Selective serotonin reuptake inhibitors and venlafaxine in early pregnancy and risk of birth defects: population based cohort study and sibling design

doi:10.1136/bmj.h1798

. 2015 Apr 17:350:h1798.

doi: 10.1136/bmj.h1798.

Selective serotonin reuptake inhibitors and venlafaxine in early pregnancy and risk of birth defects: population based cohort study and sibling design

Affiliations

¹ Department of Pharmacoepidemiology, Division of Epidemiology, Norwegian Institute of Public Health, PB 4404 Nydalen, NO 0403 Oslo, Norway kari.furu@fhi.no.
² Department of Medicine Solna, Centre for Pharmacoepidemiology, Karolinska Institutet Stockholm, Sweden.
³ Department of Pharmacoepidemiology, Division of Epidemiology, Norwegian Institute of Public Health, PB 4404 Nydalen, NO 0403 Oslo, Norway Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway.
⁴ Department of Pharmacoepidemiology, Division of Epidemiology, Norwegian Institute of Public Health, PB 4404 Nydalen, NO 0403 Oslo, Norway.
⁵ Department of Medicine Solna, Centre for Pharmacoepidemiology, Karolinska Institutet Stockholm, Sweden Department of Women's and Children's Health, Division of Obstetrics and Gynecology, Karolinska Institutet, Stockholm, Sweden.
⁶ Centre of Public Health Sciences, Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland Department of Epidemiology, Harvard T H Chan School of Public Health, Boston, MA, USA.
⁷ Centre of Public Health Sciences, Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
⁸ Department of Medical Genetics, University of Helsinki, Helsinki, Finland Department of Child Psychiatry, University of Turku, Turku, Finland.
⁹ THL National Institute for Health and Welfare, Helsinki, Finland Nordic School of Public Health, Gothenburg, Sweden.
¹⁰ Teratology Information Service, HUSLAB and Helsinki University Central Hospital, Helsinki, Finland Department of Clinical Pharmacology, Helsinki University, Helsinki, Finland.
¹¹ Department of Clinical Epidemiology, Institute of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark.

PMID: 25888213
PMCID: PMC4410618
DOI: 10.1136/bmj.h1798

Selective serotonin reuptake inhibitors and venlafaxine in early pregnancy and risk of birth defects: population based cohort study and sibling design

Kari Furu et al. BMJ. 2015.

. 2015 Apr 17:350:h1798.

doi: 10.1136/bmj.h1798.

Authors

Affiliations

¹ Department of Pharmacoepidemiology, Division of Epidemiology, Norwegian Institute of Public Health, PB 4404 Nydalen, NO 0403 Oslo, Norway kari.furu@fhi.no.
² Department of Medicine Solna, Centre for Pharmacoepidemiology, Karolinska Institutet Stockholm, Sweden.
³ Department of Pharmacoepidemiology, Division of Epidemiology, Norwegian Institute of Public Health, PB 4404 Nydalen, NO 0403 Oslo, Norway Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway.
⁴ Department of Pharmacoepidemiology, Division of Epidemiology, Norwegian Institute of Public Health, PB 4404 Nydalen, NO 0403 Oslo, Norway.
⁵ Department of Medicine Solna, Centre for Pharmacoepidemiology, Karolinska Institutet Stockholm, Sweden Department of Women's and Children's Health, Division of Obstetrics and Gynecology, Karolinska Institutet, Stockholm, Sweden.
⁶ Centre of Public Health Sciences, Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland Department of Epidemiology, Harvard T H Chan School of Public Health, Boston, MA, USA.
⁷ Centre of Public Health Sciences, Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
⁸ Department of Medical Genetics, University of Helsinki, Helsinki, Finland Department of Child Psychiatry, University of Turku, Turku, Finland.
⁹ THL National Institute for Health and Welfare, Helsinki, Finland Nordic School of Public Health, Gothenburg, Sweden.
¹⁰ Teratology Information Service, HUSLAB and Helsinki University Central Hospital, Helsinki, Finland Department of Clinical Pharmacology, Helsinki University, Helsinki, Finland.
¹¹ Department of Clinical Epidemiology, Institute of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark.

PMID: 25888213
PMCID: PMC4410618
DOI: 10.1136/bmj.h1798

Erratum in

Selective serotonin reuptake inhibitors and venlafaxine in early pregnancy and risk of birth defects: population based cohort study and sibling design.
[No authors listed] [No authors listed] BMJ. 2015 Apr 24;350:h2235. doi: 10.1136/bmj.h2235. BMJ. 2015. PMID: 25911589 Free PMC article. No abstract available.

Abstract

Objective: To assess whether use of specific selective serotonin reuptake inhibitors (SSRIs) or venlafaxine in early pregnancy is associated with an increased risk of birth defects, with emphasis on cardiovascular birth defects even when accounting for lifestyle or other familial confounding.

Design: Multicountry population based cohort study, including sibling controlled design.

Setting: Nordic population (Denmark, Finland, Iceland, Norway, and Sweden) identified from nationwide health registers at different periods in 1996-2010.

Population: The full study cohort included women giving birth to 2.3 million live singletons. The sibling cohort included 2288 singleton live births. The sibling controlled analyses included sibling pairs who were discordant for exposure to SSRIs or venlafaxine and birth defects.

Main outcome measure: Prevalence of birth defects, including subtypes of cardiac defects. Odds ratio of birth defects from logistic and conditional logistic regression.

Results: Among 36,772 infants exposed to any SSRI in early pregnancy, 3.7% (n=1357) had a birth defect compared with 3.1% of 2,266,875 unexposed infants, yielding a covariate adjusted odds ratio of 1.13 (95% confidence interval 1.06 to 1.20). In the sibling controlled analysis the adjusted odds ratio decreased to 1.06 (0.91 to 1.24). The odds ratios for any cardiac birth defect with use of any SSRI or venlafaxine were 1.15 (95% confidence interval 1.05 to 1.26) in the covariate adjusted analysis and 0.92 (0.72 to 1.17) in the sibling controlled analysis. For atrial and ventricular septal defects the covariate adjusted odds ratio was 1.17 (1.05 to 1.31). Exposure to any SSRI or venlafaxine increased the prevalence of right ventricular outflow tract obstruction defects, with a covariate adjusted odds ratio of 1.48 (1.15 to 1.89). In the sibling controlled analysis the adjusted odds ratio decreased to 0.56 (0.21 to 1.49) for any exposure to SSRIs or venlafaxine and right ventricular outflow tract obstruction defects.

Conclusions: In this large Nordic study no substantial increase was found in prevalence of overall cardiac birth defects among infants exposed to SSRIs or venlafaxine in utero. Although the prevalence of septal defects and right ventricular outflow tract defects was higher in exposed infants, the lack of an association in the sibling controlled analyses points against a teratogenic effect of these drugs.

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Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

Figures

None — **Fig 1** Selective serotonin reuptake inhibitors (SSRIs) or venlafaxine in early pregnancy and risk of birth defects. *Adjusted for maternal age, year of birth, birth order, smoking, maternal diabetes, country, and use of other prescribed drugs (antiepileptics (ATC code N03), anxiolytics and hypnotics (N05B and N05C), and angiotensin converting enzyme inhibitors (C09))

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Comment in

Safety of psychotropic drugs in pregnancy.
Khalifeh H, Dolman C, Howard LM. Khalifeh H, et al. BMJ. 2015 May 13;350:h2260. doi: 10.1136/bmj.h2260. BMJ. 2015. PMID: 25972372 No abstract available.

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References

1. O’Keane V, Marsh MS. Depression during pregnancy. BMJ 2007;334:1003-5. - PMC - PubMed
1. Kieler H. The Nordic health registers—an important source when evaluating the safety of antidepressants during pregnancy. Clin Epidemiol 2010;2:205-7. - PMC - PubMed
1. El Marroun H, Jaddoe VW, Hudziak JJ, et al. Maternal use of selective serotonin reuptake inhibitors, fetal growth, and risk of adverse birth outcomes. Arch Gen Psychiatry 2012;69:706-14. - PubMed
1. Cooper WO, Willy ME, Pont SJ, et al. Increasing use of antidepressants in pregnancy. Am J Obstet Gynecol 2007;196:544-5. - PubMed
1. Hayes RM, Wu P, Shelton RC, et al. Maternal antidepressant use and adverse outcomes: a cohort study of 228,876 pregnancies. Am J Obstet Gynecol 2012;207:49. - PMC - PubMed

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[1] O’Keane V, Marsh MS. Depression during pregnancy. BMJ 2007;334:1003-5. - PMC - PubMed

[2] O’Keane V, Marsh MS. Depression during pregnancy. BMJ 2007;334:1003-5. - PMC - PubMed

[3] Kieler H. The Nordic health registers—an important source when evaluating the safety of antidepressants during pregnancy. Clin Epidemiol 2010;2:205-7. - PMC - PubMed

[4] Kieler H. The Nordic health registers—an important source when evaluating the safety of antidepressants during pregnancy. Clin Epidemiol 2010;2:205-7. - PMC - PubMed

[5] El Marroun H, Jaddoe VW, Hudziak JJ, et al. Maternal use of selective serotonin reuptake inhibitors, fetal growth, and risk of adverse birth outcomes. Arch Gen Psychiatry 2012;69:706-14. - PubMed

[6] El Marroun H, Jaddoe VW, Hudziak JJ, et al. Maternal use of selective serotonin reuptake inhibitors, fetal growth, and risk of adverse birth outcomes. Arch Gen Psychiatry 2012;69:706-14. - PubMed

[7] Cooper WO, Willy ME, Pont SJ, et al. Increasing use of antidepressants in pregnancy. Am J Obstet Gynecol 2007;196:544-5. - PubMed

[8] Cooper WO, Willy ME, Pont SJ, et al. Increasing use of antidepressants in pregnancy. Am J Obstet Gynecol 2007;196:544-5. - PubMed

[9] Hayes RM, Wu P, Shelton RC, et al. Maternal antidepressant use and adverse outcomes: a cohort study of 228,876 pregnancies. Am J Obstet Gynecol 2012;207:49. - PMC - PubMed

[10] Hayes RM, Wu P, Shelton RC, et al. Maternal antidepressant use and adverse outcomes: a cohort study of 228,876 pregnancies. Am J Obstet Gynecol 2012;207:49. - PMC - PubMed

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Selective serotonin reuptake inhibitors and venlafaxine in early pregnancy and risk of birth defects: population based cohort study and sibling design

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Selective serotonin reuptake inhibitors and venlafaxine in early pregnancy and risk of birth defects: population based cohort study and sibling design

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