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http://www.bmj.com/cgi/content/full/339/sep23_1/b3525
Published 23 September 2009, doi:10.1136/bmj.b3525
Cite this as: BMJ 2009;339:b3525

Editorials

Selective serotonin reuptake inhibitors and congenital malformations. The small risk of harm must be balanced against risk of suboptimal or no treatment

Major depressive disorder in women is most common during their childbearing years, and about 13% of women in the United States have taken an antidepressant drug during pregnancy.1 2 In the past 20 years, selective serotonin reuptake inhibitors (SSRIs) have become a mainstay of treatment in women with major depressive disorder; however, concerns persist about safety for the developing fetus. This is counterbalanced by equally compelling concerns about the consequences of undertreatment for mother and child.3

In the linked population based cohort study from Denmark (doi:10.1136/bmj.b3569), Pedersen and colleagues confirm a previously reported doubling of risk for septal heart defects after early exposure in pregnancy to SSRIs (odds ratio 1.99, 95% confidence interval 1.12 to 3.53).4 However, in contrast to previous studies, redemptions of prescriptions for citalopram and sertraline, but not paroxetine or fluoxetine, were significantly associated with this group of heart defects.5 6 7 8 Furthermore, unlike two previous large case-control studies conducted in the US, no association was noted with anencephaly, omphalocele, craniosynostosis, or right ventricular outflow tract defects.7 8

Lack of consistency across these studies with respect to specific malformations and specific drugs makes it difficult to translate the findings into clinical practice. One of the fundamental principles of teratology is that teratogenic exposures induce specific patterns of malformation, and not an increase in the incidence of every defect. In other words, if some or all SSRIs are teratogenic, we would expect to see similar findings for specific drug exposures and specific defects in all studies.

One explanation for this inconsistency, assuming that SSRIs do cause specific birth defects, is differences in study designs. For example, although Pedersen and colleagues linked records for 496 881 singleton live born infants, they identified only 1370 mothers who redeemed multiple prescriptions for an SSRI in the perinatal period. Therefore, the study may have been insufficiently powered to detect the previously suggested twofold to threefold increased risk for anencephaly, omphalocele, craniosynostosis, or right ventricular outflow tract defects, all of which occur at least an order of magnitude less frequently than septal defects.

Alternatively, these findings could be spurious and attributable in observational studies to unmeasured or inadequately controlled confounding factors, such as maternal obesity, alcohol, tobacco, or periconceptional use of folic acid supplements; confounding by the mother's underlying condition; or detection bias, in which mothers being treated for major depressive disorders are more likely to seek out or receive more comprehensive prenatal and postnatal testing of their children.

How does Pedersen and colleagues' study contribute to clinicians' and patients' decisions about the use of SSRIs in pregnancy, and how should this be we weighed against the risks of non-treatment? The answer remains as before-if an increased risk for major congenital malformations does exist, this study and others suggest that the absolute risk for the individual pregnant woman is very low. Furthermore, each of the more commonly used drugs in this class has been implicated in at least one study, so it is difficult to conclude that one SSRI is "safer" than another.

We need information from larger studies of specific SSRIs, with study designs that control for maternal disease type and severity, comorbidities, and other exposures. In addition, studies of basic science might elucidate the mechanisms involved in inducing specific birth defects to support the biological plausibility of a causal association.

In August 2009, the American College of Obstetrics and Gynecology released a joint statement with the American Psychiatric Association on treatment recommendations for depression during pregnancy.9 Briefly, the recommendations state that women with major depressive disorder who are contemplating pregnancy or who are currently pregnant can start or continue taking their drugs. Women who prefer to avoid or discontinue drugs may benefit from psychotherapy, although this will depend on their psychiatric history. Women should be informed about the possible risks and benefits of their treatment choices, and ongoing consultation between the patient's obstetrician and psychiatrist is needed during pregnancy, to determine and carry out the most appropriate and acceptable treatment plan.

Most drugs taken by pregnant women have not been well studied, or studied at all with respect to safety of the fetus.10 Although research about SSRIs and pregnancy outcomes is plentiful, it does not necessarily provide definitive answers for clinical practice. Clinicians and patients need to balance the small risks associated with SSRIs against those associated with undertreatment or no treatment.

Cite this as: BMJ 2009;339:b3525

Christina Chambers, associate professor 1 Division of Dysmorphology and Teratology, Departments of Pediatrics and Family and Preventive Medicine, School of Medicine, University of California San Diego, 9500 Gilman Drive, MC 0828, La Jolla, CA, 92093-0828, USA, chchambers@ucsd.edu

Research, doi:10.1136/bmj.b3569

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CC has received grant funding from pharmaceutical companies including Amgen, Abbott, Bristol Myers Squibb, Sanofi-Pasteur, Teva, Sandoz, Kali, Barr, and Apotex, some of which manufacture or distribute selective serotonin reuptake inhibitors. Provenance and peer review: Commissioned; not externally peer reviewed.

References

1. Kessler RC, Berglund P, Demler O, Jin R, Koretz D, Merikangas KR, et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA 2003;289:3095-105.
2. Cooper WO, Pont ME, Ray WA. Increasing use of antidepressants in pregnancy. Am J Obstet Gynecol 2007;196:544e1.
3. Deave T, Heron J, Evans J, Emond A. The impact of maternal depression in pregnancy on early childhood development. BJOG 2008;115:1043-51.
4. Selective serotonin reuptake inhibitors in pregnancy and congenital malformations: population based cohort study. BMJ 2009;339:b3569.
5. Kallen B, Olausson PO. Maternal use of selective serotonin re-uptake inhibitors in early pregnancy and infant congenital malformations. Birth Defects Res Part A Clin Mol Teratol 2007;79:301-8.
6. Diav-Citrin O, Shechtman S, Weinbaum D, Wajnberg R, Avgil M, Di Gianantonio E, et al. Paroxetine and fluoxetine in pregnancy: a prospective, multicentre, controlled, observational study. Br J Clin Pharmacol 2008;66:695-705.
7. Louik C, Lin AE, Werler MM, Hernandez-Diaz S, Mitchell AA. First-trimester use of selective serotonin-reuptake inhibitors and the risk of birth defects. N Engl J Med 2007;356:2675-83.
8. Alwan S, Reefhuis J, Rasmussen SA, Olney RS, Friedman JM, National Birth Defec ts Prevention Study. Use of selective serotonin-reupinhibitors in pregnancy and the risk of birth defects. N Engl J Med 2007;356:2684-92.
9. Yonkers KA, Wisner KL, Stewart DE, Oberlander TF, Dell DL, Stotland N, et al. The management of depression during pregnancy: a report from the American Psychiatric Association and the American College of Obstetricians and Gynecologists. Gen Hosp Psychiatry 2009;31:403-13.
10. Lo WY, Friedman JM. Teratogenicity of recently introduced medications in human pregnancy. Obstet Gynecol 2002;100:465-73.

http://www.bmj.com/cgi/content/abstract/339/sep23_1/b3569
Published 23 September 2009, doi:10.1136/bmj.b3569
Cite this as: BMJ 2009;339:b3569

Research

Selective serotonin reuptake inhibitors in pregnancy and congenital malformations: population based cohort study

Lars Henning Pedersen, research assistant, visiting scholar 1,2, Tine Brink Henriksen, consultant3, Mogens Vestergaard, general practitioner and associate professor4, Jørn Olsen, professor and chair2, Bodil Hammer Bech, associate professor1

1 Department of Epidemiology, Institute of Public Health, Aarhus University, Bartolin Alle 2, DK-8000 Aarhus, Denmark, 2 UCLA School of Public Health, Department of Epidemiology, 650 Charles E Young Drive South, Los Angeles, CA 90095-1772, USA, 3 Department of Paediatrics, Aarhus University Hospital, DK-8200 Aarhus, Denmark, 4 Department of General Practice, Institute of Public Health, Aarhus University, Bartolin Alle 2, DK-8000 Aarhus, Denmark

Correspondence to: Lars Henning Pedersen, Department of Epidemiology, Institute of Public Health, Aarhus University, Bartolins Alle 2, 8000 Aarhus C, Denmark LHP@dadlnet.dk

Objective To investigate any association between selective serotonin reuptake inhibitors (SSRIs) taken during pregnancy and congenital major malformations. Design Population based cohort study.

Participants 493 113 children born in Denmark, 1996-2003.

Main outcome measure Major malformations categorised according to Eurocat (European Surveillance of Congenital Anomalies) with additional diagnostic grouping of heart defects. Nationwide registers on medical redemptions (filled prescriptions), delivery, and hospital diagnosis provided information on mothers and newborns. Follow-up data available to December 2005.

Results Redemptions for SSRIs were not associated with major malformations overall but were associated with septal heart defects (odds ratio 1.99, 95% confidence interval 1.13 to 3.53). For individual SSRIs, the odds ratio for septal heart defects was 3.25 (1.21 to 8.75) for sertraline, 2.52 (1.04 to 6.10) for citalopram, and 1.34 (0.33 to 5.41) for fluoxetine. Redemptions for more than one type of SSRI were associated with septal heart defects (4.70, 1.74 to 12.7)). The absolute increase in the prevalence of malformations was low-for example, the prevalence of septal heart defects was 0.5% (2315/493 113) among unexposed children, 0.9% (12/1370) among children whose mothers were prescribed any SSRI, and 2.1% (4/193) among children whose mothers were prescribed more than one type of SSRI.

Conclusion

There is an increased prevalence of septal heart defects among children whose mothers were prescribed an SSRI in early pregnancy, particularly sertraline and citalopram. The largest association was found for children of women who redeemed prescriptions for more than one type of SSRI.

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/2.0/ and http://creativecommons.org/licenses/by-nc/2.0/legalcode.

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