Aripiprazole

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
2015 		France
2004 - 2011
prospective cohort 		Two French datatbases 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 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)
Patients included in the unexposed group were 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.
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 aripiprazole 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) 523 / 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.
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 aripiprazole 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 220 / 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 aripiprazole 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 220 / 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.
Freeman
2021 		USA
2008 - 2020
prospective cohort 		The Massachusetts National Pregnancy Registry for Atypical Antipsychotics (NPRAA) Live birth of a women who had evaluable data and first trimester exposure to a aripiprazole. unexposed, sick
Live birth of a women unexposed to aripiprazole or other atypical antipsychotics during pregnancy. 		1st trimester 163 / 704 Study of the NPRAA: Cohen 2016 (related to all atypical antipsychotics ; 2008 - 2014 ; n=214), Cohen 2018 (related to Quetiapine ; 2008 - 2017; n=155); Freeman 2021 (related to Aripiprazole; 2008 - 2020; n=163).
Participants are prospectively interviewed across pregnancy and the early postpartum period by telephone, at enrollment, at 7 months’ gestation, and 12 weeks after delivery.
Habermann (Control exposed to FGA)
2013 		Germany
1997 - 2009
prospective cohort 		Teratology Information Service (TIS Berlin) Women exposed to Aripiprazole during pregnancy; comedication with First Generation Antipsycotics (FGA) was allowed. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Women exposed to First Generation Antipsycotics (FGAs) excluding comedication with Second Generation Antipsycotics (SGA) (cohort I). 		1st trimester, late pregnancy 60 / 284 Primary analyse on all Atypical Antipsychotics but Raw data are provided for some substances. Cases with potentially embryo- or fetotoxic drugs were not excluded for both the study cohort and the comparison cohort I but were assessed afterward.
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) Women exposed to Aripiprazole during pregnancy; comedication with First Generation Antipsycotics (FGA) was allowed. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, disease free
Women exposed to teratogenic, fetotoxic, or insufficiently studied agents were excluded as described elsewhere (cohort II). 		1st trimester, late pregnancy 60 / 1122 Primary analyse on all Atypical Antipsychotics but Raw data are provided for some substances. Cases with potentially embryo- or fetotoxic drugs were not excluded for both the study cohort and the comparison cohort I but were assessed afterward.
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.
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 Aripiprazole 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 4523 / 6455324 Overlapping: Data of Huybrechts 2016 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 Aripiprazole 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 3861 / 318731 Overlapping: Data of Huybrechts 2016 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.
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 Aripiprazole (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 419 / 1505 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.
Paulus
2013 		Germany
2005 - 2012
prospective cohort 		Teratology Information Service (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 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.
Raguideau
2017 		France
2011 - 2015
retrospective cohort (claims database) 		French national health insurance information system (SNIIRAM) Pregnancies exposed to Aripiprazole 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 790 / 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.
Sadowski
2013 		Canada
2005 - 2009
prospective cohort 		Motherisk Program Women who confirmed the use of Aripiprazole 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) 2 / 133
Telephone interviews of mothers.
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 Aripiprazole 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 45 / 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 Aripiprazole 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 1738 / 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.
Wang - 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 Aripiprazole 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 / 1577 Number of Aripiprazole 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.

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 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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