Atypical antipsychotics (Second generation)

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
Bellet - Aripiprazole
2015 		France
2004 - 2011
prospective cohort 		Two French databases specifically designed for collecting drug-exposed pregnancies: Terappel, a database shared by 20 pharmacovigilance centres, and the Paris TIS (Centre de Référence sur les Agents Tératogènes) database Pregnant women exposed to aripiprazole during embryogenesis, i.e. 4 to 10 gestational weeks (GW, i.e. weeks after the last menstrual period). unexposed (general population or NOS)
Pregnant women without exposure or exposed to agents known to be non-teratogenic. 		1st trimester 86 / 172 Patients were also excluded from the exposed group if they were co-exposed to known teratogen(s) during embryogenesis.
Interview of mother/clinician using structured questionnaires at initial telephone contact and after birth.
Boden - Olanzapine and/or clozapine
2012 		Sweden
2005 - 2009
population based cohort retrospective 		3 Swedish national health registers (the Swedish Prescribed Drug Register, the Medical Birth Register, and the National Patient Register) Exposure was defined as filling a prescription for olanzapine and/or clozapine from last menstrual period to parturition. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
Total population of pregnancies unexposed to antipsychotics. 		during pregnancy (anytime or not specified) 169 / 357696 Olanzapine (n=159) and Clozapine (n=11). Overlapping with Heinonen 2022a for Gestational diabetes, SGA (weight birth), LGA (weight birth) and Kallen 2013 for preterm, 2 larger studies on atypical antipshychotics as a whole => Not reported here.
The Swedish Prescribed Drug Register contains information on all prescriptions filled in Sweden, including the dispensed sub- stances’ Anatomical Therapeutic Chemical code and the amount formulation, and dates the substance was prescribed and dispensed.
Bruno - Quetiapine
2024 		Denmark, Finland, Iceland, Norway, and Sweden
2000 - 2020
population based cohort retrospective 		European Nordic national health and social registers that include information on all births, filled prescriptions. Pregnant women who filled ≥1 prescription for Quetiapine monotherapy (among antipsychotic medication) anytime between pregnancy start (based on the date of the first day of the last menstrual period) until the date of birth. unexposed, sick
Pregnant women who did not fill a prescription for any antipsychotic from 90 days before the start of pregnancy until birth. 		during pregnancy (anytime or not specified) 4492 / 197296 Authors assessed several atypical antipsychotics (adjusted results), thus to avoid redundancy of controls, only one substance was reported in class meta-analysis (this one with the higher number of pregnancies).
Data on filled or reimbursed prescriptions were obtained from the nation prescription registries.
Chan (Controls exposed to FGA)
2024 		China
2003 - 2018
retrospective cohort (claims database) 		Clinical Data Analysis and Reporting System (CDARS), a territory-wide electronic health record (EHR) database from universal health coverage to all Hong Kong residents. Pregnant women filling at least one prescription of any second generation antipsychotic only (i.e no first generation antipsychotic) during the first trimester of pregnancy, which is defined as the first 90 days after the last menstrual period (LMP). exposed to other treatment, sick
Pregnant women filling at least one prescription of any first generation antipsychotic (only, i.e no second generation antipsychotic) during the first trimester of pregnancy, which is defined as the first 90 days after the last menstrual period (LMP). 		at least 1st trimester 419 / 420 Pregnancies with gestational age < 20 weeks, chromosomal abnormalities, fetal alcohol syndrome, abnormalities due to maternal infection, or exposure to known teratogens were excluded.
The exposure data were obtained from the Clinical Data Analysis and Reporting System (CDARS), including prescribing and dispensing records.
Chan (Controls unexposed, general pop)
2024 		China
2003 - 2018
retrospective cohort (claims database) 		Clinical Data Analysis and Reporting System (CDARS), a territory-wide electronic health record (EHR) database from universal health coverage to all Hong Kong residents. Pregnant women filling at least one prescription of any second generation antipsychotic (only, i.e no first generation antipsychotic) during the first trimester of pregnancy, which is defined as the first 90 days after the last menstrual period (LMP). unexposed (general population or NOS)
Pregnant women who were not prescribed with any antipsychotic within the 90 days before the last menstrual period (LMP) and during the first trimester. 		at least 1st trimester 419 / 464017 Pregnancies with gestational age < 20 weeks, chromosomal abnormalities, fetal alcohol syndrome, abnormalities due to maternal infection, or exposure to known teratogens were excluded.
The exposure data were obtained from the Clinical Data Analysis and Reporting System (CDARS), including prescribing and dispensing records.
Chan (Controls unexposed, sick)
2024 		China
2003 - 2018
retrospective cohort (claims database) 		Clinical Data Analysis and Reporting System (CDARS), a territory-wide electronic health record (EHR) database from universal health coverage to all Hong Kong residents. Pregnant women with psychiatric diagnosis filling at least one prescription of any second generation antipsychotic (only, i.e no first generation antipsychotic) during the first trimester of pregnancy, which is defined as the first 90 days after the last menstrual period (LMP). unexposed, sick
Pregnant women with psychiatric diagnosis who were not prescribed with any antipsychotic within the 90 days before the last menstrual period (LMP) and during the first trimester. 		at least 1st trimester 363 / 6476 Pregnancies with gestational age < 20 weeks, chromosomal abnormalities, fetal alcohol syndrome, abnormalities due to maternal infection, or exposure to known teratogens were excluded.
The exposure data were obtained from the Clinical Data Analysis and Reporting System (CDARS), including prescribing and dispensing records.
Cohen
2022 		USA
2008 - 2022
prospective cohort 		The National Pregnancy Registry for Atypical Antipsychotics (NPRAA) Pregnant women who have used at least one second-generation antipsychotics (SGAs) during pregnancy. exposed to other treatment, sick
Pregnant women with a history of psychiatric illness being treated with a variety of psychotropic medications other than second-generation antipsychotics. 		1st trimester 1031 / 1551 Overlapping: Update of the study published by Cohen 2016 and Viguera 2021. Method based on the more detailed publication of the same registry (Viguera 2021). Cohen 2022 included data of Cohen 2023 and Viguera 2023a (on specific SGAs => not reported here).
Participants are prospectively interviewed across pregnancy and the early postpartum period by telephone, at enrollment, at 7 months’ gestation, and 12 weeks after delivery.
Ellfolk (Control exposed to FGA)
2019 		Finland
1996 - 2016
population based cohort retrospective 		The 'Drugs and Pregnancy' database in Finland, a population-based birth cohort study based on the Medical Birth Register, the Abortion Register, the Register of Congenital Malformations, the Prescription Register... Women who purchased second-generation antipsychotic (S-GAs: olanzapine, quetiapine, risperidone, aripiprazole, clozapine, ziprasidone, sertindole, or asenapine) at any time during pregnancy or 1 month before pregnancy. exposed to other treatment, sick
Women who purchased first-generation antipsychotic (F-GAs) at any time during pregnancy or 1 month before pregnancy but did not purchase S-GAs during the same period. 		during pregnancy (anytime or not specified) 4225 / 1576 Data reported here: exposure to SGA during pregnancy (whatever the trimester). Authors also provided outcomes after SGA during at least two trimesters. Gestational hypertension/diabetes not reported because not sure that exposure occurred before outcome.
The Finnish Prescription Registry (Kela) contains data on reimbursed prescription drug purchases.
Ellfolk (Control unexposed)
2019 		Finland
1996 - 2016
population based cohort retrospective 		The 'Drugs and Pregnancy' database in Finland, a population-based birth cohort study based on the Medical Birth Register, the Abortion Register, the Register of Congenital Malformations, the Prescription Register... Women who purchased second-generation antipsychotic (S-GAs: olanzapine, quetiapine, risperidone, aripiprazole, clozapine, ziprasidone, sertindole, or asenapine) at any time during pregnancy or 1 month before pregnancy. unexposed (general population or NOS)
Pregnant women who had no purchases of second-generation antipsychotic (S-GAs) or first-generation antipsychotic (F-GAs) during the period of 1 month prior to pregnancy until the end of pregnancy. 		during pregnancy (anytime or not specified) 4225 / 21125 Gestational hypertension and diabetes not reported because not sure that exposure occurred before outcome. Data reported here: exposure to SGA during pregnancy (whatever trimester). Authors also provided outcomes after SGA during at least 2 trimesters.
The Finnish Prescription Registry (Kela) contains data on reimbursed prescription drug purchases.
Ellfolk (Controls exposed to FGA)
2021 		Finland
1996 - 2017
population based cohort retrospective 		The 'Drugs and Pregnancy' database in Finland, a population-based birth cohort study based on the Medical Birth Register, the Abortion Register, the Register of Congenital Malformations, the Prescription Register... Pregnant women who purchased second-generation antipsychotic (S-GAs: olanzapine, quetiapine, risperidone, aripiprazole, clozapine, ziprasidone, sertindol, or asenapine) during 1 month before pregnancy until the end of first trimester. exposed to other treatment, sick
Pregnant women who purchased first-generation antipsychotic (F-GAs) during one month before pregnancy until the end of first trimester but did not purchase S-GAs during the same time period. 		1st trimester 3478 / 1030 Overlapping: for Major, cardiac malformations and oral clefts: Ellfolk 2021 included in a larger study: Huybrechts 2023 (including Finland; 1996-2016) => outcomes not reported here. Stillbirths and gestational diabetes assessed in Ellfolk et al. 2019.
Data from the Drugs and Pregnancy database which includes data from the Prescription Register.
Ellfolk (Controls unexposed, NOS)
2021 		Finland
1996 - 2017
population based cohort retrospective 		The 'Drugs and Pregnancy' database in Finland, a population-based birth cohort study based on the Medical Birth Register, the Abortion Register, the Register of Congenital Malformations, the Prescription Register... Pregnant women who purchased second-generation antipsychotic (S-GAs: olanzapine, quetiapine, risperidone, aripiprazole, clozapine, ziprasidone, sertindol, or asenapine) during 1 month before pregnancy until the end of first trimester. unexposed (general population or NOS)
Pregnant women who had no purchases of second-generation antipsychotic (S-GAs) or first-generation antipsychotic (F-GAs) during three months before pregnancy until end of first trimester. 		1st trimester 3478 / 22540 Overlapping: for Major, cardiac malformations and oral clefts: Ellfolk 2021 included in a larger study: Huybrechts 2023 (including Finland; 1996-2016) => outcomes not reported here. Stillbirths and gestational diabetes assessed in Ellfolk et al. 2019.
Data from the Drugs and Pregnancy database which includes data from the Prescription Register.
Frayne (Control exposed to antidepressants)
2018 		Australia
2007 - 2013
retrospective cohort 		Retrospective patient cohort study at the Childbirth and Mental Illness antenatal clinic (a tertiary maternity hospital) in Western Australia. Women receiving an atypical antipsychotic alone. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Women receiving antidepressants. (This is a subgroup of exposure among the whole exposed group considered in the study). 		during pregnancy (anytime or not specified) 75 / 50 Gestational Diabetes Mellitus and preeclampsia not reported because no adequate control group (ceased early in the first trimester prior to their 12-week antenatal).
Medication use was reported at each clinic attendance and recorded throughout the pregnancy. Women were grouped according to the medication prescribed for their mental health requirements in pregnancy, based on shared decision making with the perinatal psychiatrist, not by randomization.
Frayne (Control unexposed, sick)
2018 		Australia
2007 - 2013
retrospective cohort 		Retrospective patient cohort study at the Childbirth and Mental Illness antenatal clinic (a tertiary maternity hospital) in Western Australia. Women receiving an atypical antipsychotic alone. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Women receiving no medication (ceased their medication prior to conception, as part of a planned process, or ceased early in the first trimester prior to their 12-week antenatal review). (This is a subgroup of exposure among the whole exposed group considered in the study). 		during pregnancy (anytime or not specified) 75 / 58 Gestational Diabetes Mellitus and preeclampsia not reported because no adequate control group (ceased early in the first trimester prior to their 12-week antenatal).
Medication use was reported at each clinic attendance and recorded throughout the pregnancy. Women were grouped according to the medication prescribed for their mental health requirements in pregnancy, based on shared decision making with the perinatal psychiatrist, not by randomization.
Habermann (Control exposed to FGA)
2013 		Germany
1997 - 2009
prospective cohort 		Teratology Information Service (TIS Berlin) Women exposed to at least 1 Second Generation Antipsycotics (SGA) during pregnancy; comedication with First Generation Antipsycotics (FGA) was allowed. exposed to other treatment, sick
Women exposed to First Generation Antipsychotics (FGAs) excluding comedication with Second Generation Antipsychotics (SGA) (cohort I). 		1st trimester, during pregnancy (anytime or not specified), late pregnancy 561 / 284 Cases with potentially embryo- or fetotoxic drugs were not excluded for both the study cohort and the comparison cohort I but were assessed afterward. For the comparison cohort I, all available cases were included.
Data ascertainment was performed using 2 structured questionnaires at (1) the first contact and (2) 8 weeks after the estimated date of birth. A detailed history of drug use is recorded at the first contact.
Habermann (Control unexposed, disease free)
2013 		Germany
1997 - 2009
prospective cohort 		Teratology Information Service (TIS Berlin). Pregnant women exposed to at least 1 Second Generation Antipsycotics (SGA) during pregnancy; comedication with First Generation Antipsycotics (FGA) was allowed. unexposed, disease free
Pregnant women using drugs known as not harmful to the unborn (comparison cohort II). Women exposed to teratogenic, fetotoxic, or insufficiently studied agents were excluded. 		1st trimester, during pregnancy (anytime or not specified), late pregnancy 561 / 1122 Cases with potentially embryo- or fetotoxic drugs were not excluded for both the study cohort and the comparison cohort I but were assessed afterward. For the comparison cohort I, all available cases were included.
Data ascertainment was performed using 2 structured questionnaires at (1) the first contact and (2) 8 weeks after the estimated date of birth. A detailed history of drug use is recorded at the first contact.
Halfdanarson (Controls exposed to FGA)
2022 		5 nordic european countries: Denmark, Finland, Iceland, Norway, and Sweden.
1997 - 2017
population based cohort retrospective 		Nationwide population data and health registers from the five Nordic countries. Children whose mothers filled at least one atypical antipsychotics (only) prescription during pregnancy (from LMP to birth). (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Children whose mothers filled at least one typical antipsychotics (only) prescription during pregnancy (from LMP to birth). (This is a subgroup of exposure among the whole exposed group considered in the study). 		during pregnancy (anytime or not specified) 7752 / 6896 Exclusion of children with missing or invalid data on gestational age and those with a chromosomal anomaly or fetal alcohol-spectrum disorder diagnosed in the first year of life.
Medication exposure determined through the nationwide prescription registers and identified antipsychotics according to the Anatomical Therapeutic Chemical (ATC)18 classification group N05A.
Halfdanarson (Controls unexposed, NOS)
2022 		5 nordic european countries: Denmark, Finland, Iceland, Norway, and Sweden.
1997 - 2017
population based cohort retrospective 		Nationwide population data and health registers from the five Nordic countries. Children whose mothers filled at least one atypical antipsychotics prescription during pregnancy (from LMP to birth). (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
Children whose mothers did not fill a prescription for an antipsychotic drug from 90 days before LMP to birth. 		during pregnancy (anytime or not specified) 7752 / 4308620 Exclusion of children with missing or invalid data on gestational age and those with a chromosomal anomaly or fetal alcohol-spectrum disorder diagnosed in the first year of life.
Medication exposure determined through the nationwide prescription registers and identified antipsychotics according to the Anatomical Therapeutic Chemical (ATC)18 classification group N05A.
Heinonen a (Controls unexposed, NOS)
2022 		Sweden
2006 - 2017
population based cohort retrospective 		Register-based study using prospectively collected data, combining data from the Swedish Medical Birth Register (MBR) and the Prescribed Drug Register. Pregnant women who used High metabolic risk second-generation antipsychotic drugs (S-GAs) during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
All pregnant women during the study period who have not used antipsychotics during pregnancy, including those from the other control group “antipsychotics before or after but not during pregnancy”. 		during pregnancy (anytime or not specified) 1710 / 1296539 Results of High metabolic risk S-GAs (HR S-GAs) are included here: quetiapine (n = 1026), olanzapine (n = 771) and clozapine (n = 29). Gestational diabetes not reported because not sure that exposure occurred before outcome (authors' confirmation).
Exposure data were acquired from both the Medical Birth Register (MBR) and the Prescribed Drug Register. The Prescribed Drug Register stores data on drugs prescribed in ambulatory care and dispensed at pharmacies.
Heinonen a (Controls unexposed, sick)
2022 		Sweden
2006 - 2017
population based cohort retrospective 		Register-based study using prospectively collected data, combining data from the Swedish Medical Birth Register (MBR) and the Prescribed Drug Register. Pregnant women who used High metabolic risk second-generation antipsychotic drugs (S-GAs) during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Pregnant women who used antipsychotics before or after but not during the actual pregnancy. 		during pregnancy (anytime or not specified) 1710 / 34492 Results of High metabolic risk S-GAs (HR S-GAs) are included here: quetiapine (n = 1026), olanzapine (n = 771) and clozapine (n = 29). Gestational diabetes not reported here because not sure that exposure occurred before outcome (authors' confirmation).
Exposure data were acquired from both the Medical Birth Register (MBR) and the Prescribed Drug Register. The Prescribed Drug Register stores data on drugs prescribed in ambulatory care and dispensed at pharmacies.
Heinonen b (Controls exposed to FGA)
2022 		Sweden
2006 - 2017
population based cohort retrospective 		The Swedish Medical Birth Register, the Prescribed Drug Register, the Swedish Neonatal Quality Register and and the Perinatal Revision South Register. Infants exposed to second generation antipsychotics during pregnancy (early or late). exposed to other treatment, sick
Infants exposed to first generation antipsychotics during pregnancy (early or late). 		early pregnancy, late pregnancy -9 / -9 The most prescribed antipsychotics in the pregnant population during the study period were quetiapine (1021 exposures), olanzapine (771 exposures) and aripiprazole (334 exposures), all second-generation antipsychotics.
Information on drug exposure was collected from the Swedish Medical Birth Register (MBR), registered in the MBR at the first visit of the complimentary antenatal care offered to all pregnant.
Heinonen b (Controls unexposed, NOS)
2022 		Sweden
2006 - 2017
population based cohort retrospective 		The Swedish Medical Birth Register, the Prescribed Drug Register, the Swedish Neonatal Quality Register and and the Perinatal Revision South Register. Infants exposed to second generation antipsychotics during pregnancy (early or late). unexposed (general population or NOS)
Infants born of mothers not treated with antipsychotics during the entire study period. 		early pregnancy, late pregnancy -9 / 1262047 The most prescribed antipsychotics in the pregnant population during the study period were quetiapine (1021 exposures), olanzapine (771 exposures) and aripiprazole (334 exposures), all second-generation antipsychotics.
Information on drug exposure was collected from the Swedish Medical Birth Register (MBR), registered in the MBR at the first visit of the complimentary antenatal care offered to all pregnant.
Heinonen b (Controls unexposed, sick)
2022 		Sweden
2006 - 2017
population based cohort retrospective 		The Swedish Medical Birth Register, the Prescribed Drug Register, the Swedish Neonatal Quality Register and and the Perinatal Revision South Register. Infants exposed to second generation antipsychotics during pregnancy (early or late). unexposed, sick
Infants born of mothers treated with antipsychotics before or after but not during the pregnancy. 		early pregnancy, late pregnancy -9 / 34492 The most prescribed antipsychotics in the pregnant population during the study period were quetiapine (1021 exposures), olanzapine (771 exposures) and aripiprazole (334 exposures), all second-generation antipsychotics.
Information on drug exposure was collected from the Swedish Medical Birth Register (MBR), registered in the MBR at the first visit of the complimentary antenatal care offered to all pregnant.
Hironaka (Control exposed to BZD)
2011 		Japan
2005 - 2009
retrospective cohort 		Nagoya University Hospital, Japan Women with mental disorders (but without any other complications) taking atypical antipsychotics. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Women with mental disorders (but without any other complications) taking benzodiazepines. (This is a subgroup of exposure among the whole exposed group considered in the study). 		during pregnancy (anytime or not specified) 9 / 5 Gestational diabete, preeclampsia, low birth weight: not reported because neither case in exposed group nor in unexposed group
The subjects’ medical records were investigated concerning medication history.
Hironaka (Control unexposed, disease free)
2011 		Japan
2005 - 2009
retrospective cohort 		Nagoya University Hospital, Japan Women with mental disorders (but without any other complications) taking atypical antipsychotics. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, disease free
Women without mental disorders. 		during pregnancy (anytime or not specified) 9 / 278
The subjects’ medical records were investigated concerning medication history.
Hironaka (Control unexposed, sick)
2011 		Japan
2005 - 2009
retrospective cohort 		Nagoya University Hospital, Japan Women with schizophrenia (but without any other complications) taking atypical antipsychotics. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Women with schizophrenia without medication during pregnancy. 		during pregnancy (anytime or not specified) 9 / 3
The subjects’ medical records were investigated concerning medication history.
Huybrechts (Controls unexposed, NOS)
2023 		Denmark, Finland, Iceland, Norway, Sweden and USA.
1996 - 2018
population based cohort retrospective 		The International Pregnancy Safety Study (InPress) Consortium, a collaboration among research groups from the 5 Nordic countries (Denmark, Finland, Iceland, Norway, and Sweden) and the USA (nationwide Medicaid Analytic eXtract). Pregnancies with 1 or more prescriptions of the atypical antipsychotics during the first trimester, the period for organogenesis. unexposed (general population or NOS)
Pregnancies who did not fill any antipsychotic prescriptions during the 3 months prior to pregnancy until the end of the first trimester. 		1st trimester 21751 / 6455324 Overlapping: Data of Huybrechts 2016, Liu 2023 and Ellfolk 2021 totally and partially (major, cardiac, oral clefts) included in this larger study. Data of Reis 2008 (Sweden; 1995-2005) not included in Huybrechts 2023 (Sweden: 2006-2016).
Exposure to atypical and typical antipsychotics was defined based on filling 1 or more prescriptions of the respective drug class during the first trimester, the period for organogenesis. => Prescription databases.
Huybrechts (Controls unexposed, sick)
2023 		Denmark, Finland, Iceland, Norway, Sweden and USA.
1996 - 2018
population based cohort retrospective 		The International Pregnancy Safety Study (InPress) Consortium, a collaboration among research groups from the 5 Nordic countries (Denmark, Finland, Iceland, Norway, and Sweden) and the USA (nationwide Medicaid Analytic eXtract). Pregnancies with 1 or more prescriptions of the atypical antipsychotics during the first trimester, the period for organogenesis. unexposed, sick
Pregnancies in women with mental health condition, who did not fill any antipsychotic prescriptions during the 3 months prior to pregnancy until the end of the first trimester. 		1st trimester 17068 / 318731 Overlapping: Data of Huybrechts 2016, Liu 2023 and Ellfolk 2021 totally and partially (major, cardiac, oral clefts) included in this larger study. Data of Reis 2008 (Sweden; 1995-2005) not included in Huybrechts 2023 (Sweden: 2006-2016).
Exposure to atypical and typical antipsychotics was defined based on filling 1 or more prescriptions of the respective drug class during the first trimester, the period for organogenesis. => Prescription databases.
Källen
2013 		Sweden
1996 - 2011
population based cohort retrospective 		Swedish Medical Birth Register Pregnant women exposed to second generation antipsychotics. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
Not specified. 		2nd and/or 3rd trimester 258 / -9 The study was related to the Central Nervous System (CNS) active drugs. RR calculated with observed/expected numbers. All outcomes are provided for neuroleptics as a whole excepted for preterm (2nd generation antipsychotics).
The exposure data are either based on midwife interviews from the first antenatal visit (usually during weeks 10–12) or on linkage with a prescribed drug register.
Kananen - Quetiapine
2023 		Finland
2002 - 2016
retrospective cohort 		Kuopio University Hospital (KUH) Birth Register, Finland. All pregnant women who either self-reported the use or were administered quetiapine at the Kuopio University Hospital (KUH). unexposed (general population or NOS)
All pregnant women without antipsychotic exposure. 		during pregnancy (anytime or not specified) 153 / 35837 OR based on 152 and 35133 exposed and unexposed pregnancy, respectively (values excluding multifetal gestations and antiemetics users). Quetiapine with other antipsychotic agent: 3.7%.
The women self-reported their use of medications at any point during pregnancy via an online questionnaire and midwifes checked the data collected and further reported medications administrated at the Kuopio University Hospital (KUH) during pregnancy and childbirth.
Kernizan
2019 		USA
2014 - 2017
retrospective cohort 		Retrospective cohort of patients referred to Maternal Fetal Care Center, St Louis, Missouri. Pregnant women exposed to Lurasidone and 'other atypical antipsychotics' during pregnancy. unexposed, sick
Pregnant women not exposed to mood stabilizer during pregnancy. 		during pregnancy (anytime or not specified) 45 / 140 For preterm and malfo: Overlapping Kernizan 2019 and 2024: use of Kernizan 2024 because full text publication (Abstract in 2019) => outcomes not reported here.
Not reported.
Kernizan (Controls exposed to LTG)
2024 		USA
2014 - 2017
retrospective cohort 		The Maternal and Fetal Care Center at SSM Health St. Mary's Hospital Center, Missouri, USA. Pregnant women with a diagnosis of bipolar disorder who were prescribed atypical antipsychotic only (lurasidone, aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone) at some point of their pregnancy. exposed to other treatment, sick
Pregnant women with a diagnosis of bipolar disorder who were prescribed lamotrigine only at some point of their pregnancy. 		during pregnancy (anytime or not specified) 46 / 13 Addition of Lurasidone and 'other atypical antipsychotics' (authors provided data of women exposed to a single mood stabilizer and no adjustment).
Analyzed clinical data extracted from the electronic medical records. Maternal information collected included bipolar treatment regimens at the first visit, throughout pregnancy, and at delivery and illicit drug use by the mother during pregnancy.
Kernizan (Controls unexposed, sick)
2024 		USA
2014 - 2017
retrospective cohort 		The Maternal and Fetal Care Center at SSM Health St. Mary's Hospital Center, Missouri, USA. Pregnant women with a diagnosis of bipolar disorder who were prescribed atypical antipsychotic only (lurasidone, aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone) at some point of their pregnancy. unexposed, sick
Pregnant women with a diagnosis of bipolar disorder who were not prescribed mood stabilizers (lithium, antiepileptics, atypical antipsychotics) at some point of their pregnancy. 		during pregnancy (anytime or not specified) 46 / 139 Addition of Lurasidone and 'other atypical antipsychotics' (authors provided data of women exposed to a single mood stabilizer and no adjustment).
Analyzed clinical data extracted from the electronic medical records. Maternal information collected included bipolar treatment regimens at the first visit, throughout pregnancy, and at delivery and illicit drug use by the mother during pregnancy.
Kulkarni - Quetiapine
2024 		Australia
2005 - 2019
prospective cohort 		National Register of Antipsychotic Medication in Pregnancy (NRAMP), Australia. Women who had a diagnosis of a schizophrenia spectrum disorder and took quetiapine during the first trimester of pregnancy (at minimum). unexposed, sick
Women with a diagnosis of schizophrenia spectrum disorder who chose not to take any antipsychotic during the first trimester of pregnancy (at a minimum). 		at least 1st trimester 53 / 24 Authors studied 2 atypical antipsychotics => To avoid redundancy of controls only one is used in the class meta-analysis, this one with the highest number of exposed pregnancies.
Pregnant women were interviewed and monitored by the research team. With consent, information was also sought from treating clinicians and medical records.
Lin (Control exposed to FGA)
2010 		Taiwan
2001 - 2003
population based cohort retrospective 		Taiwan National Health Insurance Research Database (NHIRD, representing over 98% of the island's population) and birth certificate registry Mothers with schizophrenia who had been prescribed a monotherapy of atypical antipsychotics for more than 30 days while pregnant. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Mothers with schizophrenia who had been prescribed a monotherapy of typical antipsychotics for more than 30 days while pregnant. (This is a subgroup of exposure among the whole exposed group considered in the study). 		during pregnancy (anytime or not specified) 48 / 194
Medical claims data registered in National Health Insurance Research Dataset (NHIRD).
Lin (Control unexposed, disease free)
2010 		Taiwan
2001 - 2003
population based cohort retrospective 		Taiwan National Health Insurance Research Database (NHIRD, representing over 98% of the island's population) and birth certificate registry Mothers with schizophrenia who had been prescribed a monotherapy of atypical antipsychotics for more than 30 days while pregnant. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, disease free
Extraction from the remaining mothers in the database, excluding mothers who had once been diagnosed with any type of mental disorder (ICD-9-CM codes 290–319) or chronic diseases (such as lupus erythematosis, rheumatoid arthritis, gout, sarcoidosis, or ankylosing spondylitis) between 1996 and 2003. 		during pregnancy (anytime or not specified) 48 / 3480
Medical claims data registered in National Health Insurance Research Dataset (NHIRD).
Lin (Control unexposed, sick)
2010 		Taiwan
2001 - 2003
population based cohort retrospective 		Taiwan National Health Insurance Research Database (NHIRD, representing over 98% of the island's population) and birth certificate registry Mothers with schizophrenia who had been prescribed a monotherapy of atypical antipsychotics for more than 30 days while pregnant. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Women with schizophrenia without antipsychotics during pregnancy. 		during pregnancy (anytime or not specified) 48 / 454 To assess impact of illness, women without schizophrenia were also compared to women with schizophrenia without antispychotics during pregnancy.
Medical claims data registered in National Health Insurance Research Dataset (NHIRD).
McKenna
2005 		Canada, Israel and England
Not specified
prospective cohort 		Motherisk Program, Israeli Teratogen Information Service and Drug safety research unit database. Women who has taken an atypical antipsychotic within 3 months of pregnancy or during pregnancy. unexposed, disease free
Subsequent woman who contacted the service regarding exposure to a non-teratogenic agent. Women who reported a psychiatric diagnosis or psychotropic medication use were excluded from the comparison group. 		1st trimester, during pregnancy (anytime or not specified) 151 / 151 All of the women were exposed in the first trimester. They included women exposed to olanzapine (N = 60), risperidone (N = 49), quetiapine (N = 36), and clozapine (N = 6).
Exposure declared by women during exposure and data were achieved by sending each general practitioner a detailed questionnaire with questions regarding drug history.
Newham (Control exposed to FGA)
2008 		United Kingdom
1995 - 2006
prospective cohort 		National Teratology Information Service (NTIS), UK. Pregnant women exposed to atypical antipsychotic drugs. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Pregnant women exposed to typical antipsychotic drugs. (This is a subgroup of exposure among the whole exposed group considered in the study). 		during pregnancy (anytime or not specified) 25 / 45 45 (53% males) were exposed to typical antipsychotics (10 monotherapy antipsychotic) and 25 (24% males) to atypical antipsychotics (10 monotherapy antipsychotic)
When an enquiry is made to the NTIS (by the healthcare professionals ), the drug(s) the mother has been exposed to are recorded at the time of enquiry.
Newham (Control unexposed, disease free)
2008 		United Kingdom
1995 - 2006
prospective cohort 		National Teratology Information Service (NTIS), UK. Pregnant women exposed to atypical antipsychotic drugs. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, disease free
Pregnant women exposed to monotherapy of drugs considered to be non-teratogenic and with no associated foetal or adult weight side-effects (list compiled by the NTIS: predominantly antihistamines, antibiotics, laxatives, b2-agonist inhalants, astringents, proton pump inhibitors and antimalarials). 		during pregnancy (anytime or not specified) 25 / 38 45 (53% males) were exposed to typical antipsychotics (10 monotherapy antipsychotic) and 25 (24% males) to atypical antipsychotics (10 monotherapy antipsychotic).
When an enquiry is made to the NTIS (by the healthcare professionals), the drug(s) the mother has been exposed to are recorded at the time of enquiry.
Newport
2007 		USA
Not specified
prospective cohort 		The Emory Women’s Mental Health Program. Pregnant women receiving receiving a stable daily dose of an antipsychotic for >5 elimination half-lives at delivery. Addition of exposure to Olanzapine, Quetiapine and Risperidone. exposed to other treatment, sick
Pregnant women receiving Haloperidol. 		late pregnancy 41 / 13 Each substance is a subanalyse. For the meta-analysis, we considered Atypic antipsychotics as the exposed group and Haloperidol as the control group. In the original publication, the authors provided outcomes for each substance.
Maternal interview at monthly intervals during pregnancy (at which time maternal use of prescription and nonprescription medications was documented). Laboratory confirmation of maternal compliance with the antipsychotic medication (i.e., detectable maternal plasma concentrations).
Ozturk
2016 		Turkey
2007 - 2012
retrospective cohort 		The prenatal consultation service, Turkey. Pregnancies exposed to atypical antipsychotropic (addition of Quetiapine, Risperidone and Olanzapine). (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
Pregnancies not exposed to known teratogens, in the same year applying the same procedure for data collection and follow-up. 		during pregnancy (anytime or not specified) 15 / 275 Authors investigated Psychotropic drugs as a whole but also provided data for individual substances. Drug exposures took place in 81% during the first trimester, and 11% in all three trimesters. Distinction between miscarriage and stillbirth.
At the first contact, a detailed patient history form was used to record the following information: maternal demographic data and obstetric history, consanguineous marriage, smoking and alcohol consumption, X-ray and all drug exposures (dose, duration and timing in pregnancy).
Panchaud
2017 		USA
2008 - 2016
prospective cohort 		The National Pregnancy Registry for Atypical Antipsychotics (NPRAA) The exposed group consists of women who have used one or more second-generation antipsychotics during pregnancy. exposed to other treatment, sick
The comparison group consists mostly of women with a history of psychiatric illness being treated with a variety of psychotropic medications other than second-generation antipsychotics. 		1st trimester, during pregnancy (anytime or not specified) 303 / 149 Study with the same protocol that Cohen 2016 and 2018 but related to an other outcome. '303 with first-trimester exposure to an SGA and a comparison group of 149 who remained unexposed to an SGA throughout pregnancy '
Participants are prospectively interviewed across pregnancy and the early postpartum period by telephone, at enrollment, at 7 months’ gestation, and 12 weeks after delivery.
Park
2018 		USA
2000 - 2010
retrospective cohort (claims database) 		The Medicaid Analytic eXtract Pregnant women who had two or more prescriptions dispensed during the first 140 days of their pregnancy for the same antipsychotic medication (aripiprazole, olanzapine, quetiapine, risperidone, or ziprasidone) that they received before pregnancy. Exclusion if more than 1 studied antipsychotic. unexposed, sick
Pregnant women who had no prescriptions dispensed for an antipsychotic medication during the first 140 days of pregnancy were classified as “discontinuers.” 		at least 1st trimester 2872 / 7507 Primary analyses performed individually for each substance (not for atypic antipsychotic as a whole), but authors provide raw data and analysis for each substance. RR reported here is the pooled aOR (by meta-analysis) of each substances.
The Medicaid Analytic eXtract, nationwide claims database that contains information on pharmacy dispensing records.
Paulus
2005 		Germany
The last 15 years
prospective cohort 		Teratology Information Service, Ravensburg, Germany (TIS) Pregnant women exposed to atypical antipsychotics in the first trimester for which the TIS was contacted. unexposed, disease free
Pregnant women which was not or not severely exposed for which the TIS was contacted, in the same interval. 		1st trimester 95 / 578 This study (clozapine: n=36, risperidone: n=18, olanzapine: n=35, quetiapine: n=6) did not incorporate data published by Paulus 2013 (aripiprazole: n=68).
Not specified
Paulus - Aripiprazole only
2013 		Germany
2005 - 2012
prospective cohort 		Teratology Information Service, Ravensburg, Germany (TIS). Pregnant women exposed to Aripiprazole in the first trimester for which the TIS was contacted. unexposed (general population or NOS)
Pregnant women not exposed to aripiprazole or exposed to non-teratogenic agents for which the TIS was contacted, in the same interval. 		1st trimester 68 / 194 Study only related to Aripiprazole. This study (aripiprazole: n=68) did not incorporate data published by Paulus 2005 (clozapine: n=36, risperidone: n=18, olanzapine: n=35, quetiapine: n=6).
Teratology Information Service (TIS) was contacted by physicians and patients after exposure to aripiprazole in the first trimester.
Peng
2013 		China
2007 - 2010
prospective cohort 		Department of obstetrics/ gynecology of the Second Xiangya Hospital, Central South University, China. Women with a diagnosis of schizophrenia who were taking a targeted antipsychotic agent including clozapine, olanzapine, risperidone, sulpiride or quetiapine throughout the pregnancy. unexposed, disease free
Women who not have any mental disorder and were not treated with any antipsychotics in the same department. 		throughout pregnancy 76 / 76 Continuous variables: there were no significant differences between the two groups in the Apgar score at 1 and 5 min, as well as the mean weight, height, and brain circumference.
A detailed questionnaire completed by all enrolled pregnant women prior to delivery. Once the questionnaire was completed, permission was requested to receive a report from the physician and obstetrician.
Petersen (Control discontinued treatment before pregnancy)
2016 		United Kingdom
1995 - 2012
retrospective cohort (claims database) 		Two electronic health records data sources: The Health Improvement Network (THIN) and the Clinical Practice Research Datalink (CPRD) Women with records of atypical antipsychotic treatments two years before start of pregnancy and with records issued between 31 and 105 days (inclusive) after the start of pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Women with records of atypical antipsychotic treatment in the two years before start of pregnancy, but no prescriptions issued after four weeks prior to pregnancy start. 		1st trimester, 3rd trimester 280 / 302 Atypical antipsychotics are a subgroup of the entire analysis.
Prescriptions are issued electronically and directly recorded on the general practice computer systems.
Petersen (Control exposed to FGA)
2016 		United Kingdom
1995 - 2002
retrospective cohort (claims database) 		Two electronic health records data sources: The Health Improvement Network (THIN) and the Clinical Practice Research Datalink (CPRD) Women with records of atypical antipsychotic treatments two years before start of pregnancy and with records issued between 31 and 105 days (inclusive) after the start of pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Women with records of typical antipsychotic treatments two years before start of pregnancy and with records issued between 31 and 105 days (inclusive) after the start of pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). 		1st trimester, 3rd trimester 280 / 157
Prescriptions are issued electronically and directly recorded on the general practice computer systems.
Petersen (Control unexposed, disease free)
2016 		United Kingdom
1995 - 2002
retrospective cohort (claims database) 		Two electronic health records data sources: The Health Improvement Network (THIN) and the Clinical Practice Research Datalink (CPRD) Women with records of atypical antipsychotic treatments two years before start of pregnancy and with records issued between 31 and 105 days (inclusive) after the start of pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, disease free
Pregnant women with no records of atypical antipsychotic treatment in the two years before the start of pregnancy and through to the delivery date. 		1st trimester, 3rd trimester 280 / 318434 Atypical antipsychotics are a subgroup of the entire analysis.
Prescriptions are issued electronically and directly recorded on the general practice computer systems.
Raguideau
2017 		France
2011 - 2015
retrospective cohort (claims database) 		French national health insurance information system (SNIIRAM) Pregnancies exposed to atypical antipsychotics during the two first months of pregnancy (reimbursement occurring the month before the pregnancy or during the two first months of pregnancy). (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
Pregnancies not exposed to bipolar disorder drugs during the two first months of pregnancy (reimbursement occurring the month before the pregnancy or during the two first months of pregnancy). 		early pregnancy 2286 / 1888130 The study not considered all major malformations but 26 malfo. Authors did not analyse atypic antipsychotic as a subgroup, but provide raw data for each substance. Results included are the sum of outcomes for each substance (in monotherapy).
The French national health insurance database (DCIR) containing all individualized and anonymous health care claims reimbursed by French National Health Insurance.
Reis (Control exposed to FGA)
2008 		Sweden
1995 - 2005
population based cohort retrospective 		Swedish Medical Birth Register Women who had reported the use of 'Any second-generation antipsychotic' in early pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Women who had reported the use of 'Any first-generation antipsychotic' in early pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). 		early pregnancy 147 / 435 Atypical and typical antipsychotics are subgroups of the entire study. Atypical versus Typical. OR and adjustement performed for other groups. Relative severe malformations, with exclusion of known chromosome anomalies.
Maternal drug use in early pregnancy is recorded from interviews performed by the midwife at the first antenatal care visit, usually before the end of the first trimester.
Reis (Control unexposed, NOS)
2008 		Sweden
1995 - 2005
population based cohort retrospective 		Swedish Medical Birth Register, Register of Congenital Malformations and the Hospital Discharge Register. Women who had reported the use of 'Any second-generation antipsychotic' in early pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
All other women in the register. 		early pregnancy 147 / 958729 Atypical antipsychotics are a subgroup of the entire study. OR and adjustment performed for other groups. Relative severe malformations, with exclusion of known chromosome anomalies.
Maternal drug use in early pregnancy is recorded from interviews performed by the midwife at the first antenatal care visit, usually before the end of the first trimester.
Sadowski
2013 		Canada
2005 - 2009
prospective cohort 		Motherisk Program Women who confirmed the use of Second-generation antipsychotics (SGAs) for a minimum of 4 weeks of pregnancy. unexposed, disease free
Women who reported exposure to non-teratogenic agents (eg, acetaminophen, antihistamines, etc). Control women who reported a history of psychiatric disorders or who were exposed in their current pregnancy to a known teratogen were excluded. 		during pregnancy (anytime or not specified) 133 / 133 Gestational diabetes and hypertension not reported because not sure that exposure occurred before outcome.
Telephone interviews of mothers.
Schaffer (Controls unexposed, NOS)
2019 		Australia
2005 - 2012
retrospective cohort (claims database) 		A population-based cohort study of births using linked administrative data in New South Wales, Australia. All pregnant women where the estimated duration of use of any atypical antipsychotic overlapped with the study period. Sum of all groups exposed during pregnancy (3: Long-term use, low daily dose; 4: Use in pregnancy only; 5: Long-term use, moderate daily dose; 6: Long-term, high daily dose). unexposed (general population or NOS)
All other pregnant women were considered ‘unexposed’ (to any antipsychotics). 		during pregnancy (anytime or not specified) 1322 / 135252 Antipsychotic exposures consisted of > 90% atypical antipsychotics (1214/1322) => considered as atypical antipsychotic exposures.
The Pharmaceutical Benefits Scheme (PBS) data.
Schaffer (Controls unexposed, sick)
2019 		Australia
2005 - 2012
retrospective cohort (claims database) 		A population-based cohort study of births using linked administrative data in New South Wales, Australia. All pregnant women where the estimated duration of use of any atypical antipsychotic overlapped with the study period. Sum of all groups exposed during pregnancy (3: Long-term use, low daily dose; 4: Use in pregnancy only; 5: Long-term use, moderate daily dose; 6: Long-term, high daily dose). unexposed, sick
Pregnant women who had short-term use of antipsychotics with use commencing and ending well before pregnancy or with with use immediately preceding pregnancy. Sum of the 2 groups of exposure before pregnancy (1: Short-term use well before pregnancy and 2: Short-term use preceding pregnancy). 		during pregnancy (anytime or not specified) 1322 / 1419 Antipsychotic exposures consisted of > 90% atypical antipsychotics (1214/1322) => considered as atypical antipsychotic exposures. Exclusion of lithium (N05AN01) and prochlorperazine.
The Pharmaceutical Benefits Scheme (PBS) data.
Sorensen - Olanzapine
2015 		Denmark
1997 - 2008
population based cohort retrospective 		Nationwide Danish health registries (the Danish National Hospital Register, the Danish National Prescription Register and the Danish Medical Birth Register). Any prescription of Olanzapine redeemed by the pregnant women during the exposure window, and recorded in the Danish National Prescription Register. (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 redeem any prescription of antipsychotic medications during the exposure window. 		early pregnancy 223 / 841183 Authors assessed several antipsychotics (but not atypic antipsychotic as a subgroup), thus to avoid redundancy of controls, only one was reported here => this one with the higher number of exposures.
Any prescription recorded in the Danish National Prescription Register.
Straub
2022 		USA
2000 - 2015
retrospective cohort (claims database) 		The nationwide Medicaid Analytic eXtract (MAX) and the IBM Health MarketScan Research Database (MarketScan). Children whose mother filled a prescription for any atypical antipsychotic medication during the second half of pregnancy (>18 gestational weeks). (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
Children born to mothers with no antipsychotic dispensing from 90 days before pregnancy until birth. 		2nd and/or 3rd trimester, early pregnancy 9390 / 3309095 Estimates from both cohorts were combined through meta-analysis by authors. Children with a known chromosomal or genetic abnormality were excluded.
The nationwide Medicaid Analytic eXtract (MAX) and the IBM Health MarketScan Research Database (MarketScan). Both sources included outpatient medication dispensings.
Sutter-Dallay
2015 		France
2001 - 2010
retrospective cohort 		Database collected by French Network of Mother-Baby Units Women used at least 1 Second generation antipsychotic (SGAs: amisulpride, risperidone, olanzapine, aripiprazole, and clozapine) during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Mothers without psychotropic drug use during pregnancy. 		during pregnancy (anytime or not specified) 55 / 640 Subgroup Atypical antipsychotics NOT provided for all outcomes. The following categories were investigated: antipsychotics (FGA, SGA), antidepressants (SSRI and SNRI, others), mood stabilizers (lithium, anticonvulsivants) and anxiolytics/hypnotics.
Information on psychotropic drug use during pregnancy was collected from maternal recall and medical records.
Swetlik
2024

- 		-
during pregnancy (anytime or not specified) -9 / -9 Only the result is extracted for potential retrieval at a later stage, as the outcome is not currently considered in metaPreg (results of Ages and stages questionnaire not reported because to few questions in this questionnaire).
Vial (Control exposed to FGA)
2009 		France
1997 - 2007
prospective cohort 		Network of French Pharmacovigilance centres (Teratology Information Service) Pregnant women exposed to risperidone and/or olanzapine during the during embryogenesis for a psychiatric indication. exposed to other treatment, sick
Pregnant women exposed to conventional antipsychotics (chlorpromazine, cyamemazine and haloperidol) the during embryogenesis for a psychiatric indication. 		1st trimester, during pregnancy (anytime or not specified) 89 / 143 Data were extracted from the 2 abstracts (Vial 2009 and Garayt 2009). Exposure during embryogenesis (i.e.4 to 10weeks after the last menstrual period). Exposure: olanzapine (n = 62), risperidone (n = 26) or to both drugs successively (n = 1).
Not specified.
Vial (Control unexposed, NOS)
2009 		France
1997 - 2007
prospective cohort 		Network of French Pharmacovigilance centres. Pregnant women exposed to risperidone and/or olanzapine the during embryogenesis for a psychiatric indication unexposed (general population or NOS)
Pregnant women not exposed to antipsychotics and teratogenic agents. 		1st trimester, during pregnancy (anytime or not specified) 89 / 178 Data were extracted from the 2 abstracts (Vial 2009 and Garayt 2009). Exposure during embryogenesis (i.e.4 to 10weeks after the last menstrual period). Exposure: olanzapine (n = 62), risperidone (n = 26) or to both drugs successively (n = 1).
Not specified
Vigod
2015 		Canada
2003 - 2012
retrospective cohort (claims database) 		Multiple health administrative databases in the entire province of Ontario At least two consecutive prescriptions for any antipsychotics (about 90% of atypical antipsychotics) of filled between the conception date and the delivery date. At least one prescriptions filled prior to 27 GW. unexposed, sick
Matched women not exposed to any antipsychotic drug during pregnancy using a HDPS matching algorithm to minimise treatment selection bias (leading to similar psychiatric diagnoses before index pregnancy => considered as 'unexposed, sick'). 		1st trimester, 3rd trimester, during pregnancy (anytime or not specified) 1021 / 1021 For atypical antipsy: adjusted RR only provided on a graph (not used for the meta-analysis). We used the RRa provided for antipsychotics because about 90% were exclusively prescribed an atypical antipsychotics.
Ontario Drug Benefit (ODB) database.
Viguera b
2023 		USA
2008 - 2020
prospective cohort 		The National Pregnancy Registry for Psychiatric Medications (NPRPM). Infants exposed to a Second-generation antipsychotic (SGA) during pregnancy, without the use of any Selective serotonin reuptake inhibitors (SSRIs) or Serotonin-norepinephrine reuptake inhibitors (SNRIs) but with exposure to other psychotropics. exposed to other treatment, sick
Infants exposed to a Selective serotonin reuptake inhibitors (SSRIs) and/or Serotonin-norepinephrine reuptake inhibitors (SNRIs), without any exposure to Second-generation antipsychotics (SGAs) but with exposure to other psychotropics. 		during pregnancy (anytime or not specified) 193 / 191 The majority of women in each group used these medications across the entire course of their pregnancy, including the third trimester. Other psychotropics included lithium, anticonvulsants, stimulants, benzodiazepines, and hypnotics.
Participants are prospectively interviewed twice during pregnancy (at enrollment and at 7 months’ gestation) and once postpartum (at 3 months following delivery). Information collected includes all medication use (including prescriptions, over- the-counter medications, and supplements) and dosages.
Wang a (Controls exposed to FGA)
2021 		Hong Kong
2001 - 2019
retrospective cohort (claims database) 		The Hong Kong Clinical Data Analysis and Reporting System which contains the electronic health records of all residents (more than 7.4 million) from public hospitals and ambulatory clinics. Infants whose mother received any second-generation antipsychotics (only SGAs) during the pregnancy period. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Infants whose mother received any first-generation antipsychotics (only FGAs) during the pregnancy period. (This is a subgroup of exposure among the whole exposed group considered in the study). 		during pregnancy (anytime or not specified) 199 / 405 The pregnancy episodes with maternal exposure to antidepressants or lithium during pregnancy were removed.
Prescriptions of any antipsychotic were extracted from the prescribing and dispensing records.
Wang a (Controls unexposed, NOS)
2021 		Hong Kong
2001 - 2019
retrospective cohort (claims database) 		The Hong Kong Clinical Data Analysis and Reporting System which contains the electronic health records of all residents (more than 7.4 million) from public hospitals and ambulatory clinics. Infants whose mother received any second-generation antipsychotics (SGAs) during the pregnancy period. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
Infants whose mother did not use antipsychotics during pregnancy. 		during pregnancy (anytime or not specified) 199 / 410545 The pregnancy episodes with maternal exposure to antidepressants or lithium during pregnancy were removed.
Prescriptions of any antipsychotic were extracted from the prescribing and dispensing records.
Wang b - HK cohort
2021 		China
2001 - 2015
retrospective cohort (claims database) 		The Hong Kong Clinical Data Analysis and Reporting System (CDARS). Pregnant women who received at least 56 days coverage time of prescriptions of Second generation antipsychotics before and during pregnancy (continuers). unexposed, sick
Pregnant women who did not receive any antipsychotic during pregnancy, but did before pregnancy (discontinuers). 		at least 1st trimester 149 / 340 The most commonly used antipsychotic agents in CDARS were haloperidol (n = 443), risperidone (n = 353) and trifluoperazine (n = 317).
Prescriptions of any antipsychotic listed in Chapter 4.2.1 of the British National Formulary (BNF) were extracted from the prescribing and dispensing records.
Wang b - UK cohort
2021 		United Kingdom
1990 - 2017
retrospective cohort (claims database) 		The UK The Health Improvement Network (THIN) database. Pregnant women who received at least two prescriptions (normally 28 days for one prescription) of Second generation antipsychotics before and during pregnancy (continuers). unexposed, sick
Pregnant women who did not receive any antipsychotic during pregnancy, but did before pregnancy (discontinuers). 		at least 1st trimester 349 / 1577 The most commonly used antipsychotic agents in THIN were quetiapine (n = 571), chlorpromazine (n = 450) and olanzapine (n = 450).
Prescriptions of any antipsychotic listed in Chapter 4.2.1 of the British National Formulary (BNF) were extracted from the prescribing and dispensing records.
Wurtz
2017 		Denmark
1997 - 2012
population based cohort retrospective 		Danish National Patient Register Any prescription of the second-generation Antipsychotics registered during the exposure window (defined as 30 days before the estimated first day of the last menstrual period to the day before birth). (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
No prescription of antipsychotic medication registered in the Danish Register of Medicinal Product Statistics during the exposure window (defined as 30 days before the estimated first day of the last menstrual period to the day before birth). 		during pregnancy (anytime or not specified) -9 / 960527 The exposure of interest was the mother’s use of Antipsychotic (AP) during pregnancy. Second generation antipsychotic, quetiapine and olanzapine are subanalyses (the number of exposed pregnancies were not reported).
Danish Register of Medicinal Product Statistics.
Yakuwa
2019 		Japan
2005 - 2016
prospective cohort 		The Japan Drug Information Institute in Pregnancy. Pregnant women who had been exposed to second-generation antipsychotics (SGAs) in first-trimester. unexposed (general population or NOS)
Pregnant women who had not been exposed to second-generation antipsychotics (SGAs) and teratogenic drugs. 		1st trimester 404 / 4330 Exposures: aripiprazole (N=147), quetiapine (N=91), olanzapine (N=83), risperidone (N=71), perospirone (N=32), blonanserin (N=24), and paliperidone (N=2).
Information on the characteristics of pregnant women and their medications were collected using interview sheets by questionnaires completed by the women at the time they applied for counseling.
Yaris
2005 		Turkey
1999 - 2004
prospective cohort 		Toxicology Information and Follow-up Service, Turkey. Women who were exposed to atypical antipsychotropic drugs 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.
Yeh
2021 		Taiwan
2002 - 2011
retrospective cohort (claims database) 		The Taiwan National Health Insurance Research Database (NHIRD). Pregnant women with bipolar disorder receiving Atypical Antipsychotics (aripiprazole, risperidone, paliperidone, olanzapine, amisulpride, ziprasidone, clozapine, and quetiapine) during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Pregnant women with bipolar disorder not receiving any psychotropics before and during the pregnancy. 		1st trimester, 2nd trimester, 3rd trimester, during pregnancy (anytime or not specified) 45 / 5243
The Taiwan National Health Insurance Research Database (THIRD) provides prescriptions information about insured individuals.

Case-control studies

Study Country
Study period
Study design		 Data source Case Control Exposition Exposition period Sample size
(exposed/unexposed) Or (case / control)		 Remarks Risk of bias
Anderson
2020 		USA
1997 - 2011
case control 		The National Birth Defects Prevention Study (NBDPS), a US population-based, multisite case-control study. Infants with at least one of 30 major structural birth defects with unknown etiologies studied (among live births (all sites), stillbirths (all sites except NY before 2000 and NJ), and terminations (all sites except GA before 1999, MA before 2011, NY before 2000, and NJ)). Liveborn infants without major birth defects who were randomly sampled from the same geographic location and study years as birth defect cases using data from hospital birth logs or vital records. Mothers were invited to participate in an English or Spanish computer-assisted telephone interview 6 weeks to 24 months after delivery to report information about over-the-counter and prescription medication use (start/stop dates, duration, and frequency) before and during pregnancy. 1st trimester, during pregnancy (anytime or not specified) 22387 / 11470 Infants with recognized single-gene disorders or chromosomal abnormalities were excluded. Exposure to quetiapine, aripiprazole, olanzapine and risperidone.
Clinical data of cases were abstracted from medical records to confirm that birth defect(s) met eligibility criteria, and clinical geneticists and other expert clinicians then classified cases into homogeneous defect categories. Data of controls abstracted from hospital birth logs or vital records.
Ishikawa
2024 		Japan
2005 - 2022
nested case control 		The administrative claims database from JMDC Inc. (Tokyo, Japan), which contains all inpatient (including those during hospitalization), outpatient, and pharmacy claims received from the insurers. Women whose pregnancies ended in a miscarriage that occurred between the beginning of the fourth and 22nd weeks of gestation. Women randomly selected from the entire cohort of pregnancies by risk-set sampling with replacement and were individually matched to the cases (3:1). Exposure were identified according to the WHO-ATC or alternate entries in the administrative claims database from JMDC Inc. (Tokyo, Japan), which contains pharmacy claims received from the insurers. during pregnancy (anytime or not specified) 44118 / 132317
Birth outcomes was unavailable in the Japanese claims database. Pregnancies and birth outcomes were estimated using two methods: the first one was for those whose pregnancy-and birth outcome-related entries were available, and their pregnancies and birth outcomes were estimated using these entries.

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

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