used only Fluoxetine during pregnancy. |
unexposed (general population or NOS)
Pregnant women not using any antidepressant medication. |
during pregnancy (anytime or not specified) | 51 / 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. | ||||||||
|
Kolding (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 Fluoxetine 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 | 408 / 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 (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 Fluoxetine 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 | 408 / 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. | ||||||||
|
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 Fluoxetine 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) | 719 / 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 Fluoxetine 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) | 719 / 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 Fluoxetine 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 | 12 / 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 Fluoxetine 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) | 2771 / 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 Fluoxetine 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 | 1818 / 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 Fluoxetine 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) | 579 / 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 Fluoxetine 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 | 275 / -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 Fluoxetine (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) | 12978 / 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 Fluoxetine 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) | 32 / 192 | '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 Fluoxetine 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 | 66 / 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 Fluoxetine 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 | 105 / 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 Fluoxetine 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 | 105 / 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 Fluoxetine 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 | 51 / 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 Fluoxetine 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 | 51 / 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. | ||||||||
|
Nulman (Controls exposed to TCA) 2002 |
Canada Until 1985 prospective cohort |
The Motherisk Program | Pregnant women diagnosed as having major depression who had been counseled by the program regarding therapy with fluoxetine and who had continued taking these medications throughout gestation. |
exposed to other treatment, sick
Pregnant women diagnosed as having major depression who had been counseled by the program regarding therapy with tricyclic antidepressants and who had continued taking these medications throughout gestation. |
throughout pregnancy | 40 / 46 | Language development outcomes: overlapping with Nulman 1997 which included a little more pregnancies but exposed only 1st trimester and not throughout pregnancy. Thus for these outcomes, results of Nulman 2002 reported and not those of Nulman 1997. | |
| During the initial consultation, during early pregnancy, Details concerning the time and duration of exposure to the antidepressant drugs, and the doses of any other concomitant medications were recorded was obtained from each mother. | ||||||||
|
Nulman (Controls unexposed, disease free) 2002 |
Canada Until 1985 prospective cohort |
The Motherisk Program | Pregnant women diagnosed as having major depression who had been counseled by the program regarding therapy with fluoxetine and who had continued taking these medications throughout gestation. |
unexposed, disease free
Pregnant women who had no history of a psychiatric disorder or depressive symptoms and were unexposed to any drug, chemical, radiation, or infection known to affect the fetus adversely. |
throughout pregnancy | 40 / 36 | Language development outcomes: overlapping with Nulman 1997 which included a little more pregnancies but exposed only 1st trimester and not throughout pregnancy. Thus for these outcomes, results of Nulman 2002 reported and not those of Nulman 1997. | |
| During the initial consultation, during early pregnancy, Details concerning the time and duration of exposure to the antidepressant drugs, and the doses of any other concomitant medications were recorded was obtained from each mother. | ||||||||
|
Nulman - Fluoxetine (Controls exposed to TCA) 1997 |
Canada Since 1985 prospective cohort |
The Motherisk Program, an information and consultation service regarding exposure to drugs, chemicals, radiation, and infectious agents during pregnancy and lactation. | Pregnant women who took fluoxetine at least during the first trimester of pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
exposed to other treatment, sick
Pregnant women who took a tricyclic antidepressant drug at least during the first trimester of pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
at least 1st trimester | 55 / 80 | Overlapping of some outcomes (language development) with Nulman 2002 (with more relevant period of exposure), thus not reported here. For Cognitive Index: the nb of infants examined by Bayley or McCarthy scales not provided. => data not extractable. | |
| During the initial assessment, at the diagnosis of pregnancy or within several weeks thereafter, the Service obtained a medical history of each woman, including use of medicinal drugs. Information concerning the time of drug therapy was recorded, as were the doses and of any concomitantly drugs. | ||||||||
|
Nulman - Fluoxetine (Controls unexposed, NOS) 1997 |
Canada Since 1985 prospective cohort |
The Motherisk Program, an information and consultation service regarding exposure to drugs, chemicals, radiation, and infectious agents during pregnancy and lactation. | Pregnant women who took fluoxetine at least during 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 not exposed to any drug, chemical, radiation, or infection known to affect the fetus adversely. |
at least 1st trimester | 55 / 84 | Overlapping of some outcomes (language development) with Nulman 2002 (with more relevant period of exposure), thus not reported here. For Cognitive Index: the nb of infants examined by Bayley or McCarthy scales not provided. => data not extractable. | |
| During the initial assessment, at the diagnosis of pregnancy or within several weeks thereafter, the Service obtained a medical history of each woman, including use of medicinal drugs. Information concerning the time of drug therapy was recorded, as were the doses and of any concomitantly drugs. | ||||||||
|
Oberlander 2008 |
Canada 1997 - 2002 retrospective cohort (claims database) |
Population-based health-care utilization databases from the province of British Columbia. | Infants exposed to Fluoxetine 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 | 638 / 107320 | ||
| PharmaNet, a province-wide network recording all prescriptions dispensed by British Columbian pharmacists outside hospitals. | ||||||||
|
Oberlander 2004 |
Canada 1996 - 2000 prospective cohort |
The British Columbia Women's Hospital (Vancouver, British Columbia). | Infants prenatally exposed to Fluoxetine 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) | 7 / 23 | ||
| Measure of plasma level of maternal SSRI medications. | ||||||||
|
Ozturk 2016 |
Turkey 2007 - 2012 prospective cohort |
An observational cohort study based on a prenatal consultation service. | Pregnant women exposed to Fluoxetine 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 | 10 / 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 Fluoxetine 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 | 5650 / 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 fluoxetine 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 | 5650 / 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 Fluoxetine 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 | 3322 / 69044 | Exclusion of women who were exposed to both drugs types (polytherapy) during the five months before delivery. | |
| Data of prescription. | ||||||||
|
Pastuszak (Controls exposed to TCA) 1993 |
USA and Canada Not specified prospective cohort |
Four Teratogen Information Services (TIS): Motherisk (Toronto, Ontario), Pregnancy Healthline (Philadelphia, Pa), Pregnancy Risk Information Service (Camden,NJ) and Pregnancy Risk Line (Salt Lake City, Utah). | Pregnant women exposed to fluoxetine during the first trimester. |
exposed to other treatment, sick
Pregnant women exposed to tricyclic antidepressants (TCAs) during the first trimester. |
1st trimester | 74 / 74 | The matched cohort was considered. Authors made comparison Fluoxetine versus TCAs, thus considered as mono-exposure. | |
| Drug exposure history was obtained from both the mother and biological father of the fetus, by an interview with a team physician. | ||||||||
|
Pastuszak (Controls unexposed, NOS) 1993 |
USA and Canada Not specified prospective cohort |
Four Teratogen Information Services (TIS): Motherisk (Toronto, Ontario), Pregnancy Healthline (Philadelphia, Pa), Pregnancy Risk Information Service (Camden,NJ) and Pregnancy Risk Line (Salt Lake City, Utah). | Pregnant women exposed to fluoxetine during the first trimester. |
unexposed (general population or NOS)
Pregnant women who sought counseling at Motherisk regarding exposure to a nonteratogen. |
1st trimester | 128 / 128 | Authors made comparison Fluoxetine versus TCAs, thus considered as mono-exposure. | |
| Drug exposure history was obtained from both the mother and biological father of the fetus, by an interview with a team physician. | ||||||||
|
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 Fluoxetine 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) | 453 / 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 Fluoxetine 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) | 453 / 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 Fluoxetine 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) | 453 / 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 Fluoxetine in early pregnancy. |
exposed to other treatment, sick
Pregnant women who reported the use of tricyclic antidepressants (TCAs) in early pregnancy. |
early pregnancy | 1522 / 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 Fluoxetine in early pregnancy. |
unexposed (general population or NOS)
All other pregnant women in the register (not exposed to antidepressants during pregnancy). |
early pregnancy | 1522 / 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. | ||||||||
|
Sjaarda 2020 |
USA 2007 – 2011 prospective cohort |
A prospective cohort study of women trying to conceive and participating in the Effects of Aspirin in Gestation and Reproduction (EAGeR) clinical trial. | Women who became pregnant with exposure to Fluoxetine detected in urine samples at week 4 of pregnancy. |
unexposed (general population or NOS)
Women who became pregnant without any antidepressant exposure at the same time point. |
early pregnancy, preconception-only | 26 / 662 | 'Women with SSRI use in this cohort may be considered to represent women with mild to moderate depression self-identified'. | |
| Antidepressant medication exposure was measured in stored urine samples collected at study visits at enrollment and at the end of preconception follow-up. For women who became pregnant, samples from pregnancy visits at gestational weeks 4 and 8 were also evaluated. | ||||||||
|
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 Fluoxetine 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 | 7619 / 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. | ||||||||
|
Suarez (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 fluoxetine from 127 days after LMP (week 19 of gestation) to delivery. |
unexposed, sick
Individuals that having a dispensing for fluoxetine 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 | 26595 / 7773 | 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 (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 fluoxetine from 127 days after LMP (week 19 of gestation) to delivery. |
unexposed (general population or NOS)
Individuals with no antidepressants dispensing from 90 days prior to pregnancy start through the day prior to delivery. |
2nd and/or 3rd trimester | 26659 / 2984014 | 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. | ||||||||
|
Suri (Controls unexposed, disease free) 2004 |
USA 1997 - 2000 prospective cohort |
Data from the University of California at Los Angeles Neuropsychiatric Institute. | Pregnant women with depression treated with fluoxetine at any time during pregnancy (medicated depressed group). |
unexposed, disease free
Pregnant women without depression and no antidepressant treatment during pregnancy. |
during pregnancy (anytime or not specified) | 28 / 16 | 'Exclusion criteria included the presence of psychotic symptoms, the use of medications that are known to adversely affect the fetus, the use of other psychotropic medications, the use of alcohol, cigarettes, or substances while pregnant'. | |
| Subjects recruited in the first trimester of pregnancy and that were then followed once in each trimester (NOS). | ||||||||
|
Suri (Controls unexposed, sick) 2004 |
USA 1997 - 2000 prospective cohort |
Data from the University of California at Los Angeles Neuropsychiatric Institute. | Pregnant women with depression treated with fluoxetine at any time during pregnancy (medicated depressed group). |
unexposed, sick
Pregnant women with depression and no antidepressant treatment during pregnancy (unmedicated depressed group). |
during pregnancy (anytime or not specified) | 28 / 18 | 'Exclusion criteria included the presence of psychotic symptoms, the use of medications that are known to adversely affect the fetus, the use of other psychotropic medications, the use of alcohol, cigarettes, or substances while pregnant'. | |
| Subjects recruited in the first trimester of pregnancy and that were then followed once in each trimester (NOS). | ||||||||
|
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 Fluoxetine 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) | 458 / 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 Fluoxetine 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) | 327 / -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 Fluoxetine 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) | 17 / 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. | ||||||||
| 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 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. | |||||||||
|
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). | |||||||||
|
Dave 2019 |
USA 2011 - 2015 nested case control |
The IBM MarketScan commercial claims database, an employer- sourced health insurance database. | Neonatal abstinence syndrome (NAS) in live births. | No neonatal abstinence syndrome (NAS) in live births. | The IBM MarketScan commercial claims database, an employer- sourced health insurance database. | 3rd trimester | 659 / 621281 | ||
| Neonatal abstinence syndrome deliveries were identified using in- and outpatient encounters with the ICD-9 code 779.5 within 30 days of delivery date in either the infant or mother’s medical encounter files. | |||||||||
|
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). | |||||||||
|
Given 2017 |
14: Belgium, Croatia, Denmark, FR, Germany, Ireland, Italy, Netherlands, Norway, Ukraine, UK... 1995 - 2012 case control |
A case-malformed control study based on EUROmediCAT, a population based reproductive pharmacovigilance system, based on the European Surveillance of Congenital Anomalies (EUROCAT) network. | Infants with gastroschisis (ICD-9 with BPA extension code 75671 or ICD-10 code Q793). | Infants with a diagnosis of a major congenital anomaly not including gastroschisis. | First trimester maternal medication exposures were mostly obtained by registries from prospectively recorded maternity records. Additional data sources included the medical records of the infant, general practitioner records, maternity passports, and maternal interviews before or after birth. | 1st trimester | 1587 / 154877 | Overlapping for gastroschisis: this study updated Wemakor 2015 and totally included Jordan 2016. Medications taken in the second or third trimester or where the timing was unknown were excluded. | |
| EUROCAT registries that record all cases of major congenital anomalies among live births, foetal deaths ≥20 weeks’ gestation and termination of pregnancy for foetal anomaly (TOPFA), in their populations using International Classification of Diseases (ICD)-9/ | |||||||||
|
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. | |||||||||
|
Laspro 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. | |||||||||
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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. | |||||||||
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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). | |||||||||
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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. | |||||||||
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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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