Risperidone Paliperidone

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
Bruno
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 risperidone 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) 294 / 197296 Denmark (1 January 2000–31 December 2018), Finland (1 January 2000–31 December 2016), Iceland (1 January 2004–31 December 2017), Norway (1 January 2005–1 December 2020), and Sweden (1 July 2006–31 December 2019).
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 risperidone only (without other 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 69 / 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 risperidone only (without other 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 69 / 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 filling at least one prescription of risperidone only (without other 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 49 / 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.
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 risperidone during 1 month before pregnancy until the end of first trimester. (This is a subgroup of exposure among the whole exposed group considered in the study). 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 242 / 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 risperidone during 1 month before pregnancy until the end of 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 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 242 / 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.
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 Risperidone 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 2798 / 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 Risperidone 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 2270 / 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.
Newport
2007 		USA
Not specified
prospective cohort 		Emory Women’s Mental Health Program, USA. Pregnant women receiving receiving a stable daily dose of Risperidone for >5 elimination half-lives at delivery. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Pregnant women receiving Haloperidol. 		late pregnancy 6 / 13 Each substance is a subanalyse. The meta-analysis authors considered Atypic antipsychotics as the exposed group and Haloperidol as the control group. In the original publication, the authors provided each outcome by Substance.
Maternal interview at monthly intervals during pregnancy (at which time maternal use of prescription and nonprescription medications was documented). Pregnant women treated with antipsychotics during pregnancy proximate to delivery
Ozturk
2016 		Turkey
2007 - 2012
retrospective cohort 		The prenatal consultation service. Pregnancies exposed to Risperidone. (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) 2 / 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).
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 Risperidone (also received before pregnancy). Exclusion if more than 1 studied antipsychotic. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Pregnant women who had no prescriptions dispensed for an anti- psychotic medication during the first 140 days of pregnancy were classified as “discontinuers.” 		at least 1st trimester 343 / 1449 Primary analyses performed individually for each substance (aripiprazole, olanzapine, quetiapine, risperidone, or ziprasidone).
The Medicaid Analytic eXtract, nationwide claims database that contains information on pharmacy dispensing records.
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 risperidone 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 16 / 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.
Raguideau
2017 		France
2011 - 2015
retrospective cohort (claims database) 		French national health insurance information system (SNIIRAM) Pregnancies exposed to Risperidone 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 507 / 1888130 The study not considered all major malformations but 26 malfo.
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 		Sweded
1995 - 2005
population based cohort retrospective 		Swedish Medical Birth Register Women who had reported the use of Risperidone 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 51 / 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 (Unexposed control, NOS)
2008 		Sweden
1995 - 2005
population based cohort retrospective 		Swedish Medical Birth Register Women who had reported the use of Risperidone 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 51 / 958729 Atypical antipsychotics are a subgroup of the entire study. 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
Sadowski
2013 		Canada
2005 - 2009
prospective cohort 		Motherisk Program Women who confirmed the use of Risperidone or Paliperidone for a minimum of 4 weeks of pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). 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) 15 / 133 Women who were exposed to teratogenic medications unrelated to their psychiatric disorder treatment, such as acutane, or who abused substances (eg, alcohol, marijuana, cocaine, heroin, etc) were excluded from the study cohort.
Telephone interviews of mothers.
Shechtman (Control exposed to Haloperidol)
2009 		Israel
1999 - 2007
prospective cohort 		Isreali Teratology Information Service (TIS) in collaboration with the Clinical Pharmacology-Unit at Assa Harofeh Medical Center Pregnant women who call who the TISes in regard to risperidone exposure during pregnancy. exposed to other treatment, sick
Pregnant women, disease-matched control (DMC) who were counseled in the same time frame about exposure to another antipsychotic drug, haloperidol, with more data on its safe use in pregnancy. 		1st trimester, 3rd trimester 106 / 86
Pregnancy follow-up was performed by phone.
Shechtman (Unexposed control)
2009 		Israel
1999 - 2007
prospective cohort 		Isreali Teratology Information Service (TIS) in collaboration with the Clinical Pharmacology-Unit at Assa Harofeh Medical Center Pregnant women who call who the Teratology Information Services in regard to risperidone exposure during pregnancy. unexposed (general population or NOS)
Pregnant women who were randomly selected among women counseled in the same time frame for non-teratogenic (NTC) exposures. 		1st trimester, during pregnancy (anytime or not specified) 106 / 448
Pregnancy follow-up was performed by phone.
Sorensen
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 Risperidone 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)
Unexposed women were defined as pregnant women who did not redeem any prescription of antipsychotic medications during the exposure window. 		early pregnancy 116 / 841183 Primary analyses performed on antipsychotics versus unexposed. Authors also analysed each antipsychotic (typical and atypical) substance separately.
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 Risperidone 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 1404 / 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.
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 Risperidone filled between the conception date and the delivery date. At least one prescriptions filled prior to 27 GW. (This is a subgroup of exposure among the whole exposed group considered in the study). 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'). 		during pregnancy (anytime or not specified) 112 / 1021 Atypical antipsychotic drugs (and each substance) are a subgroup of the primary analysis on the antipsychotic drug. For those results, RRadj only provided on a graphic but raw data are provided by authors and used for this meta analysis.
Ontario Drug Benefit (ODB) database
Wang - 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 Risperidone before and during pregnancy (continuers). unexposed, sick
Pregnant women who did not receive any antipsychotic during pregnancy, but did before pregnancy (discontinuers). 		during pregnancy (anytime or not specified) -9 / 340 Number of Risperidone continuers not provided by authors.
Prescriptions of any antipsychotic listed in Chapter 4.2.1 of the British National Formulary (BNF) were extracted from the prescribing and dispensing records.
Yaris
2005 		Turkey
1999 - 2004
prospective cohort 		Toxicology Information and Follow-up Service, Turkey. Women who were exposed to Risperidone 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) 2 / 248 Multiple drug exposure. Raw data for Intrauterine exitus not reported because the nb of cases in the unexposed group not clearly stated.
Data surveyed by the interviews.

Case-control studies

Study Country
Study period
Study design		 Data source Case Control Exposition Exposition period Sample size
(exposed/unexposed) Or (case / control)		 Remarks Risk of bias
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 individu- ally 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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