Table 1.
Characteristics of included studies
| Study | Study period | Country and data source | Study design | Exposure (first trimester)/sample size | Comparison group | Relevant congenital malformations | Relevant findings (paroxetine use only) |
|---|---|---|---|---|---|---|---|
| Furu et al. 23 | 1996–2010 | Nordic countries (Denmark, Finland, Iceland, Norway,and Sweden) Nationwide health registers | Cohort | SSRIs as a class and individually
Total n = 2 303 647 Paroxetine: 2879 |
Unexposed to any antidepressant | Major congenital malformations | Adjusted OR 1.16, 95% CI 0.95, 1.41 |
| Cardiovascular defects
Atrial and ventricular septal defects Right ventricular outflow tract obstructions Conotruncal and major arch defects |
Adjusted OR 1.30, 95% CI 0.96, 1.75
Adjusted OR 1.37, 95% CI 0.96, 1.95 Adjusted OR 2.54, 95% CI 1.31, 4.90 Adjusted OR 2.27, 95% CI 1.01, 5.07 |
||||||
| Ban et al. 42 | 1990–2009 | UK The Health Improvement Network | Cohort | SSRIs as a class and individually
Total n = 349 127 Paroxetine: 1200 |
1) Depressed untreated 2) No depression (unexposed to any antidepressant) | Major congenital defects | Adjusted OR 1.08, 95% CI 0.77, 1.50 |
| Cardiovascular defects | Adjusted OR 1.79; 95% CI 1.09, 2.89 | ||||||
| Huybrechts et al. 50 | 2000–2007 | US Medicaid Analytic eXtract | Cohort | All antidepressants
Total n = 949 504 Paroxetine: 11 126 |
Unexposed to antidepressant (depressed or not depressed) | Any cardiac malformation | Adjusted OR 0.94, 95% CI 0.73, 1.21 |
| Knudsen et al. 44, †† | 1995–2008 | Denmark Medical Birth Registry; National Hospital Register; National Prescription Registry, Statistic Denmark | Cohort | SSRIs as a class and individually
Total n = 72 280 Paroxetine: 131* |
Unexposed to SSRI (not treated with SSRI from 1 year before to 1 year after pregnancy) | Congenital heart defects* | Adjusted OR (total congenital heart defects) 1.01, 95% CI 0.14, 7.22 |
| Jimenez‐Solem et al. 16 | 1997–2009 | Denmark (Nationwide) Danish Medical Birth Registry, Danish Hospital register, Register of Medicinal Product Statistics | Cohort | SSRIs as a class and individually
Total n = 848 786 Paroxetine: 568 Paused exposure (women with exposure to an SSRI 3 to 12 months before conception and 1 to 12 months after giving birth) |
Unexposed to SSRI | Major congenital malformations | Adjusted OR 1.25, 95% CI 0.84, 1.85 |
| Cardiovascular defects | Adjusted OR 1.54, 95% CI 0.77, 3.10 | ||||||
| Bulbus cordis anomalies and anomalies of cardiac septal closure | Adjusted OR 1.89, 95% CI 0.85, 4.23 | ||||||
| Nordeng et al. 52 | 1999–2005 | Norway Norwegian Mother Child Cohort (information from hospital lists and questionnaires) | Cohort | SSRIs as a class and individually
Total n = 63 395 Paroxetine: 76 |
Non‐exposed to any antidepressants (6 months before pregnancy) | Major congenital malformations | Unadjusted OR 1.70, 95% CI 0.55, 5.63 |
| Colvin et al. 48 | 2002–2005 | Australia Western Australia Data Linkage System; hospital mortality data; national pharmaceutical claims dataset | Cohort | SSRIs as a class and individually
Total n = 96 968 Paroxetine: 572 |
Non‐exposed to SSRI (can be exposed to other antidepressants) | Major congenital malformations | Adjusted OR 0.99, 95% CI 0.65, 1.51 |
| Bulbus cordis anomalies and anomalies of cardiac septal closure | Unadjusted OR 1.76, 95% CI 0.83, 3.72 | ||||||
| Malm et al. 31 | 1996–2006 | Finland Drugs and pregnancy project database (Registries for Medical Birth, Congenital Malformations, Drug reimbursement) | Cohort | SSRIs as a class and Individually
Total n = 635 583 Paroxetine: 968 |
Unexposed to SSRI in analysis of all SSRIs; For paroxetine SSRIs: Unexposed to paroxetine (includes other SSRIs) | Major congenital malformations | Adjusted OR 1.22, 95% CI 0.91, 1.64 |
| Cardiovascular defects | Adjusted OR 1.09, 95% CI 0.66, 1.79 | ||||||
| Bakker et al. 30 | 1997–2006 | Netherlands Eurocat Northern Netherlands database | Case–control | Paroxetine Total n = 1293 (678 cases, 615 controls) Paroxetine: 16 | Unexposed to any SSRIs | Congenital heart defects | Adjusted OR 1.5, 95% CI 0.5, 4.0 |
| Bulbus cordis anomalies and anomalies of cardiac septal closure | Adjusted OR 1.6, 95% CI 0.4, 5.6 | ||||||
| Reis et al. 25 | 1995–2007 | Sweden (birth register) | Cohort | SSRIs as a class and paroxetine individually Total n = 15 017 infants Paroxetine: 1208 | Unexposed to an antidepressant | ‘Relatively severe’ malformation | Adjusted OR 1.20, 95% CI 0.90, 1.61 |
| Cardiovascular defects | Adjusted OR 1.67, 95% CI 1.09, 2.53 | ||||||
| Pedersen et al. 54, † | 1996–2003 | Denmark Birth registry, fertility database, hospital register, medicinal product statistic | Cohort (population based) | SSRIs as a class and Individually
Total n = 493 113 Paroxetine: 299 |
Unexposed to an antidepressants | Any malformations | Adjusted OR 1.41, 95% CI 0.79, 2.51 |
| Diav‐Citrin et al. 55 | 1994–2002 | Israel, Italy, Germany Teratology information service | Prospective cohort | Paroxetine and fluoxetine individually Total n = 2191 Paroxetine: 463 | Unexposed to SSRIs or known teratogens (n = 1467) | Any malformations‡ | Adjusted OR 2.14, 95% CI 1.19, 3.82 |
| Cardiovascular defects | Adjusted OR 2.66, 95% CI 0.80, 8.90 | ||||||
| Einarson et al. 56 | Not specified | Italy; Switzerland; Australia; Germany; Israel; Finland Teratology information services | Case–control | Paroxetine
1174 exposure to Paroxetine identified from the TIS 2061 exposures from published studies, not used in analysis |
Unexposed to known teratogens with similar clinic characteristics to women with case infants | Cardiovascular defects | Adjusted OR 1.11, 95% CI 0.36, 2.78 |
| Oberlander et al. 53 | 1998–2001 | Canada Administrative databases (British Columbia registry of births, hospital separation records, PharmCare registry, Medical Services Plan, PharmNet | Cohort (population based) | SRIs monotherapy SRIs and benzodiazepinesTotal n = 119 547 Paroxetine (monotherapy): 993 | Unexposed to SRIs and benzodiazepines | Major congenital malformations‡ | Unadjusted OR 0.93, 95% CI 0.64, 1.35 |
| Cardiovascular malformations‡ | Unadjusted OR 1.48, 95% CI 0.70, 3.10 | ||||||
| Alwan et al. 27 | 1997–2002 | US NBDPS surveillance study | Retrospective Case–control (population bases) | SSRIs Total n = 13 714 (9622 cases, 4092 controls) Paroxetine: 88 | Controls: Infants with no birth defects Comparison: Unexposed to SSRIs | Major congenital malformations | Adjusted OR 1.60, 95% CI 0.90, 2.77 |
| Cardiovascular defects | Adjusted OR 1.70, 95% CI 0.92, 3.16 | ||||||
| Bulbus cordis anomalies and anomalies of cardiac septal closure | Adjusted OR 1.70, 95% CI 0.8, 3.5 | ||||||
| Berard et al. 29 | 1997–2003 | Canada Québec databases (Quebec Pregnancy Cohort) | Nested case–control (population based) | Paroxetine Total n = 1403 (101 cases, 1302 controls) Paroxetine: 542 | Exposure to non‐SSRI antidepressants | Major congenital malformations | Adjusted OR 1.32, 95% CI 0.79, 2.20 |
| major cardiac malformations | Adjusted OR 1.38, 95% CI 0.49, 3.94 | ||||||
| Bulbus cordis anomalies and anomalies of cardiac septal closure | Unadjusted OR 1.14, 95% CI 0.44, 2.99 | ||||||
| Cole et al. 28 | 1995–2004 | US United Healthcare Claims database | Cohort | Paroxetine
Total n = 5752 Paroxetine: 815 |
Exposed to other antidepressants as monotherapy or polytherapy. | Any congenital malformation | Adjusted OR 2.03, 95% CI 1.28, 3.25 |
| Cardiovascular malformations | Adjusted OR 1.46, 95% CI 0.74, 2.89 | ||||||
| Davis et al. 49 | 1996–2000 | US HMO research network program administrative databases) | Cohort (population based) | SSRIs as a class and individually
Total n = 805 Paroxetine: 182 |
Unexposed to SSRIs | Congenital anomalies | Unadjusted OR 1.03, 95% CI 0.73, 1.48 |
| Cardiac defects‡ | Unadjusted OR 1.03, 95% CI 0.45, 2.32 | ||||||
| Kallen et al. 26, * | 1995–2004 | Sweden Swedish medical birth register, birth defects register and hospital discharge, register | Cohort | SSRIs as a class and individuallyTotal n = 860 215 Paroxetine:959 | Unexposed to any antidepressant | Major congenital malformations | Adjusted OR 1.03, 95% CI 0.76, 1.8 |
| Cardiac malformation | Adjusted OR 1.63, 95% CI 1.05, 2.53 | ||||||
| Bulbus cordis anomalies and anomalies of cardiac septal closure | Unadjusted OR 1.81, 95% CI 0.96, 3.09 | ||||||
| Louik et al. 51 | 1993–2004 | US The birth defects study (population based) | Retrospective Case–control | SSRIs Total n = 15 709 (9849 cases, 5860 controls) Paroxetine: 97 | Controls: Infants with no birth defects Comparison: Unexposed to antidepressants | Major congenital malformations 38 | Adjusted OR 1.38, 95% CI 0.85, 2.27 |
| Any cardiac defect | Adjusted OR 1.40, 95% CI 0.79, 2.46 | ||||||
| Bulbus cordis anomalies and anomalies of cardiac septal closure | Adjusted OR 0.8, 95% CI 0.3, 2.2 | ||||||
| Malm et al. 21, § | 1996–2001 | Finland Drugs and pregnancy project database (Registries for Medical Birth, Congenital Malformations, Drug reimbursement) | Cohort (Population based) | SSRIs Total n = 1920 Paroxetine: 149 | Women with no drug purchases | Major congenital malformations | Adjusted OR 0.4, 95% CI 0.1, 3.3 |
| Cardiac malformations | Adjusted OR 0.66, 95% CI 0.09, 4.95 | ||||||
| Simon et al. 20 | 1986–1998 | US
Group Health Cooperative (claims database) |
Retrospective Cohort | SSRIs as a group TCAsTotal n = 787 Paroxetine:38 | Unexposed to SSRIs | Major and minor malformations¶ | Unadjusted OR 1.00, 95% CI 0.06, 16.78 |
| Kulin et al. 19 | Not specified | Canada, US Teratogen information service (Motherisk Program) | Controlled cohort | SSRIs as a group Total n = 534 Paroxetine: 97 | Unexposed to known teratogenic agents | Major congenital malformations¶ | Unadjusted OR 1.77, 95%CI 0.57, 5.47 |
| Cardiac malformations¶ | Unadjusted OR 0.77, 95% CI 0.09, 6.89 |
*
Information obtained from authors.
†
Potential overlap of data with Jimenez‐Solem et al. 16. However overlap is minimal and therefore considered as an independent study.
‡
Unadjusted OR (calculated via a 2 by 2 table).
§
This study overlaps with Malm et al. 31; used when restricting comparison group to: unexposed to all antidepressants.
¶
Unadjusted OR (obtained via pervious meta‐analysis).
**
Overlaps with Reis et al. 25; used in sub‐analysis.