Amitriptyline

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
Chan (Controls exposed to SSRIs)
2024 		China
2003 - 2018
retrospective cohort (claims database) 		The Clinical Data Analysis and Reporting System (CDARS), an electronic health-record database developed by the Hospital-Authority which is a statutory body delivering government-subsidized, universal health coverage to all Hong Kong residents. Infants of women with prescription of Amitriptyline only filled during the first trimester and prescriptions filled before pregnancy but with duration overlapping the first trimester. exposed to other treatment, sick
Infants of women with prescription of Selective-serotonin-reuptake-inhibitors (SSRI) only filled during the first trimester and prescriptions filled before pregnancy but with duration overlapping the first trimester. 		1st trimester 148 / 956
Study data were obtained from the Clinical Data Analysis and Reporting System, a database that contains prescribing/dispensing records.
Chan (Controls unexposed, general pop)
2024 		China
2003 - 2018
retrospective cohort (claims database) 		The Clinical Data Analysis and Reporting System (CDARS), an electronic health-record database developed by the Hospital-Authority which is a statutory body delivering government-subsidized, universal health coverage to all Hong Kong residents. Infants of women with prescription of Amitriptyline only filled during the first trimester and prescriptions filled before pregnancy but with duration overlapping the first trimester. unexposed (general population or NOS)
Infants of pregnant women who were not prescribed with any antidepressant within 90 days before the last menstrual period and during the first trimester. 		1st trimester 148 / 462377
Study data were obtained from the Clinical Data Analysis and Reporting System, a database that contains prescribing/dispensing records.
Heuvelman
2023 		United Kingdom
1995 - 2017
retrospective cohort (claims database) 		The UK Clinical Practice Research Datalink, a large, ongoing database of anonymised primary care medical records for patients registered with a general practice in the United Kingdom. Women who had initiated or continued Amitriptyline for the treatment of depressive symptoms during pregnancy. unexposed, sick
Women who did not initiate or who discontinue antidepressants during pregnancy. 		during pregnancy (anytime or not specified) 1040 / 16330 Dose–response relationships, sibling design and negative control for antidepressants use as a whole (not for the class of antidepressants).
The Clinical Practice Research Datalink (CPRD) contains an extensive code list to identify the name, formulation and dose of medications, which are mandatory fields in the prescription electronic record (according to protocol).
Kjaersgaard
2013 		Denmark
1997 - 2008
population based cohort retrospective 		Danish administrative health registries. Mother that had redeemed a prescription for Amitriptyline at any time from 30 days before conception up to 1 day before the end of pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
Mother that had not redeemed any prescription for antidepressant medication from 6 months before conception up to 1 day before the end of the pregnancy. 		during pregnancy (anytime or not specified) -9 / 983258 Molar or ectopic pregnancies (ICD-10: O00.0– O01.9) were excluded from the main analyses. Unexposed cohort: 1843 plus 981415 = 983258.
Information on all redeemed prescriptions was obtained from the Denmark Registry of Medicinal Product Statistics.
Lee (Controls exposed to SSRI)
2025 		China
2003 - 2018
retrospective cohort (claims database) 		The Clinical Data Analysis and Reporting System (CDARS) of the Hospital Authority, Hong Kong. Women filling at least one prescription of Amitriptyline only during pregnancy, that is the period between the date of the last menstrual period and the date of delivery. exposed to other treatment, sick
Women filling at least one prescription of any selective serotonin reuptake inhibitors (SSRI) only during pregnancy, that is the period between the date of the last menstrual period and the date of delivery. 		during pregnancy (anytime or not specified) 301 / 1465
The Clinical Data Analysis and Reporting System (CDARS) that captures and links all clinical data, including prescribing and dispensing records.
Lee (Controls unexposed, general pop)
2025 		China
2003 - 2018
retrospective cohort (claims database) 		The Clinical Data Analysis and Reporting System (CDARS) of the Hospital Authority, Hong Kong. Women filling at least one prescription of Amitriptyline only during pregnancy, that is the period between the date of the last menstrual period and the date of delivery. unexposed (general population or NOS)
Women who were not prescribed with any antidepressant during index pregnancy. 		during pregnancy (anytime or not specified) 301 / 463440
The Clinical Data Analysis and Reporting System (CDARS) that captures and links all clinical data, including prescribing and dispensing records.
Martin
2024 		Norway, Sweden and United Kingdom.
1996 - 2020
population based cohort retrospective 		The UK’s Clinical Practice Research Datalink (CPRD), the Norway’s Medical Birth Registry and the Sweden’s Medical Birth Register. Singleton deliveries with maternal Amitriptyline (without concurrent prescriptions for different antidepressants) use during pregnancy proxied by prescriptions in the United Kingdom and dispensations in Norway and Sweden. unexposed (general population or NOS)
Singleton deliveries without maternal antidepressants use during pregnancy proxied by prescriptions in the United Kingdom and dispensations in Norway and Sweden. 		during pregnancy (anytime or not specified) 4773 / 2408707 A group ‘multiple’ (i.e drug switching or concurrent prescriptions for different antidepressants) is available => thus individual antidepressant considered as monotherapy. Unexposed numbers: Table S4.
In the UK, prescription data were based on the prescriptions written by general practitioners (CPRD GOLD), whereas in Norway and Sweden, dispensation of prescription drugs from all ambulatory pharmacies was used (Norwegian Prescription Database, and Swedish Prescribed Drug Register).
Ozturk
2016 		Turkey
2007 - 2012
prospective cohort 		An observational cohort study based on a prenatal consultation service. Pregnant women exposed to Amitriptyline during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
Pregnant women selected from the non-teratogen exposed pregnancies in the same year. 		at least 1st trimester 4 / 275 'Drug exposures took place in 81% during the first trimester, and 11% in all three trimesters. Medical treatments were discontinued in most of recognized pregnancies.'=> considered as 'At least first trimester'.
At the first contact, initiated via gynecologists, a detailed patient history form was used to notably record all drug exposures (dose, duration and timing in pregnancy).
Palmsten a (control exposed to SSRIs)
2013 		USA
2000 - 2007
retrospective cohort (claims database) 		The US nationwide Medicaid Analytic eXtract (MAX). Pregnant women with a depression diagnosis and a dispensation of Amitriptyline in monotherapy during the exposure window. exposed to other treatment, sick
Pregnant women with a depression diagnosis and a dispensation of selective serotonin reuptake inhibitor (SSRI) in monotherapy during the exposure window. 		2nd and/or 3rd trimester 271 / 19000 Women who received only one antidepressant class during the window were classified as having either SSRI, SNRI, tricyclic, bupropion or other antidepressant (mirtazapine, nefazodone, trazodone) monotherapy.
Outpatient pharmacy-dispensing data.
Palmsten a (Controls unexposed, sick)
2013 		USA
2000 - 2007
retrospective cohort (claims database) 		The US nationwide Medicaid Analytic eXtract (MAX). Pregnant women with a depression diagnosis and a dispensation of Amitriptyline in monotherapy during the exposure window. unexposed, sick
Pregnant women with a depression diagnosis and no antidepressant exposure between the LMP and the end of the window. 		2nd and/or 3rd trimester 271 / 59219 Women who received only one antidepressant class during the window were classified as having either SSRI, SNRI, tricyclic, bupropion or other antidepressant (mirtazapine, nefazodone, trazodone) monotherapy.
Outpatient pharmacy-dispensing data.
Palmsten b
2013 		USA
2000 - 2007
retrospective cohort (claims database) 		The Medicaid Analytic eXtract (MAX) data Women with a supply of Amitriptyline monotherapy that overlapped with the delivery date. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Women who had no supply of antidepressants in the five months before delivery. 		late pregnancy 176 / 69044 Exclusion of women who were exposed to both drugs types (polytherapy) during the five months before delivery.
Data of prescription.
Yaris
2005 		Turkey
1999 - 2004
prospective cohort 		Toxicology Information and Follow-up Service Women who were exposed to Amitriptyline 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) 27 / 248 Raw data for Intrauterine exitus not reported because the nb of cases in the unexposed group not clearly stated. Raw data for premature delivery not reported because the denominator is 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
Anderson
2020 		USA
1997 - 2011
case control 		The National Birth Defects Prevention Study (NBDPS), a US population-based, multisite case-control study. The case infants were infants born alive or died at 20 SG or more and who had received a diagnosis of at least one selected birth defect. The controls were live-born infants with no major birth defects who were randomly selected from hospital or state birth-certificate records from the same geographic areas. Information on exposure to TCAs and other potential risk factors during pregnancy were collected by standardized telephone interviews with mothers of case and control infants, conducted 6 weeks to 24 months after the estimated date of delivery (EDD). 1st trimester 30630 / 11478 'Infants with recognized or strongly suspected chromosomal abnormalities or single-gene conditions were excluded from the study.'
Case infants were ascertained through population-based birth-defects surveillance systems in 10 U.S. states. Controls were selected randomly from the same geographic areas. Clinical data were abstracted from medical records and classified by clinician geneticists and other clinicians.
Dandjinou
2019 		Canada
1998 - 2015
nested case control 		The Quebec Pregnancy Cohort (QPC), a Canadian provincial database. Pregnant women with a diagnosis of gestational diabetes mellitus (GDM) identified using diagnosis codes ICD-9: 250.0–250.9, 648.0, 648.8, 790.2, 775.1 or ICD-10: E10–E14, O24, R73.0) or at least one filled prescription for an antidiabetic drug allowed during pregnancy (insulin, glyburide or metformin), both after week 20 of gestation, whichever occurred first. Pregnant women that did not have a diagnosis of gestational diabetes mellitus (GDM) at the index date. The Quebec Prescription Drug Insurance Database (drug name, start date, dosage and duration). during pregnancy (anytime or not specified) 20905 / 209050 The 10 categories of exposure were mutually exclusive.
The medical service database (RAMQ: diagnoses and medical procedures), the Hospitalisation Archive Database (MedEcho: in-hospital diagnoses and procedures) and the Quebec Statistics Database (Institut de la statistique du Québec (ISQ):patient sociodemographic information).

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

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